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)

Immunoblotting and protein microsequencing were used to identify several adipocyte proteins expressed in an obesity-related fashion in the Zucker rat. One of these was a 116-kDa particulate protein (p116). The p116 levels in adipocytes from 5- to 7-wk-old obese Zucker rats were two- to fivefold higher on a per milligram of protein basis than levels in lean animals and decreased after the induction of streptozotocin-induced diabetes mellitus. This suggests the change may be related to the actions of insulin. Hepatic levels of p116 did not change. The p116 was purified to homogeneity from obese Zucker rat adipocytes, and polyclonal antisera were prepared against the purified protein in rabbits. Microanalysis of electroblotted p116 proteolytic fragments suggested that p116 was pyruvate carboxylase (PC). Other evidence that p116 was PC included the following: 1) p116 contained biotin, 2) p116 in particulate subcellular fractions was soluble after freeze-lysis, 3) antibodies to p116 reacted with purified hepatic PC, 4) p116 and purified hepatic PC had identical pI and relative molecular weight values, and 5) similar changes were detected in adipocyte p116 and PC enzyme activity during obesity and after the induction of streptozotocin-induced diabetes mellitus. Increased adipose tissue PC probably contributes to the increased lipogenic capacity of young obese Zucker rat adipocytes.
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PMID:Pyruvate carboxylase in genetic obesity. 137 35

Currently available pharmacological agents have not been completely successful in restoring euglycemia in the non-insulin-dependent diabetes mellitus (NIDDM) patient. Several new approaches to the therapy of NIDDM have been formulated in recent years and are in various stages of laboratory or pharmaceutical development. Several of these agents are discussed in this article under categories relating to their mechanisms of lowering blood glucose: 1) inhibition of the release or action of counterregulatory hormones; 2) inhibition of postprandial glucose rise; 3) sensitization of tissues to insulin's actions; and 4) inhibition of gluconeogenesis, including inhibition of the long-chain acyl-CoA-carnitine acyltransferase I, the long-chain acylcarnitine translocase, and pyruvate carboxylase.
Diabetes Care 1992 Jun
PMID:New pharmacological approaches to therapy of NIDDM. 160 Aug 38

We have previously reported on plant mixture extract comprising of Nigella sativa, Myrrh, Gum Olibanum, Gum Asafoetida and Aloe to have a blood glucose lowering effect. The present study with streptozotocin diabetic rats is focussed on the mechanism of action, specifically on a) hepatic gluconeogenesis b) activity of key gluconeogenic enzymes, pyruvate carboxylase (PC) and phosphoenol-pyruvate carboxykinase (PEPCK). Similar studies using a biguanide, phenformin, have been conducted to compare the mode of action of these two compounds. The blood glucose levels (mean +/- SEM) before and after treatment with the plants extract were (16.7 +/- 1.7 mmol/L and 8.5 +/- 1.3 mmol/L) and with phenformin (15.1 +/- 1.3 mmol/L and 10.7 +/- 1.5 mmol/L). The rate of gluconeogenesis in isolated hepatocytes as well as activity of PC and PEPCK in liver homogenates is significantly lowered following treatment with the plants extract. Although phenformin also lowers blood glucose, it does not affect hepatic gluconeogenesis under stated experimental conditions. It is concluded that the anti-diabetic action of the plants extract may, at least partly, be mediated through decreased hepatic gluconeogenesis. The extract may prove to be a useful therapeutic agent in the treatment of non-insulin dependent diabetes mellitus (NIDDM).
Diabetes Res 1991 Dec
PMID:The effect of a plants mixture extract on liver gluconeogenesis in streptozotocin induced diabetic rats. 184 51

Biotin in high doses was given for 1-2 years to three diabetic patients suffering from severe diabetic peripheral neuropathy. Within 4-8 weeks there was a marked improvement in clinical and laboratory findings. It is suggested that in diabetes may exist a deficiency, inactivity or unavailability of Biotin, resulting in disordered activity of biotin-dependent enzyme, pyruvate carboxylase, leading to accumulation of pyruvate and/or depletion of aspartate, both of which play a significant role in nervous system metabolism. Based on our good results, regular biotin administration could be suggested for every diabetic patient for the prevention and management of peripheral neuropathy although extensive randomised clinical trials are required.
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PMID:Biotin for diabetic peripheral neuropathy. 208 65

13C-n.m.r. spectroscopy was used to determine the metabolic fate of alanine and aspartate in rat and rabbit kidney proximal tubules. The main purpose of the present study was to investigate the effect of streptozotocin-induced diabetes on the influx of 13C label from [3-13C]alanine into the tricarboxylic acid cycle and through the fructose-1,6-bisphosphatase pathway. This influx was calculated from the relative enrichment of 13C in the various glutamate and glutamine carbon atoms. The relative proportion of 13C label which entered the tricarboxylic acid cycle via pyruvate carboxylase relative to the proportion that entered via pyruvate dehydrogenase was 1.92 +/- 0.02 in fed control rats and 2.27 +/- 0.04 in streptozotocin-treated rats. However, streptozotocin-induced diabetes did not significantly affect this ratio in rabbit proximal convoluted tubular cells. Only in rat proximal convoluted tubular cells did we observe an increase in flux through the fructose-1,6-bisphosphatase pathway by streptozotocin treatment compared with fed controls. The data suggest that streptozotocin-induced diabetes in rats causes the same metabolic changes as does chronic acidosis.
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PMID:A 13C-n.m.r. investigation of the metabolism of amino acids in renal proximal convoluted tubules of normal and streptozotocin-treated rats and rabbits. 260 95

1. Measurements of the activities in rat liver of the four key enzymes involved in gluconeogenesis, i.e. pyruvate carboxylase (EC 6.4.1.1), phosphoenolpyruvate carboxykinase (EC 4.1.1.32), fructose 1,6-diphosphatase (EC 3.1.3.11) and glucose 6-phosphatase (EC 3.1.3.9), have been carried out, all four enzymes being measured in the same liver sample. Changes in activities resulting from starvation and diabetes have been studied. Changes in concentration (activity/unit wet weight of tissue) were compared with changes in the hepatic cellular content (activity/unit of DNA). 2. Each enzyme was found to increase in concentration during starvation for up to 3 days, but only glucose 6-phosphatase and phosphoenolpyruvate carboxykinase showed a significant rise in content. Fructose 1,6-diphosphatase appeared to decrease in content somewhat during the early stages of starvation. 3. There was a marked increase in the concentration of all four enzymes in non-starved rats made diabetic with alloxan or streptozotocin, for the most part similar responses being found for the two diabetogenic agents. On starvation, however, the enzyme contents in the diabetic animals tended to fall, often with streptozotocin-treated animals to values no greater than for the normal overnight-starved rat. Deprivation of food during the period after induction of diabetes with streptozotocin lessened the rise in enzyme activity. 4. The results are compared with other published values and factors such as substrate and activator concentrations likely to influence activity in vivo are considered. 5. Lack of correlation of change in fructose 1,6-diphosphatase with the other enzymes questions whether it should be included in any postulation of control of gluconeogenic enzymes by a single gene unit.
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PMID:A comparison of the effects of diabetes induced with either alloxan or streptozotocin and of starvation on the activities in rat liver of the key enzymes of gluconeogenesis. 432 34

Quantification of 2-ketoglutaric acid in plasma and cerebrospinal fluid as its O-trimethylsilyl++-quinoxalinol derivative by gas chromatography chemical ionization mass spectrometry is described with benzoylformic acid as internal standard. This technique, with ammonia as reactant gas, only detects the protonated molecular ions. The recovery of 2-ketoglutarate from perchloric-deproteinized plasma is 99.7 +/- 1.2%. The normal value of 2-ketoglutarate in children is 8.6 +/- 2.6 mumol l-1 (mean +/- standard deviation) in plasma (n = 25) and 4.8 +/- 1.4 mumol l-1 in cerebrospinal fluid (n = 20). The plasma level of 2-ketoglutarate is correlated with urea concentration (r = 0.96; p less than 0.001) in healthy subjects and in patients with chronic renal insufficiency. Increased values are found in one case of pyruvate carboxylase deficiency, and inconstantly in diabetes; physiological variations are described during fasting and after an oral glucose load.
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PMID:Microdetermination of 2-ketoglutaric acid in plasma and cerebrospinal fluid by capillary gas chromatography mass spectrometry; application to pediatrics. 670

Immunochemical techniques were used to study the effect of streptozotocin-induced diabetes on the amounts of pyruvate carboxylase and pyruvate dehydrogenase and on their rates of synthesis and degradation. Livers from diabetic rats had twice the pyruvate carboxylase activity of livers from normal rats when expressed in terms of DNA or body weight. The changes in catalytic activity closely paralleled changes in immunoprecipitable enzyme protein. Relative rates of synthesis determined by pulse-labelling studies showed that the ratio of synthesis of pyruvate carboxylase to that of average mitochondrial protein was increased 2.0-2.5 times in diabetic animals over that of control animals. Other radioisotopic studies indicated that the rate of degradation of this enzyme was not altered significantly in diabetic rats, suggesting that the increase in this enzyme was due to an increased rate of synthesis. Similar experiments with pyruvate dehydrogenase, the first component of the pyruvate dehydrogenase complex, showed that livers from diabetic rats had approximately the same amount of immunoprecipitable enzyme protein as the control animals, but a larger proportion of the enzyme was in its inactive state. The rates of synthesis and degradation of pyruvate dehydrogenase were not affected significantly by diabetes.
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PMID:Effect of streptozotocin-induced diabetes mellitus on the turnover of rat liver pyruvate carboxylase and pyruvate dehydrogenase. 747 23

A metabolic model of fuel sensing has been proposed in which malonyl-CoA and long-chain acyl-CoA esters may act as coupling factors in nutrient-induced insulin release (Prentki M, Vischer S, Glennon MC, Regazzi R, Deeney J, Corkey BE: Malonyl-CoA and long chain acyl-CoA esters as metabolic coupling factors in nutrient-induced insulin secretion. J Biol Chem 267:5802-5810, 1992). To gain further insight into the control of malonyl-CoA content in islet tissue, we have studied the short- and long-term regulation of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) in the beta-cell. These enzymes catalyze the formation of malonyl-CoA and its usage for de novo fatty acid biogenesis. ACC mRNA, protein, and enzymatic activity are present at appreciable levels in rat pancreatic islets and clonal beta-cells (HIT cells). Glucose addition to HIT cells results in a marked increase in ACC activity that precedes the initiation of insulin release. Fasting does not modify the ACC content of islets, whereas it markedly downregulates that of lipogenic tissues. This indicates differential regulation of the ACC gene in lipogenic tissues and the islets of Langerhans. FAS is very poorly expressed in islet tissue, yet ACC is abundant. This demonstrates that the primary function of malonyl-CoA in the beta-cells is to regulate fatty acid oxidation, not to serve as a substrate for fatty acid biosynthesis. The anaplerotic enzyme pyruvate carboxylase, which allows the replenishment of citric acid cycle intermediates needed for malonyl-CoA production via citrate, is abundant in islet tissue. Glucose causes an elevation in beta (HIT)-cell citrate that precedes secretion, and only those nutrients that can elevate citrate induce effective insulin release. The results provide new evidence in support of the model and explain why malonyl-CoA rises markedly and rapidly in islets upon glucose stimulation: 1) glucose elevates citrate, the precursor of malonyl-CoA; 2) glucose enhances ACC enzymatic activity; and 3) malonyl-CoA is not diverted to lipids. The data suggest that ACC is a key enzyme in metabolic signal transduction of the beta-cell and provide evidence for the concept that an anaplerotic/malonyl-CoA pathway is implicated in insulin secretion.
Diabetes 1996 Feb
PMID:Evidence for an anaplerotic/malonyl-CoA pathway in pancreatic beta-cell nutrient signaling. 854 64

The enzyme activity of the mitochondrial glycerol phosphate dehydrogenase (mGPD) in the pancreatic islet has been reported to be less than one-half of normal in the Goto-Kakizaki (GK) rat, a genetic model of NIDDM. In the current study, mGPD enzyme activity and the amount of mGPD protein, as judged by Western analysis, were 35-40% of normal in the islets of these animals. With the exception of pyruvate carboxylase, the activities of other enzymes were not abnormal. The assayable activity and amount of pyruvate carboxylase protein were decreased approximately 50% in the islets of the GK rats. Because mGPD, which is the key enzyme of the glycerol phosphate shuttle, and pyruvate carboxylase, which is the key component of the pyruvate malate shuttle, have been proposed to be essential for stimulus-secretion coupling in the pancreatic beta-cell, an important question is whether the decreases in these enzymes have a causal role in the hyperglycemia or whether the diabetic syndrome caused the decreases. To attempt to differentiate between these two possibilities, GK rats were treated with insulin to normalize their blood sugars. The activities of both mGPD and pyruvate carboxylase were also normalized by insulin treatment. An incidental discovery of this study was the identification of a high level of propionyl-CoA carboxylase activity and a lesser amount of methylcrotonyl-CoA carboxylase activity in pancreatic islets. These enzymes were normal in the islets of the GK rats. This is the first report on the presence of these two carboxylases in the islet and of low pyruvate carboxylase activity in the islet in NIDDM. We conclude that the decreased mGPD and pyruvate carboxylase in the pancreatic islet of the GK rat result from the diabetic syndrome.
Diabetes 1996 Jul
PMID:Normalization by insulin treatment of low mitochondrial glycerol phosphate dehydrogenase and pyruvate carboxylase in pancreatic islets of the GK rat. 866 38


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