Insulin-induced changes in skeletal muscle microvascular perfusion are dependent upon perivascular adipose tissue in women.

Rick I Meijer,John S Yudkin,Michiel P De Boer,H Ibrahim Korkmaz,Victor W M Van Hinsbergh,Erik H Serné,Etto C Eringa,Donald L Van Der Peet,Hans W M Niessen,Yvo M Smulders

doi:10.1007/s00125-015-3606-8

Rick I Meijer, John S Yudkin + Show 8 more

Open Access

https://doi.org/10.1007/s00125-015-3606-8

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Abstract

Aims/hypothesisObesity increases the risk of cardiovascular disease and type 2 diabetes, partly through reduced insulin-induced microvascular vasodilation, which causes impairment of glucose delivery and uptake. We studied whether perivascular adipose tissue (PVAT) controls insulin-induced vasodilation in human muscle, and whether altered properties of PVAT relate to reduced insulin-induced vasodilation in obesity.MethodsInsulin-induced microvascular recruitment was measured using contrast enhanced ultrasound (CEU), before and during a hyperinsulinaemic–euglycaemic clamp in 15 lean and 18 obese healthy women (18–55 years). Surgical skeletal muscle biopsies were taken on a separate day to study perivascular adipocyte size in histological slices, as well as to study ex vivo insulin-induced vasoreactivity in microvessels in the absence and presence of PVAT in the pressure myograph. Statistical mediation of the relation between BMI and microvascular recruitment by PVAT was studied in a mediation model.ResultsObese women showed impaired insulin-induced microvascular recruitment and lower metabolic insulin sensitivity compared with lean women. Microvascular recruitment was a mediator in the association between obesity and insulin sensitivity. Perivascular adipocyte size, determined in skeletal muscle biopsies, was larger in obese than in lean women, and statistically explained the difference in microvascular recruitment between obese and lean women. PVAT from lean women enhanced insulin-induced vasodilation in isolated skeletal muscle resistance arteries, while PVAT from obese women revealed insulin-induced vasoconstriction.Conclusions/interpretationPVAT from lean women enhances insulin-induced vasodilation and microvascular recruitment whereas PVAT from obese women does not. PVAT adipocyte size partly explains the difference in insulin-induced microvascular recruitment between lean and obese women.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-015-3606-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Highlights

Arterioles, capillaries and venules make up the microcirculation
This study demonstrates a direct relation between perivascular adipose tissue (PVAT) characteristics and insulin’s effects on muscle perfusion
Perivascular adipocyte size mediates the difference in insulin-induced microvascular recruitment between lean and obese women

Summary

Introduction

Arterioles, capillaries and venules make up the microcirculation. Important functions of the microcirculation are to dynamically optimise nutrient and oxygen supply to tissues, and to regulate peripheral resistance [1, 2]. One of the hallmarks of obesity is reduced vasoreactivity, increasing BP and insulin resistance through increased peripheral resistance and decreased delivery of insulin and glucose [3, 4]. In insulin-sensitive individuals, activation of the vasodilator pathway dominates, increasing muscle perfusion during hyperinsulinaemia, so-called ‘microvascular recruitment’. In muscle, this augments insulin-stimulated glucose uptake [4,5,6]. Insulin-induced microvascular recruitment is blunted in insulin-resistant states such as obesity, and in turn contributes to insulin resistance [5, 7, 8]. Why insulininduced microvascular recruitment is blunted in obesity is unclear

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