The Role of Pancreatic Preproglucagon in Glucose Homeostasis in Mice

Abstract

Summary 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 vs. 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 IP glucose tolerance. These findings suggest an alternative model whereby islet GLP-1 also plays an important role in regulating glucose homeostasis.

Incretin hormones: Their role in health and disease

“…Intestinal production of glucagon was suggested after total pancreatectomy in human subjects, and GLP‐1 has been found to be present in pancreatic α cells . Animal studies suggest that GLP‐1 produced in pancreatic α cells may have more impact on glucose homeostasis compared to GLP‐1 produced in the gut . This may mean that all‐too‐simple views on the physiology of incretin hormones may need to be refined.…”

“…41 Animal studies suggest that GLP-1 produced in pancreatic α cells may have more impact on glucose homeostasis compared to GLP-1 produced in the gut. 42 This may mean that all-too-simple views on the physiology of incretin hormones may need to be refined. Alternatively, the validity of these findings could be restricted to very special and rare conditions.…”

A vitamin B12 conjugate of exendin‐4 improves glucose tolerance without associated nausea or hypophagia in rodents

“…A wealth of literature provides convincing evidence that a significant portion of the increase in glucose-stimulated insulin secretion following exogenous GLP-1R ligand administration is mediated by direct activation of GLP-1R expressed on pancreatic β-cells (see References 1-3,15 for review), mimicking the paracrine effects of pancreatic-derived GLP-1 that may not occur with endogenous Lcell-derived GLP-1. [16][17][18] Importantly, activation of GLP-1R expressed on vagal afferent fibers and/or in discrete nuclei in the central nervous system (CNS) also contributes to exogenous GLP-1R agonistmediated improvements in glycaemic control. [1][2][3]15,[19][20][21] Interestingly, these dual sites of action (ie, vagal and direct CNS activation) also mediate the intake-and body weight-suppressive effects of exogenous systemic GLP-1R agonist administration.…”

Alpha the versatile: Guardians of the islets

“…They have a certain effect on the neighboring β‐cell function of insulin secretion and survival through intra‐islet effects. The central role of this α‐cell‐derived GLP‐1 on GLP‐1‐mediated systemic glucoregulation has recently been suggested by in vivo genetic studies. In other words, α‐cell function, such as glucagon secretion, is regulated in an intra‐islet manner by inputs from other endocrine cells, including insulin from β‐cells and somatostatin from δ‐cells, meanwhile α‐cells certainly influence their neighboring cells through various outputs.…”