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)

To determine the mechanism of impaired insulin-stimulated muscle glycogen metabolism in patients with poorly controlled insulin-dependent diabetes mellitus (IDDM), we used 13C-NMR spectroscopy to monitor the peak intensity of the C1 resonance of the glucosyl units in muscle glycogen during a 6-h hyperglycemic-hyperinsulinemic clamp using [1-(13)C]glucose-enriched infusate followed by nonenriched glucose. Under similar steady state (t = 3-6 h) plasma glucose (approximately 9.0 mM) and insulin concentrations (approximately 400 pM), nonoxidative glucose metabolism was significantly less in the IDDM subjects compared with age-weight-matched control subjects (37+/-6 vs. 73+/-11 micromol/kg of body wt per minute, P < 0.05), which could be attributed to an approximately 45% reduction in the net rate of muscle glycogen synthesis in the IDDM subjects compared with the control subjects (108+/-16 vs. 195+/-6 micromol/liter of muscle per minute, P < 0.001). Muscle glycogen turnover in the IDDM subjects was significantly less than that of the controls (16+/-4 vs. 33+/-5%, P < 0.05), indicating that a marked reduction in flux through glycogen synthase was responsible for the reduced rate of net glycogen synthesis in the IDDM subjects. 31P-NMR spectroscopy was used to determine the intramuscular concentration of glucose-6-phosphate (G-6-P) under the same hyperglycemic-hyperinsulinemic conditions. Basal G-6-P concentration was similar between the two groups (approximately 0.10 mmol/kg of muscle) but the increment in G-6-P concentration in response to the glucose-insulin infusion was approximately 50% less in the IDDM subjects compared with the control subjects (0.07+/-0.02 vs. 0.13+/-0.02 mmol/kg of muscle, P < 0.05). When nonoxidative glucose metabolic rates in the control subjects were matched to the IDDM subjects, the increment in the G-6-P concentration (0.06+/-0.02 mmol/kg of muscle) was no different than that in the IDDM subjects. Together, these data indicate that defective glucose transport/phosphorylation is the major factor responsible for the lower rate of muscle glycogen synthesis in the poorly controlled insulin-dependent diabetic subjects.
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PMID:Mechanism of impaired insulin-stimulated muscle glucose metabolism in subjects with insulin-dependent diabetes mellitus. 915 94

Leptin is a signaling protein that in its mutant forms has been associated with obesity and Type II diabetes. The lack of sequence similarity has precluded analogies based on structural resemblance to known systems. Backbone NMR signals for mouse leptin (13C/15N -labeled) have been assigned and its secondary structure reveals it to be a four-helix bundle cytokine. Helix lengths and disulfide pattern are in agreement with leptin as a member of the short-helix cytokine family. A three-dimensional model was built verifying the mechanical consistency of the identified elements with a short-helix cytokine core.
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PMID:Leptin is a four-helix bundle: secondary structure by NMR. 916 7

Patients suffering from vascular disease are often a challenge for the acute pain service. Ischaemia, impaired wound healing, stump and phantom limb pain often require a complex analgesic regimen. Invasive measures such as spinal or epidural catheters can be very helpful but carry the risk of infection, as shown by this case report. A 53-year-old woman with a ten-year history of diabetes developed arterial vascular disease. Her right lower leg had been amputated two years previously. She was now admitted with necroses of the left forefoot. A bypass operation was performed under general anaesthesia. Because of intractable ischaemic pain, she was provided with an epidural catheter by the acute pain service. The bypass occluded, however, and a few days later her left lower leg also had to be amputated, this operation being performed under epidural anaesthesia with bupivacaine. The catheter was subsequently used for postoperative pain control and as a means to prevent phantom limb pain. When signs of superficial catheter infection were noticed days later, the catheter was immediately removed. Intractable pain then developed in the left leg which could not be sufficiently controlled with opioids and NSAIDs, and so a second epidural catheter was inserted one segment rostrally. Several days later the infected vascular prosthesis had to be removed followed by amputation of the thigh, this operation also being performed in epidural anaesthesia. Eleven days after insertion of the first epidural catheter, the patient complained of low back pain and headache. Examination by a neurologist revealed no signs of intraspinal infection. The second epidural catheter dislocated at this point in time and it was decided to introduce a third one, this being the only means to treat the otherwise intractable stump pain. Ten days later meningism, Kernig's sign and leucocytosis developed. NMR tomography detected intraspinal fluid in the epidural space at the dorsal border of the spinal canal. A hemilaminectomy was performed. The spinal epidural space showed signs of inflammation of the adipose tissue, but no pus. A little necrotic material and residues of an old haematoma were removed and the epidural space was lavaged. Specimens taken from the epidural material revealed colonisation with staphylococcus epidermidis, which was sensitive to the broad spectrum antibiotics formerly given to the patient to treat the infection in the left stump. By the next day, all signs of epiduritis had disappeared and the patient recovered completely.
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PMID:[Epiduritis after long-term pain therapy with an epidural catheter--review of the literature with a current case report]. 932 67

Alterations in glucose metabolism have been implicated in the cardiovascular complications of diabetes. Previous work in this laboratory demonstrated that hearts from diabetic animals have an elevated cytosolic redox ratio (NADH/NAD+) and that this redox imbalance is probably due to elevated polyol pathway flux. We therefore hypothesized that 1) the elevated cytosolic redox ratio of diabetic hearts could result in inhibition of glycolytic enzymes sensitive to the redox state, 2) polyol pathway inhibition could restore the abnormal glucose metabolism of diabetic hearts, and 3) the relative incorporation of mixed substrates into hearts from diabetic animals would demonstrate less glycolytic and more fatty acid oxidation. Hearts from diabetic (BB/W) and nondiabetic control rats were perfused with buffers containing 13C-labeled substrates, and the metabolism of these hearts was analyzed using 13C NMR spectroscopy. Tissue samples were analyzed for metabolite levels using biochemical assay. Compared with controls, diabetic hearts had glyceraldeyde 3-phosphate levels that were four times greater than nondiabetic hearts and exhibited 91% less 13C labeling of lactate and 92% less 13C labeling of glutamate (P < 0.03). Aldose reductase inhibition with zopolrestat restored the metabolite labeling of diabetic hearts. Diabetic hearts perfused with a mixture of substrates used 53% more acetate than nondiabetic control hearts (P < 0.05), and aldose reductase inhibition lowered the acetate utilization of diabetic hearts by 9% (P < 0.05). These data suggest that glycolytic flux in diabetic hearts is inhibited at glyceraldehyde-3-phosphate dehydrogenase and that inhibition of the polyol pathway with zopolrestat increases glycolytic flux in these hearts. Furthermore, hearts from diabetic animals showed a marked dependence on fatty acids for substrate utilization compared with nondiabetic controls, consistent with inhibition of the pyruvate dehydrogenase complex in diabetic hearts.
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PMID:Aldose reductase inhibition improves altered glucose metabolism of isolated diabetic rat hearts. 968 98

The NIDDM patient, willingly with high blood pressure and atheroma, has frequently an abnormal renal function. Must a renal artery stenosis (RAS) be searched as a determining or favorising cause? We have searched RAS by color duplex scan, in 60 consecutive NIDDM patients with altered renal function (creatinine clearance < or = 60 mL/min). Metabolic blood pressure (ABPM), cardiovascular and renal investigations have been realised. The population was composed of 22F/38M with middle age: 70.7 +/- 6.2 yrs, diabetic duration: 11.6 +/- 8 yrs, the plasma creatinine was: 161 +/- 78 mumol/L and clearance: 40 +/- 13 mL/min. Thirty eight had albuminuria, 28 had plasma creatinine > or = 150 mumol/L. All patients had high blood pressure. Significative RAS (> or = 70%) was detected in 15 patients (25%) by color duplex scan and proved with arteriography (n = 10) or angio NMR (n = 5). Twelve (80%) had unilateral stenosis (4 thrombosis), 3 (20%) bilateral stenosis. Renal US lead the diagnosis in 10 patients (66%): unilateral or bilateral hypotrophy. Those 15 patients had these following characteristics: 4F/11M (sex R : 0.36), middle age: 70.8 +/- 7.2 yrs, diabetic duration: 14.3 +/- 7.5 yrs, HbA1c was at 8.4 +/- 2%, 8 (53%) patients require insuline and 5 have retinopathy, plasma creatinine was at 169 +/- 6 mumol/L; 32% of patients with plasma creatinine > or = 150 mumol/L had RAS (n = 9/60%), creatinine clearance was at 38 +/- 12 mL/min (7/47% < or = 30 mL/min), 9 (60%) had macroalbuminuria and 5 (33%) microalbuminuria. All hypertensive patients were treated (mean SBP: 148 +/- 16, mean DBP: 82 +/- 7 mmHg) and had 62 +/- 28% SBP escape and 33 +/- 19% DBP escape. Ten had severe hypertension (at least 3 hypotensive drugs), 12 received CEI; 8 (53%) were smokers; 14 (93%) had one or more macroangiopathies (10/66% coronary heart diseases, 7/46% lower limbs arteritis, 6/40% carotid atheroma); 13 of these macroangiopathies are severe. In conclusion, renal failure (especially evolutive and/or treated with CEI) in NIDDM must call up a RAS (25%) specially in elderly males with a long diabetes duration, severe hypertension and macroangiopathies. This patient profile must lead to a color duplex scan to confirm the diagnosis already suspected by the renal echography.
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PMID:[Renal artery stenosis and chronic renal failure in NIDDM]. 974 69

A series of 18 chrysin derivatives, prepared by alkylation and condensation, were fully characterized by NMR and other techniques and tested in vivo against the diabetes mellitus. Several modified compounds especially those with propyl, butyl, octyl and tolyl groups were found to have hypoglycemic effect on diabetec mice in spite of the fact that chrysin itself had inhibited insulin release by 40-60%. None of the test animals died at the maximum dose 500mg/kg and did not cause any significant change in general feature, water and food consumption, body weight and organ weight when we examined the acute oral toxicity of those compounds having significant hypoglycemic effect.
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PMID:Synthesis and hypoglycemic effect of chrysin derivatives. 1020 52

Acarbose is a naturally occurring pseudo-tetrasaccharide. It has been used in conjunction with other drugs in the treatment of diabetes where it acts as an inhibitor of intestinal glucosidases. To probe the interactions of acarbose with other carbohydrate recognition enzymes, the crystal structure of E. coli maltodextrin phosphorylase (MalP) complexed with acarbose has been determined at 2.95 A resolution and refined to crystallographic R-values of R (Rfree) = 0.241 (0.293), respectively. Acarbose adopts a conformation that is close to its major minimum free energy conformation in the MalP-acarbose structure. The acarviosine moiety of acarbose occupies sub-sites +1 and +2 and the disaccharide sub-sites +3 and +4. (The site of phosphorolysis is between sub-sites -1 and +1.) This is the first identification of sub-sites +3 and +4 of MalP. Interactions of the glucosyl residues in sub-sites +2 and +4 are dominated by carbohydrate stacking interactions with tyrosine residues. These tyrosines (Tyr280 and Tyr613, respectively, in the rabbit muscle phosphorylase numbering scheme) are conserved in all species of phosphorylase. A glycerol molecule from the cryoprotectant occupies sub-site -1. The identification of four oligosaccharide sub-sites, that extend from the interior of the phosphorylase close to the catalytic site to the exterior surface of MalP, provides a structural rationalization of the substrate selectivity of MalP for a pentasaccharide substrate. Crystallographic binding studies of acarbose with amylases, glucoamylases, and glycosyltranferases and NMR studies of acarbose in solution have shown that acarbose can adopt two different conformations. This flexibility allows acarbose to target a number of different enzymes. The two alternative conformations of acarbose when bound to different carbohydrate enzymes are discussed.
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PMID:The crystal structure of the Escherichia coli maltodextrin phosphorylase-acarbose complex. 1022 Mar 20

It has been previously suggested that alterations in sodium homeostasis, leading to calcium overload may play a part in the mediation of cardiac ischemic injury. It has been demonstrated that the Na+-H+ exchanger plays an important role with regard to the regulation of intracellular sodium during ischemia and reperfusion and that inhibition of the Na+-H+ exchanger during ischemia protects hearts from ischemic injury. Studies using chemically-induced diabetic animals have suggested that the cardiac Na+-H+ exchanger in the diabetic heart is impaired and is responsible for limiting the increase in sodium during ischemia. The extent to which the Na+-H+ exchanger contributes to increases in intracellular sodium during ischemia in diabetic hearts is unclear as direct measurements of exchanger activity have not been made in genetically diabetic hearts. Therefore, this paper aims to address the following issues: (a) is the Na+-H+ exchanger impaired in a genetically diabetic rat heart: (b) does this impairment result in lower [Na]i or [Ca]i during ischemia; and (c) does Na+-H+ exchanger inhibition limit injury and functional impairment in diabetic hearts during ischemia and reperfusion? These issues were examined by inhibiting the Na+-H+ exchanger with ethylisopropylamiloride (EIPA) in isolated perfused hearts from both genetically diabetic (BB/W) and non-diabetic rats. Levels of intracellular sodium, intracellular calcium, intracellular pH and high energy phosphates (using 23Na,19F, 31P NMR spectroscopies, respectively) during global ischemia and reperfusion were also measured. The impact of diabetes on Na+-H+ exchanger activity was assessed by measuring pH recovery of these hearts after an acid load. Creatine kinase release during reperfusion was used as a measure of ischemic injury. This study demonstrated that the Na+-H+ exchanger is impaired in diabetic hearts. Despite this impaired activity, inhibition of Na+-H+ exchanger protected diabetic hearts from ischemic injury and was associated with attenuation of the rise in sodium and calcium, and limitation of acidosis and preservation of ATP during ischemia. The data presented here favor the use of Na+-H+ exchanger inhibitors to protect ischemic myocardium in diabetics. Also, the data provides possible mechanisms for the altered susceptibility of diabetic hearts to ischemic injury.
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PMID:Inhibition of Na+-H+ exchanger protects diabetic and non-diabetic hearts from ischemic injury: insight into altered susceptibility of diabetic hearts to ischemic injury. 1032 6

Methylglyoxal (MG), an endogenous metabolite that increases in diabetes and is a common intermediate in the Maillard reaction (glycation), reacts with proteins and forms advanced glycation end products. In the present study, we identify a novel MG-arginine adduct and also characterize the structure of a major fluorescent adduct. In addition, we describe the immunochemical study on the MG-arginine adducts using monoclonal antibody directed to MG-modified protein. Upon incubation of Nalpha-acetyl-L-arginine with MG at 37 degrees C, two nonfluorescent products and one fluorescent product were detected as the major products. The nonfluorescent products were identified as the Ndelta-(5-hydro-5-methyl-4-imidazolon-2-yl)-L-ornithine derivatives (5-hydro-5-methylimidazolone) and a novel MG-arginine adduct having a tetrahydropyrimidine moiety (Ndelta-(4-carboxy-4,6-dimethyl-5, 6-dihydroxy-1,4,5,6-tetrahydropyrimidine-2-yl)-L-ornithine). On the basis of the following chemical and spectroscopic evidence, the major fluorescent product, putatively identified as Ndelta-(5-methylimidazolon-2-yl)-L-ornithine (5-methylimidazolone), was found to be identical to Ndelta-(5-hydroxy-4, 6-dimethylpyrimidine-2-yl)-L-ornithine (argpyrimidine): (i) the low and high resolution fast atom bombardment-mass spectrometry gave a molecular ion peak at m/z of 297 (M+H) and a molecular formula of C10H25O6N4, respectively, which coincided with argpyrimidine; (ii) the 1H NMR spectrum of this product in d6-Me2SO showed a singlet at 2.10 ppm corresponding to six protons; (iii) the peak corresponding to the 5-methylimidazolone derivative was not detected by the liquid chromatography-mass spectrometry with the mode of selected ion monitoring; (iv) incubation of 5-hydro-5-methylimidazolone, a putative precursor of 5-methylimidazolone, at 37 degrees C for 14 days scarcely generated 5-methylimidazolone. On the other hand, as an immunochemical approach to the detection of these MG adducts, we raised the monoclonal antibodies (mAb3C and mAb6B) directed to the MG-modified protein and found that they specifically recognized the major fluorescent product, argpyrimidine, as the dominant epitope. The immunohistochemical analysis of the kidneys from diabetic patients revealed the localization of argpyrimidine in intima and media of small artery walls. Furthermore, the accumulation of argpyrimidine was also observed in some arterial walls of the rat brain after middle cerebral artery occlusion followed by reperfusion. These results suggest that argpyrimidine may contribute to the progression of not only long term diabetic complications, such as nephropathy and atherosclerosis, but also the tissue injury caused by ischemia/reperfusion.
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PMID:Methylglyoxal modification of protein. Chemical and immunochemical characterization of methylglyoxal-arginine adducts. 1037 58

Dicarbonyl-containing compounds such as methylglyoxal (MG) are toxic to cells since they can interact with the nucleophilic centers of macromolecules. MG has been found to accumulate during hyperglycemia, and it has been suggested that this reactive dicarbonyl may contribute to the tissue damage and long-term complications of diabetes. A sensitive bacterial assay for investigating the ability of nucleophilic agents to interact with and detoxify MG has been developed. This assay utilizes the sensitivity of exponential phase cells of an Escherichia coli double mutant lacking the KefB and KefC potassium channels toward MG. The bidentate nucleophile, phenylacylthiazolium bromide (PTB), was found to protect and allow the growth of E. coli cells in the presence of either externally added or endogenously produced MG. In the absence of PTB, growth was completely inhibited and rapid cell death occurred under these conditions. PTB protected E. coli against MG almost as well as aminoguanidine, a compound shown previously to be involved in detoxification. The level of protection by PTB against MG was much greater than for the endogenous nucleophile, glutathione. These data suggested that PTB could interact with and detoxify MG. The mechanism of this interaction was characterized by NMR and mass spectroscopy.
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PMID:Detoxification of methylglyoxal by the nucleophilic bidentate, phenylacylthiazolium bromide. 1040 1


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