The diabetes research unit is a composed of an interdisciplinary team engaged in basic, translational and clinical diabetes research.
Sara Alexanian, MD, is a clinical investigator involved in clinical trials comparing the efficacy of medications for diabetes in both the inpatient and outpatient setting. She also participates in quality and patient safety research projects within the endocrine section.
Devin Steenkamp, MD, is a clinical investigator focusing on facilitating, collaborating and supervising research efforts that have translational impact in understanding the pathophysiological underpinnings of atypical diabetes phenotypes with a focus on atypical presentations of type 1 and monogenic diabetes phenotypes. He is particularly interested in exploring the physiology of patients with type 1 diabetes, and is currently using mixed meal tolerance tests to better characterize this patient population.
Within the obesity research center basic science environment, the laboratory of Barbara Corkey, PhD, focuses on the metabolic regulation of signal transduction and energy metabolism and fuel partitioning in fat cells, fuel-stimulated insulin secretion by the pancreatic ß-cell, and cytokine signaling in human fibroblasts from patients with inborn errors of fatty acid oxidation and Type 1 diabetes. The main questions in the Corkey laboratory concern how fuels regulate insulin secretion and how the fat cell determines whether to store or burn fat. We seek to answer these questions by studying the fuel-induced signals that modulate secretion, electrical activity, metabolism and gene expression. Recent discoveries include a putative role for reactive oxygen species in insulin secretion, digital calcium signaling in pancreatic ß-cells and a role for inhibition of the respiratory chain in regulating fat storage in adipocytes. The main tools used in the laboratory include measurement of intracellular ions such as Ca2+ and H+, plasma and mitochondrial membrane potential, oxygen consumption, the signaling consequences of cellular energy state, the influence of ROS and fatty acids on protein kinases and the role of fatty acids and long chain fatty acyl CoA on signal transduction. Work is done in collaboration with scientists at Boston University, the Karolinska Institute, the Universities of Montreal, Pennsylvania and Chicago.
Research being conducted by Jude Deeney, PhD, is designed to discern the nutrient-derived metabolic signals leading to glucose- and fatty acid (FA)-induced insulin exocytosis from the pancreatic ß-cell. FA acutely stimulates glucose-induced insulin secretion (GSIS) while chronic exposure to elevated FA and glucose can result in glucolipotoxicity (GLT) with basal hypersecretion and inhibition of GSIS. Despite the adverse effects of chronic exposure, FA is known to be required for normal exocytosis from the ß-cell. Deciphering the dual effects of FA on GSIS will lead to the possible development of therapies that would reduce the inhibitory effects while sparing the stimulatory effects of FA on the ß-cell. Studies in his laboratory are aimed at identifying the lipids or lipid classes involved in enhancing and suppressing GSIS and assessing their effects on lipid-modulated or modulating proteins.
Jose Cacicedo, PhD, is interested in 1) the study of macro- and micro-vascular complications caused by diabetes and obesity and 2) the actions of exercise on the vascular wall. Low grade vascular inflammation is an underlying cause of atherosclerotic cardiovascular disease (ASCVD) and physical exercise has been demonstrated to prevent and improve ASCVD and vascular function in patients with and without diabetes. This is evident even in the absence of overt weight loss. Exercise can also help in the control and maintenance of blood glucose levels which is key to the prevention of diabetic microvascular complications such as retinopathy. Thus, an overarching theme to his research is to discover the mechanism(s) of exercise-induced anti-inflammatory actions on the vasculature and determine whether they can be replicated pharmacologically.
Hans Dooms, PhD, is investigating the role of T cells in the pathogenesis of autoimmune diseases and to apply this knowledge for the development of new therapeutic interventions in both rheumatology and endocrinology. His laboratory uses in vivo models of autoimmune diseases, including type 1 diabetes, to follow T cell responses against tissues (e.g. pancreatic islets) and to identify molecules (e.g. cytokines) that orchestrate the autoimmune attack. In addition, his lab is developing novel gene-deficient and transgenic models to obtain mechanistic insights into the cytokine signaling pathways and transcription factors that drive autoreactive T cells.
Barb Nikolajczyk, PhD, is conducting research focused on immunometabolism, or the role the immune system plays in obesity and type 2 diabetes. She published the first comprehensive analyses identifying functions of B cells and T cells in type 2 diabetes patients. This work includes a molecular understanding of mechanisms responsible for pro-inflammatory lymphocyte functions in these patients. Complementary mouse work in Dr. Nikolajczk’s lab rigorously tests concepts identified for humans in a whole animal model. Her work in both human subjects’ material and mouse models demonstrates facility in multiple major experimental approaches and is a strong example of success from concurrent bench-to-bedside and bedside-to-bench work with cross-disciplinary impact.
The Diabetes Research Unit, is under the direction of Neil Ruderman, MD, DPhil. Investigators explore the notion that impaired oxidation of fatty acids, leading to an increase in their esterification, is a major cause of the insulin resistance that predisposes people to Type 2 diabetes, coronary heart disease, and obesity. Their work has focused on malonyl CoA, a molecule that inhibits fatty acid oxidation, and the enzyme AMP-activated protein kinase, which, among its other effects, regulates malonyl CoA metabolism.
Studies by Asish Saha, PhD, Assistant Professor of Medicine, and co-workers have helped to elucidate the enzymes controlling malonyl CoA levels in muscle. They have observed that the AMP-activated protein kinase, which is activated in muscle during exercise, both causes a decrease in malonyl CoA levels and increases insulin sensitivity. More recent work has established the possibility that AMPK may also be a target molecule for obesity therapy.
Yasuo Ido, MD, PhD, head of the vascular disease and diabetes group, and Assistant Professor of Medicine, has demonstrated that the same malonyl CoA regulatory mechanisms that the group has delineated in skeletal muscle operate in human arterial endothelial cells. Dr. Ido has shown that sustained hyperglycemia causes increases in malonyl CoA, insulin resistance, and programmed cell death (apoptosis) in these cells. In addition, activation of AMPK by the drug AICAR or by molecular biological means prevents these events from occurring. Dr. Ido has found evidence that free fatty acids, as well as glucose, may contribute to vascular damage in diabetes and that here, too, AMPK activation can exert a protective effect. He has shown that AMPK’s protective effect may be related to its ability to decrease oxidative stress and NFB-mediated gene expression.
Zhijun Luo, MD, PhD, head of the molecular biology and signal transduction group, and Assistant Professor of Medicine, has carried out seminal studies describing a novel mechanism by which insulin-signaling complexes move around in a cell. He has demonstrated that an intracellular protein, referred to as 14-3-3, plays a key role in the movement of signaling complexes containing insulin receptor substrate (IRS) and PI 3-kinase. Dr. Luo has also shown that it is likely involved in the mechanism by which insulin action in cells is down-regulated.