The Role of Pancreatic Preproglucagon in Glucose Homeostasis in Mice.
Glucagon-like peptide 1 (GLP-1) is necessary for normal gluco-regulation, and it has been widely presumed that this function reflects the actions of GLP-1 released from enteroendocrine L cells. To test the relative importance of intestinal versus pancreatic sources of GLP-1 for physiological regulation of glucose, we administered a GLP-1R antagonist, exendin-[9-39] (Ex9), to mice with tissue-specific reactivation of the preproglucagon gene (Gcg). Ex9 impaired glucose tolerance in wild-type mice but had no impact on Gcg-null or GLP-1R KO mice, suggesting that Ex9 is a true and specific GLP-1R antagonist. Unexpectedly, Ex-9 had no effect on blood glucose in mice with restoration of intestinal Gcg. In contrast, pancreatic reactivation of Gcg fully restored the effect of Ex9 to impair both oral and i.p. glucose tolerance. These findings suggest an alternative model whereby islet GLP-1 also plays an important role in regulating glucose homeostasis.
Incretin and Obesity Pharmacology, Novo Nordisk, 2880 Bagsvaerd, Denmark.
Adam P
AP
Chambers
Department of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Joyce E
JE
Sorrell
Department of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
April
A
Haller
Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
Karen
K
Roelofs
Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
Chelsea R
CR
Hutch
Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
Ki-Suk
KS
Kim
Facultad de Medicina, Universidad Nacional Autónoma de México and Laboratorio de Enfermedades Metabólicas: Obesidad y Diabetes, Hospital Infantil de México "Federico Gómez," Mexico City 06720, Mexico.
Ruth
R
Gutierrez-Aguilar
Department of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Bailing
B
Li
Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, University of Toronto, Toronto, ON M5G 1X5, Canada.
Daniel J
DJ
Drucker
Department of Medicine, Duke University, Durham, NC 27710, USA.
David A
DA
D'Alessio
Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
Randy J
RJ
Seeley
Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: darleens@umich.edu.
Darleen A
DA
Sandoval
D000284:Administration, Oral; D000818:Animals; D005260:Female; D041981:Gastrointestinal Tract / Q000378:metabolism; D005786:Gene Expression Regulation; D018390:Gene Targeting; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis; D007274:Injections, Intraperitoneal; D008297:Male; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D010179:Pancreas / Q000378:metabolism*; D010641:Phenotype; D052336:Proglucagon / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results
D000067757:Glucagon-Like Peptide-1 Receptor; D052336:Proglucagon; D005947:Glucose
GLP-1; glucose homeostasis; incretin