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Posts Tagged ‘Insulin’


Reprogrammed Human Pancreatic Cells Reprogrammed to Create Insulin

Reporter: Irina Robu, PhD

A  new study proposes that various cells can be modified to take a place of an insulin producing cell to help control sugar levels.  Researchers from University of Lincoln, UK report coaxing human pancreatic cells that don’t normally make insulin (a hormone that regulates the amount of glucose in the blood), to change their identity and begin producing the hormone. When implanted in mice, these reprogrammed cells relieved symptoms of diabetes, raising the opportunity that the method could one day be used as a treatment in people.

It is known that beta cells normally respond by releasing insulin when blood sugar levels rise after eating, which in turn stimulates to start absorbing sugars. In people with diabetes, this system breaks down, leading to high blood sugar levels that can harm the body and cause illness. In type 1 diabetes, the immune system attacks and destroys β-cells; in type 2, the β-cells do not produce enough of the hormone, or the body becomes resistant to insulin.

Scientists have previously revealed in mouse studies that if β-cells are destroyed, alternative type of pancreatic cell, called α-cells become more β-like and start making insulin. These α-cells normally yield the hormone glucagon which are originate together with β-cells in clumps of hormone-secreting cells called pancreatic islets or islets of Langerhans. Preceding studies showed that two proteins that control gene expression seemed to have an important role in coaxing α-cells to produce insulin in mice: Pdx1 and MafA.

At the same time as researchers from University of Lincoln, researchers from Pedro Herrera group at University of Geneva, wondered whether producing more of these proteins in human α-cells would have a similar result. They first took islet cells from human pancreases, and separated out the individual cell types which were then introduced DNA that encoded Pdx1 and MafA proteins into the α-cells, before clumping them back together.

After one week in culture, almost 40% of the human α-cells were producing insulin, while control cells that hadn’t been reprogrammed were not. The reprogrammed cells showed an increase in the expression of other genes related to β-cells, which were then implanted into diabetic mice, which had their β-cells destroyed and found that blood-sugar levels went down to normal levels. When the cell grafts were removed, the mice’s blood sugar shot back up.

Results of the experiment show that if α-cells or other kinds of islet cells could be made to start producing insulin in this way in diabetes patients’ quality of life will improve. According to Herrera before drawing conclusions about the efficacy of their approach, they will need to test the hybrid cells with other antibodies present in type-1 diabetes that could potentially attack those cells. But the research demonstrates that there is a lot of plasticity in the hormonal system of the human pancreas.

SOURCE

https://www.nature.com/articles/d41586-019-00578-z

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Lesson 4 Cell Signaling And Motility: G Proteins, Signal Transduction: Curations and Articles of reference as supplemental information: #TUBiol3373

Curator: Stephen J. Williams, Ph.D.

Below please find the link to the Powerpoint presentation for lesson #4 for #TUBiol3373.  The lesson first competes the discussion on G Protein Coupled Receptors, including how cells terminate cell signals.  Included are mechanisms of receptor desensitization.  Please NOTE that desensitization mechanisms like B arrestin decoupling of G proteins and receptor endocytosis occur after REPEATED and HIGH exposures to agonist.  Hydrolysis of GTP of the alpha subunit of G proteins, removal of agonist, and the action of phosphodiesterase on the second messenger (cAMP or cGMP) is what results in the downslope of the effect curve, the termination of the signal after agonist-receptor interaction.

 

Click below for PowerPoint of lesson 4

Powerpoint for lesson 4

 

Please Click below for the papers for your Group presentations

paper 1: Membrane interactions of G proteins and other related proteins

paper 2: Macaluso_et_al-2002-Journal_of_Cellular_Physiology

paper 3: Interactions of Ras proteins with the plasma membrane

paper 4: Futosi_et_al-2016-Immunological_Reviews

 

Please find related article on G proteins and Receptor Tyrosine Kinases on this Open Access Online Journal

G Protein–Coupled Receptor and S-Nitrosylation in Cardiac Ischemia and Acute Coronary Syndrome

Action of Hormones on the Circulation

Newer Treatments for Depression: Monoamine, Neurotrophic Factor & Pharmacokinetic Hypotheses

VEGF activation and signaling, lysine methylation, and activation of receptor tyrosine kinase

 

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Stroke is a leading cause of death worldwide and the most common cause of long-term disability amongst adults, more particularly in patients with diabetes mellitus and arterial hypertension. Increasing evidence suggests that disordered physiological variables following acute ischaemic stroke, especially hyperglycaemia, adversely affect outcomes.

 

Post-stroke hyperglycaemia is common (up to 50% of patients) and may be rather prolonged, regardless of diabetes status. A substantial body of evidence has demonstrated that hyperglycaemia has a deleterious effect upon clinical and morphological stroke outcomes. Therefore, hyperglycaemia represents an attractive physiological target for acute stroke therapies.

 

However, whether intensive glycaemic manipulation positively influences the fate of ischaemic tissue remains unknown. One major adverse event of management of hyperglycaemia with insulin (either glucose-potassium-insulin infusions or intensive insulin therapy) is the occurrence of hypoglycaemia, which can also induce cerebral damage.

 

Doctors all over the world have debated whether intensive glucose management, which requires the use of IV insulin to bring blood sugar levels down to 80-130 mg/dL, or standard glucose control using insulin shots, which aims to get glucose below 180 mg/dL, lead to better outcomes after stroke.

 

A period of hyperglycemia is common, with elevated blood glucose in the periinfarct period consistently linked with poor outcome in patients with and without diabetes. The mechanisms that underlie this deleterious effect of dysglycemia on ischemic neuronal tissue remain to be established, although in vitro research, functional imaging, and animal work have provided clues.

 

While prompt correction of hyperglycemia can be achieved, trials of acute insulin administration in stroke and other critical care populations have been equivocal. Diabetes mellitus and hyperglycemia per se are associated with poor cerebrovascular health, both in terms of stroke risk and outcome thereafter.

 

Interventions to control blood sugar are available but evidence of cerebrovascular efficacy are lacking. In diabetes, glycemic control should be part of a global approach to vascular risk while in acute stroke, theoretical data suggest intervention to lower markedly elevated blood glucose may be of benefit, especially if thrombolysis is administered.

 

Both hypoglycaemia and hyperglycaemia may lead to further brain injury and clinical deterioration; that is the reason these conditions should be avoided after stroke. Yet, when correcting hyperglycaemia, great care should be taken not to switch the patient into hypoglycaemia, and subsequently aggressive insulin administration treatment should be avoided.

 

Early identification and prompt management of hyperglycaemia, especially in acute ischaemic stroke, is recommended. Although the appropriate level of blood glucose during acute stroke is still debated, a reasonable approach is to keep the patient in a mildly hyperglycaemic state, rather than risking hypoglycaemia, using continuous glucose monitoring.

 

The primary results from the Stroke Hyperglycemia Insulin Network Effort (SHINE) study, a large, multisite clinical study showed that intensive glucose management did not improve functional outcomes at 90 days after stroke compared to standard glucose therapy. In addition, intense glucose therapy increased the risk of very low blood glucose (hypoglycemia) and required a higher level of care such as increased supervision from nursing staff, compared to standard treatment.

 

References:

 

https://www.nih.gov/news-events/news-releases/nih-study-provides-answer-long-held-debate-blood-sugar-control-after-stroke

 

https://www.ncbi.nlm.nih.gov/pubmed/27873213

 

https://www.ncbi.nlm.nih.gov/pubmed/19342845

 

https://www.ncbi.nlm.nih.gov/pubmed/20491782

 

https://www.ncbi.nlm.nih.gov/pubmed/21211743

 

https://www.ncbi.nlm.nih.gov/pubmed/18690907

 

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New Diabetes Treatment Using Smart Artificial Beta Cells

Reporter: Irina Robu, PhD

Researchers from University of North Carolina and North Carolina State University developed a patient friendly option that treats type 1 diabetes and in some cases type two diabetes by using “artificial beta cells, AβCs” to release insulin automatically into the bloodstream when glucose levels rise. These artificial beta cells mimic functions of the body’s natural glucose controllers, the insulin secreting beta cells of the pancreas. The AβCs could be subcutaneously implanted into patients, which would be replaced every few days or by a disposable skin patch. According to the principal investigator, Zhen Gu, PhD at joint UNC/NC State Department of Biomedical Engineering, they plan to optimize the procedure to develop a skin patch delivery system and test diabetes in patients.
Currently, the major problem with the insulin diabetes treatment is that they can’t be delivered efficiently in a pill and the only option is either by injection or a mechanical pump. Delivering the insulin treatments via transplants of pancreatic cells can solve that problem in some cases. Nevertheless, such cell transplants are expensive, require donor cells that are in short supply, require immune-suppressing drugs and fail due to the destruction of the transplanted cells.
Gu’s AβCs are built with a basic version of a normal cell’s two-layered lipid membrane and show a rapid receptiveness to excess glucose levels in lab dish test and diabetic mice without beta cells. The key novelty is what these cells contain insulin-stuffed vesicles. An increase in blood glucose levels leads to chemical changes in the vesicle coating, producing the vesicles to start fusing with the AβC’s outer membrane thus releasing the insulin.

SOURCE

https://news.unchealthcare.org/news/2017/october/smart-artificial-beta-cells-could-lead-to-new-diabetes-treatment

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Alzheimer’s Disease and Diabetes Mellitus

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Unraveling Alzheimer’s:Making Sense of the Relationship between Diabetes and Alzheimer’s Disease1

REFERENCES

[1]

((2015) ) 2015 Alzheimer’s disease facts and figures. Alzheimers Dement 11: , 332–384.

[2]

Hurd MD , Martorell P , Delavande A , Mullen KJ , Langa KM ((2013) ) Monetary costs of dementia in the United States. N Engl J Med 368: , 1326–1334.

[3]

Kavirajan H , Schneider LS ((2007) ) Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: A meta-analysis of randomised controlled trials. Lancet Neurol 6: , 782–792.

[4]

Korczyn AD ((2012) ) Why have we failed to cure Alzheimer’s disease?. J Alzheimers Dis 29: , 275–282.

[5]

Trinh NH , Hoblyn J , Mohanty SU , Yaffe K ((2003) ) Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease – A meta-analysis. JAMA 289: , 210–216.

[6]

Lanctot KL , Herrmann N , Yau KK , Khan LR , Liu BA , Loulou MM , Einarson TR ((2003) ) Efficacy and safety of cholinesterase inhibitors in Alzheimer’s disease: A meta-analysis. Can Med Assoc J 169: , 557–564.

[7]

Zissimopoulos J , Crimmins E , Clair P St. ((2014) ) The value of delaying Alzheimer disease onset. Conference: Forum for Health Economics and Policy

[8]

de la Monte SM ((2012) ) Brain insulin resistance and deficiency as therapeutic targets in Alzheimer’s disease. Curr Alzheimer Res 9: , 35–66.

[9]

de la Monte SM ((2012) ) Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer’s disease. Drugs 72: , 49–66.

[10]

Devi L , Alldred MJ , Ginsberg SD , Ohno M ((2012) ) Mechanisms underlying insulin deficiency-induced acceleration of beta-amyloidosis in a mouse model of Alzheimer’s Disease.e. PLoS One 7: , e32792.

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Insulin, Heat from Sugar, and Research on Diabetes for a Cure

Author: Danut Dragoi, PhD

Insulin

Insulin is a complex molecule, discovered in early 1916 by Paulescu. It is a relative large molecule that has a molecular mass of 5807.57 amu, that corresponds to the following chemical formula C257H383N65O77S6 .

Beyond its well known role in human being, insulin have many interesting structural features.

The picture below shows the structure of the molecule of the insulin. The colored spheres represent the atoms C, H, N, O, and S. This arrangements of atoms results from x-ray proteins crystallography of single crystals obtained from pure insulin.

Insulin molec structure

Image SOURCE: http://pdb101.rcsb.org/motm/14

The yellow spheres in the picture correspond to sulfur atoms that somehow are getting in the structure from a certain source, probably from foods like eggs. It is important to mention that if one component atom is missing in our body, for example Sulfur, the pancreas will not produce the insulin molecule we needed.

Next picture below shows single crystals grown in the lab on Earths as well as in outer space.

Insulin crystals NASA

Image SOURCE: http://science.nasa.gov/science-news/science-at-nasa/1998/notebook/msad22jul98_1/

As we see high quality crystals were obtained in low gravity conditions by NASA. The preferred instrument for producing high quality x-ray diffraction measurements is the synchrotron diffractometer, see link in here.

Heat source from sugar

Metabolic processes require an optimal temperature. . At temperatures higher or lower than 37 °C, enzymes will not function optimally. Too high – they denature opens in a new window, too low – they will slow down the rate at which metabolic processes proceed. A rise of just 2 °C will cause disruption to the internal functioning of a human and should the temperature rise between 43 °C and 45 °C, death may occur. Our tolerance to lower temperatures is much greater. The temperature needs to fall below 23 °C to cause death. So it is important to know about the thermal source generator in our body and its estimated environmental temperature.

The idea of calculating the temperature of human body impose serious computational barriers, but measuring it is not a problem. A simplified approach on this topic can be an approximation with reasonable assumptions. Complex biochemical reactions occur every second in our body. An exact consideration of all chemical reactions in human body is a complicated task, but a simplification can be done using the oxidation of sugar reaction.

Assuming an average body of 70 kg and all sugar from the blood, to be about 5 grams in 5 liters of blood, and considering the density of all blood close to 1g/cubic cm, we can consider the reaction of glucose, Equation (1):

342 g ———————–    2870 kJ

C6H12O6 + 6O2 –> 6CO2 + 6H2O + 2870 kJ ————— (1)

70 g ————————       q=?

The numbers above the chemical reaction of sugar (1) are the molecular mass in grams and the energy released in kJ. Below are the actual amount of sugar in a 70 kg human body and the q, the actual heat generated. Knowing the total amount of sugar in our body, which is approximated as 5 g/5kg (in blood)*5 kg (blood) + 5 g/5 kg *65 kg=70 g sugar and the molecular mass of sugar as 342.2965 g/mol, we have the amount of heat reduced from 2870 kJ* 70/342= 587.4 kJ which represents the heat q in Equation (1). An equation for variable q is shown in Equation (2):

q=mc(T-T’) —————————————–(2)

where we describe the thermal energy needed to raise the body temperature from T’ to T (T'<T). For body temperature T=37 C deg, normal temperature of human body,  m=70 kg-0.15*70 kg-0.15*70 kg=49 kg (where the first factor 0.15 represents the bones and second 0.15 is for the fat in which sugar is assumed not to react with Oxygen as in equation (1) and c= 2624 J/kg/C deg is the minimum specific heat of muscles . Since T’, could be the temperature of the environment in which the human body dissipates the thermal energy, is the only unknown in Equation (1), we can solve for T’, and find T’= 32.4 C deg. The value obtained is in a safe range, above room temperature with some C degrees. The modeling captures well the effect of sugar as an important source of energy for human body.

A study on diabetes indicates that heat treatment improves glucose tolerance. The structure of insulin as a protein suggests the link between our DNA programmed to producing specific proteins needed in our body including insulin. This is a promising avenue for future solutions for a cure of diabetes.

Genetics for a Cure

A recent research on converting fatty tissue into mature beta cells, shows that insulin can be produced by newly created beta like cells raising new expectations for cure of the diabetes.

An interesting posting, discusses in detail the findings of scientists at the Swiss Federal Institute of Technology (ETH) in Zurich, where the investigators added a highly complex synthetic network of genes to the stem cells to recreate precisely the key growth factors involved in this maturation process.

Source

https://en.wikipedia.org/wiki/Nicolae_Paulescu

https://pubchem.ncbi.nlm.nih.gov/compound/16132418

http://pdb101.rcsb.org/motm/14

http://science.nasa.gov/science-news/science-at-nasa/1998/notebook/msad22jul98_1/

http://tle.westone.wa.gov.au/content/file/ea6e15c5-fe5e-78a3-fd79-83474fe5d808/1/hum_bio_science_3a.zip/content/003_homeostasis/page_06.htm

http://hypertextbook.com/facts/LenaWong.shtml

http://sciencelearn.org.nz/Contexts/Digestion-Chemistry/Looking-Closer/Mitochondria-cell-powerhouses

http://hyperphysics.phy-astr.gsu.edu/hbase/organic/sugar.html

https://www.google.com/#q=density+of+blood

http://sciencelearn.org.nz/Contexts/Digestion-Chemistry/Looking-Closer/Mitochondria-cell-powerhouses

https://www.google.com/#q=molecular+mass+of+sugar

https://www.google.com/#q=percent+of+weight+bones+in+human+body

http://www.itis.ethz.ch/virtual-population/tissue-properties/database/heat-capacity/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646055/

http://www.genengnews.com/gen-news-highlights/a-new-use-for-love-handles-insulin-producing-beta-cells/81252612/

 

 

 

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Breakthrough Research on Encapsulated pancreatic cells offer possible new diabetes treatment.

Reporter: Eveline B. Cohn, PhD

No more insulin injections?

Encapsulated pancreatic cells offer possible new diabetes treatment.

It is known that in patients with Type 1 diabetes the immune system attacks the pancreas, and the monitoring of blood sugar becomes really difficult. Lately the research showed a possibility of replacing the pancreatic islets cells with healthy cells to take over glucose monitoring and insulin release. However the immune system attacked the transplanted cells, patients being obliged to take immunosuppressant drugs for the rest of their life.
Now , a new advance in this type of research by Boston Children’s Hospital designed a material that was used to encapsulate human islet before transplanted them. In animal testing it was showed that the encapsulated human cells could cure diabetes for up to six months without provoking an immune response.
This approach “has the potential to provide diabetics with a new pancreas that is protected from the immune system, which allow them to control their blood sugar without taking drugs. That’s the dream” says Daniel Anderson, The Samuel A Goldblith Associate Professor in MIT’s Department of Chemical Engineering, A member of MIT’s Koch Institute for integrative Cancer research and Institute for Medical Engineering and Science (IMES), and a research fellow in the department of Anesthesiology at Boston Children’s Hospital
The JDRF director Julia Greenstein, Anderson, Langer and colleagues explored a chemical derivative originally isolated from brown algae to encapsulate the cells without harming them, allowing sugar and proteins to go through, thus permitted to test the glucose level after transplantation of the encapsulated cells. The research was published in Nature Medicine and Nature Biotechnology. Researchers from Harvard University, University of Illinois at Chicago and Joslin Diabetes Center and University of Massachusetts Medical school also contributed to this research.
Previous research has shown that when alginate capsules are implanted in primates and humans, scar tissue builds up around the capsules, making the device ineffective. MIT/Children Hospital try to modify alginate make it less likely to provoke this kind of immune response.

A stealth material surface, shown here, has been engineered to provide an “invisibility cloak” against the body’s immune system cells. In this electron microscopy image, you can see the material's surface topography.

With The Courtesy of The Researchers

“We decided to take an approach where you cast a very wide net and see what you can catch,” says Arturo Vegas, a former MIT and Boston Children’s Hospital postdoc who is now an assistant professor at Boston University. Vegas is the first author of the Nature Biotechnology paper and co-first author of the Nature Medicine paper. “We made all these derivatives of alginate by attaching different small molecules to the polymer chain, in hopes that these small molecule modifications would somehow give it the ability to prevent recognition by the immune system.”
800 alginate derivatives were screened . Further, the known triazole thiomorpholine dioxide (TMTD) have been chosen to be tested in diabetic mice. They chose a strain of mice with a strong immune system and implanted human islet cells encapsulated in TMTD into a region of the abdominal cavity known as the intraperitoneal space.
The pancreatic islet cells used in this study were generated from human stem cells using a technique recently developed by Douglas Melton, a professor at Harvard University who is an author of the Nature Medicine paper.
Following implantation, the cells immediately began producing insulin in response to blood sugar levels and were able to keep blood sugar under control for the length of the study, 174 days.
“The really exciting part of this was being able to show, in an immune-competent mouse, that when encapsulated these cells do survive for a long period of time, at least six months,” says Omid Veiseh, a senior postdoc at the Koch Institute and Boston Children’s hospital, co-first author of the Nature Medicine paper, and an author of the Nature Biotechnology paper. “The cells can sense glucose and secrete insulin in a controlled manner, alleviating the mice’s need for injected insulin.”
The researchers also found that 1.5-millimeter diameter capsules made from their best materials (but not carrying islet cells) could be implanted into the intraperitoneal space of nonhuman primates for at least six months without scar tissue building up.
“The combined results from these two papers suggests that these capsules have real potential to protect transplanted cells in human patients,” says Robert Langer, the David H. Koch Institute Professor at MIT, a senior research associate at Boston’s Children Hospital, and co-author on both papers. “We are so pleased to see this research in cell transplantation reach these important milestones.”
Cherie Stabler, an associate professor of biomedical engineering at the University of Florida, says this approach is impressive because it tackles all aspects of the problem of islet cell delivery, including finding a source of cells, preventing an immune response, and developing a suitable delivery material.
“It’s such a complex, multipronged problem that it’s important to get people from different disciplines to address it,” says Stabler, who was not involved in the research. “This is a great first step towards a clinically relevant, cell-based therapy for Type I diabetes.”

VIEW VIDEO

VIDEO SOURCE

https://www.youtube.com/watch?v=cw3EbB8DAq8

At this point the researchers are thinking of using their new material in non human primates and eventually performing clinical trials in diabetic patients. “Our goal is to continue to work hard to translate these promising results into a therapy that can help people,” Anderson says.
“Being insulin-independent is the goal,” Vegas says. “This would be a state-of-the-art way of doing that, better than any other technology could. Cells are able to detect glucose and release insulin far better than any piece of technology we’ve been able to develop.”
In their research they found out that the new material works best with molecules containing triazole group- a ring containing two atoms of Carbon and three of N. However, they suspect that in this particular case it may interfere with the immune system’s ability to recognize the material as foreign.

The work was supported, in part, by the JDRF, the Leona M. and Harry B. Helmsley Charitable Trust, the National Institutes of Health, and the Tayebati Family Foundation.
Other authors of the papers include MIT postdoc Joshua Doloff; former MIT postdocs Minglin Ma and Kaitlin Bratlie; MIT graduate students Hok Hei Tam and Andrew Bader; Jeffrey Millman, an associate professor at Washington University School of Medicine; Mads Gürtler, a former Harvard graduate student; Matt Bochenek, a graduate student at the University of Illinois at Chicago; Dale Greiner, a professor of medicine at the University of Massachusetts Medical School; Jose Oberholzer, an associate professor at the University of Illinois at Chicago; and Gordon Weir, a professor of medicine at the Joslin Diabetes Center.

SOURCE

http://news.mit.edu/2016/pancreatic-cells-diabetes-treatment-insulin-injections-0125?elq=6d9b90a822f04183bd0b059d36eb2b7a&elqCampaignId=9&elqaid=14548&elqat=1&elqTrackId=d91b7d01a9d14b199e41b4deb2c10ac6

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