Sexual Dimorphism in Hepatic, Adipose Tissue, and Peripheral Tissue Insulin Sensitivity in Obese Humans

Abstract

Glucose and lipid metabolism differ between men and women, and women tend to have better whole-body or muscle insulin sensitivity. This may be explained, in part, by differences in sex hormones and adipose tissue distribution. Few studies have investigated gender differences in hepatic, adipose tissue, and whole-body insulin sensitivity between severely obese men and women. In this study, we aimed to determine the differences in glucose metabolism between severely obese men and women using tissue-specific measurements of insulin sensitivity. Insulin sensitivity was compared between age and body mass index (BMI)-matched obese men and women by a two-step euglycemic hyperinsulinemic clamp with infusion of [6,6-2H2]glucose. Basal endogenous glucose production (EGP) and insulin sensitivity of the liver, adipose tissue, and peripheral tissues were assessed. Liver fat content was assessed by proton magnetic resonance spectroscopy in a subset of included subjects. We included 46 obese men and women (age, 48 ± 2 vs. 46 ± 2 years, p = 0.591; BMI, 41 ± 1 vs. 41 ± 1 kg/m2, p = 0.832). There was no difference in basal EGP (14.4 ± 1.0 vs. 15.3 ± 0.5 μmol · kg fat-free mass−1 · min−1, p = 0.410), adipose tissue insulin sensitivity (insulin-mediated suppression of free fatty acids, 71.6 ± 3.6 vs. 76.1 ± 2.6%, p = 0.314), or peripheral insulin sensitivity (insulin-stimulated rate of disappearance of glucose, 26.2 ± 2.1 vs. 22.7 ± 1.7 μmol · kg−1 · min−1, p = 0.211). Obese men were characterized by lower hepatic insulin sensitivity (insulin-mediated suppression of EGP, 61.7 ± 4.1 vs. 72.8 ± 2.5% in men vs. women, respectively, p = 0.028). Finally, these observations could not be explained by differences in liver fat content (men vs. women, 16.5 ± 3.1 vs. 16.0 ± 2.5%, p = 0.913, n = 27). We conclude that obese men have lower hepatic, but comparable adipose tissue and peripheral tissue, insulin sensitivity compared to similarly obese women. Hepatic insulin resistance may contribute to the higher prevalence of diabetes in obese men. Further insight into the mechanisms underlying this gender difference may reveal novel targets for diabetes prevention and/or therapy.

Current metabolic perspective on malnutrition in obesity: towards more subgroup-based nutritional approaches?

“…In general, overweight or obese women have a lower HIRI as compared to males (15)(16)(17) . This is in line with studies in obese men and women using hyperinsulinemic euglycemic clamp techniques (23) . Individuals with HIRI or combined HIRI/MISI in general have higher plasma TAG and a larger waist (15)(16)(17) .…”

Sexual dimorphism of liver endoplasmic reticulum stress susceptibility in prepubertal rats and the effect of sex steroid supplementation

“…Oestradiol protects against an increase in body adiposity through its effects on appetite suppression and increased energy expenditure (Pedersen, Bruun, Kristensen, & Richelsen, 2001;Musatov et al, 2007). Our It is well known that, in humans and rodents, ageing is associated with an increased risk of insulin resistance, but this association is more pronounced in males than in females (Frias et al, 2001;Garcia-Carrizo et al, 2017;Krotkiewski, Bjorntorp, Sjostrom, & Smith, 1983;Marucci et al, 2015;ter Horst et al, 2015). We did not observe any differences in glycaemia, insulinaemia, HOMA-IR and QUICKI indices between males and females, either in prepubertal or in young adult rats.…”

“…It is well known that, in humans and rodents, ageing is associated with an increased risk of insulin resistance, but this association is more pronounced in males than in females (Frias et al., ; Garcia‐Carrizo et al., ; Krotkiewski, Bjorntorp, Sjostrom, & Smith, ; Marucci et al., ; ter Horst et al., ). We did not observe any differences in glycaemia, insulinaemia, HOMA‐IR and QUICKI indices between males and females, either in prepubertal or in young adult rats.…”

Animal models of obesity and diabetes mellitus

“…Sexual dimorphism in glycaemia also translates to humans. Data suggest that women are generally less likely to suffer from dietinduced consequences of T2DM than men [110][111][112][113] . This finding is reflected in the global prevalence of T2DM, with women being less frequently diagnosed with T2DM than men 114 .…”