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VENICE, ITALY — Differences in how adipose tissue responds to insulin may account for why type 2 diabetes is more common in men than in women with obesity, according to newly presented data.

A team of researchers led by Daniel P. Andersson, MD, an endocrinologist at Karolinska University Hospital Huddinge in Stockholm, Sweden, found that adipose tissue insulin resistance was greater in men. They also uncovered that isolated fat cells from men with a body mass index (BMI) ≥ 30 required a 10-fold higher concentration of insulin to block the breakdown of triglycerides to free fatty acids and glycerol, and that this blocking mechanism was also less effective in men than in women.

"We found that men [compared with women] who were living with obesity had increased adipose insulin resistance and higher levels of free fatty acids in the blood," Andersson told Medscape Medical News, adding that this was mostly related to the lesser ability of insulin to block the breakdown of triglycerides in men's adipose tissue rather than sex differences in storage capacity.

"These findings could be part of the explanation as to why type 2 diabetes is more common in men than in women," he added.

Andersson presented the findings at this year's European Congress on Obesity (ECO) 2024. The findings have also been published in the International Journal of Obesity.

Insulin's Role in Subcutaneous Abdominal Fat Storage and Release

Insulin has a key role in stimulating both the storage (conversion of free fatty acids from the circulation into triglycerides within adipocytes) and inhibiting the release (breakdown of triglycerides to free fatty acids in the circulation) of lipids.

"With insulin resistance, there is less inhibition of breakdown, and more free fatty acids are released into the circulation," explained Andersson. "At the same time, there is less storage activity, so again, more free fatty acids are left in the circulation."

Body organs then become chronically exposed to the excess of adipocyte-derived fatty acids, leading to a decrease in muscle glucose uptake, a rise in glucogenesis in the liver, and a drop in insulin secretion by the pancreas. This, in turn, leads to additional hyperglycemia, a further drop in glucose uptake, and a rise in triglyceride breakdown in the adipocytes, which Andersson described as "a vicious circle."

Key Differences Between Men and Women Discovered

To shed light on any functional differences between men and women, the researchers measured the adipose insulin resistance index (AdipolR) in the subcutaneous abdominal fat of 2344 women and 787 men (mean age, 44 years; mean BMI, 35).

Men were found to have higher AdipoIR values than women (P <  .0001), but only in those with a BMI ≥ 30 (ie, obesity). This pattern remained the same irrespective of whether the participant was physically active, had cardiometabolic disease, or used nicotine.

Andersson and colleagues then isolated adipocytes from biopsies in a subgroup of 259 women and 54 men living with obesity to compare the effect of insulin on the adipocytes from these different groups.

"Compared to women, we found a 10-fold higher concentration of insulin was needed to block the breakdown of triglycerides to fatty acids, and the blockage was also less effective in men," he said.

Weighing the Possible Implications

"We know that type 2 diabetes is connected to adipose tissue, but it is not entirely clear how the disease develops," explained Andersson. "Just removing adipose tissue doesn't improve insulin sensitivity, so we think it is something to do with the health status of the fat cells and that it is necessary to change the fat cell function to get better glucose control whether via medication, diet, or bariatric surgery, which fine-tunes the lipolysis and lipogenesis in these cells."

Commenting on the findings, Gijs Goossens, PhD, professor of cardiometabolic physiology of obesity at Maastricht University Medical Center+ in Maastricht, the Netherlands, reflected on the role of body fat on insulin.

"It is well established that premenopausal women with obesity are relatively protected against cardiometabolic complications compared to men of similar age and BMI, at least partly due to a more favorable body fat distribution pattern, with more lower body fat and higher insulin sensitivity in both skeletal muscle and the liver in these women," he told Medscape Medical News.

"The finding that insulin resistance in abdominal subcutaneous adipose tissue is more pronounced in men than women with obesity provides further evidence that there are marked sex differences in the etiology of obesity-related cardiometabolic complications."

Goossens also pointed out that, together with the known differences in the responses to lifestyle and pharmacological interventions between men and women, "this further supports the notion that sex-specific prevention and treatment strategies may yield more health benefits in both men and women living with obesity."

Andersson has received nonfinancial support in another study from COVIS Pharma (study drug donation) and is site principal investigator for Ionis 678354 for Ionis Pharmaceuticals, Inc. He is also a shareholder and has employment at Werlabs AB. None of these studies or his employment are related to the present work. Goossens has declared no conflicts of interest.