Effects of renin-angiotensin system blockade on the islet morphology and function in rats with long-term high-fat diet.

The renin-angiotensin system (RAS) has an important role in the endocrine pancreas. Multiple researches have shown that even in the insulin resistance phase, there are many abnormalities in islets morphology and function. This study aimed at investigating the effects of RAS blockade on the islets function in rats with long-term high-fat diet and its mechanisms. Wistar rats with 16-week high-fat diet were randomly divided into perindopril intervention group (FP, n = 15) and telmisartan intervention group (FT, n = 15). After 8-week intervention, insulin sensitivity and islets function were detected by hyperinsulinemic euglycemic clamp and intravenous glucose tolerance test (IVGTT), respectively. The pancreases were stained by immunohistochemistry technique to qualitatively and/or quantitatively analyze the relative content of insulin (IRC), NF-KB, uncoupling protein 2 (UCP2) and caspase-3 in islets. The apoptosis of islet cells was detected by TUNEL. The expression of angiotensin II receptor 1 (AT1R), interleukin-1ß (IL-1ß), hypoxia-inducing factor (HIF)-1α and CHOP mRNA in the islets was detected by reverse transcription polymerase chain reaction (RT-PCR). Compared with normal control group (NC, n = 15), the glucose infusion rate (GIR), area under the insulin curve (AUCI) of 0-10 min and IRC were decreased in high-fat control group (FC, n = 15). The relative content of NF-KB, UCP-2 and caspase-3 was increased significantly with the increased number of apoptotic cells in unit islets area. The relative expression of AT1R, IL-1ß, HIF-1α and CHOP was also increased evidently (all P < 0.01). After intervention, the GIR, AUCI of 0-10 min and IRC were all increased obviously with the decreased relative concentration of NF-KB, UCP-2, caspase-3 and the number of apoptotic cell in unit islets area. The relative expression of AT1R, IL-1ß, HIF-1α and CHOP mRNA was reduced significantly (all P < 0.01 or P < 0.05). There were no significant differences between groups FP and FT. So we concluded that blockade of RAS may protect islet function of rats with long-term high-fat diet via downregulation of islets inflammation, oxidative stress, endoplasmic reticulum stress and apoptosis, which have tight relationship with each other.

Blockade of renin angiotensin system increased resistance to STZ-induced diabetes in rats with long-term high-fat diet.

This study aimed to investigate whether rennin-angiotensin system (RAS) blockade through telmisartan would increase the resistance to streptozotocin- (STZ-) induced diabetes in insulin resistance rats. There were sixty Wistar rats that were divided into four groups: normal control (NC), high-fat diet (HF), high-fat diet plus STZ injection (HF+S), and high-fat diet plus STZ injection and telmisartan intervention (HF+S+T). Five rats were chosen randomly and respectively from groups NC and HF to undergo a hyperinsulinemic euglycemic clamp. Another five rats were selected randomly from the four groups, respectively, for intravenous injection insulin releasing test (IVIRT), and the other five rats for pancreas specimens used in islet cell immunohistochemistry staining (stained for insulin, NF-κB, and caspase-3), islet cell apoptosis staining, and reverse transcription PCR (AT1R and IL-1 beta). There was a significant difference of overt diabetes incidence between groups HF+S+T and HF+S (P < 0.05). Furthermore, inflammatory markers and islet cell apoptosis were found to be significantly reduced in group HF+S+T compared with group HF+S (all P < 0.01 or P < 0.05). Overall, telmisartan-treated rats were found to have reduced RAS activity, increased resistance to STZ-induced diabetes, reduced inflammatory markers, and improvement of islet cell function and morphology.

Effect of renin angiotensin system blockade on the islet microvessel density of diabetic rats and its relationship with islet function.

To investigate the effects of rennin angiotensin system blockade on the microvessel density in islets of diabetic rats and its relationship with islet function, diabetes model was created by feeding of high-caloric laboratory chow plus intraperitoneal injection of a small dose of streptozotocin (30 mg/kg). After 8 weeks intervention with perindopril (AE, n=10) or valsartan (AR, n=10), the islet function of the animals was evaluated by intravenous insulin release test (IVIRT). The pancreases were immunohistochemically stained to analyze the content of insulin and vascular endothelial growth factor (VEGF) in the islets. The microvessel density (MVD) of islets was detected by counting CD34 positive cells. The hypoxia inducible factor (HIF)-1alpha mRNA expression in the islets was detected by RT-PCR. Compared with normal control group (NC, n=10), the area under the curve for insulin from 0 to 30 min (AUCI(0-30)) of diabetes group (DM, n=8) was decreased by 66.3%; the insulin relative concentration (IRC) of betacell was decreased significantly; the relative content of VEGF was increased obviously [(-4.21+/-0.13) vs (-4.06+/-0.29)]; MVD in islets was decreased by 71.4%; the relative expression of HIF-1alpha mRNA was increased by 1.19 times (all P<0.01). Compared with DM group, the AUCI(0-30) of AE and AR group was increased by 44.6% and 34.9% respectively; IRC was also increased significantly; the relative content of VEGF was decreased by 21.2% and 21.7% respectively; MVD was increased by 62.5% and 75.0% respectively; the relative expression of HIF-1alpha was decreased by 27.2% and 29.0% respectively (all P<0.01 or P<0.05). There were no significant differences in the said indexes between group AE and AR. It is concluded that the blockade of RAS may ameliorate islets function of diabetic rats by increasing the MVD in islets.