Investigation of effect of hyperinsulinaemia on adipose tissue microvasculature.

摘要: Background: Obesity in Qatar is amongst the highest globally and constitutes a serious health risk. Obese individuals are at greater risk of vascular disease compared to lean, especially insulin resistant state. The impact obesity on endothelial vasomotor function also adipose tissue depot-dependent, with visceral environment being more pathogenic. It is, however, unclear how severe dysfunction relatively young obese population. Further, it becoming apparent that obesity-associated heterogeneous. Recent research has focussed different groups subjects order elucidate mediators differential cardiometabolic In pathological (PO) subjects, sub-cutaneous adipocyte inflammation have been reported along hypertrophy. This led following hypotheses: 1. The enlarged adipocytes susceptible hypoxia due decreased capillary density depot changes tone. Hypoxia leads cell necrosis formation immunological foci. 2. The hypoxic inflamed fat secretes less adiponectin, which then may determine increased systemic resistance dyslipidaemia seen PO. Specifically differences between metabolically healthy but (MHO) pathologically relation was determined. To facilitate overall objectives, this study: 1. A cohort MHO PO were identified. 2. Vascular versus by functional studies (myography) histological assessment carried out, and, 3. Mechanisms underlie these investigated. Methods: Patients recruited from local hospital blood adipose tissue (Omental, OM; Subcutaneous, SC) samples collected. Fasting plasma glucose and assayed status. Vascular function was assessed wire myography. Cumulative concentration-response curves generated for various vasoconstrictors (e.g. noradrenaline, potassium chloride), vasodilators acetylcholine, Sodium nitroprusside (SNP), prostaglandin E2). Relaxation acetylcholine recorded absence or presence Nω-Nitro-L¬arginine methyl ester (L-NAME), indomethacin, diclofenac, BaCl2, apamin+charybdotoxin, arginine. mRNA expression hypertension associated genes stromal fractions (SVFs) both depots real time RT-PCR. Paraffin-embedded tissues used studies. Results: OM arterioles sensitive noradrenaline-mediated vasoconstriction SC (log EC50 -5.9±0.2 vs. -6.5±0.1, p<0.05). Vasorelaxation attenuated vessels (p<0.01). contrast, relaxation SNP Acetylcholine insulin-sensitive patients insulin-resistant patients. L-NAME, apamin, charybdotoxin, BaCl2 caused right-ward shifts curves, while diclofenac arginine produced reverse. In whole group, COX2 mRNA, not eNOS COX1, up regulated SVFs. However, when analyzed separately, SVFs, several unregulated (AGT, ARG2, CLIC5, EPHX2, ITPR1 PRKG1), only two significantly (CLIC5 PDE3B). Conclusions: Hyperinsulinaemia microvessels і) vasocontractile insensitivity noradrenaline іі) NO-mediated vasodilation, least partially mediated through components pathway.