Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras(G12D) mouse model.

Pancreatic duct glands (PDGs) have been hypothesized to give rise to pancreatic intraepithelial neoplasia (PanIN). Treatment with the glucagon-like peptide (GLP)-1 analog, exendin-4, for 12 weeks induced the expansion of PDGs with mucinous metaplasia and columnar cell atypia resembling low-grade PanIN in rats. In the pancreata of Pdx1-Cre; LSL-Kras(G12D) mice, exendin-4 led to acceleration of the disruption of exocrine architecture and chronic pancreatitis with mucinous metaplasia and increased formation of murine PanIN lesions.

Glucagon like peptide-1 receptor expression in the human thyroid gland.

Background: Glucagon like peptide-1 (GLP-1) mimetic therapy induces medullary thyroid neoplasia in rodents. We sought to establish whether C cells in human medullary thyroid carcinoma, C cell hyperplasia, and normal human thyroid express the GLP-1 receptor.

Methods: Thyroid tissue samples with medullary thyroid carcinoma (n = 12), C cell hyperplasia (n = 9), papillary thyroid carcinoma (n = 17), and normal human thyroid (n = 15) were evaluated by immunofluorescence for expression of calcitonin and GLP-1 receptors.

Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies.

Background & Aims: Glucagon-like peptide-1-based therapy is gaining widespread use for type 2 diabetes, although there are concerns about risks for pancreatitis and pancreatic and thyroid cancers. There are also concerns that dipeptidyl peptidase-4 inhibitors could cause cancer, given their effects on immune function.

Methods: We examined the US Food and Drug Administration's database of reported adverse events for those associated with the dipeptidyl peptidase-4 inhibitor sitagliptin and the glucagon-like peptide-1 mimetic exenatide, from 2004-2009; data on adverse events associated with 4 other medications were compared as controls.

The Gq/G11-mediated signaling pathway is critical for autocrine potentiation of insulin secretion in mice.

A variety of neurotransmitters, gastrointestinal hormones, and metabolic signals are known to potentiate insulin secretion through GPCRs. We show here that beta cell-specific inactivation of the genes encoding the G protein alpha-subunits Galphaq and Galpha11 resulted in impaired glucose tolerance and insulin secretion in mice. Interestingly, the defects observed in Galphaq/Galpha11-deficient beta cells were not restricted to loss of muscarinic or metabolic potentiation of insulin release; the response to glucose per se was also diminished.

Suppression of KATP channel activity protects murine pancreatic beta cells against oxidative stress.

The enhanced oxidative stress associated with type 2 diabetes mellitus contributes to disease pathogenesis. We previously identified plasma membrane-associated ATP-sensitive K+ (KATP) channels of pancreatic beta cells as targets for oxidants. Here, we examined the effects of genetic and pharmacologic ablation of KATP channels on loss of mouse beta cell function and viability following oxidative stress.

Enhanced glucose tolerance by SK4 channel inhibition in pancreatic beta-cells.

Objective: Ca(2+)-regulated K(+) channels are involved in numerous Ca(2+)-dependent signaling pathways. In this study, we investigated whether the Ca(2+)-activated K(+) channel of intermediate conductance SK4 (KCa3.1, IK1) plays a physiological role in pancreatic beta-cell function.