Übergewichts-Gen könnte Diabetes Risiko senken

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    • Übergewichts-Gen könnte Diabetes Risiko senken

      Forscher haben eine Genmutation (im PTEN-Gen) entdect, die die Insulinsensivität verstärkt und gleichzeitig das Risiko übergewichtig zu werden, verstärkt. Das ist insofern "kurios," weil man stets davon ausging, dass Übergewicht auch gleichzeitig mit Insulinresistenz (und Diabetes) einhergeht.

      Umgekehrt wird dann ein Schuh draus: Beeinflusse die Aktivität des PTEN-Gens, senke die Insulinsensivität (und erkaufe das mit einem höheren Diabetes-Risiko).

      'Obesity' Gene May Lower Diabetes Risk

      A lone genetic mutation appears to simultaneously enhance insulin sensitivity while increasing the risk of obesity, researchers found.

      In a small matched cohort study, patients with a mutation in the phosphate and tensin homologue (PTEN) gene had significantly lower levels of insulin resistance than controls (P=0.001), according to Anna Golyn, DPhil, of the University of Oxford, in England, and colleagues.

      At the same time, PTEN mutation carriers were more obese than their healthy counterparts (P<0.001), the researchers reported in the Sept. 13 issue of the New England Journal of Medicine.

      This "profound insulin sensitization ... paradoxically occurs in association with adiposity," they wrote.

      Typically insulin resistance, which is considered a precursor of type 2 diabetes, is a hallmark of obesity.

      Moreover, mutation carriers had higher levels of adiponectin than controls -- a finding that is expected in patients with increased insulin sensitivity, but is unexpected in obese patients, they said.

      Recent work has suggested that cancer and type 2 diabetes may result from defects in the same pathway. Some have suspected that insulin and insulin-like growth factor 1 (IGF-1) -- both of which are growth factors -- were the main drivers of this association.

      But newer evidence points to other causes, particularly enzymes and signaling pathways common to both the cell life cycle and metabolism, the researchers said.

      One example could be the tumor suppressor PTEN gene, which plays a role in both of those functions. Germline PTEN mutations cause Cowden syndrome, which puts patients at high risk for a number of cancers while at the same time lowering their risk of type 2 diabetes.

      Golyn and colleagues assessed insulin sensitivity in 15 carriers of the mutation and 15 matched controls from the Oxford BioBank in the U.K.

      They found that measures of insulin resistance were significantly lower in patients with a PTEN mutation than in controls:
      Mean fasting plasma insulin: 60% lower (P=0.001)
      AUC for insulin: 67% lower (P<0.001)
      HOMA-IR: 59% lower (P=0.001)


      The findings were confirmed with hyperinsulinemic euglycemic clamping, which showed a glucose infusion rate among carriers that was twice as high as normal controls (P=0.009), they found.

      This insulin sensitivity could be explained by enhanced insulin signaling through the PI3K-AKT pathway, as seen by increased AKT phosphorylation, they reported.

      Yet the mutation carriers were far more obese than controls, with a significantly higher mean body mass index (BMI) (32 versus 26, P<0.001).

      In an accompanying editorial, Ulf Smith, MD, PhD, of the University of Gothenburg in Sweden, agreed that the study reports "both expected and unexpected results." While insulin sensitivity would be expected in this population, he wrote, the high adiposity with low adiponectin levels would not be.

      Smith added that researchers "need to know more about the role and complex regulation of PTEN activity in insulin-resistant states in humans."

      The findings also "further underscore concerns that therapeutic approaches aimed at increasing PTEN activity will effect a decrease in insulin sensitivity and will increase the risk of type 2 diabetes," he wrote.
      Quelle: Medpagetoday
      "Perfection is achieved, not when there is nothing more to add, but when there is nothing left to take away." - Antoine de Saint-Exupery
    • Re: Übergewichts-Gen könnte Diabetes Risiko senken

      Hier noch eine News von medicalXpress:
      Single gene cause of insulin sensitivity may offer insight for treating diabetes

      (Medical Xpress)—The first single gene cause of increased sensitivity to the hormone insulin has been discovered by a team of Oxford University researchers.

      The opposite condition – insulin resistance – is a common feature of type 2 diabetes, so finding this cause of insulin sensitivity could offer new opportunities for pursuing novel treatments for diabetes.

      Although mutations in the PTEN gene cause a rare condition with increased risk of cancer, the biological pathways the gene is involved in could offer promising targets for new drugs.

      The Oxford University researchers, along with colleagues at the Babraham Institute in Cambridge, UK, and the Churchill Hospital in Oxford, UK, report their findings in the New England Journal of Medicine. The study was funded by the Wellcome Trust, the Medical Research Council, the National Institute for Health Research Oxford Biomedical Research Centre, and the Biotechnology and Biological Sciences Research Council.

      'Insulin resistance is a major feature of type 2 diabetes,' says Dr Anna Gloyn of the Oxford Centre for Diabetes, Endocrinology and Metabolism at the University of Oxford, who led the work. 'The insulin-producing cells in the pancreas may be working hard and pumping out lots of insulin, but the body's cells no longer respond.

      'Finding a genetic cause of the opposite – insulin sensitivity – gives us a new window on the biological processes involved. Such understanding could be important in developing new drugs that restore insulin sensitivity in type 2 diabetes.'

      The PTEN gene encodes for an enzyme that is part of the insulin signalling pathway in the body. It is known to have a role in controlling the body's metabolism, and to play a part in cell growth. The Oxford team was interested in learning more about this dual role.

      There is an inherited genetic condition called Cowden syndrome caused by faults in the PTEN gene. It is very rare and is thought to affect perhaps one in 200,000 people, with around 300 people with the condition in the UK. PTEN's role in cell growth sees people with Cowden syndrome develop many benign polyps in their skin, mouth and bowel, and have a higher risk than the general population of developing breast cancer, thyroid cancer and womb cancer.

      'PTEN is a gene that is heavily involved in processes for both cell growth and metabolism,' says first author Dr Aparna Pal of the University of Oxford. 'Given PTEN's dual role, we were interested in understanding the metabolic profile of people with Cowden syndrome. It was possible that mutations in PTEN could improve metabolism.'

      The team carried out glucose tolerance tests with 15 people with Cowden syndrome and 15 matched controls. Those with Cowden syndrome had significantly higher insulin sensitivity. In collaboration with their colleagues at the Babraham Institute, the team showed that this was caused by increased activity in the insulin signalling pathway.

      The researchers also noticed that the body mass index of those with Cowden syndrome appeared greater than the controls. They carried out a comparison with a much larger control group of over 2,000 individuals from the Oxford Biobank, a data and tissue resource for research established by Professor Fredrik Karpe.

      This confirmed that those with Cowden syndrome had higher levels of obesity as a group than the controls. The extra body weight appeared to be caused by extra fat, and there were no differences in where the fat was stored compared to controls.

      'This was a surprise. Normally insulin sensitivity goes with being lean,' says Professor Karpe.

      Dr Gloyn concludes: 'We now know that mutations that inactivate the PTEN gene result in increased cancer risk and obesity, but also increase insulin sensitivity which is very likely to protect against type 2 diabetes.

      'The study shows how intimately the biological pathways governing cell growth and metabolism are linked. We need to thoroughly understand these pathways to identify which genes to target in the development of new drugs.'

      She adds: 'While there are promising research avenues to pursue here, in the meantime the best way to avoid diabetes remains exercising more and eating less.'

      More information: PTEN mutations cause constitutive insulin sensitivity and obesity in humans, New England Journal of Medicine, 2012.
      Quelle: medicalXpress
      "Perfection is achieved, not when there is nothing more to add, but when there is nothing left to take away." - Antoine de Saint-Exupery