The Role of Pancreatic Preproglucagon in Glucose Homeostasis in Mice

• Published in: Cell metabolism Vol. 25; no. 4; pp. 927 - 934.e3
• Main Authors: Chambers, Adam P., Sorrell, Joyce E., Haller, April, Roelofs, Karen, Hutch, Chelsea R., Kim, Ki-Suk, Gutierrez-Aguilar, Ruth, Li, Bailing, Drucker, Daniel J., D’Alessio, David A., Seeley, Randy J., Sandoval, Darleen A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.04.2017
• Subjects: Administration, Oral; Animals; Female; Gastrointestinal Tract - metabolism; Gene Expression Regulation; Gene Targeting; GLP-1; Glucagon-Like Peptide-1 Receptor - metabolism; Glucose - metabolism; glucose homeostasis; Glucose Tolerance Test; Homeostasis; incretin; Injections, Intraperitoneal; Male; Mice, Inbred C57BL; Organ Specificity; Pancreas - metabolism; Phenotype; Proglucagon - genetics; Proglucagon - metabolism; Reproducibility of Results; glucose homeostasis; incretin; GLP-1
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2017.02.008

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. [Display omitted] •Intestinally secreted GLP-1 is presumed to regulate glucose via incretin action•Exendin-9 does not alter glucose in mice that only produce GLP-1 in the intestine•Exendin-9 does impair glucose in mice that only produce GLP-1 in the pancreas•Alternative to the incretin model, islet GLP-1 is crucial for gluco-regulation GLP-1 is necessary for normal gluco-regulation, and it has been widely presumed that this function is the action of peptide released from enteroendocrine L cells. The data from Chambers et al. challenge this dogma and find that intestinally produced GLP-1 is dispensable, while pancreatic production of GLP-1 is necessary for gluco-regulation.