Pairing the selective estrogen receptor modulator bazedoxifene (BZA) with estrogen as a tissue-selective estrogen complex (TSEC) is a novel menopausal therapy. We investigated estrogen, BZA and TSEC effects in preventing diabetisity in ovariectomized mice during high-fat feeding. Estrogen, BZA or TSEC prevented fat accumulation in adipose tissue, liver and skeletal muscle, and improved insulin resistance and glucose intolerance without stimulating uterine growth. Estrogen, BZA and TSEC improved energy homeostasis by increasing lipid oxidation and energy expenditure, and promoted insulin action by enhancing insulin-stimulated glucose disposal and suppressing hepatic glucose production. While estrogen improved metabolic homeostasis, at least partially, by increasing hepatic production of FGF21, BZA increased hepatic expression of Sirtuin1, PPARα and AMPK activity. The metabolic benefits of BZA were lost in estrogen receptor-α deficient mice. Thus, BZA alone or in TSEC produces metabolic signals of fasting and caloric restriction and improves energy and glucose homeostasis in female mice.

Among women, the polycystic ovarian syndrome (PCOS) is considered a form of metabolic syndrome with reproductive abnormalities. Women with PCOS show increased sympathetic tone, visceral adiposity with enlarged adipocytes, hypoadiponectinemia, insulin resistance, glucose intolerance, increased inactive osteocalcin, and hypertension. Excess fetal exposure to androgens has been hypothesized to play a role in the pathogenesis of PCOS. Previously, we showed that neonatal exposure to the androgen testosterone (NT) programs leptin resistance in adult female mice. Here, we studied the impact of NT on lean and adipose tissues, sympathetic tone in cardiometabolic tissues, and the development of metabolic dysfunction in mice. Neonatally androgenized adult female mice (NTF) displayed masculinization of lean tissues with increased cardiac and skeletal muscle as well as kidney masses. NTF mice showed increased and dysfunctional white adipose tissue with increased sympathetic tone in both visceral and subcutaneous fat as well as increased number of enlarged and insulin-resistant adipocytes that displayed altered expression of developmental genes and hypoadiponectinemia. NTF exhibited dysfunctional brown adipose tissue with increased mass and decreased energy expenditure. They also displayed decreased undercarboxylated and active osteocalcin and were predisposed to obesity during chronic androgen excess. NTF showed increased renal sympathetic tone associated with increased blood pressure, and they developed glucose intolerance and insulin resistance. Thus, developmental exposure to testosterone in female mice programs features of cardiometabolic dysfunction, as can be observed in women with PCOS, including increased sympathetic tone, visceral adiposity, insulin resistance, prediabetes, and hypertension.

Aims/hypothesisPancreatic islet transplantation (PIT) offers a physiological treatment for type 1 diabetes, but the failure of islet engraftment hinders its application. The female hormone 17β-oestradiol (E2) favours islet survival and stimulates angiogenesis, raising the possibility that E2 may enhance islet engraftment following PIT.MethodsTo explore this hypothesis, we used an insulin-deficient model with xenotransplantation of a marginal dose of human islets in nude mice rendered diabetic with streptozotocin. This was followed by 4 weeks of treatment with vehicle, E2, the non-feminising oestrogen 17α-oestradiol (17α-E2), the oestrogen receptor (ER) α agonist propyl-pyrazole-triol (PPT), the ERβ agonist diarylpropionitrile (DPN) or the G protein-coupled oestrogen receptor (GPER) agonist G1.ResultsTreatment with E2, 17α-E2, PPT, DPN or G1 acutely improved blood glucose and eventually promoted islet engraftment, thus reversing diabetes. The effects of E2 were retained in the presence of immunosuppression and persisted after discontinuation of E2 treatment. E2 produced an acute decrease in graft hypoxic damage and suppressed beta cell apoptosis. E2 also acutely suppressed hyperglucagonaemia without altering insulin secretion, leading to normalisation of blood glucose.Conclusions/interpretationDuring PIT, E2 synergistic actions contribute to enhancing human islet-graft survival, revascularisation and functional mass. This study identifies E2 as a short-term treatment to improve PIT.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-012-2764-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

A widely prevalent single nucleotide polymorphism, rs13266634 in the SLC30A8 gene encoding the zinc transporter ZnT8, is associated with an increased risk for T2DM. ZnT8 is mostly expressed in pancreatic insulin-producing islets of Langerhans. The effect of this variant on the divalent metal profile in human islets is unknown. Additionally, essential and non-essential divalent metal content of human islets under normal environmental exposure conditions has not been described. We therefore examined the correlation of zinc and other divalent metals in human islets with rs13266634 genotype and demographic characteristics. We found that the diabetes risk genotype C/C at rs13266634 is associated with higher islet Zn concentration (C/C genotype: 16792 ± 1607, n = 22, C/T genotype: 11221 ± 1245, n = 18 T/T genotype: 11543 ± 6054, n = 3, all values expressed as mean nmol/g protein ± standard error of the mean, p = 0.040 by ANOVA). A positive correlation between islet cadmium content and both age (p = 0.048, R2 = 0.09) and female gender (women: 36.88 ± 4.11 vs men: 21.22 ± 3.65 nmol/g protein, p = 0.007) was observed. Our results suggest that the T2DM risk allele C is associated with higher islet zinc levels and support prior evidence of cadmium’s higher bioavailability in women and its long tissue half-life.

Polycystic ovary syndrome is a common endocrine disorder in females of reproductive age and is believed to have a developmental origin in which gestational androgenization programs reproductive and metabolic abnormalities in offspring. During gestation, both male and female fetuses are exposed to potential androgen excess. We determined the consequences of developmental androgenization in male mice exposed to neonatal testosterone (NTM). Adult NTM displayed hypogonadotropic hypogonadism with decreased serum testosterone and gonadotropins. Hypothalamic KiSS1 neurons are believed to be critical in the onset of puberty and are the target of leptin. Adult NTM showed lower hypothalamic Kiss1 expression and a failure of leptin to upregulate Kiss1 expression. NTM displayed an early reduction in lean mass, decreased locomotor activity and decreased energy expenditure. They developed a delayed increase in subcutaneous white adipose tissue. Thus, excessive neonatal androgenization disrupts reproduction and energy homeostasis and predisposes to hypogonadism and obesity in adult male mice.