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The Neurogenetics of Language – Patricia Kuhl

Posted in Autism Spectrum Disorders, Behavior, Behavioral Genetics, Biological Networks, Child and Adolescent Psychiatry, Clinical & Translational, Cognition, Curation, Discovery process, Explanatory, Genetics & Innovations in Treatment, Innovations in Neurophysiology & Neuropsychology, Interviews with Scientific Leaders, Population Health Management, tagged , , , on September 6, 2015| Leave a Comment »

The Neurogenetics of Language – Patricia Kuhl

Larry H. Bernstein, MD, FCAP, Curator

Leaders in Pharmaceutical Innovation

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Series E. 2; 5.7

2015 George A. Miller Award

In neuroimaging studies using structural (diffusion weighted magnetic resonance imaging or DW-MRI) and functional (magnetoencephalography or MEG) imaging, my laboratory has produced data on the neural connectivity that underlies language processing, as well as electrophysiological measures of language functioning during various levels of language processing (e.g., phonemic, lexical, or sentential). Taken early in development, electrophysiological measures or “biomarkers” have been shown to predict future language performance in neurotypical children as well as children with autism spectrum disorders (ASD). Work in my laboratory is now combining these neuroimaging approaches with genetic sequencing, allowing us to understand the genetic contributions to language learning.

http://www.youtube.com/watch%3Fv%3DG2XBIkHW954

http://www.youtube.com/watch%3Fv%3DM-ymanHajN8

Patricia Kuhl shares astonishing findings about how babies learn one language over another — by listening to the humans around them

Kuhl Constructs: How Babies Form Foundations for Language

MAY 3, 2013

by Sarah Andrews Roehrich, M.S., CCC-SLP

Years ago, I was captivated by an adorable baby on the front cover of a book, The Scientist in the Crib: What Early Learning Tells Us About the Mind, written by a trio of research scientists including Alison Gopknik, PhD, Andrew Meltzoff, PhD, and Patricia Kuhl, PhD.

At the time, I was simply interested in how babies learn about their worlds, how they conduct experiments, and how this learning could impact early brain development.  I did not realize the extent to which interactions with family, caretakers, society, and culture could shape the direction of a young child’s future.

Now, as a speech-language pathologist in Early Intervention in Massachusetts, more cognizant of the myriad of factors that shape a child’s cognitive, social-emotional, language, and literacy development, I have been absolutely delighted to discover more of the work of Dr. Kuhl, a distinguished speech-and-language pathologist at The University of Washington.  So, last spring, when I read that Dr. Kuhl was going to present “Babies’ Language Skills” as one part of a 2-part seminar series sponsored by the Mind, Brain, and Behavior Annual Distinguished Lecture Series at Harvard University1, I was thrilled to have the opportunity to attend. Below are some highlights from that experience and the questions it has since sparked for me:

Lip ‘Reading’ Babies
According to a study by Dr. Patricia Kuhl and Dr. Andrew Meltzoff, “Bimodal Perception of Speech in Infancy” (Science, 1982), cited in the 2005 Seattle Times article, “Infant Science: How do Babies Learn to Talk?” by Paula Bock, Drs. Patricia Kuhl and Andrew Meltzoff showed that babies as young as 18 weeks of age could listen to “Ah ah ah” or “Ee ee ee” vowel sounds and gaze at the correct, corresponding lip shape on a video monitor.
This image from Kuhl’s 2011 TED talk shows how a baby is trained to turn his head in response to a change in such vowel sounds, and is immediately rewarded by watching a black box light up while a panda bear inside pounds a drum.  Images provided courtesy of Dr. Patricia Kuhl’s Lab at the University of Washington.

Who is Dr. Patricia Kuhl and how has her work re-shaped our knowledge about how babies learn language?

Dr. Kuhl, who is co-director of the Institute for Learning and Brain Sciences at The University of Washington, has been internationally recognized for her research on early language and brain development, and for her studies on how young children learn.  In her most recent research experiments, she’s been using magnetoencephalography (MEG)–a relatively new neuroscience technology that measures magnetic fields generated by the activity of brain cells–to investigate how, where, and with what frequency babies from around the world process speech sounds in the brain when they are listening to adults speak in their native and non-native languages.

A 6-month-old baby sits in a magnetoencephalography machine, which maps brain activity, while listening to various languages in earphones and playing with a toy. Image originally printed in “Brain Mechanisms in Early Language Acquisition” (Neuron review, Cell Press, 2010) and provided courtesy of Dr. Patricia Kuhl’s Lab at the University of Washington.

Not only does Kuhl’s research point us in the direction of how babies learn to process phonemes, the sound units upon which many languages are built, but it is part of a larger body of studies looking at infants across languages and cultures that has revolutionized our understanding of language development over the last half of the 20th century—leading to, as Kuhl puts it, “a new view of language acquisition, that accounts for both the initial state of linguistic knowledge in infants, and infants’ extraordinary ability to learn simply by listening to their native language.”2

What is neuroplasticity and how does it underlie child development?

Babies are born with 100 billion neurons, about the same as the number of stars in the Milky Way.3 In The Whole Brain Child,Daniel Siegel, MD and Tina Payne Bryson, PhD explain that when we undergo an experience, these brain cells respond through changes in patterns of electrical activity—in other words, they “fire” electrical signals called “action potentials.”4

In a child’s first years of life, the brain exhibits extraordinary neuroplasticity, refining its circuits in response to environmental experiences. Synapses—the sites of communication between neurons—are built, strengthened, weakened and pruned away as needed. Two short videos from the Center on the Developing Child at Harvard, “Experiences Build Brain Architecture” and “Serve and Return Interaction Shapes Brain Circuitry”, nicely depict how some of this early brain development happens.5

Since brain circuits organize and reorganize themselves in response to an infant’s interactions with his or her environment, exposing babies to a variety of positive experiences (such as talking, cuddling, reading, singing, and playing in different environments) not only helps tune babies in to the language of their culture, but it also builds a foundation for developing the attention, cognition, memory, social-emotional, language and literacy, and sensory and motor skills that will help them reach their potential later on.

When and how do babies become “language-bound” listeners?

In her 2011 TED talk, “The Linguistic Genius of Babies,” Dr. Kuhl discusses how babies under 8 months of age from different cultures can detect sounds in any language from around the world, but adults cannot do this. 6   So when exactly do babies go from being “citizens of the world”, as Kuhl puts it, to becoming “language-bound” listeners, specifically focused on the language of their culture?”

Between 8-10 months of age, when babies are trying to master the sounds used in their native language, they enter a critical period for sound development.1  Kuhl explains that in one set of experiments, she compared a group of babies in America learning to differentiate the sounds “/Ra/” and “/La/,” with a group of babies in Japan.  Between 6-8 months, the babies in both cultures recognized these sounds with the same frequency.  However, by 10-12 months, after multiple training sessions, the babies in Seattle, Washington, were much better at detecting the “/Ra/-/La/” shift than were the Japanese babies.

Kuhl explains these results by suggesting that babies “take statistics” on how frequently they hear sounds in their native and non-native languages.  Because “/Ra/” and “/La/” occur more frequently in the English language, the American babies recognized these sounds far more frequently in their native language than the Japanese babies.  Kuhl believes that the results in this study indicate a shift in brain development, during which babies from each culture are preparing for their own languages and becoming “language-bound” listeners.

In what ways are nurturing interactions with caregivers more valuable to babies’ early language development than interfacing with technology?

If parents, caretakers, and other children can help mold babies’ language development simply by talking to them, it is tempting to ask whether young babies can learn language by listening to the radio, watching television, or playing on their parents’ mobile devices. I mean, what could be more engaging than the brightly-colored screens of the latest and greatest smart phones, iPads, iPods, and computers? They’re perfect for entertaining babies.  In fact, some babies and toddlers can operate their parents’ devices before even having learned how to talk.

However, based on her research, Kuhl states that young babies cannot learn language from television and it is necessary for babies to have lots of face-to-face interaction to learn how to talk.1  In one interesting study, Kuhl’s team exposed 9 month old American babies to Mandarin in various forms–in person interactions with native Mandarin speakers vs. audiovisual or audio recordings of these speakers–and then looked at the impact of this exposure on the babies’ ability to make Mandarin phonetic contrasts (not found in English) at 10-12 months of age. Strikingly, twelve laboratory visits featuring in person interactions with the native Mandarin speakers were sufficient to teach the American babies how to distinguish the Mandarin sounds as well as Taiwanese babies of the same age. However, the same number of lab visits featuring the audiovisual or audio recordings made no impact. American babies exposed to Mandarin through these technologies performed the same as a control group of American babies exposed to native English speakers during their lab visits.

This diagram depicts the results of a Kuhl study on American infants exposed to Mandarin in various forms–in person interactions with native speakers versus television or audio recordings of these speakers. As the top blue triangle shows, the American infants exposed in person to native Mandarin speakers performed just as well on a Mandarin phoneme distinction task as age-matched Taiwanese counterparts. However, those American infants exposed to television or audio recordings of the Mandarin speakers performed the same as a control group of American babies exposed to native English speakers during their lab visits. Diagram displayed in Kuhl’s TED TAlk 6, provided courtesy of Dr. Patricia Kuhl’s Lab at the University of Washington.

Kuhl believes that this is primarily because a baby’s interactions with others engages the social brain, a critical element for helping children learn to communicate in their native and non-native languages. 6  In other words, learning language is not simply a technical skill that can be learned by listening to a recording or watching a show on a screen.  Instead, it is a special gift that is handed down from one generation to the next.

Language is learned through talking, singing, storytelling, reading, and many other nurturing experiences shared between caretaker and child.  Babies are naturally curious; they watch every movement and listen to every sound they hear around them.  When parents talk, babies look up and watch their mouth movements with intense wonder.  Parents respond in turn, speaking in “motherese,” a special variant of language designed to bathe babies in the sound patterns and speech sounds of their native language. Motherese helps babies hear the “edges” of sound, the very thing that is difficult for babies who exhibit symptoms of dyslexia and auditory processing issues later on.

Over time, by listening to and engaging with the speakers around them, babies build sound maps which set the stage for them to be able to say words and learn to read later on.  In fact, based on years of research, Kuhl has discovered that babies’ abilities to discriminate phonemes at 7 months-old is a predictor of future reading skills for that child at age 5.7

I believe that educating families about brain development, nurturing interactions, and the benefits and limits of technology is absolutely critical to helping families focus on what is most important in developing their children’s communication skills.  I also believe that Kuhl’s work is invaluable in this regard.  Not only has it focused my attention on how babies form foundations for language, but it has illuminated my understanding of how caretaker-child interactions help set the stage for babies to become language-bound learners.

Sources

(1) Kuhl, P. (April 3, 2012.) Talk on “Babies’ Language Skills.” Mind, Brain, and Behavior Annual Distinguished Lecture Series, Harvard University.

(2) Kuhl, P. (2000). “A New View of Language Acquisition.” This paper was presented at the National Academy of Sciences colloquium “Auditory Neuroscience: Development, Transduction, and Integration,” held May 19–21, 2000, at the Arnold and Mabel Beckman Center in Irvine, CA. Published by the National Academy of Sciences.

(3) Bock, P. (2005.)  “The Baby Brain.  Infant Science: How do Babies Learn to Talk?” Pacific Northwest: The Seattle Times Magazine.

(4) Siegel, D., Bryson, T. (2011.)  The Whole-Brain Child: 12 Revolutionary Strategies to Nurture Your Child’s Developing Mind. New York, NY:  Delacorte Press, a division of Random House, Inc.

(5) Center on the Developing Child at Harvard University. “Experiences Build Brain Architecture” and “Serve and Return Interaction Shapes Brain Circuitry” videos, two parts in the three-part series, “Three Core Concepts in Early Development.

http://developingchild.harvard.edu/resources/multimedia/videos

(6) Kuhl, P.  (February 18, 2011.) “The Linguistic Genius of Babies,” video talk on TED.com, a TEDxRainier event.

www.ted.com/talks/patricia_kuhl_the_linguistic_genius_of_babies.html

(7) Lerer, J. (2012.) “Professor Discusses Babies’ Language Skills.”  The Harvard Crimson.

Andrew Meltzoff & Patricia Kuhl: Joint attention to mind

Sarah DeWeerdt  11 Feb 2013

Power couple: In addition to a dizzying array of peer-reviewed publications, Andrew Meltzoff and Patricia Kuhl have written a popular book on brain development, given TED talks and lobbied political leaders.

Andrew Meltzoff shares many things with his wife — research dollars, authorship, a keen interest in the young brain — but he does not keep his wife’s schedule.

“It’s one of the agreements we have,” he says, laying out the rule with a twinkle in his eye that conveys both the delights and the complications of working with one’s spouse.

Meltzoff, professor of psychology at the University of Washington in Seattle, and his wife, speech and hearing sciences professor Patricia Kuhl, are co-directors of the university’s Institute for Learning and Brain Sciences, which focuses on the development of the brain and mind during the first five years of life.

Between them, they have shown that learning is a fundamentally social process, and that babies begin this social learning when they are just weeks or even days old.

You could say the couple is attached at the cerebral cortex, but not at the hip: They take equal roles in running the institute, but they each have their own daily rhythms and distinct, if overlapping, scientific interests.

Kuhl studies how infants “crack the language code,” as she puts it — how they figure out sounds and meanings and eventually learn to produce speech. Meltzoff’s work focuses on social building blocks such as imitation and joint attention, or a shared focus on an object or activity. Meltzoff says these basic behaviors help children develop theory of mind, a sophisticated awareness and understanding of others’ thoughts and feelings.

All of these abilities are impaired in children with autism. Most of the couple’s studies have focused on typically developing infants, because, they say, it’s essential to understand typical development in order to appreciate the irregularities in autism.

Both also study autism, which can in turn help explain typical development.

In addition to a dizzying array of peer-reviewed publications, the duo have written a popular book on developmental psychiatry, The Scientist in the Crib, and promote their ideas through TED talks and by lobbying political leaders.

Geraldine Dawson, chief science officer of the autism science and advocacy organization Autism Speaks and a longtime collaborator, calls Meltzoff and Kuhl “the dynamic duo.” “They’re sort of bigger-than-life type people, who fill the room when they walk into it,” she says.

Making a match:

Meltzoff and Kuhl’s story began with a scientific twist on a standard rom-com meet cute.

It was the early 1980s, and Kuhl, who had recently joined the faculty at the University of Washington, wanted to understand how infants hear and see vowels. But she was having trouble designing an effective experiment.

“I kept running into Andy’s office,” which was near hers, to talk it through, Kuhl recalls.

Meltzoff had done some research on how babies integrate what they see with what they touch, a process called cross-modal matching1. Soon he and Kuhl realized that they could adapt his experimental design to her question, and decided to collaborate.

They showed babies two video screens, each featuring a person mouthing a different vowel sound – “ahhh” or “eeee.” A speaker placed between the two screens played one of those two vowel sounds.

They found that babies as young as 18 to 20 weeks look longer at the face that matches the sound they hear, integrating faces with voices2.

But that wasn’t the only significant result from those experiments.

“Speaking only for myself, I will say I became very interested in the very attractive, smart blonde that I was collaborating with,” Meltzoff says. “Criticizing each other’s scientific writing at the same time the relationship was building was… interesting.”

And effective: Their paper appeared in Science in 1982, and the couple married three years later.

Listening to Meltzoff tell that story, it’s easy to understand why some colleagues say he is funny but they can’t quite explain why. His humor is subtle and wry. More obvious is his passion, not just for science, but for working out the theory underlying empirical results. Even his wife describes his personality as “cerebral.”

“He just has this laser vision for homing in on what is the heart of the issue,” says Rechele Brooks, research assistant professor of psychiatry and behavioral sciences at the University of Washington, who collaborates with Meltzoff on studies of gaze.

For example, in one of his earliest papers, Meltzoff wanted to investigate how babies learn to imitate. He found that infants just 12 to 21 days old can imitate both facial expressions and hand gestures, much earlier than previously thought3.

“It really turned the scientific community on its head,” Brooks says.

Early insights:

Face to face: Meltzoff and Kuhl are developing a method to simultaneously record the brain activity of two people as they interact.

Meltzoff continued to study infants, tracing back the components of theory of mind to their earliest developmental source. That sparked the interest of Dawson, who had gotten to know Meltzoff as a student at the University of Washington in the 1970s, and became the first director of the university’s autism center in 1996.

Meltzoff and Dawson together applied his techniques to study young, often nonverbal, children with autism. In one study, they found that children with autism have more trouble imitating others than do either typically developing children or those with Down syndrome4.

In another study, they found that children with autism are less interested in social sounds such as clapping or hearing their name called than are their typically developing peers5.  They also found that how children with autism imitate and play with toys when they are 3 or 4 years old predicts their communication skills two years later6.

Most previous studies of autism had focused on older children, Dawson says, and this work helped paint a picture of the disorder earlier in childhood.

Kuhl began her career with studies showing that monkeys7 and even chinchillas8 can distinguish the difference between speech sounds, or phonemes, such as “ba” and “pa,” just as human infants can.

“The bottom line was that animals were sharing this aspect of perception,” Kuhl says.

So why are people so much better than animals at learning language? Kuhl has been trying to answer that question ever since, first through behavioral studies and then by measuring brain activity using imaging techniques.

Kuhl is soft-spoken, but a listener wants to lean in to catch every word. Scientists who have worked with her describe her as poised and perfectly put together, a master of gentle yet effective diplomacy.

“She has her sort of magnetic power to pull people together,” says Yang Zhang, associate professor of speech-language-hearing sciences at the University of Minnesota in Rochester, who was a graduate student and postdoctoral researcher in Kuhl’s lab beginning in the late 1990s.

Listen and learn:

At one point, Kuhl turned her considerable powers of persuasion on a famously smooth negotiator, then-President Bill Clinton.

Kuhl had shown that newborns hear virtually all speech sounds, but by 6 months of age they lose the ability to distinguish sounds that aren’t part of their native language9.

At the White House Conference on Early Childhood Development and Learning in 1997, she described how infants learn by listening, long before they can speak.

Clinton, ever the policy wonk, asked her how much babies need to hear in order to learn. Kuhl said she didn’t know — but if Clinton gave her the funds, she would find out. “Even the president could see that research on the effects of language input on the young brain had impact on society,” she says.

Kuhl used the funds Clinton gave her to design a study in which 9-month-old babies in the U.S. received 12 short Mandarin Chinese ‘lessons.’ The babies quickly learned to distinguish speech sounds in the second language, her team found — but only if the speaker was live, not in a video10.

Those results contributed to Kuhl’s ‘social gating’ hypothesis, which holds that social interaction is necessary for picking up on the sounds and patterns of language. “We’re saying that social interaction is a kind of gate to an interest in learning, the kind that humans are completely masters of,” she says.

Her results also suggest that the language problems in children with autism may be the result of their social deficits.

“Children with autism will have a very difficult time acquiring language if language requires the social gate to be open,” she says.

Over the years, Kuhl and Meltzoff have had largely independent research programs, but her recent focus on the social roots of language dovetails with his long-time focus on social interaction.

These days, they are trying to develop ‘face-to-face neuroscience,’ which involves simultaneously recording brain activity from two people as they interact with each other.

This approach would allow researchers to observe, for example, what happens in an infant’s brain when she hears her mother’s voice, and what happens in the mother’s brain as she sees her infant respond to her. “It’s going to be very special to do,” Meltzoff says enthusiastically, even though the effort is more directly related to Kuhl’s work than to his own.

It’s clear that this fervor for each other’s work goes both ways.

“That’s one of the great things about being married to a scientist,” Meltzoff says. “When you come home and think, ‘God, I really nailed this methodologically,’ your wife, instead of yawning, leans forward and says, ‘You did? Tell me about the method, that’s so exciting.’”

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1: Meltzoff A.N. and R.W. Borton Nature 282, 403-404 (1979) PubMed

2: Kuhl P.K. and A.N. Meltzoff Science 218, 1138-1141 (1982) PubMed

3: Meltzoff A.N. and M.K. Moore Science 198, 75-78 (1977) PubMed

4: Dawson G. et al. Child Dev. 69, 1276-1285 (1998) PubMed

5: Dawson G. et al. J. Autism Dev. Disord. 28, 479-485 (1998) PubMed

6: Toth K. et al. J. Autism Dev. Disord. 36, 993-1005 (2006) PubMed

7: Kuhl P.K. and D.M. Padden Percept. Psychophys. 32, 542-550 (1982) PubMed

8: Kuhl P.K. and J.D. Miller Science 190, 69-72 (1975) PubMed

9: Kuhl P.K. et al. Science 255, 606-608 (1992) PubMed

10: Kuhl P.K. et al. Proc. Natl. Acad. Sci. U.S.A. 100, 9096-9101 (2003) PubMed

Using genetic data in cognitive neuroscience: from growing pains to genuine insights

Adam E. Green, Marcus R. Munafò, Colin G. DeYoung, John A. Fossella, Jin Fan & Jeremy R. Gray
Nature Reviews Neuroscience 2008 Sep; 9, 710-720
http://dx.doi.org:/10.1038/nrn2461

Research that combines genetic and cognitive neuroscience data aims to elucidate the mechanisms that underlie human behaviour and experience by way of ‘intermediate phenotypes’: variations in brain function. Using neuroimaging and other methods, this approach is poised to make the transition from health-focused investigations to inquiries into cognitive, affective and social functions, including ones that do not readily lend themselves to animal models. The growing pains of this emerging field are evident, yet there are also reasons for a measured optimism.

NSF – Cognitive Neuroscience Award

The cross-disciplinary integration and exploitation of new techniques in cognitive neuroscience has generated a rapid growth in significant scientific advances. Research topics have included sensory processes (including olfaction, thirst, multi-sensory integration), higher perceptual processes (for faces, music, etc.), higher cognitive functions (e.g., decision-making, reasoning, mathematics, mental imagery, awareness), language (e.g., syntax, multi-lingualism, discourse), sleep, affect, social processes, learning, memory, attention, motor, and executive functions. Cognitive neuroscientists further clarify their findings by examining developmental and transformational aspects of such phenomena across the span of life, from infancy to late adulthood, and through time.

New frontiers in cognitive neuroscience research have emerged from investigations that integrate data from a variety of techniques. One very useful technique has been neuroimaging, including positron emission tomography (PET), functional magnetic resonance imaging (fMRI), magnetoencephalography (MEG), optical imaging (near infrared spectroscopy or NIRS), anatomical MRI, and diffusion tensor imaging (DTI). A second class of techniques includes physiological recording such as subdural and deep brain electrode recording, electroencephalography (EEG), event-related electrical potentials (ERPs), and galvanic skin responses (GSRs). In addition, stimulation methods have been employed, including transcranial magnetic stimulation (TMS), subdural and deep brain electrode stimulation, and drug stimulation. A fourth approach involves cognitive and behavioral methods, such as lesion-deficit neuropsychology and experimental psychology. Other techniques have included genetic analysis, molecular modeling, and computational modeling. The foregoing variety of methods is used with individuals in healthy, neurological, psychiatric, and cognitively-impaired conditions. The data from such varied sources can be further clarified by comparison with invasive neurophysiological recordings in non-human primates and other mammals.

Findings from cognitive neuroscience can elucidate functional brain organization, such as the operations performed by a particular brain area and the system of distributed, discrete neural areas supporting a specific cognitive, perceptual, motor, or affective operation or representation. Moreover, these findings can reveal the effect on brain organization of individual differences (including genetic variation), plasticity, and recovery of function following damage to the nervous system.

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Diet and Diabetes

Posted in Amino acids, Atherogenic Processes & Pathology, Behavior, Biochemical pathways, Biological Networks, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Curation, Diabetes Mellitus, Diagnostics and Lab Tests, Disease Biology, Endocrine Diseases, Fatty acids, Lipid metabolism, Lipids, Liver & Digestive Diseases Research, Metabolism, Metabolomics, Nephrology, Nutrition, Nutrition and Phytochemistry, Nutritional Supplements: Atherogenesis, Nutritional Supplements: Atherogenesis, lipid metabolism, Plant extract, Population Health Management, Nutrition and Phytochemistry, Proteomics, Signaling, tagged , , , , , , , , on March 2, 2015| Leave a Comment »

Diet and Diabetes

Writer and Curator: Larry H Bernstein, MD, FCAP 

 

Bile acid signaling in lipid metabolism: Metabolomic and lipidomic analysis of lipid and bile acid markers linked to anti-obesity and anti-diabetes in mice

Yunpeng Qi, Changtao Jiang, Jie Cheng, Kristopher W. Krausz, et al.

Biochimica et Biophysica Acta 1851 (2015) 19–29

http://dx.doi.org/10.1016/j.bbalip.2014.04.008

Bile acid synthesis is the major pathway for catabolism of cholesterol. Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme in the bile acid biosynthetic pathway in the liver and plays an important role in regulating lipid, glucose and energy metabolism. Transgenic mice overexpressing CYP7A1 (CYP7A1-tg mice) were resistant to high fat diet (HFD)-induced obesity, fatty liver, and diabetes. However the mechanism of resistance to HFD-induced obesity of CYP7A1-tg mice has not been determined. In this study, metabolomic and lipidomic profiles of CYP7A1-tg mice were analyzed to explore the metabolic alterations in CYP7A1-tg mice that govern the protection against obesity and insulin resistance by using ultra-performance liquid chromatography-coupled with electrospray ionization quadrupole time-of-flight mass spectrometry combined with multivariate analyses. Lipidomics analysis identified seven lipid markers including lysophosphatidylcholines, phosphatidylcholines, sphingomyelins and ceramides that were significantly decreased in serum of HFD-fed CYP7A1-tgmice.Metabolomics analysis identified 13metabolites in bile acid synthesis including taurochenodeoxy-cholic acid, taurodeoxycholic acid, tauroursodeoxycholic acid, taurocholic acid, and tauro-β-muricholic acid (T-β-MCA) that differed between CYP7A1-tg and wild-type mice. Notably, T-β-MCA, an antagonist of the farnesoid X receptor (FXR) was significantly increased in intestine of CYP7A1-tg mice. This study suggests that reducing 12α-hydroxylated bile acids and increasing intestinal T-β-MCA may reduce high fat diet-induced increase of phospholipids, sphingomyelins and ceramides, and ameliorate diabetes and obesity. This article is part of a Special Issue entitled Linking transcription to physiology in lipidomics.

Bile acid synthesis is the major pathway for catabolism of cholesterol to bile acids. In the liver, cholesterol 7α-hydroxylase (CYP7A1) is the first and rate-limiting enzyme of the bile acid biosynthetic pathway producing two primary bile acids, cholic acid (CA, 3α, 7α, 12α-OH) and chenodeoxycholic acid (CDCA, 3α, 7α-OH) in humans. Sterol-12α hydroxylase (CYP8B1) catalyzes the synthesis of CA. In mice, CDCA is converted to α-muricholic acid (α-MCA: 3α, 6β, 7α-OH) and β-muricholic acid (β-MCA: 3α, 6β, 7β-OH). Bile acids are conjugated to taurine or glycine, secreted into the bile and stored in the gallbladder. After a meal, bile acids are released into the gastrointestinal tract. In the intestine, conjugated bile acids are first de-conjugated and then 7α-dehydroxylase activity in the gut flora converts CA to deoxycholic acid (DCA: 3α, 12α), and CDCA to lithocholic acid (LCA: 3α), two major secondary bile acids in humans.

In humans, most bile acids are glycine or taurine-conjugated and CA, CDCA and DCA are the most abundant bile acids. In mice, most bile acids are taurine-conjugated and CA and α- and β-MCAs are the most abundant bile acids. Bile acids facilitate absorption of dietary fats, steroids, and lipid soluble vitamins into enterocytes and are transported via portal circulation to the liver for metabolism and distribution to other tissues and organs. About 95% of bile acids are reabsorbed in the ileum and transported to the liver to inhibit CYP7A1 and bile acid synthesis. Enterohepatic circulation of bile acids provides a negative feedback mechanism to maintain bile acid homeostasis. Alteration of bile acid synthesis, secretion and transport causes cholestatic liver diseases, gallstone diseases, fatty liver disease, diabetes and obesity.

 Bile acid synthesis

 

Bile acid synthesis. In the classic bile acid synthesis pathway, cholesterol is converted to cholic acid (CA, 3α, 7α, 12α) and chenodeoxycholic acid (CDCA, 3α, 7α). CYP7A1 is the rate-limiting enzyme and CYP8B1 catalyzes the synthesis of CA. In mouse liver, CDCA is converted to α-muricholic acid (α-MCA, 3α, 6β, 7α) and β-MCA (3α, 6β, 7β). Most bile acids in mice are taurine (T)-conjugated and secreted into bile. In the intestine, gut bacteria de-conjugate bile acids and then remove the 7α-hydroxyl group from CA and CDCA to form secondary bile acids deoxycholic acid (DCA, 3α, 12α) and lithocholic acid (LCA, 3α), respectively. T-α-MCA and T-β-MCA are converted to T-hyodeoxycholic acid (THDCA, 3α, 6α), T-ursodeoxycholic acid (TUDCA, 3α, 7β), T-hyocholic acid (THCA, 3α, 6α, 7α) and T-murideoxycholic acid (TMDCA, 3α, 6β). These secondary bile acids are reabsorbed and circulated to liver to contribute to the bile acid pool. Secondary bile acids ω-MCA (3α, 6α, 7β) and LCA are excreted into feces.

Two FXR-dependent mechanisms are known to inhibit bile acid synthesis.  In the liver bile acid-activated FXR induces a negative receptor small heterodimer partner (SHP) to inhibit trans-activation activity of hepatic nuclear factor 4α(HNF4α) and liver receptor homologue-1 (LRH-1) that bind to the bile acid response element in the CYP7A1 and CYP8B1 gene promoters (Fig. 2, Pathway 1). In the intestine, bile acids activate FXR to induce fibroblast growth factor (mouse FGF15, or human FGF19), which activates hepatic FGF receptor 4 (FGFR4) and cJun N-terminal kinase 1/2 (JNK1/2) and extracellular-regulated kinase (ERK1/2) signaling of mitogen-activated protein kinase (MAPK) pathways to inhibit trans-activation of CYP7A1/CYP8B1 gene by HNF4α (Pathway 2). Several FXR-independent cell-signaling pathways have been reported and are shown as Pathway 3 (Fig. 2). Conjugated bile acids are known to activate several protein kinase Cs (PKC) and growth factor receptors, epidermal growth factor receptor (EGFR), and insulin receptor (IR) signaling to inhibit CYP7A1/CYP8B1 and bile acid synthesis via activating the ERK1/2, p38 and JNK1/2 pathways.

 

Bile acid signaling pathways. Bile acids activate FXR, TGR5 and cell signaling pathways to inhibit CYP7A1 and CYP8B1 gene transcription.

1) Hepatic FXR/SHP pathway: bile acid activated-FXR induces SHP, which inhibits HNF4α and LRH-1 trans-activation of CYP7A1 and CYP8B1 gene transcription in hepatocytes. Bile acid response element binds HNF4α and LRH-1.

2) Intestinal FXR/FGF19/FGFR4 pathway: in the intestine, FXR induces FGF15 (mouse)/FGF19 (human), which is secreted into portal circulation to activate FGF receptor 4 (FGFR4) in hepatocytes. FGFR4 signaling stimulates JNK1/2 and ERK1/2 pathways of MAPK signaling to inhibit CYP7A1 gene transcription by phosphorylation and inhibition of HNF4α binding activity.

3) FXR-independent signaling pathways: Conjugated bile acids activate PKCs,which activate the MAPK pathways to inhibit CYP7A1. Bile acids also activate insulin receptor (IR) signaling IRS/PI3K/PDK1/AKT, possibly via activation of epidermal growth factor receptor (EGFR) signaling, MAPKs (MEK, MEKK), to inhibit CYP7A1 gene transcription. The secondary bile acid TLCA activates TGR5 signaling in Kupffer cells. TGR5 signaling may regulate CYP7A1 by an unknown mechanism. TCA activates sphingosine-1-phosphate (S1P) receptor 2 (S1PR2), which may activate AKT and ERK1/2 to inhibit CYP7A1. S1P kinase 1 (Sphk1) phosphorylates sphingosine (Sph) to S-1-P, which activates S1PR2. On the other hand, nuclear SphK2 interacts with and inhibits histone deacetylase (HDAC1/2) and may induce CYP7A1. The role of S1P, SphK2, and S1PR2 signaling in regulation of bile acid synthesis is not known.

 

When challenged with an HFD, CYP7A1-tg mice had lower body fat mass and higher lean mass compared to wild-type mice. As a platform for comprehensive and quantitative description of the set of lipid species, lipidomics was used to investigate the mechanism of this phenotype. By use of an unsupervised PCA model with the cumulative R2X 0.677 for serum and 0.593 for liver, CYP7A1-tg and wild-type mice were clearly separated based on the scores plot (Supplementary Fig. S2), indicating that these two groups have distinct lipidomic profiles. Supervised PLS-DA models were then established to maximize the difference of metabolic profiles between CYP7A1-tg and wild-type groups as well as to facilitate the screening of lipid marker metabolites (Fig. 3).

PLS-DA analysis of CYP7A1-tg and wild-type (WT)mice challenged with HFD. Based on the score plots, distinct lipidomic profiles of male CYP7A1-tg and wild-type groups were shown for serum (A) and liver samples (B). Based on the loading plots (C for serum and D for liver) the most significant ions that led to the separation between CYP7A1-tg and wild-type groups were obtained and identified as follows: 1. LPC16:0; 2. LPC18:0; 3. LPC18:1; 4. LPC 18:2; 5. PC16:0-20:4; 6. PC16:0-22:6; 7. SM16:0. (not shown)

Fig. 5. OPLS-DA highlighted thirteen markers in bile acid pathway that contribute significantly to the clustering of CYP7A1-tg and wild-type (WT) mice. Ileum bile acids are shown. (not shown)

(A) In the score plot, female CYP7A1-tg andWTmicewere well separated;

(B) using a statistically significant thresholds of variable confidence approximately 0.75 in the S-plot, a number of ions were screened out as potential markers, which were later identified as 13 bile acid metabolites, including α-MCA, TCA, CDCA, and TCDCA etc.

Our recent study of CYP7A1-tg mice revealed that increased CYP7A1 expression and enlarged bile acid pool resulted in significant improvement of lipid homeostasis and resistance to high-fed diet-induced hepatic steatosis, insulin resistance, and obesity in CYP7A1-tg mice. In this study, metabolomics and lipidomics were employed to characterize the metabolic profiles of CYP7A1-tg mice and to provide new insights into the critical role of bile acids in regulation of lipid metabolism and metabolic diseases. Lipidomics analysis of serum lipid profiles of high fat diet-fed CYP7A1-tg identified 7 lipidomic markers that were reduced in CYP7A1-tg mice compared to wild type mice. Metabolomics analysis identified 13 bile acid metabolites that were altered in CYP7A1-tg mice. In CYP7A1-tg mice, TCA and TDCA were reduced, whereas T-β-MCA was increased in the intestine compared to that of wild type mice. The decrease of serum LPC, PC, SM and CER, and 12α-hydroxylated bile acids, and increase of T-β-MCA may contribute to the resistance to diet-induced obesity and diabetes in CYP7A1-tg mice (Fig. 8).

The present metabolomics and lipidomics analysis revealed that even upon challenging with HFD, CYP7A1-tg mice had reduced lipid levels including LPC, PC, SM and CER. Metabolomics studies of human steatotic liver tissues and HFD-fed mice showed that serum and liver LPC and PC and other lipids levels were increased compared with non-steatotic livers, suggesting altered lipid metabolism contributes to non-alcoholic fatty liver disease (NAFLD). In HFD-fed CYP7A1-tg mice, reduced serum PC, LPC, SM and CER levels suggest a role for bile acids in maintaining phospholipid homeostasis to prevent NAFLD. SMs are important membrane phospholipids that interact with cholesterol in membrane rafts and regulate cholesterol distribution and homeostasis. A role for SM and CER in the pathogenesis of insulin resistance, diabetes and obesity and development of atherosclerosis has been reported. CER has a wide range of biological functions in cellular signaling such as activating protein kinase C and c-Jun N-terminal kinase (JNK), induction of β-cell apoptosis and insulin resistance. CER increases reactive oxidizing species and activates the NF-κB pathway, which induces proinflammatory cytokines, diabetes and insulin resistance. CER is synthesized from serine and palmitoyl-CoA or hydrolysis of SM by acid sphingomyelinase (ASM). HFD is known to increase CER and SM in liver. The present observation of decreased SM and CER levels in HFD-fed CYP7A1-tg mice indicated that bile acids might reduce HFD-induced increase of SM and CER. DCA activates an ASM to convert SM to CER, and Asm−/− hepatocytes are resistant to DCA induction of CER and activation of the JNK pathway [65]. In CYP7A1-tg mice, enlarged bile acid pool inhibits CYP8B1 and reduces CA and DCA levels. Thus, decreasing DCA may reduce ASM activity and SM and CER levels, and contribute to reducing inflammation and improving insulin sensitivity in CYP7A1-tg mice. It has been reported recently that in diabetic patients, serum 12α-hydroxylated bile acids are increased and correlated to insulin resistance [66].

Fig. 8. Mechanisms of anti-diabetic and anti-obesity function of bile acids in CYP7A1-tg mice. In CYP7A1-tg mice, overexpressing CYP7A1 increases bile acid pool size and reduces cholic acid by inhibiting CYP8B1. Lipidomics analysis revealed decreased serum LPC, PC, SM and CER. These lipidomic markers are increased in hepatic steatosis and NAFLD. Bile acids may reduce LPC, PC, SM and CER levels and protect against high fat diet-induced insulin resistance and obesity in CYP7A1-tgmice. Metabolomics analysis showed decreased intestinal TCA and TDCA and increased intestinal T-β-MCA in CYP7A1-tgmice.High fat diets are known to increase CA synthesis and intestinal inflammation. It is proposed that decreasing CA and  DCA synthesis may increase intestinal T-β-MCA,which antagonizes FXR signaling to increase bile acid synthesis and prevent high fat diet-induced insulin resistance and obesity. (not shown)

In conclusion,metabolomics and lipidomicswere employed to characterize the metabolic profiles of CYP7A1-tg mice, aiming to provide new insights into the mechanism of bile acid signaling in regulation of lipid metabolism and maintain lipid homeostasis. A number of lipid and bile acid markers were unveiled in this study. Decreasing of lipid markers, especially SM and CER may explain the improved insulin sensitivity and obesity in CYP7A1-tg mice. Furthermore, this study uncovered that enlarged bile acid pool size and altered bile acid composition may reduce de-conjugation by gut microbiota and increase tauroconjugated muricholic acids, which partially inhibit intestinal FXR signaling without affecting hepatic FXR signaling. This study is significant in applying metabolomics for diagnosis of lipid biomarkers for fatty liver diseases, obesity and diabetes. Increasing CYP7A1 activity and bile acid synthesis coupled to decreasing CYP8B1 and 12α-hydroxylated bile acids may be a therapeutic strategy for treating diabetes and obesity.

 

Bile acids are nutrient signaling hormones

Huiping Zhou, Phillip B. Hylemon
Steroids 86 (2014) 62–68
http://dx.doi.org/10.1016/j.steroids.2014.04.016

Bile salts play crucial roles in allowing the gastrointestinal system to digest, transport and metabolize nutrients. They function as nutrient signaling hormones by activating specific nuclear receptors (FXR, PXR, Vitamin D) and G-protein coupled receptors [TGR5, sphingosine-1 phosphate receptor 2 (S1PR2), muscarinic receptors]. Bile acids and insulin appear to collaborate in regulating the metabolism of nutrients in the liver. They both activate the AKT and ERK1/2 signaling pathways. Bile acid induction of the FXR-a target gene, small heterodimer partner (SHP), is highly dependent on the activation PKCf, a branch of the insulin signaling pathway. SHP is an important regulator of glucose and lipid metabolism in the liver. One might hypothesize that chronic low grade inflammation which is associated with insulin resistance, may inhibit bile acid signaling and disrupt lipid metabolism. The disruption of these signaling pathways may increase the risk of fatty liver and non-alcoholic fatty liver disease (NAFLD). Finally, conjugated bile acids appear to promote cholangiocarcinoma growth via the activation of S1PR2.

 

In the past, bile salts were considered to be just detergent molecules that were required for the solubilization of cholesterol in the gall bladder, promoting the digestion of dietary lipids and stimulating the absorption of lipids, cholesterol and fat-soluble vitamins in the intestines. Bile salts were also known to stimulate bile flow, promote cholesterol secretion from the liver, and have antibacterial properties. However, in 1999, three independent laboratories reported that bile acids were natural ligands for the farnesoid X receptor (FXR-α) . The recognition that bile acids activated specific nuclear receptors started a renaissance in the field of bile acid research. Since 1999, bile acids have been reported to activate other nuclear receptors (pregnane X receptor, vitamin D receptor), G protein coupled receptors [TGR5, sphingosine-1-phosphate receptor 2 (S1PR2), muscarinic receptor 2 (M2)] and cell signaling pathways (JNK1/2, AKT, and ERK1/2). Deoxycholic acid (DCA), a secondary bile acid, has also been reported to activate the epidermal growth factor receptor (EGFR). It is now clear that bile acids function as hormones or nutrient signaling molecules that help to regulate glucose, lipid, lipoprotein, and energy metabolism as well as inflammatory responses.

Bile acids are synthesized from cholesterol in liver hepatocytes, conjugated to either glycine or taurine and actively secreted via ABC transporters on the canalicular membrane into biliary bile. Conjugated bile acids are often referred to as bile salts. Bile acid synthesis represents a major output pathway of cholesterol from the body. Bile acids are actively secreted from hepatocytes via the bile salt export protein (BSEP, ABCB11) along with phospholipids by ABCB4 and cholesterol by ABCG5/ABCG8 in a fairly constant ratio under normal conditions. Bile acids are detergent molecules and form mixed micelles with cholesterol and phospholipids, which help to keep cholesterol in solution in the gall bladder. Eating stimulates the gall bladder to contract, emptying its contents into the small intestines. Bile salts are crucial for the solubilization and absorption of cholesterol and lipids as well as lipid soluble vitamins (A, D, E, and K). They activate pancreatic enzymes and form mixed micelles with lipids in the small intestines, promoting their absorption. Bile acids are efficiently recovered from the intestines, primarily the ileum, by the apical sodium dependent transporter (ASBT). Bile acids are secreted from ileocytes, on the basolateral side, by the organic solute OSTα/OSTβ transporter. Secondary bile acids, formed by 7α-dehydroxylation of primary bile acids by anaerobic gut bacteria, can be passively absorbed from the large bowel or secreted in the feces. Absorbed bile acids return to the liver via the portal blood where they are actively transported into hepatocytes primarily via the sodium taurocholate cotransporting polypeptide (NTCP, SLC10A1). Bile acids are again actively secreted from the hepatocytes into the bile, stimulating bile flow and the secretion of cholesterol and phospholipids. Bile acids undergo enterohepatic circulation several times each day (Fig. 1). During their enterohepatic circulation approximately 500–600 mg/day are lost via fecal excretion and must be replaced by new bile acid synthesis in the liver. The bile acid pool size is tightly regulated as excess bile acids can be highly toxic to mammalian cells.

Enterohepatic circulation of bile acids

 

Enterohepatic circulation of bile acids. Bile acids are synthesized and conjugated mainly to glycine or taurine in hepatocytes. Bile acids travel to the gall bladder for storage during the fasting state. During digestion, bile acids travel to the duodenum via the common bile duct. 95% of the bile acids delivered to the duodenum are absorbed back into blood within the ileum and circulate back to the liver through the portal vein. 5% of bile acids are lost in feces.

There are two pathways of bile acid synthesis in the liver, the neutral pathway and the acidic pathway (Fig. 2). The neutral pathway is believed to be the major pathway of bile acid synthesis in humans under normal physiological conditions. The neutral pathway is initiated by cholesterol 7α-hydroxylase (CYP7A1), which is the rate-limiting step in this biochemical pathway. CYP7A1 is a cytochrome P450 monooxygenase, and the gene encoding this enzyme is highly regulated by a feed-back repressive mechanism involving the FXR-dependent induction of fibroblast growth factor 15/19 (FGF15/19) by bile acids in the intestines. FGF15/19 binds to the fibroblast growth factor receptor 4 (FGFR4)/β-Klotho complex in hepatocytes activating both the JNK1/2 and ERK1/2 signaling cascades. Activation of the JNK1/2 pathway has been reported to down-regulate CYP7A1 mRNA in hepatocytes. FGFR4 and β-Klotho mice have increased levels of CYP7A1 and upregulated bile acid synthesis. Moreover, treatment of FXR mice with a specific FXR agonist failed to repress CYP7A1 in the liver. These results support an important role of FGF15, synthesized in the intestines by activation of FXR, in the regulation of CYP7A1 and bile acid synthesis in the liver. CYP7A1 has also been reported to be down-regulated by glucagon and pro-inflammatory cytokines and up-regulated by glucose and insulin during the postprandial period.

Fig. 2. (not shown) Biosynthetic pathways of bile acids. Two major pathways are involved in bile acid synthesis. The neutral (or classic) pathway is controlled by cholesterol 7α-hydroxylase (CYP7A1) in the endoplasmic reticulum. The acidic (or alternative) pathway is controlled by sterol 27-hydroxylase (CYP27A1) in mitochondria. The sterol 12α-hydroxylase (CYP8B1) is required to synthesis of cholic acid (CA). The oxysterol 7α-hydroxylase (CYP7B1) is involved in the formation of chenodeoxycholic acid (CDCA) in acidic pathway. The neutral pathway is also able to form CDCA by CYP27A1.

The neutral pathway of bile acid synthesis produces both cholic acid (CA) and chenodeoxycholic acid (CDCA) (Fig. 2). The ratio of CA and CDCA is primarily determined by the activity of sterol 12α-hydroxylase (CYP8B1). The gene encoding CYP8B1 is also highly regulated by bile acids. Bile acids induce the gene encoding small heterodimer partner (SHP) in the liver via activation of the farnesoid X receptor (FXR-α). SHP is an orphan nuclear receptor without a DNA binding domain. It interacts with several transcription factors, including hepatocyte nuclear factor 4 (HNF4α) and liver-related homolog-1 (LRH-1), and acts as a dominant negative protein to inhibit transcription. In this regard, a liver specific knockout of LRH-1 completely abolished the expression of CYP8B1, but had little effect on CYP7A1. These results suggest that the interaction of SHP with LRH-1, caused by bile acids, may be the key regulator of hepatic CYP8B1 and the ratio of CA/CDCA. The acidic or alternative pathway of bile acid synthesis is initiated in the inner membrane of mitochondria by sterol 27-hydroxylase (CYP27A1). This enzyme also has low sterol 25-hydroxylase activity. CYP27A1 is capable of further oxidizing the 27-hydroxy group to a carboxylic acid. Unlike, CYP7A1, CYP27A1 is widely expressed in various tissues in the body where it may produce regulatory oxysterols. Even though CYP27A1 is the initial enzyme in the acidic pathway of bile acid synthesis, it may not be the rate limiting step. The inner mitochondrial membrane is very low in cholesterol content. Hence, cholesterol transport into the mitochondria appears to be the rate limiting step.

The acidic pathway of bile acid synthesis is now being viewed as an important pathway for generating regulatory oxysterols. For example, 25-hydroxy-cholesterol and 27-hydroxycholesterol are natural ligands for the liver X receptor (LXR), which is involved in regulating cholesterol and lipid metabolism. Moreover, recent studies report that 25-hydroxycholesterol, formed by CYP27A1, can be converted into 5-cholesten-3β-25-diol-3-sulfate in the liver. The sulfated 25-hydroxycholesterol is a regulator of inflammatory responses, lipid metabolism and cell proliferation, and is located in the liver. Recent evidence suggests that sulfated 25-hydroxycholesterol is a ligand for peroxisome proliferator-activated receptor gamma (PPARc), which is a major regulator of inflammation and lipid metabolism. The 7α-hydroxylation of oxysterols is catalyzed by oxysterol 7α-hydroxylase (CYP7B1). This biotransformation allows some of these oxysterols to be converted to bile acids. Finally, oxysterols generated in extrahepatic tissues can be transported to the liver and metabolized into bile acids.

Bile acids can activate several different nuclear receptors (FXR, PXR and Vitamin D) and GPCRs (TGR5, S1PR2, and [M2] Muscarinic receptor). The ability of different bile acids to activate FXR-α occurs in the following order CDCA > LCA = DCA > CA; for the pregnane X receptor (PXR) LCA > DCA > CA and the vitamin D receptor, 3-oxo-LCA > LCA > DCA > CA. LCA is the best activator of PXR and the vitamin D receptor which correlates with the hydrophobicity and toxicity of this bile acid toward mammalian cells. Activation of PXR and the vitamin D receptor induces genes encoding enzymes which metabolize LCA into a more hydrophilic and less toxic metabolite. These nuclear receptors appear to function in the protection of cells from hydrophobic bile acids. In contrast, FXR-α appears to play a much more extensive role in the body by regulating bile acid synthesis, transport, and enterohepatic circulation. Moreover, FXR-α also participates in the regulation of glucose, lipoprotein and lipid metabolism in the liver as well as a suppressor of inflammation in the liver and intestines.

TGR5, also referred to as membrane-type bile acid receptor (MBAR), was the first GPCR to be reported to be activated by bile acids in the order LCA > DCA > CDCA > CA. TGR5 is a Gas type receptor which activates adenyl cyclase activity increasing the rate of the synthesis of c-AMP. TGR5 is widely expressed in human tissues, including: intestinal neuroendocrine cells, gall bladder, spleen, brown adipose tissue, macrophages and cholangiocytes, but not hepatocytes. TGR5 may play a role in various physiological processes in the body. TGR5 appears to be important in regulating energy metabolism. It has been postulated that bile acids may activate TGR5 in brown adipose tissue, activating type 2-iodothyroxine deiodinase and leading to increased levels of thyroid hormone and stimulation of energy metabolism. Moreover, TGR5 has been reported to promote the release of glucagon-like peptide-1 release from neuroendocrine cells, which increases insulin release in the pancreas. These results suggest that TGR5 may play a role in glucose homeostasis in the body. TGR5 is a potential target for drug development for treating type 2 diabetes and other metabolic disorders.

Interrelationship between sphingosine 1-phosphate receptor 2 and the insulin signaling pathway

 

Interrelationship between sphingosine 1-phosphate receptor 2 and the insulin signaling pathway in regulating hepatic nutrient metabolism. S1PR2, sphingosine 1-phosphate receptor 2; Src, Src Kinase; EGFR, epidermal growth factor receptor; PPARa, peroxisome proliferator-activated receptor alpha; NTCP, Na+/taurocholate cotransporting polypeptide; BSEP, bile salt export pump; PC, phosphotidylcholine; PECK, phosphoenolpyruvate carboxykinase; G6Pase, glucose-6-phosphatase; PDK1, phosphoinositide-dependent protein kinase 1; AKT, protein kinase B; SREBP, sterol regulatory element-binding protein; PKCf, protein kinase C zeta; FXR, farnesoid X receptor; SHP, small heterodimeric partner; MDR3, phospholipid transporter (ABCB4); GSK3b, glycogen synthase kinase 3 beta.

 

Both unconjugated and conjugated bile acids activate the insulin signaling (AKT) and ERK1/2 pathways in hepatocytes. Interesting, insulin and bile acids both activated glycogen synthase activity to a similar extent in primary rat hepatocytes. Moreover, the addition of both insulin and bile acids to the culture medium resulted in an additive effect on activation of glycogen synthase activity in primary hepatocytes. Infusion of taurocholate (TCA) into the chronic bile fistula rat rapidly activated the AKT and ERK1/2 signaling pathway and glycogen synthase activity. In addition, there was a rapid down-regulation of the gluconeogenic genes, PEP carboxykinase (PEPCK) and glucose-6-phophatase (G-6-Pase) and a marked up-regulation of SHP mRNA in these sample livers. These results suggest that TCA functions much like insulin to regulate hepatic glucose metabolism both in vitro and in vivo.

It has been reported that PKCζ phosphorylates FXR-α and may allow for its activation of target gene expression. In contrast, phosphorylation of FXR-α by AMPK inhibits the ability of FXR to induce target genes. PKCζ has been reported to be important for the translocation of the bile acid transporters NTCP (SLC10A1) and BSEP (ABC B11) to the basolateral and canalicular membranes, respectively. Finally, it has been recently reported that PKCζ phosphorylates SHP allowing both to translocate to the nucleus and down-regulate genes via epigenetic mechanisms. In total, these results all suggest that the insulin signaling pathway is an important regulator of FXR-α activation and bile acid signaling in the liver.

The activation of the insulin signaling pathway and FXR-α appear to collaborate in the coordinate regulation of glucose, bile acid and lipid metabolism in the liver. SHP, an FXR target gene, is an important pleotropic regulator of multiple metabolic pathways in the liver (Fig. 3). The S1PR2 appears to be an important regulator of hepatic lipid metabolism as S1PR2 mice rapidly (2 weeks) develop overt fatty livers on a high fat diet as compared to wild type mice (unpublished data). It is well established that inflammation and the synthesis of inflammatory cytokines i.e. TNFα inhibit insulin signaling by activation of the JNK1/2 signaling pathway, which phosphorylates insulin receptor substrate 1. Inflammation is believed to be an important factor in the development of type 2 diabetes and fatty liver disease. A Western diet is correlated with low grade chronic inflammation and insulin resistance. Inhibition of the insulin signaling pathway may decrease the ability of bile acids to activate FXR-α, induce SHP and other FXR target genes, leading to an increased risk of fatty liver and non-alcoholic fatty liver disease (NAFLD).

There appears to be extensive interplay between bile salts and insulin signaling in the regulation of nutrient metabolism in both the intestines and liver. Bile salts play a key role in the solubilization and absorption of nutrients from the intestines. The absorption of nutrients stimulates the secretion of insulin from the pancreas. Moreover, bile acids may also stimulate the secretion of insulin by activating TGR5 in intestinal neuroendocrine cells resulting in the secretion of glucagon-like peptide-1. In the liver, bile salts and insulin both activate the AKT and ERK1/2 signaling pathways which yields a stronger signal than either alone. The activation of PKCζ, a branch of the insulin signaling pathway, is required for the optimal induction of FXR target genes and the regulation of the cellular location of bile acid transporters

 

Fruit and vegetable consumption and risk of type 2 diabetes mellitus: A dose-response meta-analysis of prospective cohort studies

  1. Wu, D. Zhang, X. Jiang, W. Jiang
    Nutrition, Metabolism & Cardiovascular Diseases (2015) 25, 140-147
    http://dx.doi.org/10.1016/j.numecd.2014.10.004

Background and aims: We conducted a dose-response meta-analysis to summarize the evidence from prospective cohort studies regarding the association of fruit and vegetable consumption with risk of type 2 diabetes mellitus (T2DM). Methods and results: Pertinent studies were identified by searching Embase and PubMed through June 2014. Study-specific results were pooled using a random-effect model. The dose-response relationship was assessed by the restricted cubic spline model and the multivariate random-effect meta-regression. We standardized all data using a standard portion size of 106 g. The Relative Risk (95% confidence interval) [RR (95% CI)] of T2DM was 0.99 (0.98-1.00) for every 1 serving/day increment in fruit and vegetable (FV) (P < 0.18), 0.98 (0.95-1.01) for vegetable (P < 0.12), and 0.99 (0.97-1.00) for fruit (P < 0.05). The RR (95%CI) of T2DM was 0.99 (0.97-1.01), 0.98 (0.96-1.01), 0.97 (0.93-1.01), 0.96 (0.92-1.01), 0.96 (0.91-1.01) and 0.96 (0.91-1.01) for 1, 2, 3, 4, 5 and 6 servings/day of FV (P for non-linearity < 0.44). The T2DM risk was 0.96 (0.95-0.99), 0.94 (0.90-0.98), 0.94 (0.89-0.98), 0.96 (0.91-1.01), 0.98 (0.92-1.05) and 1.00 (0.93-1.08) for 1, 2, 3, 4, 5 and 6 servings/day of vegetable (P for non-linearity < 0.01). The T2DM risk was 0.95 (0.93-0.97), 0.91 (0.89-0.94), 0.88 (0.85-0.92), 0.92 (0.88-0.96) and 0.96 (0.92-1.01) for 0.5, 1, 2, 3 and 4 servings/day of fruit (P for non-linearity < 0.01). Conclusions: Two-three servings/day of vegetable and 2 servings/day of fruit conferred a lower risk of T2DM than other levels of vegetable and fruit consumption, respectively.

dose-response analysis between total fruit and vegetable consumption and risk of type 2 diabetes mellitus

 

The dose-response analysis between total fruit and vegetable consumption and risk of type 2 diabetes mellitus. The solid line and the long dash line represent the estimated relative risk and its 95% confidence interval.

 

Healthy behaviours and 10-year incidence of diabetes: A population cohort study

G.H. Long , I. Johansson , O. Rolandsson , …, E. Fhärm, L.Weinehall, et al.
Preventive Medicine 71 (2015) 121–127
http://dx.doi.org/10.1016/j.ypmed.2014.12.013

Objective. To examine the association between meeting behavioral goals and diabetes incidence over 10 years in a large, representative Swedish population. Methods. Population-based prospective cohort study of 32,120 individuals aged 35 to 55 years participating in a health promotion intervention in Västerbotten County, Sweden (1990 to 2013). Participants underwent an oral glucose tolerance test, clinical measures, and completed diet and activity questionnaires. Poisson regression quantified the association between achieving six behavioral goals at baseline – body mass index (BMI) < 25 kg/m2, moderate physical activity, non-smoker, fat intake  < 30% of energy, fibre intake ≥15 g/4184 kJ and alcohol intake ≤ 20 g/day – and diabetes incidence over 10 years. Results. Median interquartile range (IQR) follow-up time was 9.9 (0.3) years; 2211 individuals (7%) developed diabetes. Only 4.4% of participants met all 6 goals (n = 1245) and compared to these individuals, participants meeting 0/1 goals had a 3.74 times higher diabetes incidence (95% confidence interval (CI) = 2.50 to 5.59), adjusting for sex, age, calendar period, education, family history of diabetes, history of myocardial infarction and long-term illness. If everyone achieved at least four behavioral goals, 14.1% (95% CI: 11.7 to 16.5%) of incident diabetes cases might be avoided. Conclusion. Interventions promoting the achievement of behavioral goals in the general population could significantly reduce diabetes incidence.

 

Long term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): A population based study

Shira Zelber-Sagi, Dorit Nitzan-Kaluski, Rebecca Goldsmith, et al.
Journal of Hepatology 47 (2007) 711–717
http://dx.doi.org:/10.1016/j.jhep.2007.06.020

Background/Aims: Weight loss is considered therapeutic for patients with NAFLD. However, there is no epidemiological evidence that dietary habits are associated with NAFLD. Dietary patterns associated with primary NAFLD were investigated. Methods: A cross-sectional study of a sub-sample (n = 375) of the Israeli National Health and Nutrition Survey. Exclusion criteria were any known etiology for secondary NAFLD. Participants underwent an abdominal ultrasound, biochemical tests, dietary and anthropometric evaluations. A semi-quantitative food-frequency questionnaire was administered. Results: After exclusion, 349 volunteers (52.7% male, mean age 50.7 ± 10.4, 30.9% primary NAFLD) were included. The NAFLD group consumed almost twice the amount of soft drinks (P = 0.03) and 27% more meat (P < 0.001). In contrast, the NAFLD group consumed somewhat less fish rich in omega-3 (P = 0.056). Adjusting for age, gender, BMI and total calories, intake of soft drinks and meat was significantly associated with an increased risk for NAFLD (OR = 1.45, 1.13–1.85 95% CI and OR = 1.37, 1.04–1.83 95% CI, respectively). Conclusions: NAFLD patients have a higher intake of soft drinks and meat and a tendency towards a lower intake of fish rich in omega-3. Moreover, a higher intake of soft drinks and meat is associated with an increased risk of NAFLD, independently of age, gender, BMI and total calories.

 

The association between types of eating behavior and dispositional mindfulness in adults with diabetes. Results from Diabetes MILES. The Netherlands

Sanne R. Tak, Christel Hendrieckx, Giesje Nefs, Ivan Nyklícek, et al.
Appetite 87 (2015) 288–295
http://dx.doi.org/10.1016/j.appet.2015.01.006

Although healthy food choices are important in the management of diabetes, making dietary adaptations is often challenging. Previous research has shown that people with type 2 diabetes are less likely to benefit from dietary advice if they tend to eat in response to emotions or external cues. Since high levels of dispositional mindfulness have been associated with greater awareness of healthy dietary practices in students and in the general population, it is relevant to study the association between dispositional mindfulness and eating behavior in people with type 1 or 2 diabetes. We analyzed data from Diabetes MILES – The Netherlands, a national observational survey in which 634 adults with type 1 or 2 diabetes completed the Dutch Eating Behavior Questionnaire (to assess restrained, external and emotional eating behavior) and the Five Facet Mindfulness Questionnaire-Short Form (to assess dispositional mindfulness), in addition to other psychosocial measures. After controlling for potential confounders, including  demographics, clinical variables and emotional distress, hierarchical linear regression analyses showed that higher levels of dispositional mindfulness were associated with eating behaviors that were more restrained (β = 0.10) and less external (β = −0.11) and emotional (β = −0.20). The mindfulness subscale ‘acting with awareness’ was the strongest predictor of both external and emotional eating behavior, whereas for emotional eating, ‘describing’ and ‘being non-judgmental’ were also predictive. These findings suggest that there is an association between dispositional mindfulness and eating behavior in adults with type 1 or 2 diabetes. Since mindfulness interventions increase levels of dispositional mindfulness, future studies could examine if these interventions are also effective in helping people with diabetes to reduce emotional or external eating behavior, and to improve the quality of their diet.

 

Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome

Ali Abid, Ola Taha, William Nseir, Raymond Farah, Maria Grosovski, Nimer Assy
Journal of Hepatology 51 (2009) 918–924
http://dx.doi.org:/10.1016/j.jhep.2009.05.033

Background/Aims: The independent role of soft drink consumption in non-alcoholic fatty liver disease (NAFLD) patients remains unclear. We aimed to assess the association between consumption of soft drinks and fatty liver in patients with or without metabolic syndrome. Methods: We recruited 31 patients (age: 43 ± 12 years) with NAFLD and risk factors for metabolic syndrome, 29 patients with NAFLD and without risk factors for metabolic syndrome, and 30 gender- and age-matched individuals without NAFLD. The degree of fatty infiltration was measured by ultrasound. Data on physical activity and intake of food and soft drinks were collected during two 7-day periods over 6 months using a food questionnaire. Insulin resistance, inflammation, and oxidant–antioxidant markers were measured.
Results: We found that 80% of patients with NAFLD had excessive intake of  soft drink beverages (>500 cm3/day) compared to 17% of healthy controls (p < 0.001). The NAFLD group consumed five times more carbohydrates from soft drinks compared to healthy controls (40% vs. 8%, p < 0.001). Seven percent of patients consumed one soft drink per day, 55% consumed two or three soft drinks per day, and 38% consumed more than four soft drinks per day for most days and for the 6-month period. The most common soft drinks were Coca-Cola (regular: 32%; diet: 21%) followed by fruit juices (47%). Patients with NAFLD with metabolic syndrome had similar malonyldialdehyde, paraoxonase, and C-reactive protein (CRP) levels but higher homeostasis model assessment (HOMA) and higher ferritin than NAFLD patients without metabolic syndrome (HOMA: 8.3 ± 8 vs. 3.7 ± 3.7 mg/dL, p < 0.001; ferritin: 186 ± 192 vs. 87 ± 84 mg/dL, p < 0.01). Logistic regression analysis showed that soft drink consumption is a strong predictor of fatty liver (odds ratio: 2.0; p < 0.04) independent of metabolic syndrome and CRP level. Conclusions: NAFLD patients display higher soft drink consumption independent of metabolic syndrome diagnosis. These findings might optimize NAFLD risk stratification.

 

Dietary predictors of arterial stiffness in a cohort with type 1 and type 2 diabetes

K.S. Petersen, J.B. Keogh, P.J. Meikle, M.L. Garg, P.M. Clifton
Atherosclerosis 238 (2015) 175-181
http://dx.doi.org/10.1016/j.atherosclerosis.2014.12.012

Objective: To determine the dietary predictors of central blood pressure, augmentation index and pulse wave velocity (PWV) in subjects with type 1 and type 2 diabetes. Methods: Participants were diagnosed with type 1 or type 2 diabetes and had PWV and/or pulse wave analysis performed. Dietary intake was measured using the Dietary Questionnaire for Epidemiological Studies Version 2 Food Frequency Questionnaire. Serum lipid species and carotenoids were measured, using liquid chromatography electrospray ionization- tandem mass spectrometry and high performance liquid chromatography, as biomarkers  of dairy and vegetable intake, respectively. Associations were determined using linear regression adjusted for potential confounders. Results: PWV (n = 95) was inversely associated with reduced fat dairy intake (β = -0.01; 95% CI -0.02, -0.01; p = 0 < 0.05) in particular yoghurt consumption (β = 0.04; 95% CI -0.09, -0.01; p = 0 < 0.05) after multivariate adjustment. Total vegetable consumption was negatively associated with PWV in the whole cohort after full adjustment (β =0.04; 95% CI -0.07, -0.01; p < 0.05). Individual lipid species, particularly those containing 14:0, 15:0, 16:0, 17:0 and 17:1 fatty acids, known to be of ruminant origin, in lysophosphatidylcholine, cholesterol ester, diacylglycerol, phosphatidylcholine, sphingomyelin and triacylglycerol classes were positively associated with intake of full fat dairy, after adjustment for multiple comparisons. However, there was no association between serum lipid species and PWV. There were no dietary predictors of central blood pressure or augmentation index after multivariate adjustment. Conclusion: In this cohort of subjects with diabetes reduced fat dairy intake and vegetable consumption were inversely associated with PWV. The lack of a relationship between serum lipid species and PWV suggests that the fatty acid composition of dairy may not explain the beneficial effect.

In this cohort with type 1 and type 2 diabetes there was an inverse association between reduced fat dairy intake, in particular yoghurt consumption, and PWV, which persisted after multivariate adjustment. Serum lipid species, known to be of ruminant origin, were positively associated with full fat dairy consumption; however there was no association between these lipid species and PWV. In addition, higher vegetable intake was also associated with lower PWV. There were no dietary predictors of central blood pressure or augmentation index identified in this cohort.

In this study there was no relationship between augmentation index and PWV, which has been previously reported. Augmentation index is not a direct measure of arterial stiffness and is influenced by the timing and magnitude of the wave reflection. In contrast, PWV is a robust measure of arterial stiffness as it is determined by measuring the velocity of the waveform between the carotid and femoral arteries. Previously, it has been shown that in a population with diabetes PWV was elevated compared with healthy controls, however augmentation index was not different. Lacy et al.  concluded that augmentation index is not a reliable measure of arterial stiffness in people with diabetes. This may explain why we did not see an association between augmentation index and dietary intake, despite seeing correlations with PWV.

 

Curcumin ameliorates diabetic nephropathy by inhibiting the activation of the SphK1-S1P signaling pathway

Juan Huang, Kaipeng Huang, Tian Lan, Xi Xie, .., Peiqing Liu, Heqing Huang
Molecular and Cellular Endocrinology 365 (2013) 231–240
http://dx.doi.org/10.1016/j.mce.2012.10.024

Curcumin, a major polyphenol from the golden spice Curcuma longa commonly known as turmeric, has been recently discovered to have renoprotective effects on diabetic nephropathy (DN). However, the mechanisms underlying these effects remain unclear. We previously demonstrated that the sphingosine kinase 1-sphingosine 1-phosphate (SphK1-S1P) signaling pathway plays a pivotal role in the pathogenesis of DN. This study aims to investigate whether the renoprotective effects of curcumin on DN are associated with its inhibitory effects on the SphK1-S1P signaling pathway. Our results demonstrated that the expression and activity of SphK1 and the production of S1P were significantly down-regulated by curcumin in diabetic rat kidneys and glomerular mesangial cells (GMCs) exposed to high glucose (HG). Simultaneously, SphK1-S1P-mediated fibronectin (FN) and transforming growth factor-beta 1 (TGF-b1) overproduction were inhibited. In addition, curcumin dose dependently reduced SphK1 expression and activity in GMCs transfected with SphKWT and significantly suppressed the increase in SphK1-mediated FN levels. Furthermore, curcumin inhibited the DNA-binding activity of activator protein 1 (AP-1), and c-Jun small interference RNA (c-Jun-siRNA) reversed the HG-induced up-regulation of SphK1. These findings suggested that down-regulation of the SphK1-S1P pathway is probably a novel mechanism by which curcumin improves the progression of DN. Inhibiting AP-1 activation is one of the therapeutic targets of curcumin to modulate the SphK1-S1P signaling pathway, thereby preventing diabetic renal fibrosis.

The creation of the STZ-induced DN model relies on the level and continuous cycle of high blood glucose in vivo. Long-term hyperglycemia induces significant structural changes in the kidney, including glomerular hypertrophy, GBM thickening, and later glomerulosclerosis and tubulointerstitial fibrosis, leading to microalbuminuria and elevated Cr levels. These effects usually occur at around 8–12 weeks after diabetes formation. In the current study, the experimental diabetic model was induced by a single intraperitoneal injection of STZ (60 mg/kg). When the experiment was terminated at 12 weeks, FBG, KW/BW, BUN, Cr, and UP 24 h were significantly increased and body weight was remarkably decreased in the STZ-induced diabetic rats compared with those in the normal control group. Furthermore, PAS staining of the kidneys revealed the induction of glomerular hypertrophy, mesangial matrix expansion, and increased regional adhesion of the glomerular tuft to the Bowman’s capsule in the diabetic rats. This finding indicated the emergence of the diabetic renal injury model characterized by renal hypertrophy, glomerulus damage, and renal dysfunction. As the limited water solubility of curcumin, various methods such as heat treatment, mild alkali and sodium carboxymethyl cellulose are used to increase the solubility of curcumin before administration. Based on our previous study, we employed 1% sodium carboxymethyl cellulose as the vehicle to solubilize curcumin. Compared with the diabetic group, curcumin treatment slightly reduced FBG level and significantly decreased KW/BW, BUN, Cr, and UP 24 h. Moreover, curcumin remarkably improved glomerular pathological changes in the diabetic kidneys. Consistent with previous studies, the current results demonstrated that curcumin prominently ameliorated renal function and renal parenchymal alterations in the diabetic renal injury model. Previous studies revealed that the amelioration of renal dysfunction in diabetes by curcumin was partly related to its function in inhibiting inflammatory injury. Based on these findings, the current experiment further explored whether the renoprotective effects of curcumin are associated with the regulation of the SphK1-S1P signaling pathway.

S1P is a polar sphingolipid metabolite acting as an extracellular mediator and an intracellular second messenger. Ample evidence proves that S1P participates in cell growth, proliferation, migration, adhesion, molecule expression, and angiogenesis. The formation of S1P is catalyzed by SphK1. Recently, the SphK1-S1P signaling pathway has gained considerable attention because of its potential involvement in the progression of DN. Hyperglycemia, AGE, and oxidative stress can activate SphK1 and can increase the intracellular level of S1P. Geoffroy et al. (2004) reported that the treatment of cells with low AGE concentration increases SphK activity and S1P production, thereby and S1P content were significantly increased simultaneously with the up-regulated expression of FN and TGF-β1 (mRNA and protein) in the diabetic rat kidneys. These findings indicated the activation of the SphK1-S1P signaling pathway and the appearance of pathological alterations, including ECM accumulation. After curcumin treatment for 12 weeks, elevations of the said indexes were significantly inhibited. HG remarkably activated the SphK1-S1P signaling pathway and increased FN and TGF-β1 expressions in GMCs. Curcumin dramatically suppressed the SphK1-S1P pathway as well as FN and TGF-β1 levels in a dose-dependent manner. Overall, these results indicated that curcumin ameliorated the pathogenic progression of DN by inhibiting the activation of the SphK1-S1P signaling pathway, resulting in the down-regulation of TGF-β1 and the subsequent reduction of ECM accumulation.

SphK1 expression is mediated by a novel AP-1 element located within the first intron of the human SphK1 gene. AP-1 sites are also found in rat SphK1 promoter from NCBI. Numerous studies indicated that curcumin can inhibit the activity of AP-1 and is widely used as an AP-1 inhibitor. Therefore, further elucidating the link between the inhibition of the SphK1-S1P signaling pathway by curcumin and the suppression of AP-1 activity is important. The data showed that treatment with c-Jun-siRNA significantly down-regulated the basal levels of SphK1 expression. Thus, inhibiting AP-1 activity is one of the therapeutic targets of curcumin in modulating the SphK1-S1P signaling pathway, thereby inhibiting diabetic renal fibrosis.

In summary, curcumin inhibited SphK1 expression and activity, reduced S1P content, and effectively inhibited increased FN and TGF-β1 expressions mediated by the SphK1-S1P signaling pathway. Moreover, the inhibitory effect of curcumin on SphK1-S1P was independent of its hypoglycemic and anti-oxidant roles and might be closely related to the inhibition of AP-1 activity. Our findings suggested that the SphK1-S1P pathway might be a novel mechanism by which curcumin attenuates renal fibrosis and ameliorates DN. In addition, the present study provides further experimental evidence for the clinical application and new drug exploration of curcumin.

 

Antidiabetic Activity of Hydroalcoholic Extracts of Nardostachys jatamansi in Alloxan-induced Diabetic Rats

  1. A. Aleem, B. Syed Asad, Tasneem Mohammed, et al.
    British Journal of Medicine & Medical Research 4(28): 4665-4673, 2014

A review of literature indicates that diabetes mellitus was fairly well known and well conceived as an entity in India with complications like angiopathy, retinopathy, nephropathy, and causing neurological disorders. The antidiabetic study was carried out to estimate the anti-hyperglycemic potential of Nardostachys Jatamansi rhizome’s hydroalcoholic extracts in alloxan induced diabetic rats over a period of two weeks. The hydroalcoholic extract HAE1 at a dose (500mg/kg) exhibited significant antihyperglycemic activity than extract HAE2 at a dose (500mg/kg) in diabetic rats. The hydroalcoholic extracts showed improvement in different parameters associated with diabetes, like body weight, lipid profile and biochemical parameters. Extracts also showed improvement in regeneration of β-cells of pancreas in diabetic rats. Histopath-ological studies strengthen the healing of pancreas by hydroalcoholic extracts (HAE1& HAE2) of Nardostachys Jatamansi, as a probable mechanism of their antidiabetic activity.
Metabolic syndrome and serum carotenoids : findings of a cross-sectional study in Queensland, Australia

Coyne, T, Ibiebele, T,… McClintock, C and Shaw, J
Brit J Nutrition: Int J Nutr Sci 2009; 102(11). pp. 1668-1677
Several components of the metabolic syndrome, particularly diabetes and cardiovascular disease, are known to be oxidative stress-related conditions and there is research to suggest that antioxidant nutrients may play a protective role in these conditions. Carotenoids are compounds derived primarily from plants and several have been shown to be potent antioxidant nutrients. The aim of this study was to examine the associations between metabolic syndrome status and major serum carotenoids in adult Australians. Data on the presence of the metabolic syndrome, based on International Diabetes Federation criteria, were collected from 1523 adults aged 25 years and over in six randomly selected urban centers in Queensland, Australia, using a cross sectional study design. Weight, height, BMI, waist circumference, blood  pressure, fasting and 2-hour blood glucose and  lipids were determined, as well as five serum carotenoids. Mean serum alpha-carotene, beta-carotene and the sum of the five carotenoid concentrations were significantly lower (p<0.05) in persons with the metabolic syndrome (after adjusting for age, sex, education, BMI status, alcohol intake, smoking, physical activity status and vitamin/mineral use) than persons without the syndrome. Alpha, beta and total carotenoids also decreased significantly (p<0.05) with increased number of components of the metabolic syndrome, after adjusting for these confounders. These differences were significant among former smokers and non-smokers, but not in current smokers. Low concentrations of serum alpha-carotene, beta carotene and the sum of five carotenoids appear to be associated with metabolic syndrome status. Additional research, particularly longitudinal studies, may help to determine if these associations are causally related to the metabolic syndrome, or are a result of the pathologies of the syndrome.

Although there is no universal definition of the metabolic syndrome, it is generally described as a constellation of pathologies or anthropometric conditions, which include central obesity, glucose intolerance, lipid abnormalities, and hypertension. It is, however, universally accepted that the presence of the metabolic syndrome is associated with increased risk of type 2 diabetes and cardiovascular disease. The prevalence of the metabolic syndrome in developed countries varies widely depending upon definitions used and age ranges included, but is estimated to be 24% among adults 20 years and over in the US. Given the impending worldwide epidemic of obesity, diabetes and cardiovascular disease, strategies aimed at greater understanding of the pathology of the syndrome, as well as strategies aimed at preventing or treating persons with the syndrome are urgently required.

Few studies have investigated associations of antioxidant nutrients and the metabolic syndrome. Ford and colleagues reported lower levels of several carotenoids and vitamins C and E among those with metabolic syndrome present compared with those without the syndrome in the Third National Health and Nutrition Examination Survey. Sugiura et al.  suggested that several carotenoids may exert a protective effect against the development of the metabolic syndrome, especially among current smokers. Confirming these findings in another population may add strength to these associations.

Our study showed significantly lower concentrations of β-carotene, α-carotene and the sum of the five carotenoids among those with the metabolic syndrome present compared to those without. We also found decreasing concentrations of all the carotenoids tested as the number of the metabolic syndrome components increased. These findings are consistent with data reported by Ford et al. from the third 262 National Health and Nutrition Examination Survey (NHANES III). In the NHANES III study, significantly lower concentrations of all the carotenoids, except lycopene, were found among persons with the metabolic syndrome compared with those without, after adjusting for  confounding factors similar to those in our study.

 

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Anorexia Nervosa and Related Eating Disorders

Posted in Behavior, Child and Adolescent Psychiatry, Cognition, Curation, Nutrition, Nutrition Disorders, Population Health Management, Nutrition and Phytochemistry, Social Development, Statistical Methods for Research Evaluation, Stress Disorders, Substance Abuse, Translational Science, tagged , , , , , , , , on February 28, 2015| Leave a Comment »

Anorexia Nervosa and Related Eating Disorders

Writer and Curator: Larry H. Bernstein, MD, FCAP 

 

Introduction

Anorexia nervosa is a stress related disorder that occurs mainly in women, closely related to bulimia, and is related to self-esteem, or to a preoccupation with how the individual would like to see themselves. It is not necessarily driven by conscious motive, but lies in midbrain activities that govern hormonal activity and social behavior

 

Eating disorders

Christopher G Fairburn, Paul J Harrison
Lancet 2003; 361: 407–16

Eating disorders are an important cause of physical and psychosocial morbidity in adolescent girls and young adult women. They are much less frequent in men. Eating disorders are divided into three diagnostic categories: anorexia nervosa, bulimia nervosa, and the atypical eating disorders. However, the disorders have many features in common and patients frequently move between them, so for the purposes of this Seminar we have adopted a transdiagnostic perspective. The cause of eating disorders is complex and badly understood. There is a genetic predisposition, and certain specific environmental risk factors have been implicated. Research into treatment has focused on bulimia nervosa, and evidence-based management of this disorder is possible. A specific form of cognitive behavior therapy is the most effective treatment, although few patients seem to receive it in practice. Treatment of anorexia nervosa and atypical eating disorders has received remarkably little research attention.

Eating disorders are of great interest to the public, of perplexity to researchers, and a challenge to clinicians. They feature prominently in the media, often attracting sensational coverage. Their cause is elusive, with social, psychological, and biological processes all seeming to play a major part, and they are difficult to treat, with some patients actively resisting attempts to help them.

Anorexia nervosa and bulimia nervosa are united by a distinctive core psychopathology, which is essentially the same in female and male individuals; patients overevaluate their shape and weight. Whereas most of us assess ourselves on the basis of our perceived performance in various domains—eg, relationships, work, parenting, sporting prowess—patients with anorexia nervosa or bulimia nervosa judge
their self-worth largely, or even exclusively, in terms of their shape  and weight and their ability to control them. Most of the other features
of these disorders seem to be secondary to this psychopathology and to its consequences—for example, self-starvation. Thus, in anorexia nervosa there is a sustained and determined pursuit of weight loss and, to the extent that this pursuit is successful, this behavior is not seen as a problem. Indeed, these patients tend to view their low weight as an accomplishment rather than an affliction. In bulimia nervosa, equivalent attempts to control shape and weight are undermined by frequent episodes of uncontrolled overeating (binge eating) with the result that patients  often describe themselves as failed anorexics.  The core psychopathology has other manifestations; for example,  many patients mislabel certain adverse physical and emotional states as feeling fat, and some repeatedly scrutinize aspects of their shape,
which could contribute to them overestimating their size.

Panel 1: Classification and diagnosis of eating disorders

Definition of an eating disorder

  • There is a definite disturbance of eating habits or weight- control behavior
  • Either this disturbance, or associated core eating disorder features, results in a clinically significant impairment of physical health or psychosocial functioning (core eating disorder features comprise the disturbance of eating and any associated over-evaluation of shape or weight)
  • The behavioral disturbance should not be secondary to any general medical disorder or to any other psychiatric condition

Classification of eating disorders

  • Anorexia nervosa
  • Bulimia nervosa
  • Atypical eating disorders (or eating disorder not otherwise specified)

Principal diagnostic criteria

  • Anorexia nervosa
  1. Over-evaluation of shape and weight—ie, judging self-worth largely, or exclusively, in terms of shape and weight
  2. Active maintenance of an unduly low bodyweight—eg, body-mass index 17·5 kg/m2
  3. Amenorrhea in post-menarche females who are not taking an oral contraceptive. The value of the amenorrhea criterion can be questioned since most female patients who meet the other two diagnostic criteria are amenorrheic, and those who menstruate
    seem to resemble closely those who do not
  • Bulimia nervosa
  1. Over-evaluation of shape and weight—ie, judging self-worth largely,
    or exclusively, in terms of shape and weight
  2. Recurrent binge eating—i.e., recurrent episodes of uncontrolled overeating
  3. Extreme weight-control behavior—e.g., strict dietary restriction, frequent self-induced vomiting or laxative misuse

Diagnostic criteria for anorexia nervosa are not met

  • Atypical eating disorders

Eating disorders of clinical severity that do not conform to the diagnostic criteria for anorexia nervosa or bulimia nervosa

Research into the pathogenesis of the eating disorders has focused almost exclusively on anorexia nervosa and bulimia nervosa. There is undoubtedly a genetic predisposition and a range of environmental risk factors, and there is some information with respect to the identity and relative importance of these contributions. However, virtually nothing is known about the individual causal processes involved, or about how they interact and vary across the development and maintenance of the disorders.

 

Panel 3: Main risk factors for anorexia nervosa and bulimia nervosa

  • General factors
  1. Female
  2. Adolescence and early adulthood
  3. Living in a Western society
  • Individual-specific factors

Family history

  • Eating disorder of any type
  • Depression
  • Substance misuse, especially alcoholism (bulimia nervosa)
  • Obesity (bulimia nervosa)

Premorbid experiences

  • Adverse parenting (especially low contact, high expectations, parental discord)
  • Sexual abuse
  • Family dieting
  • Critical comments about eating, shape, or weight from family and others
  • Occupational and recreational pressure to be slim Premorbid characteristics

Low self-esteem

  • Perfectionism (anorexia nervosa and to a lesser extent bulimia nervosa)
  • Anxiety and anxiety disorders
  • Obesity (bulimia nervosa)
  • Early menarche (bulimia nervosa)

There has been extensive research into the neurobiology of eating disorders. This work has focused on neuropeptide and monoamine (especially 5-HT) systems thought to be central to the physiology of eating and weight regulation. Of the various central and peripheral abnormalities reported, many are likely to be secondary to the aberrant eating and associated weight loss. However, some aspects of 5-HT function remain abnormal after recovery, leading to speculation that there is a trait monoamine abnormality that might predispose to the development of eating disorders or to associated characteristics such as perfectionism. Furthermore, normal dieting in healthy women alters central 5-HT function, providing a potential mechanism by which eating disorders might be precipitated in women vulnerable for other reasons.

Specific psychological theories have been proposed to account for the development and maintenance of eating disorders. Most influential in terms of treatment have been cognitive behavioral theories. In brief, these theories propose that the restriction of food intake that characterizes the onset of many eating disorders has two main origins, both of which may operate. The first is a need to feel in control of life, which gets displaced onto controlling eating. The second is over-evaluation of shape and weight in those who have been sensitized to their appearance. In both instances, the resulting dietary restriction is highly reinforcing. Subsequently, other processes begin to
operate and serve to maintain the eating disorder.

 

Depression, coping, hassles, and body dissatisfaction: Factors associated with disordered eating

Rose Marie Ward, M. Cameron Hay
Eating Behaviors 17 (2015) 14–18
http://dx.doi.org/10.1016/j.eatbeh.2014.12.002

The objective was to explore what predicts first-year college women’s disordered eating tendencies when they arrive on campus. The 215 first-year college women completed the surveys within the first 2 weeks of classes. A structural model examined how much the Helplessness, Hopelessness, Haplessness Scale, the Brief COPE, the Brief College Student Hassle Scale, and the Body Shape Questionnaire predicted eating disordered tendencies (as measured by the Eating Attitudes Test). The Body Shape Questionnaire, the Helplessness, Hopelessness, Haplessness Scale (inversely), and the Denial subscale of the Brief COPE significantly predicted eating disorder tendencies in first-year college women. In addition, the Planning and Self-Blame subscales of the Brief COPE and the Helplessness, Hopelessness, Haplessness Scale predicted the Body Shape Questionnaire. In general, higher levels on the Helplessness, Hopelessness, Haplessness Scale and higher levels on the Brief College Student Hassle Scale related to higher levels on the Brief COPE. Coping seems to remove the direct path from stress and depression to disordered eating and body dissatisfaction.

Eating disorders and disordered eating on college campuses are a pervasive problem. Research estimates that approximately 8–13.5% of college women meet the criteria for clinically diagnosed eating disorders such as anorexia nervosa, bulima nervosa, or eating disorders not otherwise specified. In addition, negative moods and stress seem to relate eating disorders. Diagnosable eating disorders emerge in the broader context of disordered eating, that is — engaging in practices such as restricting calories, eating less fat, skipping meals, using nonprescription diet pills, using laxatives, or inducing vomiting. Whereas disordered eating is broadly associated with the dynamics of human development in adolescence in the United States and the socio-cultural pressure to be thin, college environments may particularly predispose young women to disordered eating. In a national survey, 57% of female college students reported trying to lose weight, while only 38% of female college students categorized themselves as overweight.

The mean for the overall EAT scale was 8.89 (SD=9.26, mode=2, median = 6, range 0 to 60). Over 13% (n = 22) of the sample met the criteria for potential eating disorders with overall scores of 20 or greater. One primary model was tested using the quantitative measurement data. The model fit the data, χ2 (n = 191, 72) = 89.33, p = .08, CFI N .99, TLI = .99, and RMSEA = .035.

Note: Only significant paths shown; *p < .05; **p < .01; ***p < .001; HHH = Helplessness, Hopelessness, Haplessness Scale; Hassles = Brief College Student Hassle Scale; EAT = Eating Attitudes Test-26; BSQ = Body Satisfaction Questionnaire; CFI = Comparative Fit Index; TLI = Tucker-Lewis Index; RMSEA = Root Mean Squared Error of Approximation.

Structural modeling predicting eating disorder tendencies

Structural modeling predicting eating disorder tendencies

Structural modeling predicting eating disorder tendencies. Note: Only significant paths shown; *p < .05; **p < .01; **p < .001; HHH = Helplessness, Hopelessness, Haplessness Scale; Hassles = Brief College Student Hassle Scale; EAT = Eating Attitudes Test-26; BSQ = Body Satisfaction Questionnaire; CFI = Comparative Fit Index; TLI= Tucker–Lewis Index; RMSEA = Root Mean Squared Error of Approximation.

By identifying the risk factors through research, interventions can be developed that empower people to take control of their own eating behavior. This kind of intervention is supported by the finding that those students with more agentive, active coping styles, or who did not report frequent experiences of helplessness, haplessness, and hopelessness were less likely to have disordered eating behaviors. Whereas active coping has been associated with lower disordered eating in some studies (e.g., Ball & Lee, 2000), others suggest a more complicated relationship between denial or avoidant coping and disordered eating.

 

The cognitive behavioral model for eating disorders: A direct evaluation in children and adolescents with obesity

Veerle Decaluwe, Caroline Braet
Eating Behaviors 6 (2005) 211–220
http://dx.doi.org:/10.1016/j.eatbeh.2005.01.006

Objective: The cognitive behavioural model of bulimia nervosa. The clinical features and maintenance of bulimia nervosa. In K.D. Brownell, and J.P. Foreyt (Eds.), Handbook of eating disorders: physiology, psychology and treatment of obesity, anorexia and bulimia (pp. 389–404). New York: Basic Books.] provides the theoretical framework for cognitive behavior therapy of Bulimia Nervosa. For a long time it was assumed that the model can also be used to understand the mechanism of binge eating among obese individuals. The present study aimed to test whether the specific hypotheses derived from the cognitive behavioral theory of bulimia nervosa are also valid for children and adolescents with obesity. Method: The prediction of the model was tested using structural equation modeling. Data were collected from 196 children and adolescents.  Results: In line with the model, the results suggest that a lower self-esteem predicts concerns about eating, weight and shape, which in turn predict dietary restraint, which then further is predictive of binge eating.
Discussion: The findings suggest that the mechanisms specified in the model of bulimia nervosa is also operational among obese youngsters. The cognitive behavioral model of Bulimia Nervosa (BN), outlined by Fairburn, Cooper, and Cooper (1986), provides the theoretical framework for cognitive behavior therapy of BN (Fairburn, Marcus, & Wilson, 1993; Wilson, Fairburn, & Agras, 1997). According to this model, over-evaluation of eating, weight and shape plays a central role in the maintenance of BN. It is assumed that over-concern in combination with a low self-esteem can lead to dietary restraint (e.g. strict dieting and other weight control behavior). However, the rigid and unrealistic dietary rules are difficult to follow and the eating behavior is seen as a failure. Moreover, minor dietary slips are considered as evidence of lack of control and can lead to an all-or-nothing reaction in which all efforts to control eating are abandoned. This condition makes people vulnerable to binge eating. In order to minimize weight gain as a result of overeating, some patients practice compensatory purging (compensatory vomiting or laxative misuse).

The present study aimed to directly evaluate the model among a population of children and adolescents suffering from obesity. It is justified to study this model in a group at-risk. Binge eating is [V. Decaluwe´, C. Braet / Eating Behaviors 6 (2005) 211–220] not restricted to adulthood and is recognized among children with obesity as well (Decaluwe´ & Braet, 2003). Even in childhood, associated eating and shape concerns and comorbid psychopathology are manifest. Until now, little is known about how the risk factors for BED operate. A case-control study by Fairburn et al. (1998) reported a number of adverse factors in childhood, carrying a higher risk of developing BED, including negative self-evaluation, parental depression, adverse experiences (sexual or physical abuse and parental problems), overweight and repeated exposure to negative comments about shape, weight and eating. Moreover, it seems that childhood obesity is not only a risk factor for developing BED, but also one of the risk factors for the development of BN (Fairburn, Welch, Doll, Davies, & O’Connor, 1997). If Fairburn’s model is able to predict binge eating in an obese population, we can discover how the risk factors are related to one another and how they are operating to predict disordered eating among obese youngsters.

To conclude, in the present study, we were interested whether the cognitive behavioral theory would predict disordered eating in a young obese population. Because the study focuses on subjects at risk for developing binge-eating problems, BED or BN, we considered the cognitive behavioral theory as a risk factor model for eating disorders rather than a model for the maintenance of eating disorders.

  1. Method

2.1. Design

The prediction of the models was evaluated using structural equation modeling (LISREL 8.50; Jo¨reskog & So¨rbom, 2001). The dependent variables were binge eating, over-evaluation of eating, shape and weight, and dietary restraint. The independent variable was self-esteem. Purging behavior was not included in the structural equation modeling since binge eating among children occurs in the absence of compensatory behavior. Next, it is worth noting that the concept of self-esteem is implicit in the original cognitive model of BN. In order to compare the present research with the study of Byrne and McLean (2002), self-esteem was included in the evaluation of the model.

A sample of 196 children and adolescents with obesity (78 boys and 118 girls) between the ages of 10 and 16 participated in the study (M=12.73 years, SD=1.75). All subjects were seeking help for obesity. The sample consisted of children seeking inpatient or outpatient treatment. All children seeking inpatient or outpatient treatment between July 1999 and December 2001 were invited to participate. The response rate was 72%. Children younger than 10 or older than 16 and mentally retarded children were excluded from the study. All participating children obtained a diagnosis of primary obesity. The group had a mean overweight of 172.69% (SD=27.09) with a range of 120–253%. The study was approved by the local research ethics committee. The subjects were visited at their homes before they entered into treatment. Informed consent was obtained from both the children and their parents. Two subjects (1%), both female, met the full diagnostic criteria for BED and 18 subjects (9.2%) experienced at least one binge-eating episode over the previous three months (overeating with loss of control), but did not endorse all of the other DSM-IV criteria that are required for a diagnosis of BED.

To conclude, in the present study, we were interested whether the cognitive behavioral theory would predict disordered eating in a young obese population. Because the study focuses on subjects at risk for developing binge-eating problems, BED or BN, we considered the cognitive behavioral theory as a risk factor model for eating disorders rather than a model for the maintenance of eating disorders.

A two-step procedure was followed to construct the measurement model. We first conducted a confirmatory factor analysis on the variance–covariance matrix of the items of the exogenous construct (independent latent variable) b self-esteem Q. The construct b self-esteem Q is composed of 5 items of the Global self-worth subscale of the SPPA. Goodness-of-fit statistics were generated by the analysis. Items with poor loading (absolute t-value = 1.96) were removed. This resulted in a satisfactory model, χ2 (2)=6.23, p=0.04, GFI=0.97, AGFI=0.87 after omitting 1 item. The parameter estimates between the observed items and the latent variable ranged from 0.49 to 0.88.

Self-esteem was highly negatively correlated with over-evaluation of eating, weight and shape (standardized ϒ=-0.59, t=-5.05), indicating that higher levels of concerns about eating, weight and shape were associated with a lower self-esteem. Over-evaluation of eating, weight and shape, in turn, was shown to be significantly related with dietary restraint (standardized β=0.70, t=2.71), indicating that more concerns about eating, weight or shape were associated with higher levels of dietary restraint. Finally, dietary restraint was significantly associated with binge eating (standardized β=0.45, t=2.14), indicating that higher levels of dietary restraint were associated with a higher level of binge eating. The feedback from binge eating to over-evaluation of eating, weight and shape was not significant. Overall, the results appeared to suggest that a lower self-esteem predicts concerns over eating, weight and shape, which in turn predict dietary restraint. This would then be predictive of binge eating.

To our knowledge, this was the first study that directly evaluated the CBT model of BN among children. Overall, the model was found to be a good fit of the data. The main predictions of the model were confirmed. We can conclude that the CBT model provides a relatively valid explanation of the prediction of binge-eating problems in a young obese sample. Three findings supported the model and one finding did not confirm the model.

First, in line with the model, the construct self-esteem was a predictor of the over-evaluation of eating, weight and shape. This finding is also consistent with findings of Byrne and McLean (2002) and previous research in children and adolescents, which also found an association between over-concern with weight and shape and a lower self-esteem.

Second, the over-evaluation of eating, weight and shape, in turn, was a direct predictor of dietary restraint. Our findings were in line with prospective studies that found that thin-ideal internalization and body dissatisfaction (components of the over-evaluation of shape and weight) had a significant effect on dieting. Our findings also support the cross sectional study of Womble et al. (2001), who found a direct association between body dissatisfaction and dietary restraint among obese women. As in adults, children seem to respond in the same manner by dieting to lose weight. To our knowledge, the relationship between over-evaluation and dietary restraint has never been explored before among children with obesity.

Third, in accordance with the CBT model of BN, the key pathway between dietary restraint and binge eating was confirmed: higher levels of dietary restraint were associated with higher rates of binge eating. It seems that the subjects of this study were not able to maintain their dietary restraint.

 

Transdiagnostic Theory and Application of Family-Based Treatment for Youth With Eating Disorders

Katharine L. Loeb, James Lock, Rebecca Greif, Daniel le Grange
Cognitive and Behavioral Practice 19 (2012) 17-30

This paper describes the transdiagnostic theory and application of family-based treatment (FBT) for children and adolescents with eating disorders. We review the fundamentals of FBT, a transdiagnostic theoretical model of FBT and the literature supporting its clinical application, adaptations across developmental stages and the diagnostic spectrum of eating disorders, and the strengths and challenges of this approach, including its suitability for youth. Finally, we report a case study of an adolescent female with eating disorder not otherwise specified (EDNOS) for whom FBT was effective. We conclude that FBT is a promising outpatient treatment for anorexia nervosa, bulimia nervosa, and their EDNOS variants. The transdiagnostic model of FBT posits that while the etiology of an eating disorder is unknown, the pathology affects the family and home environment in ways that inadvertently allow for symptom maintenance and progression. FBT directly targets and resolves family level variables,  including secrecy, blame, internalization of illness, and extreme active or passive parental responses to the eating disorder. Future research will test these mechanisms, which are currently theoretical.

 

The Evolution of “Enhanced” Cognitive Behavior Therapy for Eating Disorders: Learning From Treatment Nonresponse

Zafra Cooper and Christopher G. Fairburn
Cognitive and Behavioral Practice 18 (2011) 394–402

In recent years there has been widespread acceptance that cognitive behavior therapy (CBT) is the treatment of choice for bulimia nervosa. The cognitive behavioral treatment of bulimia nervosa (CBT-BN) was first described in 1981. Over the past decades the theory and treatment have evolved in response to a variety of challenges. The treatment has been adapted to make it suitable for all forms of eating disorder—thereby making it “transdiagnostic” in its scope— and treatment procedures have been refined to improve outcome. The new version of the treatment, termed enhanced CBT (CBT-E) also addresses psychopathological processes “external” to the eating disorder, which, in certain subgroups of patients, interact with the disorder itself. In this paper we discuss how the development of this broader theory and treatment arose from focusing on those patients who did not respond well to earlier versions of the treatment.

In recent years there has been widespread acceptance that cognitive behavior therapy (CBT) is the treatment of choice for bulimia nervosa (National Institute for Health and Clinical Excellence, 2004; Wilson, Grilo, & Vitousek, 2007; Shapiro et al., 2007). The cognitive behavioral treatment of bulimia nervosa (CBT-BN) was first described in 1981 (Fairburn). Several years later, Fairburn (1985) described further procedural details along with a more complete exposition of the theory upon which the treatment was based (1986). This theory has since been extensively studied and the treatment derived from it, CBT-BN (Fairburn et al., 1993), has been tested in a series of treatment trials (e.g., Agras, Crow, et al., 2000; Agras, Walsh, et al., 2000; Fairburn, Jones, et al., 1993). A detailed treatment manual was published in 1993 (Fairburn, Jones, et al.). In 1997 a supplement to the manual was published (Wilson, Fairburn, & Agras) and the theory was elaborated in the same year (Fairburn).

According to the cognitive behavioral theory of bulimia nervosa, central to the maintenance of the disorder is the patient’s over-evaluation of shape and weight, the so-called “core psychopathology” [Fig. 1 – not shown – schematic form the core eating disorder maintaining mechanisms (modified from Fairburn, Cooper, & Shafran, 2003 )]. Most other features can be understood as stemming directly from this psychopathology, including the dietary restraint and restriction, the other forms of weight-control behavior, the various forms of body checking and avoidance, and the preoccupation with thoughts about shape, weight, and eating (Fairburn, 2008).

The only feature of bulimia nervosa that is not obviously a direct expression of the core psychopathology is binge eating. The cognitive behavioral theory proposes that binge eating is largely a product of a form of dietary restraint (attempts to restrict eating), which may or may not be accompanied by dietary restriction (actual undereating). Rather than adopting general guidelines about how they should eat, patients try to adhere to multiple demanding, and highly specific, dietary rules and tend to react in an extreme and negative fashion to the (almost inevitable) breaking of these rules.

A substantial body of evidence supports CBT-BN, and the findings indicate that CBTBN is the leading treatment. However, at best, half the patients who start treatment make a full and lasting response. Between 30% and 50% of patients cease binge eating and purging, and a further proportion show some improvement while others drop out of treatment or fail to respond. These findings led us to ask the question, “Why aren’t more people getting better?”

In the light of our experience with patients, we proposed that in certain patients one or more of four additional maintaining processes interact with the core eating disorder maintaining mechanisms and that when this occurs they constitute further obstacles to change. The first of these maintaining mechanisms concerns the influence of extreme perfectionism (“clinical perfectionism”). The second concerns difficulty coping with intense mood states (“mood intolerance”). Two other mechanisms concern the impact of unconditional and pervasive low self-esteem (“core low self-esteem”), and marked interpersonal problems (“interpersonal difficulties”).  This new theory represents an extension of the original theory illustrated in Fig. 1. Fig. 2 shows in schematic form both the core maintaining mechanisms and the four hypothesized additional mechanisms.

This program of work illustrates the value of focusing attention on those patients who benefit least from treatment. Doing so resulted in the enhanced form of CBT, which appears to be markedly more effective and more useful (in terms of the full range of patients treated) than its forerunner, CBT-BN.

 

A novel measure of compulsive food restriction in anorexia nervosa: Validation of the Self-Starvation Scale (SS)

Lauren R. Godier, Rebecca J. Park
Eating Behaviors 17 (2015) 10–13
http://dx.doi.org/10.1016/j.eatbeh.2014.12.004

The characteristic relentless self-starvation behavior seen in Anorexia Nervosa (AN) has been described as evidence of compulsivity,with increasing suggestion of transdiagnostic parallels with addictive behavior. There is a paucity of standardized self-report measures of compulsive behavior in eating disorders (EDs). Measures that index the concept of compulsive self-starvation in AN are needed to explore the suggested parallels with addictions. With this aima novel measure of self-starvation was developed (the Self-Starvation Scale, SS). 126 healthy participants, and 78 individuals with experience of AN, completed the new measure along with existing measures of eating disorder symptoms, anxiety and depression. Initial validation in the healthy sample indicated good reliability and construct validity, and incremental validity in predicting eating disorder symptoms. The psychometric properties of the SS scale were replicated in the AN sample. The ability of this scale to predict ED symptoms was particularly strong in individuals currently suffering from AN. These results suggest the SS may be a useful index of compulsive food restriction in AN. The concept of ‘starvation dependence’ in those with eating disorders, as a parallel with addiction, may be of clinical and theoretical importance.

The compulsive nature of Anorexia Nervosa (AN) has increasingly been compared to the maladaptive cycle of compulsive drug-seeking behavior (Barbarich-Marsteller, Foltin, & Walsh, 2011). Individuals with AN engage in persistent weight loss behavior, such as extreme self-starvation and excessive exercise, to modulate anxiety associated with ingestion of food, in a similar way to the use of mood altering drugs in substance dependence. Substance dependence is described as a persistent state in which there is a lack of control over compulsive drug-seeking, and lack of regard for the risk of serious negative consequences, which may parallel the relentlessness with which individuals with AN pursue weight loss despite profoundly negative physiological and psychological consequences.

Considering the parallels suggested between AN and substance dependence, it may be useful to use the concept of ‘dependence’ on starvation when measuring compulsive behaviors in eating disorders (EDs) such as AN. For that reason, a novel measure of self-starvation, the Self-Starvation Scale (SS) was derived, in part by adapting the Yale Food Addiction Scale (YFAS) (Gearhardt, Corbin, & Brownell, 2009) for this construct.

The set of online questionnaires was created using Bristol Online Surveys (BOS; Institute of Learning and Research Technology, University of Bristol, UK). In addition to the new measure described below, ED symptoms were measured using the Eating Disorder Examination-Questionnaire (EDE-Q) (Fairburn & Beglin, 2008), and the Clinical Impairment Assessment (CIA) (Bohn & Fairburn, 2008). Depression symptoms were measured using the Patient Health Questionnaire-9 (PHQ-9) (Kroenke, Spitzer, & Williams, 2001). Anxiety symptoms were measured using the Generalized Anxiety Disorder Assessment-7 (GAD-7) (Spitzer, Kroenke, Williams, & Lowe, 2006). The mirror image concept of ‘food addiction’ was measured using the YFAS (Gearhardt et al., 2009). Excessive exercise was measured using the Compulsive Exercise Test (CET) (Taranis, Touyz, & Meyer, 2011). Impulsivity was measured using the Barratt Impulsivity Scale-11 (BIS-11) (Patton, Stanford, & Barratt, 1995). Substance abuse symptoms were measured using the Leeds Dependence Questionnaire (LDQ) (Raistrick et al., 1994).

The results of this study suggest that using the criteria of dependence in capturing compulsive self-starvation behavior in AN may have some validity. The utility of this criteria in capturing compulsive behavior across disorders, including AN, suggests that compulsivity as a construct of behavior may have transdiagnostic application (Godier & Park, 2014; Robbins, Gillan, Smith, de Wit, & Ersche, 2012), on which disorder-specific themes are superimposed.

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Review: Atul Gawande’s ‘Being Mortal’ – MiamiHerald.com

Posted in Behavior, Behavioral Genetics on November 3, 2014| Leave a Comment »

Review: Atul Gawande’s ‘Being Mortal’ – MiamiHerald.com

Reporter: Aviva Lev-Ari, PhD, RN

 

 

 

 

 

 

 

 

 

 

Surgeon explores difficult questions of end-of-life care and discovers that less (or none) is more.

Source: www.miamiherald.com

See on Scoop.it – Cardiotoxicity

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Social Anxiety, High Anxiety, Beta Blockers For Anxiety, Postpartum Anxiety, Existential Anxiety – YouTube

Posted in Behavior, Behavioral Genetics, Frontiers in Cardiology and Cardiovascular Disorders, Pharmacotherapy of Cardiovascular Disease on October 24, 2014| Leave a Comment »

Social Anxiety, High Anxiety, Beta Blockers For Anxiety, Postpartum Anxiety, Existential Anxiety – YouTube

Reporter: Aviva Lev-Ari, PhD, RN

 

https://www.youtube.com/v/gUKlf1PHoA4?fs=1&hl=fr_FR

Social Anxiety, High Anxiety, Beta Blockers For Anxiety, Postpartum Anxiety, Existential Anxiety http://panic-attacks-anxiety.good-info.co Why anxiety causes…

Source: www.youtube.com

See on Scoop.it – Cardiovascular Disease: PHARMACO-THERAPY

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Bees And Flowers Speak In A Secret UV Color Code

Posted in Behavior on November 29, 2013| Leave a Comment »

Bees And Flowers Speak In A Secret UV Color Code

Reporter: Aviva Lev-Ari, PhD, RN

 

 

See on Scoop.it – Cardiovascular Disease: PHARMACO-THERAPY

Flowers may use UV patterns to attract bees. See how, and check out photos that shows us approximately what a bee sees when it looks at flowers.

 

UV fluorescence may be a common trait to most flowers, but might be of temporary occurrence for parts of the flower. Anthers, style, and pollen grains occasionally are seen to fluoresce. Strong fluorescence has been noted from nectar glands (Angelica sylvestris) and several other species. Some species show fluorescence of the non-fertilised stigmas, but this trait is difficult to document with my normal technical approach. Fluorescence from outside of the bracts is exhibited by some species. As far as the photography is concerned, the main issue with flower fluorescence is its transient behaviour. It may be present, but the flowers collected for photography don’t appear to fluoresce simply because the floral development is in the “wrong” stage. With fluorescent pollen grains, their size often are at or below the detection limit unless quite high magnification is employed, thus calling for a true photomacropgraphic approach. The fluorescing pollen of Mirabilis jalapa has been documented using this method.

 

UV-absorbing substances (flavonyl glucosides) are instrumental in bringing about the fascinating pollinating guide patterns. UV marks on flowers are but a logical extension of the visual pollinating clues provided by evolution in nature. If the flower absorbs UV all over the floral parts, it may appear visually in a “UV-complementary” color even to pollinators capable of seeing in UV. We can only speculate as to the rendition of that complementary color, but if say the insect is modelled as seeing UV as “blue”, blue as “green”, and green as “red”, then the UV complementary would be yellow. Thus, a UV-absorbing yellow flower still would come across as “yellow” even for an insect (or so it might seem, but who are we to know such things anyway).

See on io9.com

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