Independent tissue contributors to obesity-associated insulin resistance
Yvo H.A.M. Kusters, Casper G. Schalkwijk, Alfons J.H.M. Houben, M. Eline Kooi, Lucas Lindeboom, Jos Op ’t Roodt, Peter J. Joris, Jogchum Plat, Ronald P. Mensink, Eugene J. Barrett, Coen D.A. Stehouwer
Yvo H.A.M. Kusters, Casper G. Schalkwijk, Alfons J.H.M. Houben, M. Eline Kooi, Lucas Lindeboom, Jos Op ’t Roodt, Peter J. Joris, Jogchum Plat, Ronald P. Mensink, Eugene J. Barrett, Coen D.A. Stehouwer
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Clinical Research and Public Health Endocrinology Metabolism

Independent tissue contributors to obesity-associated insulin resistance

Abstract

BACKGROUND. Induction of insulin resistance is a key pathway through which obesity increases risk of type 2 diabetes, hypertension, dyslipidemia, and cardiovascular events. Although the detrimental effects of obesity on insulin sensitivity are incompletely understood, accumulation of visceral, subcutaneous, and liver fat and impairment of insulin-induced muscle microvascular recruitment (MVR) may be involved. As these phenotypic changes often coincide in obesity, we aimed to unravel whether they independently contribute to insulin resistance and thus constitute separate targets for intervention. METHODS. We measured visceral (VAT) and subcutaneous adipose tissue (SAT) volumes and intrahepatic lipid (IHL) content by MRI, and whole body glucose disposal (WBGD) and MVR (using contrast-enhanced ultrasound) responses to a euglycemic insulin clamp in lean (n = 25) and abdominally obese men (n = 52). Abdominally obese men were randomized to dietary weight loss intervention or habitual diet. RESULTS. Obesity-associated increases in VAT, SAT, and IHL, along with the decrease in MVR, contributed independently to insulin resistance. Moreover, a dietary weight loss intervention reduced insulin resistance, and mediation analyses showed that decreased IHL and insulin-induced MVR, but not decreased VAT or SAT volumes, independently contributed to improved insulin resistance seen with weight loss. CONCLUSION. Quantifying the mutually independent contributions of visceral and subcutaneous adipose tissue, intrahepatic lipid, and insulin-induced muscle microvascular recruitment reveals distinct targets for treating obesity-associated insulin resistance. TRIAL REGISTRATION. Clinicaltrials.gov NCT01675401. FUNDING. Funding was from the Top Institute Food and Nutrition.

Authors

Yvo H.A.M. Kusters, Casper G. Schalkwijk, Alfons J.H.M. Houben, M. Eline Kooi, Lucas Lindeboom, Jos Op ’t Roodt, Peter J. Joris, Jogchum Plat, Ronald P. Mensink, Eugene J. Barrett, Coen D.A. Stehouwer

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Figure 2

Features of the study population and effects of weight loss.

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Features of the study population and effects of weight loss. Levels of (...
Levels of (A) BMI, (B) whole body glucose disposal (WBGD), (C) abdominal visceral adipose tissue volume (VAT), (D) abdominal subcutaneous adipose tissue volume (SAT), (E) intrahepatic lipid (IHL), and (F) insulin-induced muscle microvascular recruitment (MVR). Results for lean men (n = 25), abdominally obese men (n = 52), the control group at baseline (Ctrlpre; n = 26) and after follow-up (Ctrlpost; n = 26), and the intervention group at baseline (Intpre; n = 23) and after follow-up (Intpost; n = 23) are shown. One lean individual did not complete the MR imaging due to claustrophobia; analyses on VAT, SAT, and IHL are thus reported for 24 lean men. Box plots are as follows: black line, median; box edges, 1st and 3rd quartiles; whiskers, minimum and maximum of all data. Cross-sectional differences were assessed by means of independent Student’s t tests (lean vs. obese; ***P < 0.001), differences over time by means of paired t test (baseline vs. follow-up; ###P < 0.001), and differences between groups over time by means of 1-factor ANCOVA with baseline value as covariate (control group vs. intervention group; §§§P < 0.001).