Type 2/Adult-Onset Diabetes
Gerald I. Shulman, M.D., Ph.D. (Endocrinology, HHMI) 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. (Endocrinology) 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.
Sonia Caprio, M.D. (Pediatric Endocrinology) 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.
Gary Cline, Ph.D. (Endocrinology) 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.
Pietro DeCamilli, Ph.D. (Cell Biology, HHMI) Dr. DeCamilli is interested in the molecular mechanisms underlying membrane traffic to and from the cell surface. His laboratory focuses on neuronal synapses and neuroendocrine cells, where vesicular transport is implicated in the secretion of neurotransmitters and peptide hormones, respectively. A main goal of the lab is the elucidation of the mechanisms responsible for the biogenesis and traffic of synaptic vesicles, the secretory organelles that store and secrete fast-acting neurotransmitters. Studies of these organelles have general relevance for the understanding of mechanisms involved in the secretory and endocytic pathways in all cells. The lab is particularly interested in the role of protein-lipid interactions in vesicle traffic. These studies have led his laboratory to discover an important function of inositol phospholipids (phosphoinositides) in synaptic vesicle recycling and they are actively pursuing studies on the regulatory function of these phospholipids in brains and other selected organs. In this area, his group is investigating the role of phosphoinositide metabolism in mediating effects of insulin signaling on membrane traffic.
Tamas Horvath, Ph.D. (Comparative Medicine) Dr. Horvath’s lab focuses on the neuroendocrine regulation of homeostasis with particular emphasis on metabolic disorders, such as obesity and diabetes, and the effect of metabolic signals on higher brain functions and neurodegeneration. The work combines classical neurobiological approaches, including electrophysiology and neuroanatomy, with endocrine and genetic techniques to better understand the signaling flow and regulatory relationship within and between neuronal circuits that underlie the maintenance of physiological and pathological homeostatic conditions at the level of the organism.
Elizabeth Jonas, M.D. (Endocrinology and Neurology) 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.
Kitt Petersen, M.D. (Endocrinology) 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. (Endocrinology) 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.
Douglas Rothman, Ph.D. (Diagnostic Radiology and Biomedical Engineering) Dr Rothman's research focuses on the development and application of MRS methods to study metabolism in animal models and humans. These methods have allowed the non-invasive measurement of regional rates of carbohydrate, and amino acid metabolism in human brain, liver and muscle. In addition to the development of MRS methods, his lab is studying the metabolism of the neurotransmitters GABA and glutamate and the role of metabolism in sustaining normal brain function and the alterations in metabolism present in neurological and psychiatric diseases.
James Rothman, Ph.D. (Cell Biology) Dr. Rothman’s laboratory studies how membranes traffic within cells. His laboratory first identified proteins that catalyze and regulate membrane fusion (NSF, SNAP, SNARE proteins), and subsequently studied proteins that control vesicle budding and incorporation of protein “cargo” into transport vesicles. These processes direct vesicles to particular target membranes, and are central to organelle formation, nutrient uptake, and the secretion of hormones and neurotransmitters. Current efforts apply a wide range of technologies to address fundamental questions of function, regulation and disease association. High-resolution optical assays and nanoscale force measurements are being used to study the molecular detail of the membrane fusion mechanism. Various reconstitution platforms are being used to identify steps in the fusion reaction that are regulated by synaptotagmin and Munc-18 proteins. Finally, live cell assays are being developed to recapitulate and study essential features of various diseases, including the regulation and dysregulation of insulin release from islet beta cells.
Varman Samuel, M.D., Ph.D. (Endocrinology) 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.
Lawrence Young, M.D. (Cardiology) Dr. Young’s laboratory studies the cellular and molecular mechanisms responsible for the metabolic adaptation to myocardial ischemia, focusing on the AMP-activated protein kinase (AMPK) signaling pathway. This group is interested in the cardioprotective action of AMPK in the heart, the upstream mechanisms of AMPK activation and its downstream interaction with other pathways. They also study the regulation of glucose transport in the heart, including the molecular mechanisms responsible for GLUT 4 translocation. Dr. Young also has a long-standing interest in heart disease in patients with diabetes. He organized the Yale-based multi-center “Detection of Ischemia in Asymptomatic Diabetics (DIAD) Study”, which aims to identify new approaches to identify asymptomatic coronary artery disease in patients with type 2 diabetes. He also oversees the Yale-directed “Insulin Resistance in Stroke (IRIS) Trial”, an NIH sponsored multi-center trial involving 100 sites in the US, Canada and Israel testing whether treatment of insulin resistance will prevent heart attack and recurrent stroke in non-diabetic insulin resistant patients