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)

It has been demonstrated in in vivo and in vitro experiments that high-fat (HF) feeding causes insulin resistance. To elucidate the mechanism for this effect, we have measured the kinase activity of the insulin receptor purified from livers of HF-fed rats that showed impaired insulin action in isolated rat adipocytes. In adipocyte experiments, HF feeding led to a 65% decrease in the maximal response stimulated by insulin in a 2-deoxyglucose uptake study. Although insulin binding to adipocytes of HF-fed rats also decreased to 50% of control due to decreased binding affinity, the postbinding defect should be accounted for by decreased insulin action in view of the presence of spare receptor. In contrast to adipocytes, insulin binding to the lectin-purified insulin receptor from livers showed no difference in receptor-binding affinity between HF-fed and control rats. Insulin-stimulated phosphorylation of the beta-subunit of the insulin receptor was decreased to almost 50% throughout the entire dose-response curve. The study of glutamine-tyrosine (4:1) phosphorylation by the insulin-receptor kinase showed results similar to those of the autophosphorylation study. These results suggest that an HF diet causes insulin resistance by affecting insulin-receptor kinase, which plays an important role in transmembrane signaling between insulin binding and insulin action.
Diabetes 1988 Oct
PMID:Alteration of insulin-receptor kinase activity by high-fat feeding. 284 8

The effect of moderate insulin deficiency of 2 weeks in duration on hypothalamic catecholamine metabolism in food-deprived and meal-fed rats was evaluated. Hypothalamic tyrosine content in food-deprived (from 0700 to 1600 h), diabetic rats was normal. Also normal were the rates of 3,4-dihydroxyphenylalanine accumulation following aromatic amino acid decarboxylase inhibition, norepinephrine and 3,4-dihydroxyphenylethylamine (dopamine) clearance after tyrosine hydroxylase inhibition, and intraneuronal amine accumulation following monoamine oxidase inhibition. Differences in hypothalamic amine metabolism were apparent, however, when diabetic and normal rats were fed 2-g meals. The 3-methoxy-4-hydroxyphenylethyleneglycol sulfate accumulation rate was depressed in diabetic rats by the carbohydrate meal but was stimulated by the tyrosine-supplemented protein meal. In contrast, the tyrosine-supplemented diet had no effect on 3,4-dihydroxyphenylacetic acid accumulation in diabetic animals, whereas the production rate in normal rats was increased. We conclude that normal responses occurring in hypothalamic catecholamine metabolism after the consumption of a meal are modified by the presence of diabetes.
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PMID:Hypothalamic catecholamine metabolism in diabetic rats: the effect of insulin deficiency and meal ingestion. 286 2

Streptozotocin-diabetic and nondiabetic control male rats were fed synthetic diets varying in macronutrient content (experiment 1) or diets with or without added tyrosine (experiments 2 and 3). All rats were evaluated for stereotyped behaviors after administration of apomorphine (1 mg/kg) and amphetamine (3 and 5 mg/kg). At the end of experiments 2 and 3, rates of tyrosine hydroxylation in hypothalamus, nucleus accumbens, and striatum were determined by measuring L-3,4-dihydroxyphenylalanine concentrations after decarboxylase inhibition. In experiment 3 the ratios of tyrosine to dopamine were also measured in striatum and nucleus accumbens. Diabetic rats fed a standard high-carbohydrate diet showed decreased stereotypy relative to controls. Neither systematic alterations of fat or protein content of the diet nor selective tyrosine enrichment affected this attenuation of stereotypy in diabetics. L-3,4-dihydroxyphenylalanine concentration in nucleus accumbens was increased by dietary tyrosine enrichment in experiment 2 but not in experiment 3. However, brain tyrosine levels were elevated in rats fed tyrosine-enriched diets. These results argue against a significant contribution of precursor elevation to catecholamine function and behavior in experimental diabetes.
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PMID:Effects of dietary protein and tyrosine on behavior of diabetic rats. 294 68

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.
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PMID:Diabetes-induced functional and structural changes in insulin receptors from rat skeletal muscle. 300 51

To test the hypothesis that inhibitors of aldose reductase, a key enzyme for polyol synthesis, prevent the decrease of sympathetic nervous system (SNS) activity and improve motor nerve conduction velocity (MNCV) through the reduction of sorbitol accumulation in streptozocin (STZ)-induced diabetic rats, norepinephrine (NE) turnover (reliable indicator of SNS activity in the interscapular brown adipose tissue (IBAT), heart, and pancreas), and MNCV were measured in untreated STZ-induced diabetic rats, STZ-induced diabetic rats treated with an aldose reductase inhibitor (ARI) (ONO 2235, 50 mg X kg-1 X day-1, orally), STZ-induced diabetic rats treated with insulin therapy, control rats, and control rats treated with ARI. As expected, results from studies with the inhibition of NE biosynthesis with alpha-methyl-p-tyrosine or radiolabeled NE to measure NE turnover demonstrated significant reductions in SNS activity in IBAT, heart, and pancreas of untreated STZ-induced diabetic rats, compared with those in control rats. MNCV determined with the tail nerve was significantly reduced in untreated STZ-induced diabetic rats, compared with that of the controls. Both daily ARI treatment and insulin therapy in STZ-induced diabetic rats prevented partially but significantly the decrease of NE turnover in IBAT, heart, and pancreas, ameliorated MNCV, and reduced sorbitol accumulation in the nerve tissue and red blood cells. ARI treatment in control rats had no effect on NE turnover, MNCV, or sorbitol content. These results suggest that STZ-induced diabetic rats had not only motor neuropathy but also sympathetic nervous dysfunction and that ARI treatment might prevent these as well as insulin therapy does through the reduction of sorbitol accumulation.
Diabetes 1987 Jan
PMID:Effect of aldose reductase inhibitor ONO 2235 on reduced sympathetic nervous system activity and peripheral nerve disorders in STZ-induced diabetic rats. 302 43

Acute hormonal regulation of liver carbohydrate metabolism mainly involves changes in the cytosolic levels of cAMP and Ca2+. Epinephrine, acting through beta 2-adrenergic receptors, and glucagon activate adenylate cyclase in the liver plasma membrane through a mechanism involving a guanine nucleotide-binding protein that is stimulatory to the enzyme. The resulting accumulation of cAMP leads to activation of cAMP-dependent protein kinase, which, in turn, phosphorylates many intracellular enzymes involved in the regulation of glycogen metabolism, gluconeogenesis, and glycolysis. These are (1) phosphorylase b kinase, which is activated and, in turn, phosphorylates and activates phosphorylase, the rate-limiting enzyme for glycogen breakdown; (2) glycogen synthase, which is inactivated and is rate-controlling for glycogen synthesis; (3) pyruvate kinase, which is inactivated and is an important regulatory enzyme for glycolysis; and (4) the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase bifunctional enzyme, phosphorylation of which leads to decreased formation of fructose 2,6-P2, which is an activator of 6-phosphofructo-1-kinase and an inhibitor of fructose 1,6-bisphosphatase, both of which are important regulatory enzymes for glycolysis and gluconeogenesis. In addition to rapid effects of glucagon and beta-adrenergic agonists to increase hepatic glucose output by stimulating glycogenolysis and gluconeogenesis and inhibiting glycogen synthesis and glycolysis, these agents produce longer-term stimulatory effects on gluconeogenesis through altered synthesis of certain enzymes of gluconeogenesis/glycolysis and amino acid metabolism. For example, P-enolpyruvate carboxykinase is induced through an effect at the level of transcription mediated by cAMP-dependent protein kinase. Tyrosine amino-transferase, serine dehydratase, tryptophan oxygenase, and glucokinase are also regulated by cAMP, in part at the level of specific messenger RNA synthesis. The sympathetic nervous system and its neurohumoral agonists epinephrine and norepinephrine also rapidly alter hepatic glycogen metabolism and gluconeogenesis acting through alpha 1-adrenergic receptors. The primary response to these agonists is the phosphodiesterase-mediated breakdown of the plasma membrane polyphosphoinositide phosphatidylinositol 4,5-P2 to inositol 1,4,5-P3 and 1,2-diacylglycerol. This involves a guanine nucleotide-binding protein that is different from those involved in the regulation of adenylate cyclase. Inositol 1,4,5-P3 acts as an intracellular messenger for Ca2+ mobilization by releasing Ca2+ from the endoplasmic reticulum.(ABSTRACT TRUNCATED AT 400 WORDS)
Diabetes Metab Rev 1987 Jan
PMID:Mechanisms of hormonal regulation of hepatic glucose metabolism. 303 41

We have determined glucose transport, insulin binding, and insulin-receptor kinase activity in adipose tissue from morbidly obese patients with and without non-insulin-dependent diabetes mellitus (NIDDM). The insulin sensitivity and responsiveness of glucose transport in freshly isolated adipocytes were significantly reduced in NIDDM subjects compared with nondiabetics. This was due in part to decreased insulin binding in adipocytes. Reduced specific 125I-labeled insulin binding was also observed in crude detergent extracts and partially purified insulin receptors from adipose tissue. In addition, the basal and insulin-stimulated tyrosine-specific protein kinase activity per milligram of protein was significantly decreased in NIDDM patients compared with nondiabetics. The differences between maximally insulin-stimulated and basal kinase activities expressed by insulin-binding activity were also significantly reduced in NIDDM subjects. We conclude that insulin resistance in morbidly obese patients with NIDDM is due to both insulin-binding and postbinding defects. One of the postbinding defects in NIDDM appears to be impaired insulin-receptor kinase activity of fat tissue.
Diabetes 1987 May
PMID:Insulin-receptor kinase activity of adipose tissue from morbidly obese humans with and without NIDDM. 303 15

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)
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PMID:Cellular mechanisms of insulin resistance in non-insulin-dependent (type II) diabetes. 305 97

Previous reports have suggested that insulin may not regulate the breakdown of myofibrillar proteins in skeletal muscle. To further test the role of insulin, insulinopenia was produced by treating rats with streptozocin. After treatment, protein breakdown in skeletal muscle was evaluated with the isolated perfused rat hindquarter preparation. After the inhibition of protein synthesis with cycloheximide, total and myofibrillar protein breakdown were assessed by measuring the release of tyrosine and 3-methylhistidine, respectively, in the perfused hindquarters of diabetic and age-matched control rats. Streptozocin-induced (65 mg/kg) diabetes (3- to 28-day duration) resulted in hyperglycemia, hypoinsulinemia, hyperphagia, increased plasma lipid levels, arrested body and muscle growth, and increased urea and 3-methylhistidine excretion. Despite this, protein breakdown in skeletal muscle diminished. The release of 3-methylhistidine by the perfused hindquarters of diabetic rats decreased, whereas the release of tyrosine remained unchanged, suggesting that the breakdown of myofibrillar proteins was affected specifically. 3-Methylhistidine (unbound) levels in skeletal muscle of unperfused diabetic rats as well as in skin decreased, whereas they increased twofold in the gastrointestinal tract. More severe diabetes (125 mg/kg streptozocin), which resulted in ketoacidosis, augmented protein breakdown in muscle; however, this response was due to a marked fall in food consumption (it was also evident when control rats were pair fed). These data reinforce previous conclusions that insulin does not play a major role in the regulation of myofibrillar protein breakdown in skeletal muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1987 Jan
PMID:Myofibrillar protein breakdown in skeletal muscle is diminished in rats with chronic streptozocin-induced diabetes. 309 8

A man with diabetes mellitus, chronic hepatitis, chronic pancreatitis, and blind loop syndrome but without any previous thyroid disease developed three episodes of transient primary hypothyroidism associated with protein-calorie malnutrition (PCM). Clinical examinations suggested that this primary hypothyroidism was not caused by chronic thyroiditis, iodine deficiency, or iodine excess. Since the three times association of primary hypothyroidism with PCM suggested the possibility that the primary hypothyroidism was caused by PCM, we have tried to clarify its mechanism. For this purpose we have investigated the change of thyroid functions during protein-calorie repletion and the effect of amino acid deficiency. Total parenteral nutrition with full supplementation of amino acids resulted in a rapid increase in serum thyroxine (T4), triiodothyronine (T3), free T4, and reverse T3, and subsequently, a rapid decrease in TSH in several days after the nutrition was begun. When amino acid solution was changed to that depleted of phenylalanine and tyrosine after the restoration of thyroid functions, serum T4 and T3 showed a gradual decrease, but serum free T4 and TSH remained within normal range. However, resupplementation of phenylalanine and tyrosine after 8 weeks of depletion gave a rapid increase in serum T4, T3, free T4, and reverse T3. These results suggested that the primary hypothyroidism was caused by an impaired T4 production and that the deficiency of amino acids in PCM partly contributed to the impairment of T4 production.
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PMID:Primary hypothyroidism in an adult patient with protein-calorie malnutrition: a study of its mechanism and the effect of amino acid deficiency. 312 81


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