Insulin and Glucagon: Partners for Life

Abstract

In August 2016, several leaders in glucagon biology gathered for the European Association for the Study of Diabetes Hagedorn Workshop in Oxford, England. A key point of discussion focused on the need for basal insulin to allow for the therapeutic benefit of glucagon blockade in the treatment of diabetes. Among the most enlightening experimental results presented were findings from studies in which glucagon receptor-deficient mice were administered streptozotocin to destroy pancreatic β cells or had undergone diphtheria toxin-induced β cell ablation. This article summarizes key features of the discussion as a consensus was reached. Agents that antagonize glucagon may be of great benefit for the treatment of diabetes; however, sufficient levels of basal insulin are required for their therapeutic efficacy.

Figure 1.

Gcgr^−/− mice become hyperglycemic after efficient insulin signaling blockade. Unlike their Gcgr^+/− counterparts, Gcgr^−/− animals remain normoglycemic after two STZ injections (blue versus purple inverted triangles) but develop hyperglycemia after additional insulin blockade with the insulin receptor antagonist S961 (purple diamonds). Mice were injected with STZ at days 0 and 7 (200 and 150 mg/kg, respectively) to ablate β cells and/or treated with S961 between days 15 and 21 (osmotic pump, 40 nmol) to inhibit insulin signaling. Random-fed glycemia is shown. Modified from Damond et al. (31).

Figure 2.

The lack of glucagon action mitigates hyperketonemia development after β cell ablation. In mice with normal glucagon signaling, diphtheria toxin–mediated β cell destruction leads to a sharp increase in circulating levels of ketone bodies. This increase is attenuated but not entirely abolished in β cell–ablated Gcgr^−/− mice. The corresponding random blood glucose levels averaged over 1 month are shown on the lower panel. Experimental procedures were performed as described (31). Briefly, adult (10–12 weeks old) RIP-DTR;Gcgr^−/− males (20, 31) were injected with diphtheria toxin to induce β cell ablation. One month later, β-hydroxybutyrate levels were measured from plasma using an enzymatic assay (MAK041, Sigma-Aldrich). Error bars indicate SEM. *P < 0.05 and **P < 0.01 versus unablated Gcgr^+/− mice; ## P < 0.01; β cell–ablated: Gcgr^+/− versus Gcgr^−/−, Mann-Whitney U test.