title: α-Cell Dysfunctions and Molecular Alterations in Male Insulinopenic Diabetic Mice Are Not Completely Corrected by Insulin.
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.
authors.affiliation: Molecular Diabetes Laboratory (R.D., S.H., M.H.-M., F.V., J.P., Y.G.), Division of Endocrinology-Diabetes-Hypertension and Nutrition, University Hospital/University of Geneva Medical School, 1211 Geneva, Switzerland; Cambridge Institute for Medical Research (F.R., F.G.), Wellcome Trust/Medical Research Council, Addenbrooke's Hospital, Cambridge, United Kingdom; and Department of Cell Physiology and Metabolism (C.V.), University of Geneva Medical School, 1211 Geneva, Switzerland.
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Dusaulcy
authors.affiliation: Molecular Diabetes Laboratory (R.D., S.H., M.H.-M., F.V., J.P., Y.G.), Division of Endocrinology-Diabetes-Hypertension and Nutrition, University Hospital/University of Geneva Medical School, 1211 Geneva, Switzerland; Cambridge Institute for Medical Research (F.R., F.G.), Wellcome Trust/Medical Research Council, Addenbrooke's Hospital, Cambridge, United Kingdom; and Department of Cell Physiology and Metabolism (C.V.), University of Geneva Medical School, 1211 Geneva, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Handgraaf
authors.affiliation: Molecular Diabetes Laboratory (R.D., S.H., M.H.-M., F.V., J.P., Y.G.), Division of Endocrinology-Diabetes-Hypertension and Nutrition, University Hospital/University of Geneva Medical School, 1211 Geneva, Switzerland; Cambridge Institute for Medical Research (F.R., F.G.), Wellcome Trust/Medical Research Council, Addenbrooke's Hospital, Cambridge, United Kingdom; and Department of Cell Physiology and Metabolism (C.V.), University of Geneva Medical School, 1211 Geneva, Switzerland.
authors.forename: Mounia
authors.initials: M
authors.lastname: Heddad-Masson
authors.affiliation: Molecular Diabetes Laboratory (R.D., S.H., M.H.-M., F.V., J.P., Y.G.), Division of Endocrinology-Diabetes-Hypertension and Nutrition, University Hospital/University of Geneva Medical School, 1211 Geneva, Switzerland; Cambridge Institute for Medical Research (F.R., F.G.), Wellcome Trust/Medical Research Council, Addenbrooke's Hospital, Cambridge, United Kingdom; and Department of Cell Physiology and Metabolism (C.V.), University of Geneva Medical School, 1211 Geneva, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Visentin
authors.affiliation: Molecular Diabetes Laboratory (R.D., S.H., M.H.-M., F.V., J.P., Y.G.), Division of Endocrinology-Diabetes-Hypertension and Nutrition, University Hospital/University of Geneva Medical School, 1211 Geneva, Switzerland; Cambridge Institute for Medical Research (F.R., F.G.), Wellcome Trust/Medical Research Council, Addenbrooke's Hospital, Cambridge, United Kingdom; and Department of Cell Physiology and Metabolism (C.V.), University of Geneva Medical School, 1211 Geneva, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Vesin
authors.affiliation: Molecular Diabetes Laboratory (R.D., S.H., M.H.-M., F.V., J.P., Y.G.), Division of Endocrinology-Diabetes-Hypertension and Nutrition, University Hospital/University of Geneva Medical School, 1211 Geneva, Switzerland; Cambridge Institute for Medical Research (F.R., F.G.), Wellcome Trust/Medical Research Council, Addenbrooke's Hospital, Cambridge, United Kingdom; and Department of Cell Physiology and Metabolism (C.V.), University of Geneva Medical School, 1211 Geneva, Switzerland.
authors.forename: Franck
authors.initials: F
authors.lastname: Reimann
authors.affiliation: Molecular Diabetes Laboratory (R.D., S.H., M.H.-M., F.V., J.P., Y.G.), Division of Endocrinology-Diabetes-Hypertension and Nutrition, University Hospital/University of Geneva Medical School, 1211 Geneva, Switzerland; Cambridge Institute for Medical Research (F.R., F.G.), Wellcome Trust/Medical Research Council, Addenbrooke's Hospital, Cambridge, United Kingdom; and Department of Cell Physiology and Metabolism (C.V.), University of Geneva Medical School, 1211 Geneva, Switzerland.
authors.forename: Fiona
authors.initials: F
authors.lastname: Gribble
authors.affiliation: Molecular Diabetes Laboratory (R.D., S.H., M.H.-M., F.V., J.P., Y.G.), Division of Endocrinology-Diabetes-Hypertension and Nutrition, University Hospital/University of Geneva Medical School, 1211 Geneva, Switzerland; Cambridge Institute for Medical Research (F.R., F.G.), Wellcome Trust/Medical Research Council, Addenbrooke's Hospital, Cambridge, United Kingdom; and Department of Cell Physiology and Metabolism (C.V.), University of Geneva Medical School, 1211 Geneva, Switzerland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Philippe
authors.affiliation: Molecular Diabetes Laboratory (R.D., S.H., M.H.-M., F.V., J.P., Y.G.), Division of Endocrinology-Diabetes-Hypertension and Nutrition, University Hospital/University of Geneva Medical School, 1211 Geneva, Switzerland; Cambridge Institute for Medical Research (F.R., F.G.), Wellcome Trust/Medical Research Council, Addenbrooke's Hospital, Cambridge, United Kingdom; and Department of Cell Physiology and Metabolism (C.V.), University of Geneva Medical School, 1211 Geneva, Switzerland.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Gosmain
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000473:pathology; D005934:Glucagon / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics
chemical_list: D007328:Insulin; D005934:Glucagon