Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methylglyoxal (MG), an alpha-dicarbonyl compound, can be produced in vivo by several metabolic pathways and the Maillard reaction. It reacts rapidly with proteins to form advanced glycation end products or AGEs. We previously isolated and characterized a blue fluorescent product of the reaction between MG and arginine, which we named argpyrimidine. We found that argpyrimidine was stable to acid hydrolysis, which allowed us to hydrolyze tissue proteins with 6 N HCl and quantify argpyrimidine by high-performance liquid chromatography. Here we report argpyrimidine concentrations in human lens and serum proteins as determined by HPLC. We have also measured pentosidine, a fluorescent AGE derived from pentose sugars, and compared the concentrations of pentosidine and argpyrimidine. We found two- to threefold higher argpyrimidine concentrations in diabetic serum proteins than in nondiabetic controls (9.3 +/- 6.7 vs 4.4 +/- 3.4 pmol/mg). We found a significant correlation (P = 0.0001) between serum protein argpyrimidine and glycosylated hemoglobin. Argpyrimidine concentrations were approximately seven times greater in brunescent cataractous lenses than in aged noncataractous lenses. Pentosidine concentrations in serum and lens proteins were much lower than argpyrimidine concentrations; in general, argpyrimidine levels were 10--25 times higher than pentosidine. Results from our study confirm that MG-mediated arginine modifications occur in vivo and provide a method for assessing protein-arginine modification by MG in aging and diabetes.
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PMID:Chromatographic quantification of argpyrimidine, a methylglyoxal-derived product in tissue proteins: comparison with pentosidine. 1123 39

In combination with other factors, hyperglycemia may cause the accelerated progression of atherosclerosis in people with diabetes. Arterial smooth muscle cell (SMC) proliferation and accumulation contribute to formation of advanced atherosclerotic lesions. Therefore, we investigated the effects of hyperglycemia on SMC proliferation and accumulation in vivo and in isolated arteries and SMCs by taking advantage of a new porcine model of diabetes-accelerated atherosclerosis, in which diabetic animals are hyperglycemic without receiving exogenous insulin. We show that diabetic animals fed a cholesterol-rich diet, like humans, develop severe lesions of atherosclerosis characterized by SMC accumulation and proliferation, whereas lesions in nondiabetic animals contain fewer SMCs after 20 weeks. However, high glucose (25 mmol/l) does not directly stimulate the proliferation of SMCs in isolated arterial tissue from diabetic or nondiabetic animals, or of cultured SMCs from these animals or from humans. Furthermore, the mitogenic actions of platelet-derived growth factor, IGF-I, or serum are not enhanced by high glucose. High glucose increases SMC glucose metabolism through the citric acid cycle and the pentose phosphate pathway by 240 and 90%, respectively, but <10% of consumed glucose is metabolized through these pathways. Instead, most of the consumed glucose is converted into lactate and secreted by the SMCs. Thus, diabetes markedly accelerates SMC proliferation and accumulation in atherosclerotic lesions. The stimulatory effect of diabetes on SMCs is likely to be mediated by effects secondary to the hyperglycemic state.
Diabetes 2001 Apr
PMID:Diabetes accelerates smooth muscle accumulation in lesions of atherosclerosis: lack of direct growth-promoting effects of high glucose levels. 1128 52

The aim of this study was to understand by which intrahepatic mechanism metformin (Met) may inhibit basal hepatic glucose production (HGP) in type 2 diabetes. We studied rats that were fed for 6 weeks a high-fat (HF) diet, supplemented (HF-Met) or not (HF) with Met (50 mg x kg(-1) x day(-1)). Basal HGP, assessed by 3-[(3)H]glucose tracer dilution, was lower by 20% in HF-Met rats compared with HF-rats: 41.6 +/- 0.7 vs. 52 +/- 1.5 micromol x kg(-1) x min(-1) (means +/- SE, n = 5; P < 0.01). Glucose-6 phosphatase (Glc6Pase) activity, assayed in a liver lobe freeze-clamped in situ, was lower by 25% in HF-Met rats compared with HF-rats (7.9 +/- 0.4 vs. 10.3 +/- 0.9 micromol x min(-1) x g(-1) wet liver; P < 0.05). Glucose-6 phosphate and glycogen contents, e.g., 42 +/- 5 nmol/g and 3.9 +/- 2.4 mg/g, respectively, in HF-rats were dramatically increased by three to five times in HF-Met rats, e.g., 118 +/- 12 nmol/g and 19.6 +/- 4.6 mg/g (P < 0.05 and P < 0.01, respectively). Glucose-6 phosphate dehydrogenase activity was increased in HF-Met compared with HF rats (1.51 +/- 0.1 vs. 1.06 +/- 0.08 micromol x min(-1) x g(-1); P < 0.01). Intrahepatic lactate concentration tended to be lower in the Met-group (-30%; NS), whereas plasma lactate concentration was higher in HF-Met rats (1.59 +/- 0.15 mmol/l) than in HF rats (1.06 +/- 0.06 mmol/l; P < 0.05). We concluded that Met decreases HGP in insulin-resistant HF-fed rats mainly by an inhibition of hepatic Glc6Pase activity, promoting glycogen sparing. Additional mechanisms might involve the diversion of glucose-6 phosphate into the pentose phosphate pathway and an inhibition of hepatic lactate uptake.
Diabetes 2002 Jan
PMID:Intrahepatic mechanisms underlying the effect of metformin in decreasing basal glucose production in rats fed a high-fat diet. 1175 33

Diabetes mellitus and glycogen storage disease type I (GSDI) may initially appear disparate in metabolic profile: one characterized by uncontrolled hyperglycaemia due to disturbed insulin function and the other by fasting hypoglycaemia caused by impaired gluconeogenesis and glycogenolysis. However, they share a remarkably similar pattern and progression of renal dysfunction. This may be, we suggest, due to a convergence of their metabolic sequelae in upregulation of flux through the pentose phosphate pathway. This pathway yields triose phosphate molecules, which are precursors of the lipid, diacylglycerol (DAG). DAG plays an important role in the intrarenal renin-angiotensin system via the protein kinase C pathway. GSDI may be an interesting model which helps to unravel further the contributions of the many, varied nephropathic influences in diabetes. Conversely patients with this rare disorders would have much to gain from the innovative and vastly greater body of research carried out in diabetes.
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PMID:Glycogenosis type I and diabetes mellitus: a common mechanism for renal dysfunction? 1216 Jun 94

Glycation (nonenzymatic glycosylation of proteins) is known to be increased as a result of hyperglycaemia in diabetes. Moreover, cell glutathione concentration has been found to be lower in diabetics and such depletion may impair the cell defence against toxic radical species. Ribose being a potent reducing sugar expected to be increased in cells of diabetics where the pentose phosphate pathway is enhanced, its putative condensation with glutathione was investigated. Reduced glutathione (GSH) was incubated with ribose and the structure of the resultant product was assessed by mass spectrometry, as well as the measurement of its remaining thiol group. A covalent reaction clearly occurred between the reducing sugar and GSH, to give an adduct named N-ribosyl-1-glutathione. This adduct appears to be the Amadori product resulting from the condensation of the primary amine group of GSH with the aldehyde group of ribose. Interestingly, the adduct could not be used as a proper substrate by glutathione peroxidase although it keeps its thiol group. We conclude that the coupling of GSH with a monosaccharide such as ribose might contribute to the decreased cell GSH and glutathione peroxidase activity observed in diabetics.
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PMID:Covalent coupling of reduced glutathione with ribose: loss of cosubstrate ability to glutathione peroxidase. 1259 81

Increased glucose cycling between glucose and glucose-6-phosphate is characteristic of insulin resistance and hyperglycemia seen with Type II diabetes. Traditionally, glucose cycling is determined by the difference between hepatic glucose output measured with separate [2-3H]glucose and [6-3H]glucose infusions. We demonstrate a novel method for determining hepatic glucose recycling from an intraperitoneal glucose tolerance test (IPGTT). A single tracer, [1, 2-13C(2)]glucose (a M2 glucose isotopomer), was administered at 1mg/g body weight to 4-month-old C57BL/6 mice. Hepatic glucose recycling was monitored by the appearance of a plasma M1 isotopomer of glucose, which is produced by the action of the pentose cycle on the M2 glucose isotopomer in the liver. The initial M2 enrichment was 56% and decreased to 13% at the end of 3 h, and the M1 enrichment peaked at 2 h. The ratio of plasma M1/M2 glucose increased linearly with time to approximately 25%, and the regression of the M1/M2 ratio against time gives a slope, termed the in vivo glucose-dependent futile recycling rate constant k(HR). k(HR) estimates glucose/glucose-6-phosphate futile cycling, along with glucose recycling through the pentose cycle. These observations demonstrate complex substrate cycling during an IPGTT using a single stable isotope tracer.
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PMID:Determination of a glucose-dependent futile recycling rate constant from an intraperitoneal glucose tolerance test. 1268 33

The aim of the present study was to investigate the effects of treatment with antioxidant stobadine (ST) on the activities of enzymes related with pentose phosphate pathway and glutathione-dependent metabolism and the other markers of oxidative stress in brain and peripheral organs of diabetic rats, and to compare the effects of ST treatment alone with the effects of treatments with another antioxidant vitamin E and ST plus vitamin E. Rats were made diabetic by the injection of streptozotocin (STZ; 55 mg/kg IP), and, 2 days later, some control and diabetic rats were left untreated or treated with ST (24.7 mg/kg/day, orally), vitamin E (400-500 U/kg/day, orally), or both substances together. In the brain, although 6-phosphogluconate dehydrogenase activity (6-PGD) did not change, glucose-6-phosphate dehydrogenase activity (G-6PD) was markedly increased in diabetic rats compared with controls; only combined treatment with ST and vitamin E produced a partial prevention on this alteration. The aorta G-6PD and 6-PGD of diabetic rats were 52% and 36% of control values, respectively. Neither single treatments with each antioxidant nor their combination altered the G-6PD and 6-PGD in aorta of diabetic rats. Glutathione peroxidase (GSHPx) activity was increased by STZ-diabetes in brain, heart, and kidney. In diabetic brain, vitamin E alone or combination with ST kept GSHPx at normal levels. Diabetes-induced stimulation in GSHPx did not decrease in response to the treatment with vitamin E in heart and kidney, but was greatly prevented by ST alone. The activity of glutathione reductase (GR) was decreased in brain and heart of diabetic rats. The treatment with each antioxidant or with a combination of both agents completely prevented this deficiency and resulted in further activation of GR in diabetic tissues. Glutathione S-transferase (GST) activity did not significantly change in diabetic brain and aorta. GST was stimulated by all treatment protocols in the brain of diabetic rats and was depressed in aorta of control rats. Catalase (CAT) was activated in diabetic heart but depressed in diabetic kidney. Diabetes-induced abnormalities in CAT activity did not respond to vitamin E alone in heart, was moderately ameliorated by the treatment with this vitamin in kidney, and was completely prevented by ST alone in both tissues. Superoxide dismutase (SOD) activity of brain and heart was unchanged by the diabetes but inhibited in diabetic kidney after the treatment ST alone or ST plus vitamin E. The lipid peroxidation (MDA) was increased in diabetic brain and heart. ST or vitamin E alone partly prevented diabetes-induced increase in MDA in brain and heart; however, antioxidant combination achieved a completely amelioration in MDA of these tissues of diabetic rats. Kidney MDA levels were similar in control and untreated diabetic animals. ST and vitamin E treatments, when applied separately or together, significantly reduced kidney MDA in both control and diabetic rats; and the combined effect of antioxidants was greater than that of each alone. These results are consistent with the degenerative role of hyperglycemia on cellular reducing equivalent homeostasis and antioxidant defense, and provide further evidence that pharmacological intervention of different antioxidants may have significant implications in the prevention of the prooxidant feature of diabetes and protects redox status of the cells.
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PMID:Pentose phosphate pathway, glutathione-dependent enzymes and antioxidant defense during oxidative stress in diabetic rodent brain and peripheral organs: effects of stobadine and vitamin E. 1271 33

We have previously shown that the type I diabetic condition significantly alters meiotic regulation in mouse oocytes. In the present study, possible physiological deficiencies underlying such meiotic dysfunction were examined in oocyte-cumulus cell complexes (OCC) from type I diabetic mice. Whereas the diabetic condition did not affect glycolysis or the tricarboxylic acid cycle, the increased flux of glucose through the pentose phosphate pathway in response to FSH treatment was suppressed. De novo purine synthesis was also compromised, and ATP levels were reduced in freshly isolated OCC. Additionally, diabetes resulted in a reduction in FSH-mediated cAMP synthesis. The responsiveness of the oocyte to cAMP was also affected; fewer oocytes were induced to resume maturation after a stimulatory pulse with cAMP analogs. Meiotic induction triggered by FSH was significantly reduced, but that stimulated by phorbol ester or epidermal growth factor was affected to a much lesser extent. In addition to metabolic deficiencies, the cell-cell communication between the oocyte and the cumulus cells was reduced in diabetic mice as determined by coupling assays. Thus, numerous physiological parameters are affected by type I diabetes, and these changes may collectively contribute to altered meiotic regulation.
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PMID:Physiological changes in oocyte-cumulus cell complexes from diabetic mice that potentially influence meiotic regulation. 1272 81

The liver plays an important role in the overall negative nitrogen balance leading to muscle wasting commonly observed in patients following many conditions, including severe injury, cancer, and diabetes. In order to study changes in liver metabolism during the establishment of such catabolic states, we used a rat skin burn injury model that induces hypermetabolism and muscle wasting. At various times during the first week following the injury, livers were isolated and perfused in a recirculating system under well-defined conditions. We applied a steady-state metabolic flux analysis model of liver metabolism and then used k-means clustering to objectively group together reaction flux time profiles. We identified six distinct groups of reactions that were differentially responsive: (1) pentose phosphate pathway (PPP); (2) amino acid oxidation reactions leading to the formation of tricarboxylic acid (TCA) cycle intermediates; (3) gluconeogenesis; (4) TCA-cycle and mitochondrial oxidation; (5) lipolysis, beta-oxidation, and ketone body formation; and (6) urea-cycle. Burn injury sequentially upregulated the urea-cycle, the PPP, and the TCA-cycle, in order, while beta-oxidation and gluconeogenesis remained unchanged. The upregulation of the PPP was transient, whereas the rise in urea- and TCA-cycle fluxes was sustained. An ATP balance predicted an increased production of ATP and energy expenditure starting on day 3 post-burn, which correlated with the induction of the oxidative phosphorylation uncoupler uncoupling protein-2. We conclude that metabolic profiling using flux analysis and clustering analysis is a useful methodology to characterize the differential activation of metabolic pathways in perfused organs and to identify specific key pathways that are sensitive to a stimulus or insult without making a priori assumptions.
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PMID:Profiling of dynamic changes in hypermetabolic livers. 1280 Jan 35

Diabetes accelerates the aging process and leads to complications that include blindness, renal failure, nerve damage, stroke, and cardiovascular disease. It has been hypothesized that high plasma glucose concentrations are responsible for increased mitochondrial free radical production and subsequent inactivation of glyceraldehyde phosphate dehydrogenase (GAPDH) in vascular endothelial cells and other cells implicated in these complications. As a result of the decreased ability of GAPDH to process upstream metabolites, three pathways of metabolic damage are activated, which include the advanced glycation end-product formation pathway, the protein kinase C pathway, and the hexosamine pathway. All three pathways have been implicated in abnormal cell signaling in diabetes. A group of German and U.S. scientists has now found that treating diabetic rats with high doses of benfotiamine, a lipid-soluble form of vitamin B1, can prevent diabetic retinopathy and all three forms of metabolic damage by stimulating transketolase activity and thus diverting excess metabolites toward the pentose pathway. Although vitamin B1 is available over the counter, the researchers at this time do not advocate self-treatment without further clinical data.
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PMID:Vitamin B1 blocks damage caused by hyperglycemia. 1284 20


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