Gerald I. Shulman
Yale University
|
Primary Section: 42, Medical Physiology and Metabolism Secondary Section: 23, Physiology and Pharmacology Membership Type:
Member
(elected 2007)
|
Research Interests
As a physician and clinical physiologist I have been interested in understanding the regulation of glucose and fat metabolism in humans and its dysregulation in patients with type 2 diabetes mellitus (T2DM). To this end my group has developed several magnetic resonance spectroscopy (MRS) methods to non-invasively examine intracellular glucose and fat metabolism in humans. Using these methods we have demonstrated that defects in insulin stimulated muscle glycogen synthesis, due to defects in insulin stimulated glucose transport, is the major factor responsible for insulin resistance in patients with T2DM. Using 13C MRS we developed a method to directly assess net hepatic glycogenolysis and gluconeogenesis in humans and found that increased hepatic gluconeogenesis is the major factor responsible for fasting hyperglycemia in patients with T2DM. My group has gone on to delineate the mechanism responsible for insulin resistance in liver and skeletal muscle, which we hypothesized can be attributed to increases in diacylglycerol, which in turn activates nPKCs leading to decreased insulin signaling at the level of the insulin receptor kinase. We showed that this mechanism can explain insulin resistance in both obese T2DM patients as well as in patients with severe lipodystrophy. My group has also developed MRS methods to non invasively assess mitochondrial function and demonstrated that decreased muscle mitochondrial function is associated with increased intramyocellular triglyceride content and that it may play a role in the pathogenesis of T2DM. Most recently, we have shown that hyperinsulinemia, resulting from primary defects in insulin stimulated muscle glycogen synthesis, results in increased hepatic de novo lipogenesis leading to atherogenic dyslipidemia and non alcoholic fatty liver disease in young lean individuals who are prone to develop the metabolic syndrome. Currently, we are testing and validating these hypotheses in transgenic and gene knockout mouse models of insulin resistance and identifying novel therapeutic targets to reverse insulin resistance in patients with T2DM.
