Hyperglucagonemia in an animal model of insulin- deficient diabetes: what therapy can improve it?. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Barbetti, Fabrizio; Colombo, Carlo; Haataja, Leena; Cras-Méneur, Corentin; Bernardini, Sergio; Arvan, Peter
• Is Part Of: Clinical diabetes and endocrinology. Volume 2:Issue 1(2016)
• Page Start: 1
• Page End: 10
• Publication Date: 2016-12
• Subjects: C-peptide I -- C-peptide II -- Glucagon -- Exendin-4; Diabetes -- Periodicals; Endocrine glands -- Diseases -- Periodicals; 616.462
• DOI: 10.1186/s40842-016-0029-5
• Languages: English
• ISSNs: 2055-8260

Abstract

Abstract Background Intra-islet insulin contributes to alpha-cell suppression.Akita mice carry a toxic-gain-of- functionIns2 gene mutation encoding proinsulin-C(A7)Y, similar to that described in human MutantIns -gene induced Diabetes of Youth, which decreases intra-islet insulin. Herein, we examinedAkita 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 inAkita mice. We also usedAkita - like hProC(A7)Y-CpepGFP transgenic mice inIns2 +/+, Ins2 +/− andIns2 −/− 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 inAkita mice. Finally, the effects of treatment with insulin, exendin-4, and leptin on blood glucose were then compared inAkita mice. Results Interestingly, total insulin levels in the circulation were not frankly low inAkita mice, although they did not rise appropriately with the onset of hyperglycemia. By contrast, in severely diabeticAkita mice at 6 weeks of age, circulating glucagon levels were significantly elevated. Additionally, inIns2 +/− andIns2 −/− mice bearing theAkita -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 inAkita islets. InAkita 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 inAkita 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.