title: Functional and Molecular Adaptations of Enteroendocrine L-Cells in Male Obese Mice Are Associated With Preservation of Pancreatic α-Cell Function and Prevention of Hyperglycemia.
abstract: Glucose homeostasis depends on the coordinated secretion of glucagon, insulin, and Glucagon-like peptide (GLP)-1 by pancreas and intestine. Obesity, which is associated with an increased risk of developing insulin resistance and type 2 diabetes, affects the function of these organs. Here, we investigate the functional and molecular adaptations of proglucagon-producing cells in obese mice to better define their involvement in type 2 diabetes development. We used GLU-Venus transgenic male mice specifically expressing Venus fluorochrome in proglucagon-producing cells. Mice were subjected to 16 weeks of low-fat diet or high-fat diet (HFD) and then subdivided by measuring glycated hemoglobin (HbA1c) in 3 groups: low-fat diet mice and I-HFD (glucose-intolerant) mice with similar HbA1c and H-HFD (hyperglycemic) mice, which exhibited higher HbA1c. At 16 weeks, both HFD groups exhibited similar weight gain, hyperinsulinemia, and insulin resistance. However, I-HFD mice exhibited better glucose tolerance compared with H-HFD mice. I-HFD mice displayed functional and molecular adaptations of enteroendocrine L-cells resulting in increased intestinal GLP-1 biosynthesis and release as well as maintained pancreatic α- and β-cell functions. By contrast, H-HFD mice exhibited dysfunctional L, α- and β-cells with increased β- and L-cell numbers. Administration of the GLP-1R antagonist Exendin9-39 in I-HFD mice led to hyperglycemia and alterations of glucagon secretion without changes in insulin secretion. Our results highlight the cross-talk between islet and intestine endocrine cells and indicate that a compensatory adaptation of L-cell function in obesity plays an important role in preserving glucose homeostasis through the control of pancreatic α-cell functions.
authors.affiliation: Molecular Diabetes Laboratory (R.D., S.H., S.S., F.V., M.H.-M., J.P., Y.G.), Division of Endocrinology, Diabetes, Hypertension and Nutrition, University Hospital/Diabetes Center/University of Geneva Medical School; and Department of Cell Physiology and Metabolism (C.V.), University of Geneva School of Medicine, 1211 Geneva, Switzerland; and Wellcome Trust/Medical Research Council Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit (F.R., F.G.), University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Dusaulcy
authors.affiliation: Molecular Diabetes Laboratory (R.D., S.H., S.S., F.V., M.H.-M., J.P., Y.G.), Division of Endocrinology, Diabetes, Hypertension and Nutrition, University Hospital/Diabetes Center/University of Geneva Medical School; and Department of Cell Physiology and Metabolism (C.V.), University of Geneva School of Medicine, 1211 Geneva, Switzerland; and Wellcome Trust/Medical Research Council Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit (F.R., F.G.), University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Sandra
authors.initials: S
authors.lastname: Handgraaf
authors.affiliation: Molecular Diabetes Laboratory (R.D., S.H., S.S., F.V., M.H.-M., J.P., Y.G.), Division of Endocrinology, Diabetes, Hypertension and Nutrition, University Hospital/Diabetes Center/University of Geneva Medical School; and Department of Cell Physiology and Metabolism (C.V.), University of Geneva School of Medicine, 1211 Geneva, Switzerland; and Wellcome Trust/Medical Research Council Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit (F.R., F.G.), University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Skarupelova
authors.affiliation: Molecular Diabetes Laboratory (R.D., S.H., S.S., F.V., M.H.-M., J.P., Y.G.), Division of Endocrinology, Diabetes, Hypertension and Nutrition, University Hospital/Diabetes Center/University of Geneva Medical School; and Department of Cell Physiology and Metabolism (C.V.), University of Geneva School of Medicine, 1211 Geneva, Switzerland; and Wellcome Trust/Medical Research Council Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit (F.R., F.G.), University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Florian
authors.initials: F
authors.lastname: Visentin
authors.affiliation: Molecular Diabetes Laboratory (R.D., S.H., S.S., F.V., M.H.-M., J.P., Y.G.), Division of Endocrinology, Diabetes, Hypertension and Nutrition, University Hospital/Diabetes Center/University of Geneva Medical School; and Department of Cell Physiology and Metabolism (C.V.), University of Geneva School of Medicine, 1211 Geneva, Switzerland; and Wellcome Trust/Medical Research Council Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit (F.R., F.G.), University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Christian
authors.initials: C
authors.lastname: Vesin
authors.affiliation: Molecular Diabetes Laboratory (R.D., S.H., S.S., F.V., M.H.-M., J.P., Y.G.), Division of Endocrinology, Diabetes, Hypertension and Nutrition, University Hospital/Diabetes Center/University of Geneva Medical School; and Department of Cell Physiology and Metabolism (C.V.), University of Geneva School of Medicine, 1211 Geneva, Switzerland; and Wellcome Trust/Medical Research Council Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit (F.R., F.G.), University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Mounia
authors.initials: M
authors.lastname: Heddad-Masson
authors.affiliation: Molecular Diabetes Laboratory (R.D., S.H., S.S., F.V., M.H.-M., J.P., Y.G.), Division of Endocrinology, Diabetes, Hypertension and Nutrition, University Hospital/Diabetes Center/University of Geneva Medical School; and Department of Cell Physiology and Metabolism (C.V.), University of Geneva School of Medicine, 1211 Geneva, Switzerland; and Wellcome Trust/Medical Research Council Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit (F.R., F.G.), University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.affiliation: Molecular Diabetes Laboratory (R.D., S.H., S.S., F.V., M.H.-M., J.P., Y.G.), Division of Endocrinology, Diabetes, Hypertension and Nutrition, University Hospital/Diabetes Center/University of Geneva Medical School; and Department of Cell Physiology and Metabolism (C.V.), University of Geneva School of Medicine, 1211 Geneva, Switzerland; and Wellcome Trust/Medical Research Council Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit (F.R., F.G.), University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Fiona
authors.initials: F
authors.lastname: Gribble
authors.affiliation: Molecular Diabetes Laboratory (R.D., S.H., S.S., F.V., M.H.-M., J.P., Y.G.), Division of Endocrinology, Diabetes, Hypertension and Nutrition, University Hospital/Diabetes Center/University of Geneva Medical School; and Department of Cell Physiology and Metabolism (C.V.), University of Geneva School of Medicine, 1211 Geneva, Switzerland; and Wellcome Trust/Medical Research Council Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit (F.R., F.G.), University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Jacques
authors.initials: J
authors.lastname: Philippe
authors.affiliation: Molecular Diabetes Laboratory (R.D., S.H., S.S., F.V., M.H.-M., J.P., Y.G.), Division of Endocrinology, Diabetes, Hypertension and Nutrition, University Hospital/Diabetes Center/University of Geneva Medical School; and Department of Cell Physiology and Metabolism (C.V.), University of Geneva School of Medicine, 1211 Geneva, Switzerland; and Wellcome Trust/Medical Research Council Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit (F.R., F.G.), University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Gosmain
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000378:metabolism; D059305:Diet, High-Fat; D019858:Enteroendocrine Cells / Q000378:metabolism*; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D006943:Hyperglycemia / Q000209:etiology / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D010446:Peptide Fragments; D010641:Phenotype
chemical_list: D010446:Peptide Fragments; C083773:exendin (9-39); D052216:Glucagon-Like Peptide 1; D005934:Glucagon