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Proc Natl Acad Sci U S A. 2015 Feb 24;112(8):2503-8. doi: 10.1073/pnas.1424934112. Epub 2015 Feb 9.

Glucagon receptor antibody completely suppresses type 1 diabetes phenotype without insulin by disrupting a novel diabetogenic pathway.

Author information

1
Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
2
REMD Biotherapeutics, Inc., Camarillo, CA 93012; Beijing Cosci-REMD Biotherapeutics Inc., Beijing 102206, China;
3
Department of Biochemistry and.
4
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
5
University of Notre Dame, Notre Dame, IN 46556;
6
University of Geneva School of Medicine, 1211 Geneva, Switzerland; and.
7
Department of Biochemistry and roger.unger@utsouthwestern.edu michael.roth@utsouthwestern.edu.
8
Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Medical Service, Veteran's Administration North Texas Health Care System, Dallas, TX 75216 roger.unger@utsouthwestern.edu michael.roth@utsouthwestern.edu.

Abstract

Insulin monotherapy can neither maintain normoglycemia in type 1 diabetes (T1D) nor prevent the long-term damage indicated by elevated glycation products in blood, such as glycated hemoglobin (HbA1c). Here we find that hyperglycemia, when unaccompanied by an acute increase in insulin, enhances itself by paradoxically stimulating hyperglucagonemia. Raising glucose from 5 to 25 mM without insulin enhanced glucagon secretion ∼two- to fivefold in InR1-G9 α cells and ∼18-fold in perfused pancreata from insulin-deficient rats with T1D. Mice with T1D receiving insulin treatment paradoxically exhibited threefold higher plasma glucagon during hyperglycemic surges than during normoglycemic intervals. Blockade of glucagon action with mAb Ac, a glucagon receptor (GCGR) antagonizing antibody, maintained glucose below 100 mg/dL and HbA1c levels below 4% in insulin-deficient mice with T1D. In rodents with T1D, hyperglycemia stimulates glucagon secretion, up-regulating phosphoenolpyruvate carboxykinase and enhancing hyperglycemia. GCGR antagonism in mice with T1D normalizes glucose and HbA1c, even without insulin.

KEYWORDS:

antibody; glucagon receptor; insulin; type 1 diabetes

Comment in

PMID:
25675519
PMCID:
PMC4345619
DOI:
10.1073/pnas.1424934112
[Indexed for MEDLINE]
Free PMC Article

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