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 primary outcomes measures were rates of reported pancreatitis, pancreatic and thyroid cancer, and all cancers associated with sitagliptin or exenatide, compared with other therapies. RESULTS Use of sitagliptin or exenatide increased the odds ratio for reported pancreatitis 6-fold as compared with other therapies (P < 2 × 10−16). Pancreatic cancer was more commonly reported among patients who took sitagliptin or exenatide as compared with other therapies (P < .008, P < 9 × 10−5). All other cancers occurred similarly among patients who took sitagliptin compared with other therapies (P =.20). CONCLUSIONS These data are consistent with case reports and animal studies indicating an increased risk for pancreatitis with glucagon-like peptide-1–based therapy. The findings also raise caution about the potential long-term actions of these drugs to promote pancreatic cancer.

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-KrasG12D 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. PDGs and PanIN lesions in rodent and human pancreata express the GLP-1 receptor. Exendin-4 induced proproliferative signaling pathways in human pancreatic duct cells, cAMP–protein kinase A and mitogen-activated protein kinase phosphorylation of cAMP-responsive element-binding protein, and increased cyclin D1 expression. These GLP-1 effects were more pronounced in the presence of an activating mutation of Kras and were inhibited by metformin. These data reveal that GLP-1 mimetic therapy may induce focal proliferation in the exocrine pancreas and, in the context of exocrine dysplasia, may accelerate formation of neoplastic PanIN lesions and exacerbate chronic pancreatitis.

In humans, neoplastic and hyperplastic lesions of thyroid C cells express the GLP-1 receptor. GLP-1 receptor expression is detected in 18% papillary thyroid carcinomas and in C cells in 33% of control thyroid lobes. The consequence of long-term pharmacologically increased GLP-1 signaling on these GLP-1 receptor-expressing cells in the thyroid gland in humans remains unknown, but appropriately powered prospective studies to exclude an increase in medullary or papillary carcinomas of the thyroid are warranted.

The enhanced oxidative stress associated with type 2 diabetes mellitus contributes to disease pathogenesis. We previously identified plasma membrane-associated ATP-sensitive K + (K ATP ) channels of pancreatic β cells as targets for oxidants. Here, we examined the effects of genetic and pharmacologic ablation of K ATP channels on loss of mouse β cell function and viability following oxidative stress. Using mice lacking the sulfonylurea receptor type 1 (Sur1) subunit of K ATP channels, we found that, compared with insulin secretion by WT islets, insulin secretion by Sur1 -/-islets was less susceptible to oxidative stress induced by the oxidant H 2 O 2 . This was likely, at least in part, a result of the reduced ability of H 2 O 2 to hyperpolarize plasma membrane potential and reduce cytosolic free Ca 2+ concentration ([Ca 2+ ] c ) in the Sur1 -/-β cells. Remarkably, Sur1 -/-β cells were less prone to apoptosis induced by H 2 O 2 or an NO donor than WT β cells, despite an enhanced basal rate of apoptosis. This protective effect was attributed to upregulation of the antioxidant enzymes SOD, glutathione peroxidase, and catalase. Upregulation of antioxidant enzymes and reduced sensitivity of Sur1 -/-cells to H 2 O 2 -induced apoptosis were mimicked by treatment with the sulfonylureas tolbutamide and gliclazide. Enzyme upregulation and protection against oxidant-induced apoptosis were abrogated by agents lowering [Ca 2+ ] c . Sur1 -/-mice were less susceptible than WT mice to streptozotocin-induced β cell destruction and subsequent hyperglycemia and death, which suggests that loss of K ATP channel activity may protect against streptozotocin-induced diabetes in vivo.

A variety of neurotransmitters, gastrointestinal hormones, and metabolic signals are known to potentiate insulin secretion through GPCRs. We show here that β cell-specific inactivation of the genes encoding the G protein α-subunits Gα q and Gα 11 resulted in impaired glucose tolerance and insulin secretion in mice. Interestingly, the defects observed in Gα q /Gα 11 -deficient β cells were not restricted to loss of muscarinic or metabolic potentiation of insulin release; the response to glucose per se was also diminished. Electrophysiological recordings revealed that glucose-induced depolarization of isolated β cells was impaired in the absence of Gα q /Gα 11 , and closure of K ATP channels was inhibited. We provide evidence that this reduced excitability was due to a loss of β cell-autonomous potentiation of insulin secretion through factors cosecreted with insulin. We identified as autocrine mediators involved in this process extracellular nucleotides such as uridine diphosphate acting through the G q /G 11 -coupled P2Y6 receptor and extracellular calcium acting through the calciumsensing receptor. Thus, the G q /G 11 -mediated signaling pathway potentiates insulin secretion in response to glucose by integrating systemic as well as autocrine/paracrine mediators. IntroductionThe adequate secretion of insulin from pancreatic β cells is essential for the maintenance of normoglycemia; impaired insulin secretion results in diabetes mellitus with hyperglycemia, dyslipidemia, and consequent long-term tissue damage (1). The on-demand release of insulin from β cells is mainly regulated by blood glucose levels: high concentrations of glucose result in enhanced intracellular glucose metabolism with accumulation of ATP and consecutive closure of ATP-sensitive K + channels, leading to the opening of voltage-operated Ca 2+ channels and Ca 2+ -mediated exocytosis of insulin-containing vesicles (2, 3).While the ATP-dependent mechanism is clearly the master regulator of insulin release, various mediators potentiate insulin release in response to glucose. For example, gastrointestinal hormones such as glucose-dependent insulinotropic polypeptide (GIP) or glucagon-like peptide-1 (GLP-1) potentiate insulin secretion by activation of GPCRs, which signal through the G s family of heterotrimeric G proteins (4-6). The potentiating effect of G s on glucose-induced insulin release depends on activation of adenylyl cyclase and consecutive phosphorylation of voltage-operated Ca 2+ channels (7, 8) or opening of nonselective cation channels (9).Another important group of modulators are neurotransmitters and neuropeptides (10, 11), most prominent among them being the neurotransmitter acetylcholine, which is released from vagal nerve terminals and potentiates insulin secretion through the muscarinic receptor subtype M 3 (12)(13)(14)(15). In contrast to the receptors for GIP and GLP-1, the M 3 receptor does not elicit G smediated adenylyl cyclase activation, but was shown to signal through the G q /G 11 family of heterotrimeric G proteins. Th...