The goal of my research program is to understand the contribution of the central nervous system, and through it behavior, to the pathophysiology of non-insulin dependent diabetes mellitus (NIDDM). The major hypothesis is that a defect in autonomic control of glucose metabolism is involved in the etiology of NIDDM. Specifically, we hypothesize that a subset of individuals prone to developing NIDDM have increased sensitivity of adrenergic receptors in metabolic sites. This increased sensitivity leads to metabolic dysregulation when sympathetic outflow is increased by stress, diet or other factors, and appropriate downregulation fails to occur. The hypothesis predicts that exaggerated glycemic reactivity to adrenergic stimulation is characteristic of individuals predisposed to developing NIDDM. We are pursuing this hypothesis on a number of levels with both human and animal studies. Two series of investigations are proposed. The first series of studies will determine if non-diabetic individuals, known to be at high risk for developing NIDDM, show abnormal glycemic reactivity to behavioral and neuroendocrine challenges affecting the autonomic nervous system. To this end, two groups who are at extraordinary risk for development of NIDDM will be studied: Pima Indian Native Americans and Black and Caucasian women with a history of gestational diabetes. We will study the differential metabolic and neuroendocrine effects of a mental arithmetic task, as well as pharmacologic adrenergic and cholinergic challenges in individuals at high risk for diabetes and in appropriate controls. In this fashion, we hope to identify abnormalities in the autonomic control of glucose metabolism that may be related to the eventual development of NIDDM. My research program also includes a project designed to identify genetic factors in a mouse model of NIDDM and hypertension. In this model, developed by our research group, abnormalities in autonomic control of glucose metabolism and blood pressure appear to interact with die in producing diabetes and hypertension. Studies will focus on defining the genetics of diet-induced insulin resistance, hyperglycemia and hypertension that we have shown are characteristic of diet-induced diabetes in the C57BL/6J (BL/6) mouse. The segregation of insulin resistance, hyperglycemia, obesity and hypertension will be analyzed in recombinant inbred (RI) and recombinant congenic (RC) strains, bred from diabetes prone and diabetes resistant mice, in order to determine the genetic relationship of various abnormalities that constitute the diabetic phenotype. The location of these traits on the BL/6 genome will be determined by comparison of their strain distribution pattern with genetic markers in BXA and AXB RI strains and RC strains. Special attention will be given to candidate genes related to autonomic function to determine if molecular defects related to autonomic activity are associated with the appearance of the diabetic phenotype. In addition, reverse genetic methodology will be employed to understand the contributions of any other genes that can be defined as important in the determining the diabetic phenotype in these animals.
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