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)

Protein-tyrosine phosphatases (PTPases) have been implicated in the physiological regulation of the insulin signalling pathway. In cellular and molecular studies, the transmembrane, receptor-type PTPase LAR and the intracellular, non-receptor enzyme PTP1B have been shown to have a direct impact on insulin action in intact cell models. Since insulin signalling can be enhanced by reducing the abundance or activity of specific PTPases, pharmaceutical agents directed at blocking the interaction between individual PTPases and the insulin receptor may have potential clinical relevance to the treatment of insulin-resistant states such as obesity and Type II diabetes mellitus.
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PMID:Regulation of the insulin signalling pathway by cellular protein-tyrosine phosphatases. 960 18

The impaired glucose-induced insulin release in type 2 diabetes mellitus may be accounted for by reduced B-cell ATP/ADP ratio or decreased phosphorylation of proteins regulating exocytosis of insulin. This, in turn, could be due to enhanced phosphatase activity. Using in situ hybridization techniques to assess the expression of 11 different phosphotyrosine phosphatases (PTPases), known to be present in the B-cells, overexpression by approximately 60% of PTP sigma (also known as LAR-PTP2 or PTP NE-3) was demonstrated in pancreatic islets and liver of spontaneously type 2 diabetic Goto-Kakizaki (GK) rats. In agreement with these findings Western blot of islet lysates, using a polyclonal PTP sigma antiserum, showed increased amounts of the protein in GK relative to control rat islets. Exposure of isolated islets for 20 h to 5 muM antisense to PTP sigma, composed of an antisense PNA sequence of 15 bases linked to the cell penetrating peptide transportan, increased glucose-induced insulin secretion from GK rat islets, but not from control islets. In parallel, the amounts of the phosphatase decreased. In conclusion, increased expression of PTP sigma may be of pathogenetic significance for the defective insulin secretion in GK rat islets.
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PMID:Overexpression of protein-tyrosine phosphatase PTP sigma is linked to impaired glucose-induced insulin secretion in hereditary diabetic Goto-Kakizaki rats. 1186 57

Impaired glucose tolerance is present in many acromegalic patients and treatment with somatostatin analogs has variable effects on glycemic control. The aim of this study was to compare the effects of 2 somatostatin analogs on glucose metabolism, lanreotide slow release (L-SR) and octreotide long acting release (O-LAR), in 10 patients with acromegaly (2 of whom with overt Type 2 diabetes mellitus). Glucose and insulin levels in fasting conditions and in response to OGTT, evaluated as AUC, insulin resistance (IR) evaluated by homeostatic model assessment (HOMA-IR), glycosylated hemoglobin (HbA1c), GH, IGF-I, were assessed during L-SR and O-LAR treatment. Mean fasting glucose, glucose response to OGTT and HbA1c levels in 8 non-diabetic patients did not significantly change after L-SR therapy while they all increased after O-LAR treatment (p<0.05 vs baseline and L-SR). Mean HOMA-IR values calculated in acromegalic patients before medical therapy were higher than in normal subjects (p<0.005) and showed a significant decrease during both treatments (p<0.05). In the 2 diabetic acromegalic patients a worsening in glucose metabolism was observed during O-LAR treatment but not during L-SR. GH and IGF-I levels significantly decreased with both drugs and normalized respectively in 38% and 12% with L-SR, 50% and 25% with O-LAR. In conclusion, both drugs decreased IR in acromegalic patients; O-LAR seems to be more detrimental to glucose metabolism than L-SR, despite being more effective in reducing GH and IGF-I levels.
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PMID:Effects of two different somatostatin analogs on glucose tolerance in acromegaly. 1210 20

Type 2 diabetes is increasing at an alarming rate worldwide, and there has been a considerable effort in several laboratories to identify suitable targets for the design of drugs against the disease. To this end, the protein tyrosine phosphatases that attenuate insulin signaling by dephosphorylating the insulin receptor (IR) have been actively pursued. This is because inhibiting the phosphatases would be expected to prolong insulin signaling and thereby facilitate glucose uptake and, presumably, result in a lowering of blood glucose. Targeting the IR protein tyrosine phosphatase, therefore, has the potential to be a significant disease-modifying strategy. Several protein tyrosine phosphatases (PTPs) have been implicated in the dephosphorylation of the IR. These phosphatases include PTPalpha, LAR, CD45, PTPepsilon, SHP2, and PTP1B. In most cases, there is evidence for and against the involvement of the phosphatases in insulin signaling. The most convincing data, however, support a critical role for PTP1B in insulin action. PTP1B knockout mice are not only insulin sensitive but also maintain euglycemia (in the fed state), with one-half the level of insulin observed in wild-type littermates. Interestingly, these mice are also resistant to diet-induced obesity when fed a high-fat diet. The insulin-sensitive phenotype of the PTP1B knockout mouse is reproduced when the phosphatase is also knocked down with an antisense oligonucleotide in obese mice. Thus PTP1B appears to be a very attractive candidate for the design of drugs for type 2 diabetes and obesity.
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PMID:Protein tyrosine phosphatases: the quest for negative regulators of insulin action. 1262 22

The leukocyte common antigen-related protein, LAR, is a receptor-like protein tyrosine phosphatase (PTP) which has a wide tissue distribution. Post-translational processing cleaves the proprotein into two non-covalently associated subunits, an extracellular subunit resembling a cell adhesion molecule with three immunoglobulin-like domains and eight fibronectin III-like domains, and a phosphatase subunit containing a short extracellular domain, a transmembrane segment, and tandem cytoplasmic PTP catalytic domains. Current evidence supports a role for LAR in cadherin complexes where it associates with and dephosphorylates beta-catenin, a pathway which may be critical for cadherin complex stability and cell-cell association. LAR also localizes to focal adhesions. Evidence strongly suggests that LAR is involved in axon guidance in the developing nervous system, being localized through association with alpha-liprins. Finally, considerable data support a role for LAR in negatively regulating the insulin receptor signaling. Now that targeting of specific PTPs for therapeutic inhibition is a reality, the clinically relevant pathways requiring LAR must be identified. Inhibition of LAR might improve insulin sensitivity in patients with insulin resistance and type 2 diabetes. Unfortunately, the LAR knockout mouse displays no improvement in insulin sensitivity but rather has defects in terminal mammary gland development and in basal forebrain cholinergic neurons. With LAR being implicated in diverse pathways, additional investigations are needed before clinical targets for therapeutic inhibition of LAR can be predicted. However, selective inhibitors of LAR would be valuable reagents to probe the function of LAR, particularly in animal studies where the most susceptible LAR-dependent pathway(s) must be determined.
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PMID:The leukocyte common antigen-related protein LAR: candidate PTP for inhibitory targeting. 1267 46

Formylchromone inhibits a human protein tyrosine phosphatase PTP1B with a IC(50) value of 73 microM. The chemical reactivity of formylchromone was adjusted by substitution at various positions of the formylchromone skeleton. In an initial assessment of the structure-activity relationship, the most potent inhibitor showed an IC(50) of 4.3 microM against PTP1B and strong or medium selectivity against other human PTPases, LAR and TC-PTP. This compound, however, was not selective against microbial PTPases, YPTP1 and YOP. The potency and selectivity of the formylchromone derivatives expecting further improvements provides a novel pharmacophore for the design of drugs for the treatment of type 2 diabetes and obesity.
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PMID:Formylchromone derivatives as a novel class of protein tyrosine phosphatase 1B inhibitors. 1285 66

Exenatide [AC002993, AC2993A, AC 2993, LY2148568, exendin 4], a glucagon-like peptide-1 (GLP-1) agonist, is a synthetic exendin 4 compound under development with Amylin Pharmaceuticals for the treatment of type 2 diabetes. Both exendin 4 and its analogue, exendin 3, are 39-amino acid peptides isolated from Heloderma horridum lizard venom that have different amino acids at positions 2 and 3, respectively. Exendins are able to stimulate insulin secretion in response to rising blood glucose levels, and modulate gastric emptying to slow the entry of ingested sugars into the bloodstream. Amylin Pharmaceuticals acquired exclusive patent rights for the two exendin compounds (exendin 3 and exendin 4) from the originator, Dr John Eng (Bronx, NY, US). On 20 September 2002, Amylin and Eli Lilly signed a collaborative agreement for the development and commercialisation of exenatide for type 2 diabetes. Under the terms of the agreement, Eli Lilly has paid Amylin a licensing fee of 80 million US dollars and bought Amylin's stock worth 30 million US dollars at 18.69 US dollars a share. After the initial payment, Eli Lilly will pay Amylin up to 85 US dollars million upon reaching certain milestones and also make an additional payment of up to 130 million US dollars upon global commercialisation of exenatide. Both companies will share the US development and commercialisation costs, while Eli Lilly will pick up up to 80% of development costs and all commercialisation costs outside the US. Amylin and Eli Lilly will equally share profit from sales in the US, while Eli Lilly will get 80% of the profit outside the US and Amylin will get the rest. This agreement has also enabled Amylin to train its sales force to co-promote Lilly's human growth hormone Humatrope. Alkermes will receive research and development funding and milestone payments, and also a combination of royalty payments and manufacturing fees based on product sales. Alkermes undertakes the responsibility for the development of several initial formulations of the long-acting drug and manufacturing of the final product, while Amylin will be responsible for clinical trials, regulatory filings and worldwide marketing. The goal of the exenatide LAR programme is to develop a once-a-month injectable formulation of exenatide. In November 2003, Amylin announced positive results from the second of three pivotal, phase III studies that evaluated the effects of exenatide in combination with sulfonylureas in 377 randomised patients with type 2 diabetes. The design of the study was similar to that from the first study. The final third phase III study of exenatide was completed in November 2003. This study investigated the effects of exenatide in combination with metformin and sulfonylureas. Amylin and Eli Lilly announced that all of the pivotal phase III trials met the primary glucose control endpoint as measured by glycosylated haemoglobin. An NDA submission for exenatide is projected for mid-2004. A phase II, dose-ascending study in patients with type 2 diabetes was initiated in June 2002. This multicentre (US), double-blind, placebo-controlled study evaluated the safety, tolerability and the pharmacokinetic profile of exenatide LAR in up to 100 patients with type 2 diabetes. A phase I study of exenatide LAR began in Europe in March 2001 and was completed in Q3 2001. A long-acting, sustained-release formulation of exenatide lowered both pre- and post-meal glucose concentration during a 24h period in patients with type 2 diabetes. In November 2002, analysts at Prudential Financial estimated that exenatide, pending approval, has the potential to reach sales of 477 million US dollars in 2006.
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PMID:Exenatide: AC 2993, AC002993, AC2993A, exendin 4, LY2148568. 1472 90

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

Protein Tyrosine Phosphatase 1B (PTP1B) has been shown to be a negative regulator of insulin signaling by dephosphorylating key tyrosine residues within the regulatory domain of the beta-subunit of the insulin receptor. Recent gene knockout studies in mice have shown the mice to have increased insulin sensitivity and improved glucose tolerance. Furthermore, these mice also exhibited a resistance to diet induced obesity. Inhibitors of PTP1B would have the potential of enhancing insulin action by prolonging the phosphorylated state of the insulin receptor. In addition, recent clinical studies have shown that the haplotype ACTTCAG0 of the PTPN1 gene, which encodes PTP1B, is a major risk contributor to type 2 diabetes mellitus (T2DM). Thus, there is compelling evidence that small molecule inhibitors of PTP1B may be effective in treating insulin resistance at an early stage, thereby leading to a prevention strategy for T2DM and obesity. Based on the crystal structure of the complex of PTP1B with a known inhibitor, we have identified a tetrapeptide inhibitor with the sequence WKPD. Docking calculations indicate that this peptide is as potent as the existing inhibitors. Moreover, the peptide is also found to be selective for PTP1B with a greatly reduced potency against other biologically important protein tyrosine phosphatases such as PTP-LAR, Calcineurin, and the highly homologous T-Cell Protein Tyrosine Phosphatase (TCPTP). Thus the designed tetrapeptide is a suitable lead compound for the development of new drugs against type 2 diabetes and obesity.
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PMID:In silico structure-based design of a potent and selective small peptide inhibitor of protein tyrosine phosphatase 1B, a novel therapeutic target for obesity and type 2 diabetes mellitus: a computer modeling approach. 1636 74

Protein tyrosine phosphatases (PTPs) are important regulators of signal transduction pathways. Potent and selective PTP inhibitors are useful for probing these pathways and also may serve as drugs for the treatment of a variety of diseases including type 2 diabetes and infection by the bacterium Yersinia pestis. In this report Cu(I)-catalyzed 'click' cycloaddition reactions between azides and alkynes were employed to generate two sequential libraries of PTP inhibitors. In the first round library methyl 4-azidobenzoylformate was reacted with 56 mono- and diynes. After hydrolysis of the methyl esters, the resulting alpha-ketocarboxylic acids were assayed in crude form against the Yersinia PTP and PTP1B. Four compounds were selected for further evaluation, and one compound was chosen as the lead for generation of the second round library. This lead compound was modified by conversion of an alcohol into an azide group, and the resulting azide was reacted with the same 56 mono- and diynes that were used in the first generation library. After screening the crude inhibitors against the Yersinia PTP and PTP1B, four compounds were selected and evaluated in pure form against the Yersinia PTP, PTP1B, TCPTP, LAR, and CD45. The best bis(alpha-ketocarboxylic acid) inhibitor 34 had an IC(50) value of 550nM against the Yersinia PTP and an IC(50) value of 710nM against TCPTP. The most potent inhibitor containing a single alpha-ketocarboxylic acid group 32 had IC(50) values of 2.1, 5.7, and 2.6 microM against the Yersinia PTP, PTP1B, and TCPTP, respectively.
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PMID:A two stage click-based library of protein tyrosine phosphatase inhibitors. 1704 67


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