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α-Cell Dysfunctions and Molecular Alterations in Male Insulinopenic Diabetic Mice Are Not Completely Corrected by Insulin

Reimann, Franck
Gribble, Fiona
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Published in Endocrinology. 2016, vol. 157, no. 2, p. 536-547
Abstract Glucagon and α-cell dysfunction are critical in the development of hyperglycemia during diabetes both in humans and rodents. We hypothesized that α-cell dysfunction leading to dysregulated glucagon secretion in diabetes is due to both a lack of insulin and intrinsic defects. To characterize α-cell dysfunction in diabetes, we used glucagon-Venus transgenic male mice and induced insulinopenic hyperglycemia by streptozotocin administration leading to alterations of glucagon secretion. We investigated the in vivo impact of insulinopenic hyperglycemia on glucagon-producing cells using FACS-sorted α-cells from control and diabetic mice. We demonstrate that increased glucagonemia in diabetic mice is mainly due to increases of glucagon release and biosynthesis per cell compared with controls without changes in α-cell mass. We identified genes coding for proteins involved in glucagon biosynthesis and secretion, α-cell differentiation, and potential stress markers such as the glucagon, Arx, MafB, cMaf, Brain4, Foxa1, Foxa3, HNF4α, TCF7L2, Glut1, Sglt2, Cav2.1, Cav2.2, Nav1.7, Kir6.2/Sur1, Pten, IR, NeuroD1, GPR40, and Sumo1 genes, which were abnormally regulated in diabetic mice. Importantly, insulin treatment partially corrected α-cell function and expression of genes coding for proglucagon, or involved in glucagon secretion, glucose transport and insulin signaling but not those coding for cMAF, FOXA1, and α-cell differentiation markers as well as GPR40, NEUROD1, CAV2.1, and SUMO1. Our results indicate that insulinopenic diabetes induce marked α-cell dysfunction and molecular alteration, which are only partially corrected by in vivo insulin treatment.
Keywords AnimalsCell Differentiation/drug effects/geneticsDiabetes Mellitus, Experimental/drug therapy/pathologyGlucagon/biosynthesis/genetics/secretionGlucagon-Secreting Cells/drug effects/secretionInsulin/pharmacology/therapeutic useMaleMiceMice, TransgenicStress, Physiological/drug effects/genetics
PMID: 26696123
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Research group Diabète et régulation des gènes (36)
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DUSAULCY, Rodolphe et al. α-Cell Dysfunctions and Molecular Alterations in Male Insulinopenic Diabetic Mice Are Not Completely Corrected by Insulin. In: Endocrinology, 2016, vol. 157, n° 2, p. 536-547. doi: 10.1210/en.2015-1725 https://archive-ouverte.unige.ch/unige:89807

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Deposited on : 2016-12-02

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