Independent tissue contributors to obesity-associated insulin resistance

Yvo Ham Kusters, Casper G Schalkwijk, Alfons Jhm Houben, M Eline Kooi, Lucas Lindeboom, Jos Op 't Roodt, Peter J Joris, Jogchum Plat, Ronald P Mensink, Eugene J Barrett, Coen DA Stehouwer

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
JournalJCI insight
Volume2
Issue number13
DOIs
Publication statusPublished - 6 Jul 2017
Externally publishedYes

Keywords

  • obesity
  • insulin resistance
  • metabolism

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