Defects in glucagon response to hypoglycemia associated with progression of insulin-dependent diabetes are a major obstacle in achieving optimal glycemic control through intensive insulin therapy. However, the precise mechanisms that control glucagon counterregulation and its compromise in diabetes are not known. This proposal will start to investigate the intraiset endocrine network by studying the in vivo mechanisms controlling the secretion of glucagon in streptozotocin (STZ)-treated male Wistar rats, in which the intraislet endocrine relationships are simplified due to partial [beta]-cell destruction and the glucagon response to hypoglycemia is lost. Our general hypothesis, based on preliminary theoretical analysis, is that in STZ-treated rats the dominant factors that control the release of glucagon are unified in a minimal intraislet network (MIN) combining the dose-response interactions: (i) [delta]-cell somatostatin secretion under the positive regulation of glucagon and glucose, and (ii) [alpha]-cell glucagon release under the negative control of somatostatin. To verify this hypothesis we will study experimentally and reconstruct analytically the mechanisms within the MIN by which """"""""switch-off' signals restore and amplify the glucagon response to hypoglycemia in STZ-treated rats. The study combines experimental testing of individual system components with advanced biomathematical methods capable of estimating the integrative implications of the observed separate outcomes.
Aim 1 is to test the hypothesis that in STZ-treated rats, any signal that suppresses and releases [alpha]-cell activity, including insulin and somatostatin, will trigger a rebound-like glucagon release under low-glucose conditions.
Aim 2 is to show that glucagon response to a """"""""switch-off signal requires intrapancreatic low-glucose milieu and is mediated and amplified by interactions between glucagon and somatostatin.
Aim 3 will analyze the experimental data collected in Aim 1 and 2 to reconstruct the MIN interactions and the mechanisms recruited by switch-off signals to trigger glucagon counterregulation. The long-term goal of this project is to initiate interdisciplinary studies to identify the dominant intraislet endocrine mechanisms that regulate glucagon secretion and response to hypoglycemia, and to understand how they are altered in diabetes. ? ? ?
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