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.
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
Flow diagram of participants throughout the study.
After screening, 25 lean men were eligible for participation, and all completed the study. Baseline measurements were performed in 54 abdominally obese men; one dropped out for personal reasons before completing the measurements. For the cross-sectional analyses, all lean men and 52 abdominally obese men were included; one was excluded from analyses due to protocol violations (use of anti-hypertensive medication during participation). One lean individual did not complete the MR imaging due to claustrophobia. A total of 53 abdominally obese men were randomized to weight-loss intervention or weight-stable control groups. One individual discontinued control treatment because of illness; one dropped out because of noncompliance with the program to lose weight; and another individual dropped out for personal reasons after assignment to the weight-loss treatment. One individual completed the trial but was excluded from all analyses because of protocol violations. In agreement with the protocol, the study was stopped after 50 follow-up measurements were completed. Few harms were observed during this study; one individual had an incidental finding on MRI that required further analysis, and another individual developed thrombophlebitis after the follow-up measurements.