Richard N. Bergman Professor and Chair Physiology & Biophysics Keck School of Medicine

Research Topics: Endocrinology/Metabolism, Physiology

Research Description

There are 3 independent laboratories in this Department doing research closely related to diabetes mellitus. The directors of these laboratories are J. Youn, C. Sung and R.N. Bergman. In sum, these investigators are studying different aspects of the causes of so-called non-insulin dependent diabetes mellitus (NIDDM), a disease which afflicts 14,000,000 Americans, and which is a primary cause of heart disease, blindness, and kidney disease. Thus, if we could cure or prevent NIDDM, we would do much to improve the overall health of the U.S. population. Because NIDDM is particularly prevalent in minority communities, i.e., the Hispanic and African-American populations, it is particularly important that we study its causes and cures.

Dr. Bergman and his colleagues include approximately 20 individuals, including 10 scientists at various levels of accomplishment (faculty level, postdoctoral level and graduate students), and 10 highly qualified technical and administrative personnel. These individuals are working on many different projects, ranging from cell biology to epidemiology and population genetics, but all related to diabetes research. Our work is supported primarily by the National Institutes of Health, but also by the American Diabetes Association. The primary projects are described as follows.

Causes of NIDDM: We have focused on several conditions which contribute to diabetes. In particular we have developed the "minimal model method" which is used to measure defects which, in time, cause diabetes. These defects are insulin resistance, insulin secretory deficiency, and reduced glucose effectiveness. We are investigating the importance of insulin transport across the endothelial barrier, from blood to tissue interstitial fluid as a contributor to insulin resistance. We have discovered that the transport is not due to a receptor-mediated process.

We are studying the influence of transendothelial transport in the signal transmission from the site of insulin release (b-cells of the pancreas) to the site of insulin action (the insulin sensitive cells -- primarily muscle). We are studying the relationship between insulin action to enhance glucose utilization in muscle, and the action of insulin to suppress the endogenous production of glucose by the liver. We have discovered that these two processes are coupled via the blood-borne compounds free fatty acids (FFA). The hypothesis is being tested that peripheral and hepatic insulin resistance are related and due to a single mechanism -- reduced insulin signaling in muscle and adipose tissue which results is less glucose uptake and less suppression of FFA and hence less reduction in glucose output.

The role of glucose effectiveness in carbohydrate metabolism was pioneered in this laboratory. This process is the effect of glucose itself to enhance its own uptake (and suppress its own endogenous production) independent of insulin. We have demonstrated that effectiveness is reduced in diabetes, and are now examining its mechanisms to determine why it is so suppressed. We have demonstrated that most of the carbohydrate utilization in the NIDDM state is due to glucose effectiveness, thus enhancing its potential importance as a mechanism leading to NIDDM.

Hypoglycemia, or low blood sugar is an important companion to the treatment of Type 1 diabetes (juvenile, or insulin-dependent diabetes) with insulin. Hypoglycemia results due to overtreatment with insulin in this type of diabetes. Investigators are interested in the mechanisms by which the body responds to hypoglycemia when it occurs. We have recently demonstrated that the liver possesses specific cells which can respond to hypoglycemia and signal the brain to mount a counter-regulatory response. This latter response includes, but is not limited to an increase in "adrenaline" (i.e., epinephrine) in the blood. We are studying the mechanisms by which the liver detects the hypoglycemic signal, and how this is altered in the experimental diabetic conditions. We hope to determine the cells of the liver which respond to low blood sugar, and determine how hypoglycemia is sensed and converted to a nervous signal to the brain.

Additional studies in this laboratory relate to the use of mathematical modeling to understand the integration of the transfer of carbon amongst the various metabolic reactions in the heart and the liver. We can represent complex metabolic interactions on the computer and from these deduce how metabolic fluxes change in different metabolic conditions.

Legend to Figure: MRI images of the trunk in experimental animals. Notice increase in central fat and peripheral fat after 6 or 12 weeks of high fat diet.

Selected Publications

Chen WM, Erdos MR, Jackson AU, Saxena R, Sanna S, Silver KD, Timpson NJ, Hansen T, Orr?? M, Grazia Piras M, Bonnycastle LL, Willer CJ, Lyssenko V, Shen H, Kuusisto J, Ebrahim S, Sestu N, Duren WL, Spada MC, Stringham HM, Scott LJ, Olla N, Swift AJ, Najjar S, Mitchell BD, Lawlor DA, Smith GD, Ben-Shlomo Y, Andersen G, Borch-Johnsen K, Jørgensen T, Saramies J, Valle TT, Buchanan TA, Shuldiner AR, Lakatta E, Bergman RN, Uda M, Tuomilehto J, Pedersen O, Cao A, Groop L, Mohlke KL, Laakso M, Schlessinger D, Collins FS, Altshuler D, Abecasis GR, Boehnke M, Scuteri A, Watanabe RM. - Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels. - J Clin Invest [ 2008 ] Jun 2; . PubMed

Ionut V, Zheng D, Stefanovski D, Bergman RN. - EXENATIDE CAN REDUCE GLUCOSE INDEPENDENT OF ISLET HORMONES OR GASTRIC EMPTYING. - Am J Physiol Endocrinol Metab [ 2008 ] May 20; . PubMed

Bergman RN. - Surrogates. - Obesity (Silver Spring) [ 2008 ] Apr;16(4):721-2 . PubMed

Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, de Bakker PI, Abecasis GR, Almgren P, Andersen G, Ardlie K, Bostrom KB, Bergman RN, Bonnycastle LL, Borch-Johnsen K, Burtt NP, Chen H, Chines PS, Daly MJ, Deodhar P, Ding CJ, Doney AS, Duren WL, Elliott KS, Erdos MR, Frayling TM, Freathy RM, Gianniny L, Grallert H, Grarup N, Groves CJ, Guiducci C, Hansen T, Herder C, Hitman GA, Hughes TE, Isomaa B, Jackson AU, Jørgensen T, Kong A, Kubalanza K, Kuruvilla FG, Kuusisto J, Langenberg C, Lango H, Lauritzen T, Li Y, Lindgren CM, Lyssenko V, Marvelle AF, Meisinger C, Midthjell K, Mohlke KL, Morken MA, Morris AD, Narisu N, Nilsson P, Owen KR, Palmer CN, Payne F, Perry JR, Pettersen E, Platou C, Prokopenko I, Qi L, Qin L, Rayner NW, Rees M, Roix JJ, Sandbaek A, Shields B, Sjogren M, Steinthorsdottir V, Stringham HM, Swift AJ, Thorleifsson G, Thorsteinsdottir U, Timpson NJ, Tuomi T, Tuomilehto J, Walker M, Watanabe RM, Weedon MN, Willer CJ, Illig T, Hveem K, Hu FB, Laakso M, Stefansson K, Pedersen O, Wareham NJ, Barroso I, Hattersley AT, Collins FS, Groop L, McCarthy MI, Boehnke M, Altshuler D. - Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. - Nat Genet [ 2008 ] May;40(5):638-45 . PubMed

Bergman RN. - What for genetics? - Obesity (Silver Spring) [ 2008 ] Mar;16(3):507-8 . PubMed

Ader M, Garvey WT, Phillips LS, Nemeroff CB, Gharabawi G, Mahmoud R, Greenspan A, Berry SA, Musselman DL, Morein J, Zhu Y, Mao L, Bergman RN. - Ethnic heterogeneity in glucoregulatory function during treatment with atypical antipsychotics in patients with schizophrenia. - J Psychiatr Res [ 2008 ] Feb 22; . PubMed

Palmer ND, Goodarzi MO, Langefeld CD, Ziegler J, Norris JM, Haffner SM, Bryer-Ash M, Bergman RN, Wagenknecht LE, Taylor KD, Rotter JI, Bowden DW. - Quantitative trait analysis of type 2 diabetes susceptibility loci identified from whole genome association studies in the Insulin Resistance Atherosclerosis Family Study. - Diabetes [ 2008 ] Apr;57(4):1093-100 . PubMed

Bergman RN. - Watch out for the little guy. - Obesity (Silver Spring) [ 2008 ] Feb;16(2):219-20 . PubMed

Chiu JD, Richey JM, Harrison LN, Zuniga E, Kolka CM, Kirkman E, Ellmerer M, Bergman RN. - Direct administration of insulin into skeletal muscle reveals that the transport of insulin across the capillary endothelium limits the time course of insulin to activate glucose disposal. - Diabetes [ 2008 ] Apr;57(4):828-35 . PubMed

Sanna S, Jackson AU, Nagaraja R, Willer CJ, Chen WM, Bonnycastle LL, Shen H, Timpson N, Lettre G, Usala G, Chines PS, Stringham HM, Scott LJ, Dei M, Lai S, Albai G, Crisponi L, Naitza S, Doheny KF, Pugh EW, Ben-Shlomo Y, Ebrahim S, Lawlor DA, Bergman RN, Watanabe RM, Uda M, Tuomilehto J, Coresh J, Hirschhorn JN, Shuldiner AR, Schlessinger D, Collins FS, Davey Smith G, Boerwinkle E, Cao A, Boehnke M, Abecasis GR, Mohlke KL. - Common variants in the GDF5-UQCC region are associated with variation in human height. - Nat Genet [ 2008 ] Feb;40(2):198-203 . PubMed