Mediator Of Insulin Sensitivity Research Articles

Variable bioenergetic sensitivity of neurons and astrocytes to insulin and extracellular glucose

Energy flow within cellular elements of the brain is a well-orchestrated, tightly regulated process, however, details underlying these functions at the single-cell level are still poorly understood. Studying hypometabolism in aging and neurodegenerative diseases may benefit from experimentation on unicellular bioenergetics. Here, we examined energy status in neurons and astrocytes using mixed hippocampal cultures and PercevalHR, an ATP:ADP nanosensor. We assessed exposures of several compounds including KCl, glutamate, FCCP, insulin, and glucose. A mitochondrial stress test was performed, and PercevalHR’s fluorescence was corrected for pH using pHrodo. Results demonstrate that PercevalHR can reliably report on the energetic status of two cell types that communicate in a mixed-culture setting. While KCl, glutamate, and FCCP showed clear changes in PercevalHR fluorescence, insulin and glucose responses were found to be more subtle and sensitive to extracellular glucose. These results may highlight mechanisms that mediate insulin sensitivity in the brain.

Spermidine mediates acetylhypusination of RIPK1 to suppress diabetes onset and progression.

It has been established that N-acetyltransferase (murine NAT1 (mNAT1) and human NAT2 (hNAT2)) mediates insulin sensitivity in type 2 diabetes. Here we show that mNAT1 deficiency leads to a decrease in cellular spermidine-a natural polyamine exhibiting health-protective and anti-ageing effects-but understanding of its mechanism is limited. We identify that mNAT1 and hNAT2 modulate a type of post-translational modification involving acetylated spermidine, which we name acetylhypusination, on receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-a key regulator of inflammation and cell death. Spermidine supplementation decreases RIPK1-mediated cell death and diabetic phenotypes induced by NAT1 deficiency in vivo. Furthermore, insulin resistance and diabetic kidney disease mediated by vascular pathology in NAT1-deficient mice can be blocked by inhibiting RIPK1. Finally, we demonstrate a decrease in spermidine and activation of RIPK1 in the vascular tissues of human patients with diabetes. Our study suggests a role for vascular pathology in diabetes onset and progression and identifies the inhibition of RIPK1 kinase as a potential therapeutic approach for the treatment of type 2 diabetes.

Salubrinal promotes phospho-eIF2α-dependent activation of UPR leading to autophagy-mediated attenuation of iron-induced insulin resistance

Identification of new mechanisms mediating insulin sensitivity is important to allow validation of corresponding therapeutic targets. In this study, we first used a cellular model of skeletal muscle cell iron overload and found that endoplasmic reticulum (ER) stress and insulin resistance occurred after iron treatment. Insulin sensitivity was assessed using cells engineered to express an Akt biosensor, based on nuclear FoxO localization, as well as western blotting for insulin signaling proteins. Use of salubrinal to elevate eIF2α phosphorylation and promote the unfolded protein response (UPR) attenuated iron-induced insulin resistance. Salubrinal induced autophagy flux and its beneficial effects on insulin sensitivity were not observed in autophagy-deficient cells generated by overexpressing a dominant-negative ATG5 mutant or via knockout of ATG7. This indicated the beneficial effect of salubrinal-induced UPR activation was autophagy-dependent. We translated these observations to an animal model of systemic iron overload-induced skeletal muscle insulin resistance where administration of salubrinal as pretreatment promoted eIF2α phosphorylation, enhanced autophagic flux in skeletal muscle and improved insulin responsiveness. Together, our results show that salubrinal elicited an eIF2α-autophagy axis leading to improved skeletal muscle insulin sensitivity both in vitro and in mice.

Circulating leukocyte cell-derived chemotaxin 2 and fibroblast growth factor 21 are negatively associated with cardiorespiratory fitness in healthy volunteers

Leukocyte cell-derived chemotaxin-2 (LECT2) and fibroblast growth factor 21 (FGF21) are hepatokines that are regulated by energy balance and mediate insulin sensitivity and glycaemic control. This cross-sectional study examined the independent associations of cardiorespiratory fitness (CRF), moderate-to-vigorous intensity physical activity (MVPA), and sedentary time with circulating LECT2 and FGF21. Data were combined from two previous experimental studies in healthy volunteers (n = 141, male = 60%, mean ± SD age = 37 ± 19 years, body mass index (BMI) = 26.1 ± 6.3 kg·m-2). Sedentary time and MVPA were measured via an ActiGraph GT3X + accelerometer, while magnetic resonance imaging quantified liver fat. CRF was assessed using incremental treadmill tests. Generalized-linear models examined the association of CRF, sedentary time, and MVPA with LECT2 and FGF21 while controlling for key demographic and anthropometric variables. Interaction terms explored the moderating influence of age, sex, BMI, and CRF. In the fully adjusted models, each SD increase in CRF was independently associated with a 24% (95% CI: -37% to-9%, P = 0.003) lower plasma LECT2 concentration and 53% lower FGF21 concentration (95% CI: -73% to -22%, P = 0.004). Each SD increase in MVPA was independently associated with 55% higher FGF21 (95% CI: 12% to 114%, P = 0.006), and this relationship was stronger in those with lower BMI and higher levels of CRF. These findings demonstrate that CRF and wider activity behaviours may independently modulate the circulating concentrations of hepatokines and thereby influence inter-organ cross-talk.

Globular adiponectin ameliorates insulin resistance in skeletal muscle by enhancing the LKB1-mediated AMPK activation via SESN2

Adiponectin has been demonstrated to be a mediator of insulin sensitivity; however, the underlined mechanisms remain unclear. SESN2 is a stress-inducible protein that phosphorylates AMPK in different tissues. In this study, we aimed to validate the amelioration of insulin resistance by globular adiponectin (gAd) and to reveal the role of SESN2 in the improvement of glucose metabolism by gAd. We used a high-fat diet-induced wild-type and SESN2−/− C57BL/6J insulin resistance mice model to study the effects of six-week aerobic exercise or gAd administration on insulin resistance. In vitro study, C2C12 myotubes were used to determine the potential mechanism by overexpressing or inhibiting SESN2. Similar to exercise, six-week gAd administration decreased fasting glucose, triglyceride and insulin levels, reduced lipid deposition in skeletal muscle and reversed whole-body insulin resistance in mice fed on a high-fat diet. Moreover, gAd enhanced skeletal muscle glucose uptake by activating insulin signaling. However, these effects were diminished in SESN2−/− mice. We found that gAd administration increased the expression of SESN2 and Liver kinase B1 (LKB1) and increased AMPK-T172 phosphorylation in skeletal muscle of wild-type mice, while in SESN2−/− mice, LKB1 expression was also increased but the pAMPK-T172 was unchanged. At the cellular level, gAd increased cellular SESN2 and pAMPK-T172 expression. Immunoprecipitation experiment suggested that SESN2 promoted the formation of complexes of AMPK and LKB1 and hence phosphorylated AMPK. In conclusion, our results revealed that SESN2 played a critical role in gAd-induced AMPK phosphorylation, activation of insulin signaling and skeletal muscle insulin sensitization in mice with insulin resistance.

Glucose mediates insulin sensitivity via a hepatoportal mechanism in high-fat-fed rats.

Poor nutrition plays a fundamental role in the development of insulin resistance, an underlying characteristic of type 2 diabetes. We have previously shown that high-fat diet-induced insulin resistance in rats can be ameliorated by a single glucose meal, but the mechanisms for this observation remain unresolved. To determine if this phenomenon is mediated by gut or hepatoportal factors, male Wistar rats were fed a high-fat diet for 3 weeks before receiving one of five interventions: high-fat meal, glucose gavage, high-glucose meal, systemic glucose infusion or portal glucose infusion. Insulin sensitivity was assessed the following day in conscious animals by a hyperinsulinaemic-euglycaemic clamp. An oral glucose load consistently improved insulin sensitivity in high-fat-fed rats, establishing the reproducibility of this model. A systemic infusion of a glucose load did not affect insulin sensitivity, indicating that the physiological response to oral glucose was not due solely to increased glucose turnover or withdrawal of dietary lipid. A portal infusion of glucose produced the largest improvement in insulin sensitivity, implicating a role for the hepatoportal region rather than the gastrointestinal tract in mediating the effect of glucose to improve lipid-induced insulin resistance. These results further deepen our understanding of the mechanism of glucose-mediated regulation of insulin sensitivity and provide new insight into the role of nutrition in whole body metabolism.

Developmental programming: Changes in mediators of insulin sensitivity in prenatal bisphenol A-treated female sheep

Developmental exposure to endocrine disruptor bisphenol A (BPA) is associated with metabolic defects during adulthood. In sheep, prenatal BPA treatment causes insulin resistance (IR) and adipocyte hypertrophy in the female offspring. To determine if changes in insulin sensitivity mediators (increase in inflammation, oxidative stress, and lipotoxicity and/or decrease in adiponectin) and the intracrine steroidal milieu contributes to these metabolic perturbations, metabolic tissues collected from 21-month-old female offspring born to mothers treated with 0, 0.05, 0.5, or 5 mg/kg/day of BPA were studied. Findings showed prenatal BPA in non-monotonic manner (1) increased oxidative stress; (2) induced lipotoxicity in liver and muscle; and (3) increased aromatase and estrogen receptor expression in visceral adipose tissues. These changes are generally associated with the development of peripheral and tissue level IR and may explain the IR status and adipocyte hypertrophy observed in prenatal BPA-treated female sheep.

Subversion of Systemic Glucose Metabolism as a Mechanism to Support the Growth of Leukemia Cells

From an organismal perspective, cancer cell populations can be considered analogous to parasites that compete with the host for essential systemic resources such as glucose. Here, we employed leukemia models and human leukemia samples to document a form of adaptive homeostasis, where malignant cells alter systemic physiology through impairment of both host insulin sensitivity and insulin secretion to provide tumors with increased glucose. Mechanistically, tumor cells induce high-level production of IGFBP1 from adiposetissue to mediate insulin sensitivity. Further, leukemia-induced gut dysbiosis, serotonin loss, and incretininactivation combine to suppress insulin secretion. Importantly, attenuated disease progression and prolonged survival are achieved through disruption of the leukemia-induced adaptive homeostasis. Our studies provide a paradigm for systemic management of leukemic disease.

Plasma fatty acids in de novo lipogenesis pathway are associated with diabetogenic indicators among adults: NHANES 2003–2004

Insulin regulates fatty acids (FAs) in the blood; conversely, FAs may mediate insulin sensitivity and are potentially modifiable risk factors of the diabetogenic state. The objective of our study was to examine the associations between plasma concentrations of FAs, fasting plasma glucose (FPG), and glycated hemoglobin (HbA1c) among individuals (n=1433) in the NHANES (2003-2004). Plasma concentrations of 24 individual FAs were considered individually and in subgroups, per chemical structure. Study participants were categorized in diabetogenic groups: Group 1 (HbA1c ≥6.5% or FPG ≥126 mg/dL), Group 2 (HbA1c 5.7% to <6.5% or FPG 100 to <126 mg/dL), and Group 3 (HbA1c <5.7% and FPG <100 mg/dL). We assessed associations between diabetogenic groups and plasma FAs in multivariate multinomial regressions (with Group 3 as the reference). Overall, 7.0% of study participants were in Group 1; 33.3% were in Group 2. Plasma concentrations of several individual FAs, including even-chain saturated FAs (SFAs; myristic, palmitic, stearic acids) and monounsaturated FAs (MUFAs; cis-vaccenic, oleic acids), were respectively associated with greater odds of Groups 1 and 2 status, adjusting for covariates. Higher concentrations of SFA and MUFA subgroups (highest compared with lowest quartile) were associated with increased odds of Group 2 status [SFAs adjusted OR (aOR): 1.51 (95% CI: 1.05, 2.18); MUFAs aOR: 1.78 (95% CI: 1.11, 2.85)]. Higher eicosapentaenoic acid plasma concentration was associated with decreased odds of Group 1 status [quartile 4 aOR: 0.41 (95% CI: 0.17, 0.95)]. Higher plasma concentrations of SFAs and MUFAs, primary de novo lipogenesis products, were associated with elevated FPG and HbA1c in a nationally representative study population in the United States. Additional studies are necessary to elucidate potential causal relationships between FAs (from endogenous production and dietary consumption) and diabetogenic indicators, as well as clinical implications for managing diabetes and prediabetes.

The Adipose-Derived Insulin Sensitizer Adiponectin Can Activate Intracellular Signaling Independent of the Well Known AdipoR1 or AdipoR2 Receptors

Adiponectin (ADN) is a crucial mediator of insulin sensitivity and vascular health. The discoveries of the adiponectin receptors AdipoR1 and AdipoR2 (R1 and R2) prompted efforts to identify ADN-mimetics. R1 and R2 are especially difficult drug targets due to the complex higher-order structures of ADN as well as challenges in creating receptor knock-out cell lines. We approached R1 and R2 as possible targets beginning with a rigorous validation of the ligand and receptors. ADN preparations from multiple internal and external sources were characterized in physicochemical, cell binding and in vitro assays (pAMPK/pACC and ceramidase). It is important to note that ADN from only one source passed this evaluation. This ADN triggered in vitro activities associated with this protein, including stimulation of phosphorylation of ACC (EC50 = 9.3 ug/ml), calcium influx (EC50 = 2.2 ug/ml), glucose uptake, fatty acid oxidation and ceramidase activity. With a biologically active ADN preparation identified, we strove to understand the interactions of ADN with R1 and R2. However, both R1 and R2 are ubiquitously expressed, complicating the in vitro confirmation of receptor-dependent functional activity. We selected HAP1 cells, an ADN-responsive haploid CML derived line well-suited for gene deletion via CRISPR-Cas9 technology, to generate R1, R2 and R1/R2 deficient cells. Surprisingly, the stimulatory activity of adiponectin in pACC and ceramidase assays in HAP1 cells deficient in R1, R2 or both R1 and R2 were indistinguishable from those in wild type HAP1 cells. In addition, transient overexpression of R1 in HAP1 cells or pretreatment with antibodies to block R1 did not alter their pACC responses to ADN. These data indicate R1 and R2 are not responsible for all the in vitro biological activity attributed to ADN and suggest that there must be other yet unidentified receptors for ADN. Disclosure J.W. Gunnet: Employee; Self; Janssen Research &amp; Development. W. Li: None. Y. Wang: None. J.A. Chavez: None. M. Husovsky: None. R. Meng: None. W. Lang: None. J.R. Jeyaseelan: Employee; Self; Janssen Pharmaceuticals, Inc.. G.W. Caldwell: None. S. Edavettal: Employee; Self; Janssen Research &amp; Development.

Peroxiredoxin 2 mediates insulin sensitivity of skeletal muscles through regulation of protein tyrosine phosphatase oxidation.

Insulin signaling is essential for regulating glucose homeostasis. Numerous studies have demonstrated that reactive oxygen species (ROS) affect insulin signaling, and low ROS levels can act as a signal to regulate cellular function. Peroxiredoxins (Prxs) are highly abundant and widely expressed antioxidant enzymes. However, it is unclear whether antioxidant enzymes, such as Prx2, mediate insulin signaling. The aim of our study was to investigate the influence of Prx2 deficiency on insulin signaling. Our western blot results showed that Prx2 deficiency enhanced insulin signaling and increased oxidation of protein tyrosine phosphatase 1B (PTP1B) and phosphatase and tensin homologue (PTEN) in mouse embryonic fibroblasts (MEFs) treated with insulin. In addition, we assessed ROS levels with a Cytosol-HyPer H2O2 sensor. As a result, increased ROS levels and Akt activation were decreased by N-acetyl-cysteine (Nac), which acted as an antioxidant in Prx2-deficient MEFs. Body weight measurements and glucose tolerance test (GTT) revealed significant body weight reduction and increase in glucose clearance in Prx2-/- mice fed a high-fat diet. Interestingly, glucose transporter type 4 (GLUT4) was significantly higher in Prx2-/- mice than in wild-type mice according to western blotting results. Western blotting also revealed that Akt phosphorylation was higher in Prx2-/- MEFs and muscle tissue than in wild-type. Together, our findings indicate that increased ROS due to Prx2 deficiency promotes insulin sensitivity and glucose clearance in skeletal muscles by increasing protein tyrosine phosphatase (PTPs) oxidation. These results provide novel insights into the fundamental mechanisms of insulin signaling induced by Prx2 deficiency and suggest that ROS-based therapeutic strategies can be used to suppress insulin resistance.

Abstract 040: The Effects of Coffee Consumption on Insulin Sensitivity and Other Risk Factors for Type 2 Diabetes

Background: In observational studies, coffee consumption has been consistently associated with a lower risk of type 2 diabetes mellitus. Trials examining the effect of coffee consumption on glucose metabolism have been limited by the use of surrogate insulin sensitivity indices, small sample sizes, lack of blinding, and short follow-up duration. We aimed to overcome these limitations in a randomized placebo-controlled trial examining the effects of coffee consumption on insulin sensitivity. Methodology: We conducted a 24-week randomized placebo-controlled trial in 126 overweight, insulin-resistant (HOMA-IR ≥ 1.30), Chinese, Malay and Asian-Indian males and females aged 35-69 years. Participants were randomly assigned to receive 4 cups of instant regular coffee (n=62) or 4 cups of a coffee-like placebo beverage (n=64) per day. The primary outcome was bodyweight-standardized M-value (M bw ) assessed with a hyperinsulinemic euglycemic clamp. Secondary outcomes included other clamp-based insulin sensitivity measures, biological mediators of insulin sensitivity, and measures of fasting glucose metabolism, body weight and composition. Results: Coffee consumption did not significantly change insulin sensitivity as compared with placebo [% mean difference in M bw : 0.3% (95% CI: -12.0% to 14.2%), P =0.97]. Furthermore, no significant differences in fasting plasma glucose [3.0% (-1.1% to 7.3%), P =0.16] or biological mediators of insulin resistance, such as plasma adiponectin [1.5% (-3.4% to 6.6%), P =0.55], were observed between coffee and placebo groups after 24 weeks of intervention. Coffee consumption led to a loss of body weight as compared with placebo [-1.2% (-2.3% to -0.1%), P =0.03] resulting from a decrease in fat mass [-3.7% (-7.1% to -0.2%), P =0.04] . Conclusions: Consuming 4 cups per day of caffeinated coffee for 24 weeks had no significant effect on insulin sensitivity or biological mediators of insulin resistance. Coffee consumption led to a modest decrease in body fat as compared with coffee abstinence. Trial Registration: ClinicalTrials.gov identifier: NCT01738399. Registered on 28 November 2012. Trial Sponsor: Nestlé Research Center, Lausanne, Switzerland. Trial Site: National University of Singapore.

Developmental Programming: Impact of Gestational Steroid and Metabolic Milieus on Mediators of Insulin Sensitivity in Prenatal Testosterone-Treated Female Sheep.

Prenatal testosterone (T) excess in sheep leads to peripheral insulin resistance (IR), reduced adipocyte size, and tissue-specific changes, with liver and muscle but not adipose tissue being insulin resistant. To determine the basis for the tissue-specific differences in insulin sensitivity, we assessed changes in negative (inflammation, oxidative stress, and lipotoxicity) and positive mediators (adiponectin and antioxidants) of insulin sensitivity in the liver, muscle, and adipose tissues of control and prenatal T-treated sheep. Because T excess leads to maternal hyperinsulinemia, fetal hyperandrogenism, and functional hyperandrogenism and IR in their female offspring, prenatal and postnatal interventions with antiandrogen, flutamide, and the insulin sensitizer rosiglitazone were used to parse out the contribution of androgenic and metabolic pathways in programming and maintaining these defects. Results showed that (1) peripheral IR in prenatal T-treated female sheep is related to increases in triglycerides and 3-nitrotyrosine, which appear to override the increase in high-molecular-weight adiponectin; (2) liver IR is a function of the increase in oxidative stress (3-nitrotyrosine) and lipotoxicity; (3) muscle IR is related to lipotoxicity; and (4) the insulin-sensitive status of visceral adipose tissue appears to be a function of the increase in antioxidants that likely overrides the increase in proinflammatory cytokines, macrophages, and oxidative stress. Prenatal and postnatal intervention with either antiandrogen or insulin sensitizer had partial effects in preventing or ameliorating the prenatal T-induced changes in mediators of insulin sensitivity, suggesting that both pathways are critical for the programming and maintenance of the prenatal T-induced changes and point to potential involvement of estrogenic pathways.

Fibroblast growth factor 21 reverses suppression of adiponectin expression via inhibiting endoplasmic reticulum stress in adipose tissue of obese mice.

Fibroblast growth factor 21 (FGF21) has recently emerged as a novel endocrine hormone involved in the regulation of glucose and lipid metabolism. However, the exact mechanisms whereby FGF21 mediates insulin sensitivity remain not fully understood. In the present study, FGF21was administrated in high-fat diet-induced obese mice and tunicamycin-induced 3T3-L1 adipocytes, and metabolic parameters, endoplasmic reticulum (ER) stress indicators, and insulin signaling molecular were assessed by Western blotting. The administration of FGF21 in obese mice reduced body weight, blood glucose and serum insulin, and increased insulin sensitivity, resulting in alleviation of insulin resistance. Meanwhile, FGF21 treatment reversed suppression of adiponectin expression and restored insulin signaling via inhibiting ER stress in adipose tissue of obese mice. Additionally, suppression of ER stress via the ER stress inhibitor tauroursodeoxycholic acid increased adiponectin expression and improved insulin resistance in obese mice and in tunicamycin-induced adipocytes. In conclusion, our results showed that the administration of FGF21 reversed suppression of adiponectin expression and restored insulin signaling via inhibiting ER stress under the condition of insulin resistance, demonstrating the causative role of ER stress in downregulating adiponectin levels.

The Glucose Sensor ChREBP Links De Novo Lipogenesis to PPARγ Activity and Adipocyte Differentiation.

Reduced de novo lipogenesis in adipose tissue, often observed in obese individuals, is thought to contribute to insulin resistance. Besides trapping excess glucose and providing for triglycerides and energy storage, endogenously synthesized lipids can function as potent signaling molecules. Indeed, several specific lipids and their molecular targets that mediate insulin sensitivity have been recently identified. Here, we report that carbohydrate-response element-binding protein (ChREBP), a transcriptional inducer of glucose use and de novo lipogenesis, controls the activity of the adipogenic master regulator peroxisome proliferator-activated receptor (PPAR)γ. Expression of constitutive-active ChREBP in precursor cells activated endogenous PPARγ and promoted adipocyte differentiation. Intriguingly, ChREBP-constitutive-active ChREBP expression induced PPARγ activity in a fatty acid synthase-dependent manner and by trans-activating the PPARγ ligand-binding domain. Reducing endogenous ChREBP activity by either small interfering RNA-mediated depletion, exposure to low-glucose concentrations, or expressing a dominant-negative ChREBP impaired differentiation. In adipocytes, ChREBP regulated the expression of PPARγ target genes, in particular those involved in thermogenesis, similar to synthetic PPARγ ligands. In summary, our data suggest that ChREBP controls the generation of endogenous fatty acid species that activate PPARγ. Thus, increasing ChREBP activity in adipose tissue by therapeutic interventions may promote insulin sensitivity through PPARγ.

Association between hyperleptinemia and oxidative stress in obese diabetic subjects.

BackgroundObesity is a worldwide metabolic disorder affecting all types of people. The mechanism by which increased body fat mass that leads to insulin resistance and type 2 diabetes is not yet clearly known. There is a possible crosstalk between leptin, an adipokine and insulin signaling. Leptin mediates insulin sensitivity in hepatocytes; however, its concentration has found to be increased in obese and diabetic subjects. These subjects also have high incidence of oxidative stress status. Therefore, knowing the level of leptin present in obese diabetic subjects will be informative along with its relation to oxidative stress.MethodsA small population study was performed to explore the association between leptin concentration and oxidative stress status in control and obese type 2 diabetic subjects. Oxidative stress status parameters like malondialdehyde (MDA), superoxide dismutase activity (SOD), glutathione peroxidase activity (GSH-Px), and protein carbonyl (PCO) groups content was measured spectrophotometrically in serum of 43 subjects. Serum Leptin concentration was measured by quantikine sandwich ELISA assay.ResultsThe strong positive correlation between MDA (malondialdehyde) and leptin in obese diabetic patients (ρ = 0.787, P < 0.05) suggests close association between lipid peroxidation and hyperleptinemia. In addition, observed positive correlation between protein carbonyl groups and leptin level in obese diabetic subjects (ρ = 0.599, P = 0.001) suggest that hyperleptinemia might also be associated with increased protein oxidation. In multiple logistic regression analysis, leptin has shown a significant association with obese type 2 diabetes [odds ratio (OR): 1.161, 95% confidence interval (Cl): 1.027-1.312, P < 0.05], but the significance is lost after adjusting for Age, BMI, MDA and anti-oxidant parameters.ConclusionsIn the subjects with both obesity and diabetes, there is a significant degree of association between hyperleptinemia and oxidative stress. This association reinforces the existing understanding that obese subjects who also have diabetes are vulnerable to cardiovascular complications driven by increased oxidative stress and hyperleptinemia.

Validation of insulin sensitivity surrogate indices and prediction of clinical outcomes in individuals with and without impaired renal function

As chronic kidney disease (CKD) progresses with abnormalities in glucose and insulin metabolism, commonly used insulin sensitivity indices (ISIs) may not be applicable in individuals with CKD. Here we sought to validate surrogate ISIs against the glucose disposal rate by the gold-standard hyperinsulinemic euglycemic glucose clamp (HEGC) technique in 1074 elderly men of similar age (70 years) of whom 495 had and 579 did not have CKD (estimated glomerular filtration rate (eGFR) under 60 ml/min per 1.73 m(2) (median eGFR of 46 ml/min per 1.73 m(2))). All ISIs provided satisfactory (weighted κ over 0.6) estimates of the glucose disposal rate in patients with CKD. ISIs derived from oral glucose tolerance tests (OGTTs) agreed better with HEGC than those from fasting samples (higher predictive accuracy). Regardless of CKD strata, all ISIs allowed satisfactory clinical discrimination between the presence and absence of insulin resistance (glucose disposal rate under 4 mg/kg/min). We also assessed the ability of both HEGC and ISIs to predict all-cause and cardiovascular mortality during a 10-year follow-up. Neither HEGC nor ISIs independently predicted mortality. Adjustment for renal function did not materially change these associations. Thus, ISIs can be applied in individuals with moderately impaired renal function for diagnostic purposes. For research matters, OGTT-derived ISIs may be preferred. Our data do not support the hypothesis of kidney function mediating insulin sensitivity (IS)-associated outcomes nor a role for IS as a predictor of mortality.

Therapeutic Potential of the Natural Product Mangiferin in Metabolic Syndrome

Natural products have long been and continue to be attractive source of nutritional and pharmacological therapeutics. Interest in natural compounds as potential therapies for metabolic syndrome have recently focused on hydroxylated aromatics, such as resveratrol. Another compound of interest in this regard is mangiferin, the predominant constituent of extracts of the mango plant Mangifera indica. Mangiferin has documented antioxidant, cardioprotective and anti-inflammatory effects. Recently, pilot studies indicate bioactivity of this compound in mediating insulin sensitivity and modulating lipid metabolism. In this review we provide information on what we know about the impact of mangiferin on important biological processes involved in metabolic disorders.

Ablation of Calcineurin Aβ Reveals Hyperlipidemia and Signaling Cross-talks with Phosphodiesterases

Insulin resistance, hyperlipidemia, and cardiovascular complications are common dysregulations of metabolic syndrome. Transplant patients treated with immunosuppressant drugs such as cyclosporine A (CsA), an inhibitor of calcineurin phosphatase, frequently develop similar metabolic complications. Although calcineurin is known to mediate insulin sensitivity by regulating β-cell growth and adipokine gene transcription, its role in lipid homeostasis is poorly understood. Here, we examined lipid homeostasis in mice lacking calcineurin Aβ (CnAβ(-/-)). We show that mice lacking calcineurin Aβ are hyperlipidemic and develop age-dependent insulin resistance. Hyperlipidemia found in CnAβ(-/-) mice is, in part, due to increased lipolysis in adipose tissues, a process mediated by β-adrenergic G-protein-coupled receptor signaling pathways. CnAβ(-/-) mice also exhibit additional pathophysiological phenotypes caused by the potentiated GPCR signaling pathways. A cell autonomous mechanism with sustained cAMP/PKA activation is found in CnAβ(-/-) mice or upon CsA treatment to inhibit calcineurin. Increased PKA activation and cAMP accumulation in CnAβ(-/-) mice, however, are sensitive to phosphodiesterase inhibitor. Indeed, we show that calcineurin regulates degradation of phosphodiesterase 3B, in addition to phosphodiesterase 4D. These results establish a role for calcineurin in lipid homeostasis. These data also indicate that potentiated cAMP signaling pathway may provide an alternative molecular pathogenesis for the metabolic complications elicited by CsA in transplant patients.

Differentially expressed genes in adipocytokine signaling pathway of adipose tissue in pregnancy.

ObjectiveTo profile the differential gene expression of the KEGG Adipocytokine Signaling pathway in omental compared to subcutaneous tissue in normal pregnancy.Study DesignSubjects included 14 nonobese, normal glucose tolerant, healthy pregnant women. Matched omental and subcutaneous tissue were obtained at elective cesarean delivery. Gene expression was evaluated using microarray and validated by RT-PCR. Differential gene expression was defined as ≥1.5 fold increase at p < 0.05.ResultsSix genes were significantly downregulated with two upregulated genes in omental tissue. Downregulation of Adiponectin and Insulin Receptor substrate, key genes mediating insulin sensitivity, were observed with borderline upregulation of GLUT-1. There were downregulations of CD36 and acyl-CoA Synthetase Long-chain Family Member 1which are genes involved in fatty acid uptake and activation. There was a novel expression of Carnitine palmitoyltransferase 1C.ConclusionDifferential gene expression of Adipocytokine Signaling Pathway in omental relative to subcutaneous adipose tissue in normal pregnancy suggests a pattern of insulin resistance, hyperlipidemia, and inflammation.