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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance has been shown to be the major contributing factor to the metabolic syndrome, which comprises a cluster of risk factors for metabolic aberrations such as obesity, dyslipidemia, hypertension, and hyperglycemia. Additionally, insulin resistance has been associated with the occurrence of cardiovascular disease and type 2 diabetes. Epidemiological studies indicate that obesity and diabetes have become alarmingly prevalent in recent years. Substantial evidence suggests that dietary interventions and regular exercise greatly improve body mass index and lipid profile as well as alleviate insulin resistance. Therefore, dietary supplements such as insulin-sensitizing agents may be beneficial in the prevention and treatment of obesity and type 2 diabetes. Numerous in vitro and in vivo studies suggest that chromium supplements, particularly niacin-bound chromium or chromium-nicotinate, may be effective in attenuating insulin resistance and lowering plasma cholesterol levels. Utilizing the powerful technology of nutrigenomics to identify the genes regulated by chromium supplementation may shed some light on the underlying mechanisms of chromium-gene interactions, and thus provide strategies to mitigate and prevent insulin-resistance-related disorders.
Mol Cell Biochem 2008 Oct
PMID:Nutrigenomic basis of beneficial effects of chromium(III) on obesity and diabetes. 1863 17

Aldoketoreductase 1C3 (AKR1C3) is a functional prostaglandin F synthase and a negative modulator of the availability of ligands for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma). AKR1C3 expression is known to be associated with adiposity, one of the components of the metabolic syndrome. The aim of this study was to characterize the expression of AKR1C3 in the adipose tissue and adipocytes and to investigate its potential role in the metabolic syndrome. Using microarray analysis and realtime PCR, we studied the expression of AKR1C3 in adipose tissue samples from obese subjects with or without metabolic complications, during very low calorie diet-induced weight loss, and its expression in isolated human adipocytes of different sizes. The adipose tissue AKR1C3 expression levels were marginally lower in obese subjects with the metabolic syndrome compared with the levels in healthy obese subjects when analyzed using microarray (p = 0.078) and realtime PCR (p < 0.05), suggesting a secondary or compensatory effect. The adipose tissue mRNA levels of AKR1C3 were reduced during and after dietinduced weight-loss compared to the levels before the start of the diet (p < 0.001 at all time-points). The gene expression of AKR1C3 correlated with both adipose tissue mRNA levels and serum levels of leptin before the start of the diet (p < 0.05 and p < 0.01, respectively). Furthermore, large adipocytes displayed a higher expression of AKR1C3 than small adipocytes (1.5-fold, p < 0.01). In conclusion, adipose tissue AKR1C3 expression may be affected by metabolic disease, and its levels are significantly reduced in response to dietinduced weight loss and correlate with leptin levels.
Cell Mol Biol Lett 2008
PMID:Regulation of human aldoketoreductase 1C3 (AKR1C3) gene expression in the adipose tissue. 1864 23

Daily rhythms in behavior and physiology are observed in most organisms. These rhythms are controlled by internal self-sustained circadian ( approximately 24 h) clocks, which are present in virtually all cells. The 24-h oscillations are generated by a molecular mechanism entrained by external or internal time cues and which, in turn, regulate rhythmic outputs. In mammals, the circadian system comprises a master clock located in the hypothalamus that is directly entrained by the light-dark cycle and which coordinates the phases of local clocks in the periphery in order to ensure optimal timing of the physiology. Nuclear receptors (NRs) form a large family of transcription factors that include both ligand-inducible and orphan receptors. These NRs are key regulators of major biological processes such as reproduction, development, cell growth and death, inflammation, immunity, and metabolic homeostasis. Recent observations indicate that several NR signaling pathways play a critical role in central and peripheral circadian clocks. The REV-ERB/retinoid-related orphan receptor orphan NR subfamily regulates the expression of core clock genes and contributes to the robustness of the clock mechanism. Glucocorticoid and retinoic acid receptors are involved in the resetting of peripheral clocks. Several other NRs such as peroxisome proliferator-activated receptor-alpha, short heterodimer partner, and constitutive androstane receptor act as molecular links between clock genes and specific rhythmic metabolic outputs. The expanding functional links between NRs and circadian clocks open novel perspectives for understanding the hormonal regulation of the mammalian circadian system as well as for exploring the role of circadian clocks in the pathogenesis of NR-related diseases such as cancer and metabolic syndrome.
Mol Endocrinol 2008 Dec
PMID:The nuclear hormone receptor family round the clock. 1865 80

Recent studies have shown that insulin and insulin-like growth factor (IGF)-1 signaling are involved in the control of ageing and longevity in model organisms. Based on these studies, genes involved in the insulin/IGF-1 signaling pathway are believed to play a role in longevity throughout evolution and could also be important in determining human longevity. However, human studies have yielded conflicting and controversial results. In human, defects in insulin receptor signaling cause insulin resistance and diabetes, and IGF-1 deficiency is associated with an increased risk of cardiovascular disease and atherosclerosis. Interestingly, insulin sensitivity normally decreases during aging; however, centenarians were reported to maintain greatly increased insulin sensitivity and had a lower prevalence of the metabolic syndrome as compared to younger subjects. Additionally, a longitudinal study revealed that insulin-sensitizing hormones, including leptin and adiponectin, were significantly associated with the survival of centenarians, indicating that an efficient insulin response may influence human longevity.
Mol Cell Endocrinol 2009 Feb 05
PMID:The metabolic syndrome, IGF-1, and insulin action. 1867 19

Fat cell lipolysis, the cleavage of triglycerides and release of fatty acids and glycerol, evolved to enable survival during prolonged food deprivation but is paradoxically increased in obesity, in which a surfeit of all energy metabolites is found. Essential, previously-unsuspected components have been discovered in the lipolytic machinery, at the protective interface of the lipid droplet surface and in the signaling pathways that control lipolysis. At least two adipocyte lipases are important for controlling lipolysis, hormone-sensitive lipase (HSL) and adipocyte triglyceride lipase (ATGL). Perilipin (PLIN) and possibly other proteins of the lipid droplet surface are master regulators of lipolysis, protecting or exposing the triglyceride core of the droplet to lipases. The prototypes for hormonal lipolytic control are beta adrenergic stimulation and suppression by insulin, both of which affect cyclic AMP levels and hence the protein kinase A-mediated phosphorylation of HSL and PLIN. Newly-recognized mediators of lipolysis include atrial natriuretic peptide, cyclic GMP, the ketone body 3-hydroxybutyrate, AMP kinase and mitogen-activated kinases. Lipolysis must be interpreted in its physiological context since similar rates of basal or stimulated lipolysis occur under different conditions and by different mechanisms. Age, sex, anatomical site, genotype and species differences are each important variables. Manipulation of lipolysis has therapeutic potential in several inborn errors and in the metabolic syndrome that frequently complicates obesity.
Mol Genet Metab 2008 Nov
PMID:Lipolysis and the integrated physiology of lipid energy metabolism. 1876 40

Fatty liver is one of the local morphological manifestations of metabolic syndrome and is frequently associated with insulin resistance. Insulin resistance is also common in patients with chronic hepatitis C. Hyperinsulinemia is an independent risk factor for hypertension and cardiovascular mortality. The aim of this study was to evaluate the therapeutic efficacy of angiotensin II receptor blockers (ARBs), telmisartan and olmesartan, for patients with non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CH-C). We analyzed the incidence of obesity, insulin resistance, and other disorders in patients with NAFLD (Group A), CH-C (Group B), or other liver diseases (Group C). We evaluated whether the ARBs, telmisartan and olmesartan, improved insulin resistance and liver injury by measuring the homeostasis model assessment ratio of insulin resistance (HOMA-IR) and serum alanine aminotransferase (ALT). The incidence of obesity (BMI > or =25 kg/m2) was significantly higher in Group A than in Groups B and C. The incidence of insulin resistance (HOMA-IR > or =2.5) in Groups A and B was significantly higher than in Group C. Regular doses of telmisartan and olmesartan significantly improved HOMA-IR and ALT levels not only in NAFLD patients but also in patients with CH-C. The effects tended to be more notable with telmisartan. In conclusion, telmisartan and olmesartan improved insulin sensitivity and may possibly be used as liver protecting agents in CH-C as well as NAFLD patients.
Int J Mol Med 2008 Oct
PMID:Therapeutic effect of ARBs on insulin resistance and liver injury in patients with NAFLD and chronic hepatitis C: a pilot study. 1881 60

Considering the numerous features of the metabolic syndrome found in rats depleted in long-chain polyunsaturated (n-3) fatty acids and in the perspective of further work conducted in (n-3)-depleted mice, the fatty acid profile of plasma and liver lipids was assessed in both male and female control and second-generation (n-3)-depleted mice. In addition to gender differences, the major alteration found in the (n-3)-depleted animals consisted in the expected severe depletion of plasma triacylglycerols and phospholipids, as well as liver phospholipids, in C20:5(n-3), C22:5(n-3) and C22:6(n-3). In plasma triacylglycerols, the weight percentages of C18:2(n-6) and C18:3(n-6) were lower in (n-3)-depleted mice than in control animals. In both plasma and liver phospholipids, however, the weight percentages of long-chain polyunsaturated (n-6) fatty acids (C20:4(n-6) and C22:4(n-6)) were higher in (n-3)-depleted mice than in control animals. The C16:1(n-7)/C16:0 and C18:1(n-9)/C18:0 ratio in both plasma and liver phospholipids were also increased in female (n-3)-depleted mice but not so in male animals. Highly significant correlations were found between the weight percentage of each fatty acid in liver versus plasma phospholipids. Taken as a whole, these findings indicate that second-generation mice depleted in (n-3) fatty acids represent a suitable model, in terms of the remodelling of the fatty acid profile in plasma and liver lipids, to investigate the metabolic and functional consequences of such a depletion.
Int J Mol Med 2008 Oct
PMID:Fatty acid profile of plasma and liver lipids in mice depleted in long-chain polyunsaturated (n-3) fatty acids. 1881 65

Non-alcoholic fatty liver disease (NAFLD) is considered to be associated with metabolic syndrome; however, a number of NAFLD patients are not obese. To explore any differences in lipid metabolism between obese and non-obese patients, we determined the expression of fatty acid metabolism-related genes. Expression levels of target genes were quantified by real-time PCR using liver biopsy samples from NAFLD patients and normal controls. Serum adipocytokine levels were also determined. The expression of genes related to fatty acid synthesis and uptake was generally up-regulated in NAFLD patients; however, no significant difference was seen between obese and non-obese groups. Most of the genes tested related to fatty acid and reactive oxygen species (ROS) elimination, were overexpressed in NAFLD and the levels were significantly higher in non-obese patients. As an exception, peroxisome proliferator-activated receptor alpha expression was suppressed in NAFLD and the levels were lower in the obese group. Triglyceride synthesis-related genes were up-regulated and lipolytic enzymes were decreased in NAFLD, but there was no significant difference between the obese and non-obese groups. In NAFLD, increased de novo synthesis and uptake of fatty acids led to further hepatocyte accumulation of fatty acids. The up-regulation of fatty acid oxidation and the antioxidant pathway and the suppression of lipolysis seemed to be involved in this process. Expression of genes related to fatty acid oxidation and ROS elimination were higher in the non-obese group than in the obese group, which contributes to the trend of more severe liver injury, insulin resistance and steatosis in obese patients.
Int J Mol Med 2008 Nov
PMID:The significance of differences in fatty acid metabolism between obese and non-obese patients with non-alcoholic fatty liver disease. 1894 88

The microsomal triglyceride transfer protein (MTTP) is a key regulator in the assembly and secretion of chylomicrons and very low density lipoprotein (VLDL) in the intestine and in liver. Associations between MTTP variants and traits of the metabolic syndrome are carried out in relatively small cohorts and are not consistent. We analysed MTTP polymorphisms in 7582 participants of the KORA study cohort. Seven htSNPs covering a 52kb region of the MTTP locus and two cSNPs (I128T, H297Q) were selected. A MTTP haplotype containing the minor allele of H297Q showed a significant decrease of -0.636 (95% CI: -1.226, -0.046; p=0.035) BMI units in females but not in males. In comparison to homozygous H-carriers for the major allele of the MTTP H297Q polymorphism, homozygous Q297Q carriers showed a significant decrease in BMI of -0.425B MI units (95% CI: -0.74, -0.12; p=0.007), in waist circumference of -0.990 cm (95% CI: 1.74, -0.24; p=0.01) and in total cholesterol of -0.039 mmol/l (95% CI: -0.07, 0; p=0.03). Heterozygous Q-carriers displayed a reduction in BMI of -0.183 BMI unit (95% CI: -0.33, -0.04; p=0.012), in waist circumference of -0.45 cm (95% CI: 0.8, -0.1; p=0.01) and in total cholesterol of -0.103 mmol/l (95% CI: -0.18, -0.03; p=0.01). Gender stratified statistics revealed a significant reduction of -0.657 BMI units (95% CI: -1.14, -0.18; p=0.007), -1.437 cm waist circumference (95% CI: -2.55, -0.32; p=0.01) and -0.052 mmol/l total cholesterol (95% CI: -0.1, -0.01; p=0.03) for females homozygous for the Q297Q polymorphism. Females carrying the Q-allele showed a decrease of -0.259 BMI unit (95% CI: -0.48, -0.04; p=0.023), -0.662 cm waist circumference (95% CI: -1.18, -0.14; p=0.01) and -0.111 mmol/l total cholesterol (95% CI: -0.21, -0.01; p=0.03). Our association analysis in a large population based study cohort provides evidence that the minor allele of the MTTP H297Q polymorphism is associated with lower BMI, waist circumference and total cholesterol in females but not in males.
Mol Genet Metab 2008 Dec
PMID:MTTP variants and body mass index, waist circumference and serum cholesterol level: Association analyses in 7582 participants of the KORA study cohort. 1895 Oct 54

Cardiovascular disease is by far the most common complication of type 2 diabetes and also the most serious one. Suffering from type 2 diabetes mellitus not only dramatically increases the risk of cardiovascular disease but is also associated with poor survival, both acutely and in the long term after a myocardial infarction. In fact, total mortality from coronary artery disease in subjects with type 2 diabetes mellitus, without a previous myocardial infarction, is as high as that of non-diabetic individuals with a previous infarction. Intense research efforts have thus been directed towards exploring the reasons for why particularly type 2 diabetic patients have such a poor prognosis suffering from cardiovascular disease. Obesity-related type 2 diabetes ("diabesity"), including the metabolic syndrome, is rapidly rising in prevalence. About 80% of all type 2 diabetes co-exists with insulin resistance. Endothelial dysfunction is a ubiquitous abnormality in insulin-resistant states that might contribute to premature atherosclerosis in a multifactorial and complex way. Low grade inflammation may play a role in development insulin resistance and type 2 diabetes and it has been proposed that atherosclerosis is basically an inflammatory disease. Thus, the pathophysiology of insulin resistance, the metabolic syndrome, and atherosclerosis may share inflammatory basis as a common denominator. Also, insulin resistance is not confined to skeletal muscle, adipose tissue and the liver, but also to the endothelium. Insulin resistance and endothelial dysfunction co-exist, where chronic inflammation may be a crucial factor. Accordingly, the possibility that physical activity or pharmacological agents that increase insulin sensitivity also improve endothelial function, or vice versa, has been investigated. Many different alterations in life style and drugs that improve endothelial function are known to lower the risk of contracting diabetes. In this review, the pharmacological treatment available against type 2 diabetes mellitus is discussed with particular emphasis on its impact on the endothelium.
Mol Cell Endocrinol 2009 Jan 15
PMID:Hypoglycemic pharmacological treatment of type 2 diabetes: targeting the endothelium. 1903 7


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