Mechanisms of Insulin Resistance in Man

Mayo Clinic Rochester, Rochester MN

Investigators

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Abstract

DESCRIPTION (provided by applicant): Almost ~ 100 million people in the US have type 2 diabetes (T2D) or pre-diabetes that accounts for 1 in 5 health care dollars. The prevalence of these metabolic disorders is increasing exponentially. Understanding the pathogenesis of, and developing rational therapies based on the pathogenic factors for these conditions is a very high priority. The exact mechanism of nocturnal regulation of glucose production in humans remains poorly understood. There is controversy regarding whether the higher fasting glucose concentration observed in T2D is due to inappropriate counter-regulatory hormone secretion (i.e., glucagon and cortisol) for the prevailing glucose concentrations throughout the night or during early morning hours alone resulting in insulin resistance and consequent higher glucose production; or perhaps to a disruption of the biological clock in the overnight fasted state. In th previous grant cycle we have shown that people with T2D have higher fasting and post prandial glucose concentrations as a result of abnormal regulation of glucose production and glucose uptake. The current application is designed to systematically investigate the pathophysiology of overnight regulation of glucose production in T2D in specific aim 1, the relative contributions of cortisol and glucagon to nocturnal glucose homeostasis in specific aim 2, and the extent to which these effects differ from anthropometrically matched nondiabetic subjects. Finally, in specific aim 3, we will conduct a clinical trial to determine the effect of metformin vs. insulin glargine on hepatic response to glucagon in T2D. Specific Aim 1 will determine the rates of endogenous glucose production in T2D and nondiabetic subjects at 1, 4 and 7 AM. To minimize confounding effects of sleep, subjects with a history of sleep disorders will be excluded. Moreover, subjects will stay at clinical research unit (CRU) for 2 nights and 1 day so as to be familiarized to the CRU environment on the first night and measures in place to minimize sleep disruption during study period on the second night. Rates of gluconeogenesis will be measured using 2H2O. Specific Aim 2A will test the effects of nocturnal cortisol concentrations on glucose production in T2D and nondiabetic subjects. Endogenous cortisol production will be blocked by metyrapone during constant vs. rising overnight cortisol infusions in random order. Rates of endogenous glucose production will be estimated overnight and at 7 AM. We will also evaluate insulin induced suppression of endogenous glucose production in each group at constant vs. rising cortisol concentrations during matched portal insulin and glucagon concentrations with a somatostatin clamp. Specific Aim 2B will determine the effects of nocturnal glucagon concentrations on rates of endogenous glucose production in T2D and nondiabetic subjects. Endogenous glucagon secretion will be blocked by somatostatin during constant vs. rising overnight glucagon infusions in random order. We will test whether insulin induced suppression of endogenous glucose production is lower in T2D than nondiabetic subjects during rising glucagon concentrations. We will also determine whether glycogenolysis rates are higher in T2D in the presence of rising glucagon concentrations. To explore the extent to which metformin therapy alters the hepatic response to glucagon in people with T2D in Specific Aim 3, T2D subjects will undergo euglycemic clamp studies with glucagon doses at 0.65, 1.5 and 3.0 ng/kg/min (in the presence of somatostatin) to estimate rates of endogenous glucose production before and following randomization to either two weeks of metformin or insulin glargine therapy. A better understanding of factors that impact the nocturnal regulation of glucose metabolism will help to develop rational therapeutic approaches to manage individuals with T2D in the future.