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)

Metformin is a biguanide. Due to its effects in suppressing the hepatic production of endogenous glucose and in increasing insulin sensitivity in adipose tissue and skeletal muscle, the agent is used particularly in type 2 diabetes mellitus and metabolic syndrome, in which insulin resistance is especially pronounced. Lactic acidosis is one of the most important side effects of metformin. A male patient, born in 1923, was admitted to the emergency unit of our hospital for sudden vertigo, weakness, dyspnea, cyanosis, and lethargy. His history data showed that the patient had been suffering from type 2 diabetes mellitus for 10 years and taking Glargin (insulin), 12 U/kg, once daily and Glucophage (metformin), 850 mg thrice daily. The patient's general condition was fair; stupor, time and spatial orientation were absent. Analysis of arterial blood gases showed the presence of metabolic acidosis, hypokalemia, hypoxemia, and hypercapnia. Thereafter the patient was transferred to the intensive care unit of the hospital; intubated and connected to a T-bird ventilation apparatus. On the following day, an analysis of arterial blood gases indicated the proximity of the results to their physiological parameters. Ventilation was stopped; and monitoring of the patient continued by following the T-shape type of ventilation discontinuation. There were no X-ray signs of pneumonia or pulmonary edema. On the same day, the patient was extubated and oxygen inhalation in a dose of L/min was continued through a mask. On day 4 since therapy was initiated, the patient's vital signs, serum sugar and lactate levels became normal. By determining a new treatment regimen, the patient was discharged from the intensive care unit. Dyspnea, acidosis, and hypoxia developed in the patient resulted from lactic acidosis caused by the use of metformin. It should be remembered that dyspnea, acidosis, and hypoxia, which suddenly developed in metformin-treated patients with type 2 diabetes mellitus, may be caused by lactic acidosis.
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PMID:[A clinical case of development of lactic acid acidosis in a diabetic patient taking metformin]. 1675 49

A 47-year-old white male came to the hospital emergency department complaining of chest pain. At admission, it was noted that the patient had numerous lesions on his buttocks, abdomen, back, and all extremities. These lesions had been there for approximately 5 months--they developed after he discontinued his cholesterol medication due to lapsed insurance coverage. He had a similar eruption when he went off cholesterol medication on another occasion. The patient's medical history included type 2 diabetes mellitus, hypertension, coronary artery disease, and hyperlipidemia. He has had multiple heart catheterizations with stent placement, most recently 2 years ago. His mother also had diabetes mellitus, and she died at age 58 from a myocardial infarction. On examination, his lesions were painless and nonpruritic. He had numerous yellow papules on his buttocks, abdomen, back, and upper and lower extremities. He had no lesions on his face. The rest of the physical exam showed no abnormal results. What is your diagnosis? What laboratory tests should be done to help make the diagnosis?
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PMID:A 47-year-old man with eruptions on his trunk. 1682 46

Islet amyloid deposits are a characteristic pathological hallmark of type 2 diabetes mellitus. Islet amyloid polypeptide (IAPP), also referred to as amylin, aggregates in the islet extracellular space to form amyloid deposits in up to 95% of patients with the disease. IAPP is stored with insulin in beta-islet cells and is processed in parallel by subtilisin-like prohormone convertases prior to secretion. There is indirect evidence that normal processing of the prohormone precursor, proIAPP, at the N-terminal cleavage site is defective in type 2 diabetes and results in secretion of an N-terminal extended proIAPP intermediate. The N-terminal flanking region of proIAPP is detected in amyloid deposits; however, the C-terminal flanking region is not. Immunohistochemical studies implicate the presence of the heparan sulfate proteoglycan (HSPG) perlecan in islet amyloid deposits, suggesting a role for HSPGs in mediating amyloid deposition in type 2 diabetes and implicating a binding domain in the N-terminus of proIAPP. Initial studies of proIAPP indicated that the HSPG binding region is contained within the first 30 residues. Here, we characterize the potential HSPG binding site of proIAPP in detail by analyzing a set of peptide fragments. Binding is tighter at low pH due to protonation of histidine residues. Deletion studies show that Arg-22 and His-29 play a role in binding. Reduction of the Cys-13 to Cys-18 disulfide leads to a noticeable decrease in binding. We demonstrate the ability of heparan sulfate to induce amyloid formation in N-terminal fragments of proIAPP. The oxidized peptide forms amyloid more rapidly than the reduced variant in the presence of heparan sulfate, but the reduced peptide ultimately forms more extensive amyloid deposits. The potential implications for islet amyloid formation in vivo are discussed.
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PMID:Characterization of the heparin binding site in the N-terminus of human pro-islet amyloid polypeptide: implications for amyloid formation. 1686 69

PEGylation has been considered to be a good biotechnique for improving the therapeutic value of glucagon-like peptide-1 (GLP-1) analogs for the treatment of type 2 diabetes. Despite the attractive anti-diabetic potentials, GLP-1 does not exert its full biological action because of its extremely short life-time in vivo due to rapid proteolytic degradation. Here, the enzyme-resistant mono-PEGylated GLP-1 isomers substituted at Lys(26)- or Lys(34)-amine were prepared through a newly devised site-specific PEGylation process using a maleic anhydride-protection/deprotection method. The therapeutic potentials of these site-specific PEGylated GLP-1 isomers (Lys(26)- or Lys(34)-PEG-GLP-1) along with His(7)-(N-terminus) PEG-GLP-1 were evaluated by examining their insulinotropic activity, glucose-stabilizing capability, and proteolytic stability. Lys(34)-PEG-GLP-1 was found to have the well-preserved insulinotropic activity (93% efficacy versus GLP-1) in isolated rat pancreatic islets. Furthermore, Lys(34)-PEG-GLP-1 showed the most prominent glucose-stabilizing capability, evaluated via an oral glucose tolerance test in db/db mice by considering the following three crucial factors: (i) maximum blood glucose level (BGL), (ii) required time to lower the BGL below 100mg/dl, and (iii) total hypoglycemic degree. Additionally, Lys(34)-PEG-GLP-1 had longer half-lives than the other PEGylated GLP-1s in the dipeptidyl peptidase IV (DPP IV) inhibitor-treated liver or kidney homogenate, and its stability against DPP IV was also comparable to that of Lys(26)-PEG-GLP-1. Taken together, Lys(34)-PEG-GLP-1 displayed the promising characteristics in all evaluations versus His(7)- or Lys(26)-PEG-GLP-1. This site-specific PEGylated GLP-1 analog would have therapeutic usefulness for treating type 2 diabetes on account of the well-preserved insulinotropic activity, the increased proteolytic stability, and thereby the improved glucose-stabilizing capability.
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PMID:Evaluation of therapeutic potentials of site-specific PEGylated glucagon-like peptide-1 isomers as a type 2 anti-diabetic treatment: Insulinotropic activity, glucose-stabilizing capability, and proteolytic stability. 1705 19

Human L-glutamine: D-fructose-6-phosphate amidotransferase (Gfat1), a recognized target in type 2 diabetes complications, was expressed in Sf9 insect cells with an internal His(6)-tag and purified to homogenity. Two different microplate assays that quantify, respectively D-glucosamine-6-phosphate and L-glutamate were used to analyze the enzyme kinetic properties. The recombinant human L-glutamine: D-fructose-6-phosphate amidotransferase isoform 1 exhibits Michaelis parameters K(m)(Fru-6P)=0.98 mM and K(m)(Gln)=0.84 mM which are similar to the values reported for the same enzyme from different sources. The stimulation of hydrolysis of the alternate substrate L-glutamine para-nitroanilide by D-fructose-6P (Fru-6P) afforded a K(d) of 5 microM for Fru-6P.
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PMID:Expression and purification of active human internal His(6)-tagged L-glutamine: D-Fructose-6P amidotransferase I. 1737 37

Resistin, an adipocyte-secreted hormone, has been associated with obesity, insulin resistance and type 2 diabetes mellitus (T2DM) in some, but not all, rodent models. In humans, the exact function of resistin is unkown. Because 3'-untranslated region (3'-UTR) single nucleotide substitutions (SNPs) have been shown to affect gene expression, we examined the EX4-44G-->A SNP in the 3'-UTR of exon 3 within the resistin gene. The objective of this study was to investigate, for the first time in a Turkish study group, whether the 3'-UTR EX4-44G-->A variation in the resistin gene influences the development of T2DM, obesity and insulin-related phenotypes. We analyzed the genotype frequencies of the EX4-44G-->A polymorphism of the resistin gene in 116 type 2 diabetic and 102 normal subjects. Serum lipids, obesity-related and insulin-related phenotypes were analyzed. No significant difference for genotypic frequencies were observed for the BseRI restriction site in type 2 diabetic patients as compared to controls. Waist-to-hip ratio, BMI, body fat and apoAI levels were found to be affected by resistin genotype. In the control group, BMI (p < 0.01), HIS (p < 0.05) and BF (p < 0.05) levels were found to be elevated, whereas HOMA beta-cell index (p < 0.01) and apo AI (p < 0.05) levels were found to be decreased in GG genotype carriers. In the diabetic group, the GG genotype carriers were found to have higher BMI levels (p < 0.001), waist-to-hip ratio (p < 0.05), body fat (p < 0.01), HOMA (p < 0.001) and fasting insulin (p < 0.05), but lower HbA1c levels in comparison to GC + AA carriers. These data suggest that, in the Turkish study group, the EX4-44G-->A polymorphism of the resistin gene is associated with insulin and obesity-related phenotypes.
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PMID:Association of Resistin Gene 3'-Untranslated Region EX4-44G-->A Polymorphism with Obesity- and Insulin-Related Phenotypes in Turkish Type 2 Diabetes Patients. 1756 16

The outer mitochondrial membrane protein mitoNEET was discovered as a binding target of pioglitazone, an insulin-sensitizing drug of the thiazolidinedione class used to treat type 2 diabetes (Colca, J. R., McDonald, W. G., Waldon, D. J., Leone, J. W., Lull, J. M., Bannow, C. A., Lund, E. T., and Mathews, W. R. (2004) Am. J. Physiol. 286, E252-E260). We have shown that mitoNEET is a member of a small family of proteins containing a 39-amino-acid CDGSH domain. Although the CDGSH domain is annotated as a zinc finger motif, mitoNEET was shown to contain iron (Wiley, S. E., Murphy, A. N., Ross, S. A., van der Geer, P., and Dixon, J. E. (2007) Proc. Natl. Acad. Sci. U. S. A. 104, 5318-5323). Optical and electron paramagnetic resonance spectroscopy showed that it contained a redox-active pH-labile Fe-S cluster. Mass spectrometry showed the loss of 2Fe and 2S upon cofactor extrusion. Spectroscopic studies of recombinant proteins showed that the 2Fe-2S cluster was coordinated by Cys-3 and His-1. The His ligand was shown to be involved in the observed pH lability of the cluster, indicating that loss of this ligand via protonation triggered release of the cluster. mitoNEET is the first identified 2Fe-2S-containing protein located in the outer mitochondrial membrane. Based on the biophysical data and domain fusion analysis, mitoNEET may function in Fe-S cluster shuttling and/or in redox reactions.
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PMID:The outer mitochondrial membrane protein mitoNEET contains a novel redox-active 2Fe-2S cluster. 1758 44

GPR40 was formerly an orphan G protein-coupled receptor whose endogenous ligands have recently been identified as free fatty acids (FFAs). The receptor, now named FFA receptor 1, has been implicated in the pathophysiology of type 2 diabetes and is a drug target because of its role in FFA-mediated enhancement of glucose-stimulated insulin release. Guided by molecular modeling, we investigated the molecular determinants contributing to binding of linoleic acid, a C18 polyunsaturated FFA, and GW9508, a synthetic small molecule agonist. Twelve residues within the putative GPR40-binding pocket including hydrophilic/positively charged, aromatic, and hydrophobic residues were identified and were subjected to site-directed mutagenesis. Our results suggest that linoleic acid and GW9508 are anchored on their carboxylate groups by Arg(183), Asn(244), and Arg(258). Moreover, His(86), Tyr(91), and His(137) may contribute to aromatic and/or hydrophobic interactions with GW9508 that are not present, or relatively weak, with linoleic acid. The anchor residues, as well as the residues Tyr(12), Tyr(91), His(137), and Leu(186), appear to be important for receptor activation also. Interestingly, His(137) and particularly His(86) may interact with GW9508 in a manner dependent on its protonation status. The greater number of putative interactions between GPR40 and GW9508 compared with linoleic acid may explain the higher potency of GW9508.
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PMID:Identification of residues important for agonist recognition and activation in GPR40. 1769 19

We report the first kinetic characterization of human liver cytosolic GTP-dependent phosphoenolpyruvate carboxykinase (GTP-PEPCK), which plays a major role in the development of type 2 diabetes in human. In this work two recombinant forms of the enzyme were studied. One form had a His10-tag and the other was His-tag-free, and with one exception, both exhibited similar kinetic properties. When Mn2+ was used as the sole divalent cation, the His10-tagged enzyme, but not the His-tag-free enzyme, was increasingly inhibited at Mn2+ concentrations greater than 0.7 mM. This inhibition did not pose any problem in kinetic analysis, for within the relevant Mn2+ concentration range the His-tagged human PEPCK behaved almost identically to the tag-free enzyme. This property will bring simplicity and speed to purifying and studying multiple structural variants of this important enzyme. Apparent Km values of tag-free enzyme for phosphoenolpyruvate, GDP and bicarbonate were 450, 79 and 20,600 microM, respectively, while those for oxaloacetate and GTP were 4 and 23 microM, respectively, emphasizing the enzyme's gluconeogenic character. Bicarbonate (>100 mM) inhibited OAA-forming activity, which was a new observation with a GTP-PEPCK. The apparent Km for Mn2+ in the PEP-forming direction was 30-fold lower than that for the OAA-forming direction. Mn2+ and bicarbonate or CO2 might regulate the enzyme in vivo.
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PMID:Kinetic characterization of recombinant human cytosolic phosphoenolpyruvate carboxykinase with and without a His10-tag. 1788 79

Exenatide is an incretin mimetic indicated for the treatment of type 2 diabetes mellitus in combination with a sulfonylurea, a thiazolidinedione, metformin, or metformin plus a sulfonylurea or thiazolidinedione. Exenatide lowers postprandial blood glucose levels by stimulating glucose-dependent insulin secretion, inhibiting glucagon secretion, slowing gastric emptying, and increasing satiety. Therapy with exenatide often results in weight loss, which further assists in decreasing insulin resistance. This feature makes the drug an attractive therapeutic option for obese patients. We report the successful off-label use of exenatide in an obese, 40-year-old man with type 1 diabetes and human immunodeficiency virus (HIV) infection who had gastrointestinal intolerance to pramlintide. The patient had experienced a dramatic weight gain secondary to his antiretroviral drugs. This weight gain led to insulin resistance and the development of type 2 diabetes; thus he had characteristics of both types 1 and 2 diabetes, or double diabetes. Before the start of exenatide therapy, he weighed 123 kg, had a body mass index of 42.3 kg/m(2), and had a suboptimal hemoglobin A(1c) value of 8.7%. After 11 months of therapy, the patient lost 24 kg (19.5% of his body weight) and achieved a hemoglobin A(1c) value of 7.3%. His basal insulin requirement was reduced by 25%, and his use of short-acting insulin before breakfast and before dinner was discontinued. In addition, the patient's quality of life substantially improved, as he was able to return to work and exercise after being nearly incapacitated by his weight. To our knowledge, this is the first published case report of the use of exenatide in a patient with type 1 diabetes mellitus or human immunodeficiency virus infection. Given this experience, exenatide may prove to be a useful alternative in selected patients with type 1 diabetes.
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PMID:Off-label use of exenatide for the management of insulin-resistant type 1 diabetes mellitus in an obese patient with human immunodeficiency virus infection. 1789


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