Female sex protective against obesity-driven dysregulation of glucose metabolism

Insulin sensitivity and secretion differ by sex among Asians without diabetes, reveals a study, noting that female sex is protective on obesity-driven dysregulation of glucose metabolism.

“Obesity reduces insulin sensitivity to a greater extent in males than in females,” the investigators said. “[A]ccordingly, the degree of β-cell compensation to maintain glycaemic status due to obesity is higher in males than in females.”

A total of 727 males and 952 females with normal body weight (n=602; body mass index [BMI] <23 kg/m²), overweight (n=662; BMI 23 to 27.5 kg/m²), or obesity (n=415; BMI ≥27.5 kg/m²) were included in this analysis.

The investigators measured glucose tolerance using the oral glucose tolerance test, insulin-mediated glucose uptake using the hyperinsulinaemic-euglycaemic clamp, acute insulin response using an intravenous glucose challenge, and insulin secretion rates in the fasting state and in response to glucose ingestion using mathematical modeling.

No sex differences were observed among lean individuals. On the other hand, obesity led to a gradual worsening of metabolic function, and the progressive adverse effects of obesity on insulin action and secretion were more significant among males than females. [Obesity 2023;31:2304-2314]

Among obese participants, females showed greater insulin sensitivity, lower insulin secretion, and lower fasting insulin concentration than males. In addition, males had greater increase in waist-to-hip ratio with increasing BMI compared with females.

The mitigating effect of the female sex on obesity-driven insulin resistance among Asians was consistent with than among White individuals. [Obesity 2012;20:1966-1973]

Visceral adiposity

“Body composition differences between males and females may play a significant role in our observations,” the investigators said. “We found that, despite having a higher body fat percentage, females had a favourable lipid profile as compared with males in our study, which is usually observed in the general population.” [J Clin Endocrinol Metab 2011;96:885-893]

Moreover, visceral fat is significantly associated with metabolic syndrome, insulin resistance, and cardiometabolic disease due to its altered metabolic profile under nutrient excess and proximity to the liver. Visceral vs subcutaneous adipose tissue has a higher lipolysis rate, and its lipolytic rate is higher in males than in females. [Ann Med 1995;27:435-438; Arterioscler Thromb Vasc Biol 1997;17:1472-1480]

“The increased lipolysis of visceral fat in males may thus expose the liver to a higher influx of free fatty acids through the portal vein that can potentially impair hepatic insulin action and alter hepatic glucose metabolism,” the investigators said. [Gastroenterology 2007;133:496-506; Metabolism 2017;67:80-89]

In addition, visceral obesity induces systemic inflammation, partly through the production of a proinflammatory secretome, and may result in greater adverse effects on insulin sensitivity. [Endocrinology 2022;163:bqac140]

“These findings have important health policy implications in diabetes prevention in Asian populations,” the investigators said. “As males are at higher risk for obesity-induced T2DM than females, an effective population-wide risk reduction strategy would be to account to a greater degree for sex differences in obesity-related dysregulation of glucose homeostasis.”