Incretin action in the pancreas: potential promise, possible perils, and pathological pitfalls

Abstract

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones that control the secretion of insulin, glucagon, and somatostatin to facilitate glucose disposal. The actions of incretin hormones are terminated via enzymatic cleavage by dipeptidyl peptidase-4 (DPP-4) and through renal clearance. GLP-1 and GIP promote β-cell proliferation and survival in rodents. DPP-4 inhibitors expand β-cell mass, reduce α-cell mass, and inhibit glucagon secretion in preclinical studies; however, whether incretin-based therapies sustain functional β-cell mass in human diabetic subjects remains unclear. GLP-1 and GIP exert their actions predominantly through unique G protein-coupled receptors expressed on β-cells and other pancreatic cell types. Accurate localization of incretin receptor expression in pancreatic ductal or acinar cells in normal or diabetic human pancreas is challenging because antisera used for detection of the GLP-1 receptor often are neither sufficiently sensitive nor specific to yield reliable data. This article reviews recent advances and controversies in incretin hormone action in the pancreas and contrasts established mechanisms with areas of uncertainty. Furthermore, methodological challenges and pitfalls are highlighted and key areas requiring additional scientific investigation are outlined.

FIG. 1.

Characterization of the sensitivity and specificity of antisera against the human GLP-1R. Baby hamster kidney cells were transiently transfected with the vector pcDNA3.1 alone (lane 1) or with a human Glp1r cDNA tagged at the C-terminus with green fluorescent protein (GFP) cloned into pcDNA3.1 (lane 2). Whole-cell extracts were prepared 48 h after transfection and analyzed by immunoblotting with the indicated commercial GLP-1R antibodies or with a rabbit polyclonal antibody against GFP (Abcam ab6556). Molecular mass standards are indicated on the right. Both the anti-GLP-1R antibody Novus1940002 and the anti-GFP antibody detected similar immunoreactive proteins of ∼68 and ∼87 kDa, likely representing species of the GLP-1R-GFP fusion protein that were glycosylated differently.

FIG. 2.

GLP-1 and DPP-4 inhibitor action in the endocrine pancreas. GLP-1R agonists and DPP-4 inhibitors enhance insulin and reduce glucagon secretion. In preclinical studies, these agents expand β-cell mass and reduce α-cell mass. Genetic mutations that disrupt glucagon receptor signaling or eliminate production of bioactive glucagon result in islet α-cell hyperplasia.