Search

In the current study, we investigated the role of tribbles homolog 3 (TRIB3) in glucose-induced insulin resistance and whether the induction of TRIB3 by glucose is dependent on the nutrient-sensing hexosamine biosynthetic pathway (HBP) known to mediate glucose toxicity in diabetes. In diabetic rats, TRIB3 expression in skeletal muscle was increased after 10 days of hyperglycemia and glycemia and muscle TRIB3 were both restored toward normal by insulin therapy. In L6 myocytes, the induction of TRIB3 by high glucose or glucosamine was reversible upon removal of these substrates. To assess the role of HBP in the induction of TRIB3, we demonstrated that the ability of high glucose to augment TRIB3 expression was prevented by azaserine, an inhibitor of glutamine: fructose-6-phosphate amidotransferase (GFAT), which is the rate-limiting enzyme in the HBP pathway. TRIB3 expression was also substantially stimulated by glucosamine, which bypasses GFAT, accompanied by a decrease in the insulin-stimulated glucose transport rate, and neither response was affected by azaserine. Further, knockdown of TRIB3 inhibited, and TRIB3 overexpression enhanced, the ability of both high glucose and glucosamine to induce insulin resistance. These data provide the mechanistic link between the HBP flux and insulin resistance and point to TRIB3 as a novel target for treatment of glucose-induced insulin resistance., Insulin resistance is a major metabolic defect that helps establish and sustain hyperglycemia in type 2 diabetes mellitus (T2DM) and involves impaired insulin-stimulated glucose uptake into skeletal muscle (1,2). A [...]

In established obesity, inflammation and macrophage recruitment likely contribute to the development of insulin resistance. In the current study, we set out to explore whether adipose tissue infiltration by neutrophils that occurs early (3 days) after initiating a high-fat diet (HFD) could contribute to the early occurrence of hepatic insulin resistance and to determine the role of cytosolic phospholipase [A.sub.2]α ([cPLA.sub.2]α) in this process. The 3-day HFD caused a significant upregulation of [cPLA.sub.2]α) in periepididymal fat and in the liver. A specific antisense oligonucleotide (AS) effectively prevented [cPLA.sub.2]α) induction, neutrophil infiltration into adipose tissue (likely involving MIP-2), and protected against 3-day HFD--induced impairment in hepatic insulin signaling and glucose over-production from pyruvate. To sort out the role of adipose neutrophil infiltration independent of [cPLA.sub.2]α) induction in the liver, mice were injected intraperitoneally with anti-intracellular adhesion molecule-1 (ICAM-1) antibodies. This effectively prevented neutrophil infiltration without affecting [cPLA.sub.2]α) or MIP-2, but like AS, prevented impairment in hepatic insulin signaling, the enhanced pyruvate-to-glucose flux, and the impaired insulin-mediated suppression of hepatic glucose production (assessed by clamp), which were induced by the 3-day HFD. Adipose tissue secretion of tumor necrosis factor-α) (TNF-α)) was increased by the 3-day HFD, but not if mice were treated with AS or ICAM-1 antibodies. Moreover, systemic TNF-α) neutralization prevented 3-day HFD--induced hepatic insulin resistance, suggesting its mediatory role. We propose that an acute, [cPLA.sub.2]α)-dependent, neutrophil-dominated inflammatory response of adipose tissue contributes to hepatic insulin resistance and glucose overproduction in the early adaptation to high-fat feeding., Established obesity, particularly if associated with insulin resistance--related morbidities, is characterized by systemic and adipose tissue inflammation (1-3). The complexity of the adipocytokines and inflammatory cell types involved in adipose [...]

The melanocortin-4 receptor (MC4R) is well recognized as an important mediator of body weight homeostasis. Activation of MC4R causes dramatic weight loss in rodent models, and mutations in human are associated with obesity. This makes MC4R a logical target for pharmacological therapy for the treatment of obesity. However, previous studies in rodents and humans have observed a broad array of side effects caused by acute treatment with MC4R agonists, including increased heart rate and blood pressure. We demonstrate that treatment with a highly-selective novel MC4R agonist (BIM-22493 or RM-493) resulted in transient decreases in food intake (35%), with persistent weight loss over 8 weeks of treatment (13.5%) in a diet-induced obese nonhuman primate model. Consistent with weight loss, these animals significantly decreased adiposity and improved glucose tolerance. Importantly, we observed no increases in blood pressure or heart rate with BIM-22493 treatment. In contrast, treatment with LY2112688, an MC4R agonist previously shown to increase blood pressure and heart rate in humans, caused increases in blood pressure and heart rate, while modestly decreasing food intake. These studies demonstrate that distinct melanocortin peptide drugs can have widely different efficacies and side effects., Maintenance of body weight and energy homeostasis requires balance between energy intake and expenditure and is achieved via the interaction between central and peripheral signals. The central melanocortin system is [...]

Accumulating evidence has demonstrated that S-nitrosation of proteins plays a critical role in several human diseases. Here, we explored the role of inducible nitric oxide synthase (iNOS) in the S-nitrosation of proteins involved in the early steps of the insulin-signaling pathway and insulin resistance in the skeletal muscle of aged mice. Aging increased iNOS expression and S-nitrosation of major proteins involved in insulin signaling, thereby reducing insulin sensitivity in skeletal muscle. Conversely, aged iNOS-null mice were protected from S-nitrosation-induced insulin resistance. Moreover, pharmacological treatment with an iNOS inhibitor and acute exercise reduced iNOS-induced S-nitrosation and increased insulin sensitivity in the muscle of aged animals. These findings indicate that the insulin resistance observed in aged mice is mainly mediated through the S-nitrosation of the insulin-signaling pathway., In recent decades, S-nitrosation, the reaction of nitric oxide (NO) with cysteine residues in proteins to form S-nitrosothiol adducts, in addition to phosphorylation, acetylation, and ubiquitination, has become one of [...]

Long-term reduced hypothalamic estrogen signaling leads to increased food intake and decreased locomotor activity and energy expenditure, and ultimately results in obesity and insulin resistance. In the current study, we aimed to determine the acute obesity-independent effects of hypothalamic estrogen signaling on glucose metabolism. We studied endogenous glucose production (EGP) and insulin sensitivity during selective modulation of systemic or intrahypothalamic estradiol (E2) signaling in rats 1 week after ovariectomy (OVX). OVX caused a 17% decrease in plasma glucose, which was completely restored by systemic E2. Likewise, the administration of E2 by microdialysis, either in the hypothalamic paraventricular nucleus (PVN) or in the ventromedial nucleus (VMH), restored plasma glucose. The infusion of an E2 antagonist via reverse microdialysis into the PVN or VMH attenuated the effect of systemic E2 on plasma glucose. Furthermore, E2 administration in the VMH, but not in the PVN, increased EGP and induced hepatic insulin resistance. E2 administration in both the PVN and the VMH resulted in peripheral insulin resistance. Finally, sympathetic, but not parasympathetic, hepatic denervation blunted the effect of E2 in the VMH on both EGP and hepatic insulin sensitivity. In conclusion, intrahypothalamic estrogen regulates peripheral and hepatic insulin sensitivity via sympathetic signaling to the liver., Estradiol (E2) plays a major role in the control of energy homeostasis (1,2), as is exemplified by increased body weight after ovariectomy (OVX) in female rats, and is reversible with [...]

In obesity, white adipose tissue (WAT) inflammation is linked to insulin resistance. Increased adipocyte chemokine (C-C motif) ligand 2 (CCL2) secretion may initiate adipose inflammation by attracting the migration of inflammatory cells into the tissue. Using an unbiased approach, we identified adipose microRNAs (miRNAs) that are dysregulated in human obesity and assessed their possible role in controlling CCL2 production. In subcutaneous WAT obtained from 56 subjects, 11 miRNAs were present in all subjects and downregulated in obesity. Of these, 10 affected adipocyte CCL2 secretion in vitro and for 2 miRNAs (miR-126 and miR-193b), regulatory circuits were defined. While miR-126 bound directly to the 3'-untranslated region of CCL2 mRNA, miR-193b regulated CCL2 production indirectly through a network of transcription factors, many of which have been identified in other inflammatory conditions. In addition, overexpression of miR-193b and miR-126 in a human monocyte/macrophage cell line attenuated CCL2 production. The levels of the two miRNAs in subcutaneous WAT were significantly associated with CCL2 secretion (miR-193b) and expression of integrin, α-X, an inflammatory macrophage marker (miR-193b and miR-126). Taken together, our data suggest that miRNAs may be important regulators of adipose inflammation through their effects on CCL2 release from human adipocytes and macrophages. Diabetes 61:1986-1993, 2012, Obesity is associated with a low-grade inflammatory state in white adipose tissue (WAT), which influences fat cell function and may promote insulin resistance and type 2 diabetes (1,2). Adipocytes and [...]

OBJECTIVE--Increase in adipose cAMP-responsive element-binding protein (CREB) activity promotes adipocyte dysfunction and systemic insulin resistance in obese mice. This is achieved by increasing the expression of activating transcription factor 3 (ATF3). In this study, we investigated whether impaired expression of the inducible cAMP early repressor (ICER), a transcriptional antagonist of CREB, is responsible for the increased CREB activity in adipocytes of obese mice and humans. RESEARCH DESIGN AND METHODS--Total RNA and nuclear proteins were prepared from visceral adipose tissue (VAT) of human nonobese or obese subjects and white adipose tissue (WAT) of C57B16-Rj mice that were fed with normal or high-fat diet for 16 weeks. The expression of genes was monitored by real-time PCR, Western blotting, and electromobility shift assays. RNA interference was used to silence the expression of Icer. RESULTS--The expression of Icer/ICER was reduced in VAT and WAT of obese humans and mice, respectively. Diminution of Icer/ICER was restricted to adipocytes and was accompanied by a rise of Atf3/ATF3 and diminution of Adipoq/ADIPOQ and Glut4/GLUT4. Silencing the expression of Icer in 3T3-L1 adipocytes mimicked the results observed in human and mice cells and hampered glucose uptake, thus confirming the requirement of Icer for appropriate adipocyte function. CONCLUSIONS--Impaired expression of ICER contributes to elevation in CREB target genes and, therefore, to the development of insulin resistance in obesity. Diabetes 60:3169-3174, 2011, Accumulation of visceral fat in obesity is a strong risk factor for life-threatening diseases, such as type 2 diabetes, atherosclerosis, polycystic ovary syndrome, nonalcoholic fatty liver disease, and certain types [...]

OBJECTIVE--Digenic causes of human disease are rarely reported. Insulin via its receptor, which is encoded by INSR, plays a key role in both metabolic and growth signaling pathways. Heterozygous INSR mutations are the most common cause of monogenic insulin resistance. However, growth retardation is only reported with homozygous or compound heterozygous mutations. We describe a novel translocation [t(7,19)(p15.2; p13.2)] cosegregating with insulin resistance and pre- and post-natal growth deficiency. Chromosome translocations present a unique opportunity to identify modifying loci; therefore, our objective was to determine the mutational mechanism resulting in this complex phenotype. RESEARCH DESIGN AND METHODS--Breakpoint mapping was performed by fluorescence in situ hybridization (FISH) on patient chromosomes. Sequencing and gene expression studies of disrupted and adjacent genes were performed on patient-derived tissues. RESULTS--Affected individuals had increased insulin, C-peptide, insulin-to-C-peptide ratio, and adiponectin levels consistent with an insulin receptoropathy. FISH mapping established that the translocation hreakpoints disrupt INSR on chromosome 19p15.2 and CHN2 on chromosome 7p13.2. Sequencing demonstrated INSR haploinsufficiency accounting for elevated insulin levels and dysglycemia. CHN2 encoding β-2 chimerin was shown to be expressed in insulin-sensitive tissues, and its disruption was shown to result in decreased gene expression in patient-derived adipose tissue. CONCLUSIONS--We present a likely digenic cause of insulin resistance and growth deficiency resulting from the combined heterozygous disruption of INSR and CHN2, implicating CHN2 for the first time as a key element of proximal insulin signaling in vivo., The genetic susceptibility to insulin resistance can involve the disruption of a single gene (e.g., INSR) or may involve the interplay of many genetic loci (including PPARG, FTO, HNF1B, etc.). [...]

OBJECTIVE--The RETN gene encodes the adipokine resistin. Associations of RETN with plasma reslstin levels, type 2 diabetes, and related metabolic traits have been inconsistent. Using comprehensive linkage disequilibrium mapping, we genotyped tag single nucleotide polymorphisms (SNPs) in RETN and tested associations with plasma resistin levels, risk of diabetes, and glycemic traits. RESEARCH DESIGN AND METHODS--We examined 2,531 Framingham Offspring Study participants for resistin levels, glycemic phenotypes, and incident diabetes over 28 years of follow-up. We genotyped 21 tag SNPs that capture common (minor allele frequency >0.05) or previously reported SNPs at [r.sup.2] > 0.8 across RETN and its flanking regions. We used sex- and age-adjusted linear mixed-effects models (with/without BMI adjustment) to test additive associations of SNPs with traits, adjusted Cox proportional hazards models accounting for relatedness for incident diabetes, and generated empirical P values ([P.sub.e]) to control for type 1 error. RESULTS--Four tag SNPs (rs1477341, rs4804765, rs1423096, and rs10401670) on the 3' side of RETN were strongly associated with resistin levels (all minor alleles associated with higher levels, [P.sub.e] CONCLUSIONS--SNPs in the 3' region of RETN are associated with resistin levels, and one of them is also associated with glucose levels, although replication is needed., Adipose tissue is now recognized as a prolific endocrine organ. In the past few years, several proteins, called adipokines, produced by adipose tissue have been discovered (1). In the process [...]

OBJECTIVE--Observations of elevated circulating concentrations of visfatin (PBEF/Nampt) in obesity and diabetes suggest that this recently described adipokine is involved in the regulation of body weight and metabolism. We examined in humans whether visfatin is found in cerebrospinal fluid (CSF) and, if so, how CSF visfatin concentrations relate to adiposity and metabolic parameters. RESEARCH DESIGN AND METHODS--We measured visfatin concentrations in the plasma and CSF of 38 subjects (18 men and 20 women; age 19-80 years) with a wide range of body weight (BMI 16.24-38.10 kg/[m.sup.2]). In addition, anthropometric parameters and endocrine markers were assessed. Bivariate correlation coefficients were determined and stepwise multiple regression analyses were performed to detect associations of CSF and plasma visfatin levels with relevant parameters. RESULTS--Plasma visfatin levels increased with rising BMI (P < 0.0001) and body fat mass (P < 0.0001). In contrast, CSF visfatin levels decreased with increasing plasma visfatin concentrations (P < 0.03), BMI (P < 0.001), body fat mass (P < 0.0001), and insulin resistance (P < 0.05). Body fat was the only factor independently associated with CSF visfatin, explaining 58% of the variation of CSF visfatin levels (P < 0.0001). Neither plasma (P > 0.13) nor CSF (P > 0.61) visfatin concentrations differed between men and women. CONCLUSIONS--Our data indicate that visfatin concentrations in human CSF decrease with rising body fat, supporting the assumption that visfatin transport across the blood-brain barrier is impaired in obesity and that central nervous visfatin insufficiency or resistance are linked to pathogenetic mechanisms of obesity. Diabetes 58:637-640, 2009, Body weight regulation critically depends on the interplay between the central nervous system and endocrine messengers from the periphery, adipokines like leptin and adiponectin in particular (1). Visfatin is a [...]

OBJECTIVE--We previously detected an association between a region of the estrogen receptor-α (ESR1) gene and type 2 diabetes in an African-American case-control study; thus, we investigated this region for associations with the metabolic syndrome and its component traits in African-American families from the Insulin Resistance Atherosclerosis Family Study. RESEARCH DESIGN AND METHODS--A total of 17 single nucleotide polymorphisms (SNPs) from a contiguous 41-kb intron 1-intron 2 region of the ESR1 gene were genotyped in 548 individuals from 42 African-American pedigrees. Generalized estimating equations were computed using a sandwich estimator of the variance and exchangeable correlation to account for familial correlation. RESULTS--Significant associations were detected between ESR1 SNPs and the metabolic syndrome (P = 0.005 to P = 0.029), type 2 diabetes (P = 0.001), insulin sensitivity (P = 0.0005 to P = 0.023), fasting insulin (P - 0.022 to P = 0.033), triglycerides (P 0.021), LDL (P = 0.016 to P = 0.034), cholesterol (P = 0.046), BMI (P = 0.016 to P = 0.035), waist circumference (P = 0.012 to P = 0.023), and subcutaneous adipose tissue area (P = 0.016). CONCLUSIONS--It appears likely that ESR1 contributes to type 2 diabetes and CVD risk via pleiotropic effects, leading to insulin resistance, a poor lipid profile, and obesity., Variants in the estrogen receptor-α (ESR1) gene have been associated with components of the metabolic syndrome, including obesity (1), HDL cholesterol (2), LDL metabolism (3), blood pressure (4,5), and type [...]

Insulin resistance and declining insulin production define a spectrum of metabolic diseases afflicting a growing portion of the population (1). Current estimates suggest that 26 million Americans have diabetes, with [...]

According to the authors of a study from Mexico City, Mexico, 'We undertook this study to assess the relationship between circulating adipokines and insulin resistance during pregnancy and postpartum in [...]