Hyperglucagonemia in an Animal Model of Insulin- Deficient Diabetes: What Therapy Can Improve It?

Background: Intra-islet insulin contributes to alpha-cell suppression. mice carry a toxic-gain-of- function gene mutation encoding proinsulin-C(A7)Y, similar to that described in human Mutant -gene induced Diabetes of Youth, which decreases intra-islet insulin. Herein, we examined mice for examination of circulating insulin and circulating glucagon levels. The possibility that loss of intra-islet suppression of alpha-cells, with increased circulating glucagon, contributes to diabetes under conditions of intra-islet insulin deficiency, raises questions about effective treatments that may be available.

Methods: Blood glucose, plasma insulin, C-peptide I, C-peptide II, and glucagon were measured at various times during development of diabetes in mice. We also used - like hProC(A7)Y-CpepGFP transgenic mice in , and genetic backgrounds (providing animals with greater or lesser defects in islet insulin production, respectively) in order to examine the relative abundance of immunostainable intra-islet glucagon-positive and insulin-positive cells. Similar measurements were made in mice. Finally, the effects of treatment with insulin, exendin-4, and leptin on blood glucose were then compared in mice.

Results: Interestingly, total insulin levels in the circulation were not frankly low in mice, although they did not rise appropriately with the onset of hyperglycemia. By contrast, in severely diabetic mice at 6 weeks of age, circulating glucagon levels were significantly elevated. Additionally, in and mice bearing the -like hProC(A7)Y-CpepGFP transgene, development of diabetes correlated with an increase in the relative intra-islet abundance of immunostainable glucagon-positive cells, and a similar observation was made in islets. In mice, whereas a brief treatment with exendin-4 resulted in no apparent improvement in hyperglycemia, leptin treatment resulted in restoration of normoglycemia. Curiously, leptin treatment also suppressed circulating glucagon levels.

Conclusions: Loss of insulin-mediated intra-islet suppression of glucagon production may be a contributor to hyperglycemia in mice, and leptin treatment appears beneficial in such a circumstance. This treatment might also be considered in some human diabetes patients with diminished insulin reserve.