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.
Highlights
Obesity is the most important risk factor for insulin resistance and type 2 diabetes [1], and an increasing threat to both men and women worldwide [2]
Subjects were eligible for Abbreviations: 1H-MRS, proton magnetic resonance spectroscopy; BMI, body mass index; EGP, endogenous glucose production; FFA, free fatty acids; fat-free mass (FFM), fatfree mass; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; Rd, rate of disappearance; SEM, standard error of the mean
The basal rate of EGP did not differ between men and women (Figure 1A), but men had markedly lower insulin-mediated suppression of EGP (Figure 1B), indicating that severely obese men are characterized by lower hepatic insulin sensitivity compared to obese women
Summary
Obesity is the most important risk factor for insulin resistance and type 2 diabetes [1], and an increasing threat to both men and women worldwide [2]. Most [13,14,15,16,17,18,19], but not all [20, 21], of the available evidence from euglycemic hyperinsulinemic clamp or arterial–venous balance studies suggests that insulin-stimulated glucose uptake is higher in women than men, indicating that women generally show higher peripheral insulin sensitivity This may be related to a more favorable adipose tissue distribution in women [more subcutaneous and less visceral fat compared to men [4]] as well as to levels of circulating sex hormones, with estrogen having insulinsensitizing [12] and anti-inflammatory [22] properties. Administration of gonadotropinreleasing hormone agonists (to induce short-term hypogonadism) or testosterone does not affect whole-body insulin sensitivity in healthy men [25]
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