Why do men get diabetes at lower BMIs, face more complications?

Evan Walker
Evan Walker TheMediTary.Com |
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New research investigates why men tend to develop diabetes at lower BMIs and younger ages than women. Image credit: Halfpoint/Getty Images.
  • Men and women have different fat distribution, and doctors already know that this can affect men’s risk of cardiovascular disease and type 2 diabetes.
  • Men tend to develop type 2 diabetes earlier and at a lower BMI than women.
  • Researchers from Karolinska Institutet in Stockholm, Sweden have shown that abdominal fat in obese men with type 2 diabetes has higher insulin resistance and different levels of gene expression than women.
  • Another set of researchers from Australia have shown that men are more likely to develop type 1 and type 2 diabetes-related complications than women.

Men with type 2 diabetes and obesity exhibit a higher level of insulin resistance in their adipose tissue than women.

This sex difference in people with type 2 diabetes was observed by scientists from the Karolinska Institutet in Stockholm, Sweden.

Researchers discovered that this higher level of insulin resistance in men was due to a less efficient inhibition of fat cell lipolysis, the process of metabolizing fat.

Evidence suggests that the breakdown of fat cells by lipolysis leads to raised levels of free fatty acids, which can contribute to inflammation and insulin resistance. They also pinpointed a gene that could play a role in the greater level of insulin resistance seen in men.

First author Daniel Andersson, PhD, MD, consultant cardiologist and assistant professor at Karolinska Institutet, told Medical News Today:

“Our research group has been interested in studying different aspects of insulin resistance in adipose tissue for several years. It is well known that there are sex differences between men and women and the risk of getting type 2 diabetes. However, the underlying mechanisms for the sex difference in risk and the impact of local insulin resistance in adipose tissue is not fully understood.”

The results of this study first appeared in the International Journal of Obesity in March 2024, and were presented at the European Congress on Obesity (ECO) in Venice, Italy held between 12–15 May.

People with type 2 diabetes were recruited to the study from the Stockholm area between 1993 to 2020 for a range of studies on metabolism.

For this part of the study, 2,344 women and 787 men were recruited, who self-reported stable weight for 3 months. They were invited to attend a clinic at 8 a.m., after overnight fasting.

Data was also collected on their BMI, age, physical activity, cardiometabolic disease and tobacco use. Researchers performed a blood test that measured circulating levels of fatty acids and insulin in male and female participants, and adjusted this for BMI, physical activity, cardiometabolic disease and tobacco use.

A subset of a subset of 259 female and 54 male participants also had subcutaneous fat samples taken from their abdominal area.

The blood test, called Adipo-IR, indicated that men had higher circulating levels of fatty acids and insulin values than women but only when they had obesity.

These sex differences occurred regardless of the level of physical activity, the presence of cardiometabolic disease, or nicotine use.

The researchers discovered that there were differences in the levels of lipolysis and lipogenesis (fat production), and cells’ sensitivity to them, between men and women with obesity, but not in those without obesity.

In fact, the adipose tissue of women with obesity exhibited 10 times higher insulin sensitivity than men. Fat cells taken from men with obesity exhibited twice the rate of lipolysis than women.

The genetic expression of a second group was also investigated, with a group of 115 men and 234 women with obesity included in the study.

Researchers looked at the mRNA expressed in the fat cells to determine which genes were being expressed. They discovered that the gene encoding insulin receptor substrate 1 IRS1 was expressed less in men than in women.

Further analysis showed that there were differences in the expression of certain genes, including testosterone receptors in male fat tissue, compared to fat tissue taken from women.

The study authors propose that the sex differences seen are due to the different hormone profiles of men and women affecting the metabolic pathways in the adipose tissue.

Alexandra Kautzky-Willer, MD, from the Medical University of Vienna, specialist in endocrinology and gender medicine, not involved in this studies, told MNT that “[w]e know that women have to put on more weight to develop diabetes,” which means that they often have a higher BMI than men at the time of diagnosis, and that is why they exhibit similar insulin resistance to men at that point.

The reasons for the differences in fat distribution and behavior needed to be further investigated, said Kautzky-Willer.

“We need to investigate sex and gender differences in therapies and interventions. Most studies are underpowered to give valuable insights and in most studies women are only 30% [of the cohort],“ she pointed out.

“However, in obesity studies there are usually much more women (70%), and thus even in some obesity randomized control trials we have approximately 50% women,“ she further suggested. “So we have the chance to explore sex differences in pathophysiology and response to treatments.“

To do improve diabetes research, Kautzky-Willer argued:

“[I]t will be necessary to measure more than just weight reduction as an outcome! We need to explore the changes in body fat distribution and lean mass (muscle!), and study changes in intraorgan fat deposits — [fat deposits inside organs, such as the] pancreas, heart etc. Then we could be able to detect new targets and start real precision therapy in men and women.”

Around 95% of the cohort of the first study were of white European origin, so it is not possible to extrapolate its findings to people of different ancestries, despite people of African and Asian ancestry being more likely to develop type 2 diabetes. Another step forward, therefore, should also be to diversify participant cohorts in studies on diabetes.

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