Streamson Chua - US grants

Type II or non-insulin dependent diabetes mellitus (NIDDM) is estimated to affect 5% of the world's population. Considering the additional 10-11% of the adult population with impaired glucose tolerance (which imposes a greater than 6-fold increased risk of developing NIDDM), 8-10% of adults either have, or will develop, NIDDM. Approximately 20% of the members of the US population over 65 years of age are diabetic. The medical consequences of this disorder are staggering. The complication rates in NIDDM patients are equivalent (per year of disease) to the much smaller number of individuals with type I, insulin-dependent diabetes. Diabetes is the leading cause of blindness, end stage renal disease and amputations in the US, and contributes significantly to the high prevalence of dyslipidemias and hypertension. The enormous physical and psychological burdens imposed by this disease are only partly reflected in the estimated $25 billion dollars spent annually on its treatment in the US alone. There is a strong genetic predisposition to NIDDM, the expression of which is facilitated by the presence of obesity. Over 60% of individuals with NIDDM are obese. The mechanisms by which obesity predisposes to NIDDM is not known, but it is likely that obesity stresses the pancreatic beta cells by diminishing the action of insulin on glucose metabolism. The goal of this proposal is to identify the genes which, in the presence of obesity, predispose to the development of NIDDM. The complexity of the genetics of NIDDM in humans favors the initial use of simpler animals models to identify candidate genes for NIDDM- susceptibility and resistance. Using well characterized mouse and rat genetic models of obesity-diabetes, such genes will be identified. These genes will be then be examined by genetic linkage techniques in human families in which NIDDM is present. Ultimately, knowledge of the structure/action of such genes can be used to prevent or treat NIDDM.

The mouse phenotyping core will provide expertise and training in the characterization of rodent models of diabetes. To achieve this mission, the Core will provide assistance in the histopathological characterization of mouse models of diabetes and training in the performance of basic metabolic assays, such as glucose and insulin tolerance tests. The Core will also provide consultation on the proper approach to generating recombinant and inbred strains of transgenic and knockout mice, and interact with the Genomics Core to help investigators design appropriate genotyping strategies for genome scans. In addition, the Core is in the process of developing expertise in performing glucose clamp studies to investigate whole body and organ-specific metabolic parameters. Through collaborative efforts with the other Cores of the proposed DERC, the effects of defined genetic alterations in rodents can be thoroughly characterized for their effects on metabolism, ingestive behavior, energy balance, body composition, and endocrine function. The Core will serve an important training and education function for many DERC investigators by providing advice on how to prevent common mistakes in breeding programs.

The genetic basis of type 2 diabetes mellitus has been shown to be complex. This is not surprising given the large number of tissues that are engaged in regulating glucose metabolism: liver, muscle, fat, endocrine pancreas, the gut, and the brain. Alterations in numerous genes that affect pancreatic beta cell function and hepatic carbohydrate metabolism (all of the known MODY genes) can produce carbohydrate intolerance and hyperglycemia. Mutations in adipocytes can confer diabetes susceptibility, such as leptin deficiency, or diabetes resistance, as is the case in perilipin deficiency. Thus, loss of function mutations can provide both susceptibility to and protection from diabetes. Much more remains to be discovered about the complex relationships between the genome and the soma that regulate carbohydrate metabolism. To this end, we have utilized the existence of genetic modifiers of the obesity/diabetes syndrome of leptin receptor (Lepr) deficiency to identify novel diabetes genes. We have generated and characterized a novel diabetes phenotype of LEPR-null mice on the FVB strain. Obese LEPR-deficient mice of the FVB strain develop persistent hyperglycemia and concomitant hyperinsulinemia due to massive pancreatic beta cell mass expansion. This apparent resistance of the FVB mouse's beta cell to glucotoxicity is a genetically determined trait controlled by one major locus on mouse Chromosome 5 and we will provide evidence in support of this statement. Moreover, we will provide an experimental strategy to isolate and identify the genetic variants that confer resistance or susceptibility to glucotoxicity in the beta cell. We have three specific aims: 1. Identify a major locus (Modbl) that regulates the pancreatic beta cell response to hyperglycemia. 2. Define a critical genetic interval for Modbl at subcentimorgan resolution. 3. Identify the Modbl gene and the sequence variants that control beta cell responses to hyperglycemia.