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)

In type 2 diabetes (T2D), postprandial and fasting hyperglycemia are important predictors of cardiovascular diseases; however, few drugs are currently available to simultaneously suppress these conditions. Here, we report an enduring antidiabetic effect of the heme oxygenase (HO) inducer hemin on Goto-Kakizaki rats (GK), a nonobese insulin-resistant T2D model. HO breaks down the heme-moiety-generating antioxidants (biliverdin/bilirubin and ferritin) and carbon monoxide, which stimulate insulin secretion. Hemin induces HO-1 to potentiate HO activity and the HO-derived products. Chronically applied hemin (30 mg/kg ip) for a month reduced and maintained fasting glucose at physiological levels for 3 mo. Before therapy, glucose levels were 9.3 +/- 0.3 mmol/l (n = 14). At 1, 2, and 3 mo posttherapy, we recorded 6.7 +/- 0.13, 5.9 +/- 0.2, and 7.2 +/- 0.2 mmol/l, respectively. Hemin was also effective against postprandial hyperglycemia (14.6 +/- 1.1 vs. 7.5 +/- 0.4 mmol/l; n = 14; P < 0.01), and the effect remained sustained for 3 mo after therapy. The reduction of hyperglycemia was accompanied by enhanced HO-1, HO activity, and cGMP of the soleus muscle, alongside increased plasma bilirubin, ferritin, SOD, total antioxidant capacity, and insulin levels, whereas markers/mediators of oxidative stress like urinary-8-isoprostane and soleus muscle nitrotyrosine, NF-kappaB, and activator protein-1 and -2 were abated. Furthermore, inhibitors of insulin signaling including soleus muscle glycogen synthase kinase-3 and JNK were reduced, while the insulin-sensitizing adipokine, adiponectin, alongside AMPK were increased. Correspondingly, hemin improved glucose tolerance, suppressed insulin intolerance, reduced insulin resistance, and overturned the inability of insulin to enhance glucose transporter 4, a protein required for glucose uptake. Hemin also upregulated HO-1/HO activity and cGMP and lowered glucose in euglycemic Sprague-Dawley control rats albeit less intensely, suggesting greater selectivity of the HO system in diabetic conditions. In conclusion, reduced oxidative stress alongside the concomitant and paradoxical enhancement of insulin secretion and insulin-sensitizing pathways may account for the 3-mo-enduring antidiabetic effect. The synergistic interaction among HO, adiponectin, and GLUT4 may be explored against insulin-resistant diabetes.
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PMID:Upregulation of the heme oxygenase system ameliorates postprandial and fasting hyperglycemia in type 2 diabetes. 1920 58

Increases in adiposity trigger metabolic and inflammatory changes that interfere with insulin action in peripheral tissues, culminating in beta cell failure and overt diabetes. We found that the cAMP Response Element Binding protein (CREB) is activated in adipose cells under obese conditions, where it promotes insulin resistance by triggering expression of the transcriptional repressor ATF3 and thereby downregulating expression of the adipokine hormone adiponectin as well as the insulin-sensitive glucose transporter 4 (GLUT4). Transgenic mice expressing a dominant-negative CREB transgene in adipocytes displayed increased whole-body insulin sensitivity in the contexts of diet-induced and genetic obesity, and they were protected from the development of hepatic steatosis and adipose tissue inflammation. These results indicate that adipocyte CREB provides an early signal in the progression to type 2 diabetes.
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PMID:Adipocyte CREB promotes insulin resistance in obesity. 1925 72

Under the activation of insulin receptors, glucose transporter 4 (Glut4) translocation is regulated by two signal transduction pathways. These pathways are the PI 3-kinase-dependent pathway and the CAP/TC10 pathway. The adaptor protein Rap guanine exchange factor 1 (RAPGEF1) also known as C3G is a component of the CAP/TC10 pathway. Defects in the RAPGEF1 protein may contribute to insulin resistance and type 2 diabetes. Recently, the RAPGEF1 gene was suggested to be involved in the development of type 2 diabetes by FUSION study. To investigate this association in the Korean population, we sequenced the RAPGEF1 gene in 24 unrelated individuals and identified 39 sequence variants. Eleven single nucleotide polymorphisms (SNPs) were selected and genotyped in 1122 Korean patients with type 2 diabetes. There were 1138 non-diabetic controls. Using a logistic regression analysis, a significant association was found between SNP rs11243444 in the RAPGEF1 gene and type 2 diabetes [OR=0.490 (95% CI 0.296-0.813), p=0.006] in the recessive model, leading the protective effect of the GG genotype on the disease development. The present study examines genetic polymorphisms in the RAPGEF1 gene, and the positive association between one polymorphism and type 2 diabetes in the Korean population.
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PMID:RAPGEF1 gene variants associated with type 2 diabetes in the Korean population. 1929 53

Advanced glycation end products (AGEs) contribute to the pathogenesis of diabetes-associated complications. Previously, we reported the possible effect of pyridoxamine (K-163), an AGE inhibitor, on improvement of glucose intolerance in type 2 diabetes mellitus KK-A(y)/Ta mice. Recently, AGEs and oxidative stress have been shown to induce insulin resistance. The objective of the present study is to examine the effect of pyridoxamine on glucose intolerance and oxidative stress. C57BL/6J mice were divided into 3 groups as follows: low-fat diet, high-fat diet, and high-fat diet with pyridoxamine treatment. Body and adipose tissue weight, serum insulin, hydrogen peroxide, malondialdehyde and AGE, and urinary 8-hydroxy-2'-deoxyguanosine levels were measured. Nicotinamide adenine dinucleotide phosphate subunits, antioxidant enzymes, and adipocytokine messenger RNA expressions in the adipose tissues were evaluated. Akt/protein kinase B activity and glucose transporter 4 translocation in skeletal muscle were also evaluated. Body and adipose tissue weights of the pyridoxamine treatment group were significantly decreased compared with those of the high-fat diet group. Pyridoxamine attenuated serum hydrogen peroxide, malondialdehyde and AGE, and urinary 8-hydroxy-2'-deoxyguanosine and nicotinamide adenine dinucleotide phosphate oxidase expression; increased antioxidant enzyme expression; and improved dysregulation of adipocytokines in adipose tissues. Pyridoxamine improved blood glucose levels after glucose injection and fasting hyperinsulinemia. Suppressed Akt/protein kinase B activity and glucose transporter 4 translocation in skeletal muscle in high-fat diet mice were improved by pyridoxamine treatment. It appears that the antioxidative effect of pyridoxamine is associated with improvement of glucose intolerance and obesity in C57BL/6J mice fed a high-fat diet. We assume that pyridoxamine may be useful in the treatment of the obesity-associated metabolic syndrome.
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PMID:Effects of pyridoxamine (K-163) on glucose intolerance and obesity in high-fat diet C57BL/6J mice. 1942 56

Ginseng has been reported to ameliorate hyperglycemia in experimental and clinical studies; however, its mechanism of action remains unclear. In this study, we investigated the metabolic effects and putative molecular mechanisms of Korean red ginseng (KRG, Panax ginseng) in animal models for type 2 diabetes mellitus (T2DM) and peripheral insulin-responsive cell lines. Korean red ginseng was administered orally at a dose of 200 mg/(kg d) to Otsuka Long-Evans Tokushima fatty rats for 40 weeks. Initially, chronic administration of KRG reduced weight gain and visceral fat mass in the early period without altering food intake. The KRG-treated Otsuka Long-Evans Tokushima fatty rats showed improved insulin sensitivity and significantly preserved glucose tolerance compared with untreated control animals up to 50 weeks of age, implying that KRG attenuated the development of overt diabetes. KRG promoted fatty acid oxidation by the activation of adenosine monophosphate-activated protein kinase (AMPK) and phosphorylation of acetyl-coenzyme A carboxylase in skeletal muscle and cultured C2C12 muscle cells. Increased expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, nuclear respiratory factor-1, cytochrome c, cytochrome c oxidase-4, and glucose transporter 4 by KRG treatment indicates that activated AMPK also enhanced mitochondrial biogenesis and glucose utilization in skeletal muscle. Although these findings suggest that KRG is likely to have beneficial effects on the amelioration of insulin resistance and the prevention of T2DM through the activation of AMPK, further clinical studies are required to evaluate the use of KRG as a supplementary agent for T2DM.
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PMID:Korean red ginseng (Panax ginseng) improves insulin sensitivity and attenuates the development of diabetes in Otsuka Long-Evans Tokushima fatty rats. 1947 71

The TALLYHO/Jng (TH) mouse strain is a polygenic model for type 2 diabetes (T2D) characterized by moderate obesity, impaired glucose tolerance and uptake, insulin resistance, and hyperinsulinemia. The goal of this study was to elucidate the molecular mechanisms responsible for the reduced glucose uptake and insulin resistance in the adipose tissue of this model. The translocation and localization of glucose transporter 4 (GLUT4) to the adipocyte plasma membrane were impaired in TH mice compared to control C57BL6/J (B6) mice. These defects were associated with decreased GLUT4 protein, reduced phosphatidylinositol 3-kinase activity, and alterations in the phosphorylation status of insulin receptor substrate 1 (IRS1). Activation of c-Jun N-terminal kinase 1/2, which can phosphorylate IRS1 on Ser307, was significantly higher in TH mice compared with B6 controls. IRS1 protein but not mRNA levels was found to be lower in TH mice than controls. Immunoprecipitation with anti-ubiquitin and western blot analysis of IRS1 protein revealed increased total IRS1 ubiquitination in adipose tissue of TH mice. Suppressor of cytokine signaling 1, known to promote IRS1 ubiquitination and subsequent degradation, was found at significantly higher levels in TH mice compared with B6. Immunohistochemistry showed that IRS1 colocalized with the 20S proteasome in proteasomal structures in TH adipocytes, supporting the notion that IRS1 is actively degraded. Our findings suggest that increased IRS1 degradation and subsequent impaired GLUT4 mobilization play a role in the reduced glucose uptake in insulin resistant TH mice. Since low-IRS1 levels are often observed in human T2D, the TH mouse is an attractive model to investigate mechanisms of insulin resistance and explore new treatments.
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PMID:Degradation of IRS1 leads to impaired glucose uptake in adipose tissue of the type 2 diabetes mouse model TALLYHO/Jng. 1958 64

Epidemiological investigations reveal a concomitant increase in sleep loss and metabolic diseases, including type 2 diabetes mellitus, over the past several decades. An increasing body of scientific evidence indicates that acute sleep loss induces insulin resistance and glucose intolerance profiles similar to those of type 2 diabetes mellitus patients. Experimentally, cassia cinnamon (Cinnamomum cassia) supplementation facilitates glucose disposal in healthy humans, which may be achieved by enhancing (1) insulin sensitivity via increased phosphorylation of signaling proteins and (2) insulin-sensitive glucose transporter 4-mediated glucose uptake into muscle cells. Because peripheral insulin resistance is primarily a consequence of reduced muscle insulin sensitivity, C. cassia and C. cassia extracts may attenuate insulin resistance and glucose intolerance observed following sleep loss.
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PMID:Cassia cinnamon for the attenuation of glucose intolerance and insulin resistance resulting from sleep loss. 1962 93

The development of rBAY, a recombinant peptide with the similar sequence of synthetic BAY55-9837, as a potential peptide therapeutic for type 2 diabetes is still a challenge mainly because of its poor stability in aqueous solution. To improve the peptide stability and bioactivity and investigate its biological effects for VPAC2-specific activation, RBAYL with 31 aa was designed based on sequence alignments of pituitary adenylate cyclase-activating peptides (PACAPs), vasoactive intestinal peptide (VIP), and related analogs and generated through sitedirected mutagenesis. Stability analysis showed that the prepared RBAYL with three mutations (N9Q, V17L, and N28K) were much more stable than rBAY. rRBAYL (the recombinant RBAYL) was expressed and purified by gene-recombination technology via native thiol ligation on solid beads. As much as 27.7 mg rRBAYL peptide with purity over 98% was obtained from 1 L of LB medium without expensive high-performance liquid chromatography refinements. The bioactivity assay of rRBAYL showed that it displaced [(125)I]PACAP38 and [(125)I]VIP from VPAC2 with a half-maximal inhibitory concentration of 51+/-6 and 50+/-4 nM, respectively, which were similar to those of the chemically synthesized RBAYL (sRBAYL) and lower than those of Ro25-1553, an established VPAC2 agonist. rRBAYL enhances the cAMP accumulation in CHO cells expressing human VPAC2 with a half-maximal stimulatory concentration (EC50) of 0.91 nM, whereas the receptor potency of rRBAYL at human VPAC1 (EC50 of 719 nM) was only 1/790 of that at human VPAC2, and rRBAYL had no activity toward human PAC1 receptor. Western-blot assay for glucose transporter 4 (GLUT4) indicated that the rRBAYL could significantly induce GLUT4 expression more efficiently than rBAY or Ro25-1553 in adipocytes. Compared with rBAY, rRBAYL can more efficiently promote insulin release and decrease plasma glucose level in ICR mice. Our results suggested that rRBAYL is a novel recombinant VPAC2-specific agonist with high stability and bioactivity.
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PMID:Expression, identification and biological effects of a novel VPAC2-specific agonist with high stability and bioactivity. 2004 43

Blueberries or bilberries contain large amounts of anthocyanins, making them one of the richest sources of dietary anthocyanin. These berries are widely consumed as fresh and dried fruits, jams, or juices. Considerable attention has been focused on the health benefits of bilberry fruits beyond their antioxidant content or their ability to improve vision. In this study, we tested the effect of dietary bilberry extract (BBE) on hyperglycemia and insulin sensitivity in type 2 diabetic mice. We found that dietary BBE ameliorates hyperglycemia and insulin sensitivity via activation of AMP-activated protein kinase (AMPK). Dietary BBE significantly reduced the blood glucose concentration and enhanced insulin sensitivity. AMPK was activated in white adipose tissue (WAT), skeletal muscle, and the liver of diabetic mice fed BBE. This activation was accompanied by upregulation of glucose transporter 4 in WAT and skeletal muscle and suppression of glucose production and lipid content in the liver. At the same time, acetyl-CoA carboxylase was inactivated and PPARalpha, acyl-CoA oxidase, and carnitine palmitoyltransferase-1A were upregulated in the liver. These changes resulted in improved hyperglycemia and insulin sensitivity in type 2 diabetes. These findings provide a biochemical basis for the use of bilberry fruits and have important implications for the prevention and treatment of type 2 diabetes via activation of AMPK.
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PMID:Dietary anthocyanin-rich bilberry extract ameliorates hyperglycemia and insulin sensitivity via activation of AMP-activated protein kinase in diabetic mice. 2008 85

This study was performed to establish whether only 2 sessions per week of combined aerobic and resistance exercise are enough to reduce glycated hemoglobin (HbA(1c)) and to induce changes in skeletal muscle gene expression in Type 2 diabetes mellitus (DM2) subjects with metabolic syndrome. Eight DM2 subjects underwent a 1-yr exercise program consisting of 2 weekly sessions of 140 min that combined aerobic [at 55-70% of maximal oxygen uptake (VO(2max))] and resistance circuit training [at 60-80% of 1 repetition maximum (RM)]. The training significantly improved VO(2max) (from 33.5+/-3.8 ml/kg/min to 38.2+/-3.5 ml/kg/min, p=0.0085) and muscle strength (p<0.05). Changes over baseline were significant for HbA(1c), reduced by 0.45% (p=0.0084), fasting blood glucose (from 8.8+/-1.5 to 6.9+/-2.2 mmol/l, p=0.0132), waist circumference (from 98.9+/-4.8 to 95.9+/-4.6 cm, p=0.0054), body weight (from 87.5+/-10.7 to 85.7+/-10.1 kg, p=0.0375), systolic blood pressure (from 137+/-15 to 126+/-8 mmHg, p=0.0455), total cholesterol (from 220+/-24 to 184+/-13 mg/dl, p=0.0057), and LDL-cholesterol (from 150+/-16 to 105+/-15 mg/dl, p=0.0004). Mitochondrial DNA/nuclear DNA ratio at 6 and 12 months did not change. There was a significant increase of mRNA of peroxisome proliferator- activated receptor (PPAR)-gamma after 6 months of train - ing (p=0.024); PPARalpha mRNA levels were significantly increased at 6 (p=0.035) and 12 months (p=0.044). The mRNA quantification of other genes measured [mitochondrially encoded cytochrome c oxidase subunit II (MTCO2), cytochrome c oxidase subunit Vb (COX5b), PPARgamma coactivator 1alpha (PGC- 1alpha), glucose transporter 4 (GLUT 4), forkhead transcription factor BOX O1 (FOXO-1), carnitine palmitoyltransferase 1 (CPT-1), lipoprotein lipase (LPL), and insulin receptor substrate 1 (IRS-1)] did not show significant changes at 6 and 12 months. This study suggests that a twice-per-week frequency of exercise is sufficient to improve glucose control and the expression of skeletal muscle PPARgamma and PPARalpha in DM2 subjects with metabolic syndrome.
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PMID:Two weekly sessions of combined aerobic and resistance exercise are sufficient to provide beneficial effects in subjects with Type 2 diabetes mellitus and metabolic syndrome. 2014 34


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