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)

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.
 ...
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

The basal and total pyruvate dehydrogenase activities were assayed in circulating lymphocytes from children with juvenile diabetes at diagnosis and after five days of insulin therapy and from control subjects. In untreated diabetic children, basal and total pyruvate dehydrogenase activities were deeply decreased and both showed very similar values; whereas, in control subjects basal activity was about 30% lower than total activity. In diabetic patients treated with insulin (in vivo situation), both basal and total activity levels were equal or even higher than those of the control subjects. The incubation of lymphocytes from diabetic patients with insulin (5 microU/ml) (in vitro situation) stimulates, but less than in vivo, the basal and total pyruvate dehydrogenase activities.
 ...
PMID:The behaviour of pyruvate dehydrogenase in circulating lymphocytes from diabetic children. 266 78

This study investigated possible mechanisms underlying insulin resistance in the New Zealand Obese (NZO) mouse, an animal model for obese, non-insulin-dependent diabetes. Insulin binding, mediator generation, and action both at the level of glucose utilization and enzyme modulation were compared in adipocytes from lean control New Zealand Chocolate (NZC) mice and NZO mice during the development of the syndrome. Abnormalities of insulin stimulation of glucose transport and utilization in NZO mouse adipocytes were found which involved both decreased sensitivity and responsiveness to insulin. The defects were evident at an early age (4 weeks) and could not be attributed to differences in nonstimulated glucose metabolism, which was similar in the control NZC and obese NZO strains of mouse. Insulin binding to its receptor was only moderately decreased in adipocytes of NZO mice. Pyruvate dehydrogenase (PDH) activity of NZO mouse adipocytes was totally unresponsive to insulin in contrast to the impaired but still significant insulin stimulation of glucose transport and utilization, suggesting a postreceptor defect at the level of insulin stimulation of this enzyme. Insulin stimulated the production of a low molecular weight factor which activated pyruvate dehydrogenase in NZC mouse adipocytes (insulin mediator) but, paradoxically, caused a decrease in mediator production or activity in adipocytes from NZO mice. Thus, insulin either inhibited mediator production or stimulated generation of an inhibitory mediator in adipocytes from this strain. No evidence for the latter mechanism was found. This study demonstrates in adipocytes of NZO mice: (1) a receptor defect and (2) a postreceptor defect of insulin action at the level of pyruvate dehydrogenase activation.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Impaired insulin action in adipocytes of New Zealand obese mice: a role for postbinding defects in pyruvate dehydrogenase and insulin mediator activity. 305 Mar 67

To determine whether 1) insulin stimulates pyruvate dehydrogenase (PDH) and glycogen synthase (GS) in isolated human adipocytes and 2) adipocytes from subjects with obesity or noninsulin-dependent diabetes mellitus (NIDDM) are resistant to the effects of insulin, PDH and GS were assayed in adipocytes from 11 control, 8 obese, and 9 NIDDM subjects. Basal PDH activities were 123 +/- 20, 129 +/- 21, and 128 +/- 25 pmol pyruvate oxidized/min per 2 X 10(5) adipocytes in these groups. Insulin stimulated PDH activity to a maximum of 223 +/- 38 pmol/min per 2 X 10(5) in adipocytes from control subjects, but did not significantly increase values from obese subjects. Insulin significantly decreased PDH activity in cells from NIDDM subjects (99 +/- 20 pmol/min per 2 X 10(5) cells, P less than 0.05). PDH activity assayed with high magnesium and calcium concentrations was significantly stimulated by insulin in adipocytes from control, but not obese or NIDDM subjects. GS assayed with 1 mM glucose 6-phosphate did not differ significantly among control, obese, or NIDDM subjects (446 +/- 110, 451 +/- 156, and 291 +/- 35 pmol incorporated into glycogen, respectively). Insulin significantly stimulated glycogen synthase in all three groups (827 +/- 179, 764 +/- 177, and 569 +/- 51 pmol incorporated) to a similar extent. Glycogen synthase assayed with 10 mM glucose 6-phosphate was decreased in NIDDM (1,335 +/- 131 pmol incorporated) compared with obese or control subjects (2,512 +/- 451 and 2,239 +/- 230 pmol incorporated, respectively, P less than 0.01).
 ...
PMID:Adipocyte glycogen synthase and pyruvate dehydrogenase in obese and type II diabetic subjects. 309 77

The mechanisms of insulin insensitivity in diabetes are poorly understood. We have therefore assessed the relationship between glucose disposal during a euglycaemic clamp, muscle glycogen formation, and the activities of insulin regulated enzymes within skeletal muscle in five Type 1 (insulin-dependent) diabetic patients, both on conventional injection therapy (HbA1 11.0 +/- 1.0 (SD) %) and after 6 weeks continuous subcutaneous insulin infusion (HbA1 7.6 +/- 1.4%, p less than 0.01). On both regimens, overnight euglycaemia before the clamp was maintained with an intravenous insulin infusion. The increase in clamp glucose requirements (insulin 0.1 U X kg-1 X h-1) between injection therapy and continuous subcutaneous insulin infusion was significant (6.2 +/- 0.9 (SE) to 7.0 +/- 0.9 mg X kg-1 X min-1, p less than 0.05), but small compared to differences between subjects. Glucose requirement remained lower than in control subjects (10.4 +/- 0.7 mg X kg-1 X min-1, p less than 0.05). The increase in muscle glycogen with the clamp was slightly higher on continuous subcutaneous insulin infusion (9.5 +/- 2.5 mg/g protein) than on injection therapy (8.5 +/- 2.4 mg/g, p less than 0.05), but less than in control subjects (17.9 +/- 2.1 mg/g, p less than 0.05). The expressed activity of glycogen synthase and pyruvate dehydrogenase increased significantly between fasting and the end of the clamps in the patients (p less than 0.001 and less than 0.005), but was not significantly different between the two treatment regimens. Expressed glycogen synthase activity at the end of the clamp was lower on both treatments than in control subjects (p less than 0.05). Both enzyme activities were, however, highly correlated with glucose requirement between patients, (r = 0.89-0.94, p less than 0.05-0.02), and glycogen synthase was similarly correlated in the control subjects (r = 0.84, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Muscle enzyme activity and insulin sensitivity in type 1 (insulin-dependent) diabetes mellitus. 310 Mar 72

Groups of young adult rats with body weights of 125-135 g (group A) or 300-400 g (group B) were subjected to one bout of prolonged exercise to exhaustion on a treadmill and were studied 2 h postexercise. Liver glycogen levels were markedly depleted in the exercised rats. Adipocytes from group A exercised rats showed a significantly greater increase in pyruvate dehydrogenase (PDH) activity in response to insulin than those from sedentary controls. Incubation with insulin of liver particulate fractions from exercised group A rats resulted in an increased production of a mitochondrial PDH activator compared with preparations from sedentary controls. The tissues of both exercised and sedentary group B rats were less responsive to insulin than those of the smaller rats. A significant effect of exercise on increased production of a PDH activator in response to insulin was found only in experiments in which adipocyte plasma membranes were coincubated with mitochondria and insulin. For group B rats exercise provided no significant enhancement of insulin activation of intact adipocyte PDH or stimulation of the production of a PDH activator by liver particulate preparations. Insulin binding to fat cells was not affected by exercise. Group A rats made insulin resistant by a high-fat diet did not respond to exercise by significantly increasing the insulin stimulation of PDH activator by liver membranes. The enhancing effect of a single bout of exercise on insulin response was not readily demonstrable in rats resistant to insulin either in association with age and weight or with a high-fat diet.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1986 Jul
PMID:Effect of acute exercise on insulin generation of pyruvate dehydrogenase activator by rat liver and adipocyte plasma membranes. 352 20

The effects of putative insulin mediators on the pyruvate dehydrogenase (PDH) activity of intact mitochondria isolated from rat liver were investigated. The mitochondria were judged intact on the basis of electron microscopic examination and demonstrated respiratory control. Only mitochondria having respiratory control ratios of greater than 4, using succinate as a substrate, were used in these studies. Addition of physiologic concentrations of insulin to these mitochondria caused stimulation of PDH activity, attributed to generation of an insulin mediator from plasma membranes contaminating the mitochondrial preparation. Exogenous plasma membranes from rat adipocytes or liver caused further stimulation of PDH activity, which was proportional to the amount of plasma membranes added. Addition of insulin to the mixture of mitochondria and plasma membranes stimulated PDH still further. The stimulation was proportional to the insulin concentration, with maximal effects observed at 50 microU/ml insulin. Partially purified mediators from liver, muscle, H4-II-E hepatoma cells, and IM9 lymphocytes also stimulated PDH activity in intact mitochondria. Mediators prepared from insulin-treated liver, muscle, and cultured hepatoma cells stimulated PDH more than did mediators from the corresponding untreated source. Mediator from insulin-treated IM9 lymphocytes stimulated PDH less than did mediator from untreated IM9 lymphocytes. These findings are consistent with the known effects of insulin on these tissues and with the reported effects of the various mediators on PDH activity in non-intact mitochondria. These observations support the proposal that these mediators are physiologically significant modulators of insulin's effects on PDH activity.
Diabetes 1985 Jan
PMID:Insulin mediator stimulates pyruvate dehydrogenase of intact liver mitochondria. 388 May 52

Insulin-exposed liver particulate fraction supernatants from control rats stimulated mitochondrial pyruvate dehydrogenase (PDH) activity by 26%, while the stimulation by similar preparations from indomethacin-injected rats (5 mg/kg twice daily, i.p., for 2 days) was 4%. In vitro addition of indomethacin to the particulate fraction during insulin exposure also inhibited stimulation of PDH by insulin. This inhibitory effect of indomethacin was completely overcome by the in vitro addition of prostaglandin E2 (PGE2) to the liver particulate incubation mixture. Intact adipocytes showed a similar (62%) decrease in insulin activation of PDH in the presence of indomethacin. In a cell-free adipocyte system (co-incubation of mitochondria and plasma membrane), indomethacin addition resulted in 90% decrease in insulin-stimulated PDH response. PGE2 addition completely reversed this inhibition. In contrast to its effects on PDH activation, indomethacin had no effect on insulin-stimulated glucose oxidation. In vitro incubation of fat cells with dexamethasone (1 microM) also resulted in decreased insulin activation of PDH. Inclusion of arachidonic acid during dexamethasone exposure of fat cells resulted in partial restoration of the insulin effect on PDH in fat cells and in cell-free preparations. However, addition of PGE2 during insulin exposure of plasma membranes from dexamethasone-treated preparations showed no significant restoration of the insulin effect on PDH. These studies suggest that: (1) PG metabolism is involved in insulin's generation of the second messenger, and (2) the mechanism of dexamethasone-induced inhibition of insulin effect on PDH is a complex phenomenon involving the synthesis and action of eicosanoids.
Diabetes 1985 Jan
PMID:Studies on the possible involvement of prostaglandins in insulin generation of pyruvate dehydrogenase activator. 391 58

In heart muscle regulation of pyruvate dehydrogenase (PDH) complex activity by reversible phosphorylation is the major determinant of glucose oxidation under physiological conditions and in diabetes. Altered mitochondrial concentrations of effectors of PDH kinase and phosphatase (metabolites, Ca2+, H+) appear to explain effects of oxidation of lipid fuels, myocardial contraction and ischaemia on PDH complex activity. The effects of diabetes and starvation are mediated in addition by protein(s) which increase the activity of PDH kinase. End product inhibition by NADH may be important in ischaemia.
 ...
PMID:Molecular mechanisms regulating myocardial glucose oxidation. 406 41

1. The extractions of glucose, lactate, pyruvate and free fatty acids by dog heart in vivo were calculated from measurements of their arterial and coronary sinus blood concentration. Elevation of plasma free fatty acid concentrations by infusion of intralipid and heparin resulted in increased extraction of free fatty acids and diminished extractions of glucose, lactate and pyruvate by the heart. It is suggested that metabolism of free fatty acids by the heart in vivo, as in vitro, may impair utilization of these substrates. These effects of elevated plasma free fatty acid concentrations on extractions by the heart in vivo were reversed by injection of dichloroacetate, which also improved extraction of lactate and pyruvate by the heart in vivo in alloxan diabetes. 2. Sodium dichloroacetate increased glucose oxidation and pyruvate oxidation in hearts from fed normal or alloxan-diabetic rats perfused with glucose and insulin. Dichloroacetate inhibited oxidation of acetate and 3-hydroxybutyrate and partially reversed inhibitory effects of these substrates on the oxidation of glucose. In rat diaphragm muscle dichloroacetate inhibited oxidation of acetate, 3-hydroxybutyrate and palmitate and increased glucose oxidation and pyruvate oxidation in diaphragms from alloxan-diabetic rats. Dichloroacetate increased the rate of glycolysis in hearts perfused with glucose, insulin and acetate and evidence is given that this results from a lowering of the citrate concentration within the cell, with a consequent activation of phosphofructokinase. 3. In hearts from normal rats perfused with glucose and insulin, dichloroacetate increased cell concentrations of acetyl-CoA, acetylcarnitine and glutamate and lowered those of aspartate and malate. In perfusions with glucose, insulin and acetate, dichloroacetate lowered the cell citrate concentration without lowering the acetyl-CoA or acetylcarnitine concentrations. Measurements of specific radioactivities of acetyl-CoA, acetylcarnitine and citrate in perfusions with [1-(14)C]acetate indicated that dichloroacetate lowered the specific radio-activity of these substrates in the perfused heart. Evidence is given that dichloroacetate may not be metabolized by the heart to dichloroacetyl-CoA or dichloroacetylcarnitine or citrate or CO(2). 4. We suggest that dichloroacetate may activate pyruvate dehydrogenase, thus increasing the oxidation of pyruvate to acetyl-CoA and acetylcarnitine and the conversion of acetyl-CoA into glutamate, with consumption of aspartate and malate. Possible mechanisms for the changes in cell citrate concentration and for inhibitory effects of dichloroacetate on the oxidation of acetate, 3-hydroxybutyrate and palmitate are discussed.
 ...
PMID:Effects of dichloroacetate on the metabolism of glucose, pyruvate, acetate, 3-hydroxybutyrate and palmitate in rat diaphragm and heart muscle in vitro and on extraction of glucose, lactate, pyruvate and free fatty acids by dog heart in vivo. 476 52


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