Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retinol-binding protein-4 (RBP4), a novel protein secreted mainly by adipose tissue, has been associated with insulin resistance in obese subjects and in individuals with type 2 diabetes mellitus (T2DM). We examined the relationship between plasma RBP4 levels, expression of RBP4 in skeletal muscle and adipose tissue, and insulin sensitivity in Mexican Americans with varying degrees of obesity and glucose tolerance. Seventy-two subjects [16 lean normal-glucose-tolerant (NGT), 17 obese NGT, and 39 subjects with impaired fasting glucose/impaired glucose tolerance/T2DM] received an oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp. Insulin secretion was measured as insulinogenic index during OGTT. In a subset of subjects, hepatic glucose production was measured by 3-[3H]glucose infusion, biopsies of the vastus lateralis muscle and subcutaneous adipose tissue were obtained under basal conditions, and quantitative RT-PCR was performed to measure the RBP4 mRNA gene expression. Plasma RBP4 was significantly elevated in impaired glucose tolerance/T2DM compared with NGT lean or obese subjects. Plasma RBP4 levels correlated with 2-h glucose, triglycerides, and hemoglobin A1c. There was no association between RBP4 levels and whole body insulin sensitivity measured with either the euglycemic insulin clamp or OGTT, basal hepatic glucose production rates, and the hepatic insulin resistance index. There was no correlation between plasma RBP4 levels and indexes of insulin secretion. RBP4 mRNA expression in skeletal muscle was similar in lean NGT subjects, obese NGT subjects, and T2DM subjects. There was no difference in RBP4 mRNA expression in adipose tissue between lean and obese NGT subjects or between NGT and T2DM individuals. Plasma RBP4 levels are elevated in T2DM and associated with impaired glucose tolerance, but not associated with obesity or insulin resistance or impaired insulin secretion in Mexican Americans.
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PMID:Retinol-binding protein 4 is associated with impaired glucose tolerance but not with whole body or hepatic insulin resistance in Mexican Americans. 1919 Feb 63

The vitamin A status has been studied in type 2 diabetes and it is known that plasma retinol levels of patients with type 2 diabetes are elevated. However, the details of vitamin A metabolism in type 2 diabetes are unclear. beta-Carotene exhibits biological activity as provitamin A and beta-carotene 15,15'-monooxygenase (BCM) cleaves beta-carotene to form retinal. We studied BCM gene expression in type 2 diabetic Goto-Kakizaki (GK) rats. BCM gene expression was analyzed in the liver, intestine, and testis of 8- and 13-week-old GK rats and Wistar rats (control). The plasma and liver retinol levels were measured, and plasma retinol-binding protein (RBP) was detected. BCM gene expression in the liver, intestine and testis of GK rats was increased compared with that in controls. Plasma retinol levels and RBP levels were increased in GK rats, but hepatic retinol levels did not differ between GK rats and controls. BCM gene expression in the liver and intestine might affect retinol levels in type 2 diabetes. Conversion of beta-carotene to retinal might be accelerated in the presence of insulin resistance status, so that plasma retinol levels are increased in type 2 diabetes.
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PMID:Expression of beta-carotene 15,15'-monooxygenase gene and retinol status in type 2 diabetic Goto-Kakizaki rats. 1927 38

Retinol-binding protein (RBP4) transports retinol in the circulation from hepatic stores to peripheral tissues. Since little is known regarding the regulation of this gene, we analysed the cis-regulatory sequences of the mouse RBP4 gene. Our data show that transcription of the gene is regulated through a bipartite promoter: a proximal region necessary for basal expression and a distal segment responsible for cAMP-induction. This latter region contains several binding sites for the structural HMGA1 proteins, which are important to promoter regulation. We further demonstrate that HMGA1s play a key role in basal and cAMP-induction of Rbp4 transcription and the RBP4 and HMGA1 genes are coordinately regulated in vitro and in vivo. HMGA1 acts to recruit transcription factors to the RBP4 promoter and we specifically identified p54(nrb)/NonO and protein-associated splicing factor (PSF) as components that interact with this complex. Steroidogenic factor 1 (SF1) or the related liver receptor homologue 1 (LRH-1) are also associated with this complex upon cAMP-induction. Depletion of SF1/LRH-1 by RNA interference resulted in a dramatic loss of cAMP-induction. Collectively, our results demonstrate that basal and cAMP-induced Rbp4 transcription is regulated by a multiprotein complex that is similar to ones that modulate expression of genes of steroid hormone biosynthesis. Since genes related to glucose metabolism are regulated in a similar fashion, this suggests that Rbp4 expression may be regulated as part of a network of pathways relevant to the onset of type 2 diabetes.
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PMID:Transcriptional activity of the murine retinol-binding protein gene is regulated by a multiprotein complex containing HMGA1, p54 nrb/NonO, protein-associated splicing factor (PSF) and steroidogenic factor 1 (SF1)/liver receptor homologue 1 (LRH-1). 1938 84

Retinol-binding protein-4 (RBP4) is an emerging candidate drug target for type 2 diabetes and lipofuscin-mediated macular degeneration. The retinoic acid derivative fenretinide (N-(4-hydroxyphenyl) retinamide; HPR) exerts therapeutic effects in mouse models of obesity, diabetes, and Stargardt's disease by targeting RBP4. Fenretinide competes with retinoids for RBP4 binding, disrupts RBP4-transthyretin (TTR) complexes, and results in urinary secretion of RBP4 and systemic depletion of retinol. To enable the search for nonretinoid molecules with fenretinide-like activities we developed a HTS-compatible homogeneous TR-FRET assay monitoring the displacement of retinoic acid derivatives from RBP4 in high-density 384-well and 1536-well microtiter plate formats. The retinoid displacement assay proved to be highly sensitive and robust after miniaturization with IC(50)s for fenretinide and retinol ranging around 50 and 100 nM, respectively, and Z'-factors around 0.7. In addition, a surface plasmon resonance (SPR)-based secondary assay was developed to interrogate small molecule RBP4 binders for their ability to modulate the RBP4-TTR interaction. Finally, a 1.6 x 10(6) compound library was screened against the retinoid displacement assay. Several potent retinoid competitors were identified that also appeared to disrupt RBP4-TTR complexes. Some of these compounds could potentially serve as valuable tools to further probe RBP4 biology in the future.
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PMID:Time-resolved fluorescence resonance energy transfer and surface plasmon resonance-based assays for retinoid and transthyretin binding to retinol-binding protein 4. 1948 4

Retinol-binding protein 4 (RBP4) is an adipokine bound in plasma to transthyretin (TTR), which prevents its glomerular filtration and subsequent catabolism in the kidney. Alterations of this interaction have been suggested to be implicated in the elevation of RBP4 that are thought to contribute to the development of insulin resistance associated with obesity and type 2 diabetes mellitus (T2DM). However, the factors linking RBP4 to TTR in humans are not clear. Therefore, this study evaluated parameters influencing the RBP4-TTR interaction and their relation to obesity and T2DM. The RBP4 and TTR levels were quantified in plasma of 16 lean controls, 28 overweight controls, and 14 overweight T2DM patients by enzyme-linked immunosorbent assay. Transthyretin isoforms involved in RBP4 binding were determined by linear matrix-assisted laser desorption/ionization-time of flight-mass spectrometry after RBP4 coimmunoprecipitation. Holo-RBP4 (retinol-bound) and apo-RBP4 (retinol-free) were assessed by immunoblotting using nondenaturating polyacrylamide gel electrophoresis. Plasma levels of both RBP4 and TTR did not differ among the groups of lean controls, overweight controls, and overweight T2DM subjects. Using RBP4 immunoprecipitation, 4 mass signals were observed for TTR representing native, S-cysteinylated, S-cysteinglycinylated, and S-glutathionylated TTR. No differences in peak intensity of TTR isoforms were observed among the groups. Moreover, no differences in the ratio of holo- and apo-RBP4 were evident. The results suggest that circulating RBP4 and TTR were not affected by human obesity or T2DM, which might be attributed to the absence of alterations of TTR isoforms and the ratio of holo- and apo-RBP4 that might modify the TTR-RBP4 interaction.
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PMID:Factors that influence retinol-binding protein 4-transthyretin interaction are not altered in overweight subjects and overweight subjects with type 2 diabetes mellitus. 1950 59

Some clinical studies and animal researches have evaluated the efficacy of Traditional Chinese Medicine (TCM) and compared its effects with placebo or other antidiabetic drugs. TCM involves three particular plants, as an antidiabetic drug. Our present research planned to evaluate the efficacy of TCM on insulin sensitivity and other related metabolic factors in type 2 diabetic patients. There were 43 newly diagnosed type 2 diabetic patients enrolled in this study, who did not use any antidiabetic drugs before. They were randomly assigned into TCM and placebo groups, administrated with TCM and placebo, respectively. Glucose disposal rate, fasting plasma glucose, postprandial plasma glucose, glycated hemoglobin, and other metabolic components were assessed at baseline and end point. Glucose disposal rate increased from 5.12 +/- 2.20 to 6.37 +/- 3.51 mg kg(-1) min(-1) in the TCM group, ANCOVA analysis showed that glucose disposal rate in the TCM group was significantly improved as compared to that in the placebo group (P < 0.05). Other metabolic related components such as fasting plasma glucose, postprandial plasma glucose, glycated hemoglobin, systolic blood pressure, diastolic blood pressure, body mass index, retinol binding protein 4 were improved in TCM group, but no statistical differences was detected between the two groups. No severe side effect was found in TCM group. TCM can ameliorate insulin resistance in type 2 diabetes and it is safe and effective in newly diagnosed diabetic patients.
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PMID:Improving insulin resistance with traditional Chinese medicine in type 2 diabetic patients. 1972 83

Recent investigations have demonstrated that elevated serum retinol-binding protein 4 (RBP4) secreted from adipose tissue plays a role in the development of systemic insulin resistance, and lowering RBP4 improves insulin sensitivity. These observations provide a rationale for the development of new antidiabetic agents aimed at reducing serum RBP4 concentrations. In this study, we sought to determine whether retinoic acid (RA) administration decreases serum RBP4 and suppresses insulin resistance in diabetic ob/ob mice. All-trans RA [100 mug/(moused) in corn oil] was administered by stomach intubation to a group of ob/ob mice, with the control group receiving the vehicle for 16 d. Body weight and food intake were monitored. Glucose and insulin tolerance tests were performed. We quantified serum RBP4 and retinol by Western blotting and HPLC, respectively. RA treatment reduced body weight (P < 0.05), basal serum glucose (P < 0.001), serum retinol (P < 0.01), and RBP4 (P < 0.05). It improved insulin sensitivity and decreased the retinol:RBP4 ratio (P < 0.05). These studies suggest that RA is an effective antidiabetic agent that could be considered in the treatment of type 2 diabetes.
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PMID:All-trans retinoic acid lowers serum retinol-binding protein 4 concentrations and increases insulin sensitivity in diabetic mice. 2003 83

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent causes of hepatic dysfunction and is highly correlated with components of the metabolic syndrome such as obesity, insulin resistance and type 2 diabetes. Among others, nutritional factors, physical inactivity, genetic variants and visceral obesity have been identified as risk parameters for NAFLD. The complex pathophysiology of fatty liver degeneration, however, and especially the interaction between hepatocytes and adipose tissue has not been completely elucidated. Furthermore, it is not entirely understood whether insulin resistance generates fatty liver disease or vice versa. Nevertheless, adipocytokines are likely to be involved in the pathogenesis of NAFLD since they are secreted not only from adipose tissue but also from the liver. For several adipocytokines such as leptin, adiponectin, tumor necrosis factor-alpha, retinol binding protein 4 (RBP4) or fetuin-A a crucial role in the development and progression of fatty liver disease has been suggested. It has been accepted that obesity is an independent risk factor for NAFLD. Dysregulation of adipocytokines may represent an important mechanism linking increased fat mass in obesity with the development of fatty liver disease. Here, we discuss the association of RBP4 and other recently discovered adipocytokines and their relation with NAFLD.
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PMID:Retinol-binding protein 4 and new adipocytokines in nonalcoholic fatty liver disease. 2037 Jun 70

INTRODUCTION: Early detection, assessment of disease progression, and application of an appropriate therapeutic intervention are all important for the care of patients with type 2 diabetes. Currently, however, there is no simple test for early detection of type 2 diabetes. Established diagnostic tests for the disease including oral glucose tolerance, fasting blood glucose, and hemoglobin A1c are relatively late markers where the disease has already progressed. Since blood is in direct contact with many tissues, we hypothesized that pathological tissue changes are likely to be reflected in proteomic profiles of plasma. METHODS: Mice were reared either on regular chow or a high-fat diet at weaning and several physiological responses (i.e., weight, fasting plasma glucose and insulin, and glucose tolerance) were monitored at regular time intervals. Plasma was collected at regular intervals for proteomic analysis by two-dimensional gel electrophoresis and subsequent mass spectrometry. RESULTS: Onset of hyperinsulinemia with corresponding glucose intolerance was observed in 2 weeks and fasting blood glucose levels rose significantly after 4 weeks on the high-fat diet. Many proteins were found to exist in multiple forms (isoforms). Levels of some isoforms including plasma retinol binding protein, transthyretin, Apolipoprotein A1, and kininogen showed significant changes as early as 4 weeks which coincided with the very early development of glucose intolerance. CONCLUSIONS: These results show that a proteomic approach to study the development of type 2 diabetes may uncover unknown early post-translationally modified diagnostic and/or therapeutic protein targets.
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PMID:Plasma Protein Biomarkers Correlated with the Development of Diet-Induced Type 2 Diabetes in Mice. 2062 78

Our study wants to evaluate the effects of one year treatment with orlistat plus L-carnitine compared to orlistat alone on body weight, glycemic and lipid control, and insulin resistance state in type 2 diabetic patients. Two hundred and fifty-eight patients with uncontrolled type 2 diabetes mellitus (T2DM) [glycated hemoglobin (HbA(1c)) > 8.0%] in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomised to take orlistat 120 mg three times a day plus L-carnitine 2 g one time a day or orlistat 120 mg three times a day. We evaluated at baseline, and after 3, 6, 9, and 12 months these parameters: body weight, body mass index (BMI), HbA(1c), fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tg), retinol binding protein-4 (RBP-4), resistin, visfatin, high sensitivity-C reactive protein (Hs-CRP). We observed a faster, and better decrease of body weight, HbA(1c), FPG, PPG, LDL-C, HOMA-IR with orlistat plus L-carnitine compared to orlistat. A faster improvement of TC, Tg, FPI, resistin, RBP-4, visfatin, and Hs-CRP was reached with orlistat plus L-carnitine compared to orlistat. We can safely conclude that the association of orlistat plus L-carnitine was better than orlistat in improving body weight, glycemic and lipid profile, insulin resistance, and inflammatory parameters and no significant adverse events were recorded.
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PMID:Orlistat and L-carnitine compared to orlistat alone on insulin resistance in obese diabetic patients. 2068 73


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