Glucagon-Like Peptide-1 Receptor Activation Modulates Pancreatitis-Associated Gene Expression But Does Not Modify the Susceptibility to Experimental Pancreatitis in Mice

Koehler, Jacqueline A.; Baggio, Laurie L.; Lamont, Benjamin J.; Ali, Safina; Drucker, Daniel J.

doi:10.2337/db09-0626

Cited by 151 publications

(141 citation statements)

References 33 publications

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“…There was a nonsignificant difference in duct cell proliferation after 6 weeks of treatment. These observations and the findings of other studies [27][28][29][30][31][32] raise the issue of whether GLP-1-based therapies are a potential risk for pancreatitis; some studies did not observe this effect [33,34], however, which may reflect the animal model used, the age of the animals and/or the labelling and counting methods used for proliferating cells. In our study, there was no indication of a systemic inflammatory state.…”

Section: Discussionmentioning

confidence: 49%

Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice

et al. 2013

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Aims/hypothesis Incretin-based therapies improve glycaemic control in patients with type 2 diabetes. In animal models of diabetes, glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase beta cell mass. GLP-1RAs are also evaluated in nondiabetic individuals with obesity and cardiovascular disease. However, their effect on beta cell mass in normoglycaemic conditions is not clear. Here, we investigate the effects of the GLP-1RA liraglutide on beta cell mass and function in normoglycaemic mice. Methods C57BL/6J mice were treated with the GLP-1RA liraglutide or PBS and fed a control or high-fat diet (HFD) for 1 or 6 weeks. Glucose and insulin tolerance tests were performed after 6 weeks. BrdU was given to label proliferating cells 1 week before the animals were killed. The pancreas was taken for either histology or islet isolation followed by a glucose-induced insulin-secretion test. Results Treatment with liraglutide for 6 weeks led to increased insulin sensitivity and attenuation of HFD-induced insulin resistance. A reduction in beta cell mass was observed in liraglutide-treated control and HFD-fed mice at 6 weeks, and was associated with a lower beta cell proliferation rate after 1 week of treatment. A similar reduction in alpha cell mass occurred, resulting in an unchanged alpha to beta cell ratio. In contrast, acinar cell proliferation was increased. Finally, islets isolated from liraglutide-treated control mice had enhanced glucose-induced insulin secretion. Conclusions/interpretation Our data show that GLP-1RA treatment in normoglycaemic mice leads to increases in insulin sensitivity and beta cell function that are associated with reduced beta cell mass to maintain normoglycaemia.

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Section: Discussionmentioning

confidence: 49%

Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice

et al. 2013

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“…Exendin-4 is known to cause human weight loss [12], and indeed, the animals in the present study lost significant weight with exendin-4. In another study by Koehler et al, the authors found that GLP-1 receptor activation increased the pancreatic mass and selectively modulated expression of genes associated with pancreatitis [16]. Also, in a study looking at sitagliptin, an inhibitor of dipeptidyl peptidase-4, Fig.…”

Section: Effect Of Exendin-4 On Pancreatic Cellsmentioning

confidence: 99%

Biochemical and histological effects of exendin-4 (exenatide) on the rat pancreas

et al. 2009

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Aims/hypothesis Exendin-4 is a 39 amino acid agonist of the glucagon-like peptide receptor and has been approved for treatment of type 2 diabetes. Many reports describe an increased incidence of acute pancreatitis in humans treated with exendin-4 (exenatide). Previous studies have evaluated the effect of exendin-4 on beta cells and beta cell function. We evaluated the histological and biochemical effects of exendin-4 on the pancreas in rats. Methods We studied 20 Sprague-Dawley male rats, ten of which were treated with exendin-4 and ten of which were used as controls. The study period was 75 days. Serum and pancreatic tissue were removed for biochemical and histological study. Blood glucose, amylase, lipase, insulin and adipocytokines were compared between the two groups. Results Animals treated with exendin-4 had more pancreatic acinar inflammation, more pyknotic nuclei and weighed significantly less than control rats. They also had higher serum lipase than control animals. Exendin-4 treatment was associated with lower insulin and leptin levels as well as lower HOMA values than in the untreated control group. Conclusions/interpretation Although the use of exendin-4 in rats is associated with decreased weight gain, lower insulin resistance and lower leptin levels than in control animals, extended use of exendin-4 in rats leads to pancreatic acinar inflammation and pyknosis. This raises important concerns about the likelihood of inducing acute pancreatitis in humans receiving incretin mimetic therapy.

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“…Some studies in rats and mice have shown an increased pancreas weight induced by DPP-4is or GLP-1RAs (14,15), and a recent ex vivo study with human pancreata suggested an increase in glucagonomas as well as increased pancreas weight (16). Here, pancreas weight in Cynomolgus monkeys is reported for liraglutide in toxicology studies with 4, 13, 52, and 87 weeks' dosing, and for semaglutide in toxicology studies with 13 and 52 weeks' dosing, as well as a full histopathological evaluation of these same studies, except the 87 weeks' study, which has been reported previously (13).…”

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confidence: 99%

The Human GLP-1 Analogs Liraglutide and Semaglutide: Absence of Histopathological Effects on the Pancreas in Nonhuman Primates

et al. 2014

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Increased pancreas mass and glucagon-positive adenomas have been suggested to be a risk associated with sitagliptin or exenatide therapy in humans. Novo Nordisk has conducted extensive toxicology studies, including data on pancreas weight and histology, in Cynomolgus monkeys dosed with two different human glucagon-like peptide-1 (GLP-1) receptor agonists. In a 52-week study with liraglutide, a dose-related increase in absolute pancreas weight was observed in female monkeys only. Such dose-related increase was not found in studies of 4, 13, or 87 weeks’ duration. No treatment-related histopathological abnormalities were observed in any of the studies. Quantitative histology of the pancreas from the 52-week study showed an increase in the exocrine cell mass in liraglutide-dosed animals, with normal composition of endocrine and exocrine cellular compartments. Proliferation rate of the exocrine tissue was low and comparable between groups. Endocrine cell mass and proliferation rates were unaltered by liraglutide treatment. Semaglutide showed no increase in pancreas weight and no treatment-related histopathological findings in the pancreas after 13 or 52 weeks’ dosing. Overall, results in 138 nonhuman primates showed no histopathological changes in the pancreas associated with liraglutide or semaglutide, two structurally different GLP-1 receptor agonists.

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Glucagon-Like Peptide-1 Receptor Activation Modulates Pancreatitis-Associated Gene Expression But Does Not Modify the Susceptibility to Experimental Pancreatitis in Mice

Cited by 151 publications

References 33 publications

Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice

Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice

Biochemical and histological effects of exendin-4 (exenatide) on the rat pancreas

The Human GLP-1 Analogs Liraglutide and Semaglutide: Absence of Histopathological Effects on the Pancreas in Nonhuman Primates

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