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.