Rosiglitazone Aggravates Nonalcoholic Fatty Pancreatic Disease in C57BL/6 Mice Fed High-Fat and High-Sucrose Diet

After the first description of fatty pancreas in 1933, the effects of pancreatic steatosis have been poorly investigated, compared with that of the liver. However, the interest of research is increasing. Fat accumulation, associated with obesity and the metabolic syndrome (MetS), has been defined as “fatty infiltration” or “nonalcoholic fatty pancreas disease” (NAFPD). The term “fatty replacement” describes a distinct phenomenon characterized by death of acinar cells and replacement by adipose tissue. Risk factors for developing NAFPD include obesity, increasing age, male sex, hypertension, dyslipidemia, alcohol and hyperferritinemia. Increasing evidence support the role of pancreatic fat in the development of type 2 diabetes mellitus, MetS, atherosclerosis, severe acute pancreatitis and even pancreatic cancer. Evidence exists that fatty pancreas could be used as the initial indicator of “ectopic fat deposition”, which is a key element of nonalcoholic fatty liver disease and/or MetS. Moreover, in patients with fatty pancreas, pancreaticoduodenectomy is associated with an increased risk of intraoperative blood loss and post-operative pancreatic fistula.

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“…drugs reported are corticosteroids, gemcitabine, rosiglitazone and, more recently, octreotide[17,49,126-130]. …”

Section: Pathogenesis and Risk Factorsmentioning

confidence: 99%

Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease

Catanzaro¹,

Cuffari²,

Italia³

et al. 2016

WJG

162

132

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“…V v of pancreatic steatosis was estimated by point counting for pancreatic fat (interlobular, intralobular and perilobular) [14] estimated as:…”

Section: Pancreas Structurementioning

confidence: 99%

Comparative effects of telmisartan, sitagliptin and metformin alone or in combination on obesity, insulin resistance, and liver and pancreas remodelling in C57BL/6 mice fed on a very high-fat diet

et al. 2010

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The aim of the present study was to evaluate the effects of monotherapies and combinations of drugs on insulin sensitivity, adipose tissue morphology, and pancreatic and hepatic remodelling in C57BL/6 mice fed on a very HF (high-fat) diet. Male C57BL/6 mice were fed on an HF (60% lipids) diet or SC (standard chow; 10% lipids) diet for 10 weeks, after which time the following drug treatments began: HF-T (HF diet treated with telmisartan; 5.2 mg x kg-1 of body weight x day-1), HF-S (HF diet treated with sitagliptin; 1.08 g x kg-1 of body weight.day-1), HF-M (HF diet treated with metformin; 310.0 mg x kg-1 of body weight x day-1), HF-TM (HF diet treated with telmisartan+metformin), HF-TS (HF diet treated with telmisartan+sitagliptin) and HF-SM (HF diet treated with sitagliptin+metformin). Treated groups also had free access to the HF diet, and treatments lasted for 6 weeks. Morphometry, stereological tools, immunostaining, ELISA, Western blot analysis and electron microscopy were used. The HF diet yielded an overweight phenotype, an increase in oral glucose intolerance, hyperinsulinaemia, hypertrophied islets and adipocytes, stage 2 steatosis (>33%), and reduced liver PPAR-alpha (peroxisome-proliferator-activated receptor-alpha) and GLUT-2 (glucose transporter-2) levels, concomitant with enhanced SREBP-1 (sterol-regulatory-element-binding protein-1) expression (P<0.0001). Conversely, all drug treatments resulted in significant weight loss, a reversal of insulin resistance, islet and adipocyte hypertrophy, and alleviated hepatic steatosis. Only the HF-T and HF-TS groups had body weights similar to the SC group at the end of the experiment, and the latter treatment reversed hepatic steatosis. Increased PPAR-alpha immunostaining in parallel with higher GLUT-2 and reduced SREBP-1 expression may explain the favourable hepatic outcomes. Restoration of adipocyte size was consistent with higher adiponectin levels and lower TNF-alpha (tumour necrosis factor-alpha) levels (P<0.0001) in the drug-treated groups. In conclusion, all of the drug treatments were effective in controlling the metabolic syndrome. The best results were achieved using telmisartan and sitagliptin as monotherapies or as a dual treatment, combining partial PPAR-gamma agonism and PPAR-alpha activation in the liver with extended incretin action.

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“…16 Obese humans treated with a thiazolidinedione for 21 days had decreases in neutrophil and macrophage markers in skeletal adipose tissue. 27 Rosiglitazone given chronically increases fat infiltration of the pancreas in obese mice, 28 an effect that is expected to exacerbate AP severity. 4 We did not quantitate the fat infiltration of pancreata in this study, but it seems unlikely that three doses of rosiglitazone would increase fat infiltration.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Administration of Orlistat, Rosiglitazone, or the Chemokine Receptor Antagonist RS102895 Fails to Improve the Severity of Acute Pancreatitis in Obese Mice

Malecki¹,

Castellanos²,

Cabay³

et al. 2014

Pancreas

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Objectives Currently there is no therapy for severe acute pancreatitis except for supportive care. The lipase inhibitor orlistat, the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone, and chemokine receptor-2 antagonists attenuate the severity of acute pancreatitis in rodents if administered prior to or at the time of induction of pancreatitis. However, it is unknown whether these treatments are effective if administered therapeutically after induction of pancreatitis. Methods Male C57BL6 mice with diet-induced obesity received two injections of mrIL-12 (150 ng/mouse) and mrIL-18 (750 ng/mouse) intraperitoneally at 24 h intervals. Mice were injected 2, 24, and 48 hours after the second injection of IL-12+IL-18 with orlistat (2 mg/mouse), rosiglitazone (0.4 mg/mouse), RS102895 (0.3 mg/mouse), or vehicle (20μL DMSO and 80 μL canola oil) and euthanized after 72 hours. Results Orlistat decreased intraabdominal fat necrosis compared to vehicle (p<0.05). However, none of the drug treatments produced significant decreases in pancreatic edema, acinar necrosis, or intrapancreatic fat necrosis. Conclusions Drugs previously shown to improve the severity of acute pancreatitis when given prior to or at the time of induction of pancreatitis, failed to do so when administered therapeutically in the IL-12+IL-18 model.

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Rosiglitazone Aggravates Nonalcoholic Fatty Pancreatic Disease in C57BL/6 Mice Fed High-Fat and High-Sucrose Diet

Abstract: Rosiglitazone is shown for the first time to exacerbate pancreatic fat infiltration; therefore, precaution has to be taken when rosiglitazone is prescribed to obese patients.

Cited by 53 publications

References 44 publications

Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease

Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease

Comparative effects of telmisartan, sitagliptin and metformin alone or in combination on obesity, insulin resistance, and liver and pancreas remodelling in C57BL/6 mice fed on a very high-fat diet

Therapeutic Administration of Orlistat, Rosiglitazone, or the Chemokine Receptor Antagonist RS102895 Fails to Improve the Severity of Acute Pancreatitis in Obese Mice

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