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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 effect of insulin-dependent diabetes mellitus (IDDM) on rates and pathways of hepatic glycogen synthesis, as well as flux through hepatic pyruvate dehydrogenase, we used 13C-nuclear magnetic resonance spectroscopy to monitor the peak intensity of the C1 resonance of the glucosyl units of hepatic glycogen, in combination with acetaminophen to sample the hepatic UDP-glucose pool and phenylacetate to sample the hepatic glutamine pool, during a hyperglycemic-hyperinsulinemic clamp using [1-13C]-glucose. Five subjects with poorly controlled IDDM and six age-weight-matched control subjects were clamped at a mean plasma glucose concentration of approximately 9 mM and mean plasma insulin concentrations approximately 400 pM for 5 h. Rates of hepatic glycogen synthesis were similar in both groups (approximately 0.43 +/- 0.09 mumol/ml liver min). However, flux through the indirect pathway of glycogen synthesis (3 carbon units-->-->glycogen) was increased by approximately 50% (P < 0.05), whereas the relative contribution of pyruvate oxidation to TCA cycle flux was decreased by approximately 30% (P < 0.05) in the IDDM subjects compared to the control subjects. These studies demonstrate that patients with poorly controlled insulin-dependent diabetes mellitus have augmented hepatic gluconeogenesis and relative decreased rates of hepatic pyruvate oxidation. These abnormalities are not immediately reversed by normalizing intraportal concentrations of glucose, insulin, and glucagon and may contribute to postprandial hyperglycemia.
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PMID:13C-nuclear magnetic resonance spectroscopy studies of hepatic glucose metabolism in normal subjects and subjects with insulin-dependent diabetes mellitus. 798 93

A causative factor in the development of diabetes-induced heart dysfunction may be abnormalities in myocardial energy metabolism. Using 13C-NMR spectroscopy, we investigated the effects of experimentally induced diabetes (streptozotocin 65 mg/kg, i.v.) on glucose metabolism and contractile function in the isolated perfused rat heart. Hearts from streptozotocin-treated and untreated control rats were perfused with 11 mM [1-13C]glucose as substrate and 1H-decoupled 13C-spectra recorded for up to 90 min. Incorporation of label from [1-13C]glucose into lactate and glutamate was observed in hearts from control animals, consistent with metabolism through glycolysis and TCA cycle, respectively. Diabetic hearts did not incorporate label into lactate or glutamate. Addition of insulin (0.05 U/ml) to the buffer resulted in the appearance of [3-13C]lactate, although glutamate labeling was not observed. Addition of insulin plus dichloroacetate (2 mM) resulted in incorporation of label from [1-13C]glucose into 2-, 3- and 4-13C-glutamate, indicating glucose entry into the TCA cycle. Addition of insulin, or insulin plus dichloroacetate to control hearts did not alter labeling of either lactate or glutamate. Cardiac function in hearts from the diabetic group was depressed compared to controls and declined significantly over the duration of the experiment. These studies show that concomitant with a decrease in cardiac function, glucose oxidation is profoundly inhibited following the induction of diabetes with streptozotocin. These observations are consistent with a combination of decreased glucose transport and a decrease in pyruvate dehydrogenase activity.
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PMID:A 13C-NMR study of glucose oxidation in the intact functioning rat heart following diabetes-induced cardiomyopathy. 826 54

The activities of two enzymes viz: Na(+)-K(+)-ATPase and succinic dehydrogenase (SDH) in brain and liver of alloxan diabetic Swiss albino mice are reported. Alloxan diabetes caused significant decrease in the activity of Na(+)-K(+)-ATPase reflecting reduced glucose transport across the cell membrane. On the contrary, the observed enhanced activity of the enzyme SDH is attributed to increased supply of TCA cycle substrates from accelerated oxidation of fatty acids.
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PMID:Alloxan diabetes in Swiss mice: activity of Na(+)-K(+)-ATPase and succinic dehydrogenase. 855 Jan 24

Mitochondrial FAD-linked glycerophosphate dehydrogenase (mGPDH) is thought to be an important factor for glucose sensing in pancreatic beta cells. To evaluate the significance of the mGPDH gene in the development of non-insulin-dependent diabetes mellitus (NIDDM), we set up primers and conditions for polymerase chain reaction (PCR) amplification of the coding exons and flanking regions. Screening of 100 Japanese NIDDM patients for mutations using the PCR-single strand conformation polymorphism (SSCP) method revealed four variants (ACA:Thr243-ACG:Thr243, CAT:His264-CGT:Arg264, GCA:Ala305-GCC:Ala305, GCA:Ala 306-TCA:Ser306). The His264-Arg264 variant was found in 36 patients, while the other variants were found in only one patient each. Neither the genotypic (chi 2 = 3.15, p = 0.21) nor the allelic (chi 2 = 2.27, p = 0.13) frequency of the His264-Arg264 mutation differed between 253 Japanese NIDDM patients and 157 non-diabetic subjects. In addition, in NIDDM patients, neither the treatment modality nor body mass index differed between those with and without this mutation. These results suggest that inherited defects at this locus do not make a major contribution to genetic susceptibility to NIDDM in the Japanese population.
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PMID:Detection of variants in the mitochondrial glycerophosphate dehydrogenase gene in Japanese NIDDM patients. 908 74

We proposed a simple analytical procedure for measurement of serum advanced glycosylation end products (AGEs) based on simultaneous detection of low-molecular-mass peptides and AGEs with a flow system and two detectors connected on-line: spectrophotometric for peptides (lambda = 280 nm) and spectrofluorometric for AGEs (lambda ex = 247 nm, lambda em = 440 nm). Sample pretreatment was carried out in microcentrifuge tubes: Serum (20 microL) was deproteinized with trichloroacetic acid (480 microL, 0.15 mol/L) and lipids were extracted with chloroform (100 microL). Twenty microliters of the filtered aqueous layer was injected to the flow system and the relation between fluorescence and absorption signals was measured. A peptide-derived AGE calibrator was used for calibration. Within-day and between-day CVs were 6.7% and 9.1%, respectively, at an AGE concentration corresponding approximately to that in healthy individuals. Mean results (+/-SD) in 10 healthy individuals were 10.1% +/- 1.0%, in 21 patients with diabetes without complications 18.0% +/- 6.2%, in 25 patients with complications 24.1% +/- 15.4%, and in 12 diabetic patients in end-stage renal disease 92% +/- 30%. Comparison with an ELISA procedure (x, in arbitrary units/L) yields a regression equation y = 0.713x + 1.24 (Sy [symbol: see text] x = 6777, r = 0.8477, n = 41).
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PMID:Novel analytical approach to monitoring advanced glycosylation end products in human serum with on-line spectrophotometric and spectrofluorometric detection in a flow system. 929 34

Recently, significant incorporation of labeled carbon into plasma glucose was documented during infusion of 14C-labeled glutamine in postabsorptive humans. Such labeling of plasma glucose can occur as a result of two different processes: either 1) through incorporation of glutamine carbon into glucose via glutamine entering Krebs cycle at alpha-ketoglutarate or 2) through simple fixation of labeled CO2 resulting from oxidation of labeled glutamine. Therefore, these studies were designed to determine 1) whether glutamine contributes carbon to gluconeogenesis other than through mere CO2 fixation, and, if so, 2) whether the apparent transfer of carbon from glutamine to glucose increases with fasting. Eight healthy adults were studied on two consecutive days: once after an overnight (18-h) fast and again on the second day of fasting (42-h fast). On each study day, subjects received a simultaneous 5-h infusion of D-[6,6-2H2lglucose, L-[3,4-13C2lglutamine, and L-[1-14C]leucine. Apparent rates of incorporation of glutamine carbon into glucose were estimated from the appearance of 13C into plasma glucose; glucose and glutamine production rates (appearance rate [Ra]) were determined from plasma [2H2]glucose and [13C2]glutamine enrichments, respectively. The appearance of 14C into plasma glucose was used to correct the measured rates of carbon transfer from glutamine to glucose as a result of CO2 fixation. We observed that of the apparent contribution of labeled glutamine to gluconeogenesis, only 4% occurred as a result of fixation of labeled CO2, while 96% seemed to occur through other routes. We also observed that between 18 and 42 h of fasting, 1) the relative contribution of protein breakdown to glutamine production was enhanced, while that of de novo synthesis declined; 2) the apparent contribution of glutamine to glucose production rose from 8 +/- 1 to 16 +/- 3% of overall glucose Ra; and 3) the relative apparent contribution of glutamine to gluconeogenesis remained constant. From the current data, it cannot be ascertained to what extent the apparent carbon transfer from glutamine to glucose represents a true contribution of glutamine to gluconeogenesis or mere carbon exchange between the trichloroacetic acid cycle and the gluconeogenic pathway. These findings are nevertheless compatible with a role of glutamine as a significant precursor of glucose in fasting humans.
Diabetes 1997 Oct
PMID:Role of glutamine as a glucose precursor in fasting humans. 931 46

Selected esters of succinic acid are currently under investigation as possible insulinotropic tools in the treatment of non-insulin-dependent diabetes mellitus. Novel esters with high insulinotropic efficiency were recently synthesized. The present study concerns the effects of two of these novel esters, namely glycerol-1,2-dimethylsuccinate (2.5 mM) and propanediol-1,2-dimethylsuccinate (1.0 mM), upon the release of insulin and the de novo biosynthesis of peptides in islets from hereditarily diabetic Goto-Kakizaki rats. Whereas D-glucose (2.8 to 16.7 mM) caused a concentration-related stimulation of insulin release in the islets of the diabetic rats, the two esters of succinic acid only increased modestly, and often not significantly, insulin secretion. Nevertheless, they both markedly increased the incorporation of L-[4-3H]phenylalanine into trichloroacetic acid-precipitable material in islets deprived of any other exogenous nutrient. These findings indicate that, at variance with all pharmaceutical agents presently used or proposed as insulin secretagogues in the treatment of type 2 diabetes, glycerol-1,2-dimethylsuccinate and propanediol-1,2-dimethylsuccinate, considered as islet cell nutrients, display, in addition to their insulinotropic action, the property of stimulating biosynthetic activity in the endocrine pancreas of animals affected by this disease.
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PMID:Effects of glycerol-1,2-dimethylsuccinate and propanediol-1,2-dimethylsuccinate on insulin release and protein biosynthesis in islets of Goto-Kakizaki rats. 943 19

This study aims at gaining further insight into the mode of action of repaglinide in pancreatic islet B-cells. At a 1.0 mumol/L concentration, the meglitinide analog failed to affect the metabolism of exogenous D-glucose and that of endogenous nutrients in islets prelabeled with either L-[U-14C]glutamine or [U-14C]palmitate. Likewise, repaglinide (1.0 mumol/L) failed to modify significantly the incorporation of L-[4-3H]phenylalanine into TCA-precipitable material in islets exposed to a close-to-physiological concentration of D-glucose (7.0 mmol/L). The threshold concentration for the insulinotropic action of repaglinide was close to 0.1-1.0 mumol/L and a maximal response was reached at 10.0 mumol/L in islets incubated in the presence of 5.6-8.3 mmol/L D-glucose. At a higher hexose concentration (16.7 mmol/L), however, an enhancing action of repaglinide (10 mumol/L) upon glucose-stimulated insulin release was only observed over 25 min stimulation in perifused islets, no significant increase in insulin output being detected when islets were exposed to repaglinide (0.1 mumol/L to 0.1 mmol/L) over 90 min incubation at the high D-glucose level. The increase in insulin output evoked by repaglinide in the islets perifused at 16.7 mmol/L D-glucose coincided with a modest increase in 86Rb outflow and a marked stimulation of 45Ca efflux from prelabeled islets, suggesting stimulation of Ca2+ influx into the islet cells and subsequent activation of Ca(2+)-responsive K+ channels. When the administration of repaglinide was halted, the reversibility of its cationic and secretory effects was more pronounced in islets perifused at a high (16.7 mmol/L), rather than a low (6.0 mmol/L), D-glucose concentration. These findings support the view that the primary site of action of repaglinide consists in a remodeling of cationic fluxes, and document that this drug displays favorable attributes as an insulinotropic agent for the treatment of non-insulin-dependent diabetes, such as its lack of interference with nutrient metabolism and biosynthetic activity in isolated islets, the low threshold concentration for its insulin-releasing action and its capacity to augment, at least transiently, insulin release at a high concentration of D-glucose.
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PMID:Effect of repaglinide upon nutrient metabolism, biosynthetic activity, cationic fluxes and insulin release in rat pancreatic islets. 958 90

Selected esters of succinic acid are currently under investigation as possible insulinotropic agents for the treatment of noninsulin-dependent diabetes mellitus. The aim of the present study was to investigate the effects of ten novel esters of succinic acid upon biosynthetic activity in rat pancreatic islets. In the absence of any other exogenous nutrient, glycerol-3-hydroxy-1,2-dimethyl succinate (0.5 mM), D-arabitol-5-hydroxy-1,2,3,4-tetramethylsuccinate (0.5 mM), and 4-tert-butylsuccinate (2.5 mM) exerted little or no effect upon L-[4-3H]phenylalanine incorporation into trichloroacetic acid-precipitable material. A modest but significant increase in biosynthetic activity to approximately 150% of basal value was found in the presence of L-threitol-1,2,4-trimethylsuccinate (2.0 mM) and ethanediol-1,2-diethylsuccinate (2.5 mM). A two- to five-fold increase in protein biosynthesis was observed in islets exposed to propanediol-1,2-dimethylsuccinate, glycerol-1,2-dimethylsuccinate-3-hydrogenosuccinate, L-threitol-3-succinoyl-1,2,4-trimethylsuccinate, glycerol-1,2-dimethylsuccinate or ethanediol-1,2-dimethylsuccinate (2.5 mM each), these esters being mentioned in order of increasing biological efficiency. There was a significant correlation between these results and the insulinotropic action of the same esters. The present findings thus reinforce the view that such esters act as nutrients in islet cells and, therefore, offer the advantage over pharmacological agents currently used for the treatment of type-2 diabetes in stimulating both the biosynthetic and secretory activity of insulin-producing B-cells.
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PMID:Stimulation of biosynthetic activity by novel succinate esters in rat pancreatic islets. 958 65

Tight glycemic control during diabetic pregnancy has been shown to significantly reduce the occurrence of congenital malformations and other effects of maternal diabetes on the offspring. However, intensive insulin therapy often causes recurring acute maternal hypoglycemia, which has been found to be harmful to the developing fetus, although the mechanisms involved are not clear. The aim of our work was to study the effect of acute insulin-induced maternal hypoglycemia on glucose metabolism in the fetal brain. To this end, near-term pregnant New Zealand rabbits were rendered hypoglycemic, and [U-(13)C]glucose was infused into maternal circulation. The metabolic fate of the (13)C-labeled glucose was then studied in fetal brain extracts by (13)C NMR isotopomer analysis, together with conventional biochemical assays of glucose and lactate levels in both plasma and brain. For comparison [U-(13)C]glucose was also administered to insulin-induced hypoglycemic young adult rabbits. Our results showed that while plasma glucose levels were significantly reduced (approximately 70%) relative to controls, no changes in cerebral glucose levels could be detected. Lactate levels were found to be significantly decreased in hypoglycemic fetal plasma and brain. No differences in lactate levels between control and hypoglycemic young rabbit plasma and brain were observed. These differences were attributed to the utilization of lactate as an energy substrate in the fetal brain, but not in the adult brain. Higher relative (13)C enrichments of most glucose metabolites, except lactate, in the hypoglycemic fetal and young rabbit brains, observed by (13)C NMR, stem from reduced endogenous plasma glucose pools, thereby diluting the labeled glucose to a lower extent. The relative glucose (or glucose-derived lactate) flux via the pyruvate carboxylase and pyruvate dehydrogenase pathways (PC/PDH ratio) was not altered under hypoglycemic conditions in the fetal brain for both glutamine and glutamate, but significantly increased in the adult brain for both glutamine and glutamate. The presented data indicate the ability of the fetal brain to maintain energy metabolism during acute hypoglycemia, via lactate utilization. The increase in the adult PC/PDH ratio was suggested by us to stem from increased PC activity, in order to replenish TCA cycle intermediates.
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PMID:Effect of acute insulin-induced hypoglycemia on fetal versus adult brain fuel utilization, assessed by (13)C MRS isotopomer analysis of [U-(13)C]glucose metabolites. 1111 Nov 61


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