Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Six weeks after induction of diabetes, the rate of ouabain-sensitive 86Rb+ accumulation, a parameter which reflects Na+ + K+-ATPase pumping activity, was significantly reduced in endoneurial preparations of sciatic nerve from untreated diabetic rats compared with that in control rats (Trial, 1, 0.19 +/- 0.09 versus 0.48 +/- 0.13 pmol/min per mg wet weight of tissue, p less than 0.001; Trial 2, 0.27 +/- 0.16 versus 0.47 +/- 0.18, p less than 0.01). This decrease in ouabain-sensitive 86Rb+ uptake was not observed in nerves from diabetic rats maintained on sorbinil (an aldose reductase inhibitor) or myo-inositol diets. Protein kinase C activity was demonstrated in the soluble fraction of a sciatic nerve homogenate by assaying for lipid-activated, Ca+-dependent phosphorylation of calf thymus histone. No significant difference in the time course of kinase C activity was observed between cytosol fractions of nerve homogenates from control and diabetic rats (control, 6.22 +/- 0.97 pmol 32P incorporated/mg cytosol protein in 50 min; diabetic, 5.32 +/- 0.71). Three low molecular weight neural proteins (each with Mr less than 29,000) were identified as substrates for protein kinase C.
 ...
PMID:Reduced Na+ + K+-ATPase activity in peripheral nerve of streptozotocin-diabetic rats: a role for protein kinase C? 284 Mar 14

The effect of diabetes on the structure and function of insulin receptors was studied in rats 7 d after streptozotocin injection, using solubilized, partially purified receptors from rat hindlimb muscles. Diabetes increased the number of insulin receptors per gram of muscle 60-70% without apparent change in insulin binding affinity. Incubation of receptors at 4 degrees C with [gamma-32P]ATP and insulin resulted in dose-dependent autophosphorylation of the beta-subunit on tyrosine residues; receptors from diabetic rats showed decreased base-line phosphorylation, as well as a decrease in autophosphorylation at maximally stimulating insulin concentrations. These receptors also showed diminished exogenous substrate kinase activity using histone H2b and angiotensin II as phosphoacceptors. The electrophoretic mobility (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) of a subpopulation of beta-subunits derived from diabetics was slightly decreased; differences in electrophoretic mobility between control- and diabetic-derived beta-subunits were enhanced by generating fragments by partial Staphylococcus aureus V8 protease digestion. Endoglycosidase-H or neuraminidase treatment increased the electrophoretic mobility of beta-subunits in both groups, but only neuraminidase appeared to decrease or abolish differences in electrophoretic mobility between controls and diabetics, suggesting that excess sialilation may account, in part, for the altered mobility of diabetic derived beta-subunits. All structural and functional alterations in insulin receptors were prevented by treating diabetic rats with insulin for 60 h. Peripheral insulin resistance associated with insulinopenic diabetes may be related to modifications in insulin receptor structure, resulting in impaired signal transmission.
 ...
PMID:Diabetes-induced functional and structural changes in insulin receptors from rat skeletal muscle. 300 51

Protamines are cationic fish chromosomal proteins that retard absorption of isophane (NPH) insulins. Protamines are also administered in large doses for heparin neutralization in cardiac procedures. This study used a rapid enzyme-linked immunosorbent assay to examine frequency of protamine antibodies in diabetic and control populations. Antigen specificity of the IgG binding to protamine-coated plates was verified by competitive inhibition with other protamines, histone, glucagon, thyroid-stimulating hormone, arginine, and lysine. All antibodies tested cross-reacted completely with all protamines. Only 4 of 18 had any cross-reactivity with histones. None cross-reacted with the other inhibitors. In population surveys, 122 (38%) of 319 NPH insulin-treated diabetic subjects, 3 (8%) of 39 diabetic subjects treated with protamine-free lente insulins, and 5 (2.5%) of 202 normal control subjects had protamine antibody. No correlation was found between insulin and protamine antibodies. Because more than one-third of insulin-treated diabetic subjects have circulating IgG specific for protamine, they are potentially at risk for acute immunologic or anaphylactoid reactions when protamine is administered for heparin neutralization.
Diabetes 1988 Feb
PMID:Frequency and specificity of protamine antibodies in diabetic and control subjects. 329 13

The substrate specificities of calcium/phospholipid-dependent kinase-C (PKC) were examined in rat kidney cortex, and localization of the protein was studied after the induction of diabetes. The cytosolic kinase was eluted from an anion exchange resin using a linear gradient of 0-0.15 M NaCl. A sharp peak of activity was demonstrated at approximately 80 mM using histone as a substrate. The kinase demonstrated a broad pH optimum of 6.5-8.0. ATP was the preferred phosphorus donor. The Ka for ATP averaged 2.6 +/- 0.1 microM (n = 4) and was not different in diabetic animals. Lysine-rich histones, but not arginine-rich or mixed histones, were the most suitable phosphorus acceptors. Phosphatidylserine stimulated kinase activity with Ka of 4.5 +/- 0.7 microM in the presence of 20 microM diolein (n = 3). Twenty micromolar diolein in the presence of 25 microM phosphatidylserine lowered the apparent Ka for calcium from 17.2 +/- 1.4 to 3.3 +/- 1.5 microM (n = 3; P less than 0.01). Similar data were evident in diabetic animals. Diabetic renal growth was induced by the injection of streptozotocin (35 mg/kg, iv). At the end of 4 weeks, blood glucose averaged 119.6 +/- 7.4 mg/dl in vehicle-injected controls and 548.7 +/- 21.6 mg/dl in diabetic animals (n = 5; P less than 0.001). Despite reduced weight gains in diabetic animals, renal protein content was increased in this group compared to the control value. Neither cytosolic nor proximal tubule basolateral membrane PKC activity changed after the induction of diabetes; however, luminal brush border PKC activity increased from 83.8 +/- 4.6 pmol/mg.min in control animals to 107.3 +/- 55 pmol/mg.min in diabetic animals (n = 5; P less than 0.02). The increased activity in the brush border membrane may have important consequences for the growth response of the kidney in diabetes.
 ...
PMID:Characterization and localization of calcium/phospholipid-dependent protein kinase-C during diabetic renal growth. 340 97

Highly purified insulin receptor was shown to be a substrate for cAMP kinase. Approximately 1 phosphate was incorporated per molecule of receptor, and the cAMP kinase's affinity for the receptor was at least as high as its affinity for histone. The sites phosphorylated by cAMP kinase seemed distinct from those phosphorylated by the protein kinase C. Phosphorylation by cAMP kinase had no effect on the ability of several monoclonal antibodies to recognize the receptor or on the insulin-binding activity of the receptor. However, cAMP phosphorylation partially inhibited the tyrosine kinase activity of the receptor (approximately 25%). These results suggest that catecholamine-induced resistance to insulin may be partly due to a direct phosphorylation of the receptor by cAMP kinase and a subsequent inhibition of the ability of the receptor kinase to be activated by insulin.
Diabetes 1987 Jan
PMID:Phosphorylation of purified insulin receptor by cAMP kinase. 353 74

The effect of heparin, a polyanionic glycosaminoglycan known to alter the function of many proteins, on insulin binding and bioactivity was studied. Cultured human lymphocytes (IM-9) were incubated with varying concentrations of heparin, then extensively washed, and 125I-labeled insulin binding was measured. Heparin at concentrations used clinically for anticoagulation (1-50 U/ml) inhibited binding in a dose-dependent manner; 50% inhibition of binding occurred with 5-10 U/ml. Scatchard analysis indicated that the decrease in binding was due to a decrease in both the affinity and the apparent number of available insulin receptors. The effect occurred within 10 min at 22 degrees C and persisted even after the cells were extensively washed. Inhibition of insulin binding also occurred when cells were preincubated with heparinized plasma or heparinized serum but not when cells were incubated with normal serum or plasma from blood anticoagulated with EDTA. By contrast, other polyanions and polycations, e.g., poly-L-glutamic acid, poly-L-lysine, succinylated poly-L-lysine, and histone, did not inhibit binding. Heparin also inhibited insulin binding in Epstein-Barr (EB) virus-transformed lymphocytes but had no effect on insulin binding to isolated adipocytes, human erythrocytes, or intact hepatoma cells. When isolated adipocytes were incubated with heparin, there was a dose-dependent inhibition of insulin-stimulated glucose oxidation and, to a lesser extent, of basal glucose oxidation. Although heparin has no effect on insulin binding to intact hepatoma cells, heparin inhibited both insulin binding and insulin-stimulated autophosphorylation in receptors solubilized from these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1987 Feb
PMID:Effects of heparin on insulin binding and biological activity. 354 43

Cellular signaling by insulin is initiated by specific membrane receptors that have been characterized as large multimeric disulfide-linked protein complexes with a minimal subunit structure of (beta-S-S-alpha)-S-S-(alpha-S-S-beta), where the alpha- and beta-subunits are about 125,000 and 90,000 daltons, respectively. The disulfides in this structure are of two classes based on their differential sensitivity to reductants (Massague, J., and Czech, M. P., J. Biol. Chem. 1982; 257:6729-35). An important recent discovery is that the insulin receptor, either in crude detergent extracts or after purification by affinity chromatography, is associated with insulin-activatable tyrosine phosphokinase activity and is itself autophosphorylated (Kasuga, M., et al., Proc. Natl. Acad. Sci. USA 1983; 80:2137-41). We demonstrate here that insulin receptor kinase activity is readily monitored while the receptor is absorbed onto insulin-agarose, using [gamma-32]ATP and histone as substrate. Phosphorylation of histone and the receptor beta-subunit on tyrosine residues is dependent on time, temperature, and Mn2+ in this system. The immobilized insulin receptor kinase is activated by prior phosphorylation with ATP, indicating that the autophosphorylation plays an important role in regulating receptor kinase activity. That the insulin receptor tyrosine kinase activity may be involved in initiating the mechanism of insulin action is currently an attractive hypothesis. A second working model of insulin action proposes that one or more soluble factors are released into the cell in response to insulin as suggested by studies using muscle and fat cell extracts.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes Care
PMID:Cellular signaling by the insulin receptor. 637 32

Circulating insulin-like growth factor I (IGF-I) concentrations are known to be reduced in experimental and clinical diabetes mellitus. The IGF-I mRNA content was measured in several tissues of rats treated with streptozotocin to determine whether a correlation with neuropathy could be found. IGF-I mRNA content was sharply reduced relative to total and poly(A)+ RNA in diabetic liver and adrenal glands. In contrast, histone 3.3 mRNA content was not significantly reduced relative to poly(A)+ RNA in liver, and alpha-tubulin mRNA content instead was increased in adrenal glands, showing that the decline in IGF-I mRNAs in these tissues was selective. In addition, spinal cord IGF-I mRNA content was significantly reduced per tissue, total RNA, and poly(A)+ RNA after 1 and 2 weeks of diabetes. This was correlated with a concurrent and significant decrease in conduction velocity in both spinal cord and peripheral nerves in a separate study. The decline in liver and spinal cord IGF-I mRNA was not due to streptozotocin toxicity, because it was significantly opposed by insulin which was continuously infused beginning the day after diabetes induction. These results, when taken together with those of others, indicate that the reduction in IGF-I mRNA content may be widespread among diabetic tissues, and might contribute in part to certain syndromes of diabetes, such as neuropathy.
 ...
PMID:Reduced insulin-like growth factor-I mRNA content in liver, adrenal glands and spinal cord of diabetic rats. 753 99

In a recent report we have demonstrated the in vitro formation of advanced glycation end products (AGEs) on histones in a time and sugar concentration dependent fashion. In the present work we examined histone advanced glycation in vivo. Diabetes was induced in rats by streptozotocin injection and the hyperglycemic state was maintained and surveyed for up to 24 weeks. Diabetic rats showed accumulation of early glycation products in plasma proteins and in hemoglobin. Histones from the liver of diabetic rats showed AGEs levels three-fold higher than those of their age-matched controls. Histone AGEs increased with the duration of diabetes and tended to increase with the age as well. Similar tendencies were apparent in skin collagen. Our data demonstrate that diabetes induces an increase in the accumulation of AGE products on histones. This reinforces the concept that advanced glycation occurs in intracellular proteins and suggests a possible role for intracellular glycation in the increased theratogeny associated with diabetes mellitus.
 ...
PMID:Histones from diabetic rats contain increased levels of advanced glycation end products. 761 18

Diabetic neuropathy is a common and disabling complication of diabetes mellitus whose pathogenesis remains unknown. Insulin-like growth factors (IGFs) have been recently implicated in the development and maintenance of the peripheral nervous system, and circulating IGF levels are decreased in experimental and clinical diabetes. Therefore, we tested the hypothesis that IGF gene expression is reduced in peripheral nerves early after the onset of diabetes. Sciatic nerves from nondiabetic and streptozotocin-treated rats were removed 5-7 days after the induction of diabetes. RNA was isolated and analyzed by Northern and slot blots. IGF-I mRNA content was significantly decreased per milligram wet weight nerve (P < 0.025) as well as per poly(A)+ RNA (P < 0.01) in diabetic vs nondiabetic nerves. Likewise, the amount of IGF-II mRNA was significantly decreased per milligram wet weight nerve (P < 0.01) as well as per poly(A)+ RNA (P < 0.005). These effects were selective because histone 3.3 mRNA content, as well as poly(A)+ mRNA content, per milligram nerve were unchanged. Insulin treatment partially prevented this decline in IGF-I and IGF-II mRNA levels. The diminished IGF mRNA content is one of the earliest biochemical abnormalities to be observed in the diabetic nerve, supporting the hypothesis that a reduction in IGF activity in diabetic nerves precedes and contributes to the development of neuropathy.
 ...
PMID:Early reduction in insulin-like growth factor gene expression in diabetic nerve. 782 85


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>