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 phosphatase 1B (PTP1B) has been implicated in the regulation of the insulin signaling pathway and represents an attractive target for the design of inhibitors in the treatment of type 2 diabetes and obesity. Inspection of the structure of PTP1B indicates that potent PTP1B inhibitors may be obtained by targeting a secondary aryl phosphate-binding site as well as the catalytic site. We report here the crystal structures of PTP1B in complex with first and second generation aryldifluoromethyl-phosphonic acid inhibitors. While all compounds bind in a previously unexploited binding pocket near the primary binding site, the second generation compounds also reach into the secondary binding site, and exhibit moderate selectivity for PTP1B over the closely related T-cell phosphatase. The molecular basis for the selectivity has been confirmed by single point mutation at position 52, where the two phosphatases differ by a phenylalanine-to-tyrosine switch. These compounds present a novel platform for the development of potent and selective PTP1B inhibitors.
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PMID:The structural basis for the selectivity of benzotriazole inhibitors of PTP1B. 1451 96

The prevalence and medical and economic impact of type 2 diabetes mellitus is increasing in Western societies. New agents have been developed that act primarily to reduce postprandial glucose excursions, which may be of particular significance now that postprandial glucose excursions are known to be correlated with cardiovascular morbidity and mortality. Nateglinide is a phenylalanine derivative that blocks K+ channels in pancreatic beta-cells, facilitating insulin secretion. Nateglinide sensitises beta-cells to ambient glucose, reducing the glucose concentration needed to stimulate insulin secretion. The pharmacokinetics of nateglinide are characterised by rapid absorption and elimination, with good (73%) bioavailability. Nateglinide is more rapidly absorbed when given 0-30 minutes prior to meal ingestion than if given during the meal. Nateglinide is extensively metabolised, primarily by cytochrome P450 2C9, and eliminated primarily by the kidney. Nateglinide pharmacokinetics are linear over the dose range 60-240 mg. No significant pharmacokinetic alterations occur in renally impaired patients, in the elderly, or in mildly hepatically impaired patients. Nateglinide administered prior to meals stimulates rapid, short-lived insulin secretion in a dose-dependent manner, thus decreasing mealtime plasma glucose excursions. Its effects on insulin secretion are synergistic with those of a meal. With increasing nateglinide doses, the risk of hypoglycaemia also increases, but its incidence is low. Even if a meal is missed, and the patient skips the dose of nateglinide (as recommended in the event of a missed meal), the incidence of subsequent hypoglycaemia remains low compared with long-acting agents. The postprandial insulinotropic effects of nateglinide are more rapid than those of repaglinide and more rapid and greater than those of glibenclamide (glyburide), while producing less prolonged insulin exposure and less risk of delayed hypoglycaemia. Further investigation is required to determine if nateglinide inhibition of postprandial glucose excursions will help to prevent diabetic complications or preserve pancreatic beta-cell function.
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PMID:Clinical pharmacokinetics of nateglinide: a rapidly-absorbed, short-acting insulinotropic agent. 1474 19

Here we report the first cloned N-ethyl-nitrosourea (ENU)-derived mouse model of diabetes. GENA348 was identified through free-fed plasma glucose measurement, being more than 2 SDs above the population mean of a cohort of >1,201 male ENU mutant mice. The underlying gene was mapped to the maturity-onset diabetes of the young (MODY2) homology region of mouse chromosome 11 (logarithm of odds 6.0). Positional candidate gene analyses revealed an A to T transversion mutation in exon 9 of the glucokinase gene, resulting in an isoleucine to phenylalanine change at amino acid 366 (I366F). Heterozygous mutants have 67% of the enzyme activity of wild-type littermates (P < 0.0012). Homozygous mutants have less enzyme activity (14% of wild-type activity) and are even less glucose tolerant. The GENA348 allele is novel because no mouse or human diabetes studies have described a mutation in the corresponding amino acid position. It is also the first glucokinase missense mutation reported in mice and is homozygous viable, unlike the global knockout mutations. This work demonstrates that ENU mutagenesis screens can be used to generate models of complex phenotypes, such as type 2 diabetes, that are directly relevant to human disease.
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PMID:A new mouse model of type 2 diabetes, produced by N-ethyl-nitrosourea mutagenesis, is the result of a missense mutation in the glucokinase gene. 1516 64

We investigated amino acid metabolism in the Zucker diabetic fatty (ZDF Gmi fa/fa) rat during the prediabetic insulin-resistant stage and the frank type 2 diabetic stage. Amino acids were measured in plasma, liver, and skeletal muscle, and the ratios of plasma/liver and plasma/skeletal muscle were calculated. At the insulin-resistant stage, the plasma concentrations of the gluconeogenic amino acids aspartate, serine, glutamine, glycine, and histidine were decreased in the ZDF Gmi fa/fa rats, whereas taurine, alpha-aminoadipic acid, methionine, phenylalanine, tryptophan, and the 3 branched-chain amino acids were significantly increased. At the diabetic stage, a larger number of gluconeogenic amino acids had decreased plasma concentrations. The 3 branched-chain amino acids had elevated plasma concentrations. In the liver and the skeletal muscles, concentrations of many of the gluconeogenic amino acids were lower at both stages, whereas the levels of 1 or all of the branched-chain amino acids were elevated. These changes in amino acid concentrations are similar to changes seen in type 1 diabetes. It is evident that insulin resistance alone is capable of bringing about many of the changes in amino acid metabolism observed in type 2 diabetes.
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PMID:Amino acid metabolism in the Zucker diabetic fatty rat: effects of insulin resistance and of type 2 diabetes. 1538 98

The formation of amyloid fibril is associated with major human diseases, including Alzheimer's disease, prion diseases, and type 2 diabetes. Methods for efficient inhibition of amyloid fibril formation are therefore highly clinically important. A principal approach for the inhibition of amyloid formation is based on the use of modified molecular recognition elements. Here, we demonstrate efficient inhibition of amyloid formation of the type 2 diabetes-related human islet amyloid polypeptide (hIAPP) by a modified aromatic peptide fragment and a small aromatic polyphenol molecule. A molecular recognition assay using peptide array analysis suggested that molecular recognition between hIAPP and its core amyloidogenic module is mediated by aromatic rather than hydrophobic interactions. To study the possible effect of aromatic interactions on inhibition of hIAPP fibril formation, we have used peptide and small molecule inhibitors. The addition of a nonamyloidogenic peptide analogue of the core module NFGAILSS, in which phenylalanine was substituted with tyrosine (NYGAILSS), resulted in substantial inhibition of fibril formation by hIAPP. The inhibition was significantly stronger than the one achieved using a beta-sheet breaker-conjugated peptide NFGAILPP. On the basis of the molecular arrangement of the tyrosine-phenylalanine interaction, we suggest that the inhibition stems from the geometrical constrains of the heteroaromatic benzene-phenol interaction. In line with this notion, we demonstrate remarkable inhibition of hIAPP fibril formation and cytotoxicity toward pancreatic beta-cells by a small polyphenol molecule, the nontoxic phenol red compound. Taken together, our results provide further experimental support for the potential role of aromatic interactions in amyloid formation and establish a novel approach for its inhibition.
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PMID:Inhibition of islet amyloid polypeptide fibril formation: a potential role for heteroaromatic interactions. 1553 50

The effect of N-benzoyl-D-phenylalanine (NBDP) and metformin combination treatment on circulatory lipids, lipoproteins and lipid peroxidation markers were studied in neonatal streptozotocin (nSTZ) non-insulin dependent diabetic rats. Non-insulin dependent diabetes mellitus (NIDDM) was induced by a single dose injection of streptozotocin (100 mg kg(-1), i. p.) to two-day-old rats. After 10-12 weeks, rats weighing above 150 g were selected for screening for the NIDDM model. The rats were checked for fasting blood glucose levels to confirm the status of NIDDM. NBDP (50,100 or 200 mg kg(-1) ) was administered orally for six weeks to the confirmed diabetic rats (to evaluate the effective dose). The levels of serum lipids and lipid peroxidation markers were significantly increased, whilst the activity of glucose-6-phosphate dehydrogenase was significantly decreased in nSTZ diabetic rats. NBDP and metformin were able to restore the altered serum lipids, lipoproteins, lipid peroxidation marker levels and glucose-6-phosphate dehydrogenase activity to almost control levels. The results showed the antihyperlipidaemic properties of NBDP and metformin in addition to its antidiabetic action. Combination treatment was more effective then either drug alone. The results indicated that the coadministration of NBDP with metformin to nSTZ diabetic rats normalized blood glucose and caused marked improvement in altered serum lipids, lipoproteins and lipid peroxidation markers during diabetes. The data indicated that NBDP represented an effective antihyperglycaemic and antihyperlipidaemic adjunct for the treatment of diabetes, and may be a potential source of new orally active agents for future therapy.
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PMID:Effect of N-benzoyl-D-phenylalanine on streptozotocin-induced changes in the lipid and lipoprotein profile in rats. 1580 92

Therapy for type 2 diabetes mellitus should aim to control not only fasting, but also postprandial glucose levels. Nateglinide, a d-phenylalanine derivative, restores postprandial early phase insulin secretion in a transient and glucose-sensitive manner without affecting basal insulin levels. As nateglinide is administered immediately before meals it provides greater lifestyle flexibility than agents that require patients to eat to avoid hypoglycemic events (e.g. long-acting sulfonylureas). In randomised, double-blind trials in patients with type 2 diabetes, nateglinide monotherapy (mealtime treatment of 120 mg three times daily) significantly improved long-term glycaemic control by significantly reducing glyated haemoglobin (HbA 1c) and preventing mealtime glucose spikes. The combination of nateglinide with insulin-sensitising agents, for example, metformin and thiazolidinediones, addresses the dual defects of loss of insulin secretion and insulin resistance to provide optimal management of type 2 diabetes, and more patients achieve HbA 1c goal with nateglinide combination therapy rather than with monotherapy with other oral agents. Nateglinide also restores early insulin secretion and reduces postprandial hyperglycaemia in prediabetic subjects with impaired glucose tolerance (IGT) and appears similarly effective in elderly and non-elderly populations with type 2 diabetes. It has an excellent safety and tolerability profile, with a low propensity to cause hypoglycaemia due to its transient, selective effect on early phase insulin secretion. Nateglinide as monotherapy or combination therapy is an effective option to reduce mealtime glucose in patients with type 2 diabetes. The results of ongoing research into its potential role in delaying progression to overt diabetes, and protecting against cardiovascular events, in prediabetic patients with IGT are awaited.
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PMID:Nateglinide--current and future role in the treatment of patients with type 2 diabetes mellitus. 1617 91

Post-translational modifications of lens proteins play a crucial role in the formation of cataract during ageing. The aim of our study was to analyze protein composition of the cataractous lenses by electrophoretic and high-performance liquid chromatographic (HPLC) methods. Samples were obtained after extracapsular cataract surgery performed by phacoemulsification technique from cataract patients with type 2 diabetes mellitus (DM CAT, n = 22) and cataract patients without diabetes (non-DM CAT, n = 20), while non-diabetic non-cataractous lenses obtained from cadaver eyes served as controls (CONTR, n = 17). Lens fragments were derived from the surgical medium by centrifugation. Samples were homogenized in a buffered medium containing protease inhibitor. Soluble and insoluble protein fractions were separated by centrifugation. The electrophoretic studies were performed according to Laemmli on equal amounts of proteins and were followed by silver intensification. Oxidized amino acid and Phe content of the samples were also analyzed by HPLC following acid hydrolysis of proteins. Our results showed that soluble proteins represented a significantly lower portion of the total protein content in cataractous lenses in comparison with the control group (CONTR, 71.25%; non-DM CAT, 32.00%; DM CAT, 33.15%; p < 0.05 vs CONTR for both). Among the proteins, the crystallin-like proteins with low-molecular weight can be found both in the soluble and insoluble fractions, and high-molecular weight aggregates were found mainly in the total homogenates. In our HPLC analysis, oxidatively modified derivatives of phenylalanine were detected in cataractous samples. We found higher levels of m-Tyr, o-Tyr and DOPA in the total homogenates of cataractous samples compared to the supernatants. In all three groups, the median Phe/protein ratio of the total homogenates was also higher than that of the supernatants (total homogenates vs supernatants, in the CONTR group 1102 vs 633 micromol/g, in the DM CAT group 1187 vs 382 micromol/g and in the non-DM CAT group 967 vs 252 micromol/g; p < 0.05 for all). In our study we found that oxidized amino acids accumulate in cataractous lenses, regardless of the origin of the cataract. The accumulation of the oxidized amino acids probably results from oxidation of Phe residues of the non-water soluble lens proteins. We found the presence of high-molecular weight protein aggregates in cataractous total homogenates, and a decrease of protein concentration in the water-soluble phase of cataractous lenses. The oxidation of lens proteins and the oxidative modification of Phe residues in key positions may lead to an altered interaction between protein and water molecules and thus contribute to lens opacification.
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PMID:Accumulation of the hydroxyl free radical markers meta-, ortho-tyrosine and DOPA in cataractous lenses is accompanied by a lower protein and phenylalanine content of the water-soluble phase. 1629 66

In humans, mice, and other mammals, the melanocortin system consists of four peptide hormones with a core amino acid sequence of histidine-phenylalanine-arginine-tryptophan and five melanocortin receptors. Both the melanocortin hormones and their receptors are produced in diverse tissues throughout the body. The ligand of primary interest for treatment of insulin resistance is alpha-melanocyte-stimulating hormone (alpha-MSH), which is derived, as are all melanocortins, from tissue-specific post-translational proteolytic processing of the pro-opiomelanocortin (POMC) precursor protein. Recent results have shown that alpha-MSH is the complement of leptin in the endocrine circuit, regulating bodyweight, food intake, and metabolic rate. alpha-MSH can decrease bodyweight, weight gain, and food intake in mice with diet-induced and genetic obesity. As obesity is a major risk factor for type 2 diabetes mellitus, it was reasonable to investigate the endocrine agents involved in obesity for their involvement in diabetes. alpha-MSH analogs have also been shown to affect blood glucose levels in some mouse models of obesity. For instance, the POMC null mouse is extremely sensitive to insulin in an insulin tolerance test, while being otherwise euglycemic. The results from rodent studies with alpha-MSH suggest reciprocal effects: alpha-MSH appears to increase sensitivity to insulin when present in the CNS, while alpha-MSH in the periphery is necessary for insulin resistance. Should these trends be validated in humans, alpha-MSH-based therapeutics specifically active in the CNS or peripheral circulation may be promising for the treatment of type 2 diabetes.
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PMID:The role of melanocyte-stimulating hormone in insulin resistance and type 2 diabetes mellitus. 1639 14

Amyloid-associated diseases affect millions of people worldwide. Phenol red exhibits modest inhibition toward fibril formation of human Islet amyloid polypeptide (hIAPP) and its toxicity, which is associated with type II diabetes mellitus. However, the molecular level mechanisms of interactions remain elusive. The binding of phenol red molecules to the protofibrils of an amyloidogenic fragment (NFGAIL) of hIAPP has been investigated by molecular dynamics simulations with explicit solvent. The phenol red molecules were observed to bind primarily along either beta-sheet stacking or beta-strand directions. Through its three aromatic rings, the phenol red molecule preferentially interacted with the hydrophobic side chains of Phe, Leu, and Ile; and the polar sulfone and hydroxyl groups were mainly exposed in solvent. Thus, phenol red improves the solubility of the early protofibrils and represses further growth. Interestingly, there was no obvious preference toward the aromatic Phe residue in comparison to the hydrophobic Leu or Ile residues. The lack of binding along the hydrogen bond direction indicates that phenol red does not directly block the beta-sheet extension. Further free energy analysis suggested that a phenol red analog may potentially improve the binding affinity.
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PMID:Phenol red interacts with the protofibril-like oligomers of an amyloidogenic hexapeptide NFGAIL through both hydrophobic and aromatic contacts. 1693 48


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