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)

Several studies have been carried out to evaluate the alterations in mitochondrial functions of diabetic rats. However, some of the results reported are controversial, since experimental conditions, such as aging, and/or strain of animals used were different. The purpose of this study was to evaluate the metabolic changes in liver mitochondria, both in the presence of severe hyperglycaemia (STZ-treated rats) and mild hyperglycaemia (Goto-Kakizaki (GK) rats). Moreover, metabolic alterations were evaluated both at initial and at advanced states of the disease. We observed that both models of type 1 and type 2 diabetes presented alterations on respiratory chain activity. Because of continual severe hyperglycaemia, 9 weeks after the induction of diabetes, the respiratory function declined in STZ-treated rats, as observed by membrane potential and respiratory ratios (RCR, P/O, and FCCP-stimulated respiration) assessment. In contrast, GK rats of 6 months age presented increased respiratory ratios. To localize which respiratory complexes are affected by diabetes, enzymatic respiratory chain activities were evaluated. We observed that succinate dehydrogenase and cytochrome c oxidase activities were significantly augmented both in STZ-treated rats and GK rats of 6 months age. Moreover, H(+)-ATPase activity was also significantly increased in STZ-treated rats with 3 weeks of diabetes and in GK rats of 6 months age as compared to controls. Therefore, these results clearly suggest that both animal models of diabetes present some metabolic adjustments in order to circumvent the deleterious effects promoted by the high glucose levels typical of the disease.
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PMID:Diabetes and mitochondrial bioenergetics: alterations with age. 1289 45

The development of complications does not depend entirely on diabetes duration and control. Red-blood-cell Na/K-ATPase plays a central role in the regulation of intra- and extracellular cation homeostasis. Alteration of this transport enzyme is thought to be linked to several complications of diabetes mellitus. The aim of this study was to find out any association between diabetic complications and red-blood-cell Na/K-ATPase activities in type 2 diabetes mellitus. Sixty-seven patients and 25 controls were enrolled in the study. Patients were evaluated for retinopathy, neuropathy, and nephropathy. The membrane Na/K-ATPase activities were measured. The studies were done twice with and without ouabain. The results of the calculations are written as micromol Pi/mg protein/h. The duration of diabetes and enzyme levels were negatively correlated (r = -0.38, p = 0.001). Na/K-ATPase enzyme activity was significantly lower in the diabetic patients than the control group (p < 0.0001). In neuropathic patients the activity was also significantly lower (p < 0.0001). The enzyme activities of the people with retinopathy were significantly lower than the ones without retinopathy (p < 0.001). The enzymatic activities did not differ among the degrees of nephropathy. The results indicate that erythrocyte Na/K-ATPase enzyme activities are decreased in type 2 diabetes and the decrement of the enzyme is correlated with the diabetes duration.
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PMID:The relationship between red blood cell Na/K-ATPase activities and diabetic complications in patients with type 2 diabetes mellitus. 1451 13

Atp10c is a novel type IV P-type ATPase and is a putative phospholipid transporter. The purpose of this study was to assess the overall effect of the heterozygous deletion of Atp10c on obesity-related phenotypes and metabolic abnormalities in mice fed a high-fat diet. Heterozygous mice with maternal inheritance of Atp10c were compared with heterozygous mice with paternal inheritance of Atp10c and wild-type controls. Body weight, adiposity index, and plasma insulin, leptin and triglyceride concentrations were significantly greater in the mutants inheriting the deletion maternally compared with their sex- and age-matched control male mice fed a 10% fat (% energy) diet and female mice fed a 45% fat (% energy) diet. Glucose and insulin tolerance tests were performed after mice consumed the diets for 4 and 8 wk. Mutants had altered glucose tolerance and insulin response compared with controls, suggesting insulin resistance in both sexes. Mice were killed at 12 wk and routine gross and histological evaluations of the liver, pancreas, adipose tissue, and heart were performed. Histological evaluation showed micro- and macrovesicular lipid deposition within the hepatocytes that was more severe in the mutant mice than in age-matched controls. Although sex differences were observed, our data suggest that heterozygous deletion along with an unusual pattern of maternal inheritance of the chromosomal region containing the single gene, Atp10c, causes obesity, type 2 diabetes, and nonalcoholic fatty liver disease in these mice.
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PMID:Mice heterozygous for Atp10c, a putative amphipath, represent a novel model of obesity and type 2 diabetes. 1505 28

Na+,K(+)-ATPase is an ubiquitous membrane enzyme that allows the extrusion of three sodium ions from the cell and two potassium ions from the extracellular fluid. Its activity is decreased in many tissues of streptozotocin-induced diabetic animals. This impairment could be at least partly responsible for the development of diabetic complications. Na+,K(+)-ATPase activity is decreased in the red blood cell membranes of type 1 diabetic individuals, irrespective of the degree of diabetic control. It is less impaired or even normal in those of type 2 diabetic patients. The authors have shown that in the red blood cells of type 2 diabetic patients, Na+,K(+)-ATPase activity was strongly related to blood C-peptide levels in non-insulin-treated patients (in whom C-peptide concentration reflects that of insulin) as well as in insulin-treated patients. Furthermore, a gene-environment relationship has been observed. The alpha-1 isoform of the enzyme predominant in red blood cells and nerve tissue is encoded by the ATP1A1 gene. A polymorphism in the intron 1 of this gene is associated with lower enzyme activity in patients with C-peptide deficiency either with type 1 or type 2 diabetes, but not in normal individuals. There are several lines of evidence for a low C-peptide level being responsible for low Na+,K(+)-ATPase activity in the red blood cells. Short-term C-peptide infusion to type 1 diabetic patients restores normal Na+,K(+)-ATPase activity. Islet transplantation, which restores endogenous C-peptide secretion, enhances Na+,K(+)-ATPase activity proportionally to the rise in C-peptide. This C-peptide effect is not indirect. In fact, incubation of diabetic red blood cells with C-peptide at physiological concentration leads to an increase of Na+,K(+)-ATPase activity. In isolated proximal tubules of rats or in the medullary thick ascending limb of the kidney, C-peptide stimulates in a dose-dependent manner Na+,K(+)-ATPase activity. This impairment in Na+,K(+)-ATPase activity, mainly secondary to the lack of C-peptide, plays probably a role in the development of diabetic complications. Arguments have been developed showing that the diabetes-induced decrease in Na+,K(+)-ATPase activity compromises microvascular blood flow by two mechanisms: by affecting microvascular regulation and by decreasing red blood cell deformability, which leads to an increase in blood viscosity. C-peptide infusion restores red blood cell deformability and microvascular blood flow concomitantly with Na+,K(+)-ATPase activity. The defect in ATPase is strongly related to diabetic neuropathy. Patients with neuropathy have lower ATPase activity than those without. The diabetes-induced impairment in Na+,K(+)-ATPase activity is identical in red blood cells and neural tissue. Red blood cell ATPase activity is related to nerve conduction velocity in the peroneal and the tibial nerve of diabetic patients. C-peptide infusion to diabetic rats increases endoneural ATPase activity in rat. Because the defect in Na+,K(+)-ATPase activity is also probably involved in the development of diabetic nephropathy and cardiomyopathy, physiological C-peptide infusion could be beneficial for the prevention of diabetic complications.
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PMID:C-peptide, Na+,K(+)-ATPase, and diabetes. 1519 70

Acarbose, a pseudomaltotetraose, is produced by strains of the genus Actinoplanes and is a potent inhibitor of alpha-glucosidases, including those from the human intestine. Therefore, it is used in the treatment of patients suffering from type 2 diabetes. The benefits of acarbose for the producer are not known; however, besides acting as an inhibitor of alpha-amylases secreted by competitors, a role as a 'carbophor' has been proposed. This would require a transport system mediating its uptake into the cytoplasm of Actinoplanes sp. A putative sugar ATP binding cassette (ABC) transport system, the genes of which are included within the biosynthetic gene cluster for acarbose, was suggested to be a possible candidate. The genes acbHFG encode a possible sugar binding protein (AcbH) and two membrane integral subunits (AcbFG). A gene coding for an ATPase component is missing. Since Actinoplanes sp. cannot yet be genetically manipulated we performed experiments to identify the substrate(s) of the putative transporter by assessing the substrate specificity of AcbH. The protein was overproduced in Escherichia coli as His10-fusion protein, purified under denaturating conditions and renatured. Refolding was verified by circular dichroism spectroscopy. Surface plasmon resonance studies revealed that AcbH binds acarbose and longer derivatives, but not maltodextrins, maltose or sucrose. Immunoblot analysis revealed the association of AcbH with the membrane fraction of Actinoplanes cells that were grown in the presence of maltose, maltodextrins or acarbose. Together, these findings suggest that the AcbHFG complex might be involved in the uptake of acarbose and are consistent with a role for acarbose as a 'carbophor'.
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PMID:The acbH gene of Actinoplanes sp. encodes a solute receptor with binding activities for acarbose and longer homologs. 1580 35

Werner syndrome is a genetic disease characterized by early ageing, excess cancer risk, high incidence of type II diabetes mellitus, early atherosclerosis, ocular cataracts, and osteoporosis. The protein encoded by the defective gene, WRN (WRNp) associates with three activities, that is, a RecQ DNA helicase, 3'-5'-exonuclease and ATPase activities. By highlighting the DNA helicase activity, a widespread consensus in WS-associated defect(s) has been established, pointing toward a deficiency in maintaining DNA integrity. However, a possible involvement of redox pathways in WS may be suggested by several lines of evidence that include: (i) the multiple functions and interactions of WRNp with oxidative stress-related activities and factors; (ii) the pleiotropic WS clinical phenotype encompassing a number of oxidative stress-related pathologies; (iii) redox-related toxicity mechanisms of several xenobiotics exerting excess toxicity in WS cells; (iv) recent in vivo and in vitro findings of redox abnormalities in WS patients and in WS cells. The working hypothesis is raised that a deficiency in WRNp, and the pleiotropic clinical phenotype in WS patients may provide the basis to envision an underlying in vivo prooxidant state, which causes oxidative damage to biomolecules, with multiple oxidative stress-related alterations, resulting in multi-faceted clinical consequences.
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PMID:Multiple involvement of oxidative stress in Werner syndrome phenotype. 1633 57

The Otsuka-Long-Evans Tokushima Fatty rat represents a model for spontaneous non-insulin-dependent type II diabetes mellitus (DM), characterized by diastolic dysfunction and associated with abnormal calcium handling and decrease in sarcoplasmic reticulum Ca2+ -ATPase (SERCA2a) expression. The aim of this study was to examine whether SERCA2a gene transfer can restore the energetic deficiency and left ventricular (LV) function in this model. DM rats were randomized to receive adenovirus carrying either the SERCA2a gene (DM + Ad.SERCA2a) or the beta-galactosidase gene (DM + Ad.betaGal) or saline (DM + saline). LV mechanoenergetic function was measured in cross-circulated heart preparations 3 days after infection. In DM, end-systolic pressure at 0.1 ml intraballoon water (ESP0.1) was low and end-diastolic pressure at 0.1 ml intraballoon water (EDP0.1) was high (22 mm Hg), compared with non-DM (EDP0.1 12 mm Hg). In DM + Ad.SERCA2a, however, ESP0.1 was increased over 200 mm Hg and EDP(0.1) was decreased to 7 mm Hg. LV relaxation rate was fast in DM + Ad.SERCA2a, but slow in the other DM groups. There was no difference in relation between cardiac oxygen consumption per beat and systolic pressure-volume area among all groups. Finally, the oxygen cost of LV contractility in DM was about three times as high as that of normal. In DM + Ad.SERCA2a, the oxygen cost decreased to control levels, but in DM + Ad.betaGal/DM + saline it remained high. In DM failing hearts, the high oxygen cost indicates energy wasting, which contributes to the contractile dysfunction observed in diabetic cardiomyopathy. SERCA2a gene transfer transforms this inefficient energy utilization into a more efficient state and restores systolic and diastolic function to normal.
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PMID:Mechanical and metabolic rescue in a type II diabetes model of cardiomyopathy by targeted gene transfer. 1658 3

The sulfonylurea receptors (SURs) ABCC8/SUR1 and ABCC9/SUR2 are members of the C-branch of the transport adenosine triphosphatase superfamily. Unlike their brethren, the SURs have no identified transport function; instead, evolution has matched these molecules with K(+) selective pores, either K(IR)6.1/KCNJ8 or K(IR)6.2/KCNJ11, to assemble adenosine triphosphate (ATP)-sensitive K(+) channels found in endocrine cells, neurons, and both smooth and striated muscle. Adenine nucleotides, the major regulators of ATP-sensitive K(+) (K(ATP)) channel activity, exert a dual action. Nucleotide binding to the pore reduces the activity or channel open probability, whereas Mg-nucleotide binding and/or hydrolysis in the nucleotide-binding domains of SUR antagonize this inhibitory action to stimulate channel openings. Mutations in either subunit can alter this balance and, in the case of the SUR1/KIR6.2 channels found in neurons and insulin-secreting pancreatic beta cells, are the cause of monogenic forms of hyperinsulinemic hypoglycemia and neonatal diabetes. Additionally, the subtle dysregulation of K(ATP) channel activity by a K(IR)6.2 polymorphism has been suggested as a predisposing factor in type 2 diabetes mellitus. Studies on K(ATP) channel null mice are clarifying the roles of these metabolically sensitive channels in a variety of tissues.
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PMID:ABCC8 and ABCC9: ABC transporters that regulate K+ channels. 1689 43

The Otsuka Long-Evans Tokushima fatty rat is an animal model of Type 2 diabetes mellitus (DM), which is characterized by diastolic dysfunction associated with decreased sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a). The aim of this study was to examine whether gene transfer of SERCA2a can influence coronary blood flow and cardiomyocyte diameter in this model. DM rats were injected with adenovirus carrying SERCA2a (DM+SERCA) or beta-galactosidase gene (DM+betaGal). Coronary blood flow was measured in cross-circulated excised hearts 3 days after infection. Although in all groups coronary blood flow remained unchanged even if left ventricular (LV) volume or intracoronary Ca(2+) infusion was increased, the DM+SERCA group showed a sustained increase in coronary blood flow compared with the other groups. This result suggests that the sustained high coronary blood flow is a specific response in SERCA2a-overexpressed hearts. Although the LV weight-to-body weight ratio (LV/BW) and cardiomyocyte diameter were higher in the DM and DM+betaGal groups than in the non-DM group, in the DM+SERCA group, these measurements were restored to non-DM size. The percentages of collagen area in the three DM groups was significantly higher than results shown in non-DM rats, and there were no significant differences in collagen area percentage among the three DM groups. These results suggest that a lowered LV/BW by SERCA2a overexpression is due mainly to reduced size of cardiomyocytes without any changes in collagen area percentage. In conclusion, in DM failing hearts, SERCA2a gene transfer can increase coronary blood flow and reduce cardiomyocyte size without reduction in collagen production.
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PMID:Transcoronary gene transfer of SERCA2a increases coronary blood flow and decreases cardiomyocyte size in a type 2 diabetic rat model. 1701 46

Resistance training results in muscle hypertrophy and improves glycemic control in patients with type 2 diabetes. Whether resistance training modulates inflammation in muscles of diabetic patients remains unknown. We examined the expression of genes encoding the cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and transforming growth factor-beta1 (TGF-beta1) as well as the pan-leukocyte marker CD18. Thirty men and women (67+/-7 years) were randomized to either 16 weeks of resistance training and usual diabetes care (EX) or to usual diabetes care only (CON). Muscle biopsies were obtained from the vastus lateralis muscle prior to the 16-week intervention, and 72 h following the maximal strength test post-intervention. Fiber cross-sectional area (CSA) was determined following ATPase staining. Cytokine and CD18 transcript levels were assessed by real-time PCR. Resistance training increased CSA of type I and II fibers (both P <0.05) and IL-1beta transcript levels (P = 0.05). TNF-alpha (P<0.05) and TGF-beta1 transcripts (P<0.05) increased over time in the EX group, but these increases did not differ from those in the CON group. In both groups, the increase in CD18 transcripts remained minimal. The two groups differ by the relationship between changes in CD18 and changes in cytokine transcripts, suggesting that resistance training affects the source of cytokines in muscle. Our studies establish that resistance training in older adults with type 2 diabetes results in muscle fiber hypertrophy, despite a greater accumulation of inflammatory cytokine transcripts in muscle.
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PMID:Resistance training alters cytokine gene expression in skeletal muscle of adults with type 2 diabetes. 1716 96


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