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)

INSR gene mutations have been described in multiple individuals with extreme insulin resistance, but the INSR gene has not been implicated in familial NIDDM. We previously have screened members of 18 familial NIDDM pedigrees for mutations in exons encoding the tyrosine kinase domain of the INSR gene (exons 13-21) by SSCP. That analysis initially detected only patterns consistent with silent polymorphisms, but on direct sequence analysis of exon 17 we detected a Met-for-Val substitution at position 985 in 1/18 pedigrees. We confirmed the substitution by sequence analysis of subcloned, PCR-amplified DNA from two pedigree members and by hybridization to labeled primers for the normal and mutant sequences. We did not find the mutation in any other individuals. Pedigree members were typed for presence or absence of the Met985 substitution by hybridization of PCR-amplified exon 17 DNA to allele-specific oligonucleotide probes, and typing was confirmed by segregation of INSR haplotypes and by SSCP analysis. The substitution was present in 3 NIDDM individuals in 3 generations, including a lean individual with onset at age 24. The substitution was present in only 50% of NIDDM siblings in generation 2, however. To determine the clinical effect of the Met985 substitution, we compared the 5 nondiabetic pedigree members who carried the mutation with the 9 nondiabetic pedigree members without the mutation and with 266 members of other pedigrees. Fasting and 1-h postglucose insulin levels were not different between carriers and noncarriers (fasting, 71.4 pM vs. 74.5 pM; 1-h, 381 pM vs. 354 pM), even after correction for age, sex, and BMI.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Methionine for valine substitution in exon 17 of the insulin receptor gene in a pedigree with familial NIDDM. 843 14

The aim of this study was determine the effect of a 15-week individualized exercise conditioning program on glycosylated hemoglobin (HbAlc) levels on Type 2 diabetes. Thirty-nine participants were sedantary, Type 2 diabetics, on an oral hypo-glycemic drug and no specified diet regimen at study onset. Pre and post 15 weeks subjects underwent: maximal incremental exercise tests, blood analysis, body composition analysis. Twenty-one subjects were prescribed an individualized exercise program for 15 weeks. Significant differences were found in the exercise group after 15 weeks in: total body fat, trunk fat, peak oxygen consumption and MET values. Correlations existed in the exercise group between HbAlc, arm muscle area and leg lean mass. Sixty-two percent of this group showed a reduction in HbAlc values. For this group, dietary intakes of riboflavin and potassium maybe associated with HbAlc levels. Exercise in conjunction with oral drug therapy prescribed for the NIDDM individual did not directly modify HbAlc levels, but did result in favorable effects on blood lipid values, fitness levels, and body composition values.
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PMID:The effect of exercise conditioning, diet, and drug therapy on glycosylated hemoglobin levels in type 2 (NIDDM) diabetics. 877 76

We studied 68 Japanese NIDDM patients (38 men and 30 women), aged 56.9+/-1.2 years (range 33-75 years), with a BMI of 23.1+/-0.5 kg/m2 without hypertension, dyslipidemia, and diabetic macroangiopathy for evaluating the relationship between serum soluble vascular cell adhesion molecule-1 (sVCAM-1) levels and the severity of diabetic retinopathy. Fundus examination was performed by an ophthalmologist using an ophthalmoscope, and the findings were graded as: (1) no signs of diabetic retinopathy (NDR), (2) background diabetic retinopathy (BDR), or (3) proliferative diabetic retinopathy (PDR). Serum sVCAM-1 levels were measured in duplicate by enzyme-linked immunosorbent assay using the soluble VCAM-1 KIT (R&D Systems Ltd., Ablingdon, Oxfordshire, UK). There was no difference in serum sVCAM-1 levels between patients with BDR (n = 17) and patients with NDR (n = 40) (1035.3+/-104.4 and 978.8+/-48.9 ng/ml, respectively, P = 0.8), but patients with PDR (n = 11) showed a significant increase of serum sVCAM-1 levels compared with patients with NDR (1281.8+/-166.3 and 978.8+/-48.9 ng/ml, respectively, P = 0.02). Although serum sVCAM-1 levels were correlated, not only with age but also with the known diabetic duration (r = 0.39, P = 0.001, and r = 0.40, P = 0.0007, respectively), age-adjusted sVCAM-1 levels were still significantly higher in the PDR group than in the NDR group. In contrast. serum sVCAM-1 levels were not related to the presence of diabetic nephropathy or HbA1c levels. Our results suggest that sVCAM-1 might be implicated in the development of the diabetic retinopathy, and measurement of serum sVCAM-1 levels in NIDDM patients maybe clinically useful for assessing the severity and possibly the activity of diabetic retinopathy.
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PMID:Elevated serum levels of soluble vascular cell adhesion molecule-1 in NIDDM patients with proliferative diabetic retinopathy. 988 35

Diabetes is associated with impaired cardiac dysfunction in both humans and animals. Specific phenotypic changes-prolonged action potentials, slowed cytosolic Ca2+ clearing, and slowed relaxation-that contribute to this whole heart dysfunction occur in isolated ventricular myocytes. The present study was designed to determine whether cardiomyocyte abnormalities occur early in the development of type 2 diabetes (in this case, insulin resistance) and whether an insulin-sensitizing drug (metformin) is cardioprotective. In the study, high-sucrose feeding was used to induce whole-body insulin resistance. Wistar rats were maintained for 7-10 weeks on a starch (ST) diet, sucrose (SU) diet, or diet supplemented with metformin (SU + MET). Whole-body insulin resistance was measured in SU and SU + MET rats by performing euglycemic-hyperinsulinemic clamps. Mechanical properties of isolated ventricular myocytes were measured by high-speed video edge detection, and [Ca2+]i transients were evaluated with Fura-2 AM. Untreated SU rats were insulin-resistant (glucose infusion rate [GIR] = 14.5 +/- 1.1 mg.kg(-1).min(-1)); metformin treatment in SU + MET rats prevented this metabolic abnormality (GIR = 20.0 +/- 2.2 mg.kg(-1).min(-1)). Indexes of myocyte shortening and relengthening were significantly longer in SU rats (area under the relaxation phase [AR/peak] = 103 +/- 3 msec) when compared to ST and SU + MET rats (AR/peak = 73 +/- 2 and 80 +/- 1 msec, respectively). The rate of intracellular Ca2+ decay and the integral of the Ca2+ transient through the entire contractile cycle were significantly longer in myocytes from SU than from ST rats (Ca2+ signal normalized to peak amplitude = 152 +/- 8 vs. 135 +/- 5 msec, respectively). Collectively, our data showed the presence of cardiomyocyte abnormalities in an insulin-resistant stage that precedes frank type 2 diabetes. Furthermore, metformin prevented the development of sucrose-induced insulin resistance and the consequent cardiomyocyte dysfunction.
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PMID:Cardiomyocyte dysfunction in sucrose-fed rats is associated with insulin resistance. 1133 25

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

Hyperhomocysteinemia is a well established risk factor for cardiovascular disease, and multiple factors likely lead to abnormal regulation of plasma homocysteine in patients with diabetes. To examine a possible role for insulin and glucose in homocysteine metabolism, we examined the activity of two important enzymes of homocysteine metabolism in hepatocytes. In various tissues of six mice, methylene tetrahydrofolate reductase (MTHFR) activity was present in all tissues tested and the highest concentration (per gram) was in the brain. In contrast, cystathionine beta-synthase (CBS) activity appeared to be present only in the liver and to a small extent in the kidney. Using HEP G2 cells in culture, MTHFR activity was 3.3+/-0.8 nmol/h when the glucose concentration in the medium was 100 mg/dl and fell to 2.3+/-0.3 nmol/h when glucose was increased to 300 mg/dl. MTHFR activity was 3.4+/-0.3 nmol/h when cells were exposed to an insulin concentration of 5 mU/ml and fell to 2.8+/-0.3 nmol/h when insulin concentration was increased to 200 mU/ml (P<0.01). In contrast CBS activity increased from 0.017 to 0.13 U/ml by increasing the glucose concentration in the medium (P<0.01), but decreased from 0.04 to 0.02 (P<0.01) when the insulin concentration was increased from 5 to 200 mU/ml, respectively. We conclude that CBS and MTHFR have different tissue distributions, with CBS being present predominantly in liver and kidney, and MTHFR found in many tissues. In addition, both insulin and glucose affect the activity of the two enzymes when added to hepatocytes in vitro. If such effects occur in humans with hyperglycemia and hyperinsulinemia, then alterations in homocysteine metabolism may contribute to the accelerated macrovascular disease associated with insulin resistance or type 2 diabetes.
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PMID:The effect of glucose and insulin on the activity of methylene tetrahydrofolate reductase and cystathionine-beta-synthase: studies in hepatocytes. 1158 7

The combination of insulin resistance, dyslipidemia, hypertension, and obesity has been described as a "metabolic syndrome" that is a strong determinant of type 2 diabetes. Factor analysis was used to identify components of this syndrome in 1,918 Pima Indians. Prospective analyses were conducted to evaluate associations of identified factors with incidence of diabetes. Factor analysis identified 4 factors that accounted for 79% of the variance in the original 10 variables. Each of these factors reflected a proposed component of the metabolic syndrome: insulinemia, body size, blood pressure, and lipid metabolism. Among 890 originally nondiabetic participants with follow-up data, 144 developed diabetes in a median follow-up of 4.1 years. The insulinemia factor was strongly associated with diabetes incidence (incidence rate ratio [IRR] for a 1-SD difference in factor scores = 1.81, P < 0.01). The body size and lipids factors also significantly predicted diabetes (IRR 1.52 and 1.37, respectively, P < 0.01 for both), whereas the blood pressure factor did not (IRR 1.11, P = 0.20). Identification of four unique factors with different associations with incidence of diabetes suggests that the correlations among these variables reflect distinct metabolic processes, about which substantial information may be lost in the attempt to combine them into a single entity.
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PMID:Components of the "metabolic syndrome" and incidence of type 2 diabetes. 1235 57

Defective insulin secretion is a feature of type 2 diabetes that results from inadequate compensatory increase of beta cell mass and impaired glucose-dependent insulin release. beta cell proliferation and secretion are thought to be regulated by signaling through receptor tyrosine kinases. In this regard, we sought to examine the potential proliferative and/or antiapoptotic role of IGFs in beta cells by tissue-specific conditional mutagenesis ablating type 1 IGF receptor (IGF1R) signaling. Unexpectedly, lack of functional IGF1R did not affect beta cell mass, but resulted in age-dependent impairment of glucose tolerance, associated with a decrease of glucose- and arginine-dependent insulin release. These observations reveal a requirement of IGF1R-mediated signaling for insulin secretion.
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PMID:Defective insulin secretion in pancreatic beta cells lacking type 1 IGF receptor. 1237 Feb 79

Accumulating evidence suggests that the pathophysiology of diabetes is analogous to chronic inflammatory states. Circulating levels of inflammatory cytokines such as IL-6 and tumor necrosis factor alpha (TNFalpha) are increased in both type 1 and type 2 diabetes. TNFalpha plays an important role in the pathogenesis of insulin resistance in type 2 diabetes. However, the reason for this increase remains unclear. Levels of the dicarbonyl methylglyoxal (MGO) are elevated in diabetic plasma and MGO-modified bovine serum albumin (MGO-BSA) can trigger cellular uptake of TNF. Therefore we tested the hypothesis that MGO-modified proteins may cause TNFalpha secretion in macrophage-like RAW 264.7 cells. Treatment of cells with MGO-BSA induced TNFalpha release in a dose-dependent manner. MGO-modified ribonuclease A and chicken egg ovalbumin had similar effects. Cotreatment of cells with antioxidant reagent N-acetylcysteine (NAC) inhibited MGO-BSA-induced TNFalpha secretion. MGO-BSA stimulated the simultaneous activation of p44/42 and p38 mitogen-activated protein kinase. PD98059, a selective MEK inhibitor, inhibited MGO-BSA-induced TNFalpha release as well as ERK phosphorylation. Pretreatment of cells with NAC also resulted in inhibition of MGO-BSA-induced ERK phosphorylation. MGO-BSA induced dose-dependent NFkappaB activation as shown by electrophoresis mobility shift assay. The MGO-BSA-induced NFkappaB activation was prevented in the presence of PD98059, NAC, and parthenolide, a selective inhibitor of NFkappaB. Furthermore, the NFkappaB inhibitor parthenolide suppressed MGO-BSA-induced TNFalpha secretion. Confocal microscopy using dichlorofluorescein to demonstrate intracellular reactive oxygen species (ROS) showed that MGO-BSA produced more ROS compared with native BSA. MGO-BSA could also stimulate protein kinase C (PKC) translocation to the cell membrane, considered a key signaling pathway in diabetes. However, there was no evidence that PKC was involved in TNFalpha release based on inhibition by calphostin C and staurosporine. Our findings suggest that the presence of chronically elevated levels of MGO-modified bovine serum albumin may contribute to elevated levels of TNFalpha in diabetes.
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PMID:Methylglyoxal-bovine serum albumin stimulates tumor necrosis factor alpha secretion in RAW 264.7 cells through activation of mitogen-activating protein kinase, nuclear factor kappaB and intracellular reactive oxygen species formation. 1250 94

Although it is known that diabetic nephropathy is accelerated by hypertension, the mechanisms involved in this process are not clear. In this study we aimed to clarify these mechanisms using male Wistar fatty rats (WFR) as a type 2 diabetic model and male Wistar lean rats (WLR) as a control. Each group was fed a normal or high sodium diet from the age of 6 to 14 weeks. We determined the blood pressure and urinary albumin excretion (UAE). At the end of the study, the expressions of mitogen-activated protein kinases (MAPK) and transforming growth factor-beta1 (TGF-beta1) were examined in the isolated glomeruli by Western blot analysis, and the number of glomerular lesions was determined by conventional histology. High sodium load caused hypertension and a marked increase in UAE in the WFR but not in the WLR. Glomerular volume was increased in the hypertensive WFR. There was no difference among the four groups in the expression of c-Jun-NH2-terminal kinase (JNK). In contrast, the expressions of extracellular signal-regulated kinase 1/2 (ERK1/2) and its upstream regulator, MAPK/ERK kinase 1 (MEK1), were augmented in the hypertensive WFR. Expression of p38 MAPK was increased in the normotensive WFR, and further enhanced in the hypertensive WFR. Moreover, administration of high sodium load to WFR augmented the expression of TGF-beta1. In conclusion, systemic hypertension in WFR accelerates the diabetic nephropathy in type 2 diabetes via MEK-ERK and p38 MAPK cascades. TGF-beta1 is also involved in this mechanism.
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PMID:Hypertension accelerates diabetic nephropathy in Wistar fatty rats, a model of type 2 diabetes mellitus, via mitogen-activated protein kinase cascades and transforming growth factor-beta1. 1273 3


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