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)

The aim of the present study was to investigate whether altered serum total sialic acid (TSA), lipid-associated sialic acid (LSA), copper (Cu), manganese (Mn), zinc (Zn), chromium (Cr), iron (Fe), and magnesium (Mg) levels had an interactive connection with diabetes and also whether they were correlated with each other in diabetic patients. Two study groups (control and type 2 diabetic subjects) were included. Two hundred patients (108 female and 92 male), diagnosed and treated for type 2 diabetes in the Yuzuncu Yil University Hospital (Van, Turkey), were selected consecutively to represent type 2 diabetic patients. Fifty healthy individuals (29 female and 21 male) served as the control group matched for age, sex, body mass index, and smoking status were selected from hospital staff and other outpatient clinics. All participants had not taken vitamin or mineral supplements for at least 2 wk before sampling. Blood samples were drawn after an overnight fasting in both groups for the determination of serum glucose, TSA, LSA, Cu, Zn, Mn, Cr, Fe, and Mg. It was found that diabetics had higher TSA, LSA, Fe, Mn, Fe/Zn, and Cu/Zn levels, and lower Zn and Mg levels than those of controls. Although, Cu levels were higher, and Cr levels were lower in total and male diabetic patients, they were not different in female diabetic patients than in controls. The Cu/Fe ratio was lower in total and female diabetic patients, but not different in male diabetic patients than controls. The Zn/Cr ratio, on the other hand, was not different in diabetics than in controls. There was only a positive correlation between Fe-Mn levels in male diabetic patients. There was a negative correlation in LSA-Mn, Fe-Cu, Cu-Fe/Zn, and Mn-Cu/Zn levels in total diabetic patients. There was a positive correlation in TSA-Cr, TSA-Mg, LSA-Cu/Fe, LSA-Zn/Cr levels, and a negative correlation in TSA-Cu/Zn, LSA-Mn, Fe-Cu, Mn-Cu, Cu-Fe/Zn, Fe-cholesterol, and Cr-cholesterol in female diabetic patients. Our results showed that TSA, LSA, and selected minerals have interactive connections with diabetes mellitus (DM). There are also many sex-related positive or negative correlations between the altered parameters in diabetic patients. These parameters might be used as diagnostic index in patients with DM.
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PMID:Serum sialic acid levels and selected mineral status in patients with type 2 diabetes mellitus. 1297 87

Zinc ions in the secretory granules of beta-cells are known to glue insulin molecules, creating osmotically stable hexamers. When the secretory granules open to the surface, the zinc ion pressure decreases rapidly and pH levels change from acid to physiological, which results in free insulin monomers and zinc ions. The released zinc ions have been suggested to be involved in a paracrine regulation of alpha- and beta-cells. Since zinc is intimately involved in insulin metabolism and because zinc homeostasis is known to be disturbed in type 2 diabetes, we decided to study the ultrastructural localisation of zinc ions in insulin-resistant and type 2 diabetic rats as compared to controls. By means of autometallography, the only method available for demonstrating zinc ions at ultrastructural levels, we found zinc ions in the secretory granules and adjacent to the plasma membrane. The membrane-related staining outside the plasma membrane reflects release of zinc ions during exocytosis. No apparent difference was found in the ultrastructural localisation of zinc ions when we compared the obese Zucker (fa/fa) rats, representing the insulin resistance syndrome, and the GK rats, representing type 2 diabetes, with controls. This suggests that the ultrastructural localisation of zinc ions is unaffected by the development of type 2 diabetes in rats in a steady state of glycaemia.
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PMID:Zinc ions in beta-cells of obese, insulin-resistant, and type 2 diabetic rats traced by autometallography. 1467 25

Obesity is accompanied by a high incidence of atherosclerosis, arterial hypertension and non-insulin dependent diabetes mellitus in the pathogenesis of which is associated with oxygen-derived free radicals. The aim of the study was to compare blood oxidation status in obese women without coexisting diseases and in healthy women with normal body mass index (BMI). Studies were performed in 29 premenopausal obese (BMI 35.79 +/- 4.62 kg/m2) and 31 lean (BMI 22.29 +/- 1.05 kg/m2) women. Plasma lipid profile, activities of antioxidant enzymes: copper/zinc (Cu/ZnSOD) and manganese-containing superoxide dismutase (MnSOD) and glutathione peroxidase (GSH-Px), as well as concentrations of malondialdehyde (MDA)--a product of lipid peroxidation, were examined. In obese women there were significantly higher concentrations of total cholesterol (5.02 +/- 0.83 vs. 4.15 +/- 0.43 mmol/l; p < 0.05), LDL-cholesterol (3.12 +/- 0.90 vs. 2.35 +/- 0.42 mmol/l; p < 0.05) and triglycerides (1.72 +/- 0.85 vs. 1.02 +/- 0.18 mmol/l; p < 0.01), while HDL-cholesterol level was lower (1.01 +/- 0.16 vs. 1.25 +/- 0.2 mmol/l; p < 0.05). Moreover, in comparison to the control group, obese women showed increased activities of plasma MnSOD (6.72 +/- 1.43 vs. 4.99 +/- 0.58 NU/ml; p < 0.05) and erythrocyte GSH-Px (35.38 +/- 10.31 vs. 19.15 +/- 7.12 mumol NADPH2/g Hb/min; p < 0.001), and concentrations of plasma MDA (2.93 +/- 0.53 vs. 2.16 +/- 0.31 mumol/l; p < 0.05) and erythrocyte MDA (2.24 +/- 0.30 vs. 1.59 +/- 0.36 mumol/g Hb; p < < 0.001). There were no differences between the two groups in activities of plasma and erythrocyte Cu/ZnSOD. In conclusion, the results demonstrate disturbances in oxidation status in premenopausal obese women with abnormal lipid profile, which may indicate the association between oxygen-derived free radicals and the increase in the incidence of obesity-related diseases.
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PMID:[Assessment of blood superoxide dismutase, glutathione peroxidase activity and malondialdehyde concentration as oxidation status parameters in obese women]. 1468 7

The blood glucose lowering effects in KK-Ay mice with type 2 diabetes mellitus (DM) receiving daily an intraperitoneal (i.p.) administration of Zn(II) complexes with maltol, L-threonine, and picolinic acid for 14 days were estimated under the same conditions, and dose-dependent blood glucose lowering effects in the dose range of 0.2-3.0 mg Zn/kg body weight were found. Among them, the bis(maltolato)Zn(II) complex exhibited the highest blood sugar lowering effect at the dose of 3.0 mg Zn/kg. The improvement of DM was confirmed with oral glucose tolerance tests as well as blood HbA1c levels after the administration of the three Zn(II) complexes at the dose of 3.0 mg Zn/kg. For the purpose of the clinical trial of the complexes in the future, we examined the toxic effects of these three Zn(II) complexes in regard of the LD50 values and hepatic cytochrome P450 levels. The LD50 values of the three Zn(II) complexes exhibited high values compared with that of ZnCl2. No changes of both CYP1A1 and CYP2E1 levels in the liver of KK-Ay mice treated with the three Zn(II) complexes were observed. The obtained results will be important when the complexes are tried for clinical use.
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PMID:Blood glucose lowering and toxicological effects of zinc (II) complexes with maltol, threonine, and picolinic acid. 1508 May

A wide variety of vanadium-containing complexes have been tested, both in vivo and in vitro, as possible therapeutic agents for the oral treatment of type 2 diabetes mellitus. None so far has surpassed bis(maltolato)oxovanadium(IV) (BMOV) for glucose- and lipid-lowering in an orally available formulation. Ligand choice is clearly an important factor in pharmacological efficacy of vanadium compounds as insulin enhancing agents. In this study, we kept the ligand and dose the same, varying instead the metal ion bound to the maltolato ligand in a series of binary complexes of neutral charge. A requirement for vanadyl ion as the metal ion of choice was apparent; no other metal ion tested served as a suitable substitute. Amongst [MoO(2)](2+), Co(II), Cu(II), Cr(III), and Zn(II), only [MoO(2)](2+) and Co(II) showed any hypoglycemic activity at the ED(50) dose for bis(maltolato)oxovanadium(IV), 0.6 mmolkg(-1) by oral gavage in streptozotocin (STZ)-diabetic rats within 72 h of administration of compound.
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PMID:Comparison of anti-hyperglycemic effect amongst vanadium, molybdenum and other metal maltol complexes. 1513 13

The insulin-regulated aminopeptidase (IRAP) is a member of the family of zinc-dependent membrane aminopeptidases. It is the homolog of the human placental leucine aminopeptidase (P-LAP). IRAP is expressed in different cell types but has been best characterized in two major insulin target cells, muscle and fat. In these cells IRAP localizes to intracellular membrane compartments under basal conditions. In response to insulin IRAP redistributes to the cell surface. IRAP shares this behavior with the insulin-responsive glucose transporter GLUT4. It is established that insulin's dramatic effect on glucose disposal is mediated through its action on GLUT4. The role IRAP plays in insulin action is unknown. IRAP cleaves several peptide hormones in vitro. In insulin-treated cells, concomitant with the appearance of IRAP at the cell surface, aminopeptidase activity toward extracellular substrates increases. Thus, insulin, by bringing IRAP to the cell surface, could increase the processing of extracellular peptide hormones and thereby change their activities. Investigations are underway to determine the in vivo substrates for IRAP and to measure the effect of insulin on the cleavage of identified substrates. In individuals with type 2 diabetes the insulin-stimulated translocation of IRAP to the cell surface of muscle and fat cells is impaired. This defect may lead to decreased cleavage and consequently increased action of peptide hormones that are substrates for IRAP. Impaired IRAP action may thus play a role in the development of complications in type 2 diabetes. The findings of decreased expression of GLUT4 and increased heart size in mice in which IRAP was deleted support this hypothesis.
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PMID:Role of the insulin-regulated aminopeptidase IRAP in insulin action and diabetes. 1518 12

IDE (insulin-degrading enzyme) is a widely expressed zinc-metallopeptidase that has been shown to regulate both cerebral amyloid beta-peptide and plasma insulin levels in vivo. Genetic linkage and allelic association have been reported between the IDE gene locus and both late-onset Alzheimer's disease and Type II diabetes mellitus, suggesting that altered IDE function may contribute to some cases of these highly prevalent disorders. Despite the potentially great importance of this peptidase to health and disease, many fundamental aspects of IDE biology remain unresolved. Here we identify a previously undescribed mitochondrial isoform of IDE generated by translation at an in-frame initiation codon 123 nucleotides upstream of the canonical translation start site, which results in the addition of a 41-amino-acid N-terminal mitochondrial targeting sequence. Fusion of this sequence to the N-terminus of green fluorescent protein directed this normally cytosolic protein to mitochondria, and full-length IDE constructs containing this sequence were also directed to mitochondria, as revealed by immuno-electron microscopy. Endogenous IDE protein was detected in purified mitochondria, where it was protected from digestion by trypsin and migrated at a size consistent with the predicted removal of the N-terminal targeting sequence upon transport into the mitochondrion. Functionally, we provide evidence that IDE can degrade cleaved mitochondrial targeting sequences. Our results identify new mechanisms regulating the subcellular localization of IDE and suggest previously unrecognized roles for IDE within mitochondria.
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PMID:Alternative translation initiation generates a novel isoform of insulin-degrading enzyme targeted to mitochondria. 1528 18

During the investigation of the development of insulin-mimetic zinc(II) complexes with a blood glucose-lowering effect in experimental diabetic animals, we found a potent bis(maltolato)zinc(II) complex, Zn(ma)(2), exhibiting significant insulin-mimetic effects in a type 2 diabetic animal model. By using this Zn(ma)(2) as the leading compound, we examined the in vitro and in vivo structure-activity relationships of Zn(ma)(2) and its related complexes. The in vitro insulin-mimetic activity of these complexes was determined by the inhibition of free fatty acid release and the enhancement of glucose uptake in isolated rat adipocytes treated with epinephrine. A new Zn(II) complex with allixin isolated from garlic, Zn(alx)(2), exhibited the highest insulin-mimetic activity among the complexes analyzed. The insulin-mimetic activity of the Zn(II) complexes examined strongly correlated (correlation coefficient=0.96) with the partition coefficient (log P) of the ligand, indicating that the activity of Zn(ma)(2)-related complexes depends on the lipophilicity of the ligand. The blood glucose-lowering effects of Zn(alx)(2) and Zn(ma)(2) were then compared, and both complexes were found to normalize hyperglycemia in KK- A(y) mice after a 14-day course of daily intraperitoneal injections. However, Zn(alx)(2) improved glucose tolerance in KK- A(y) mice much more than did Zn(ma)(2), indicating that Zn(alx)(2) possesses greater in vivo anti-diabetic activity than Zn(ma)(2). In addition, Zn(alx)(2) improved leptin resistance and suppressed the progress of obesity in type 2 diabetic KK- A(y) mice. On the basis of these observations, we conclude that the Zn(alx)(2) complex is a novel potent candidate for the treatment of type 2 diabetes mellitus.
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PMID:A new insulin-mimetic bis(allixinato)zinc(II) complex: structure-activity relationship of zinc(II) complexes. 1537 7

In order to understand the insulinomimetic activity of zinc(II) complexes, we studied the metallokinetic features of zinc in the blood of normal rats given the zinc complexes, bis(maltolato)zinc(II) (Zn(mal)(2)) and bis(6-methylpicolinato)zinc(II) (Zn(6mpa)(2)) by comparing each of them with an ionic form of zinc chloride (ZnCl(2)). The bioavailability of the zinc(II) complexes following oral administration was enhanced to 1.4-1.5-fold that of ZnCl(2) with respect to zinc level. Based on the results of a metallokinetic analysis and administration method in normal rats, we examined the antidiabetic ability of the zinc(II) complexes in GK rats, a model animal of type 2 diabetes mellitus. High blood glucose levels of GK rats were normalized following intraperitoneal injections and oral administration of the zinc(II) complexes, in which the Zn(6mpa)(2) complex was found to be more effective than Zn(mal)(2). The present results are noteworthy, not only due to their potential relevance for clinical application, but also for the development of new zinc(II) complexes.
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PMID:Metallokinetic study of zinc in the blood of normal rats given insulinomimetic zinc(II) complexes and improvement of diabetes mellitus in type 2 diabetic GK rats by their oral administration. 1561 84

At least 16 distinct clinical syndromes including Alzheimer's disease (AD), Parkinson's disease (PD), rheumatoid arthritis, type II diabetes mellitus (DM), and spongiform encephelopathies (prion diseases), are characterized by the deposition of amorphous, Congo red-staining deposits known as amyloid. These "misfolded" proteins adopt beta-sheet structures and aggregate spontaneously into similar extended fibrils despite their widely divergent primary sequences. Many, if not all, of these peptides are capable of forming ion-permeable channels in vitro and possibly in vivo. Common channel properties include irreversible, spontaneous insertion into membranes, relatively large, heterogeneous single-channel conductances, inhibition of channel formation by Congo red, and blockade of inserted channels by Zn2+. Physiologic effects of amyloid, including Ca2+ dysregulation, membrane depolarization, mitochondrial dysfunction, inhibition of long-term potentiation (LTP), and cytotoxicity, suggest that channel formation in plasma and intracellular membranes may play a key role in the pathophysiology of the amyloidoses.
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PMID:Amyloid peptide channels. 1570 75


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