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)

Administration of insulin (2 IU/kg, i.p.) produced a significant decrease (18%) in forebrain norepinephrine and a significant increase in the major metabolite of norepinephrine, 3-methoxy-4-hydroxyphenylglycol-sulfate (MOPEG-SO4, +19%) in rats. Streptozotocin-induced diabetes produced the opposite effects, resulting in an increase in forebrain norepinephrine (+17%) and a decrease in MOPEG-SO4 (-26%). In addition, insulin increased (+143%) and diabetes decreased (-41%) the turnover rate of norepinephrine, as measured by the rate of decrease of norepinephrine following inhibition of tyrosine hydroxylase by alpha-methyl-p-tyrosine. All of these effects in diabetic rats were reversed by insulin replacement therapy. These data are discussed within the context of mood disorders characteristic of diabetic patients.
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PMID:Effects of insulin and streptozotocin-induced diabetes on brain norepinephrine metabolism in rats. 388 46

A 68-year-old male patient without any previous thyroidal disease developed three times of transient primary hypothyroidism associated with protein-calorie malnutrition (PCM). Because of his diabetes mellitus, alcoholic hepatitis, chronic pancreatitis and blind loop syndrome, his nutritional balance was easily disturbed leading to PCM. Although he recurrently developed primary hypothyroidism associated with PCM, this condition was completely restored by protein-calorie repletion. The possibility of dietary iodine deficiency was negated by the observation that his daily urinary iodine secretion was more than 4 mg/day. Plasma amino acid analysis revealed severe depletion of phenylalanine, tyrosine and other essential amino acids and raised the possibility that this hypothyroidism was caused by amino acid deficiency. In order to clarify the mechanisms of this primary hypothyroidism, we have investigated the change of thyroid functions during protein-calorie repletion by total parenteral nutrition (TPN). We then removed iodine from the nutrients for TPN to ascertain that iodine deficiency was not the cause of the primary hypothyroidism in the present case. In spite of the removal of iodine, serum T4 and T3 suddenly increased from 1.1 micrograms/dl and less than 25 ng/dl to 3.5 micrograms/dl and 59 ng/dl, respectively, in a few days after the beginning of TPN. They continued to increase thereafter and reached 6.3 micrograms/dl and 115 ng/dl in 6 weeks. Serum free T4 also showed a sudden increase from 0.56 ng/dl to 1.7 ng/dl after TPN and remained above 1.3 ng/dl thereafter. Serum reverse T3 showed a rapid increase after TPN, but, 4 weeks later, returned to the previous level before TPN. Serum TSH decreased from 120 microU/ml to 17 microU/ml in a few days after TPN and reached a level within normal range in 4 weeks. Serum TBG gradually increased from 10.7 micrograms/ml to 29.2 micrograms/ml in 6 weeks. These results show that the T4 synthesis was extremely impaired by PCM in spite of the strong stimulation by TSH and that this suppression of T4 synthesis by PCM led the patient recurrently to the primary hypothyroidism. We have next investigated the possibility whether the deficiency of phenylalanine and tyrosine could cause a suppression of T4 synthesis because tyrosine is an important substrate of T4. For this purpose we removed phenylalanine and tyrosine from TPN and added iodine to prevent iodine deficiency due to prolonged iodine-depleted nutrition. Reduction of phenylalanine and tyrosine resulted in a marked decrease in serum T4, T3 and TBG in 7 weeks, but gave no change to free T4. Serum TSH remained within normal range.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Contribution of amino acid deficiency to primary hypothyroidism associated with protein-calorie malnutrition]. 393 44

Flux through, and maximal activities of, key enzymes of phenylalanine and tyrosine degradation were measured in liver cells prepared from adrenalectomized rats and from streptozotocin-diabetic rats. Adrenalectomy decreased the phenylalanine hydroxylase flux/activity ratio; this was restored by steroid treatment in vivo. Changes in the phosphorylation state of the hydroxylase may mediate these effects; there was no significant change in the maximal activity of the hydroxylase. Tyrosine metabolism was enhanced by adrenalectomy; this was not related to any change in maximal activity of the aminotransferase. Steroid treatment increased the maximal activity of the aminotransferase. Both acute (3 days) and chronic (10 days) diabetes were associated with increased metabolism of phenylalanine; insulin treatment in vivo did not reverse these changes. Although elevated hydroxylase protein concentration was a major factor, changes in the enzyme phosphorylation state may contribute to differences in phenylalanine degradation in the acute and chronic diabetic states. Tyrosine metabolism, increased by diabetes, was partially restored to normal by insulin treatment in vivo. These changes can, to a large extent, be interpreted in terms of changes in the maximal activity of the aminotransferase.
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PMID:The metabolism of L-phenylalanine and L-tyrosine by liver cells isolated from adrenalectomized rats and from streptozotocin-diabetic rats. 400 13

The effect of diabetes (streptozotocin, 65 mg/kg ip), dietary protein intake (15-60%), and plasma amino acid concentrations on brain large neutral amino acid levels in rats was examined. After 20 days, the plasma concentrations of methionine and the branched chain amino acids (BCAA), valine, isoleucine, and leucine were increased in diabetic rats. In brain tissue, methionine and valine levels were increased but threonine, tyrosine, and tryptophan concentrations were depressed. Increased protein consumption promoted a diabetic-like plasma amino acid pattern in normal rats while enhancing that of diabetic animals. However, with the exception of threonine, glycine, valine, and tyrosine, there was little effect on brain amino acid levels. A good association was found between the calculated brain influx rate and the actual brain concentration of threonine, methionine, tyrosine, and tryptophan in diabetic animals. There was no correlation, however, between brain influx rate and brain BCAA levels. Thus, the brain amino acid pattern in diabetes represents the combined effects of insulin insufficiency and composition of the diet ingested on plasma amino acid levels as well as metabolic adaptation within the brain itself.
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PMID:The effect of insulin deficiency, dietary protein intake, and plasma amino acid concentrations on brain amino acid levels in rats. 404 90

Free amino acid concentrations have been determined in plasma and urine of nonketotic, severely diabetic dogs and age-matched normal controls. Plasma from fasted (as well as fed) diabetics contained supranormal concentrations of several amino acids, including the branched-chain amino acids. In contrast to other species, however, the concentration of only one plasma amino acid (tryptophan) was subnormal in fasted diabetic dogs. Urine collected at the same time showed that the excretion of most amino acids was not abnormal in diabetes. Urinary concentrations of some amino acids were not abnormal despite supranormal levels in plasma. Nevertheless, eight of the 21 amino acids studied reached concentrations significantly greater than normal in the urine of diabetic dogs. Six of the eight amino acids (arginine, histidine, phenylalanine, tyrosine, tryptophan, glutamic acid) showed elevated concentrations in urine even though their plasma concentrations were not elevated. The observed disturbance in the urine/plasma ratio of certain amino acids suggests a possible defect in the renal handling of amino acids in diabetes.
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PMID:Abnormal amino acid concentrations in plasma and urine of experimentally diabetic dogs. 613 39

The cyclic hexapeptide, cyclo (Pro-Phe-D-Trp-Lys-Thr-Phe), I, has been shown to have the biological properties of somatostatin. We now report structure-activity studies which optimize the potency of this cyclic hexapeptide series with the synthesis of cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe), II, which is 50-100 times more potent than somatostatin for the inhibition of insulin, glucagon and growth hormone release. The hydroxyl group of tyrosine is seen to lend a 10-fold enhancement to the potency. Potency also is found to be correlated with hydrophobicity. II is found to improve the control of postprandial hyperglycemia in diabetic animals when given in combination with insulin. The analog is found to be quite stable in the blood and in the gastrointestinal tract, but the bioavailability after oral administration is only 1-3%. The biological properties and long duration of II should allow clinical evaluation of the inhibition of glucagon release as an adjunct to insulin in the treatment of patients with diabetes.
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PMID:A super active cyclic hexapeptide analog of somatostatin. 614 33

Patients studied during recovery from an episode of ketoacidotic diabetes had raised blood glucose, plasma free fatty acid and plasma free tryptophan concentrations. Plasma total tryptophan was decreased. Well controlled diabetics showed normal values. The ketoacidotic patients had increased lumbar CSF tryptophan and 5-hydroxyindoleacetic acid concentrations. Plasma tyrosine and CSF tyrosine and homovanillic acid concentrations were normal in both diabetic groups. The results are discussed in relation to somewhat similar findings in uraemic and hepatic encephalopathy and to changes in rats with streptozotocin diabetes.
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PMID:Brain transmitter precursors and metabolites in diabetic ketoacidosis. 618 Dec 9

Male rats treated 3 wk earlier with streptozotocin showed abnormally high blood levels of leucine, isoleucine, and valine throughout the 24-h period. Serum phenylalanine levels were slightly increased, while those of tryptophan and tyrosine were occasionally reduced. In brain, the level of each branched-chain amino acid was significantly increased above normal at all times. The brain concentration of each aromatic amino acid was always below normal. These changes were restored almost to normal by exogenous insulin therapy. Since the ingestion of protein is normally a major factor influencing blood amino acid levels, the effect of ingesting single, protein-containing meals on the blood and brain levels of these amino acids was also studied. After an overnight fast, the ingestion of a protein-containing meal by diabetic rats increased substantially both blood and brain levels of each branched-chain amino acid. No such increases occurred in normal rats. Ingestion of this meal produced only small changes in the brain and blood levels of the aromatic amino acids in both diabetic and normal rats. The changes in the brain level of each large neutral amino acid in some cases paralleled those in its blood level. More often, they paralleled the changes in the blood ratio of each amino acid to the sum of the other aromatic and branched-chain amino acids. This ratio is often a good predictor of the competitive transport of these amino acids into brain (Fernstrom and Faller, 1978). The observed changes in the brain levels of these amino acids in diabetes may influence the rates at which they are consumed in metabolic pathways within this organ.
Diabetes 1983 Mar
PMID:Effect of experimental diabetes on the levels of aromatic and branched-chain amino acids in rat blood and brain. 633 1

We have investigated the fate of 125I-insulin after binding by rat hepatocytes. Approximately 30% of the bound radioactivity dissociated from the cells as intact 125I-insulin; approximately 56% dissociated as 125I- and 125I-Tyr. The remaining radioactivity was recovered as peptides that we postulate are intermediate products of insulin metabolism. Experiments were performed in the presence of chloroquine (0.1 mM), an agent known to inhibit the intracellular processing of 125I-insulin. As expected, chloroquine increased the amount of radioactivity recovered as intact 125I-insulin (P less than 0.005) and decreased the amount of 125I- and 125I-Tyr (P less than 0.005). In addition, chloroquine decreased the amount of one of the insulin peptides (P less than 0.005), but increased the amount of the other (P less than 0.01). These data suggest the presence of two pathways of insulin metabolism in rat hepatocytes, one of which is inhibited by chloroquine. We have found a second pathway by which insulin is degraded due to the removal of several amino acids from the carboxy-terminus of the B-chain. The resulting fragment bound poorly to insulin receptors on IM-9 cultured human lymphocytes, and probably has little if any biologic activity. However, this fragment bound well to anti-insulin antibody and constituted about 20% of the immunoreactive radioactivity that dissociated from the hepatocytes.
Diabetes 1984 Apr
PMID:The fate of insulin in rat hepatocytes. Evidence for the release of an immunologically active fragment. 636 92

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


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