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)

Human lens crystallins become progressively yellow-brown pigmented with age. Both fluorescent and non-fluorescent protein adducts and cross-links are formed, many of which result from the advanced Maillard reaction. One of them, LM-1, is a blue fluorophore that was earlier tentatively identified as a cross-link involving lysine residues (1). A two-step chromatographic system was used to unequivocally identify and quantitatively prepare a synthetic fluorescent cross-link with lysine residues that had identical UV, fluorescent, and chromatographic properties with both acetylated and non-acetylated LM-1. Proton, (13)C NMR, and molecular mass of the synthetic compound were identical with vesperlysine A, a fluorescent cross-link discovered by Nakamura et al. (2). The fragmentation patterns of vesperlysine A and LM-1 were identical as determined by NMR/mass spectrometry. Lenticular levels of vesperlysine A increase curvilinearly with age and reach 20 pmol/mg at 90 years. Levels correlate with degree of lens crystallin pigmentation and fluorescence and are increased in diabetes, in contrast to N(epsilon)-(carboxymethyl)lysine and pentosidine. Ascorbate, D-pentoses, and D-threose, but neither D-glucose under oxidative conditions, DL-glyceraldehyde, methylglyoxal, glyoxal, nor glycolaldehyde, are precursors. However, addition of C-2 compounds greatly catalyzes vesperlysine A formation from ribose. Thus, vesperlysine A/LM-1 is a novel product of the advanced Maillard reaction in vivo and a specific marker of a diabetic process in the lens that is different from glyco- and lipoxidation.
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PMID:Structure and mechanism of formation of human lens fluorophore LM-1. Relationship to vesperlysine A and the advanced Maillard reaction in aging, diabetes, and cataractogenesis. 1040 19

Carbon nuclear magnetic resonance (13C NMR) spectroscopy and phosphorus (31p) NMR spectroscopy have been used to help define the contribution of insulin-stimulated muscle glycogen synthesis to whole-body insulin-stimulated glucose metabolism in normal individuals and the extent to which this process is defective in patients with type 2 (non-insulin-dependent) diabetes. Assessments of the response to hyperglycemic-hyperinsulinemic clamping have shown that abnormalities of muscle glycogen synthesis, apparently mediated by a defect in GLUT-4 transport and/or hexokinase activity, play a major role in causing insulin resistance in type 2 diabetes. Studies of the mechanisms by which free fatty acids (FFA) cause insulin resistance in humans indicate that increased FFA levels inhibit glucose transport, which may be a consequence of decreased insulin receptor substrate (IRS-1)-associated phosphatidylinositol 3-kinase activity. 13C NMR spectroscopy studies have documented that liver glycogen concentrations are reduced and the rate of hepatic gluconeogenesis is increased in subjects with type 2 diabetes; thus, the higher rate of glucose production in type 2 diabetes can be attributed entirely to increased rates of hepatic gluconeogenesis. These cellular mechanisms of insulin resistance can be addressed through combination therapy with agents that reverse the principal pathophysiologic defects of type 2 diabetes. The biguanide metformin appears to lower glucose by suppressing hepatic glucose production, whereas the thiazolidinedione troglitazone appears to increase glucose clearance by peripheral tissues. The two agents together have been shown to provide better glucose control than either drug alone, without stimulating insulin secretion.
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PMID:Cellular mechanisms of insulin resistance in humans. 1041 51

The aim of this study was to investigate the effect of increasing exogenous palmitate concentration on carbohydrate and palmitate oxidation in hearts from control and 1-wk diabetic rats. Hearts were perfused with glucose, [3-(13)C]lactate, and [U-(13)C]palmitate. Substrate oxidation rates were determined by combining (13)C-NMR glutamate isotopomer analysis of tissue extracts with measurements of oxygen consumption. Carbohydrate oxidation was markedly depressed after diabetes in the presence of low (0.1 mM) but not high (1.0 mM) palmitate concentration. Increasing exogenous palmitate concentration 10-fold resulted in a 7-fold increase in the contribution of palmitate to energy production in controls but only a 30% increase in the diabetic group. Consequently, at 0.1 mM palmitate, the rate of fatty acid oxidation was higher in the diabetic group than in controls; however, at 1.0 mM fatty acid oxidation, it was significantly depressed. Therefore, after 1 wk of diabetes, the major differences in carbohydrate and fatty acid metabolism occur primarily at low rather than high exogenous palmitate concentration.
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PMID:Impact of 1 wk of diabetes on the regulation of myocardial carbohydrate and fatty acid oxidation. 1044 31

Bioartificial pancreatic constructs based on immunoisolated, insulin-secreting cells have the potential for providing effective, long-term treatment of type I (insulin-dependent) diabetes. Use of insulinoma cells, which can be amplified in culture, relaxes the tissue availability limitation that exists with normal pancreatic islet transplantations. We have adopted mouse insulinoma betaTC3 cells entrapped in calcium alginate/poly-L-lysine/alginate (APA) beads as our model system for a bioartificial pancreas, and we have characterized the effects of long-term propagation and of glucose concentration step changes on the bioenergetic status and on the metabolic and secretory activities of the entrapped cells. Cell bioenergetics were evaluated nonivasively by phosphorus-31 nuclear magnetic resonance ((31)P NMR) spectroscopy, and metabolic and secretory parameters by assaying cell culture medium. Data indicate that net cell growth occurred between days 3 and 10 of the experiment, resulting in an approximate doubling of the overall metabolic and secretory rates and of the intracellular metabolite levels. Concurrently, a reorganization of cell distribution within the beads was observed. Following this growth period, the measured metabolic and secretory parameters remained constant with time. During glucose step changes in the perfusion medium from a high concentration of 12 to 15 mM to 0 mM for 4.5 h to the same high glucose concentration, the oxygen consumption rate was not affected, whereas insulin secretion was always glucose-responsive. Intracellular nucleotide triphosphates did not change during 0 mM glucose episodes performed early in culture history, but they declined by 20% during episodes performed later in the experiment. It is concluded that the system of APA-entrapped betaTC3 cells exhibits several of the desirable characteristics of a bioartificial pancreas device, and that a correlation between ATP and the rate of insulin secretion from betaTC3 cells exists for only a domain of culture conditions. These findings have significant implications in tissue engineering a long-term functional bioartificial endocrine pancreas, in developing noninvasive methods for assessing construct function postimplantation, and in the biochemical processes associated with insulin secretion.
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PMID:Development of a bioartificial pancreas: I. long-term propagation and basal and induced secretion from entrapped betaTC3 cell cultures. 1057 92

Tissue-engineered pancreatic constructs based on immunoisolated, insulin-secreting cells are promising in providing an effective, relatively inexpensive, long-term treatment for type I (insulin-dependent) diabetes. An in vitro characterization of construct function under conditions mimicking the in vivo environment is essential prior to any extensive animal experimentation. Encapsulated cells may experience hypoxic conditions postimplantation as a result of one or more of the following: the design of the construct; the environment at the implantation site; or the development of fibrosis around the construct. In this work, we studied the effects of 3- and 4-day-long hypoxic episodes on the metabolic and secretory activities and on the levels of intracellular metabolites detectable by phosphorus-31 nuclear magnetic resonance ((31)P NMR) of alginate/poly-L-lysine/alginate entrapped betaTC3 mouse insulinomas continuously perfused with culture medium. Results show that, upon decreasing the oxygen concentration in the surrounding medium, the encapsulated cell system reached a new, lower metabolic and secretory state. Hypoxia drove the cells to a more anaerobic glycolytic metabolism, increased the rates of glucose consumption (GCR) and lactate production (LPR), and reduced the rates of oxygen consumption (OCR) and insulin secretion (ISR). Furthermore, hypoxia reduced the levels of intracellular nucleotide triphosphates (NTP) and phosphorylcholine (PC) and caused a rapid transient increase in inorganic phosphate (P(i)). Upon restoration of the oxygen concentration in the perfusion medium, all parameters returned to their prehypoxic levels within 2 to 3 days following either gradual unidirectional changes (ISR, NTP, PC) or more complicated dynamic patterns (OCR, GCR, LPR). A further increase in oxygen concentration in the perfusion medium drove OCR, ISR, NTP, PC, and P(i) to new, higher levels. It is concluded that (31)P NMR spectroscopy can be used for the prolonged noninvasive monitoring of the bioenergetic changes of encapsulated betaTC3 cells occurring with changes in oxygen tension. The data also indicate that the oxygen-dependent states might be related to the total number of viable, metabolically active cells supported by the particular oxygen level to which the system is exposed. These findings have significant implications in developing and non-invasively monitoring a tissue-engineered bioartificial pancreas based on transformed beta cells, as well as in understanding the biochemical events pertaining to insulin secretion from betaTC3 insulinomas.
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PMID:Development of a bioartificial pancreas: II. Effects of oxygen on long-term entrapped betaTC3 cell cultures. 1057 93

Vanadium has well-documented blood-glucose-lowering properties both in vitro and in vivo. The design of new oxovanadium(IV) coordination compounds, intended for use as insulin-enhancing agents in the treatment of diabetes mellitus, can potentially benefit from a synergistic approach, in which the whole complex has more than an additive effect from its component parts. Biguanides, most importantly metformin, are oral hypoglycemic agents used today to treat type 2 diabetes mellitus. In this study, biguanide, metformin, and phenformin, all biguanides, were coordinated to oxovanadium(IV) to form potential insulin-enhancing compounds. Highly colored, air-stable, bis(biguanidato)oxovanadium(IV), [VO(big)2], bis(N'N'-dimethylbiguanidato)oxovanadium(IV), [VO(metf)2], and bis(beta-phenethyl-biguanidato)oxovanadium(IV), [VO(phenf)2], were prepared. Solvation with dimethylsulfoxide occurred with VO(metf)2 to form a six-coordinate complex. Precursor ligands and oxovanadium(IV) coordination complexes were characterized by infrared spectroscopy, mass spectrometry, elemental analyses, magnetic susceptibility, and, where appropriate, 1H NMR spectroscopy. Biological testing with VO(metf)2, a representative compound, for insulin-enhancing potential included acute (72 h) administration, both by intraperitoneal (i.p.) injection and by oral gavage (p.o.) in streptozotocin (STZ)-diabetic rats. VO(metf)2 administration resulted in significant blood-glucose lowering at doses of 0.12 mmol kg-1 i.p. and 0.60 mmol kg-1 p.o. (previously established as ED50 doses for organically chelated oxovanadium(IV) complexes); however, no positive associative effects due to the presence of biguanide in the complex were apparent.
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PMID:Vanadyl-biguanide complexes as potential synergistic insulin mimics. 1060 40

Glucose reacts nonenzymatically with the amino groups of proteins to form stable, cross-linking adducts called advanced glycation end products or AGEs. While several lines of evidence have established that AGEs accumulate in tissues and contribute to the pathological sequelae of diabetes and aging, the identity of the major cross-link(s) that forms in vivo has remained enigmatic. This has been considered to be due to the labile nature and to the low fluorescence properties of this cross-link, despite the fact that fluorescence has been generally associated with AGE formation in vivo. Accordingly, the few AGE adducts that have been isolated thus far from proteins in vivo or from model systems in vitro have been found to account for only a fraction of the glucose-derived cross-links that occur in tissues. This situation has been further underscored by the development of a well-characterized class of antibodies that recognize in vivo AGEs but which fail to react with the structurally defined AGEs that have been identified to date. This particular class of anti-AGE antibodies has proven valuable in the quantification of AGE-modified forms of hemoglobin, low-density lipoprotein (LDL), and beta-amyloid peptide, and can provide prognostic information on the course of certain diabetic complications. To obtain insight into the structure of this immunoreactive, AGE adduct, we used an anti-AGE antibody (RU) as a probe to isolate novel AGE(s) that formed within a reaction mixture of glucose and the model glycation substrate, N(alpha)-CBZ-Arg-Lys. HPLC purification of an immunoreactive fraction that accumulated in this preparation showed the presence of a compound that was determined by (1)H NMR and electrospray ionization mass spectrometry (ESI-MS) to be a stable, imidazole-based cross-link (termed arginine-lysine imidazole or ALI). The properties of ALI, immunoreactivity, acid-lability, nonfluorescence, and inhibition of formation by aminoguanidine, suggest that ALI is likely to typify an important class of the AGE cross-links that form in vivo.
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PMID:Structure of a synthetic glucose derived advanced glycation end product that is immunologically cross-reactive with its naturally occurring counterparts. 1063 83

To determine whether the decreased contractile performance in diabetic hearts is associated with a reduced energy reserve due to decreased creatine kinase (CK) activity, we measured total CK activity (V(max)) in vitro and CK reaction velocity in vivo using(31)P NMR spectroscopy in isolated perfused rat hearts after 4 and 6 weeks of diabetes. After 4 weeks of diabetes, V(max)decreased by 22% with a larger decrease of CK MB than of CK MM and mitochondrial-CK isoenzymes. There was no further decrease in these parameters after 6 weeks of diabetes. Isovolumic contractile performance of 4 and 6 week diabetic hearts, estimated as rate-pressure product under identical perfusion and loading conditions (EDP set at 6-8 mmHg), was only 50% of that of control. ATP, PCr and total creatine concentrations were not different in control and 4 or 6 weeks diabetic rat hearts. After 4 weeks of diabetes, CK reaction velocity decreased by 22%. This was in proportion to the decline of V(max)and therefore predicted by the rate equation for the CK reaction. However, the further decline in the CK reaction velocity after 6 weeks of diabetes (45%) was greater than that predicted from the CK rate equation (17% decrease), and cannot be explained by substrate control of the enzyme. When hearts were inotropically stimulated by increasing perfusate calcium concentration, CK reaction velocity increased slightly (approximately 15%) in both control and diabetic hearts, thereby maintaining a constant ATP concentration. We conclude that in the diabetic myocardium, the CK reaction velocity decreases but does not limit the availability of high-energy phosphates for contraction over the range of workloads studied. We also conclude that a mechanism(s) in addition to substrate control regulates CK reaction velocity in the 6 week diabetic hearts.
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PMID:Altered creatine kinase enzyme kinetics in diabetic cardiomyopathy. A(31)P NMR magnetization transfer study of the intact beating rat heart. 1064 Apr 45

The wide acceptance of the diene conjugation-method in monitoring low-density lipoprotein (LDL) oxidation ex vivo has led to development of an assay, which measures the amount of baseline diene conjugation (BDC) in circulating LDL, and is an indicator of oxidized LDL in vivo. The LDL-BDC assay is based on precipitation of serum LDL with buffered heparin, and spectrophotometric determination of baseline level of conjugated dienes in lipids extracted from LDL. Compared to existing methods for oxidized LDL, LDL-BDC is fast and simple to perform. Chemical studies by HPLC and NMR have verified that LDL-BDC is a specific indicator of circulating mildly oxidized LDL. Validity of the assay is further indicated by strong correlation with the titer of autoantibodies against oxidized LDL. Clinical studies have shown that LDL-BDC is closely related to coronary, carotid, and brachial atherosclerosis. Moreover, several independent studies have demonstrated surprisingly strong associations between LDL-BDC and known atherosclerosis risk factors (obesity, physical inactivity, hypertension, diabetes, and arterial functions). Indeed, these studies seem to indicate that as an indicator of the risk of atherosclerosis LDL-BDC clearly exceeds sensitivity and specificity of the common lipid markers of atherosclerosis. It is concluded that LDL-BDC is a promising candidate in search for methods for the evaluation of in vivo LDL oxidation and the risk of atherosclerosis.
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PMID:Baseline diene conjugation in LDL lipids: an indicator of circulating oxidized LDL. 1064 5

Ten amniotic fluid samples obtained from third trimester pregnant women suffering from insulin dependant diabetes mellitus were analysed by 1H-NMR and compared to ten samples from a group of normal volunteers. A subset of the metabolites identified; valine, lactate, alanine, acetate, citrate and glucose were quantitated using standard addition methods. Apart from valine and citrate, a general diminution in the concentration of each of these species was found, especially glucose, in the diabetic group. The abnormally low glucose levels in the diabetic group are suggestive of infection in the patient group. However, the depressed lactate levels in the diabetic group suggest that in these cases the fetus was not subjected to stress.
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PMID:1H NMR as a non-invasive probe of amniotic fluid in insulin dependent diabetes mellitus. 1064 63


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