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)

Diabetes is known to cause impaired endothelium-dependent relaxation of blood vessels. The purpose of this study was to determine whether this endothelial dysfunction is a permanent defect or is reversible after acute arginine supplementation in vitro or by surgical intervention in vivo using syngeneic pancreatic islet transplantation. Lewis rats were injected with streptozotocin to induce diabetes and were studied either 8 or 12 weeks later. Another group received syngeneic islets via intraportal injection at 8 weeks of diabetes and were allowed to become euglycemic for 4 weeks before study. Thoracic aortic rings were tethered in isolated muscle baths, contracted with a submaximal concentration of norepinephrine, and challenged with either the endothelium-dependent vasodilator acetylcholine or the endothelium-independent vasodilator nitroglycerin. Relaxation to acetylcholine (but not nitroglycerin) was reduced in both 8- and 12-week diabetic rings compared with age-matched control rings. Preincubation of diabetic rings in vitro with L-arginine (but not D-arginine) restored relaxation to acetylcholine to normal to rings from 8-week but not 12-week diabetic animals. Plasma basic amino acids (arginine, lysine, and histidine) were reduced by diabetes, whereas other neutral or acidic amino acids were unchanged (phenylalanine, proline, and glutamate), reduced (serine, cysteine, threonine, tyrosine, tryptophan, and aspartate), or elevated (isoleucine, leucine, and valine). Islet transplantation restored to normal the changes in plasma amino acids. Elevation in blood glucose and total glycosylated hemoglobin in diabetic animals was normalized after islet transplantation. Furthermore, islet transplantation completely restored the defective endothelium-dependent relaxation to acetylcholine in diabetic rings.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Sep
PMID:Syngeneic pancreatic islet transplantation reverses endothelial dysfunction in experimental diabetes. 765 36

To elucidate the mechanism of insulin's anticatabolic effect in humans, protein dynamics were evaluated in the whole-body, splanchnic, and leg tissues in six C-peptide-negative type I diabetic male patients in the insulin-deprived and insulin-treated states using two separate amino acid models (leucine and phenylalanine). L-(1-13C,15N)leucine, L-(ring-2H5)phenylalanine, and L-(ring-2H2) tyrosine were infused intravenously, and isotopic enrichments of [1-13C,15N]-leucine, (13C)leucine, (13C)ketoisocaproate, (2H5)phenylalanine, [2H4]tyrosine, (2H2)tyrosine, and 13CO2 were measured in arterial, hepatic vein, and femoral vein samples. Whole-body leucine flux, phenylalanine flux, and tyrosine flux were decreased (< 0.01) by insulin treatment, indicating an inhibition of protein breakdown. Moreover, insulin decreased (< 0.05) the rates of leucine oxidation and leucine transamination (P < 0.01), but the percent rate of ketoisocaproate oxidation was increased by insulin (P < 0.01). Insulin also reduced (< 0.01) whole-body protein synthesis estimated from both the leucine model (nonoxidative leucine disposal) and the phenylalanine model (disposal of phenylalanine not accounted by its conversion to tyrosine). Regional studies demonstrated that changes in whole body protein breakdown are accounted for by changes in both splanchnic and leg tissues. The changes in whole-body protein synthesis were not associated with changes in skeletal muscle (leg) protein synthesis but could be accounted for by the splanchnic region. We conclude that though insulin decreases whole-body protein breakdown in patients with type I diabetes by inhibition of protein breakdown in splanchnic and leg tissues, it selectively decreases protein synthesis in splanchnic tissues, which accounted for the observed decrease in whole-body protein synthesis. Insulin also augmented anabolism by decreasing leucine transamination.
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PMID:Protein dynamics in whole body and in splanchnic and leg tissues in type I diabetic patients. 776 35

Suppression of tissue proteolysis is an important mechanism of postprandial protein anabolism, and it may be mediated by insulin, hyperaminoacidemia, or both. To evaluate whether insulin is essential in the regulation of this process, we have investigated the effect of mixed-meal ingestion on whole-body protein breakdown in insulin-deprived insulin-dependent diabetes mellitus (IDDM) patients and normal control subjects. Endogenous phenylalanine and leucine rate of appearance (Ra) from proteolysis were measured at steady-state conditions using a multiple stable isotope technique before and after the constant administration of a synthetic mixed meal. In the postabsorptive state, the IDDM patients exhibited accelerated intracellular leucine Ra (IDDM, 2.64 +/- 0.19 mumol.min-1.kg-1; control, 2.02 +/- 0.08 mumol.min-1.kg-1; P < 0.05) and plasma phenylalanine Ra (IDDM, 0.73 +/- 0.03 mumol.min-1.kg-1; control, 0.61 +/- 0.04 mumol.min-1.kg-1; P < 0.05). During meal ingestion, endogenous phenylalanine and leucine Ra values were suppressed in both the insulin-deficient IDDM (P < 0.05) and control subjects (P < 0.05). Although postmeal endogenous leucine and phenylalanine Ra values remained greater (P < 0.05) in IDDM, the delta changes from the basal endogenous leucine Ra (IDDM, -0.56 +/- 0.11 mumol.min-1.kg-1; control, -0.56 +/- 0.09 mumol.min-1.kg-1) and phenylalanine Ra (IDDM, -0.13 +/- 0.01 mumol.min-1.kg-1; control, -0.14 +/- 0.02 mumol.min-1.kg-1) were similar in both groups. In the IDDM patients, the postmeal increases from the basal leucine concentration were onefold greater (P < 0.05) than in the control-subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Feb
PMID:Regulation of postprandial whole-body proteolysis in insulin-deprived IDDM. 785 42

Human hexokinase (HK) II, a glucose phosphorylating enzyme in muscle tissue, plays a central role in glucose metabolism. Since reduced insulin-stimulated glucose uptake and reduced glucose-6-phosphate content in muscle have been demonstrated in pre-non-insulin-dependent diabetes mellitus (pre-NIDDM) and NIDDM subjects, we have examined the coding region of the HKII gene in NIDDM patients to determine whether these patients show genetic polymorphisms that are associated with or contribute to the disease. Single-strand conformational polymorphism analysis and nucleotide sequencing were initially performed on the entire coding region of the HKII gene of 38 insulin-resistant NIDDM patients and 5 healthy control subjects. This analysis revealed four missense mutations at codons 142 (Gln to His), 148 (Leu to Phe), 497 (Arg to Gln), and 844 (Arg to Lys) and an additional six exon polymorphisms that did not predict any change in amino acid composition of the protein. One homozygous and nine heterozygous carriers of the codon 142 mutation were found among the NIDDM patients. The mutations at codons 148, 497, and 844 were each found in one diabetic subject and only on one allele. There were no carriers of compound heterozygous mutations. A subsequent study of 301 patients with NIDDM and 151 healthy control subjects revealed no additional mutations at codons 148, 497, or 844. The total frequency of the mutated allele at codon 142 was 18.9% among the control subjects and 17.0% among the NIDDM patients (chi 2 = 0.56, P = 0.45).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Mar
PMID:Identification of four amino acid substitutions in hexokinase II and studies of relationships to NIDDM, glucose effectiveness, and insulin sensitivity. 788 23

The effects of metformin therapy on whole body and splanchnic amino acid turnover are not known. Therefore, we have studied fasting and postprandial phenylalanine kinetics in type 2 diabetic subjects (non-insulin-dependent diabetes mellitus), previously treated with diet only, both before and after 4 weeks of either metformin (850 mg twice a day) (n = 11) or placebo administration (n = 6). Phenylalanine kinetic was evaluated by means of a multiple isotope technique: tritiated phenylalanine was infused i.v., whereas carbon-labeled phenylalanine was incorporated into a chemically-defined meal. Compared with placebo, metformin administration decreased both fasting (from 162 +/- 17 to 141 +/- 20 mg/dl) and postprandial (from 217 +/- 20 to 164 +/- 20 mg/dl) glucose concentrations (P < 0.05-P < 0.01). Fasting insulin concentrations were unaffected, but postmeal insulin tended to be lower (P < 0.06) after metformin. Compared with the pretreatment period, metformin administration did not change total phenylalanine rate of appearance (fasted state, 0.74 +/- 0.10 vs. 0.71 +/- 0.08 mumol/kg.min; fed state, 0.77 +/- 0.10 vs. 0.75 +/- 0.08 mumol/kg.min, respectively), dietary and endogenous phenylalanine rate of appearance, dietary phenylalanine oxidation, and splanchnic uptake, similar to what was observed in the placebo group. Our data indicate that, at least after a 4-week treatment, metformin does not affect fasting and postprandial protein turnover, as indicated by phenylalanine data, in subjects with mild non-insulin-dependent diabetes mellitus.
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PMID:Effects of metformin treatment on whole-body and splanchnic amino acid turnover in mild type 2 diabetes. 798 55

This paper is a study to identify the clinical significance of high-molecular-mass alkaline phosphatase (ALP:E:C..3.1.3.1.), ALP-lipoprotein-X complex (LP-X) and intestinal variant ALP. We used cellulose acetate and agarose gels and techniques including wheat germ lectin, cetavlon-diethyl ether, thermostatability, neuraminidase and L-phenylalanine to improve the electrophoretic separation of the alkaline phosphatase isoenzymes. Patients' serum samples were electrophoresed from a diverse group of individuals ill with cholestasis, neoplastic disease metastatic to the liver, hepatocellular carcinoma, cirrhosis, diabetes mellitus, and chronic renal disease. Agarose gels provided better separation of ALP isoenzymes than cellulose acetate gels. The results also indicated that high-molecular mass ALP is present in patient's serum in conditions associated with cholestasis especially caused by hepatic malignancy. High-molecular mass ALP was frequently found to co-exist with the liver isoenzyme and LP-XALP complex. The intestinal variant was identified in patients with malignancy, cirrhosis, chronic renal disease and diabetes mellitus. Intestinal ALP coexisted concomitantly with a variant intestinal ALP. Intestinal variant ALP is most likely composed of intestinal ALP attached to a cellular membrane-binding domain, or may be an artifact produced by neuraminidase incubation.
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PMID:Clinical significance of serum high-molecular-mass alkaline phosphatase, alkaline phosphatase-lipoprotein-X complex, and intestinal variant alkaline phosphatase. 804 46

Obesity-associated hyperaminoacidemia is traditionally interpreted as a consequence of insulin resistance. We performed two different experiments to investigate the effects of both obesity-associated insulin resistance and the insulin resistance of non-insulin-dependent diabetes mellitus (NIDDM) on amino acid metabolism. In the first experiment, we measured postabsorptive amino acid concentrations and their decline in response to an oral carbohydrate load in 19 obese nondiabetic women and 19 normal-weight nondiabetic controls. Obese subjects were more resistant to insulin with respect to its effects on glucose metabolism than normal-weight controls, as calculated by the method described by Matthews. However, postabsorptive plasma concentrations of the so-called large neutral amino acids (LNAA), namely phenylalanine, tyrosine, valine, leucine, and isoleucine, and their decrease in response to carbohydrate consumption were similar in both groups. In the second experiment, we compared the decrease of plasma concentrations of LNAA during a euglycemic, hyperinsulinemic clamp in obese subjects with and without NIDDM. Peripheral glucose uptake (PGU) was more impaired in NIDDM subjects compared with obese controls. Furthermore, hepatic glucose production (HGP) was less attenuated by insulin infusion in NIDDM than in control subjects. Postabsorptive plasma LNAA concentrations were not different in the two groups. Values obtained in either group were not different from the postabsorptive concentrations in the normal-weight control subjects of experiment 1. All amino acid levels decreased substantially in response to insulin infusion. The magnitude of the decrease was not significantly different in the two groups, except for a slightly greater decrease of the plasma isoleucine concentration in obese control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin-induced decline of plasma amino acid concentrations in obese subjects with and without non-insulin-dependent diabetes. 817 54

Levels of insulin autoantibodies (IAA) vary among different first degree relatives of insulin-dependent diabetes mellitus patients, suggesting genetic regulation. We previously reported elevated IAA among DR4-positive at risk relatives. In this study, 72/82 at risk relatives were IAA positive, of whom 75% (54/72) carried DR4 versus 20% (2/10) of IAA-negative relatives (P = 0.0004). However, 69% (18/26) of DR4-negative relatives were IAA positive. Since DR4 did not account for all IAA positivity, we analyzed DQA1 and DQB1 alleles. Homozygosity for DQA1 alleles deriving from the evolutionary lineage 4 (*0401, *0501, *0601) was associated with low IAA levels, while lineage 1-3 alleles (*0101, *0102, *0103, *0201, *0301) correlated with higher levels. Most (93%, 65/70) relatives with lineage 1-3 alleles were IAA positive (mean = 360 +/- 63 SEM nU/ml). Only 7/12 relatives homozygous for lineage 4 alleles were IAA-positive, with lower levels than relatives with lineage 1-3 alleles (mean = 55 +/- 15 SEM nU/ml, P < 0.0001; 7/12 vs 65/70, P = 0.004). The amino acid sequences of lineage 1-3 alleles uniquely share glutamic acid (E) and phenylalanine (F) at positions 40 and 51 (EF alleles). Lineage 4 alleles have glycine (G) and leucine (L) at those positions (GL alleles). 90% (65/72) of IAA-positive relatives had an EF allele, while only 75% (54/72) had DR4 (P = 0.01). Homozygosity for GL alleles (often DQA1 *0501 on DR3 haplotypes) correlated with little or no humoral response to insulin. Thus, HLA-DQB1 GL alleles, or other genes on haplotypes (e.g., DR3) that carry these DQA1 alleles, may confer recessive low responsiveness to insulin.
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PMID:Two subsets of HLA-DQA1 alleles mark phenotypic variation in levels of insulin autoantibodies in first degree relatives at risk for insulin-dependent diabetes. 820 Sep 80

Nonenzymatic glycation of proteins occurs at an accelerated rate in diabetes and can lead to the formation of advanced glycation end products of proteins (AGEs), which bind to mononuclear phagocytes (MPs) and induce chemotaxis. We have isolated two cell surface-associated binding proteins that mediate the interaction of AGEs with bovine endothelial cells. One of these proteins is a new member of the immunoglobulin superfamily of receptors (termed receptor for AGEs or RAGE); and the second is a lactoferrin-like polypeptide (LF-L). Using monospecific antibodies to these two AGE-binding proteins, we detected immunoreactive material on Western blots of detergent extracts from human MPs. Radioligand-binding studies demonstrated that antibody to the binding proteins blocked 125I-AGE-albumin binding and endocytosis by MPs. Chemotaxis of human MPs induced by soluble AGE-albumin was prevented in a dose-dependent manner by intact antibodies raised to the AGE-binding proteins, F(ab')2 fragments of these antibodies and by soluble RAGE. When MP migration in response to N-formyl-Met-Leu-Phe was studied in a chemotaxis chamber with AGE-albumin adsorbed to the upper surface of the chamber membrane, movement of MPs to the lower compartment was decreased because of interaction of the glycated proteins with RAGE and LF-L on the cell surface. The capacity of AGEs to attract and retain MPs was shown by implanting polytetrafluoroethylene (PTFE) mesh impregnated with AGE-albumin into rats: within 4 d a florid mononuclear cell infiltrate was evident in contrast to the lack of a significant cellular response to PTFE with adsorbed native albumin. These data indicate that RAGE and LF-L have a central role in the interaction of AGEs with human mononuclear cells and that AGEs can serve as a nidus to attract MPs in vivo.
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PMID:Regulation of human mononuclear phagocyte migration by cell surface-binding proteins for advanced glycation end products. 838 41

Glucagon stimulates in vitro liver phenylalanine (Phe) degradation, thus inducing net protein catabolism. Whether these effects occur also in vivo in humans is not known. Therefore, we studied the effects of physiological hyperglucagonemia on Phe rate of appearance (Ra), hydroxylation, and oxidation in seven normal volunteers during infusions of somatostatin with replacement doses of insulin and growth hormone. Steady-state Phe kinetics were evaluated using the L-[1-14C]Phe tracer both at the end of a 3-h basal glucagon replacement period (glucagon concentration: 212 +/- 115 ng/l) and after a 3-h hormone infusion at the rate of approximately 3 ng x kg-1 x min-1 (--> 654 +/- 280 ng/l). Hyperglucagonemia did not change plasma Phe concentration and Ra but increased Phe oxidation by approximately 30% (P < 0.01). Oxidation was also increased by approximately 24% (P < 0.01) using plasma [14C]tyrosine (Tyr) specific activity as a precursor pool. Phe hydroxylation to Tyr estimated by assuming a fixed ratio of Tyr to Phe Ra (0.73) did not change. Nonhydroxylated Phe disposal decreased by approximately 6% (P = 0.08). These data show that in humans in the postabsorptive state, hyperglucagonemia, with near maintenance of basal insulin and growth hormone concentrations, stimulates Phe oxidation but not Phe hydroxylation, suggesting a different regulation of these two Phe catabolic steps. Glucagon may also reduce Phe availability for protein synthesis.
Diabetes 1996 Apr
PMID:Hyperglucagonemia stimulates phenylalanine oxidation in humans. 860 68


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