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.
Emerging evidence suggests that glucagon-mediated improvements in lipid and energy metabolism may be quite desirable in patients with the metabolic syndrome. Likewise, the addition of glucagon to the wearable, bionic (insulin) pancreas prevents not only the life-threatening hypoglycemic episodes that plague diabetics, but also results in a reduction in average glycemic levels. As such, a targeted search to elucidate the underlying molecular mechanism/s of glucagon-mediated improvements in insulin action, especially in light of glucagon?s diabetogenic program, will provide insight into current and future therapies for multiple components of the metabolic syndrome.
|Kim, Teayoun; Holleman, Cassie L; Nason, Shelly et al. (2018) Hepatic Glucagon Receptor Signaling Enhances Insulin-Stimulated Glucose Disposal in Rodents. Diabetes 67:2157-2166|
|Rivero-Gutierrez, Belen; Haller, April; Holland, Jenna et al. (2018) Deletion of the glucagon receptor gene before and after experimental diabetes reveals differential protection from hyperglycemia. Mol Metab 17:28-38|
|Kim, Teayoun; Nason, Shelly; Holleman, Cassie et al. (2018) Glucagon Receptor Signaling Regulates Energy Metabolism via Hepatic Farnesoid X Receptor and Fibroblast Growth Factor 21. Diabetes 67:1773-1782|