In individuals with type 2 diabetes and obesity, men display a heightened level of insulin resistance in their adipose tissue compared to women. This sex disparity among individuals with type 2 diabetes was noted by researchers at the Karolinska Institutet in Stockholm, Sweden. Their findings revealed that the elevated insulin resistance in men stemmed from less efficient inhibition of fat cell lipolysis, the process of fat metabolism. Studies indicate that the breakdown of fat cells through lipolysis results in increased levels of free fatty acids, which may contribute to inflammation and insulin resistance. Furthermore, researchers identified a gene that may play a role in the heightened insulin resistance observed in men.

Gender Disparities in Fat Production and Metabolism

Individuals with type 2 diabetes were enrolled in the study from the Stockholm area over a span of 27 years, from 1993 to 2020, for various metabolism studies. A total of 2,344 women and 787 men, reporting stable weight for three months, were recruited for this segment of the research. Participants were scheduled for clinic visits at 8 a.m. following an overnight fast. Data collection included BMI, age, physical activity, cardiometabolic disease status, and tobacco use. Blood samples were obtained to measure circulating fatty acid and insulin levels, adjusted for BMI, physical activity, cardiometabolic disease, and tobacco use. Additionally, a subset of 259 women and 54 men had subcutaneous fat samples taken from their abdominal region. The study found that men exhibited higher circulating levels of fatty acids and insulin than women, but specifically among those with obesity. These sex differences persisted regardless of physical activity level, cardiometabolic disease presence, or nicotine use. Differences were observed in lipolysis, lipogenesis, and cellular sensitivity between obese men and women, but not among those without obesity. Women with obesity demonstrated significantly higher insulin sensitivity in adipose tissue compared to men, while fat cells from obese men exhibited a higher rate of lipolysis than those from women. Genetic analysis revealed differences in gene expression, including insulin receptor substrate 1 (IRS1) expression, between men and women with obesity. The study suggests that hormonal profiles may influence metabolic pathways in adipose tissue, contributing to these sex differences. Alexandra Kautzky-Willer, MD, a specialist in endocrinology and gender medicine from the Medical University of Vienna, who was not involved in the study, noted that women often have a higher BMI at the time of diabetes diagnosis, leading to similar insulin resistance levels as men.

Men face higher risk of diabetes complications

Previous studies have indicated that men have a higher likelihood of developing type 2 diabetes at lower BMIs compared to women, often at younger ages, potentially due to differences in fat distribution. Additionally, recent research published in the Journal of Epidemiological Community Health revealed that men face a greater risk of developing complications associated with both type 1 and type 2 diabetes, regardless of the duration of the condition. An analysis of a cohort comprising 25,713 men and women aged 45 and above in Australia demonstrated that men had a 51% increased risk of cardiovascular disease, a 47% increased risk of lower limb complications, a 55% increased risk of kidney complications, and a 14% increased risk of diabetic retinopathy compared to women.

Should Gender-Specific Diabetes Treatments be Considered?

If differences in insulin resistance and the risk of diabetes-related complications exist between sexes, it prompts the question: Should treatment approaches be tailored differently for men and women?

Dr. Kautzky-Willer suggested, “Weight-reducing medications are particularly beneficial for women with type 2 diabetes.” She noted that certain GLP-1 agonists show greater efficacy in women compared to men.

She elaborated on how women experience varying insulin sensitivity throughout life stages, being more resistant during puberty but more sensitive afterward until menopause. They also exhibit superior insulin response, lipid profiles, and lower blood pressure. Despite advantages like enhanced fat storage for potential pregnancies, menopause brings about a shift, leading to an androgen phenotype.

The authors of the initial study propose that targeting insulin resistance in obese men through pharmaceutical and lifestyle interventions could prevent type 2 diabetes. However, they emphasize the necessity for further prospective studies to validate their findings.

Exploring Gender Disparities in Diabetes: Future Research Directions

Kautzky-Willer emphasized the necessity of delving deeper into the reasons behind variations in fat distribution and behavior.

“We must delve into the disparities in therapies and interventions based on sex and gender,” she stressed. “Many studies lack the statistical power to provide meaningful insights, with women typically comprising only 30% of cohorts.”

She further noted, “Interestingly, obesity studies often involve a higher proportion of women, around 70%, even reaching parity in some randomized controlled trials. This offers a unique opportunity to explore sex-specific differences in both pathophysiology and treatment responses.”

To advance diabetes research, Kautzky-Willer advocated for broader participant diversity. She highlighted that while the first study primarily involved individuals of white European descent, it’s essential to include diverse ancestries, particularly given the heightened susceptibility of individuals of African and Asian ancestry to type 2 diabetes. Thus, diversifying participant cohorts is crucial for advancing our understanding of diabetes.