Absence of Glucagon and Insulin Action Reveals a Role for the GLP-1 Receptor in Endogenous Glucose Production

Abstract

The absence of insulin results in oscillating hyperglycemia and ketoacidosis in type 1 diabetes. Remarkably, mice genetically deficient in the glucagon receptor (Gcgr) are refractory to the pathophysiological symptoms of insulin deficiency, and therefore, studies interrogating this unique model may uncover metabolic regulatory mechanisms that are independent of insulin. A significant feature of Gcgr-null mice is the high circulating concentrations of GLP-1. Hence, the objective of this report was to investigate potential noninsulinotropic roles of GLP-1 in mice where GCGR signaling is inactivated. For these studies, pancreatic β-cells were chemically destroyed by streptozotocin (STZ) in Gcgr−/−:Glp-1r−/− mice and in Glp-1r−/− animals that were subsequently treated with a high-affinity GCGR antagonist antibody that recapitulates the physiological state of Gcgr ablation. Loss of GLP-1 action substantially worsened nonfasting glucose concentrations and glucose tolerance in mice deficient in, and undergoing pharmacological inhibition of, the GCGR. Further, lack of the Glp-1r in STZ-treated Gcgr−/− mice elevated rates of endogenous glucose production, likely accounting for the differences in glucose homeostasis. These results support the emerging hypothesis that non–β-cell actions of GLP-1 analogs may improve metabolic control in patients with insulinopenic diabetes.

Glucagon – Early breakthroughs and recent discoveries

“…Glucagon is, however, not the only contributor to this effect, since it was later shown that immunoneutralization of FGF-21 could reduce glucose even further in glucagon-receptor knockout mice given streptozotocin, and that administration of a GLP-1 receptor antagonist increased glycemia [57]. Similar results were recently presented also in mice with double genetic deletion of the glucagon receptor and the GLP-1 receptor [58]. This suggests that glucagon is very important for the development of diabetes in this model, but that also FGF-21 contributes and that the elevated GLP-1 levels associated with this model masks a hyperglycemia and therefore overexaggerates the influence of glucagon.…”

Islet α cells and glucagon—critical regulators of energy homeostasis

“…4,49 The rise in GLP-1 levels is a major contributor to the metabolic improvements that ensue from reductions in GCGR signalling in mice. 54,63 Genetic interruption 54,55,63,64 or pharmacological blockade of GLP-1 action 64 substantially attenuates the gluco regulatory benefits that arise from reducing glucagon action in experimental models of diabetes mellitus. Fasting increases the secretion of both glucagon and FGF-21; somewhat paradoxically, both activation and reduction of glucagon actions can trigger induction of FGF-21 expression.…”

Hepatogenous diabetes: Is it time to separate it from type 2 diabetes?

“…Third, the reduced incretin effect associated with NAFLD itself as well as with obesity and T2DM independently of one another contributes to insulin resistance in NAFLD via several mechanisms. In fact, in addition to inhibiting glucagon secretion, incretin hormones directly suppress endogenous glucose production through an islet‐independent mechanism . Moreover, glucagon‐like peptide (GLP)‐1 stimulates lipid oxidation and inhibits de novo lipogenesis within the liver, thus reducing lipotoxicity and inflammation, and also affects lipid metabolism at the adipose tissue and intestine level.…”