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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The actions of insulin are mediated by an integral plasma membrane protein, the insulin receptor. The processed receptor is a tetramer composed of two alpha-subunits that bind insulin and two beta-subunits that traverse the plasma membrane and are, in their cytosolic domains, protein tyrosine kinases. The insulin proreceptor cDNA has been cloned and its complete amino acid sequence deduced. The availability of cDNA permitted an analysis of both the role of protein tyrosine kinase activity in insulin action and the autophosphorylation sites that regulate kinase activity. The human cDNA probe has also been used to identify a putative Drosophila insulin receptor. This work is reviewed, and approaches that may be used to identify physiological substrates for the receptor kinase are suggested.
Diabetes 1989 Dec
PMID:Banting lecture 1989. Structure and function of insulin receptors. 255 39

To clarify the significance of insulin autoantibodies (IAA) in insulin-dependent diabetes mellitus, we measured the IAA longitudinally in non-obese diabetic (NOD) mice, and in high-dose streptozotocin-induced diabetes (high-SZ) and EMC virus-induced diabetes (EMC) in mice, and compared the data with the occurrence of insulitis. The IAA were detected by the polyethylene glycol (PEG) method using 125I-(Tyr A14) human insulin. The IAA were found in 38% of NOD mice and correlated with the occurrence of insulitis. The prevalence of IAA was 0% before the appearance of insulitis, 80% at 12-14 weeks of age and 30% after 20 weeks of age in female NOD mice. In male NOD mice, IAA were found in 45% at 12-14 weeks of age and 20% after 20 weeks. In high-SZ mice, IAA were detected in several mice while insulitis was not present. In EMC-virus induced diabetic mice, IAA and lymphocytic infiltration into the islets were detected 4-14 days after EMC virus infection. These results suggest that (a) IAA are markers for islet autoimmunity in NOD mice, (b) the presence of IAA does not always reflect insulitis, (c) the presence of IAA is not sufficient for the development of overt diabetes and (d) the appearance of IAA may reflect a difference of the immune response genotype.
Diabetes Res 1989 Jun
PMID:Insulin autoantibodies in mouse models of insulin-dependent diabetes. 262 Apr 86

In order to examine the effects of streptozotocin-induced diabetes, dietary protein, and starvation on protein degradation in skeletal muscle of perfused rat hindquarters, rates of myofibrillar and total protein degradation were estimated from the release of 3-methylhistidine (N tau-methylhistidine, 3-MH) and tyrosine, respectively. In rats fed a 20% protein diet (controls), the fractional degradation rate of myofibrillar protein was approximately 56% of the total muscle protein. In streptozotocin-induced diabetic rats, 3-MH release by perfused muscle increased significantly on d 1 of treatment and sustained a high level thereafter. By contrast, tyrosine release did not change. Feeding a 50% protein diet for 1 wk altered neither 3-MH nor tyrosine release. Protein-free feeding, though, suppressed tyrosine release to 49% of controls, but did not affect 3-MH release. Starvation for 3 d did not affect tyrosine release, but did increase 3-MH release to 203% of controls. These results indicate that in diabetic and starved rats myofibrillar protein is preferentially degraded, while in protein-deficient rats, non-myofibrillar protein degradation is selectively suppressed. From these observations, we conclude that the degradation of myofibrillar and non-myofibrillar proteins in skeletal muscle can be differentially regulated.
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PMID:Differential regulation of the degradation of myofibrillar and total proteins in skeletal muscle of rats: effects of streptozotocin-induced diabetes, dietary protein and starvation. 264 2

The degradation of intracellular protein and other cytoplasmic macromolecules in liver is an ongoing process that regulates cytoplasmic mass and provides amino acids for energy and other metabolic uses early in starvation. Cellular proteins are conveniently divided into two general classes according to readily discernable differences in average rates of turnover. A short-lived class, having a half-life of approximately 10 min, comprises about 0.6% of total protein. Its degradation is not physiologically controlled, and the mechanism is probably nonlysosomal in nature. The second or long-lived group, with an average half-life 250 times greater, constitutes more than 99% of the cell's protein. By contrast, its breakdown is strongly regulated, and the site of catabolism is believed to be the vacuolar-lysosomal system. Cytoplasmic sequestration by lysosomes can be divided into two categories; macro- and microautophagy. The first is induced by amino acid and/or insulin deprivation. Amino acids are considered to be primary regulators, since they can control this process over the full range of induced proteolysis in the absence of hormones. Glucagon, cyclic AMP, and beta-agonists also stimulate macroautophagy in hepatocytes but have opposite effects in myocytes. Micrautophagy differs from the former in that the cytoplasmic "bite" is smaller and the uptake process is not acutely regulated. However, the latter does decrease during starvation in parallel with basal proteolysis, effects that might be linked to the loss of endoplasmic reticulum. The primary control of macroautophagy is accomplished through a small group of direct regulators (Leu, Tyr/Phe, Gln, Pro, Met, His, and Trp) and a specific coregulatory action of alanine. As a group, regulatory amino acids produce direct inhibitory responses in the perfused rat liver that are identical to those of the complete amino acid mixture at 0.5x and 4x (times) normal plasma concentrations. However, they lose effectiveness almost completely within a narrow zone centered at normal levels, a loss that can be abolished by the addition of alanine at its normal plasma concentration (0.5 mM). At this level, alanine does not inhibit directly. Interestingly, this zonal loss is also eliminated by insulin. Glucagon, though, specifically blocks the initial inhibition evoked by 0.5x amino acid mixtures and thus induces maximal rates of protein degradation at normal amino acid concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)
Diabetes Metab Rev 1989 Feb
PMID:Mechanism and regulation of protein degradation in liver. 264 36

To overcome the difficulties encountered in quantifying the insulin receptor number by Scatchard analysis, a radioimmunoassay (RIA) for the human insulin receptor (hIR) has been developed that uses an antibody raised against a synthetic peptide (Gly-Lys-Lys-Asn-Gly-Arg-Ile-Leu-Thr-Leu-Pro-Arg-Ser-Asn-Pro-Ser) corresponding to the carboxyl terminal of the hIR. A second peptide (Tyr-Gly-Arg-Ile-Leu-Thr-Leu-Pro-Arg-Ser-Asn-Pro-Ser) was used as a standard and allowed preparation of monoiodinated derivative of theoretical specific activity for use as the radioactive ligand. The assay is specific, highly reproducible, and sensitive, with a detection limit of 10 fmol of receptor. One mole of purified receptor, measured by Scatchard analysis or amino acid analysis, is read as one mole of receptor in the RIA with peptide being the standard. The assay is effective with receptor from multiple sources and could determine the decrease in number of insulin receptors seen in IM-9 lymphocytes after treatment with insulin (downregulation).
Diabetes 1989 Aug
PMID:Peptide-based radioimmunoassay for insulin receptor. Detection of insulin-stimulated downregulation in IM-9 lymphocytes. 266 3

Skeletal muscle proteolysis was studied in rats 1 day after induction of diabetes with 65 mg/kg streptozocin. An evisceration procedure, including functional hepatectomy-nephrectomy, was performed, and the rate of proteolysis in the remaining tissues, primarily skeletal muscles, was evaluated over 2 h. With cycloheximide to block protein synthesis, total protein breakdown was measured from the rate of rise in plasma tyrosine concentration. The rate of degradation of contractile (myofibrillar) protein was estimated from the rate of rise in plasma concentration of 3-methylhistidine released from the breakdown of actomyosin. Compared with nondiabetic control preparations, the total protein degradation rate was increased 30% by diabetes (P less than .001), and myofibrillar catabolism was accelerated by 60% (P less than .005). In diabetes, the increase in proteolysis was accompanied by reductions in circulating insulin to 25-50% of normal level, whereas food intake did not differ from control. Treatment of diabetic rats with exogenous insulin, including acute infusions postoperatively, completely reversed the proteolytic effects of diabetes. The findings demonstrate that the hypoinsulinemia of acute diabetes increases the catabolism of skeletal muscle protein and that the inhibitory effect of normal levels of insulin includes a specific action to restrain myofibrillar proteolysis.
Diabetes 1989 Sep
PMID:Skeletal muscle proteolysis in rats with acute streptozocin-induced diabetes. 267 Jun 42

The aromatic 1H NMR resonances of the insulin monomer are assigned at 500 MHz by comparative studies of chemically modified and genetically altered variants, including a mutant insulin (PheB25----Leu) associated with diabetes mellitus. The two histidines, three phenylalanines, and four tyrosines are observed to be in distinct local environments; their assignment provides sensitive markers for studies of tertiary structure, protein dynamics, and protein folding. The environments of the tyrosine residues have also been investigated by photochemically induced dynamic nuclear polarization (photo-CIDNP) and analyzed in relation to packing constraints in the crystal structures of insulin. Dimerization involving specific B-chain interactions is observed with increasing protein concentration and is shown to depend on temperature, pH, and solvent composition. In the monomer large variations are observed in the line widths of amide resonances, suggesting intermediate exchange among conformational substates; such substates may relate to conformational changes observed in different crystal states and proposed to occur in the hormone-receptor complex. Additional evidence for multiple conformations in solution is provided by comparative studies of an insulin analogue containing a peptide bond between residues B29 and A1 (mini-proinsulin). This analogue forms dimers and higher-order oligomers under conditions in which native insulin is monomeric, suggesting that the B29-A1 peptide bond stabilizes a conformational substate favorable for dimerization. Such stabilization is not observed in corresponding studies of native proinsulin, in which a 35-residue connecting peptide joins residues B30 and A1; this extended tether is presumably too flexible to constrain the conformation of the B-chain. The differences between proinsulin and mini-proinsulin suggest a structural mechanism for the observation that the fully reduced B29-A1 analogue folds more efficiently than proinsulin to form the correct pattern of disulfide bonds. These results are discussed in relation to molecular mechanics calculations of insulin based on the available crystal structures.
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PMID:Two-dimensional NMR and photo-CIDNP studies of the insulin monomer: assignment of aromatic resonances with application to protein folding, structure, and dynamics. 269 17

The insulin receptor purified from skeletal muscle of patients with non-insulin-dependent diabetes mellitus (NIDDM) displayed a 25-55% reduction in insulin-stimulated autophosphorylation and tyrosyl-specific phosphotransferase activity relative to controls. This decrease was not explained by alterations of muscle fiber composition, insulin binding affinity or capacity, or the Km values for ATP; the lower kinase activity was entirely attributed to a decrease in the Vmax of the enzyme. Phosphorylation sites in the beta-subunit of the control and diabetic receptor were identified by tryptic digestion and reverse-phase high performance liquid chromatography. Autophosphorylation occurred primarily in two regions of the beta-subunit: the regulatory region containing Tyr-1146, Tyr-1150, and Tyr-1151, and the C terminus containing Tyr-1316 and 1322. Autophosphorylation of the regulatory region at all three tyrosyl residues (tris-phosphorylation) appears to be necessary to activate the receptor kinase (White, M. F., Shoelson, S. E., Stepman, E. W., Keutmann, H. & Kahn, C. R. (1988) J. Biol. Chem. 263, 2969-2980). The receptor from NIDDM patients showed a decreased level of tris-phosphorylation of the regulatory region which was closely associated (r2 = 0.97) with the decreased kinase activity. In contrast, weak associations were found between kinase activity and the bis-phosphorylated forms of the regulatory region (r2 = 0.51) and the C terminus (r2 = 0.35). Therefore, the reduced formation of the tris-phosphorylated regulatory region in the diabetic receptors suggests that a defective autophosphorylation cascade leading to tris-phosphorylation of the regulatory region may cause, in part, the reduced insulin-stimulated kinase activity of the insulin receptor in muscle of NIDDM patients.
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PMID:A defective intramolecular autoactivation cascade may cause the reduced kinase activity of the skeletal muscle insulin receptor from patients with non-insulin-dependent diabetes mellitus. 272 45

The insulin receptor contains in its beta-subunit a tyrosine (-) specific protein kinase. It is believed that transmission of an insulin signal across the plasma membrane of target cells of insulin action occurs through activation of this kinase, autophosphorylation of the insulin receptor beta-subunit and subsequent phosphorylation of other cellular substrates. We studied the insulin receptor kinase in a number of insulin resistant cell systems in order to elucidate if defects of this kinase are a possible cause of cellular insulin resistance. Three different patterns of kinase abnormalities were found, in different insulin resistant cells: 1. In an insulin resistance melanoma cell line a reduced receptor kinase autophosphorylation was found apparently due to a defect of the tyrosine autophosphorylation sites of this receptor; 2. Catecholamine and phorbol ester induced insulin resistance of isolated rat fat cells as well as human fat cells was associated with a decreased activity of the insulin receptor tyrosine kinase which was apparently due to a modulation of the ATP binding site of the insulin receptor tyrosine kinase; 3. The receptor kinase isolated from the skeletal muscle of diabetic Zucker rats (fa/fa) was found to be insulin insensitive with no major alteration of maximal responsiveness. These results suggested that different forms of kinase defects exist which can contribute to the pathogenesis of cellular insulin resistance. Based on these data studies in skeletal muscle from type II diabetic patients were started. Results from five patients so far suggest that, here as well, an abnormality of the insulin receptor kinase exists which might be involved in the pathogenesis of insulin resistance in type II diabetes.
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PMID:Insulin receptor kinase defects as a possible cause of cellular insulin resistance. 282 Aug 11

Using the insulin-glucose clamp technique, we have previously shown that an increased sensitivity to insulin in vivo is a characteristic of the liver in rats with non-insulin-dependent diabetes induced by neonatal streptozotocin administration. We have thus studied the properties of liver insulin receptor in that model. 125I-porcine insulin binding was found normal both in isolated plasma membranes and in solubilized, wheat germ agglutinin purified receptors prepared from livers of rats with non-insulin-dependent diabetes, when compared to controls. Basal and insulin-stimulated insulin receptor kinase activities were also found normal for both the autophosphorylation of the beta subunit of the insulin receptor and the phosphorylation of the artificial substrate poly (Glu-Tyr) 4:1. Thus, in that model of chronic insulin deficiency and mild hyperglycemia: 1) liver insulin receptors are not up-regulated; 2) tyrosine kinase activity remains unaffected. This last observation supports the hypothesis that the increased insulin effect in the liver of rats with non-insulin-dependent diabetes is probably distal to the insulin receptor kinase.
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PMID:Insulin binding and insulin receptor tyrosine kinase activity are not altered in the liver of rats with non-insulin-dependent diabetes. 283 75


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