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.
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.
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.
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.
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.
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.
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.
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.
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