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)

The muscle protein lost in uncontrolled diabetes may be due to decreased synthesis, increased catabolism, or to any combination of alteration in these rates that results in net loss. Differing methods of examining these rates in vivo and in vitro have given conflicting results. We assessed the rate of catabolism of proteins containing 3-methylhistidine (3-MH) by measurement of its urinary excretion in spontaneously diabetic "BB" Wistar rats. Prior to overt diabetes, rates of excretion were appropriate to the age of the rats (1.46 +/- 0.15 mumole/day), with 34%-47% as the nonacetylated form. Accompanying diabetes there was an increase in urine urea nitrogen of two to threefold over 4-14 days, and an increase in ammonium nitrogen of sixfold. 3-MH excretion doubled by 4 days, and 81%-96% was excreted as the nonacetylated form. Subcutaneous insulin in doses sufficient to improve glycosuria and hyperglycemia was associated with normalized total 3-MH excretion (N-acetyl 3-MH plus 3-MH) but a greater proportion than normal appeared in the nonacetylated form. These results suggest that muscle protein catabolism increased with insulin deficiency and that this defect can be corrected by therapy. Both untreated and treated diabetic rats appear to have a limited capacity for acetylation of 3-MH prior to its excretion.
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PMID:Muscle protein catabolism in diabetes: 3-methylhistidine excretion in the spontaneously diabetic "BB" rat. 700 19

The fractional excretion of uric acid, calcium, phosphorus, magnesium and other ions, and the urinary acidifying capacity were studied in then patients with juvenile diabetes of short evolution and in a control group matched for age, sex, and body surface. The diabetic patients showed a hyperexcretion of uric acid, sodium, potassium, chloride and ammonium which was unrelated to the increment of glomerular filtration rate or to glucosuria, and could not be ascribed to diet. The pathophysiologic interpretation of these findings is discussed, concluding that they might be the result of an increase in the filtered load and the behaviour of the tubules in front of the glomerular hyperfunction or metabolic disturbance inherent to the diabetic condition.
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PMID:[Tubular function and renal acidifying in juvenile diabetes mellitus of short evolution]. 720 83

The selective inhibition of individual carnitine acyltransferases may be useful in the therapy of diabetes and heart disease. Aminocarnitine (3) is a weak competitive inhibitor (K(i) = 4.0 mM) for carnitine acetyltransferase (CAT), although the N-acetyl derivative 4 is about 165 times more potent (K(i) = 0.024 mM) than 3. Compound 3 is also a potent competitive inhibitor for carnitine palmitoyltransferases 1 and 2 (CPT-1 and CPT-2) (IC50 for CPT-2 = 805 nM). We synthesized 3-amino-5,5-dimethylhexanoic acid (7) and its N-acetyl derivative (8) as isosteric analogs of 3 and 4 that lack the quaternary ammonium positive charge. Like 3 and 4, compounds 7 and 8 were competitive inhibitors of CAT with significantly different potencies, but in this case, 8 (K(i) = 25 mM) was 10 times less potent than 7 (K(i) = 2.5 mM). R-(-)-7 and S-(+)-7 were stereoselective inhibitors of CAT (K(i) = 1.9 and 9.2 mM, respectively). Racemic 7 was a weak competitive inhibitor of CPT-2 (K(i) = 20 mM) and had no effect on CPT-1. These results are consistent with differences among the carnitine-binding sites on carnitine acyl-transferases that may be useful in selective inhibitor design. Furthermore, the data suggest that the quaternary ammonium positive charge of carnitine may be important for the proper orientation of carnitine and its analogs in the binding site.
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PMID:3-Amino-5,5-dimethylhexanoic acid. Synthesis, resolution, and effects on carnitine acyltransferases. 793 52

Glutamic acid dimethyl ester (GME; 3.0-10.0 mM) enhanced insulin release evoked by 6.0-8.3 mM D-glucose, 1.0-10.0 mM L-leucine, or 5.0-10.0 mM 2-amino-bicyclo(2,2,1)heptane-2-carboxylic acid, causing a shift to the left of the sigmoidal relationship between insulin output and D-glucose concentration. In the absence of D-glucose, GME also unmasked the insulinotropic potential of glibenclamide. In islets exposed to L-leucine, the insulinotropic action of GME coincided with an early fall and later increase in 86Rb outflow and augmentation of 45Ca outflow from prelabeled islets. The measurement of O2 uptake, NH4+ output, production of 14CO2 from islets prelabeled with [U-14C]palmitate, generation of 14C-labeled amino acids and 14CO2 from the dimethyl ester of either L-[1-14C]glutamic acid or L-[U-14C]glutamic acid, and D-[2-14C]glucose as well as D-[6-14C]glucose oxidation in the presence or absence of GME indicated that the latter ester was efficiently converted to L-glutamate and its further metabolites. The overall gain in O2 uptake represented the balance between GME oxidation and its sparing action on the catabolism of endogenous fatty acids and exogenous D-glucose. It is proposed that GME might represent a new tool to bypass beta-cell defects in D-glucose transport, phosphorylation, and further metabolism and, hence, to stimulate insulin release in experiments conducted in animal models of non-insulin-dependent diabetes mellitus.
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PMID:Insulinotropic action of glutamic acid dimethyl ester. 794 7

We previously reported the generation and characterization of a panel of CD4(+) autoreactive T cell clones that suppress development of autoimmune diabetes in non-obese diabetic (NOD) mice. We showed that the protective capacity of the T cell clones correlated with secretion of an activity that potently inhibits allogeneic mixed lymphocyte reaction (allo-MLR). In this report, we describe the biological characteristics of the allo-MLR inhibitory activity (MLR-IA, short for mixed lymphocyte reaction inhibitory activity) secreted by the protective T cell clone, NOD-5. MLR-IA has little effect on initiation of proliferation in an allo-MLR, but it potently inhibits the maintenance and amplification of the proliferative response. MLR-IA is also capable of inhibiting concanavalin A (Con A) stimulated splenic responder T cell proliferation. MLR-IA is reversible in vitro and is not restricted by MHC class I or II proteins. MLR-IA does not affect IL-2 receptor expression of responding T cells and has no effect on IL-2-dependent proliferation of CTLL-20 T cells. Partially purified MLR-IA inhibits IL-2 production in a primary allo-MLR, and decreases IFN-gamma production during secondary allo-MLR and Con A activation, whereas it enhances IL-4 production in both primary and secondary Con A activation. MLR-IA is not neutralized by combination of antibodies specific for transforming growth factor-beta, IL-10, tumor necrosis factor-alpha/beta or IFN-gamma, suggestive of a novel activity. MLR-IA is ammonium sulfate precipitable, sensitive to protease digestion and is destroyed by boiling, indicating that a protein moiety is part of its active structure. Our work suggests that a potentially novel immunoregulatory activity, capable of inhibiting T lymphocyte proliferation and IFN-gamma production, and stimulating IL-4 production, may regulate development of autoimmune diabetes in NOD mice.
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PMID:Biological characteristics of an immunoregulatory activity secreted by an autoreactive CD4+ T cell clone that suppresses autoimmune diabetes in non-obese diabetic mice. 867 56

To establish whether altered proteolysis contributes to the increase in protein content in hypertrophying kidneys, we studied protein turnover in proximal renal tubules isolated from rats with three forms of renal hypertrophy, diabetes mellitus (DM), ammonium chloride-induced acidosis and compensatory renal growth (CRG). We found that in DM and in chronic acidosis the normal balance in protein turnover is altered due to attenuated proteolysis and accelerated protein synthesis. Together this favors an increase in kidney protein content. In contrast, in CRG, the increase in protein content is entirely due to increased protein synthesis. Thus, the changes in protein turnover leading to the net gain in kidney protein content in renal hypertrophy depends on the cause of hypertrophy.
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PMID:Protein turnover in the hypertrophying kidney. 867 9

We have previously shown that diabetes is associated with a decrease in Na(+)-H+ exchange activity in rat cardiac papillary muscle. The present work has been carried out in order to elucidate the factors responsible for such an alteration. Thus, we have studied the effects of pH0 and intracellular Ca2+ on Na(+)-H+ exchange in ventricular myocytes isolated from streptozotocin-induced diabetic rat hearts. pH1 was recorded using carboxy-seminaphthorhodafluor (SNARF-1). The NH4+ (10 mmol/L) prepulse method was used to induce an acid load in order to activate Na(+)-H+ exchange in HEPES-buffered Tyrode's solution. Whereas diabetes did not change intracellular buffering power, it significantly decreased acid efflux through Na(+)-H+ exchange (acid efflux, 4.32 +/- 0.4 [n = 32, normal cells] versus 2.5 +/- 0.2 [n = 43, diabetic cells] meq/L per minute at pHi 6.9; P < .02). Upon changes of pH0 (at a range of 8.0 to 6.8), acid efflux similarly varied in normal and diabetic cells, thus pointing to an unchanged pH0 sensitivity of Na(+)-H+ exchange. Buffering of intracellular Ca2+ by pretreatment of the cells with BAPTA-AM (25 mumol/L Ca2(+)-chelator) resulted in a decrease by approximately 58% of acid efflux in the diabetic group. This decrease was even more marked in normal cells (by approximately 74%). Interestingly, the pH1 dependence of the acid efflux carried by Na(+)-H+ exchange then became identical in both groups of cells, thus pointing to a role for intracellular Ca2+ in the diabetes-related alterations of the exchange. Inhibition of calmodulin (by 1.5 mumol/L calmidazolium) and of Ca2+/calmodulin-dependent protein kinase II (by 2 mumol/L 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazin e [KN-62]) significantly slowed down pH1 recovery in both normal and diabetic cells. However, the effect of KN-62 was significantly lower in diabetic cells (efflux decreased by approximately 17%) compared with normal cells (decrease by 45%). In conclusion, these data, in light of recent observations showing a decreased [Ca2+]i associated with diabetes in isolated ventricular myocytes, suggest that changes in intracellular Ca2+ may play an important role in altering Na(+)-H+ exchange activity in diabetic ventricular myocytes. They also point to diabetes-related alterations in the Ca2+/calmodulin protein kinase II-dependent phosphorylation of Na(+)-H+ exchange.
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PMID:Modulation by pH0 and intracellular Ca2+ of Na(+)-H+ exchange in diabetic rat isolated ventricular myocytes. 901 47

The D variant of the encephalomyocarditis (EMC-D) virus is diabetogenic in mice by infecting and destroying pancreatic beta cells, but the EMC-B and EMC-DV viruses are not diabetogenic. We have presumed that the nondiabetogenicity of EMC-B and EMC-DV is mainly caused by release of some viral inhibitory factors from lymphocytes or phagocytic cells. Mice were infected with EMC-B and their splenocytes were fused with myeloma cells. The splenocyte hybridoma 12D8 releases the viral inhibitory substance (VIS) which is neither immunoglobulin nor interferon. VIS has inhibitory effects against EMC-D in several kinds of cell lines, and against EMC-D, EMC-B, coxsackie B4, reovirus and the vesicular stomatitis virus in the L cell. VIS has a strong preventive effect (100%) against EMC-D induced diabetes in SJL/J mice and DBN/2N mice. In both pre- and post-treatment studies, VIS remarkably decreased the incidence of both illness and death in SJL/J mice infected with the EMC-D virus. VIS, culture supernate itself of hybridoma, had viral inhibitory activities equivalent to 10(6)-10(7) IU/ml of interferon. VIS was very labile to heat (75% loss of activities at 37 degrees C for 18 h), stable only at pH 5-9, and precipitated at 50% (NH4)2SO4 solution. VIS activities existed in supernatant and pellet prepared from ultracentrifugation, but the properties of their activities could be differentiated quantitatively and qualitatively. It is speculated that VIS may be composed of at least two factors even though interferon may partially participate in one component of supernatant. The prevention and treatment effect of VIS on EMC-D infection in SJL/J mice might be due to the inhibition of the virus replication by VIS.
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PMID:Characterization of viral inhibitory substance released from fused splenocyte. 916 27

This paper describes an operationally simple, rapid hydrogenation of unsaturated sterols and bile alcohols in a domestic microwave oven. This has been achieved by the addition of catalytic amounts of Pd/C in methylene chloride/propylene glycol solvents in the presence of ammonium formate followed by microwave irradiation. It is suggested that this methodology will be helpful in the identification of saturated and unsaturated sterols with different side-chain structures in rare diseases: sitosterolemia, cerebrotendinous xanthomatosis (CTX), as well as atherosclerosis and diabetes mellitus. Sterols, such as cholesterol, campesterol, sitosterol, and bile alcohols with unsaturated side chains, were converted to their reduced congeners with high yield and purity.
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PMID:Rapid hydrogenation of unsaturated sterols and bile alcohols using microwaves. 917 33

Renal acid excretion and proximal and distal nephron acidification were evaluated 20 days after induction of diabetes, in rats, by intraperitoneal injection of streptozotocin (45 mg/kg). Titratable acidity in urine was measured by microtitration and ammonium excretion (NH4+) by spectrophotometry. Proximal tubular acidification was evaluated by the kinetics of reabsorption of perfused HCO3-. Distal nephron acidification was evaluated by measuring urine - blood pCO2 differences under alkaline overload. The net acid excretion (titratable acidity + NH4+ - HCO3-) was higher (p < 0.001) in diabetic rats (9.82+/-0.65 micromol/min/kg, n = 26) than in the control group (6.34+/-0.14, n = 24). Proximal HCO3- reabsorption was also higher (p < 0.001) in diabetic rats (8.38+/-0.11 nmol/cm2/s, n = 12) than in the control group (2.30+/-0.10, n = 22); however, evaluation of distal nephron H+ secretion by urine - blood pCO2 methodology was similar in both groups. We concluded that in rats with induced diabetes mellitus there is an increased rate of proximal HCO3- reabsorption, possibly effected by a higher density of Na+/H+ antiporter in the luminal membrane of the proximal tubule and by an increased proton-motive force of the H+ secretory mechanism. The higher rates of H+ secretion generate lower stationary proximal luminal pH and probably maintain the blood pH within the physiological range.
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PMID:Alterations of the renal handling of H+ in diabetic rats. 939 31


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