Reporter: Aviva Lev-Ari, PhD, RN
Word Cloud By Danielle Smolyar
PTEN Mutations as a Cause of Constitutive Insulin Sensitivity and Obesity
Aparna Pal, M.R.C.P., Thomas M. Barber, D.Phil., M.R.C.P., Martijn Van de Bunt, M.D., Simon A. Rudge, Ph.D., Qifeng Zhang, Ph.D., Katherine L. Lachlan, M.R.C.P.C.H., Nicola S. Cooper, M.R.C.P., Helen Linden, M.R.C.P., Jonathan C. Levy, M.D., F.R.C.P., Michael J.O. Wakelam, Ph.D., Lisa Walker, D.Phil., M.R.C.P.C.H., Fredrik Karpe, Ph.D., F.R.C.P., and Anna L. Gloyn, D.Phil.
N Engl J Med 2012; 367:1002-1011 September 13, 2012DOI: 10.1056/NEJMoa1113966
BACKGROUND
Epidemiologic and genetic evidence links type 2 diabetes, obesity, and cancer. The tumor-suppressor phosphatase and tensin homologue (PTEN) has roles in both cellular growth and metabolic signaling. Germline PTEN mutations cause a cancer-predisposition syndrome, providing an opportunity to study the effect of PTENhaploinsufficiency in humans.
METHODS
We measured insulin sensitivity and beta-cell function in 15 PTENmutation carriers and 15 matched controls. Insulin signaling was measured in muscle and adipose-tissue biopsy specimens from 5 mutation carriers and 5 well-matched controls. We also assessed the effect of PTEN haploinsufficiency on obesity by comparing anthropometric indexes between the 15 patients and 2097 controls from a population-based study of healthy adults. Body composition was evaluated by means of dual-emission x-ray absorptiometry and skinfold thickness.
RESULTS
Measures of insulin resistance were lower in the patients with aPTEN mutation than in controls (e.g., mean fasting plasma insulin level, 29 pmol per liter [range, 9 to 99] vs. 74 pmol per liter [range, 22 to 185]; P=0.001). This finding was confirmed with the use of hyperinsulinemic euglycemic clamping, showing a glucose infusion rate among carriers 2 times that among controls (P=0.009). The patients’ insulin sensitivity could be explained by the presence of enhanced insulin signaling through the PI3K-AKT pathway, as evidenced by increased AKT phosphorylation. The PTEN mutation carriers were obese as compared with population-based controls (mean body-mass index [the weight in kilograms divided by the square of the height in meters], 32 [range, 23 to 42] vs. 26 [range, 15 to 48]; P<0.001). This increased body mass in the patients was due to augmented adiposity without corresponding changes in fat distribution.
CONCLUSIONS
PTEN haploinsufficiency is a monogenic cause of profound constitutive insulin sensitization that is apparently obesogenic. We demonstrate an apparently divergent effect of PTEN mutations: increased risks of obesity and cancer but a decreased risk of type 2 diabetes owing to enhanced insulin sensitivity. (Funded by the Wellcome Trust and others.)
Supported by grants from the Wellcome Trust (095101/Z/10Z, to Dr. Gloyn), the Medical Research Council (G0700222, to Dr. Gloyn; and G0800467, to Drs. Pal and Gloyn), the National Institute for Health Research Oxford Biomedical Research Centre (to Drs. Pal, Karpe, and Gloyn), the Biotechnology and Biological Sciences Research Council (to Drs. Rudge, Zhang, and Wakelam), and the European Union Seventh Framework Program LipodomicNet (202272, for adipocyte signaling work, to Drs. Wakelam and Karpe).
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank the clinicians Trevor R.P. Cole, Louise Izatt, Carole McKeown, Eamonn R. Maher, and Mary Porteous for referring patients for this study; the research nurses Beryl Barrow and Jane Cheeseman for assistance with collecting clinical data; Amy Barrett for analysis of PTEN expression; Sandy Humphries for analysis of apolipoprotein B; Tim James and colleagues at the John Radcliffe Hospital, Oxford, for analysis of glucose and insulin; the NIHR Cambridge Biomedical Research Centre Core Biochemical Assay Laboratory for analysis of leptin and adiponectin; Leanne Hodson and Barbara Fielding for access to control dual-emission x-ray absorptiometry scans and phenotypic data on postmenopausal controls; and Jonathan Clark and Izabella Niewczas for providing lipid standards for the mass-spectrometry analysis.
SOURCE INFORMATION
From the Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford (A.P., T.M.B., M.V.B., J.C.L., F.K., A.L.G.); the Oxford National Institute for Health Research Biomedical Research Centre (A.P., J.C.L., F.K., A.L.G.) and the Oxford Regional Genetics Centre (H.L., L.W.), Churchill Hospital, Oxford; the Inositide Laboratory, the Babraham Institute, Babraham, Cambridge (S.A.R., Q.Z., M.J.O.W.); Wessex Clinical Genetics Service, University Hospital Southampton, Southampton (K.L.L.); the Department of Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton (K.L.L.); and West Midlands Regional Clinical Genetics Service, Birmingham Women’s Hospital, Birmingham (N.S.C.) — all in the United Kingdom.
Address reprint requests to Dr. Gloyn at the Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LE, United Kingdom, or atanna.gloyn@drl.ox.ac.uk.
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[…] Increased risks of obesity and cancer, Decreased risk of type 2 diabetes: The role of Tumor-suppress… […]
[…] Increased risks of obesity and cancer, Decreased risk of type 2 diabetes: The role of Tumor-suppress… […]
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
This is very insightful. There is no doubt that there is the bias you refer to. 42 years ago, when I was postdocing in biochemistry/enzymology before completing my residency in pathology, I knew that there were very influential mambers of the faculty, who also had large programs, and attracted exceptional students. My mentor, it was said (although he was a great writer), could draft a project on toilet paper and call the NIH. It can’t be true, but it was a time in our history preceding a great explosion. It is bizarre for me to read now about eNOS and iNOS, and about CaMKII-á, â, ã, ä – isoenzymes. They were overlooked during the search for the genome, so intermediary metabolism took a back seat. But the work on protein conformation, and on the mechanism of action of enzymes and ligand and coenzyme was just out there, and became more important with the research on signaling pathways. The work on the mechanism of pyridine nucleotide isoenzymes preceded the work by Burton Sobel on the MB isoenzyme in heart. The Vietnam War cut into the funding, and it has actually declined linearly since.
A few years later, I was an Associate Professor at a new Medical School and I submitted a proposal that was reviewed by the Chairman of Pharmacology, who was a former Director of NSF. He thought it was good enough. I was a pathologist and it went to a Biochemistry Review Committee. It was approved, but not funded. The verdict was that I would not be able to carry out the studies needed, and they would have approached it differently. A thousand young investigators are out there now with similar letters. I was told that the Department Chairmen have to build up their faculty. It’s harder now than then. So I filed for and received 3 patents based on my work at the suggestion of my brother-in-law. When I took it to Boehringer-Mannheim, they were actually clueless.