Richard Surwit - US grants

The purpose of this study is to determine if behavioral anxiolytic (relaxation) therapy can be of clinical benefit in the treatment of Type 2 diabetes.

There is now considerable evidence that behavioral variables are important determinants of hyperglycemia in NIDDM. We have shown that the obese mouse, a common animal model of NIDDM, is not hyperglycemic unless exposed to stress; that hyperglycemia can be induced both acutely and chronically through a variety of behavioral manipulations and that stress-hyperglycemia can be attenuated with alprazolam - a benzodiazepine. Furthermore, we have demonstrated that a brief trial of relaxation training can significantly improve glucose tolerance in patients with NIDDM and we have gathered preliminary data to suggest that alprazolam also improves glucose tolerance in these patients. The research proposed for the next five year period of this RSDA will focus on furthering our understanding of the role of behavior in the expression of hyperglycemia in NIDDM. We will restrict our focus to NIDDM because we have already accumulated considerable evidence that stress plays a major role in at least one animal model of this condition and because research in our laboratory and elsewhere has suggested that relaxation training may improve glucose metabolism in NIDDM but not in NIDDM. Utilizing two animal models of NIDDM we will continue to explore the mechanism by which chronic stress can influence the course of hyperglycemia over an extended period and see if this stress response can be attenuated with benzodiazepine treatment. We will investigate the relationship of diet and obesity to the degree to which stress produces hyperglycemia in animals genetically predisposed to diabetes and we will study the relationship of controllability and predictability of aversive stimulation to the development of hyperglycemia. Finally, we will re-examine the use of relaxation training and benzodiazepine therapy in the treatment of NIDDM. We will attempt to determine the mechanism by which relaxation and alprazolam improve glucose metabolism and we will assess whether the observed therapeutic effects are long lasting. In the conduct of these investigations we will try to identify both physiologic and behavioral individual differences which predict successful outcome of behavioral and pharmacologic anxiolytic therapy in the treatment of NIDDM.

The objective of this proposal is to identify genetic factors in a mouse model that predispose individuals to type 2 diabetes. The project will focus on defining the genetics of diet-induced insulin resistance and hyperglycemia which are characteristic of the C57BL/6J (BL/6) mouse. The segregation of insulin resistance, hyperinsulinemia, hyperglycemia and obesity on a high fat, high simple carbohydrate diet will be analyzed in crosses between diabetes susceptible C57BL/6J and resistant A/J mice utilizing backcrosses, recombinant inbred (RI) and recombinant congenics (RC) of these strains. We will examine whether the loci which result in each manifestation of this disease segregate traits on the BL/6 genome will be determined by their strain distribution pattern in at least 14 BXA and 19 AXB RI strains by comparison with previously typed genetic markers and additional markers to be characterized. Restriction fragment length variants (RFLV) will be determined for both disease candidate loci and evenly spaced genetic markers throughout genome in order to enhance the probability of identifying a genetic locus. Similarly, evenly spaced RFLV markers will be typed in 25 RC strains. Finally, DNA from appropriate backcross mice will be analyzed to confirm the identification of candidate genetic loci. These studies will determine the feasibility of reverse genetic approaches to cloning of "diabetagenic" gene(s) in the mouse and identity possible candidate loci for human genetic linkage studies.

There is now considerable evidence that behavioral variables are important determinants of hyperglycemia in NIDDM. We have shown that the obese mouse, a common animal model of NIDDM, is not hyperglycemic unless exposed to stress; that hyperglycemia can be induced both acutely and chronically through a variety of behavioral manipulations and that stress-hyperglycemia can be attenuated with alprazolam - a benzodiazepine. Furthermore, we have demonstrated that a brief trial of relaxation training can significantly improve glucose tolerance in patients with NIDDM and we have gathered preliminary data to suggest that alprazolam also improves glucose tolerance in these patients. The research proposed for the next five year period of this RSDA will focus on furthering our understanding of the role of behavior in the expression of hyperglycemia in NIDDM. We will restrict our focus to NIDDM because we have already accumulated considerable evidence that stress plays a major role in at least one animal model of this condition and because research in our laboratory and elsewhere has suggested that relaxation training may improve glucose metabolism in NIDDM but not in NIDDM. Utilizing two animal models of NIDDM we will continue to explore the mechanism by which chronic stress can influence the course of hyperglycemia over an extended period and see if this stress response can be attenuated with benzodiazepine treatment. We will investigate the relationship of diet and obesity to the degree to which stress produces hyperglycemia in animals genetically predisposed to diabetes and we will study the relationship of controllability and predictability of aversive stimulation to the development of hyperglycemia. Finally, we will re-examine the use of relaxation training and benzodiazepine therapy in the treatment of NIDDM. We will attempt to determine the mechanism by which relaxation and alprazolam improve glucose metabolism and we will assess whether the observed therapeutic effects are long lasting. In the conduct of these investigations we will try to identify both physiologic and behavioral individual differences which predict successful outcome of behavioral and pharmacologic anxiolytic therapy in the treatment of NIDDM.

We have previously hypothesized that enhanced sympathetic receptor sensitivity contributes to the etiology of type 2 diabetes mellitus (1). The goal of the present proposal is to determine if non-diabetic individuals, known to be at high risk for developing type 2 diabetes, show increased glycemic reactivity to behavioral and neuroendocrine challenges affecting the sympathetic nervous system. To this end, two groups who are at extraordinary risk for development of type 2 diabetes will be studied; Pima Indian Native Americans and women with a history of gestational diabetes. Two specific sets of studies are proposed. First, we will study the differential effect of mental arithmetic task on glucose, insulin, glucagon, catecholamines and cortisol in obese and lean subjects at high risk for diabetes and obese and lean appropriate controls. Data from these studies will allow us to determine if behavioral tasks differentially affect the metabolic responses of diabetes prone and diabetes resistant individuals and will give us some idea as to likely neuroendocrine mediators. Second, the differential glucose and insulin responses to adrenergic and opioid pharmacologic challenges which have been shown to differentiate normal individuals from diabetic patients and diabetes prone mice from diabetes resistant animals will be studied in both lean and obese subjects from the same high risk populations and in appropriate normal control subjects. If our hypothesis is confirmed, then glycemic responses to behavioral and/or neuroendocrine stimulation may be used as biologic markers to identify those individuals with a family history of diabetes who are at significant risk for the disease later in life.

We have previously hypothesized that enhanced sympathetic receptor sensitivity contributes to the etiology of type w diabetes mellitus (1). The goal of the present proposal is to plan a study to determine if non-diabetic Black females, known to be at high risk for developing type 2 diabetes, show increased glycemic reactivity to behavioral and neuroendocrine challenges affecting the sympathetic nervous system. Two specific sets of studies are proposed. First, we will study the differential effect of mental arithmetic task on glucose, insulin, glucagon, catecholamines and cortisol in obese and lean Black and White subjects. Data from these studies will allow us to determine if behavioral tasks differentially affect the metabolic responses of Black and White females and will suggest likely neuroendocrine mediators. Second, the differential glucose and insulin responses to adrenergic pharmacologic challenges which have been shown to differentiate normal individuals from diabetic patients and diabetes prone mice from diabetes resistant animals will be studied in both lean and obese Black and White subjects.

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.

DESCRIPTION (adapted from investigator's abstract): Extensive literature documents increased incidence of depression in patients with diabetes mellitus. However, the degree to which the treatment of depression impacts on diabetes control is not clear. Some investigators have found a strong association between depression and diabetes control, while others have found a weak association. A review of existing literature as well as preliminary data from our laboratory suggest that this discrepancy may be due, in part, from failure of many studies to clearly differentiate type 1 and type 2 diabetes in their patient samples. The strongest association between depression and diabetes control has been reported in studies of patients with type 1 diabetes. Preliminary data from our group suggests that the Beck Depression Inventory (BDI) scores may be more significantly related to hemoglobin A1C (HbA1c) in type 1, than in type 2, diabetes mellitus. Studies assessing the effects of pharmacologic antidepressant therapy on diabetes have been confounded by the combined use of both diagnostic categories as well as by the direct metabolic effects of most antidepressant drugs. An emerging literature on the use of Cognitive Behavior Therapy (CBT) suggests that improving affect through behavioral intervention can improve diabetes control, particularly in type 1 patients. The overall aim of this proposal is to determine if CBT differentially improves glucose control in type 1 and type 2 diabetes patients. We hypothesize that CBT will produce a greater reduction in HbA1c in type 1 diabetes than in type 2 diabetes and that CBT-induced improvement in HbA1c is mediated by an improvement in depression. We will measure the effects of CBT on changes in HbA1c and daily blood glucose in a sample of 150 depressed patients with type 1 and type 2 diabetes over one year. To evaluate the mechanism by which CBT-induced changes in depression affect blood glucose, we will determine the role of cortisol and the role of diabetes self-care behaviors as mediating variables. Changes in cortisol and self-care are predicted to impact blood glucose levels to a greater extent in type 1 diabetes because these individuals are metabolically more sensitive to any variation.

DESCRIPTION (provided by applicant): Recent research in our laboratory has provided evidence that the metabolic correlates of hostility may play a role in the racial disparity in the prevalence of type 2 diabetes. We propose to study how hostility is differentially related to glucose metabolism in healthy African-Americans and Caucasians, to determine the underlying behavioral and physiologic mechanisms of these relationships, and to investigate the possibility that race and sex interact in determining this relationship. We will assess the multi-factorial nature of hostility in 400 healthy African-American and Caucasian men and women. These psychometric measures will be examined in relation to fasting and two-hour post-prandial glucose and insulin as well as hemoglobin AIC (HbAIC) on all subjects. We will test the hypothesis that hostility is related to insulin resistance in Caucasians and to glucose production and defective glucose-stimulated insulin secretion in African-Americans, putting hostile African-Americans at greater risk for developing diabetes. Accordingly, we will assess glucose-stimulated insulin release, insulin resistance, hepatic glucose production and glucose effectiveness utilizing an IV GTT with labeled glucose in a subset of our sample. We will begin to determine the mechanism by which hostility impacts glucose metabolism in an African-American and Caucasian population. Three sets of mediators will be examined in the subjects studied parameters of hypothalamic-pituitary-adrenal (HPA) axis activity, measures of body mass and fat distribution, and measures of behavioral factors including calorie intake and exercise habits. It is further hypothesized that while the relationship of hostility to fasting insulin and insulin sensitivity in Caucasians is mediated by BMI and behavioral variables, the relationship of hostility to fasting glucose in African-Americans will depend on neuroendocrine factors influencing hepatic glucose production and insulin secretion. These studies will further our understanding of the differences in the etiology of diabetes in these ethnic groups and may help explain the racial disparity in this disease.

Studies from this project have shown that hostility is related to various measures of glucose metabolism. Furthermore, hostility is differentially related to glucose metabolism in Caucasian and African American male and female subjects. While high hostile Caucasian subjects are relatively hyperinsulinemic and insulin resistant compared to low hostile Caucasian subjects, high hostile African Americans have higher fasting glucose levels than low hostile African Americans. Furthermore, the effects of hostility on insulin resistance are more pronounced in females. We have also shown that polymorphisms of two genes that are critically involved in regulation of serotonergic function throughout the body are associated with increased fasting glucose and insulin in subjects with high 5HIAA in cerebral spinal fluid. To further explore these findings, this project will assess measures of glucose metabolism (fasting glucose and insulin, glucose tolerance, HbA1C, and insulin sensitivity) as well as other variables related to the metabolic syndrome (lipids, BMI, central adiposity and blood pressure) in a sample comprised of a minimum of 400 probands (half African American and half Caucasian, half men and half women, and half scoring in the top and half in the bottom 20% on a valid, measure of hostility that predicts CVD and has heritability estimates of 40-55%) and at least one sibling for every proband, to make a total sample of 800-1200 subjects who will participate in the protocol of this project. Our first goal will be to evaluate a minimum of 4 l candidate genes/loci that act either directly or in interaction with environmental factors, or as a function of linkage disequilibrium with other sites or membership in haplotypes, to influence expression of hostility and the individual components of the metabolic syndrome as well as their tendency to cluster. Furthermore, in collaboration with Projects 1 and 3, we will identify candidate genes/loci that account for the clustering of these metabolic abnormalities with cardiovascular, neuroendocrine, platelet function and inflammatory markers assessed in those Projects. Such knowledge could increase understanding of the contribution of gene-environment interactions to pathogenic mechanisms whereby psychosocial and biobehavioral risk factors increase CVD risk, thereby helping to identify highly susceptible persons who might be targets for primary prevention trials.