Insulin resistance plays a role in the pathogenesis of diabetes, including gestational diabetes. The glucose clamp is considered the gold standard for determining in vivo insulin sensitivity, both in human and in animal models. However, the clamp is laborious, time consuming and, in animals, requires anesthesia and collection of multiple blood samples. In human studies, a number of simple indexes, derived from fasting glucose and insulin levels, have been obtained and validated against the glucose clamp. However, these indexes have not been validated in rats and their accuracy in predicting altered insulin sensitivity remains to be established. In the present study, we have evaluated whether indirect estimates based on fasting glucose and insulin levels are valid predictors of insulin sensitivity in nonpregnant and 20-day-pregnant Wistar and Sprague-Dawley rats. We have analyzed the homeostasis model assessment of insulin resistance (HOMA-IR), the quantitative insulin sensitivity check index (QUICKI), and the fasting glucose-toinsulin ratio (FGIR) by comparing them with the insulin sensitivity (SIClamp) values obtained during the hyperinsulinemic-isoglycemic clamp. We have performed a calibration analysis to evaluate the ability of these indexes to accurately predict insulin sensitivity as determined by the reference glucose clamp. Finally, to assess the reliability of these indexes for the identification of animals with impaired insulin sensitivity, performance of the indexes was analyzed by receiver operating characteristic (ROC) curves in Wistar and Sprague-Dawley rats. We found that HOMA-IR, QUICKI, and FGIR correlated significantly with SIClamp, exhibited good sensitivity and specificity, accurately predicted SI Clamp , and yielded lower insulin sensitivity in pregnant than in nonpregnant rats. Together, our data demonstrate that these indexes provide an easy and accurate measure of insulin sensitivity during pregnancy in the rat.homeostasis model assessment of insulin resistance; quantitative insulin sensitivity check index; fasting glucose-to-insulin ratio; hyperinsulinemic isoglycemic clamp; calibration model LATE PREGNANCY IS CHARACTERIZED BY THE DEVELOPMENT of insulin resistance both in humans (8, 9, 33) and rats (23,30). Different procedures can be employed to assess insulin sensitivity, including the euglycemic-hyperinsulinemic clamp, the oral glucose tolerance test (OGTT), and various derivations of fasting glucose and insulin levels. The euglycemic-hyperinsulinemic clamp is considered the "gold standard" for measuring whole body insulin sensitivity in vivo because it directly measures the capacity of insulin to promote glucose utilization under steady-state conditions (12,17). Although this method can provide a precise measure of the insulin sensitivity under physiological conditions, it is, however, a complicated and labor-intensive procedure. Therefore, simple but accurate estimates of insulin sensitivity are required to perform large-scale studies.In the past, surrogate measures of insulin resis...

Objective: To test whether enhancing the capability of adipose tissue to store lipids using antioxidant supplementation may prevent the lipotoxic effects and improve the metabolic profile of long-term obesity. Methods: C57BL/6J mice were randomized into three experimental groups for 28 weeks: control group (n 5 10) fed chow diet (10% kcal from fat), obese group (O, n 5 12) fed high-fat (HF) diet (45% kcal from fat), and obese group fed HF diet and supplemented twice a week with 150 mg of a-tocopherol (vitamin E) by oral gavage (OE, n 5 12). Results: HF diet resulted in an obese phenotype with a marked insulin resistance, hypertriglyceridemia, and hepatic steatosis in O mice. Histological analysis of obese visceral adipose tissue (VAT) revealed smaller adipocytes surrounded by a fibrotic extracellular matrix and an increased macrophage infiltration, with the consequent release of proinflammatory cytokines. Vitamin E supplementation decreased oxidative stress and reduced collagen deposition in the VAT of OE mice, allowing a further expansion of the adipocytes and increasing the storage capability. As a result, circulating cytokines were reduced and hepatic steasosis, hypertriglyceridemia, and insulin sensitivity were improved. Conclusions: Our results suggest that oxidative stress is implicated in extracellular matrix remodeling and may play an important role in metabolic regulation.

Insulin resistance is a hallmark of late pregnancy both in human and rat. Adipose tissue is one of the tissues that most actively contributes to this reduced insulin sensitivity. The aim of the present study was to characterize the molecular mechanisms of insulin resistance in adipose tissue at late pregnancy. To this end, we analyzed the insulin signaling cascade in lumbar adipose tissue of nonpregnant and pregnant (d 20) rats both under basal and insulin-stimulated conditions. We found that the levels of relevant signaling proteins, such as insulin receptor (

Aims/hypothesis Pleiotrophin, a developmentally regulated and highly conserved cytokine, exerts different functions including regulation of cell growth and survival. Here, we hypothesise that this cytokine can play a regulatory role in glucose and lipid homeostasis. Methods To test this hypothesis, we performed a longitudinal study characterising the metabolic profile (circulating variables and tissue mRNA expression) of gene-targeted Ptn-deficient female mice and their corresponding wild-type counterparts at different ages from young adulthood (3 months) to older age (15 months). Metabolic cages were used to investigate the respiratory exchange ratio and energy expenditure, at both 24°C and 30°C. Undifferentiated immortalised mouse brown adipocytes (mBAs) were treated with 0.1 μg/ml pleiotrophin until day 6 of differentiation, and markers of mBA differentiation were analysed by quantitative real-time PCR (qPCR). Results Ptn deletion was associated with a reduction in total body fat (20.2% in Ptn +/+ vs 13.9% in Ptn −/− mice) and an enhanced lipolytic response to isoprenaline in isolated adipocytes from 15-month-old mice (189% in Ptn +/+ vs 273% in Ptn −/− mice). We found that Ptn −/− mice exhibited a significantly lower QUICKI value and an altered lipid profile; plasma triacylglycerols and NEFA did not increase with age, as happens in Ptn +/+ mice. Furthermore, the contribution of cold-induced thermogenesis to energy expenditure was greater in Ptn −/− than Ptn +/+ mice (42.6% and 33.6%, respectively). Body temperature and the activity and expression of deiodinase, T 3 and mitochondrial uncoupling protein-1 in the brown adipose tissue of Ptn −/− mice were higher than in wild-type controls. Finally, supplementing brown pre-adipocytes with pleiotrophin decreased the expression of the brown adipocyte markers Cidea (20% reduction), Prdm16 (21% reduction), and Pgc1-α (also known as Ppargc1a, 11% reduction). Conclusions/interpretation Our results reveal for the first time that pleiotrophin is a key player in preserving insulin sensitivity, driving the dynamics of adipose tissue lipid turnover and plasticity, and regulating energy metabolism and thermogenesis. These findings open therapeutic avenues for the treatment of metabolic disorders by targeting pleiotrophin in the crosstalk between white and brown adipose tissue.

Insulin resistance is a characteristic of late pregnancy, and adipose tissue is one of the tissues that most actively contributes to the reduced maternal insulin sensitivity. There is evidence that pregnancy is a condition of moderate inflammation, although the physiological role of this low-grade inflammation remains unclear. The present study was designed to validate whether low-grade inflammation plays a role in the development of insulin resistance in adipose tissue during late pregnancy. To this end, we analyzed proinflammatory adipokines and kinases in lumbar adipose tissue of nonpregnant and late pregnant rats at d 18 and 20 of gestation. We found that circulating and tissue levels of adipokines, such as IL-1β, plasminogen activator inhibitor-1, and TNF-α, were increased at late pregnancy, which correlated with insulin resistance. The observed increase in adipokines coincided with an enhanced activation of p38 MAPK in adipose tissue. Treatment of pregnant rats with the p38 MAPK inhibitor SB 202190 increased insulin-stimulated tyrosine phosphorylation of the insulin receptor (IR) and IR substrate-1 in adipose tissue, which was paralleled by a reduction of IR substrate-1 serine phosphorylation and an enhancement of the metabolic actions of insulin. These results indicate that activation of p38 MAPK in adipose tissue contributes to adipose tissue insulin resistance at late pregnancy. Furthermore, the results of the present study support the hypothesis that physiological low-grade inflammation in the maternal organism is relevant to the development of pregnancy-associated insulin resistance.

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