Roles of interleukin 17 in angiotensin II type 1 receptor-mediated insulin resistance.
ABSTRACT Interleukin 17 (IL-17) is known to contribute to the pathogenesis of hypertension, atherosclerosis, and adipocyte differentiation; however, the roles of IL-17 in glucose metabolism remain to be elucidated. Angiotensin II type 1 receptor blockers improve insulin resistance at least in part because of the amelioration of inflammation. Therefore, we examined the possible roles of IL-17 in the pathogenesis of insulin resistance in type 2 diabetes mellitus using a mouse model, KK-Ay, and angiotensin II type 1 receptor-mediated insulin resistance. KK-Ay mice were administered control-IgG(2A) or anti-IL-17 antibody 5 times at a dose of 100 μg every second day by IP injection. KK-Ay mice were administered telmisartan for 2 weeks. C57BL/6J mice treated with angiotensin II infusion for 2 weeks were administered telmisartan or hydralazine. Insulin resistance was evaluated by oral glucose tolerance test, insulin tolerance test, and uptake of 2-[(3)H]deoxy-d-glucose in peripheral tissues. Serum IL-17 concentration in KK-Ay mice was significantly higher than that in C57BL/6J mice. Treatment of KK-Ay mice with anti-IL-17 antibody significantly increased 2-[(3)H]deoxy-d-glucose uptake in skeletal muscle but not in white adipose tissue and attenuated the increase in blood glucose level after a glucose load. Blockade of IL-17 enhanced the expression of adipocyte differentiation markers and adiponectin. Treatment with telmisartan decreased serum IL-17 concentration in KK-Ay and ameliorated angiotensin II-induced insulin resistance with a decrease in serum IL-17 level in C57BL/6J. In conclusion, IL-17 could play an important role in the pathogenesis of angiotensin II type 1 receptor-induced insulin resistance.
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ABSTRACT: This study aims to investigate the effects of telmisartan, pioglitazone and metformin administration on the prevention of new-onset type 2 diabetes mellitus in pre-diabetes Otsuka Long-Evans Tokushima Fatty (OLETF) rats fed with a high-fat diet (HFD). OLETF rats 22 weeks of age were treated with pioglitazone (O-P), metformin (O-M), telmisartan (O-T) and low telmisartan starting from their pre-diabetes period. The weight, glucose tolerance and insulin sensitivity were measured. The lipid profiles were obtained. The abdominal subcutaneous (SC) and omental (OM) fat pads were dissected to measure the expression of mRNA and protein levels (adiponectin, proinflammatory cytokines, etc.). Telmisartan significantly reversed glucose tolerance and improved insulin resistance. The incidence rates of impaired glucose tolerance and type 2 diabetes in the O-P (χ(2) = 11.025, p=0.001) and O-T (χ(2)=5.495, p=0.019) groups were significantly reduced. The mRNA expression of proinflammatory cytokines was downregulated by telmisartan. The expression of adiponectin, PPARγ1 and γ2 was markedly improved by telmisartan and pioglitazone compared with the OLETF control (O-C) group. The correlation analysis showed that the systolic and diastolic blood pressures were not correlated with the homeostasis model assessment-insulin resistance (p>0.05). Telmisartan acts beneficially against diabetes-induced inflammation and improves insulin resistance in pre-diabetes OLETF rats fed with HFD. In view of this improved responsiveness to insulin sensitivity, telmisartan may prove to be a promising candidate for the intervention treatment of the pre-diabetes state.Canadian Journal of Diabetes 06/2013; 37(3):156-68. · 0.46 Impact Factor
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ABSTRACT: The combination of obesity and hypertension is associated with high morbidity and mortality because it leads to cardiovascular and kidney disease. Potential mechanisms linking obesity to hypertension include dietary factors, metabolic, endothelial and vascular dysfunction, neuroendocrine imbalances, sodium retention, glomerular hyperfiltration, proteinuria, and maladaptive immune and inflammatory responses. Visceral adipose tissue also becomes resistant to insulin and leptin and is the site of altered secretion of molecules and hormones such as adiponectin, leptin, resistin, TNF and IL-6, which exacerbate obesity-associated cardiovascular disease. Accumulating evidence also suggests that the gut microbiome is important for modulating these mechanisms. Uric acid and altered incretin or dipeptidyl peptidase 4 activity further contribute to the development of hypertension in obesity. The pathophysiology of obesity-related hypertension is especially relevant to premenopausal women with obesity and type 2 diabetes mellitus who are at high risk of developing arterial stiffness and endothelial dysfunction. In this Review we discuss the relationship between obesity and hypertension with special emphasis on potential mechanisms and therapeutic targeting that might be used in a clinical setting.Nature Reviews Endocrinology 04/2014; · 11.03 Impact Factor
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ABSTRACT: Insulin resistance is a hallmark of obesity, the cardiorenal metabolic syndrome and type 2 diabetes mellitus (T2DM). The progression of insulin resistance increases the risk for cardiovascular disease (CVD). The significance of insulin resistance is underscored by the alarming rise in the prevalence of obesity and its associated comorbidities in the Unites States and worldwide over the last 40-50years. The incidence of obesity is also on the rise in adolescents. Furthermore, premenopausal women have lower CVD risk compared to men, but this protection is lost in the setting of obesity and insulin resistance. Although systemic and cardiovascular insulin resistance is associated with impaired insulin metabolic signaling and cardiovascular dysfunction, the mechanisms underlying insulin resistance and cardiovascular dysfunction remain poorly understood. Recent studies show that insulin resistance in obesity and diabetes is linked to a metabolic inflammatory response, a state of systemic and tissue specific chronic low grade inflammation. Evidence is also emerging that there is polarization of macrophages and lymphocytes towards a pro-inflammatory phenotype that contributes to progression of insulin resistance in obesity, cardiorenal metabolic syndrome and diabetes. In this review, we provide new insights into factors, such as, the renin-angiotensin-aldosterone system, sympathetic activation and incretin modulators (e.g., DPP-4) and immune responses that mediate this inflammatory state in obesity and other conditions characterized by insulin resistance.Metabolism: clinical and experimental 08/2013; · 3.10 Impact Factor