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Abstract
Previously, we found that male JYD mice developed type 2 diabetes but female mice did not, and that decreased expression levels of caveolin-1 were correlated with the development of a diabetic phenotype in these mice. Therefore, we hypothesized that sex hormones affect the expression of caveolin-1 and contribute to the development of insulin resistance and hyperglycemia in JYD mice. We used glucose and insulin tolerance tests to examine insulin sensitivity in male, female and orchidectomized male JYD mice. Glucose uptake was analyzed by using (18)F-fluorodeoxyglucose positron emission tomography. We also examined insulin-signaling molecules and caveolin proteins in various tissues in these mice by Western blotting. In addition, we examined changes of caveolin-1 expression in L6 skeletal muscle cells treated with 17-β estradiol or dihydroxytestosterone. We found that glucose and insulin tolerance were impaired and hyperglycemia developed in male, but not female, JYD mice. Expression of insulin-signaling molecules such as insulin receptor, protein kinase B, and glucose transporter-4 were decreased in male JYD mice compared with female mice. Orchidectomized JYD male mice showed improved glucose and insulin tolerance with a concomitant increase in the expression of insulin-signaling molecules and caveolin-1 in adipose tissue and skeletal muscle. Moreover, 17-β-estradiol treatment increased the expression of caveolin-1 in differentiated skeletal muscle cells. We conclude that sex hormones modulate the expression of caveolin-1 and insulin-signaling molecules, subsequently affecting insulin sensitivity and the development of type 2 diabetes in JYD mice.
Highlights
Onset of type 2 diabetes and metabolic syndrome in old age has been observed to be more prevalent in men than in women [1], suggesting that sex hormones may affect the development of type 2 diabetes
We investigated whether sex hormones affect the development of insulin resistance and diabetes in JYD mice, and if so, whether this effect is correlated with modulation of caveolin-1 expression
It was recently reported that type 2 diabetes is significantly more common in women, but the prevalence increases with old age in men whereas it remains unchanged in women [1]
Summary
Onset of type 2 diabetes and metabolic syndrome in old age has been observed to be more prevalent in men than in women [1], suggesting that sex hormones may affect the development of type 2 diabetes. Circulating levels of sex hormone binding protein, which binds strongly to testosterone and to a lesser extent to estradiol, is a predictor of the risk of type 2 diabetes [2,3,4]. It was previously reported that high serum levels of testosterone in polycystic ovary syndrome is a risk factor for type 2 diabetes and impaired glucose tolerance [5,6]. Sex hormones such as estrogen and testosterone are known to modulate glucose and lipid metabolism [7], and administration of testosterone to women impaired glucose tolerance and induced hyperinsulinemia [8]. Insulin sensitivity was reduced in skeletal muscle of ovarectomized female rats, and treatment of these rats with estradiol restored insulin sensitivity and glucose uptake [9].
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