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)

Risk of diseases of metabolism such as atherosclerosis and adult onset diabetes mellitus is increased by fetal malnutrition. Deficiencies of micronutrients essential for methylation are believed to contribute to the phenomenon in part through epigenetic abnormalities. Zinc is one of the nutrients essential for the epigenome. Because the worldwide prevalence of zinc deficiency is at least 20%, fetal zinc deficiency is common. We suggest fetal zinc deficiency contributes to the pathogenesis of metabolic diseases in adults. In support of our thesis, research in experimental models and humans established the essentiality of zinc at all stages of intrauterine and infant life. Experiments in rodents and/or non-human primates found that fetal and/or suckling zinc deficiency impairs neuropsychological functions of progeny and that the effects persist in spite of nutritional rehabilitation. In addition, maternal zinc deficiency in mice is reported to impair immunity of progeny; effects persist in spite of nutritional rehabilitation into the next generation. We suspect that zinc deficiency is a far greater human health problem than is generally recognized.
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PMID:Possible roles of zinc nutriture in the fetal origins of disease. 1803 64

This study aimed to investigate the interrelationship of plasma lipid profile, lipid peroxidation, and erythrocyte antioxidative defense in patients with insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus. Plasma levels of total cholesterol, triglycerides, and lipid peroxides and the activities of copper, zinc superoxide dismutase (CuZnSOD), catalase, glutathione peroxidase (GSH-Px), as well as the amount of glutathione in erythrocytes, were determined in IDDM, NIDDM, and nondiabetic control subjects. Additionally, morphology of erythrocytes in all subjects was examined. Plasma levels of total cholesterol and triglycerides were significantly increased in NIDDM compared with controls. Also, the lipid peroxide level was higher in NIDDM than in either control or IDDM subjects. CuZnSOD activity in erythrocytes was elevated in NIDDM patients compared with the control. In NIDDM patients, more extensive erythrocyte spherocytosis and echinocytosis compared with both control and IDDM subjects were observed. In contrast with the IDDM group, the observed abnormality in lipid metabolism in NIDDM patients is closely associated with increased lipid peroxidation, changes in antioxidative defense, and erythrocyte morphology.
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PMID:Interrelationship of antioxidative status, lipid peroxidation, and lipid profile in insulin-dependent and non-insulin-dependent diabetic patients. 1806

Insulin glulisine injection [3(B)-Lys, 29(B)-Glu-human insulin] is the newest human insulin analogue product for the control of mealtime blood sugar. As with insulin aspart and insulin lispro products, the insulin glulisine product displays faster absorption and onset of action, with a shorter duration of action than that of regular human insulin. The modifications of the amino acid sequence at positions 3 and 29 in the B chain of human insulin simultaneously provide stability to the molecular structure and render the insulin glulisine molecule less likely to self-associate, compared with human insulin, while still allowing the formation of dimers at pharmaceutical concentrations. Unlike other insulin analogue products, this allows for a viable drug product in the absence of hexamer-promoting zinc and, thus, provides immediate availability of insulin glulisine molecules at the injection site for absorption. Pharmacokinetic studies with insulin glulisine have shown an absorption profile with a peak insulin concentration approximately twice that of regular human insulin, which is reached in approximately half the time. Dose proportionality in early, maximum and total exposure is observed for insulin glulisine over the therapeutic relevant dose range up to 0.4 U/kg. The pharmacodynamic profile of insulin glulisine reflects the absorption kinetics by demonstrating a greater rate of glucose utilization, which is completed earlier and at equipotency on a molar base compared with regular human insulin. Dose-proportionality in glucose utilization has been established for insulin glulisine in patients with type 1 diabetes mellitus in the dose range of 0.075-0.15 U/kg, and a less than dose-proportional increase above 0.15 U/kg, indicating saturation of insulin action in general. The rapid absorption and action of insulin glulisine show similar low intrasubject variability compared with insulin lispro and regular human insulin when given repeatedly, and have been confirmed in healthy subjects of different body mass indices (BMIs) and ethnic groups, as well as adults and children with type 1 and type 2 diabetes. Furthermore, the early insulin exposure and action of insulin glulisine were slightly -- but consistently -- greater than those of insulin lispro in healthy volunteers across a wide range of BMIs.Meal studies in patients with type 1 diabetes show that insulin glulisine provides better postprandial blood glucose control than regular human insulin when administered immediately pre-meal, and equivalent control when given after the meal. In a study in patients with type 2 diabetes, the overall postprandial blood glucose excursions were lower with insulin glulisine than with insulin lispro. Therefore, by virtue of its primary structure, insulin glulisine demonstrates both low self-association in solution and stability for a viable insulin product in the absence of zinc, thereby maintaining immediate availability for absorption after subcutaneous injection. This confers the most rapid onset of glucose-lowering activity and adds to the flexibility in postprandial blood glucose control.
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PMID:Clinical pharmacokinetics and pharmacodynamics of insulin glulisine. 1807 15

Until recently, progress in identification of the genetic variants influencing predisposition to common forms of diabetes and obesity has been slow, a sharp contrast to the large number of genes implicated in rare monogenic forms of both conditions. Recent advances have transformed the situation, however, enabling researchers to undertake well-powered scans able to detect association signals across the entire genome. For type 2 diabetes, the six high-density genome-wide association studies so far performed have extended the number of loci harboring common variants implicated in diabetes susceptibility into double figures. One of these loci, mapping to the fat mass and obesity associated gene (FTO), influences diabetes risk through a primary effect on fat mass, making this the first common variant known to influence weight and individual risk of obesity. These findings offer two main avenues for clinical translation. First, the identification of new pathways involved in disease predisposition-for example, those influencing zinc transport and pancreatic islet regeneration in the case of type 2 diabetes-offers opportunities for development of novel therapeutic and preventative approaches. Second, with continuing efforts to identify additional genetic variants, it may become possible to use patterns of predisposition to tailor individual management of these conditions.
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PMID:Mechanisms of disease: genetic insights into the etiology of type 2 diabetes and obesity. 1821 65

The gut hormone glucagon-like peptide-1 (GLP-1) is proposed for treatment of Type II diabetes mellitus. However, the short half life of GLP-1 in vivo is a major limitation for its application due to the frequent invasive administrations. To provide a optimal formulation to overcome this limitation, we developed a GLP-1 entrapped microspheres to achieve sustained release GLP-1 for 4-week. GLP-1 was stabilized by GLP-1-zinc complexation with zinc carbonate and encapsulated in poly(D,L-lactic-co-glycolic acid) (PLGA) with S/O/O solvent extraction to obtain GLP-1 loaded PLGA microspheres (MS). The characteristics of MS were evaluated as follows: The surface morphology was assessed by scanning electron microscopy (SEM); The drug encapsulation efficiency and GLP-1 controlled release profile was tested by HPLC; The sustained release of GLP-1 MS in vivo and pharmacological efficacy were studied in normal mice and streptozotocin (STZ)-induced diabetic mice model after subcutaneous administration of GLP-1 MS. GLP-1-zinc complexation significantly reduced initial burst release from 37.2 to 7.5%. The controlled release bioactive GLP-1 in vitro was achieved for 4-week period by zinc complexation and addition of ZnCO(3). The optimal and complete cumulative release of GLP-1 from MS was increased from 23 to 63% in 28 d by using low MW PLGA (MW 14000). The in vivo testing in normal mice and diabetic mice suggest that this zinc-stabilized technique combined with S/O/O method in the presence of water insoluble antacid additive ZnCO(3) preserve the biological activity of GLP-1. GLP-1 MS formulation achieved controlled released in vivo for 28 d and exhibit sustained long term pharmacological efficacy to decrease blood glucose level in diabetic mice. This GLP-1 MS formulation provides a practical formulation for long-term sustained delivery of GLP-1 to treat Type II diabetes.
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PMID:Preparation of glucagon-like peptide-1 loaded PLGA microspheres: characterizations, release studies and bioactivities in vitro/in vivo. 1823 99

Diabetes mellitus is a chronic disease characterized by an overproduction of reactive oxygen species, which perturbs zinc metabolism and promotes the onset of cardiovascular disease (CVD) in diabetic patients. Metallothioneins (MT) are cysteine-rich metal-binding proteins which, by means of their antioxidant and zinc-buffering properties, might prevent the development of diabetic cardiovascular complications. A recent investigation shows that a polymorphism (+647 A/C) in the human MT-1A gene, affects the intracellular zinc ion release (iZnR) from the proteins and is associated with longevity in Italian population. The aim of the present study is to assess the involvement of +647 A/C and +1245 A/G MT1A polymorphisms with the susceptibility to type 2 diabetes (DM2) and cardiovascular complications. The study included 694 old individuals: 242 old healthy controls, 217 DM2 patients without clinical evidence of CVD (DNC) and 235 diabetic patients with diagnosis of CVD (DCVD). +647 A/C MT1A polymorphism, but not the second SNP, was associated with DM2. C allele carriers were more prevalent in DNC and DCVD patients than in control group (OR=1.37, p=0.034; OR=1.54, p=0.002, respectively). C+ carriers was associated with higher glycemia and glycosylated hemoglobin in DCVD patients, but not in DNC or control subjects. No differences in plasma zinc, but a modulation of MT levels and iZnR in PBMCs were observed in DCVD cohort when related to +647 A/C MT1A polymorphism. In summary, this work provides novel evidence on the association of the +647 A/C MT1A polymorphism with DM2. Moreover, C+ carriers in DCVD patients presented a worse glycemic control, a reduced iZnR and a higher MT levels, suggesting a possible role of MT in diabetic cardiovascular complications.
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PMID:+647 A/C and +1245 MT1A polymorphisms in the susceptibility of diabetes mellitus and cardiovascular complications. 1832 46

The number of patients suffered from diabetes mellitus has increased over the decades probably because of both lifestyle- and diet-changes. There are two types of diabetes mellitus. Type 1 diabetes mellitus is due to the autoimmune-mediated destruction of pancreatic B cells, which results in absolute insulin deficiency, thus the patients require insulin injections. Type 2 diabetes mellitus is due to the insulin resistance and abnormal insulin secretion, thus the patients require exercise, diet control and/or oral hypoglycemic medicines. Each treatment, however, has some problems involving physical and mental burden, and formation of self-antibodies for insulin injections, and the severe side effects and discontinuation of insulin synthesis in the pancreas for hypoglycemic medicines. To overcome these important problems and find the replacements for the insulin injections and synthetic medicines, we attempted to develop new antidiabetic metallocomplexes with novel structures and mechanisms. In 1990, we first presented orally active vanadyl (+4 oxidation state of oxo-vanadium) complexes including vanadyl-cysteine methyl ester complex, which normalized hyperglycemia in the streptozocin (STZ)-induced type 1 diabetic rats. Based on these findings, we have developed a wide variety of vanadyl complexes with different coordination environments around vanadyl ion. Following the study, we also challenged to develop orally active zinc complexes since 2002. This review focuses on our recent development of vanadyl and zinc complexes for anti-diabetic and anti-metabolic syndromes, together with the propose for the possible action mechanism of these complexes in adipocytes.
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PMID:[Treatment of diabetes in experimental animals by metallocomplexes]. 1831 Oct 49

The widely clinically used benzothiadiazines and high ceiling diuretics, such as hydrochlorothiazide, hydroflumethiazide, quinethazone, metolazone, chlorthalidone, indapamide, furosemide and bumetanide, contain SO(2)NH(2) moieties acting as an effective zinc-binding function in carbonic anhydrases (CAs, EC 4.2.1.1) inhibitors. These drugs were launched in a period when only isoform CA II was known and considered physiologically/pharmacologically relevant. Although acting as moderate-weak inhibitors of CA II, all these drugs considerably inhibit other CA isozymes known nowadays to be involved in critical physiologic processes, among the 16 CAs present in vertebrates. Some low nanomolar (or even subnanomolar) inhibitors against such isoforms were recently detected, such as metholazone against CA VII, XII and XIII, chlorthalidone against CA VB, VII, IX, XII and XIII, indapamide against CA VII, IX, XII and XIII, furosemide against CA I, II and XIV, and bumethanide against CA IX and XII. The X-ray crystal structure of the CA II-indapamide adduct was also reported recently, revealing interesting aspects useful for the drug design of CA inhibitors. It has also been proposed that the recently observed beneficial effect of indapamide for the treatment of patients with hypertension and type 2 diabetes might be due to its potent inhibition of CA isoforms present in kidneys and blood vessels, which would thus explain both the blood pressure lowering effects as well as organ-protective activity of the drug. Thus, these old drugs may be useful as leads for new applications.
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PMID:Diuretics: from classical carbonic anhydrase inhibitors to novel applications of the sulfonamides. 1833 9

Genome-wide association scans in type 2 diabetes (T2D) have identified a risk variant, rs13266634 (Arg325Trp), in SLC30A8 on chromosome 8. SLC30A8 encodes a beta-cell specific zinc-ion transporter and rs13266634 has been shown to affect insulin secretion. Recently, autoantibodies for Slc30A8 with high predictive value were demonstrated in individuals with type 1 diabetes (T1D), making this gene an interesting T1D candidate gene. We genotyped rs13266634 in 3008 cases and controls and 246 families from Denmark. Association to T1D could not be demonstrated.
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PMID:A non-synonymous variant in SLC30A8 is not associated with type 1 diabetes in the Danish population. 1840 May 35

Insulin-degrading enzyme (IDE) is a ubiquitous zinc-metalloprotease that hydrolyzes several pathophysiologically relevant peptides, including insulin and the amyloid beta-protein (Abeta). IDE is inhibited irreversibly by compounds that covalently modify cysteine residues, a mechanism that could be operative in the etiology of type 2 diabetes mellitus (DM2) or Alzheimer's disease (AD). However, despite prior investigation, the molecular basis underlying the sensitivity of IDE to thiol-alkylating agents has not been elucidated. To address this topic, we conducted a comprehensive mutational analysis of the 13 cysteine residues within IDE. Our analysis implicates C178, C812, and C819 as the principal residues conferring thiol sensitivity. The involvement of C812 and C819, residues quite distant from the catalytic zinc atom, provides functional evidence that the active site of IDE comprises two separate domains that are operational only in close apposition. Structural analysis and other evidence predict that alkylation of C812 and C819 disrupts substrate binding, whereas alkylation of C178 interferes with the apposition of active-site domains and subtly repositions zinc-binding residues. Unexpectedly, alkylation of C590 was found to activate hydrolysis of Abeta significantly, while having no effect on insulin, demonstrating that chemical modulation of IDE can be both bidirectional and highly substrate selective. Our findings resolve a long-standing riddle about the basic enzymology of IDE with important implications for the etiology of DM2 and AD. Moreover, this work uncovers key details about the mechanistic basis of the unusual substrate selectivity of IDE that may aid the development of pharmacological agents or IDE mutants with therapeutic value.
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PMID:Molecular basis for the thiol sensitivity of insulin-degrading enzyme. 1862 27


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