Thursday, April 25, 2024
4/25/2024
Abstract The sedentary and dietary life style that evolved during the last decades has been paralleled by an unprecedented increase in the incidence of metabolic disturbances such as hypertension, dyslipidemia, obesity and type-2 diabetes. Glucagon, the key counter-regulatory hormone opposing insulin action, is released during periods of hypoglycemia by pancreatic alpha-cells to stimulate hepatic glucose production and restore euglycemia. Accordingly, excessive glucagon signaling is a crucial pathophysiological component of diabetes mellitus and these actions have been widely studied in both type 1 and 2 diabetic patients. Emerging evidence suggests that glucagon regulates a range of actions that may be quite desirable in patients with the metabolic syndrome. Indeed, potential drug targets that contain glucagon agonism have emerged as promising therapeutic candidates for obesity and diabetes. Yet, the targeted tissues and molecular mechanisms responsible for these beneficial effects are yet unknown. The scientific hypothesis that guides this proposal is that glucagon, via its hepatic receptors (GcgR), potentiates TORC2-dependent components of insulin-signaling cascade, which is further potentiated by hypothalamic GcgR signaling, to prime an individual for enhanced whole-body glucose disposal. Under our hypothesis, the counterregulatory actions of glucagon that maintain euglycemia during fasting, also engage mechanisms to potentiate subsequent insulin action. Our hypothesis is formulated both on our preliminary and published data demonstrating enhanced glucose tolerance and improved insulin sensitivity during hyperinsulinemic-euglycemic clamp in mice pretreated with glucagon, or a potent glucagon-receptor agonist. However, how glucagon regulates insulin action, and the tissues responsible for these combined insulin/glucagon-effects remain unresolved.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
