There is extensive experimental evidence that sex steroids and insulin interact in their actions on tissues. At physiological levels, testosterone and oestradiol are thought to be involved in maintaining normal insulin sensitivity. However, outside this 'physiological window' these steroids may promote insulin resistance. Considerable research has been carried out on polycystic ovarian syndrome, a common disorder associated with excessive androgen production and insulin resistance. Hyperinsulinaemia in patients with this condition is believed to stimulate ovarian androgen production, and there is also evidence that androgens act directly on peripheral tissues to promote insulin resistance. There is the potential for a vicious circle to develop with increasing androgen production and insulin resistance. The molecular basis of this insulin resistance has been reported to involve reduced insulin receptor autophosphorylation, reduced expression and translocation of insulin-responsive glucose transporters and defects of the insulin signalling pathway distal to the insulin receptor. These defects await full characterization. Insulin-sensitizing agents can reverse many of the effects of insulin resistance and may have a future place in the treatment of polycystic ovarian syndrome and other conditions associated with steroid-induced insulin resistance. Recognition and treatment of sex steroid-associated insulin resistance at an early stage in patients may reduce their risk of developing Type II (non-insulin-dependent) diabetes mellitus, hypertension and dyslipidaemia, and so may improve fertility and reduce cardiovascular risk. Here we review the interplay between sex steroids and insulin resistance, and consider the implications this has for clinical conditions.

Insulin resistance is of pathogenic importance in several common human disorders including type 2 diabetes, hypertension, obesity and hyperlipidemia, but the underlying mechanisms are unknown. The spontaneously hypertensive rat (SHR) is a model of these human insulin resistance syndromes. Quantitative trait loci (QTLs) for SHR defects in glucose and fatty acid metabolism, hypertriglyceridemia, and hypertension map to a single region on rat chromosome 4. Genetic analysis of an SHR derived from a National Institutes of Health colony led to the identification of a causative mutation in the SHR Cd36. We have investigated glucose and fatty acid metabolism in the stroke-prone SHR (SHRSP). We demonstrate defects in insulin action on 2-deoxy-D-glucose transport (SHRSP 3.3 ± 1.5 vs. 21.0 ± 7.4 pmol · min -1 · [20 µl packed cells] -1 , SHRSP vs. WKY, respectively, P = 0.01) and inhibition of catecholaminestimulated lipolysis (P < 0.05 at all concentrations of insulin) in adipocytes isolated from SHRSP. In contrast, basal levels of catecholamine-stimulated nonesterified free fatty acid (NEFA) release and plasma levels of NEFA are similar in SHRSP and WKY. These results are in agreement with the data on the SHR.4 congenic strain, which suggested that the QTL containing Cd36 mutations accounted for the entire defect in basal catecholamine action but only for ~40% of the SHR defect in insulin action. In the SHR, both abnormalities appear consequent of defective Cd36 expression. Because Cd36 sequence and expression are apparently normal in SHRSP, it is likely that the molecular mechanism for defective insulin action in this strain is caused by a gene(s) different than Cd36. Diabetes

Cardiovascular disease in postmenopausal women represents a major health care concern because a third of all women between the ages of 50 and 75 are thought to be affected and a sixth die of the consequences of artherosclerosis. Recent studies have clearly shown a strong correlation between insulin sensitivity and the development of cardiovascular disease [1±3]: thus factors that diminish insulin sensitivity in women have been the subject of considerable interest [4,5]. Evidence for an association between sex hormones and insulin sensitivity is provided by studies of women with hyperandrogenic conditions, such as polycystic ovary syndrome [6,7]. These studies have argued strongly for a link between sex hormones and insulin resistance, as an improvement of insulin sensitivity is often observed upon correction of the hyperandrogenism [8±10]. Further correlative evidence for a link between insulin sensitivity and sex hormones is provided by other studies, including the induction of insulin resistance in the surgically Diabetologia (2000) Abstract Aim/hypothesis. Numerous studies have suggested a relation between sex hormones and insulin sensitivity but the ability of sex hormones to directly influence insulin action in peripheral tissues has not been investigated. Methods. We have examined the effects of estriol, estradiol and estrone on insulin action in cultured 3T3-L1 adipocytes, a useful model of adipocytes. Results. Treatment of these cells with each of these sex hormones resulted in a statistically significant reduction in the ability of insulin to stimulate glucose transport independently of a reduction in total cellular GLUT-4 content. This diminished ability of insulin to stimulate glucose transport was accompanied by a reduction in the total cellular content of insulin receptor substrates ±1 and ±2 and the p85a subunit of phosphatidylinositol 3'-kinase. By contrast, cellular content of protein kinase B was unchanged by hormone treatment but the magnitude of insulin-stimulated kinase activity was statistically significantly reduced after incubation with each of the sex hormones tested. We have further shown that treatment of 3T3-L1 adipocytes with these hormones alters the subcellular distribution of insulin receptor substrate proteins such that the particulate and soluble pools of these proteins were differentially affected by hormone treatment. Conclusion/interpretation. These data show that sex hormones can directly induce a state of insulin resistance in 3T3-L1 adipocytes in culture. The mechanism of this defect seems to be at least in part due to decreased cellular content and altered subcellular distribution of insulin receptor substrate proteins which in turn results in a reduction in proximal insulin-stimulated signalling cascades. [Diabetologia (2000

We report on two Aboriginal patients with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. Both presented with acute hepatic failure with severe hypertransaminasemia and coagulopathy, prompting evaluation for emergent liver transplantation. The diagnosis of HHH syndrome was based on the presence of typical metabolic abnormalities. A protein-restricted diet and L-arginine or L-citrulline supplementation were immediately started, with rapid normalization of liver function test results and other biochemical abnormalities. Molecular analysis of the SLC25A15 gene showed that the two patients were homozygous for the common French Canadian mutation (F188Delta). The diagnosis of HHH syndrome should be considered in patients with unexplained fulminant hepatic failure. There does not appear to be a genotype-phenotype correlation for this presentation, inasmuch as the only other reported patient presenting with this picture had two different point mutations. Early identification and prompt treatment of these patients is crucial to avoid liver transplantation and can be life saving.

Aims/hypothesis: Insulin-stimulated glucose transport is impaired in a genetic model of hypertension, the stroke-prone spontaneously hypertensive rat (SHRSP), yet the molecular mechanisms that underlie this defect in the animals remain unclear. Methods: We examined the effects of insulin on the trafficking of the insulin-responsive glucose transporter GLUT4 to the plasma membrane in isolated adipocytes from SHRSP and normotensive control WistarKyoto (WKY) rats. Results: Treatment of isolated adipocytes with insulin resulted in trafficking of GLUT4 to the plasma membrane. There was no significant difference in the magnitude of insulin-stimulated GLUT4 trafficking from intracellular membranes to the plasma membrane between strains. In contrast, we demonstrated that there is a significant reduction in GLUT4 accessible to the glucose photolabel Bio-LC-ATB-BGPA at the plasma membrane of SHRSP adipocytes compared with control rats. Conclusions/ interpretation: We propose that a large proportion of GLUT4 translocated to the plasma membrane in response to insulin is not able to bind substrate and catalyse transport in the SHRSP. Therefore, there is a reduction in bioavailable GLUT4 in SHRSP animals that is likely to account, at least in part, for the reduced insulin-stimulated glucose uptake.