title: Hyperglycemia in rodent models of type 2 diabetes requires insulin-resistant alpha cells.
abstract: To determine the role of glucagon action in diet-induced and genetic type 2 diabetes (T2D), we studied high-fat-diet-induced obese (DIO) and leptin receptor-defective (LepR(-/-)) rodents with and without glucagon receptors (GcgRs). DIO and LepR(-/-),GcgR(+/+) mice both developed hyperinsulinemia, increased liver sterol response element binding protein 1c, and obesity. DIO GcgR(+/+) mice developed mild T2D, whereas LepR(-/-),GcgR(+/+) mice developed severe T2D. High-fat-fed (HFF) glucagon receptor-null mice did not develop hyperinsulinemia, increased liver sterol response element binding protein 1c mRNA, or obesity. Insulin treatment of HFF GcgR(-/-) to simulate HFF-induced hyperinsulinemia caused obesity and mild T2D. LepR(-/-),GcgR(-/-) did not develop hyperinsulinemia or hyperglycemia. Adenoviral delivery of GcgR to GcgR(-/-),LepR(-/-) mice caused the severe hyperinsulinemia and hyperglycemia of LepR(-/-) mice to appear. Spontaneous disappearance of the GcgR transgene abolished the hyperinsulinemia and hyperglycemia. In conclusion, T2D hyperglycemia requires unsuppressible hyperglucagonemia from insulin-resistant α cells and is prevented by glucagon suppression or blockade.
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine.
authors.forename: Young
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Advanced Imaging Center and Department of Pharmacology, and.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Berglund
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Yu
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine.
authors.forename: May-Yun
authors.initials: MY
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390; and.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Evans
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine.
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine.
authors.forename: William L
authors.initials: WL
authors.lastname: Holland
authors.affiliation: Departments of Biochemistry, Obstetrics and Gynecology and Woman's Health, and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Charron
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390; and michael.roth@utsouthwestern.edu.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Roth
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine.
authors.forename: Roger H
authors.initials: RH
authors.lastname: Unger
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D002518:Ceramides / Q000494:pharmacology; D006224:Cricetinae; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000473:pathology*; D004032:Diet; D004195:Disease Models, Animal; D005247:Feeding Behavior / Q000187:drug effects; D005934:Glucagon / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006943:Hyperglycemia / Q000097:blood / Q000150:complications* / Q000473:pathology*; D006946:Hyperinsulinism / Q000097:blood / Q000150:complications / Q000473:pathology; D007328:Insulin / Q000097:blood / Q000235:genetics / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050155:Lipogenesis / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018027:Receptors, Glucagon / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D002518:Ceramides; D007328:Insulin; D012333:RNA, Messenger; D018027:Receptors, Glucagon; D005934:Glucagon
keywords: insulin resistance; type two diabetes