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 this review, tumor necrosis factor-alpha (TNF-alpha) is identified as the uniting principle linking the pathogenesis of insulin-dependent diabetes mellitus (IDDM), non-insulin dependent diabetes mellitus (NIDDM) and carcinoma. Elevated TNF-alpha initially increases, and then inhibits, the activity of a number of key enzymes involved in energy metabolism and major histocompatibility (MHC) class I molecule expression. These enzymes include: protein-tyrosine kinase (PTKase) and protein-tyrosine phosphatase (PTPase--enzymes involved in energy metabolism, cell proliferation and stimulation of the MHC class I molecule pathway. Of primary importance is the inhibiting effect of TNF-alpha on PTKase, since this induces insulin resistance in NIDDM and carcinoma, and PTPase, which inhibits MHC class I molecule expression. Studies have shown that IDDM is associated with an increase in PTPase activity which leads to overexpression of MHC class I molecules and a concomitant destruction of pancreatic beta cells. Conversely, carcinoma is associated with an inhibition of PTPase activity, which reduces the expression of MHC class I antigen expression on the cell surface thereby allowing malignant cells to escape immune surveillance. It will be argued that there is continuum of liability between these three conditions, initiated by the effect of TNF-alpha on these key enzymes.
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PMID:Tumor necrosis factor-alpha: a continuum of liability between insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus and carcinoma (review). 1046 70

Protein-tyrosine phosphatase 1B (PTP1B) has recently received much attention as a potential drug target in type 2 diabetes. This has in particular been spurred by the finding that PTP1B knockout mice show increased insulin sensitivity and resistance to diet-induced obesity. Surprisingly, the highly homologous T cell protein-tyrosine phosphatase (TC-PTP) has received much less attention, and no x-ray structure has been provided. We have previously co-crystallized PTP1B with a number of low molecular weight inhibitors that inhibit TC-PTP with similar efficiency. Unexpectedly, we were not able to co-crystallize TC-PTP with the same set of inhibitors. This seems to be due to a multimerization process where residues 130-132, the DDQ loop, from one molecule is inserted into the active site of the neighboring molecule, resulting in a continuous string of interacting TC-PTP molecules. Importantly, despite the high degree of functional and structural similarity between TC-PTP and PTP1B, we have been able to identify areas close to the active site that might be addressed to develop selective inhibitors of each enzyme.
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PMID:Structure determination of T cell protein-tyrosine phosphatase. 1190 34

The role of protein-tyrosine phosphatase 1B (PTP1B) in diabetes was investigated using an antisense oligonucleotide in ob/ob and db/db mice. PTP1B antisense oligonucleotide treatment normalized plasma glucose levels, postprandial glucose excursion, and HbA(1C). Hyperinsulinemia was also reduced with improved insulin sensitivity. PTP1B protein and mRNA were reduced in liver and fat with no effect in skeletal muscle. Insulin signaling proteins, insulin receptor substrate 2 and phosphatidylinositol 3 (PI3)-kinase regulatory subunit p50alpha, were increased and PI3-kinase p85alpha expression was decreased in liver and fat. These changes in protein expression correlated with increased insulin-stimulated protein kinase B phosphorylation. The expression of liver gluconeogenic enzymes, phosphoenolpyruvate carboxykinase, and fructose-1,6-bisphosphatase was also down-regulated. These findings suggest that PTP1B modulates insulin signaling in liver and fat, and that therapeutic modalities targeting PTP1B inhibition may have clinical benefit in type 2 diabetes.
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PMID:PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice. 1216 59

Resistance to the cellular action of insulin, a fundamental pathophysiological defect accompanying the worldwide epidemic of obesity, is closely associated with the development of type 2 diabetes mellitus and the set of cardiovascular risk factors that constitute the "metabolic" syndrome. The development of novel pharmaceutical agents that help ameliorate insulin resistance will be potentially important not only for the prevention and treatment of diabetes, but also in reducing its associated cardiovascular risk profile. Studies on the cellular role of the protein-tyrosine phosphatase PTP1B have now clearly shown that it serves as a key negative regulator of the tyrosine phosphorylation cascade integral to the insulin signaling pathway. Genetically-modified mice that lack PTP1B protein expression and animals treated with a specific PTP1B antisense oligonucleotide have provided crucial "proof-of-concept" data to show that eradicating or reducing PTP1B enhances insulin signaling and glucose tolerance. PTP1B inhibition also reduces adipose tissue storage of triglyceride under conditions of over-nutrition and was not associated with any obvious toxicity. The effects of the loss of PTP1B in vivo were also remarkably specific for components of the insulin action cascade, in spite of cellular studies suggesting that PTPIB may exert a regulatory influence on a variety of other signaling pathways. Overall, these studies have paved the way for the commercial development of PTP1B inhibitors that may serve as a novel type of "insulin sensitizer" in the management of type 2 diabetes and the cardiovascular / metabolic syndrome.
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PMID:Protein-tyrosine phosphatase 1B (PTP1B): a novel therapeutic target for type 2 diabetes mellitus, obesity and related states of insulin resistance. 1247 92

Insulin resistance, which is pathogenic for type 2 diabetes (T2D), is under the control of largely unknown genetic determinants. LAR, a protein-tyrosine phosphatase which inhibits insulin signalling, is overexpressed in animal and human models of insulin resistance. We studied the entire sequence of the LAR gene by SSCP analysis and automatic DNA sequencing, with the aim of verifying whether its sequence variants might be associated with insulin resistance. In the 276 bp sequence upstream of the transcriptional start site (i.e. a region we have identified as having basal promoter activity) a -127 bp T-->A SNP (5% frequency) was associated with lower body mass index (BMI) ( P=0.03), waist circumference ( P=0.01), blood pressure ( P=0.01) and urinary albumin/creatinine ratio ( P=0.04) in 589 non-diabetic unrelated individuals from the Gargano region (central east coast of Italy). To quantify the risk for a high body weight conferred by the -127 T-->A SNP, the whole cohort was divided into tertiles according to the individual BMI. The risk of belonging to the heavier tertile, as compared to the leaner one, was reduced by approximately 60%. In a population from East Sicily ( n=307), T/A genotype carriers ( n=13) showed lower triglyceride levels ( P=0.04) and higher insulin sensitivity as indicated by lower plasma glucose ( P=0.03) and serum insulin ( P=0.006) during oral glucose tolerance testing (OGTT). Promoter activity, studied by cDNA transfection experiments, was similar for the A and T alleles. In conclusion, a genetic variant of the LAR gene promoter is consistently associated with features of insulin resistance in two different Caucasian populations. Although the biological relevance of this variant has yet to be determined, this finding underlines the potential importance of the LAR gene in dysregulation of insulin sensitivity and related disorders.
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PMID:The allelic variant of LAR gene promoter -127 bp T-->A is associated with reduced risk of obesity and other features related to insulin resistance. 1515 Jun 50

The inhibition of protein-tyrosine phosphatase 1B (PTP1B) is a potential target for treatment of type 2 diabetes. Vanadium and zinc metal coordinated complexes have insulin-enhancing activities, and while vanadium compounds inhibit PTP1B, little is known on the mode of action of zinc compounds. In this study we developed an automated PTP1B inhibition assay that allows for a rapid assessment of the PTP1B inhibition strength of candidate compounds. Synthetic vanadium(IV) and zinc(II) complexes were evaluated: IC50 values for vanadium complexes ranged from 0.06 to 0.8 microM whereas for zinc compounds, values were above 10 microM. Vanadium sulfate, a non-conjugated inorganic salt, had stronger inhibition activity than any of the conjugated metal complexes.
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PMID:Development of an automated protein-tyrosine phosphatase 1B inhibition assay and the screening of putative insulin-enhancing vanadium(IV) and zinc(II) complexes. 1574 40

Type 2 diabetics have an increased risk of developing atherosclerosis, suggesting the mechanisms that cause this disease are enhanced by insulin resistance. In this study we examined the effects of gene knock-out (KO) of lipocalin-type prostaglandin D(2) synthase (L-PGDS), a protein found at elevated levels in type 2 diabetics, on diet-induced glucose tolerance and atherosclerosis. Our results show that L-PGDS KO mice become glucose-in-tolerant and insulin-resistant at an accelerated rate when compared with the C57BL/6 control strain. Adipocytes were significantly larger in the L-PGDS KO mice compared with controls on the same diets. Cell culture data revealed significant differences between insulin-stimulated mitogen-activated protein kinase phosphatase-2, protein-tyrosine phosphatase-1D, and phosphorylated focal adhesion kinase expression levels in L-PGDS KO vascular smooth muscle cells and controls. In addition, only the L-PGDS KO mice developed nephropathy and an aortic thickening reminiscent to the early stages of atherosclerosis when fed a "diabetogenic" high fat diet. We conclude that L-PGDS plays an important role regulating insulin sensitivity and atherosclerosis in type 2 diabetes and may represent a novel model of insulin resistance, atherosclerosis, and diabetic nephropathy.
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PMID:Accelerated glucose intolerance, nephropathy, and atherosclerosis in prostaglandin D2 synthase knock-out mice. 1597 May 90

To investigate the role of low molecular weight protein-tyrosine phosphatase (LMW-PTP) in glucose metabolism and insulin action, a specific antisense oligonucleotide (ASO) was used to reduce its expression both in vitro and in vivo. Reduction of LMW-PTP expression with the ASO in cultured mouse hepatocytes and in liver and fat tissues of diet-induced obese (DIO) mice and ob/ob mice led to increased phosphorylation and activity of key insulin signaling intermediates, including insulin receptor-beta subunit, phosphatidylinositol 3-kinase, and Akt in response to insulin stimulation. The ASO-treated DIO and ob/ob animals showed improved insulin sensitivity, which was reflected by a lowering of both plasma insulin and glucose levels and improved glucose and insulin tolerance in DIO mice. The treatment did not decrease body weight or increase metabolic rate. These data demonstrate that LMW-PTP is a key negative regulator of insulin action and a potential novel target for the treatment of insulin resistance and type 2 diabetes.
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PMID:Reduction of low molecular weight protein-tyrosine phosphatase expression improves hyperglycemia and insulin sensitivity in obese mice. 1735 88

Obesity and type 2 diabetes are characterized by insulin resistance. Mice lacking the protein-tyrosine phosphatase PTP1B in all tissues are hypersensitive to insulin but also have diminished fat stores. Because adiposity affects insulin sensitivity, the extent to which PTP1B directly regulates glucose homeostasis has been unclear. We report that mice lacking PTP1B only in muscle have body weight and adiposity comparable to those of controls on either chow or a high-fat diet (HFD). Muscle triglycerides and serum adipokines are also affected similarly by HFD in both groups. Nevertheless, muscle-specific PTP1B(-/-) mice exhibit increased muscle glucose uptake, improved systemic insulin sensitivity, and enhanced glucose tolerance. These findings correlate with and are most likely caused by increased phosphorylation of the insulin receptor and its downstream signaling components. Thus, muscle PTP1B plays a major role in regulating insulin action and glucose homeostasis, independent of adiposity. In addition, rosiglitazone treatment of HFD-fed control and muscle-specific PTP1B(-/-) mice revealed that rosiglitazone acts additively with PTP1B deletion. Therefore, combining PTP1B inhibition with thiazolidinediones should be more effective than either alone for treating insulin-resistant states.
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PMID:Improved glucose homeostasis in mice with muscle-specific deletion of protein-tyrosine phosphatase 1B. 1772 80

Emerging evidence indicates that aldosterone causes oxidative stress by stimulating proinflammatory/oxidative mediators, including nuclear factor-kappaB, activating protein (AP-1), and c-Jun N-terminal kinase. Thus, in insulin-resistant type 2 diabetes (T2D), oxidative stress generated by hyperglycemia and aldosterone would potentiate the oxidative destruction of tissue and important regulators of glucose metabolism like adiponectin and insulin. Although heme oxygenase (HO)-1 is cytoprotective, its effects on T2D have not been fully characterized. Here we report an enduring antidiabetic effect of the HO inducer, hemin, on Zucker diabetic-fatty rat (ZDF), a model of insulin-resistant T2D. Chronically applied hemin to ZDF reduced and maintained significantly low fasting and postprandial hyperglycemia for 4 months after therapy. The antidiabetic effect was accompanied by enhanced HO activity, catalase, cyclic GMP, bilirubin, ferritin, total antioxidant capacity, and insulin. In contrast, reduced aldosterone alongside markers/mediators of oxidative stress, including 8-isoprostane, c-Jun N-terminal kinase, nuclear factor-kappaB, AP-1, and AP-2 were observed. Interestingly, in hemin-treated ZDF, inhibitory proteins of insulin-signaling, such as glycogen synthase kinase-3 and protein-tyrosine phosphatase-1B were reduced, whereas agents that promote insulin signaling including adiponectin, cAMP, AMP-activated protein kinase, aldolase-B, and glucose transporter-4 (GLUT4), were robustly increased. Correspondingly, hemin improved ip glucose tolerance, reduced insulin intolerance, and lowered insulin resistance (homeostasis model assessment of insulin resistance), and the inability of insulin to enhance GLUT4 was overturned. These results suggest that the suppression of hyperglycemia and aldosterone-induced oxidative stress alongside the potentiation of insulin-sensitizing pathways may account for the 4-month enduring antidiabetic effect. The synergistic interaction between the HO system, aldolase-B, adiponectin, AMP-activated protein kinase, and GLUT4 may be explored for novel strategies against postprandial/fasting hyperglycemia and insulin-resistant T2D.
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PMID:The heme oxygenase system abates hyperglycemia in Zucker diabetic fatty rats by potentiating insulin-sensitizing pathways. 1910 28


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