Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type 2 diabetes is characterized by insulin resistance in skeletal muscle. Since the molecular mechanism of insulin resistance is still unknown, insulin receptor dysfunction including abnormal IRS-1 phosphorylation is considered to be responsible for insulin resistance in some pathological states. Obesity is one of major factors to induce insulin receptor dysfunction. Regarding the mechanism of insulin resistance related obesity, the increased expression of Tumor necrosis factor alpha and abnormality in PTPase in skeletal muscle are postulated. As well as obesity, prolonged hyperglycemia, dyslipidemia and hypertension also induce the impairment of insulin receptor function. Therefore, the enhancement of insulin sensitivity by modulating these factors is a possible treatment modality in insulin resistant states.
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PMID:[Impairments of insulin receptor function in insulin resistant states]. 1070 49

The protein tyrosine phosphatases (PTPases) are a group of regulatory enzymes that are critically important to a wide variety of cellular functions. A number of these PTPases have significant potential as targets for therapeutic intervention, for instance, in diabetes and autoimmune disease treatment. The hydroxylamine complex, bis(N,N-dimethylhydroxamido)hydroxooxovanadate (DMHAV), is an excellent inhibitor of the two PTPases, protein tyrosine phosphatase 1B (PTP1B) and leucocyte common antigen related phosphatase (LAR). However, because of the similarity of the active site architecture within the group of known PTPases, DMHAV is probably an effective inhibitor of most PTPases. Information gleaned from studies of the mechanism of inhibition of PTPases by peptide-derived inhibitors, together with information from comparative protein modelling and studies of the aqueous chemistry of DMHAV, has provided insights for the development of selective PTPase inhibitors. In cell cultures, DMHAV is effective in increasing phosphotyrosine levels on the insulin receptor and greatly facilitates glucose transport and glycogen synthesis. Selective PTPase inhibitors that are developed from the basis of the hydroxylamine motif may lead to effective vanadate-based complexes that have potential as therapeutic agents.
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PMID:Hydroxamido vanadates: aqueous chemistry and function in protein tyrosine phosphatases and cell cultures. 1088 57

Protein-tyrosine phosphatases (PTPases) form a large family of enzymes that serve as key regulatory components in signal transduction pathways. Defective or inappropriate regulation of PTPase activity leads to aberrant tyrosine phosphorylation, which contributes to the development of many human diseases including cancers and diabetes. For example, recent gene knockout studies in mice identify PTP1B as a promising target for anti-diabetes/obesity drug discovery. Thus, there is intense interest in obtaining specific and potent PTPase inhibitors for biological studies and pharmacological development. However, given the highly conserved nature of the PTPase active site, it is unclear whether selectivity in PTPase inhibition can be achieved. We describe a combinatorial approach that is designed to target both the active site and a unique peripheral site in PTP1B. Compounds that can simultaneously associate with both sites are expected to exhibit enhanced affinity and specificity. We also describe a novel affinity-based high-throughput assay procedure that can be used for PTPase inhibitor screening. The combinatorial library/high-throughput screen protocols furnished a small molecule PTP1B inhibitor that is both potent (K(i) = 2.4 nm) and selective (little or no activity against a panel of phosphatases including Yersinia PTPase, SHP1, SHP2, LAR, HePTP, PTPalpha, CD45, VHR, MKP3, Cdc25A, Stp1, and PP2C). These results demonstrate that it is possible to acquire potent, yet highly selective inhibitors for individual members of the large PTPase family of enzymes.
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PMID:Acquisition of a specific and potent PTP1B inhibitor from a novel combinatorial library and screening procedure. 1158 2

Protein tyrosine phosphatases (PTPases) are important targets for the treatment of insulin resistance in patients with type II diabetes and as antibacterial agents. As a result, there is a growing interest in the development of potent and specific inhibitors for these enzymes. This paper describes a series of inhibitors that contain two or three alpha-ketocarboxylic acid groups that are designed to form multiple contacts with residues inside or near the active site of phosphatases. The inhibitors have been assayed against three PTPases: the Yersinia PTPase, PTP1B, and LAR. The best of the inhibitors has IC(50) values against the Yersinia PTPase and PTP1B of 0.7 and 2.7 microM, respectively. These divalent and trivalent compounds are significantly more potent than their corresponding monovalent analogues. In addition, they show good selectivity for PTP1B and the Yersinia PTPase as compared to LAR.
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PMID:Divalent and trivalent alpha-ketocarboxylic acids as inhibitors of protein tyrosine phosphatases. 1219 Mar 16

Phosphotyrosine phosphatase (PTPase) activity and its regulation by overnight food deprivation were studied in Psammomys obesus (sand rat), a gerbil model of insulin resistance and nutritionally induced diabetes mellitus. PTPase activity was measured using a phosphopeptide substrate containing a sequence identical to that of the major site of insulin receptor (IR) beta-subunit autophosphorylation. The PTPase activity in membrane fractions was 3.5-, 8.3-, and 5.9-fold lower in liver, fat, and skeletal muscle, respectively, compared with corresponding tissues of albino rat. Western blotting of tissue membrane fractions in Psammomys showed lower PTPase and IR than in albino rats. The density of PTPase transmembrane protein band was 5.5-fold lower in liver and 12-fold lower in adipose tissue. Leukocyte antigen receptor (LAR) and IR were determined by specific immunoblotting and protein bands densitometry and were also found to be 6.3-fold lower in the liver and 22-fold lower in the adipose tissue in the hepatic membrane fractions. Liver cytosolic PTPase activity after an overnight food deprivation in the nondiabetic Psammomys rose 3.7-fold compared with postprandial PTPase activity, but it did not change significantly in diabetic fasted animals. Similar fasting-related changes were detected in the activity of PTPase derived from membrane fraction. In conclusion, the above data demonstrate that despite the insulin resistance, Psammomys is characterized by low level of PTPase activities in membrane and cytosolic fractions in all 3 major insulin responsive tissues, as well as in liver. PTPase activity does not rise in activity as a result of insulin resistance and nutritionally induced diabetes.
Int J Exp Diabetes Res
PMID:Protein tyrosine phosphatase activity in insulin-resistant rodent Psammomys obesus. 1245 62

Protein tyrosine phosphatases (PTPases) have been suggested to modulate the insulin receptor signal transduction pathways. We studied PTPases in Psammomys obesus, an animal model of nutritionally induced insulin resistance. No changes in the protein expression level of src homology PTPase 2 (SHP-2) (muscle, liver) or leukocyte antigen receptor (LAR) (liver) were detected. In contrast, the expression level of PTPase 1B (PTP 1B) in the skeletal muscle, but not in liver, was increased by 83% in the diabetic animals, compared with a diabetes-resistant line. However, PTP 1B-specific activity (activity/protein) significantly decreased (50% to 56%) in skeletal muscle of diabetic animals, compared with both the diabetes-resistant line and diabetes-prone animals. In addition, PTP 1B activity was inversely correlated to serum glucose level (r = -.434, P < .02). These findings suggest that PTP 1B, though overexpressed, is not involved in the susceptibility to insulin resistance in Psammomys obesus and is secondarily attenuated by hyperglycemia or other factors in the diabetic milieu.
Int J Exp Diabetes Res
PMID:Protein tyrosine phosphatase 1B is impaired in skeletal muscle of diabetic Psammomys obesus. 1245 63

Protein tyrosine phosphatases (PTPases) regulate intracellular signal transduction pathways by controlling the level of tyrosine phosphorylation in cells. These enzymes play an important role in a variety of diseases including type II diabetes and infection by the bacterium Yersinia pestis, which is the causative agent of bubonic plague. This report describes the synthesis, using parallel solution-phase methods, of a library of 104 potential inhibitors of PTPases. The library members are based on the bis(aryl alpha-ketocarboxylic acid) motif that incorporates a carboxylic acid on the central benzene linker. This carboxylic acid was coupled with a variety of different aromatic amines through an amide linkage. The aromatic component of the resulting amides is designed to make contacts with residues that surround the active site of the PTPase. The library was screened against the Yersinia PTPase and PTP1B. Based upon the screening results, four members of the library were selected for further study. These four compounds were evaluated against the Yersinia PTPase, PTP1B, TCPTP, CD45, and LAR. Compound 14 has an IC(50) value of 590nM against PTP1B and is a reversible competitive inhibitor. This affinity represents a greater than 120-fold increase in potency over compound 2, the parent structure upon which the library was based. A second inhibitor, compound 12, has an IC(50) value of 240nM against the Yersinia PTPase. In general, the selectivity of the inhibitors for PTP1B was good compared to LAR, but modest when compared to TCPTP and CD45.
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PMID:Parallel synthesis of a library of bidentate protein tyrosine phosphatase inhibitors based on the alpha-ketoacid motif. 1515 97

Compounds of the trace element vanadium exert various insulin-like effects in in vitro and in vivo systems. These include their ability to improve glucose homeostasis and insulin resistance in animal models of Type 1 and Type 2 diabetes mellitus. In addition to animal studies, several reports have documented improvements in liver and muscle insulin sensitivity in a limited number of patients with Type 2 diabetes. These effects are, however, not as dramatic as those observed in animal experiments, probably because lower doses of vanadium were used and the duration of therapy was short in human studies as compared with animal work. The ability of these compounds to stimulate glucose uptake, glycogen and lipid synthesis in muscle, adipose and hepatic tissues and to inhibit gluconeogenesis, and the activities of the gluconeogenic enzymes: phosphoenol pyruvate carboxykinase and glucose-6-phosphatase in the liver and kidney as well as lipolysis in fat cells contributes as potential mechanisms to their anti-diabetic insulin-like effects. At the cellular level, vanadium activates several key elements of the insulin signal transduction pathway, such as the tyrosine phosphorylation of insulin receptor substrate-1, and extracellular signal-regulated kinase 1 and 2, phosphatidylinositol 3-kinase and protein kinase B activation. These pathways are believed to mediate the metabolic actions of insulin. Because protein tyrosine phosphatases (PTPases) are considered to be negative regulators of the insulin-signalling pathway, it is suggested that vanadium can enhance insulin signalling and action by virtue of its capacity to inhibit PTPase activity and increase tyrosine phosphorylation of substrate proteins. There are some concerns about the potential toxicity of available inorganic vanadium salts at higher doses and during long-term therapy. Therefore, new organo-vanadium compounds with higher potency and less toxicity need to be evaluated for their efficacy as potential treatment of human diabetes.
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PMID:Insulino-mimetic and anti-diabetic effects of vanadium compounds. 1560 84

Protein tyrosine phosphatases (PTPases) and protein tyrosine kinase (PTKases) regulate the phosphorylation and dephosphorylation of tyrosine residues in proteins, events that are essential for a variety of cellular functions. PTPases such as PTP1B and the Yersinia PTPase play an important role in diseases including type II diabetes and bubonic plague. A library of 67 bidentate PTPase inhibitors that are based on the alpha-ketocarboxylic acid motif has been synthesized using parallel solution-phase methods. Two aryl alpha-ketocarboxylic acids were tethered to a variety of different diamine linkers through amide bonds. The compounds were assayed in crude form against the Yersinia PTPase, PTP1B, and TCPTP. Six compounds were selected for further evaluation, in purified form, against the Yersinia PTPase, PTP1B, TCPTP, LAR, and CD45. These compounds had IC50 values in the low micromolar range against the Yersinia PTPase, PTP1B, and TCPTP, showed good selectivity for PTP1B over LAR, and modest selectivity over CD45. The correlation between linker structure and inhibitor activity shows that aromatic groups in the linker can play an important role in determining binding affinity in this class of inhibitors.
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PMID:Investigations of linker structure on the potency of a series of bidentate protein tyrosine phosphatase inhibitors. 1578 8

Protein tyrosine phosphatases (PTPases) are the enzymes responsible for the selective dephosphorylation of tyrosine residues. PTPases function to regulate a wide array of biological responses mediated by growth factors and other stimuli by balancing the cellular level of phosphotyrosine in concert with their counterparts, protein tyrosine kinases. The important roles which PTPases play in regulating intracellular signalling and, ultimately, biological function along with the recent availability of information regarding their structural features has highlighted them as potential targets for pharmacological modulation. This is demonstrated by the increased level of activity directed towards the identification of novel small-molecule PTPase inhibitors. The rationale and potential utility of this drug discovery approach is discussed here, with particular emphasis on its application for the treatment of insulin resistance and Type 2 diabetes.
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PMID:Protein tyrosine phosphatases: their role in insulin action and potential as drug targets. 1599 69


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