Troglitazone stimulates pancreatic growth in congenitally CCK-A receptor-deficient OLETF rats

Abstract

We examined the effect of troglitazone treatment on pancreatic growth in the CCK-A receptor-deficient Otsuka Long-Evans Tokushima fatty (OLETF) rat, an animal model for type 2 diabetes mellitus. A troglitazone-rich diet (0.2%) was given from 12 to 28 wk of age or from 12 or 28 wk of age to 72 wk of age. Fasting serum glucose concentrations in control OLETF rats increased progressively with age, which was almost completely prevented by troglitazone treatment. Insulin levels in serum and pancreatic content in the control rat markedly increased at 28 wk of age but significantly decreased at 72 wk of age compared with those at 12 wk of age, whereas those in troglitazone-treated rats were nearly the same at all ages and were similar to those in control rats at 12 wk of age. Pancreatic wet weight in control rats decreased with age irrespective of whether they were hyperinsulinemic (28 wk old) or hypoinsulinemic (72 wk old). Troglitazone treatment significantly increased pancreatic wet weight and protein, DNA, and enzyme contents compared with those in the control rats. Moreover, troglitazone treatment completely prevented or reversed histological alterations such as fibrosis, fatty replacement, and inflammatory cell infiltration. Our results indicate that troglitazone stimulates pancreatic growth in the congenitally CCK-A receptor-deficient OLETF rat not only by reducing insulin resistance and potentiating insulin action but also by suppressing inflammatory changes in the pancreas.

Synthetic protease inhibitor camostat prevents and reverses dyslipidemia, insulin secretory defects, and histological abnormalities of the pancreas in genetically obese and diabetic rats

“…However, several studies have demonstrated that oral administration of camostat prevents the development of diabetes and pancreatic fibrosis in WBN/Kob rats without affecting [16,17] or even increasing body weight [18]. Moreover, we have found in our previous studies that impairment of insulin secretion appears before the onset of abnormal lipid metabolism in OLETF rats [3,35]. Although these results suggest that the effects of camostat in OLETF rats are unlikely to be solely caused by weight loss or failure of weight gain, it is difficult to rule out the scenario of camostat-induced reduction of visceral adipose deposits as a cause of improved b-cell function.…”

“…During pancreatic injury, PSCs are activated by proinflammatory cytokines such as tumor necrosis factor a (TNF-a), IL-1, and IL-6 [9] and transform into a myofibroblastic phenotype, exhibiting positive staining for a-smooth muscle actin (a-SMA), a marker of activated PSCs [2,[8][9][10]. These results suggest that induction of IL-1b in the islets is involved in islet destruction and that activation of PSCs in response to proinflammatory cytokines contributes to the development of pancreatic fibrosis and atrophy in OLETF rats [1][2][3].…”

“…During the hyperplastic stage, pancreatic islets of OLETF rats show islet enlargement with inflammatory cell infiltration and connective tissue proliferation [1][2][3]. During the chronic course of the hyperplastic stage, OLETF rats eventually become hypoinsulinemic and develop extreme atrophy of the pancreas and a significant reduction of the number and size of islets after 50 weeks of age [1][2][3].…”

Mechanisms of pancreatic fibrosis and applications to the treatment of chronic pancreatitis

“…We and other groups have reported fi nding that the TZD troglitazone contributes to the prevention of the progression of chronic pancreatitis in a rodent model of chronic pancreatitis by inhibiting ECM production. [57][58][59][60][61]63 TZD has also been shown to stimulate pancreatic growth in the congenitally cholecystokinin-A receptor defi cient OLETF rat, not only by reducing insulin resistance and potentiating insulin action but also by suppressing infl ammatory changes in the pancreas. 60 The levels of infl ammation marker within the pancreas [myeloperoxidase (MPO) activity, TGF-β1] and in the circulation (IL-6, soluble TNFR1) decrease when mice with chronic pancreatitis induced by repeated injections of cerulein are treated with TZD.…”

“…[57][58][59][60][61]63 TZD has also been shown to stimulate pancreatic growth in the congenitally cholecystokinin-A receptor defi cient OLETF rat, not only by reducing insulin resistance and potentiating insulin action but also by suppressing infl ammatory changes in the pancreas. 60 The levels of infl ammation marker within the pancreas [myeloperoxidase (MPO) activity, TGF-β1] and in the circulation (IL-6, soluble TNFR1) decrease when mice with chronic pancreatitis induced by repeated injections of cerulein are treated with TZD. 61 In an in vitro study, TZD was found to inhibit ECM production and PDGF-stimulated cell proliferation by inducing G1 cell-cycle arrest, 62 but the precise mechanism of the antifi brogenic action of TZD is not fully understood.…”