Exenatide does not evoke pancreatitis and attenuates chemically induced pancreatitis in normal and diabetic rodents

Abstract

The risk of developing pancreatitis is elevated in type 2 diabetes and obesity. Cases of pancreatitis have been reported in type 2 diabetes patients treated with GLP-1 (GLP-1R) receptor agonists. To examine whether the GLP-1R agonist exenatide potentially induces or modulates pancreatitis, the effect of exenatide was evaluated in normal or diabetic rodents. Normal and diabetic rats received a single exenatide dose (0.072, 0.24, and 0.72 nmol/kg) or vehicle. Diabetic ob/ob or HF-STZ mice were infused with exenatide (1.2 and 7.2 nmol·kg Ϫ1 ·day Ϫ1 ) or vehicle for 4 wk. Post-exenatide treatment, pancreatitis was induced with caerulein (CRN) or sodium taurocholate (ST), and changes in plasma amylase and lipase were measured. In ob/ob mice, plasma cytokines (IL-1␤, IL-2, IL-6, MCP-1, IFN␥, and TNF␣) and pancreatitis-associated genes were assessed. Pancreata were weighed and examined histologically. Exenatide treatment alone did not modify plasma amylase or lipase in any models tested. Exenatide attenuated CRN-induced release of amylase and lipase in normal rats and ob/ob mice but did not modify the response to ST infusion. Plasma cytokines and pancreatic weight were unaffected by exenatide. Exenatide upregulated Reg3b but not Il6, Ccl2, Nfkb1, or Vamp8 expression. Histological analysis revealed that the highest doses of exenatide decreased CRN-or ST-induced acute inflammation, vacuolation, and acinar single cell necrosis in mice and rats, respectively. Ductal cell proliferation rates were low and similar across all groups of ob/ob mice. In conclusion, exenatide did not modify plasma amylase and lipase concentrations in rodents without pancreatitis and improved chemically induced pancreatitis in normal and diabetic rodents. diabetes; mouse; rat; caerulein; sodium taurocholate; pancreatic duct GLUCAGON-LIKE PEPTIDE-1 (GLP-1) exerts multiple glucoregulatory actions by enhancing glucose-dependent insulin secretion, regulating gastric emptying, decreasing postprandial glucagon secretion, and decreasing food intake. Moreover, GLP-1 has been observed to improve ␤-cell mass by augmenting ␤-cell survival and proliferation in rodents (7,19,42). In recent years, the therapeutic potential of GLP-1 receptor (GLP-1R) agonists or dipeptidyl peptidase IV (DPP IV) inhibitors for treatment of type 2 diabetes gained widespread attention, and several drugs affecting the GLP-1 pathway were approved to control hyperglycemia, including the GLP-1R agonists exenatide and liraglutide (12, 18) and the DPP IV inhibitors sitagliptin and saxagliptin.Cases of pancreatitis have been observed in patients treated with GLP-1 receptor agonists and DPP IV inhibitors (1, 9, 10, 13, 38). Acute pancreatitis is a complex clinical condition that ranges in severity from mild to life-threatening. Abdominal pain, ultrasound-confirmed pancreatic pathological changes and increased plasma amylase and lipase concentrations are the most common markers of acute pancreatitis in the clinic (21). Type 2 diabetes and/or obesity are risk factors for the development of pa...

Glucagon-Like Peptide-1 Receptor Agonists Increase Pancreatic Mass by Induction of Protein Synthesis

“…We did not observe increases in pancreatic amylase gene expression, and lipase mRNA transcripts were significantly lower after Ex-4 administration. Furthermore, studies of pancreatic enzyme levels in rodents have been inconsistent, demonstrating either no change or small increases in amylase following administration of GLP-1R agonists (17,(33)(34)(35). Our current studies demonstrate that serum lipase levels were lower, whereas amylase levels and pancreatic content of amylase and lipase proteins (Supplementary Table 2) remained similar after treatment with Ex-4.…”

Impaired expression of sex hormone receptors in male reproductive organs of diabetic rat in response to oral antidiabetic drugs

“…This experimental study was approved by the King Abdulaziz University Research Ethics Committee (KAU--REC) and adhered to the international guidelines for use of experimental animals. Sprague-Dawley male rats aged three months and weighing 250-300 g were recruited from King Fahd Research Center, KAU, SA, were acclimated for 6 days before use and were housed in plastic cages in an air-conditioned room at 24°C in a 12 h light-dark cycle with food and water available ad libitum [22].…”

“…The second part (0.5 mL) was placed in an EDTA tube for measurement of glycated hemoglobin (HbA 1c ). All kits were purchased from Biocompare (South San Francisco, CA, USA) and measurements were done in accordance with the manufacturer's protocol [22,26].…”

Hope and fear for new classes of type 2 diabetes drugs: is there preclinical evidence that incretin-based therapies alter pancreatic morphology?

“…The effects of GLP1R agonists have also been assessed in the ob/ob mouse. In this obese and mildly hyperglycaemic (but non-diabetic) model, exenatide is able to lower blood glucose levels (K0.8% HbA1c) and also reduce body weight by about 10% (Tatarkiewicz et al 2010). Interestingly, even though the genetic background of ob/ob mice is very close to that of the C57BL/6 mice discussed above, exenatide administration in these mice for 4 weeks did not result in any changes in pancreas weight (Tatarkiewicz et al 2010).…”