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)

Islet amyloid deposits are a characteristic pathologic lesion of the pancreas in type 2 diabetes and are composed primarily of the islet beta cell peptide islet amyloid polypeptide (IAPP or amylin) as well as the basement membrane heparan sulfate proteoglycan perlecan. Impaired processing of the IAPP precursor has been implicated in the mechanism of islet amyloid formation. The N- and C-terminal cleavage sites where pro-IAPP is processed by prohormone convertases contain a series of basic amino acid residues that we hypothesized may interact with heparan sulfate proteoglycans. This possibility was tested using affinity chromatography by applying synthetic fragments of pro-IAPP to heparin-agarose and heparan sulfate-Sepharose. An N-terminal human pro-IAPP fragment (residues 1-30) was retained by both heparin-agarose and heparan sulfate-Sepharose, eluting at 0.18 m NaCl at pH 7.5. Substitution of alanine residues for two basic residues in the N-terminal cleavage site abolished heparin and heparan sulfate binding activity. At pH 5.5, the affinity of the wild-type peptide for heparin/heparan sulfate was increased, implying a role for histidine residues at positions 6 and 28 of pro-IAPP. A C-terminal pro-IAPP fragment (residues 41-67) had no specific affinity for either heparin or heparan sulfate, and the N- or C-terminal fragments had only weak affinity for chondroitin sulfate. These data suggest that monomeric N-terminal human pro-IAPP contains a heparin binding domain that is lost during normal processing of pro-IAPP.
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PMID:Identification of a heparin binding domain in the N-terminal cleavage site of pro-islet amyloid polypeptide. Implications for islet amyloid formation. 1114 57

The Pro(12)Ala (P12A) variant of exon B of the peroxisome proliferator-activated receptor gamma(2) (PPAR gamma) been variably associated with obesity, insulin sensitivity, diabetes, and dyslipidemia, but its role in insulin resistance-associated traits remains uncertain. We tested the hypothesis that this variant is associated with the insulin resistance syndrome by genotyping 619 members of 52 familial type 2 diabetes kindreds. A subset of 124 family members underwent iv glucose tolerance tests and minimal model determination of insulin sensitivity. We estimated the frequency of the A12 allele as 0.12, within the range observed in random Caucasian samples. We were unable to demonstrate any effect on direct measures of insulin sensitivity, and no trait was linked to markers near PPAR gamma on chromosome 3q. However, body mass index, serum total cholesterol levels, triglyceride levels, systolic and diastolic blood pressures, and glucose concentration showed at least a trend to association (P < 0.1) when tested separately for a family-based association. When these 6 traits were included in a multivariate analysis, body mass index, systolic and diastolic blood pressures, triglyceride levels, and glucose concentration remained significantly associated with the P12A variant (P < 0.05), whereas the effect of P12A on liability for diabetes was not significant. The predicted means for each trait and each genotype suggested that the P12A variant acted most like a recessive mutation, with the major effect among homozygous individuals who comprise only 1--2% of the population. We confirm an association of the P12A variant in traits commonly ascribed to the insulin resistance syndrome, but not with direct measures of insulin sensitivity. The tendency for this variant to act in a recessive manner with effects on multiple traits may explain the inconsistent associations noted in previous studies.
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PMID:Effect of the peroxisome proliferator-activated receptor-gamma 2 pro(12)ala variant on obesity, glucose homeostasis, and blood pressure in members of familial type 2 diabetic kindreds. 1115 5

Several studies have demonstrated an association of CTLA4 (IDDM12) alanine-17 with type 1 diabetes, but CTLA4 variants have not yet been investigated in type 2 diabetes. The CTLA4 exon 1 polymorphism (49 A/G) was analyzed in 300 Caucasian patients with type 2 diabetes and 466 healthy controls. All patients were negative for glutamate decarboxylase and islet cell antibodies. CTLA4 alleles were defined by PCR, single-strand conformational polymorphism, and restriction length fragment polymorphism analysis using BBV:I. The distribution of alleles as well as the genotypic and phenotypic frequencies were similar among patients and controls [AA, 42 vs. 39%; AG, 47 vs. 46%; GG, 11 vs. 15%, P = not significant (n.s.); A/G, 65/35% vs. 62/38%, P = n.s.; alanine/threonine 92/58% vs. 85/61%, P = n.s.]. However, detailed analysis of clinical and biochemical parameters revealed a tendency of GG (alanine/alanine) toward younger age at disease manifestation (46.8 +/- 0.8 vs. 49.5 +/- 0.8 yr, mean +/- SEM), lower body mass index (21.4 +/- 0.5 vs. 24.4 +/- 0.5 kg/m(2), P = 0.042), and basal C-peptide level (0.33 +/- 0.07 vs. 0.53 +/- 0.07nmol/L), as well as earlier start of insulin treatment (5.8 +/- 1.2 vs. 8.7 +/- 0.6 yr) and higher portion of patients on insulin (71 vs. 61%). Patients with the AA genotype were significantly less likely to develop microangiopathic lesions (P < 0.0005). No differences were found for hypertension or family history of type 2 diabetes. In conclusion, CTLA4 alanine-17 does not represent a major risk factor for type 2 diabetes. Additional studies on larger groups and different ethnic groups are warranted to clarify the association of the GG genotype with faster ss-cell failure and the lower rate of microvascular complications in AA carriers.
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PMID:The codon 17 polymorphism of the CTLA4 gene in type 2 diabetes mellitus. 1115 25

Amino acid catabolism and urea synthesis are increased in type 2 diabetes mellitus in poor metabolic control. In different catabolic conditions, prostaglandins (PGs) of the E series produced metabolic effects on nitrogen metabolism, decreasing urea formation. In 10 patients with type 2 diabetes in poor metabolic control, urea synthesis and amino acid to urea nitrogen exchange were measured in the basal state and during an alanine load (6 hours) with 2-hour superinfusion of a PGE1 analog (30 microg/h) or saline in random order. The urea synthesis rate was calculated as the sum of urinary urea excretion and urea accumulation in total body water (TBW); total nitrogen exchange was calculated as the difference between infused amino acid-nitrogen and urea appearance. Plasma alpha-aminonitrogen (alpha-amino-N) increased 100% in response to alanine, to a steady-state without differences in relation to PG superinfusion. The urea synthesis rate (mean +/- SD) was 34.0 +/- 11.4 mmol/h in the basal period and increased to 161.2 +/- 37.0 during alanine + saline and to 113.5 +/- 34.6 during alanine + PG (P < .001). Nitrogen exchange was negative at baseline (-25.0 +/- 9.0 mmol/h). It became moderately positive during alanine + saline (14.6 +/- 25.1) and far more positive during alanine + PG (53.5 +/- 21.4), with the difference due to reduced urea formation. The metabolic effects of PG were not related to differences in insulin and glucagon. We conclude that PGE1 slows the high rate of hepatic urea-N synthesis in poorly controlled type 2 diabetes. Such metabolic effects have therapeutic implications.
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PMID:Systemic prostaglandin E1 infusion and hepatic aminonitrogen to urea nitrogen conversion in patients with type 2 diabetes in poor metabolic control. 1122 38

Membrane peptidases are a group of ectoenzymes with a broad functional repertoire. In protein metabolism, their importance is well known, especially in peptide degradation and amino acid scavenging at the intestinal and renal brush border. However, they also perform more subtle tasks; not only do they provide or extinguish signals by cleaving exterior peptide mediators, but they also may function as receptors or participate in signal transduction or in adhesion. Dipeptidyl peptidase IV (DPPIV), which is identical to the lymphocyte surface glycoprotein CD26, is unique among these peptidases because of its ability to liberate Xaa-Pro and less efficiently Xaa-Ala dipeptides from the N-terminus of regulatory peptides. It occurs in the plasma membrane as a homodimer with a total molecular mass of 22-240 KdA and the C-terminal domain probably forms on alpha/beta hydrolase fold. In addition to, but independent of its serine type catalytic activity, DPPIV binds closely to the soluble extracellular enzyme adenosine deaminase. The in vivo expression on epithelial, endothelial and lymphoid cells of DPPIV is compatible with a role as physiological regulator of a number of peptides that serve as biochemical reporters between and within the immune and neuroendocrine system. Surprisingly, not cytokines with a N-terminal Xaa-Pro motif, but a number of chemokines have recently been identified as substrates. Despite DPPIV mediates only a minimal N-terminal truncation, important alterations in chemokine activities and receptor specificitIes were observed in vitro together with modified inflammatory and antiviral responses. Most probably the great flexibility of the N-terminus of a number of chemokines facilitates the accessibIlity to the catalytic site of DPPIV. Other known substrates which are subject in vitro to receptor-specific changes induced by DPPIV truncation include neuropeptides such as substance P, peptidE YY and neuropeptide Y. On the other hand, DPPIV mediated cleavage of the N-terminal His-Ala or Tyr-Ala dipeptides from circulating incretin hormones like, glucagon-like peptides (GLP)-1 and -2, gastric inhibitory polypeptide (GIP), all members of the enteroglucagon/GRF superfamily, results in their biological inactivation in vitro and in vivo. Administration of specific DPPIV inhibitors closes this pathway of incretin degradation and greatly enhances insulin secretion. The improved glucose tolerance in several animal models for type II diabetes points to specific DPPIV inhibition as a pharmaceutical approach for type 2 diabetes drug development.
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PMID:Peptide truncation by dipeptidyl peptidase IV: a new pathway for drug discovery? 1128 88

Recent studies have identified a common proline-to-alanine substitution (Pro12Ala) in the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2), a nuclear receptor that regulates adipocyte differentiation and possibly insulin sensitivity. The Pro12Ala variant has been associated in some studies with diabetes-related traits and/or protection against type 2 diabetes. We examined this variant in 935 Finnish subjects, including 522 subjects with type 2 diabetes, 193 nondiabetic spouses, and 220 elderly nondiabetic control subjects. The frequency of the Pro12Ala variant was significantly lower in diabetic subjects than in nondiabetic subjects (0.15 vs. 0.21; P = 0.001). We also compared diabetes-related traits between subjects with and without the Pro12Ala variant within subgroups. Among diabetic subjects, the variant was associated with greater weight gain after age 20 years (P = 0.023) and lower triglyceride levels (P = 0.033). Diastolic blood pressure was higher in grossly obese (BMI >40 kg/m2) diabetic subjects with the variant. In nondiabetic spouses, the variant was associated with higher fasting insulin (P = 0.033), systolic blood pressure (P = 0.021), and diastolic blood pressure (P = 0.045). These findings support a role for the PPAR-gamma2 Pro12Ala variant in the etiology of type 2 diabetes and the insulin resistance syndrome.
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PMID:The peroxisome proliferator-activated receptor-gamma2 Pro12A1a variant: association with type 2 diabetes and trait differences. 1128 57

The allele frequencies for a Pro12-->Ala substitution in peroxisome proliferator-activated receptor-gamma differ among ethnic groups, and its relationship with diabetes and associated diseases is controversial. The prevalence of this polymorphism and its effects on clinical characteristics have now been evaluated with a large number of Japanese individuals with type 2 diabetes (n = 2,201) and normal control subjects (n = 1,212) recruited by 10 institutions located in seven different cities in Japan. The allele frequency for the Ala12 variant was significantly lower in the type 2 diabetic group than in the control group (2.39 vs. 4.13%, P = 0.000054). However, compared with subjects without the Ala12 variant, the diabetic subjects with this variant exhibited a significantly higher serum concentration of total cholesterol (P = 0.001), manifested a reduced capacity for insulin secretion as evaluated by homeostasis model assessment (P = 0.007), and tended to possess a higher level of HbA1c. These data suggest that the Ala12 variant is associated with a reduced risk for the development of diabetes in the general population, but that it may be also a risk factor for insulin deficiency and disease severity in individuals with type 2 diabetes.
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PMID:The Pro12 -->Ala substitution in PPAR-gamma is associated with resistance to development of diabetes in the general population: possible involvement in impairment of insulin secretion in individuals with type 2 diabetes. 1128 58

We have sequenced the insulin gene in 72 unrelated Japanese subjects (52 with type 2 diabetes mellitus and 20 with normal glucose tolerance). We identified 6 mutations and all were found at a low frequency (1% to 4%). Three mutations were new. These included a C-to-G substitution in the promoter region, a G-to-A substitution in codon-2 resulting in an Ala-to-Thr replacement in amino acid -2 of the signal peptide, and a G-to-A substitution in intron 2. We have no evidence that any of the mutations that we found are the cause of diabetes. Thus, mutations in the insulin gene do not appear to be an important genetic factor contributing to the development of diabetes in this population.
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PMID:Polymorphisms of the insulin gene among Japanese subjects. 1139 36

Platelet levels of 19 amino acids were measured in 20 outpatients with type 1 (age [mean +/- SE], 35.5 +/- 2.0 years) and 27 with type 2 (age, 58.4 +/- 1.4 years) diabetes, and 20 young (age 33.7 +/- 1.3 years) and 20 older (age 57.4 +/- 1.5 years) healthy volunteers. Platelet levels of most amino acids tended to be lower in patients with type 1 diabetes than in healthy controls. In particular, asparagine, glycine, taurine, alanine, valine, cysteine, leucine, phenylalanine, and lysine levels, expressed as nmol/10(8) platelets, were significantly lower. Only taurine significantly decreased in patients with type 2 diabetes, whereas threonine, alanine, and isoleucine increased.
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PMID:Preliminary report: Amino acid profile in platelets of diabetic patients. 1143 75

Metformin (1,1-dimethylbiguanide; MET) is used in the treatment of type 2 diabetes mellitus. MET's antihyperglycemic action depends at least in part on its inhibitory effect on hepatic gluconeogenesis. As to gluconeogenesis from amino acids (e.g. L-alanine), this is associated with an inhibition of L-alanine uptake into hepatocytes. Since this uptake is mediated by an electrogenic transport mechanism, the aim of the present study was to investigate whether MET has an influence on the liver cell membrane potential which might explain its inhibitory effect on L-alanine uptake. The experiments were performed in vivo in anesthetized rats and in vitro using superfused mouse liver slices with the conventional microelectrode technique. In vivo, MET (160 mg/kg intraperitoneally (i.p.)) significantly depolarized (dV) the liver cell membrane by 6 mV. MET (1 mmol/l) also depolarized the liver cell membrane in vitro (e.g. 15 min after start of superfusion: dV=8 mV). MET's effect was at least partly reversible. Glucagon (10(-7) mol/l), which hyperpolarized the liver cell membrane, abolished MET's effect. Further, the MET-induced depolarization was completely absent during superfusion with low Cl(-) ([Cl(-)]=27 mmol/l) medium, and significantly attenuated by the Cl(-) channel blocker NPPB (25 micromol/l). While MET's effect was only somewhat attenuated by blockade of the Na(+)/K(+)/2Cl(-) cotransporter or by superfusion with (HCO(-)(3)-free) HEPES buffer, the carboanhydrase blocker acetazolamide (1 mmol/l) or blockade of the HCO(-)(3)/Cl(-) exchanger by DIDS (100 micromol/l), which, however, also blocks Cl(-) channels, abolished its effect. The depolarization of the liver cell membrane by MET was unaffected by a blockade of K(+) channels with Ba(2+), a blockade of the Na(+)/K(+) pump or superfusion with low Na(+) medium ([Na(+)]=26 mmol/l). According to these results, the MET-induced depolarization of the liver cell membrane could be due to an activation of the Cl(-)/HCO(-)(3) exchanger and thus depend on intracellular HCO(-)(3) formation. This activation could then lead to a disturbance of the equilibrium between intra- and extracellular Cl(-) and therefore to an enhanced Cl(-) efflux via Cl(-) channels. It is plausible that the depolarizing effect induced by MET is associated with its inhibitory effect on gluconeogenesis by inhibiting uptake of L-alanine and other amino acids into hepatocytes.
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PMID:Depolarization of the liver cell membrane by metformin. 1147 89


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