Sex Differences of Age-Dependent Changes of Insulin Sensitivity in Japanese Nondiabetic Subjects

Impaired insulin sensitivity is associated with type 2 diabetes, hypertension, and atherosclerosis. This abnormality occurs by various causes such as genetic background, obesity, high-calorie diet, and low physical activity. Sex hormones also influence insulin sensitivity, which might be a cause for sex differences of the development of diabetes, hypertension, and atherosclerosis (1, 2). Collectively, however, there is no population-based study of sex differences in insulin sensitivity. Here, we aimed to determine whether there are sex and age differences of insulin sensitivity and insulin secretory activity in middle-aged nondiabetic subjects.

Of 1,934 Japanese subjects who visited the Kinki Central Hospital between April and October 2003 for their health examinations, we evaluated 1,395 subjects (854 men and 541 women) after exclusion of subjects with diabetes, malignant diseases, chronic or acute inflammatory diseases, elevated serum creatinine levels (≥106 μmol/l), autoimmune disorders, or subjects aged ≤40 years or ≥61 years.

Glucose tolerance status, homeostasis model assessment (HOMA) determinants (3), and BMI stratified by sex and age-groups (40–49 and 50–59 years) are shown in Table 1. Prevalence of impaired glucose tolerance was significantly higher in men than in women of both age-groups. In the 41–50 age-group, the index for insulin sensitivity (HOMA-%S) was higher in women than in men, whereas in the 51–60 age-group, there was no sex difference. The index for pancreatic β-cell function (HOMA-%β) was not different between men and women of both age-groups. BMI was lower in women than in men of both age-groups. In women, HOMA-%S was significantly higher in the 41–50 age-group than in 51–60 age-group (P = 0.0275), whereas in men it was lower in the 41–50 age-group than in the 51–60 age-group (P = 0.0348).

We found that there were sex differences of age-dependent changes of insulin sensitivity, but not of insulin secretory activity, in Japanese nondiabetic subjects. Serum sex hormone levels differ between men and women, and in women, serum estrogens rapidly fall after menopause occurring around age 50. Therefore, sex hormones may be involved in the sex differences of age-dependent changes of insulin sensitivity. It has been reported that postmenopausal hormone replacement therapy lowered fasting glucose and insulin levels in nondiabetic women (4) and improved glycemic control in type 2 diabetic women (5), although disparate results have also been shown (6, 7). In men, serum testosterone levels have been shown to be inversely related to serum insulin level and BMI (8). In addition, it has been shown that androgens decreased the insulin-sensitizing adipocyte-derived protein adiponectin (9). Thus, as a whole, estrogens may have favorable effects on insulin sensitivity, whereas androgens may have undesirable effects on it.

In summary, insulin sensitivity depends on sex and age. Insulin sensitivity is higher in women than in men until age 50, but it falls to levels similar to men after age 50. Therapeutic strategies for eliminating insulin resistance for the prevention of diabetes and atherosclerosis should be classified by sex and age.