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

Nachnani, Jagdish; Bulchandani, Deepti; Nookala, Anantha Ram; Herndon, Betty; Molteni, Agostino; Pandya, Prashant; Taylor, Richard; Quinn, Tim; Weide, Lamont G.; Alba, Laura

doi:10.1007/s00125-009-1515-4

Cited by 174 publications

(165 citation statements)

References 17 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: 86%

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: 86%

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

et al. 2013

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“…As a consequence thereof, the statistical power is low. Three of the four studies that have described adverse effects of DPP-4is or GLP-1RAs on the pancreas were performed in rodents (15,25,26). Thus, at the current point in time with the very few studies available in nonhuman primates, the cumulative data in these studies have a strong relevance for the assessment of adverse pancreas effects in humans, despite the relatively limited number of animals per group.…”

Section: Discussionmentioning

confidence: 99%

“…The four studies that have suggested adverse effect of DPP-4is or GLP-1RAs on the pancreas have described or discussed increased risk for pancreatitis, metaplasia, or inflammation and pancreatic adenocarcinomas and glucagonomas (15,16,25,26). In contrast, hundreds of other studies have investigated effects of these drugs on the pancreas but have not reported adverse effects; a few are referenced here for liraglutide (37)(38)(39).…”

Section: Discussionmentioning

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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“…It has been stated in a literature review that new islets do develop under certain experimental conditions, such as after partial pancreatectomy, where the formation of new islets has been clearly demonstrated (Nachnani et al, 2010). Other anatomical structures, such as kidney glomeruli, also lack the ability of hyperplasia and instead become hypertrophic with an increased demand, probably because of the highly specific structure of the neurovascular and tubular systems necessary for appropriate function.…”

Section: Discussionmentioning

confidence: 99%

“…In spite of numerous experimental studies about EX-4 effects on various tissues in non-diabetic subjects, only one study has investigated its effects on the pancreas (Nachnani et al, 2010). In the present study, the effect of EX-4 on islet volume and number in the mouse pancreas was investigated by using stereological procedures.…”

Section: Introductionmentioning

confidence: 94%

Exendin-4 effects on islet volume and number in mouse pancreas

Khorsandi

Nejaddehbashi

2013

Braz. J. Pharm. Sci.

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The aim of this study was to evaluate Exendin-4 (EX-4) effects on islet volume and number in the mouse pancreas. Thirty-two healthy adult male NMRI mice were randomly divided into control and experimental groups. EX-4 was injected intraperitoneally (i. p.) at doses of 0.25 (E1 group), 0.5 (E2 group), and 1 μg/kg (E3 group), twice a day for 7 consecutive days. One day after the final injection, the mice were sacrificed, and the pancreas from each animal dissected out, weighed, and fixed in 10% formalin for measurement of pancreas and islet volume, and determination of islet number by stereological assessments. There was a significant increase in the weight of pancreases in the E3 group. Islet and pancreas volumes in E1 and E2 groups were unchanged compared to the control group. The E3 group showed a significant increase in islet and pancreas volume (P < 0.05). There were no significant changes in the total number of islets in all three experimental groups. The results revealed that EX-4 increased pancreas and islet volume in non-diabetic mice. The increased total islet mass is probably caused by islet hypertrophy without the formation of additional islets.Uniterms: Exendin-4/effects/experimental study. Pancreas/effects fo Exendin-4. Islet/hypertrophy. Stereology.O objetivo deste estudo foi avaliar os efeitos do Exendin-4 (EX-4) sobre o volume e número de ilhotas no pâncreas. Trinta e dois camundongos NMRI machos saudáveis e adultos foram divididos ao acaso em grupos controle e grupos experimentais. EX-4 foi injetado intraperitonealmente (i. p.) nas doses de 0,25 (grupo E1), 0,5 (grupo E2) e 1 (grupo E3), duas vezes por dia durante 7 dias consecutivos. Um dia após a injeção final, os camundongos foram sacrificados e o pâncreas de cada animal foi dissecado, pesado e fixado em solução de formaldeído 10% para avaliação do volume do pâncreas e ilhotas e do número de ilhotas por métodos estereológicos. Observou-se aumento significativo no peso de pâncreas no grupo E3. O volume do pâncreas assim como das ilhotas não apresentou alterações nos grupos E1 e E2, quando comparados ao grupo controle No grupo E3 houve aumento significativo no volume do pâncreas e das ilhotas (P<0,05). Não se observaram alterações significativas no número de ilhotas nos três grupos experimentais. Os resultados revelaram que o EX-4 provoca aumento no volume do pâncreas, bem como no volume das ilhotas em camundongos não-diabéticos. O aumento no volume total de ilhotas deve-se, provavelmente, a hipertrofia das ilhotas sem a formação de ilhotas adicionais.Unitermos: Exendina-4/efeitos/estudo experimental. Pâncreas/efeito do Exendina-4. Ilhotas/hipertrofia. Estereologia.

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

Cited by 174 publications

References 17 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

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

Exendin-4 effects on islet volume and number in mouse pancreas

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