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.
