Search

Obesity is closely linked with type 2 diabetes and the effective therapies on obesity-associated diabetes are under development. The aim of this study was undertaken to investigate whether the inhibition of the augmented CCR5-mediated signaling could be a common target for treatment of obesity-associated insulin resistance and impairment of pancreatic insulin secretion in high-fat diet (HFD) fed rats and CCR5 knockout mice and also in isolated islets and RIN-m5F cells. Conducted with SD rats, HFD-induced body weight gain was significantly decreased in those combined with Maraviroc treatment, but food intake remained similar compared to control. Maraviroc also significantly improved the impaired oral glucose tolerance test (OGTT). As compared with wild-type mice, CCR5 deletion significantly attenuated the HFD-induced increases in glucose area under curve of OGTT and the value of HOMA-IR as well as plasma lipid profile. It also reversed the HFD-suppressed gene expressions of GLUT4 and IRS-1 in adipose tissue. On the other hand, the HFD-associated islet macrophage and T-cell infiltration were significantly decreased in CCR5 KO mice. H 2 O 2 significantly suppressed glucose-stimulated insulin secretion (GSIS) is isolated islets, which were significantly reversed in those cotreated with CCR5 mAb. H 2 O 2 failed to change GSIS in those of CCR5 KO mice. The palmitate-induced reactive oxygen species production was significantly decreased in those cotreated with CCR5 antagonist in RIN-m5F cells. Collectively, it is suggested that targeting inhibition of the CCR5 mediated inflammatory pathway could not only improve obesity-associated insulin resistance but also directly alleviate pancreatic β-cell dysfunction., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Elevations in C-reactive protein (CRP) levels are positively correlated with the progress of type 2 diabetes mellitus. However, the effect of CRP on pancreatic insulin secretion is unknown. Here, we showed that purified human CRP impaired insulin secretion in isolated mouse islets and NIT-1 insulin-secreting cells in dose- and time-dependent manners. CRP increased NADPH oxidase-mediated ROS (reactive oxygen species) production, which simultaneously promoted the production of nitrotyrosine (an indicator of RNS, reactive nitrogen species) and TNFα, to diminish cell viability, insulin secretion in islets and insulin-secreting cells. These CRP-mediated detrimental effects on cell viability and insulin secretion were significantly reversed by adding NAC (a potent antioxidant), apocynin (a selective NADPH oxidase inhibitor), L-NAME (a non-selective nitric oxide synthase (NOS) inhibitor), aminoguanidine (a selective iNOS inhibitor), PDTC (a selective NFκB inhibitor) or Enbrel (an anti-TNFα fusion protein). However, CRP-induced ROS production failed to change after adding L-NAME, aminoguanidine or PDTC. In isolated islets and NIT-1 cells, the elevated nitrotyrosine contents by CRP pretreatment were significantly suppressed by adding L-NAME but not PDTC. Conversely, CRP-induced increases in TNF-α production were significantly reversed by administration of PDTC but not L-NAME. In addition, wild-type mice treated with purified human CRP showed significant decreases in the insulin secretion index (HOMA-β cells) and the insulin stimulation index in isolated islets that were reversed by the addition of L-NAME, aminoguanidine or NAC. It is suggested that CRP-activated NADPH-oxidase redox signaling triggers iNOS-mediated RNS and NFκB-mediated proinflammatory cytokine production to cause β cell damage in state of inflammation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Portal endotoxaemia has been speculated to be crucially involved in the pathogenesis of chronic hepatic inflammation, which is highly associated with the development of type 2 diabetes mellitus. This study tests whether portal endotoxaemia is a pathogenic link between chronic subacute hepatic inflammation and pancreatic beta-cell dysfunction., Materials and Methods: Rats were randomly assigned into two groups: rats with intraportal saline or low-dose lipopolysaccharide (LPS) infusion for 4 weeks. Pathological changes in the liver were evaluated via histological and biochemical examination. Pancreatic insulin secretion was evaluated by in vivo hyperglycaemic clamp study., Results: White blood cell count was significantly increased after intraportal LPS infusion for 4 weeks. Plasma amylase and chemoluminescence counts indicating superoxide levels were significantly increased after LPS treatments for 2 and 4 weeks. Intraportal low-dose LPS infusion significantly increased tumour necrosis factor-alpha and interleukin-6 contents in liver and pancreas. Circulating C-reactive protein, thiobarbituric acid reactive substances (TBARS) and endotoxin levels were not different among groups. The first- and second-phase insulin secretions in hyperglycaemic clamp were significantly decreased in LPS-treated rats. The histopathological scores, de novo production of reactive oxygen substrate and TBARS contents in the liver and pancreas were significantly increased in LPS-infused rats. Leucocyte infiltration was clearly visible in pancreatic islets of LPS-treated rats., Conclusions: The present study demonstrated that mild portal endotoxaemia caused subacute hepatic inflammation and impaired pancreatic insulin secretion, implicating that portal endotoxaemia is a potential risk factor to link chronic subacute hepatic inflammation and pancreatic beta-cell dysfunction.

Background: This study tested whether subacute inflammatory change of fatty liver induced by portal endotoxaemia is detrimental to pancreatic insulin secretion in fructose-fed rats (FFRs) with fatty liver., Methods: Rats were randomly assigned into two groups with a regular or fructose-enriched diet for 8 weeks. Rats, after fructose feeding for 4 weeks, were further divided into three subgroups: on fructose diet alone, on fructose diet combined with intraportal saline or lipopolysaccharide (LPS) infusion (n=8 per group) for the next 4 weeks. In another set of experiments, the liver and pancreatic tissues were obtained for histological examination in these four groups. Pancreatic insulin secretion was evaluated by in vivo hyperglycaemic clamp study., Results: Fasting plasma insulin concentrations and homoeostasis model assessment-insulin resistance, an insulin resistance score, were significantly increased in FFRs but failed to change in rats with LPS treatment. The 4-week intraportal LPS infusion significantly increased circulating aspartate transaminase, alanine transaminase and C-reactive protein levels but did not alter endotoxin levels in FFRs. The increased white blood cell count was also noted in rats after intraportal LPS infusion for 2 and 4 weeks. The attenuated first-phase and second-phase insulin responses in FFRs shown in hyperglycaemic clamp were further deteriorated in those with intraportal LPS infusion. Increased histopathological scores of liver and pancreas shown in FFRs were further increased in those combined with portal endotoxaemia., Conclusion: This study demonstrates that the chronic subacute inflammatory change of fatty liver induced by mild portal endotoxaemia could deteriorate insulin secretion in a rodent model of metabolic syndrome and fatty liver.

Objective: Estradiol (E(2)) is known to modulate insulin sensitivity and, consequently, glucose homeostasis. Resveratrol (RSV), an agonist of estrogen receptor (ER), has exerted antihyperglycemic effects in streptozotocin-induced type 1 diabetic rats in our previous study and was also shown to improve insulin resistance in other reports. However, it remains unknown whether activation of ER is involved in the metabolic effects of RSV via insulin-dependent and -independent mechanisms., Research Design and Methods: Male Sprague-Dawley rats were given a high cholesterol-fructose (HCF) diet for 15 weeks and were treated with RSV for either 15 days or 15 weeks., Results: Here, we show that RSV shifts the metabolic characteristics of rats on an HCF diet toward those of rats on a standard diet. RSV treatment increased insulin-stimulated whole-body glucose uptake and steady-state glucose uptake of soleus muscle and liver in HCF-fed rats as well as enhanced membrane trafficking activity of GLUT4 and increased phosphorylation of insulin receptor in insulin-resistant soleus muscles. Interestingly, the phosphorylated ER level in insulin-resistant soleus muscle was significantly elevated in rats with RSV treatment in both basal and euglycemic-hyperinsulinemic conditions. RSV exerted an insulin-like stimulatory effect on isolated soleus muscle, epididymal fat and hepatic tissue, and C2C12 myotubes. The RSV-stimulated glucose uptake in C2C12 myotubes was dependent on extracellular signal-related kinase/p38 (early phase, 1 h) and p38/phosphoinositide 3-kinase (late phase, 14 h) activation. Inhibition of ER abrogated RSV-induced glucose uptake in both early and late phases., Conclusions: Collectively, these results indicate that ER is a key regulator in RSV-stimulating insulin-dependent and -independent glucose uptake, which might account for the protective effects of RSV on diet-induced insulin resistance syndrome.

Background: The present study was undertaken to compare the effects of chronic hyperinsulinemia with or without insulin resistance on the autonomic control of heart rate (HR) in rats., Methods: Male Sprague-Dawley rats were implanted subcutaneously with insulin (3 mU/kg x min) or vehicle-filled osmotic minipumps for 8 weeks. Insulin-infused rats were further divided into insulin resistant (IR) and insulin sensitive (IS) groups according to the results of the homeostasis model assessment method and euglycemic hyperinsulinemic clamp study. Autonomic function in HR control was indicated by arterial baroreflex sensitivity (BRS) after a bolus injection of phenylephrine or sodium nitroprusside., Results: Compared with those in control group, plasma insulin levels were elevated about threefold and 1.5-fold in the IR and IS groups at the end of week 8, respectively. Blood glucose level remained basal in the IR group, but was significantly lower in the IS group. The elevated mean arterial pressure (MAP) observed in IR was not exhibited in IS. The HR and BRS in reflex tachycardia were significantly increased in the IR and IS groups, but the BRS in reflex bradycardia was not different among all rats. Propranolol eliminated the tachycardia and enhanced BRS responses in both groups. Methylatropine further accelerated tachycardia and diminished the enhanced BRS in the IR group. However, in IS, the enhanced BRS remained after methylatropine was given. The intrinsic HR was similar among all groups. The baseline MAP, HR, and BRS in reflex tachycardia were significantly correlated to plasma insulin levels but not to the Si value, an index of insulin sensitivity., Conclusions: The present results demonstrate that hyperinsulinemia but not insulin resistance is a dominant contributing factor to the development of arterial baroreflex abnormalities in this chronic hyperinsulinemic model, which may simultaneously enhance sympathetic nerve activity and possibly vagal withdrawal if insulin resistance coexisted.

Hyperinsulinemia and insulin resistance frequently coexist and have been implicated in the pathogenesis of hypertension. This study aimed to identify the specific effect of hyperinsulinemia on blood pressure and nitric oxide (NO) release in fructose-induced hyperinsulinemic, insulin-resistant rats. Male Sprague-Dawley rats were fed either standard chow or a 60% fructose-enriched diet for 8 weeks before acute study. After basal period, somatostatin (1.3 microg/kg/min) and a variable glucose infusion (to maintain euglycemia) were given intravenously to all groups of rats. In control rats (C) and fructose-fed rats (F) with insulin infusion, insulin (4 mU/kg/min) was given to create a similar hyperinsulinemic condition. In C and F without insulin infusion, a vehicle instead of insulin was infused to produce a hypoinsulinemic state. In C, somatostatin reduced plasma insulin level but did not alter mean arterial pressure (MAP) and heart rate. Insulin infusion significantly increased MAP and NOx (sum of nitrate and nitrite) levels after 90 min and thereafter the elevated MAP and NOx responses were sustained throughout the study. In the basal period, F exhibited significantly higher MAP and plasma insulin levels than C. The index of insulin sensitivity (M) was significantly lower in F than in C with insulin infusion. Somatostatin significantly reduced plasma insulin level but did not affect MAP and NOx level in F. The stimulatory effects of insulin on MAP and NO levels were significantly smaller in F than in C. In conclusion, acute insulin-induced pressor response and NO release were attenuated in rats with fructose-treated insulin resistance, suggesting that hyperinsulinemia-associated attenuation of NO production contributes, at least partly, to the development of fructose-induced hypertension in rats., (Copyright 2004 American Journal of Hypertension, Ltd.)

We tested the hypothesis that the loss of hepatic nerves decreases peripheral insulin sensitivity. Surgical hepatic denervation (DN) was performed in 22 dogs approximately 16 days before study; 7 dogs (Sham-Sal) had a sham procedure. A euglycemic hyperinsulinemic (1 mU x kg(-1) x min(-1); arterial insulin 35 +/- 1 microU/ml in all dogs) clamp was performed in conscious dogs. From 0 to 90 min of the clamp, all dogs received the same treatment; then the DN dogs were divided into three groups. From 90 to 180 min, DN-PeA (n = 7) and DN-PoA (n = 7) groups received acetylcholine 2.5 microg x kg(-1) x min(-1) via peripheral or portal vein, respectively, and DN-Sal (n = 8) received no acetylcholine. During 150-180 min, the Sham-Sal, DN-Sal, DN-PeA, and DN-PoA groups exhibited glucose infusion rates of 12.4 +/- 0.8, 9.3 +/- 0.8 (P < 0.05 vs. Sham-Sal), 9.1 +/- 0.1 (P < 0.05 vs. Sham-Sal), and 12.7 +/- 1.6 mg. kg(-1) x min(-1); nonhepatic glucose uptakes of 11.5 +/- 0.9, 8.9 +/- 0.7 (P < 0.05 vs. Sham-Sal), 8.6 +/- 0.9 (P < 0.05 vs. Sham-Sal), and 11.9 +/- 1.7 mg. kg(-1). min(-1); net hindlimb glucose uptakes of 18.4 +/- 2.1, 13.7 +/- 1.1 (P < 0.05 vs. Sham-Sal), 17.5 +/- 1.9, and 16.7 +/- 3.2 mg/min; and glucose utilization rates of 14.4 +/- 1.4, 10.4 +/- 0.8 (P < 0.05 vs. Sham-Sal), 9.8 +/- 0.9 (P < 0.05 vs. Sham-Sal), and 13.6 +/- 1.8 mg. kg(-1) x min(-1), respectively. DN caused peripheral insulin resistance, and intraportal but not peripheral acetylcholine restored insulin sensitivity.