Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The single-nucleotide polymorphism A/G in the type 2 deiodinase (D2) gene predicts a threonine (Thr) to alanine (Ala) substitution at codon 92 (D2 Thr92Ala) and is associated with insulin resistance in obese patients. Here, this association was investigated in 183 patients with type 2 diabetes mellitus, using homeostasis model assessment. The median fasting plasma insulin in Ala/Ala individuals was significantly higher than in patients with Ala/Thr or Thr/Thr genotypes (19.6 vs. 12.0 vs. 14.8 mIU/ml, respectively; P = 0.004). Assuming a recessive model, the homeostasis model assessment index was higher in the Ala/Ala group when compared with Ala/Thr-Thr/Thr group (8.50 vs. 4.85, P = 0.003). Although this polymorphism has not been associated with changes in D2 kinetics as measured in HEK-293 cells transiently expressing D2 Thr92Ala, we investigated whether such association could be detected in human tissue samples. Remarkably, in thyroid and skeletal muscle samples from subjects homozygous for the Ala allele, D2 velocity was significantly lower than in subjects with Ala/Thr-Thr/Thr genotypes (P = 0.05 and 0.04, respectively). In conclusion, the A/G polymorphism is associated with greater insulin resistance in type 2 diabetes mellitus patients and with lower D2 velocity in tissue samples. These findings suggest that the D2-generated T(3) in skeletal muscle plays a role in insulin resistance.
 ...
PMID:The type 2 deiodinase A/G (Thr92Ala) polymorphism is associated with decreased enzyme velocity and increased insulin resistance in patients with type 2 diabetes mellitus. 1579 63

The separate and combined effects of the PPARG Pro(12)Ala polymorphism and the KCNJ11 Glu(23)Lys polymorphisms on risk of type 2 diabetes were investigated in relatively large-scale, case-control studies. Separate effects of the variants were examined among 1187/1461 type 2 diabetic patients and 4791/4986 middle-aged, glucose-tolerant subjects. The combined analysis involved 1164 type 2 diabetic patients and 4733 middle-aged, glucose-tolerant subjects. In the separate analyses, the K allele of the KCNJ11 Glu(23)Lys associated with type 2 diabetes (odds ratio, 1.19; P = 0.0002), whereas the PPARG Pro(12)Ala showed no significant association with type 2 diabetes. The combined analysis indicated that the two polymorphisms acted in an additive manner to increase the risk of type 2 diabetes, and we found no evidence for a synergistic interaction between them. Analysis of a model with equal additive effects of the two variants showed that the odds ratio for type 2 diabetes increased with 1.14/risk allele (P = 0.003). Together, the two polymorphisms conferred a population-attributable risk for type 2 diabetes of 28%. In conclusion, our results showed no evidence of a synergistic interaction between the KCNJ11 Glu(23)Lys and PPARG Pro(12)Ala polymorphisms, but indicated that they may act in an additive manner to increase the risk of type 2 diabetes.
 ...
PMID:Analysis of separate and combined effects of common variation in KCNJ11 and PPARG on risk of type 2 diabetes. 1579 64

Mitochondrial dysfunction has been reported to contribute to insulin resistance (IR) in the elderly and type 2 diabetes. To test this hypothesis, we examined relations of insulin resistance in young men to their mother's body mass index (BMI) and compared with those to their father's BMI, because as a rule, mitochondrial DNA is exclusively maternally inherited and because mitochondria are fundamental in mediating effects on energy dissipation. We measured heights, weights, waist circumference, systolic and diastolic blood pressure (BP), and biochemical variables in sera from 193 male college students aged 18 to 20 years after an overnight fast. Birth weight was available from 184 students. Self-reported heights and weights of their parents were obtained from 148 students. Insulin resistance and insulin secretion were estimated using homeostasis model assessment (HOMA-IR and HOMA-beta, respectively). Mother's BMI was associated with their son's birth weight (r=0.23, P=.008), BMI (r=0.37, P<.0001), waist circumference (r=0.42, P<.0001), fasting insulin (r=0.19, P=.02), and HOMA-IR (r=0.18, P=.03) but not with fasting glucose, HOMA-beta , and systolic and diastolic BP. In addition, high-density lipoprotein cholesterol and lipoprotein(a) [Lp(a)] were inversely associated with mother's BMI (r=-0.21, P=.01 and r=-0.17, P=.03, respectively). Furthermore, there were significant associations with aspartate (r=0.20, P=.01) and alanine (r=0.28, P=.0008) aminotransferase and gamma-glutamyl transpeptidase (r=0.30, P=.0003), all of which are associated with mitochondrial function. In contrast, none of those variables were associated with father's BMI, except for Lp(a), which showed a significant and inverse association (r=-0.17, P=.05). After adjustment for sons' BMI, waist circumference and 3 hepatic enzymes were associated with mother's BMI, whereas Lp(a) was associated with both mother's and father's BMI. In multiple regression analysis for HOMA-IR as a dependent variable, BMI of their own (beta=.10, P<.0001) and of their mothers (beta=.04, P=10) and birth weight (beta=-.27, P=.10) emerged as determinants of HOMA-IR of the students(R2=0.30). Our results are consistent with clinical observations of a greater risk of transmission of type 2 diabetes from the mother than the father and suggest that son's IR may be influenced by maternal effect as well as their adiposity.
 ...
PMID:Associations of middle-aged mother's but not father's body mass index with 18-year-old son's waist circumferences, birth weight, and serum hepatic enzyme levels. 1579 52

The force fields used in classical modeling studies are semiempirical in nature and rely on their validation by comparison of simulations with experimental data. The all-atom replica-exchange molecular dynamics (REMD) methodology allows us to calculate the thermodynamics of folding/unfolding of peptides and small proteins, and provides a way of evaluating the reliability of force fields. We apply the REMD to obtain equilibrium folding/unfolding thermodynamics of a 21-residue peptide containing only alanine residues in explicit aqueous solution. The thermodynamics of this peptide is modeled with both the OPLS/AA/L and the A94/MOD force fields. We find that the helical content and the values for the helix propagation and nucleation parameters for this alanine peptide are consistent with measurements on similar peptides and with calculations using the modified AMBER force field (A94/MOD). The nature of conformations, both folded and unfolded, that contributes to the helix-coil transition profile, however, is quite different between these two force fields.
 ...
PMID:Helix-coil transition of alanine peptides in water: force field dependence on the folded and unfolded structures. 1581 75

The ionic selectivity of ligand-gated ion channels (LGICs) determines whether receptor activation produces an excitatory or inhibitory response. The determinants of anion/cation selectivity were investigated for a new member of the LGIC superfamily, MOD-1, a serotonin-gated chloride channel cloned from the nematode Caenorhabditis elegans. In common with other anionic LGICs (glycine receptors and GABA(A) receptors), the selectivity triple mutant in the pore-forming M2 segment (proline insertion, Ala --> Glu substitution at the central ring, and Thr --> Val at the hydrophobic ring) converted the selectivity of MOD-1 from anionic to cationic. Unlike other LGICs, however, this mutant in MOD-1 was highly selective for K+ over other cations. Subsets of this selectivity triple mutant were studied to define the minimal change required for conversion from anion-permeable to cation-permeable. The double mutant at the central ring of charge (deltaPro-269/A270E) produced a non-selective cation channel. Charge reversal at the central ring alone (A270E) was sufficient to convert MOD-1 to cation-permeable. These results refine the determinants of ion-charge selectivity in LGICs and demonstrate the critical role of the central ring of charge formed by the M2 segments.
 ...
PMID:Chimeric mutations in the M2 segment of the 5-hydroxytryptamine-gated chloride channel MOD-1 define a minimal determinant of anion/cation permeability. 1587 44

Type 2 diabetes is a disorder of hyperglycemia resulting from failure of beta cells to produce adequate insulin to accommodate an increased metabolic demand. Here we show that regulation of mRNA translation through phosphorylation of eukaryotic initiation factor 2 (eIF2alpha) is essential to preserve the integrity of the endoplasmic reticulum (ER) and to increase insulin production to meet the demand imposed by a high-fat diet. Accumulation of unfolded proteins in the ER activates phosphorylation of eIF2alpha at Ser51 and inhibits translation. To elucidate the role of this pathway in beta-cell function we studied glucose homeostasis in Eif2s1(tm1Rjk) mutant mice, which have an alanine substitution at Ser51. Heterozygous (Eif2s1(+/tm1Rjk)) mice became obese and diabetic on a high-fat diet. Profound glucose intolerance resulted from reduced insulin secretion accompanied by abnormal distension of the ER lumen, defective trafficking of proinsulin, and a reduced number of insulin granules in beta cells. We propose that translational control couples insulin synthesis with folding capacity to maintain ER integrity and that this signal is essential to prevent diet-induced type 2 diabetes.
 ...
PMID:Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis. 1598 Aug 66

Oxidative stress has been implicated in pancreatic beta-cell damage, insulin resistance and vascular function in diabetic patients and the dysfunction of antioxidant enzymes may be associated with the pathogenesis of diabetes. Extracellular superoxide dismutase (EC-SOD) is found in the extracellular matrix of tissues and the major scavenger of superoxide radical. To investigate the role of genetic variability for the pathogenesis of type 2 diabetes, we scanned the protein coding exon and flanking introns of EC-SOD gene for mutation in Japanese type 2 diabetic patients. We identified two missense mutations, Ala40Thr (GCG-->ACG) and Arg213Gly (CGG-->GGG), and a silent mutation, Leu53Leu (CTG-->TTG). For one of these variants, the Ala40Thr polymorphism, the frequency of Thr allele and the number of subjects with Thr allele (Ala/Thr+Thr/Thr) were higher in type 2 diabetic patients (n=205) than those in non-diabetic subjects (n=220) (33.2% versus 24.1%, p=0.003 and 55.6% versus 42.7%, p=0.008, respectively). The patients with Thr allele also showed earlier age at diagnosis of diabetes (42.2+/-7.8 years versus 44.4+/-6.9 years, p=0.037) and higher prevalence of hypertension (53.5% versus 38.5%, p=0.032) than those without the allele. Insulin sensitivity, furthermore, was evaluated in 71 type 2 diabetic patients with short insulin tolerance test (SITT). The patients with Thr allele showed lower insulin sensitivity (Kitt value of SITT) than those without the allele (1.78+/-0.78%/min versus 2.33+/-1.02%/min, p=0.012), although no significant differences in other clinical and biochemical characteristics were observed between two groups. These results suggest that the genetic variant of EC-SOD gene is associated with insulin resistance and the susceptibility to type 2 diabetes.
 ...
PMID:Extracellular superoxide dismutase gene polymorphism is associated with insulin resistance and the susceptibility to type 2 diabetes. 1599 Jan 93

Previously, we reported high hepatotoxic sensitivity of type 2 diabetic (DB) rats to three dissimilar hepatotoxicants. Additional work revealed that a normally nonlethal dose of CCl4 was lethal in DB rats due to inhibited compensatory tissue repair. The present study was conducted to investigate the importance of compensatory tissue repair in determining the final outcome of hepatotoxicity in diabetes, using another structurally and mechanistically dissimilar hepatotoxicant, thioacetamide (TA), to initiate liver injury. A normally nonlethal dose of TA (300 mg/kg, ip), caused 100% mortality in DB rats. Time course studies (0 to 96 h) showed that in the non-DB rats, liver injury initiated by TA as assessed by plasma alanine or aspartate aminotransferase and hepatic necrosis progressed up to 48 h and regressed to normal at 96 h resulting in 100% survival. In the DB rats, liver injury rapidly progressed resulting in progressively deteriorating liver due to rapidly expanding injury, hepatic failure, and 100% mortality between 24 and 48 h post-TA treatment. Covalent binding of 14C-TA-derived radiolabel to liver tissue did not differ from that observed in the non-DB rats, indicating similar bioactivation-based initiation of hepatotoxicity. S-phase DNA synthesis measured by [3H]-thymidine incorporation, and advancement of cells through the cell division cycle measured by PCNA immunohistochemistry, were substantially inhibited in the DB rats compared to the non-DB rats challenged with TA. Thus, inhibited cell division and compromised tissue repair in the DB rats resulted in progressive expansion of liver injury culminating in mortality. In conclusion, it appears that similar to type 1 diabetes, type 2 diabetes also increases sensitivity to dissimilar hepatotoxicants due to inhibited compensatory tissue repair, suggesting that sensitivity to hepatotoxicity in diabetes occurs in the absence as well as presence of insulin.
 ...
PMID:Type 2 diabetic rats are sensitive to thioacetamide hepatotoxicity. 1615 71

Peroxisome proliferator activated receptor (PPAR) gamma is present in two isoforms generated by alternative splicing, PPAR gamma 1 and PPAR gamma 2. A Pro12Ala polymorphism in human PPAR gamma 2 moderately reduces its transcriptional activity, and thus PPAR gamma 2 is thought to be a promising candidate gene for several human disorders, including obesity and type 2 diabetes mellitus. In this report, we examined the polymorphism of the PPAR gamma 2 gene in people at high and low altitudes in Bolivia, and found a significant difference in the frequency of Ala carriers (Pro/Ala and Ala/Ala) between 153 native high-altitude Bolivian subjects (64.1%) and 288 low-altitude Bolivian subjects (37.9%). The frequency of this Ala allele in Bolivian subjects was fairly higher than that in other ethnic groups. As body mass index, however, was not associated with Pro12Ala polymorphism of the PPAR gamma 2 gene among either the high altitude Bolivians or low altitude Bolivians, Pro12Ala polymorphism of the gene has little relationship to obesity in Bolivians.
 ...
PMID:The difference of mutation in the peroxisome proliferator activated receptor gamma2 gene among people at high altitudes and low altitudes in Bolivia. 1618 May 11

The authors conducted a prospective, open-label, pilot trial of the effects of the antidiabetic thiazolidinedione (TZD) rosiglitazone in two patients with moderate to severe plaque psoriasis. Case 1: A lean, euglycemic 43-year-old nondiabetic man with a 2-year history of plaque psoriasis presented with lesions involving 10% of his body surface (Figures 1A, 1B, 1C). He had no other chronic or acute medical problems. He had previously been managed sporadically with topical triamcinolone acetonide, an intermediate-strength glucocorticoid, and was off antipsoriatic medication for 5 months. He was started on rosiglitazone p.o., 8 mg q.d. After 10 weeks on rosiglitazone, the lesions developed increased erythema, spreading, and shedding of scale (Figures 2A, 2B, 2C). After an additional 26 weeks, the lesions had largely disappeared (Figures 3A, 3B, 3C). The patient remained euglycemic throughout the study. His liver function enzymes (alanine transferase [ALT] and aspartate transferase [AST]) remained normal throughout the study: ALT, 23 IU/L; AST, 47 IU/L before treatment; ALT, 25 IU/L; AST, 33 IU/L after treatment. There were no adverse events. Case 2: An overweight 68-year-old woman (body mass index, 29 kg/m2; with a 12-year history of type 2 diabetes and 5-year history of psoriasis presented with generalized plaque psoriasis over 20% of her body, including two large, thick, silvery plaques with the texture of leather over the lower part of the back (Figure 4A). She was given rosiglitazone p.o., 4 mg b.i.d. for 24 weeks, which resulted in significant improvement in psoriasis (Figure 4B). After an additional 26 weeks on rosiglitazone, the plaques had cleared on her back (Figure 4C) and over her entire body, including scalp, ears, and posterior forearms (not shown). Her glycemic control improved (hemoglobin A1c decreased from 7.7% to 7.2%) and liver function remained normal throughout the study (ALT, 24 IU/L; AST, 14 IU/L before treatment; and ALT, 26 IU/L; AST, 15 IU/L after treatment). There were no adverse events.
 ...
PMID:Improvement in psoriasis with rosiglitazone in a diabetic and a nondiabetic patient. 1627 61


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>