The program in type 2 diabetes includes Drs. Bogan, Petersen, Shulman, Cline, Inzucchi, Caprio, Samuel and Kibbey. Research in this program spans a variety of topics including the mechanisms of insulin resistance and signaling; the coupling of metabolism to insulin secretion in beta-cells; in vivo imaging of islets, the molecular mechanisms regulating glucose transport; the development of insulin resistance and diabetes in adolescents; the regulation of appetite and obesity; and the outcome of vascular disease in diabetics.
Professor Emeritus of Medicine (Endocrinology); Director, Analytical Core, Mouse Metabolic Phenotyping Center at Yale Univ. School of Medicine; Co-Director, Clinical Metabolism Core, Yale Diabetes Research Center
Dr. Cline laboratory specializes in the use of MR spectroscopy, Mass Spectroscopy and stable isotopic tracer methodologies to make real-time measurements of metabolic flux. He is currently utilizing these techniques to study how metabolism is functionally coupled to insulin secretion in pancreatic beta-cells and what biochemical mechanisms lead to loss of this coupling in T2DM. His lab is also developing NMR, SPECT and PET methodologies to study beta-cell mass, viability and inflammation in vivo.
Gerald I. Shulman , M.D., Ph.D.
Dr. Shulman’s research is focused on understanding the regulation of glucose and fat metabolism in humans and its dysregulation in patients with T2DM. To this end, his group has developed several magnetic resonance spectroscopy (MRS) methods to examine intracellular glucose and fat metabolism non-invasively in humans. Using these methods they have demonstrated that defects in insulin stimulated glucose transport and muscle glycogen synthesis are the major factors responsible for insulin resistance.
Using 13C MRS his group 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. His group has gone on to show that insulin resistance in liver and skeletal muscle 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. His group has also developed MRS methods to assess mitochondrial function non-invasively and demonstrated that decreased muscle mitochondrial function is associated with increased intramyocellular triglyceride content, which may lead to insulin resistance.
Most recently, this group has shown that hyperinsulinemia 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, his lab is testing and validating these hypotheses in transgenic and gene knockout mouse models of insulin resistance and is identifying novel therapeutic targets to reverse insulin resistance in patients with T2DM.
Jonathan Bogan, M.D.
Dr. Bogan’s research seeks to understand how GLUT4-mediated glucose uptake is regulated in adipose and muscle. His laboratory developed and used a functional screen to identify TUG as a major regulator of GLUT4 trafficking and glucose uptake. TUG binds GLUT4 and retains it intracellularly in unstimulated cells, causing the accumulation of these transporters in specialized “insulin-responsive vesicles.” To mobilize these vesicles, insulin stimulates the release of GLUT4 from TUG, thus targeting GLUT4 to the cell surface and enhancing glucose uptake.
Current work is directed to understand how TUG retains GLUT4 intracellularly in unstimulated cells, what proteins and membranes are involved in the formation of insulin-responsive vesicles, and how insulin stimulates the dissociation of a protein complex containing TUG, GLUT4, and other proteins to target GLUT4 to the cell surface. A second area of research uses transgenic and gene knockout mouse models to study proteins involved in GLUT4 targeting, to determine if insulin acts through similar mechanisms in fat and in muscle, and to test the importance of these pathways for overall glucose homeostasis.
Finally, studies to determine if dysregulated GLUT4 targeting contributes to insulin resistance in vivo are now under way.
Kitt Petersen, M.D.
Dr. Petersen’s group is interested in clinical studies examining the pathogenesis of insulin resistance in humans. Dr. Petersen’s recent research activities include impaired mitochondrial activity in insulin-resistant offspring of type 2 diabetics; cellular mechanisms of insulin resistance and potential links with inflammation; and severe insulin resistance and altered myocellular and abdominal fat partitioning.
Richard Kibbey, M.D., Ph.D.
Dr. Kibbey is interested in the mechanisms of insulin secretion by beta-cells and the pathogenesis of beta-cell exhaustion in Type 2 Diabetes Mellitus. Recent studies have demonstrated that the production of mitochondrial GTP is an important indicator of TCA cycle flux and may represent a key regulator of insulin secretion. His lab is also developing animal models of chronic hyperglycemia in order to study the effects of glucose toxicity on insulin secretion by pancreatic islet cells.
Varman Samuel, M.D., Ph.D.
Dr. Samuel is interested in the pathogenesis of insulin resistance in hepatocytes. In both human and animal studies, he has shown that increased hepatic fat accumulation can impair insulin action in the liver. In addition, recent studies have demonstrated that hyperinsulinemia itself can induce de novo hepatic lipid synthesis and promote atherogenic dyslipidemia.
Ongoing studies are examining the interactions between insulin signaling and fat metabolism in the liver as well as the transition between hepatic steatosis and steatohepatitis.
Endocrinology and Neurology
Elizabeth Jonas, M.D.
Dr. Jonas’ laboratory is interested in the release of neurotransmitters and neuropeptides, and how the opening of ion channels on intracellular organelles can potentiate or suppress such release. They have determined that ion channel activity of mitochondrial membranes increases greatly during synaptic transmission, and that this activity depends on influx of calcium through the plasma membrane and into mitochondria.
They are also investigating the regulation of neuropeptide release by the insulin receptor tyrosine kinase, and have found that this signaling pathway can trigger release by activating ion channels both in the plasma membrane and on secretory granules. Regulation of ion channels during neurosecretion by the insulin receptor may play a role in neuronal or synaptic longevity.
Sonia Caprio, M.D.
Dr. Caprio’s group is studying the metabolic complications of childhood obesity. Using epidemiological and physiological approaches, she reported a high prevalence of impaired glucose tolerance (IGT) in a multiethnic clinic based cohort of obese children and adolescents. This work set the stage for a series of studies aimed at understanding the metabolic phenotype of pre-diabetes in youth, greatly emphasizing the emerging problem of T2DM in childhood obesity.
Insulin resistance emerged as the best predictor of the 2hr glucose level and her group demonstrated that alterations in the partitioning of fat in both muscle and abdominal tissues are closely linked to insulin sensitivity in obese adolescents with IGT. A key question that her group is currently investigating is whether dysfunctional fat cells found in obese youths can be converted to healthy adipocytes and whether the abnormal pattern of fat distribution can be reversed in obese adolescents with IGT, thereby leading to enhanced muscle insulin sensitivity and improved beta-cell function.