Brial François, Lussier Carine R, Belleville Karine, Sarret Philippe, Boudreau François
Department of Anatomy and Cell Biology, Université de Sherbrooke, Quebec, Canada.
Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Quebec, Canada.
Diabetes. 2015 Sep;64(9):3314-20. doi: 10.2337/db15-0124. Epub 2015 May 15.
Hepatocyte nuclear factor-1α (HNF1α) is a transcription factor expressed in tissues of endoderm origin. Mutations in HNF1A are associated with maturity-onset diabetes of the young 3 (MODY3). Mice deficient for Hnf1α are hyperglycemic, with their pancreatic β-cells being defective in glucose-sensing insulin secretion. The specific mechanisms involved in this defect are unclear. Gut hormones control glucose homeostasis. Our objective was to explore whether changes in these hormones play a role in glucose homeostasis in the absence of Hnf1α. An increase in ghrelin gene transcript and a decrease in glucose-dependent insulinotropic polypeptide (GIP) gene transcripts were observed in the gut of Hnf1α-null mice. These changes correlated with an increase of ghrelin and a decrease of GIP-labeled cells. Ghrelin serological levels were significantly induced in Hnf1α-null mice. Paradoxically, GIP levels were also induced in these mice. Treatment of Hnf1α-null mice with a ghrelin antagonist led to a recovery of the diabetic symptoms. We conclude that upregulation of ghrelin in the absence of Hnf1α impairs insulin secretion and can be reversed by pharmacological inhibition of ghrelin/GHS-R interaction. These observations open up on future strategies to counteract ghrelin action in a program that could become beneficial in controlling non-insulin-dependent diabetes.
肝细胞核因子-1α（HNF1α）是一种在内胚层起源组织中表达的转录因子。HNF1A基因的突变与青年发病的成年型糖尿病3型（MODY3）相关。缺乏Hnf1α的小鼠会出现高血糖，其胰腺β细胞在葡萄糖感应胰岛素分泌方面存在缺陷。这种缺陷所涉及的具体机制尚不清楚。肠道激素控制着葡萄糖稳态。我们的目的是探讨在缺乏Hnf1α的情况下，这些激素的变化是否在葡萄糖稳态中起作用。在缺乏Hnf1α的小鼠肠道中，观察到胃饥饿素基因转录本增加，而葡萄糖依赖性促胰岛素多肽（GIP）基因转录本减少。这些变化与胃饥饿素增加和GIP标记细胞减少相关。在缺乏Hnf1α的小鼠中，胃饥饿素血清水平显著升高。矛盾的是，这些小鼠中的GIP水平也升高。用胃饥饿素拮抗剂治疗缺乏Hnf1α的小鼠可使糖尿病症状得到缓解。我们得出结论，在缺乏Hnf1α的情况下胃饥饿素的上调会损害胰岛素分泌，并且可以通过胃饥饿素/GHS-R相互作用药理学抑制来逆转。这些观察结果为未来在一个可能对控制非胰岛素依赖型糖尿病有益的方案中对抗胃饥饿素作用的策略开辟了道路。
