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)

Insulin receptor complementary DNA has been cloned from an insulin-resistant patient with leprechaunism whose receptors exhibited multiple abnormalities in insulin binding. The patient is a compound heterozygote, having inherited two different mutant alleles of the insulin receptor gene. One allele contains a missense mutation encoding the substitution of glutamic acid for lysine at position 460 in the alpha subunit of the receptor. The second allele has a nonsense mutation causing premature chain termination after amino acid 671 in the alpha subunit, thereby deleting both the transmembrane and tyrosine kinase domains of the receptor. Interestingly, the father is heterozygous for this nonsense mutation and exhibits a moderate degree of insulin resistance. This raises the possibility that mutations in the insulin receptor gene may account for the insulin resistance in some patients with non-insulin-dependent diabetes mellitus.
 ...
PMID:Two mutant alleles of the insulin receptor gene in a patient with extreme insulin resistance. 283 24

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.
 ...
PMID:Insulin binding and insulin receptor tyrosine kinase activity are not altered in the liver of rats with non-insulin-dependent diabetes. 283 75

Recent studies have led to an enhanced understanding of cellular alterations that may play an important role in the pathophysiology of non-insulin-dependent diabetes mellitus (NIDDM). The insulin receptor links insulin binding at the cell surface to intracellular activation of insulin's effects. This transducer function involves the tyrosine kinase property of the beta-subunit of the receptor. It was found that adipocytes from subjects with NIDDM had a 50 to 80 percent reduction in insulin-stimulated receptor kinase activity compared with their non-diabetic counterparts. This defect was relatively specific for the diabetic state since no decrease was observed in insulin-resistant non-diabetic obese subjects. The reduction in kinase activity was accounted for by changes in the ratio of two pools of receptors, both of which bind insulin but only one of which is capable of tyrosine autophosphorylation and subsequent kinase activation; 43 percent of the receptors from non-diabetic subjects were capable of autophosphorylation compared with only 14 percent in the NIDDM group. A major component of cellular insulin resistance in NIDDM involves the glucose transport system. Exposure of cells to insulin normally results in enhanced glucose transport mediated by translocation of glucose transporters from a low-density microsomal intracellular pool to the plasma membrane. It was found that cells from NIDDM subjects had a marked depletion of glucose transporters in both plasma membranes and low-density microsomes, relative to obese non-diabetic control participants. Obese non-diabetic persons had a normal number of plasma membrane transporters but a reduced number of low-density microsome transporters in the basal state compared with lean control volunteers; insulin induced the translocation of relatively fewer transporters from the low-density microsome to the plasma membrane in the obese subgroups. In addition to the diminished number of glucose transporters, cells from both NIDDM and obese subjects had impaired functional activity of glucose carriers since decreased whole-cell glucose transport rates could not be entirely explained by the magnitude of the decrement in the number of plasma membrane transporters. Thus, impaired glucose transport is due to both a numerical and functional defect in glucose transporters. The cellular content of high-density microsomal transporters was the same in lean and obese control volunteers and NIDDM subjects, suggesting that transporter synthesis is normal and that cellular depletion results from increased protein turnover once transporters leave the high-density microsomal subfraction.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Cellular mechanisms of insulin resistance in non-insulin-dependent (type II) diabetes. 305 97

Protein kinase C (PKC) has been suggested as a mediator of insulin's effect on glucose transport, and PKC-mediated modulation of tyrosine kinase activity in the insulin receptor has been implicated in regulating the insulin sensitivity of tissues. Because skeletal muscle is a major target of insulin action, we examined the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA), 1-oleoyl-2-acetyl-rac-glycerol, and dioctanoyl diacylglycerol, known activators of PKC, on glucose metabolism in rat skeletal muscles. In contrast to results reported for other tissues, incubation of muscles with PKC activators produced only small increases in glucose transport and had minimal effects on the ability of insulin to stimulate transport. However, TPA treatment of muscles produced a significant decrease in basal glycogen synthesis. Incubation of muscles with TPA did not affect insulin binding or the tyrosine kinase activity of partially purified insulin receptors measured under basal conditions or after stimulation by insulin in situ or in vitro. Our findings do not support activation of PKC as a major mechanism for regulating glucose uptake or insulin receptor activity in skeletal muscle. However, the data do not rule out the possibility that glucose transport in skeletal muscle may respond to physiological activators of PKC.
Diabetes 1988 May
PMID:Minimal effects of phorbol esters on glucose transport and insulin sensitivity of rat skeletal muscle. 328 40

Insulin binding and receptor tyrosine kinase activity were investigated in the insulin-responsive R3230AC mammary adenocarcinoma. Insulin receptors, partially purified by wheat germ agglutinin-agarose chromatography, displayed electrophoretic properties similar to those of normal tissues and demonstrated autophosphorylation of the beta subunit. Tyrosine kinase activity of tumor preparations was measured by incorporation of 32P from ATP into the synthetic polypeptide substrate glutamic acid80:tyrosine20. The Km (app) for ATP, 15 to 30 microM in tumors from ovariectomized or intact rats, appeared to be increased by 10(-7) M insulin in vitro, with the calculated Vmax increased by 3- to 5-fold; the Km (app) for glutamic acid80:tyrosine20 was 2 to 3 microM and insulin increased the Vmax by 25 to 50%. The effects of diabetes and insulin treatment and of various doses of estradiol, progesterone, estradiol plus progesterone, or tamoxifen on insulin binding, basal tyrosine kinase activity, and insulin-inducible tyrosine kinase activity in vitro were studied in tumors from treated animals. Preparations from diabetic rats had elevated insulin binding and basal tyrosine kinase activity and displayed a striking dose-related increase in the ability for insulin induction of tyrosine kinase activity in vitro compared to intact animals; these effects of diabetes were prevented by administration of insulin. Over comparable doses, insulin growth factor 1 added in vitro induced tyrosine kinase activity minimally versus that seen for insulin. Treatment of rats with pharmacological doses of sex steroid hormones produced changes in insulin binding capacity and/or basal tyrosine kinase activity and, depending on dose, usually resulted in increased basal kinase activity relative to insulin binding. The insulin-inducible increase in tyrosine kinase activity in vitro was not altered by treatment with estradiol or estradiol plus progesterone in vivo, whereas high doses of progesterone attenuated the response. A consistent finding with increasing doses of sex steroids was an increase in the half-maximum dose or 50% maximum induction dose for insulin, implying reduced responsiveness. Tamoxifen administered to intact rats increased insulin binding and blunted the insulin-induced increase in tyrosine kinase in vitro; these effects were not seen in ovariectomized rats...
 ...
PMID:Effects of diabetes and sex steroid hormones on insulin receptor tyrosine kinase activity in R3230AC mammary adenocarcinomas. 328 34

We evaluated the possibility that impaired insulin-receptor kinase activity contributes to insulin resistance by examining in vitro receptor tyrosine kinase activity and in situ receptor phosphorylation in four models of insulin resistance. Adipocytes from streptozocin-induced nonketotic diabetic (STZ-D), glucocorticoid-treated, fasted, and chronically uremic rats showed reduced basal and maximally insulin-stimulated 2-deoxy-D-glucose transport compared with matched controls. Adipocytes from these models were also resistant to stimulation of hexose transport by hydrogen peroxide, a postbinding insulin mimicker. Changes in the number of insulin receptors per cell could not account for these alterations in transport. Cell surface 125I-labeled insulin binding was 142% of control in STZ-D and 129% with fasting and unchanged in glucocorticoid excess and chronic uremia. Insulin-stimulated tyrosine kinase was measured by means of a synthetic substrate, Glu80Tyr20. Partially purified receptors from these resistant models had unaltered kinase activity when normalized to soluble 125I-insulin binding. In situ stimulation of receptor phosphorylation by 7 and 100 nM insulin was determined after equilibration of adipocytes with 32PO4. Compared with matched controls, these intact cells, from all four resistant models, had insulin-stimulated receptor phosphorylation that was unchanged per unit of cell surface binding. Similar to results with insulin, hydrogen peroxide stimulation of in situ receptor phosphorylation was unchanged in each model. Thus, both in vitro and in situ measures of receptor phosphorylation suggest that the cellular alterations leading to insulin resistance in these adipocytes resides beyond phosphorylation of the insulin receptor.
Diabetes 1988 Feb
PMID:Intact adipocyte insulin-receptor phosphorylation and in vitro tyrosine kinase activity in animal models of insulin resistance. 339 39

Insulin-receptor binding and tyrosine kinase activity have been studied in brown adipose tissue from lean and obese mice. Brown adipose tissue carries functional insulin receptors comparable with those of conventional insulin target tissues. The alpha-subunit (Mr, 130,000) was labeled with photoreactive insulin; the beta-subunit (Mr, 95,000) was phosphorylated in a cell-free system, and its level of phosphorylation was increased in a dose-dependent manner by insulin. Two types of obese mice, mice rendered obese by gold thioglucose injection (GTG obese) and genetically obese ob/ob mice, were used. Insulin-receptor number was decreased by 60-70% in obese mice, when expressed per milligram of plasma membrane protein or per microgram of glycoprotein, whereas only a 30-40% diminution was observed in skeletal muscle, indicating that insulin receptors from brown adipose tissue are greatly affected by the downregulation process. Insulin-stimulated autophosphorylation of the insulin-receptor beta-subunit was decreased by 60-70% in preparations of obese mice compared with lean mice in direct proportion to the diminished level of insulin-receptor number. Similarly, the ability of receptors to catalyze the phosphorylation of a synthetic substrate (copolymer glutamate-tyrosine) was reduced. These results suggest that the decrease in insulin-receptor number and in associated tyrosine kinase activity could explain the insulin-resistant glucose uptake and the alteration in diet-induced thermogenesis described in obese animals.
Diabetes 1986 Nov
PMID:Brown adipose tissue in lean and obese mice. Insulin-receptor binding and tyrosine kinase activity. 353 Aug 52

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 tyrosine kinase activity of the insulin receptor was examined with partially-purified insulin receptors from adipocytes obtained from 13 lean nondiabetics, 14 obese nondiabetics, and 13 obese subjects with non-insulin-dependent diabetes (NIDDM). Incubation of receptors at 4 degrees C with [gamma-32P]ATP and insulin resulted in a maximal 10-12-fold increase in autophosphorylation of the 92-kDa beta-subunit of the receptor with a half maximal effect at 1-3 ng/ml free insulin. Insulin receptor kinase activity in the three experimental groups was measured by means of both autophosphorylation and phosphorylation of the exogenous substrate Glu4:Tyr1. In the absence of insulin, autophosphorylation and Glu4:Tyr1 phosphorylation activities, measured with equal numbers of insulin receptors, were comparable among the three groups. In contrast, insulin-stimulated kinase activity was comparable in the control and obese subjects, but was reduced by approximately 50% in the NIDDM group. These findings indicate that the decrease in kinase activity in NIDDM resulted from a reduction in coupling efficiency between insulin binding and activation of the receptor kinase. The insulin receptor kinase defects observed in NIDDM could be etiologically related to insulin resistance in NIDDM and the pathogenesis of the diabetic state.
 ...
PMID:Decreased kinase activity of insulin receptors from adipocytes of non-insulin-dependent diabetic subjects. 354 10

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


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