Modulation of Insulin Sensitivity and Caveolin-1 Expression by Orchidectomy in a Nonobese Type 2 Diabetes Animal Model

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.

Dexamethasone downregulates caveolin-1 causing muscle atrophy via inhibited insulin signaling

“…Notably, Cav1-deficient mice have a lean phenotype (Razani et al 2002). Furthermore, CAV1 expression is dependent on androgens and exercise (Baehr et al 2011, Oh et al 2011. These data from Cav-deficient mice indicate that Cav1 may play a key role in glucocorticoid regulation of the insulin pathway, thereby contributing to muscle atrophy.…”

Sex-Dependent Expression of Caveolin 1 in Response to Sex Steroid Hormones Is Closely Associated with Development of Obesity in Rats

“…A variety of studies have raised the possibility that estrogens have more prominent effects than testosterone in diabetes and cancer [35]. Moreover, conflicting results have been obtained regarding the role of testosterone in diabetes [19], [36], [37].…”

“…Recently, it has been reported that CAV1 is an important target protein in E2- as well as DHT-dependent regulation of various metabolic pathways, particularly in cancer and diabetes [33], [35], [41], [42].…”

A Chromosome 13 locus is associated with male-specific mortality in mice

“…Several lines of previous work in relevant animal models (and humans) indicate that estrogens protect pancreatic islet cells from loss of function and degeneration [43]. With particular reference to this cross, in B6D2F1 hybrid mice-the F1 offspring of B6 dams crossed with D2 sires-males spontaneously develop adult onset, non-obese type II diabetes [44,45]. Thus, there is a rich literature indicating strong genetic effects on glucose metabolism in the B6 and D2 genetic background, and a male-specific form of diabetes is known to spontaneously occur in hybrids of this strain.…”