Barbetti Fabrizio, Colombo Carlo, Haataja Leena, Cras-Méneur Corentin, Bernardini Sergio, Arvan Peter
Department of Experimental Medicine and Surgery, University of Tor Vergata, Rome, Italy.
Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Clin Diabetes Endocrinol. 2016 May 2;2:11. doi: 10.1186/s40842-016-0029-5. eCollection 2016.
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.
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.
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.
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.
胰岛内胰岛素有助于抑制α细胞。小鼠携带一种功能获得性毒性基因突变，该突变编码胰岛素原-C(A7)Y，类似于人类青年期突变基因诱导的糖尿病中所描述的情况，这种突变会降低胰岛内胰岛素水平。在此，我们检测了小鼠的循环胰岛素和循环胰高血糖素水平。在胰岛内胰岛素缺乏的情况下，α细胞的胰岛内抑制作用丧失，循环胰高血糖素增加，这可能导致糖尿病，这引发了关于可能有效的治疗方法的疑问。
在糖尿病小鼠发育的不同时间测量血糖、血浆胰岛素、C肽I、C肽II和胰高血糖素。我们还使用了在、和遗传背景下的类似hProC(A7)Y-CpepGFP转基因小鼠（分别为胰岛胰岛素产生缺陷程度不同的动物），以检测胰岛内可免疫染色的胰高血糖素阳性和胰岛素阳性细胞的相对丰度。在小鼠中进行了类似的测量。最后，比较了胰岛素、艾塞那肽-4和瘦素治疗对小鼠血糖的影响。
有趣的是，小鼠循环中的总胰岛素水平并非明显降低，尽管随着高血糖的出现其并未适当升高。相比之下，在6周龄的重度糖尿病小鼠中，循环胰高血糖素水平显著升高。此外，在携带类似hProC(A7)Y-CpepGFP转基因的和小鼠中，糖尿病的发展与胰岛内可免疫染色的胰高血糖素阳性细胞相对丰度的增加相关，并且在胰岛中也观察到了类似现象。在小鼠中，虽然短暂使用艾塞那肽-4治疗对高血糖没有明显改善，但瘦素治疗可使血糖恢复正常。奇怪的是，瘦素治疗还可抑制循环胰高血糖素水平。
胰岛素介导的胰岛内对胰高血糖素产生的抑制作用丧失可能是小鼠高血糖的一个原因，在这种情况下瘦素治疗似乎有益。对于一些胰岛素储备减少的人类糖尿病患者，也可考虑这种治疗方法。
