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 study the mechanism of action of sulfonylurea agents on peripheral tissues without the potentially confounding influences of insulin, the direct effect of glyburide (i.e., in the absence of insulin) was evaluated in the L6 cultured myogenic cell line. Glyburide approximately doubled the incorporation of [14C]-glucose into glycogen. The rate-determining enzymes of glycogen metabolism, glycogen synthase and glycogen phosphorylase, were unaffected by the drug. Glucose transport (2-deoxyglucose uptake) was also approximately doubled. The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) also doubled glucose transport and showed the same lag period (4-6 h) as glyburide before an effect occurred. Blockade of protein kinase C activity by either 1-(5-isoquinolinesulfonyl)-2 methyl piperazine (H7) or chronic exposure to TPA completely abolished the stimulation by glyburide. Cycloheximide, a protein synthesis inhibitor, also completely eliminated the effect of glyburide. The presence of ATP-sensitive K+ channels was assessed by measuring 86Rb efflux in ATP-depleted L6 muscle cells and RINm5F cells (which served as a positive control). Such channels were present and responded appropriately to glyburide and diazoxide in pancreatic beta-cells but were not present in muscle cells. Glyburide stimulation of glucose transport was completely eliminated by both Quin 2, an intracellular chelator of Ca2+, and verapamil, a Ca2+ channel blocker. However, glyburide did not raise intracellular Ca2+ levels. We conclude that glyburide stimulates glucose transport in cultured L6 muscle cells by a protein kinase C-mediated pathway that requires new protein synthesis. Although intracellular Ca2+ metabolism may also be involved, the initial step in the mechanism of action is probably different between pancreatic beta-cells and muscle cells.
Diabetes 1991 Nov
PMID:Glyburide-stimulated glucose transport in cultured muscle cells via protein kinase C-mediated pathway requiring new protein synthesis. 193 11

Hepatic insulin proreceptors and receptors were studied in control and in ketotic diabetic rats 2-4 wk after streptozotocin treatment. Solubilized preparations were partially purified by wheat germ agglutinin-agarose (WGA) and lentil lectin agarose (LLA) chromatography to enrich eluates in insulin receptors and proreceptors, respectively. After phosphorylation with [gamma-32P]ATP, an approximately 190-kDa glycoprotein was identified in LLA eluates as the insulin proreceptor, based on insulin dose-dependent tyrosine autophosphorylation, immunoprecipitation with insulin receptor-specific antibodies, and high-mannose glycosylation. Mature approximately 95 kDa phosphorylated beta-subunits were present in both LLA and WGA eluates. LLA also showed phosphorylated partially processed beta-subunits (approximately 85 kDa) and proreceptors (approximately 190 kDa). Proreceptors comprised less than 1% of the total yield of hepatic insulin receptors. The incorporation of 32P into proreceptors (per gram liver or DNA) was 4.7- or 4.5-fold greater in diabetic vs. control rats, whereas receptor labeling increased only 1.8- or 1.5-fold in diabetic rats. beta-Subunit autophosphorylation per receptor was identical in control and diabetic rats. The phosphorylation data suggested a diabetes-associated 2.6-fold increase in proreceptor-to-receptor ratios. When assessed by cross-linking with 125I-labeled insulin or by immunoblotting, proreceptor-to-receptor ratios were increased 1.5- and 3.1-fold, respectively, in diabetic rats. The data suggest that uncontrolled diabetes may alter insulin receptor processing.
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PMID:Increased hepatic insulin proreceptor-to-receptor ratio in diabetes: a possible processing defect. 195 80

Clustering of cell-surface insulin receptors has led to the speculation that intermolecular phosphorylation of unoccupied receptors catalyzed by ligand-occupied receptors within the cluster could be a mechanism by which the insulin-binding signal is amplified. We examined whether insulin receptors can be phosphorylated by an intermolecular mechanism. In this study, we used highly purified insulin receptors isolated from rat liver plasma membranes and human placental membranes. Rat liver insulin receptors were "activated" by incubation with 10 nM insulin in the presence of ATP. Subsequent to removal of insulin by immunodepletion, these receptors were used as an enzyme source to study phosphorylation of unphosphorylated "substrate" human receptors. Initially, we found no evidence that the addition of activated rat receptors increased phosphorylation of human receptors, when assessed by immunoprecipitation with a human-specific monoclonal antibody. To examine the possibility that these negative results were due to insufficient receptor concentration, activated human receptors were mixed with unphosphorylated substrate receptors at concentrations up to 60 micrograms/ml. In this study, we found that addition of activated receptors resulted in increased phosphorylation of the substrate receptors at the highest concentrations employed. These are the first data indicating that insulin receptors per se are capable of intermolecular phosphorylation. In vivo, this could be the initial step in amplifying the insulin-binding signal.
Diabetes 1991 Feb
PMID:Intermolecular phosphorylation of insulin receptor as possible mechanism for amplification of binding signal. 199 77

The nature of insulin degradation within endosomes was studied in vitro. Radiolabeled insulin was perfused into rat liver via the portal vein, and insulin-containing endosomes were prepared by differential centrifugation. The endosomes were incubated in various buffers, and hormone degradation was monitored by Sephadex G-50 chromatography and high-performance liquid chromatography (HPLC). Endosomes incubated in simple imidazole or HEPES (pH 7.4) buffers rapidly degraded insulin to intermediate- and then to low-molecular-weight products that were lost from the vesicles. HPLC analysis of insulin-sized material showed the products to be the same as those produced by intact cells. The endosomes did not acidify in these buffers (as assessed by the acridine orange method), and ATP had no effects. When the endosomes were incubated in a chloride-containing buffer, degradation was greatly inhibited, and acidification did not occur. Both insulin degradation and acidification were activated when Mg-ATP was added to this buffer system. HPLC analysis of the products generated in this system revealed not only typical cellular products but additional less hydrophobic products. Western-blot analysis of endosomal protein with anti-insulin-degrading enzyme antibody showed this enzyme to be present. In conclusion, isolated endosomes rapidly and completely degrade insulin through products that are typical of cellular degradation without requiring acidification. Chloride-containing buffers inhibit endosomal degradation, which is reversed by Mg-ATP, but this system does not mimic cellular degradation. At least one of the enzymes responsible for insulin degradation is insulin-degrading enzyme.
Diabetes 1991 Apr
PMID:Degradation of intraendosomal insulin by insulin-degrading enzyme without acidification. 201 43

AMP deaminase from normal and diabetic rat hearts was separated on cellulose phosphate and quantitated by HPLC. From soluble fractions three different AMP deaminase activities, according to KCl elution from cellulose phosphate and percent of total activity were: 170 mM (85%), 250 mM (8%) and 330 mM (7%) KCl. The AMP deaminase activity which eluted with 170 mM KCl was resolved to two distinct peaks by HPLC anionic exchange. After 4 weeks of diabetes the heart enzyme profile change to: 170 mM (10%), 250 mM (75%) and 330 mM (15%). Once purified the four activities were kinetically distinct: 170 mM KCl cytosolic, AMP Km = 1.78, stimulated by ATP, GTP, NADP and strongly inhibited by NAD; 170 mM KCl mitochondria AMP Km = 17.9, stimulated by ATP, ADP; 250 mM KCl isozyme, AMP Km = 0.66, stimulated by ADP; and 330 mM KCl isozyme, AMP Km = 0.97, inhibited by ATP, NAD(P).
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PMID:Changes in AMP deaminase activities in the hearts of diabetic rats. 202 37

1. The effects of insulin treatment on in vivo and in vitro urinary bladder function in streptozotocin-diabetic rats were investigated. 2. Diabetes of 2 months duration resulted in decreases in body weight and increases in fluid consumption, urine volume, frequency of micturition, and average volume per micturition; effects which were prevented by insulin treatment. 3. Insulin treatment also prevented the increases in contractile responses of bladder body strips from diabetic rats to nerve stimulation, ATP, and bethanechol. 4. Diabetes of 4 months duration also resulted in decreases in body weight, and increases in fluid consumption, urine volume, frequency of micturition, and average volume per micturition, effects which were reversed by insulin treatment for the final 2 months of the study. 5. Insulin treatment reversed the increases in contractile responses of bladder body strips from diabetic rats to nerve stimulation, ATP, and bethanechol. 6. The data indicate that the effects of streptozotocin-induced diabetes on urinary bladder function are both prevented and reversed by insulin treatment.
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PMID:The ability of insulin treatment to reverse or prevent the changes in urinary bladder function caused by streptozotocin-induced diabetes mellitus. 205 25

Linogliride is a nonsulfonylurea drug that lowers blood glucose levels in nondiabetic and diabetic humans and animals. Linogliride also stimulates insulin release in vitro. In the perfused pancreas, pretreatment with tolbutamide desensitizes beta-cells to the action of linogliride. We tested the hypothesis that linogliride, like tolbutamide, affects the activity of ATP-sensitive K+ channels, which are thought to control insulin release. We used the whole-cell voltage-clamping technique to measure the K+ current through ATP-sensitive K+ channels in the plasma membrane of single rat beta-cells, which were dialyzed with 30 microM ATP. Linogliride (10-300 microM) inhibited the K+ current; half-maximal inhibition was observed at 6-25 microM, depending on how much time was allowed for equilibration of the drug. Reversal of the inhibition was slow (t1/2 approximately 4 min). In summary, linogliride leads to a decrease in the activity of ATP-sensitive K+ channels.
Diabetes 1991 Jul
PMID:Inhibition of ATP-sensitive K+ channels in pancreatic beta-cells by nonsulfonylurea drug linogliride. 206 Jul 25

The triad of insulin, diet and exercise has been the basis for treatment of diabetes for several decades. However, the choice of sporting activities for young diabetics requires an understanding of: a) the energy metabolism and the adaptation to physical activity in the healthy; b) the metabolic adaptation during physical activity in the diabetic child; and c) the practical recommendations concerning diet and insulin that have to be learned by the children themselves. The healthy child utilises immediately available substrates, such as ATP and creatine phosphate in much the same fashion as the adult. However, the capacity for anaerobic degradation of glycogen and glucose seems limited in the muscles of children relative to that of adults. Consequently, the adaptation to resistance exercise should be undertaken with prudence in children and adolescents. The release of insulin tends to decrease during effort. Diverse hypotheses have been proposed to explain this phenomenon. However a low concentration of insulin is required: insulin is said to play a "permissive" role. In diabetic children, an adequate insulin therapy is required to allow the full benefit of muscular activity on glucose assimilation and to reach the same level of physical performance as the non-diabetic. In the case of insufficient metabolic control, exercise can provoke severe hypoglycaemic episodes, even after muscle activity has ceased, or increase glucose levels and lead to ketoacidosis. Regular physical training induces a reduction in postexercise proteinuria measured in diabetic adolescents but its role in metabolic control remains controversial.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Sports and diabetes in children and adolescents]. 206 55

Erythrocyte membranes drawn from diabetic patients with poor metabolic control have increased protein glycosylation and decreased Ca2(+)-ATPase activity. A significant relationship was found between these two parameters. Similar results were obtained when protein glycosylation and Ca2(+)-ATPase activity were measured in membranes from normal erythrocytes preincubated with glucose. In this condition, both parameters showed a clear time and dose dependence. Incubation of erythrocyte membranes instead of intact erythrocytes with glucose and glucose-6-phosphate strongly suggests that only the glycosylation of the membrane inner-surface proteins can affect Ca2(+)-ATPase activity. The simultaneous presence of 10 mM glucose and 5 mM ATP in the incubation medium did not affect the degree of erythrocyte membrane protein glycosylation but significantly blocked the inhibitory effect of glucose on Ca2(+)-ATPase activity. However, 5 mM ATP only partially blocked the inhibitory effect of 100 mM glucose, suggesting a competitive mechanism of glucose and ATP for the enzyme active site. Our results show that glycosylation of erythrocyte membrane proteins significantly inhibits Ca2(+)-ATPase activity. This effect could contribute to the development of the capillary closure process observed in diabetic patients. Furthermore, it could represent an index of a general impairment of enzyme function arising in cells chronically exposed to high glucose levels.
Diabetes 1990 Jun
PMID:Decreased Ca2(+)-ATPase activity after glycosylation of erythrocyte membranes in vivo and in vitro. 214 Aug 3

Phosphatidylethanolamine N-methylation was examined in cardiac subcellular membranes after inducing chronic experimental diabetes in rats (65 mg streptozotocin/kg, i.v.). The incorporation of radiolabeled methyl groups from S-adenosyl-L-methionine in diabetic sarcolemma was significantly depressed at all three catalytic sites (I, II, and III) of the methyltransferase system. An increase in methyl group incorporation was evident at site I without any changes at sites II and III in diabetic sarcoplasmic reticulum and mitochondria. Similar changes were also seen for the individual N-methylated lipids (monomethyl-, dimethylphosphatidylethanolamine, and phosphatidylcholine) specifically formed at each catalytic site in all cardiac membranes from diabetic animals. These alterations in N-methylation were reversible by a 14-d insulin therapy to the diabetic animals. In the presence of 10 microM ATP and 0.1 microM Ca2+, N-methylation was maximally activated at site I in both control and diabetic sarcolemma and sarcoplasmic reticulum, but not in mitochondria. Incubation of cardiac membranes with of S-adenosyl-L-methionine showed that Ca2(+)-stimulated ATPase activities in both sarcolemma and sarcoplasmic reticulum were augmented; however, the activation of diabetic sarcolemma was lesser and that of diabetic sarcoplasmic reticulum was greater in comparison with the control preparations. These results identify alterations in phosphatidylethanolamine N-methylation in subcellular membranes from diabetic heart, and it is suggested that these defects may be crucial in the development of cardiac dysfunction in chronic diabetes.
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PMID:Alterations in phospholipid N-methylation of cardiac subcellular membranes due to experimentally induced diabetes in rats. 214 1


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