Richard N. Bergman - US grants

Previous studies supported by this grant have elucidated a central role played by free fatty acids (FFA) in the regulation of glucose output by the liver. In the competitive renewal the potential significance of this interrelationship between adipocytes and liver function to the metabolic syndrome (Syndrome "X") will be investigated. We examine the hypothesis that overproduction of FFA by the visceral adipose depot is responsible for hepatic insulin resistance in the face of visceral adiposity. Animal model is the conscious dog, either lean, or with central adiposity induced by moderate (2g/kg/day) or enhanced (6g/kg/day) fat feeding. These diets produce an animal with central adiposity and insulin resistance, but with limited increase in body weight which represents central obesity but not morbid obesity. We will measure the flux of FFA and cytokines (leptin, TNF-alpha, IL-6) from the visceral adipose depot to liver under lean and fat fed conditions. Specific aims include 1) The individual roles of the direct (i.e., antiglucagon) versus indirect (i.e., via suppression of lipolysis) effects of insulin on glucose production will be assessed. Dose-response effects will be examined for basal, fasting insulin levels as well elevated levels achieved after meals. 2) Release of glucose from the gut as well as insulin secretion into portal blood will be measured after oral glucose. Changes in portal glucose and insulin will be induced, alone or together, by direct intraportal infusion and direct versus indirect effect of insulin on liver glucose output will be determined. 3) Changes in intraportal flux of FFA as well as cytokines measured in lean vs. obese animals will be simulated by direct infusion of Liposyn or cytokines into portal veins to examine the chronic effects of visceral release of these compounds to liver and peripheral insulin resistance. 4) We have identified powerful oscillations in lipolysis from the central adipose depot, and shown that they are driven by the sympathetic nervous system. We will examine the importance of sympathetic drive of central oscillations in extended fasting as well as changes in sympathetic drive as a function of time of day. These studies will reveal the importance of the "visceral-hepatic axis" in the pathogenesis of liver insulin resistance in the metabolic syndrome, and may reveal the linkage between central adiposity, insulin resistance and risk for Type 2 diabetes mellitus.

Type 2 diabetes is a complex disease which is caused by a slow progression of decreased glucose tolerance, followed by hyperglycemia. it is of great interest to understand the complex patterns of changes in metabolic function which precede overt hyperglycemia. Three components which can contribute to glucose intolerance are insulin resistance, impaired B-cell function, and reduced glucose effectiveness. The latter process is the ability of glucose itself to enhance carbohydrate disposal and suppress endogenous glucose output. We have obtained data supporting the concept that in normal individuals B-cell function increases to compensate for insulin resistance caused by hereditary or environmental factors. In fact, the mathematical product of insulin sensitivity and insulin secretion is approximately constant. The mechanisms responsible for the hyperbolic relationship between insulin sensitivity and insulin secretion are studied in this proposal. The time course of changes in glucose tolerance and B-cell response will be monitored to elucidate the events which account for the hyperbolic interaction, and to identify the signals in blood which are responsible for this striking relationship. Whether a similar, but less efficient hyperbolic relationship can be maintained when B-cell function is impaired will be examined. Also, we will examine the importance of individual metabolic precesses to glucose effectiveness. The role of glucose production by liver or kidney, as well as glucose uptake by insulin independent and insulin dependent tissues will be assessed. Also examined will be the changes which take place in function of individual tissues when glucose effectiveness changes. These studies should provide an integrated picture of the means by which the intact organism maintains normal maintenance of glucose tolerance when small changes in B-cell function are imposed, and could well provide new insights into the pathogenesis and potential treatment targets for Type 2 diabetes and the prediabetic state.

Noninsulin dependent diabetes mellitus is associated with increased risk for coronary artery peripheral vascular and cerebrovascular disease (CVD). This could be attributed to metabolic derangements typical of diabetes, disorders of platelet function and coagulation mechanisms, and hypertension. However, the major part of excess risk of CVD in NIDDM cannot be attributed to diabetes per se, because the risk precedes NIDDM, and is uncorrelated with the degree of hyperglycemia. Because insulin resistance is a major cause of NIDDM and appears to precede overt diabetes, it is hypothesized that insulin resistance, per se, and/or the hyperinsulinemia which characterizes resistance without full blown diabetes may be the factor(s) which are responsible for CVD in individuals at risk for NIDDM. This application is for a Central Laboratory Facility, and is responsive to an NIH Request for Cooperative Agreement (RFA NIH-91-HL-03-P). It is submitted in cooperation with a Field Center Application also submitted from the University of Southern California (M. Saad, P.I.). In this application, we propose to make a series of measurements which will establish the degree of insulin resistance as well as cardiovascular risk factors in a group of 1600 subjects to be tested in specific field centers. In this application we propose the formation of two cores: an Assay Core, to carry out a series of biochemical measurements, and a Kinetic Analysis Core, to calculate insulin sensitivity (SI) and glucose effectiveness (SG) from the assay results. This laboratory conceived, validated and developed the minimal model approach which is proposed to be used to assess insulin sensitivity (i.e., resistance). Assays will be performed in 4 laboratories at USC: Bergman (insulin, glucose, C-peptide), Meiselman (blood and plasma viscosity, red blood cell aggregation, zeta sedimentation ratio, and hematological indices), Francis (Fibrinogen, factor VIIc, plasminogen activator inhibitor a, prothrombin factor F1.2, and fibrin D-dimer fragment). In addition, lipoprotein risk factors for CVD will be measured off-site by Dr. Barbara Howard and Dr. Linda Curtiss. Additionally, we propose a Kinetic Analysis Core, which will calculate SI and SG from our assay results. Minimal model calculations will additionally be compared to the same parameters calculated by different software. Results of these determinations will be transferred electronically to a Coordinating Center for analysis. It is believed that this combined Assay/Kinetic Analysis facility will provide an efficient, accurate and precise assessment of insulin resistance in different subject groups, and as such will yield an accurate assessment of the importance of insulin resistance and hyperinsulinemia in the development of cardiovascular disease.

The proposal is for a collaborative research project between the University of Southern California (USC) and the Department of Liver and Metabolic Surgery (DLMS), at the Moscow Sechenov Medical Academy in Russia. R. N. Bergman and T. Buchanan in Los Angeles has long been interested in the pathogenesis and etiology of diabetes mellitus. In particular, he is funded by the NIH (DK29867 -"parent grant") to study the factors which control glucose output by liver. It is clear that the hyperglycemia which characterizes diabetes results from an elevated rate of hepatic glucose output (HGO) in the fasting state, and a reduced ability of insulin to suppress HGO after carbohydrate ingestion. Clearly lack of insulin is an important factor in the overproduction of glucose in the Type 1 ("juvenile-onset") diabetic. Less clear is the possible importance of elevated portal levels of the glycogenolytic, gluconeogenic hormone glucagon. The role of glucagon in hyperglycemia of diabetes, as well as in stress and exercise conditions has been controversial for many years. Confusion has resulted from the inability to specifically suppress glucagon secretion in Type 1 patients. However, a surgical operation pioneered in Moscow by Dr. Galperin should allow us to examine the significance of hyperglucagonemia in the etiology of diabetes. He has performed the spleno-renal venous anastomoses in over 400 diabetic patients in the former Soviet Union (most in Russia). Thus, because the pancreatic venous outflow enters the systemic rather than the portal circulation, it is to be expected that the levels of glucagon entering the liver in the operated patients should be considerably lower than in non- operated diabetic patients. We propose to take advantage of the availability of this large population of operated diabetic patients to evaluate the importance of hyperglucagonemia in the etiology of Type 1 diabetics. Dr. Galperin and his colleagues will perform clinical. protocols in Moscow on 2 groups of diabetic patients: those who have had, and those who have not had the spleno-renal shunt procedure. We will test the hypotheses that I) glucagon levels entering the liver are lower in operated subjects; 2) fasting glucose production rates are lower in operated patients and this is related to the relative hypoglucagonemia; 3) due to lower glucagon, livers of operated patients are more sensitive to insulin due to lower glucagon. Protocols will be performed in Moscow, and plasma samples will be shipped to Los Angeles for chemical and statistical analysis.

Noninsulin dependent diabetes mellitus is associated with increased risk for coronary artery peripheral vascular and cerebrovascular disease (CVD). This could be attributed to metabolic derangements typical of diabetes, disorders of platelet function and coagulation mechanisms, and hypertension. However, the major part of excess risk of CVD in NIDDM cannot be attributed to diabetes per se, because the risk precedes NIDDM, and is uncorrelated with the degree of hyperglycemia. Because insulin resistance is a major cause of NIDDM and appears to precede overt diabetes, it is hypothesized that insulin resistance, per se, and/or the hyperinsulinemia which characterizes resistance without full blown diabetes may be the factor(s) which are responsible for CVD in individuals at risk for NIDDM. This application is for a Central Laboratory Facility, and is responsive to an NIH Request for Cooperative Agreement (RFA NIH-91-HL-03-P). It is submitted in cooperation with a Field Center Application also submitted from the University of Southern California (M. Saad, P.I.). In this application, we propose to make a series of measurements which will establish the degree of insulin resistance as well as cardiovascular risk factors in a group of 1600 subjects to be tested in specific field centers. In this application we propose the formation of two cores: an Assay Core, to carry out a series of biochemical measurements, and a Kinetic Analysis Core, to calculate insulin sensitivity (SI) and glucose effectiveness (SG) from the assay results. This laboratory conceived, validated and developed the minimal model approach which is proposed to be used to assess insulin sensitivity (i.e., resistance). Assays will be performed in 4 laboratories at USC: Bergman (insulin, glucose, C-peptide), Meiselman (blood and plasma viscosity, red blood cell aggregation, zeta sedimentation ratio, and hematological indices), Francis (Fibrinogen, factor VIIc, plasminogen activator inhibitor a, prothrombin factor F1.2, and fibrin D-dimer fragment). In addition, lipoprotein risk factors for CVD will be measured off-site by Dr. Barbara Howard and Dr. Linda Curtiss. Additionally, we propose a Kinetic Analysis Core, which will calculate SI and SG from our assay results. Minimal model calculations will additionally be compared to the same parameters calculated by different software. Results of these determinations will be transferred electronically to a Coordinating Center for analysis. It is believed that this combined Assay/Kinetic Analysis facility will provide an efficient, accurate and precise assessment of insulin resistance in different subject groups, and as such will yield an accurate assessment of the importance of insulin resistance and hyperinsulinemia in the development of cardiovascular disease.

The Insulin Resistance and Atherosclerosis Study (IRAS) is a multicenter study of the relationship between insulin resistance and cardiovascular disease (CVD) and its risk factors in a tri-ethnic (African-American, Hispanic, and non-Hispanic white) population aged 40 to 69 years at baseline. The study population was selected to insure adequate numbers of participants within gender and glucose tolerance groups (normal, impaired glucose tolerance, and non-insulin dependent diabetes mellitus [NIDDM]). IRAS is the first large epidemiologic study to include detailed measurements of insulin sensitivity and secretion. During the first four years of funding the IRAS investigators successfully designed and implemented the first phase of the study--a cross-sectional evaluation of 1,626 participants. The current proposal requests an additional five years of funding for the prospective follow-up and reexamination of the IRAS cohort. The requested funding period consists of three phases. During the first phase (Y05 and Y06), the investigators propose to conduct two substudies. The first will address the measurement of insulin sensitivity in individuals with NIDDM. This study will evaluate four alternative techniques for measuring insulin sensitivity in 50 non-IRAS volunteers. The second substudy will examine methodologic issues in the measurement of obesity and body fat distribution in a tri-ethnic subgroup of 240 IRAS participants. In addition, all IRAS participants will be contacted annually for incident cardiovascular and other major health events. During the second phase, (Y07 and Y08), a follow-up examination of the IRAS cohort will be conducted with the goal of determining predictors of changes in insulin sensitivity, cardiovascular risk factors, measures of atherosclerosis development, and incident cardiovascular events. Additionally, throughout the first fours (Y05-08) a major effort will continue to be devoted to the analysis and reporting of the cross- sectional data from the first IRAS examination. The final phase (Y09) will include database closure and archival, and analysis and reporting of the longitudinal results.

glucose clamp technique; endocrine disorder diagnosis; noninsulin dependent diabetes mellitus; insulin sensitivity /resistance; diagnosis design /evaluation; pancreatic islet function; metabolism disorder diagnosis; clinical research; glucose tolerance test; human subject;

The purpose of this study is to investigate the effects of different levels of glycemia on the derivation of measures of insulin sensitivity using the euglycemic clamp and minimum model techniques.

insulinlike growth factor; hormone regulation /control mechanism; hemodynamics; drug screening /evaluation; hormone metabolism; endocrine gland /system; clinical research; human subject;

Insulin resistance is an important risk factor for atherosclerosis. Insulin resistance varies widely within populations, and substantial evidence indicates that much of this variation can be attributed to genetic sources. Visceral adiposity, another important atherosclerosis risk factor, is strongly correlated with insulin resistance, and this trait also appears to be under substantial genetic control. The overall goals of the proposed research project are to: 1) identify the genetic determinants of insulin resistance and visceral adiposity; and 2) determine the extent to which insulin resistance visceral adiposity, and metabolic cardiovascular disease risk factors share common genetic influences. To address these goals, we will enroll 160 families of African-American and Hispanic background who are participating in the Insulin Resistance Atherosclerosis Study (ERAS). Approximately 1280 additional family members will be recruited. Insulin resistance will be measured using the frequently sampled intravenous glucose tolerance test, and visceral adiposity will be measured using computed tomography. A panel of other metabolic cardiovascular disease risk factors will also be assessed. A panel of 370 microsatellite markers will be genotyped from DNA, and a genome-wide scan will be performed to detect chromosomal regions containing loci that influence phenotypic variation. We will then saturate the regions of linkage identified in these analyses with additional markers and will then perform linkage disequilibrium analyses in effort to localize further the putative loci. The organization of this study will be similar to that of IRAS, with three clinical centers, a coordinating center, a central laboratory and a genetic laboratory. This center at the University of Southern California will be responsible for performing and coordinating laboratory measurements, as well as for analysis of insulin sensitivity and other metabolic parameters. This project will contribute substantially to our understanding of the genetic determinants of insulin sensitivity, and consequently to risk of atherosclerosis.

deuterium; vestibuloocular reflex; body water; clinical research; human subject;

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