Regulation of pyruvate dehydrogenase by insulin and polyamines within electropermeabilized fat-cells and isolated mitochondria

Rutter, Guy A.; Diggle, Tricia A.; Denton, Richard M.

doi:10.1042/bj2850435

Cited by 21 publications

(13 citation statements)

References 40 publications

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“…, PDH was activated, in parallel with a rise in blood insulin that was much greater than in normal subjects. PDH activation in both groups should rely on the rise in blood insulin, in line with in vitro findings (see the Introduction) and with evidence that PDH is an insulin target [1][2][3][4][5][6][7][8][9][10][11][12]. However, other possible causes must be examined.…”

Section: Discussionmentioning

confidence: 86%

“…In several tissues and cell types [1][2][3][4][5][6], including human circulating lymphocytes (CL) [7][8][9], insulin controls PDH by targeting PDH phosphatase signalling pathways [10][11][12][13]. PDH is poorly active in various cells and tissues of animals with experimentally induced diabetes mellitus or obesity [1][2][3][14][15][16][17], and in the skeletal muscle of obese individuals with Type II diabetes [18] ; this is due to an increased proportion of PDHb, and not to a decrease in the total amount of PDC [2,3,15,16].…”

Section: Introductionmentioning

confidence: 99%

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Enhanced blood insulin overcomes pyruvate dehydrogenase derangements that reflect systemic insulin resistance in obese adolescents

et al. 2002

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Pyruvate dehydrogenase (PDH) has low activity in the circulating lymphocytes (CL) of obese adolescents and adults. In vitro, it is unresponsive to insulin at 5 micro-units/ml and is activated at 50 micro-units/ml, in contrast with activation and inhibition respectively at these concentrations in CL from controls. These changes are seen as being indicative of a molecular disorder underlying insulin resistance. The aims of the present study were to determine whether a substantial enhancement of blood insulin levels restores the PDH activity in CL from obese adolescents and abolishes the in vitro alterations, and whether PDH activity and indices of insulin resistance are correlated. Six obese adolescents and six normal-weight controls underwent a 4 h frequently sampled intravenous glucose test with minimal model analysis, to bring about a sharp rise in blood insulin and provide a reliable index of insulin sensitivity (S(I)). PDH activity was evaluated in CL obtained from blood samples at set times before and after their exposure to insulin in vitro. Insulin levels rose in all subjects in the first 10 min, although to a much greater extent in the obese group, and then decreased until the end of the test (240 min; t(240)). PDH activity in CL paralleled the insulin pattern in the control subjects, whereas in the obese subjects it was below normal 3 min before the start of the test (t(-3)), but rose significantly throughout the test. PDH responses in vitro to insulin in CL taken from the control subjects at t(-3) and t(240) and in CL taken from the obese subjects at t(-3) were as reported above, but were normal (i.e. the same as in control CL) in CL taken from the obese subjects at t(240). Baseline PDH activity was inversely correlated with body mass index and with fasting insulin, and directly correlated with S(I). These results show that a brief and sharp enhancement of blood insulin overcomes derangements in PDH that reflect systemic insulin resistance in obese adolescents.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Enhanced blood insulin overcomes pyruvate dehydrogenase derangements that reflect systemic insulin resistance in obese adolescents

et al. 2002

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“…Insulin is known to activate ornithine decarboxylase, which is thought to regulate polyamine synthesis by increasing translation of its mRNA, but a causal link between the activation of ornithine decarboxylase and that of PDH has not been demonstrated to date. Insulin does not activate PDH in the heart, and therefore it may be relevant that addition of polyamines to incubations of intact fat-cell mitochondria leads to the activation of PDH, whereas addition to heart mitochondria does not [20].…”

Section: Molecular Mechanisms Involved In the Activation Of Pdh By Inmentioning

confidence: 99%

Signalling pathways involved in the stimulation of fatty acid synthesis by insulin

Denton

Heesom

Moule

et al. 1997

Biochemical Society Transactions

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An important effect of insulin after a carbohydrate meal is to increase the conversion of glucose into fatty acids in fat, liver and mammary cells. Both short-term and long-term mechanisms are involved. A main interest of this laboratory for a number of years has been the short-term mechanisms involved in insulin signalling in rat epididymal fat cells, and this will be the subject of this brief article. Three different steps in the pathway are activated in parallel within 5 min of exposing these cells to insulin, and the overall result is a 10-fold increase in the rate of fatty acid synthesis. These steps are: glucose transport across the cell membrane, pyruvate dehydrogenase (PDH) in the mitochondria, and the cytoplasmic enzyme acetyl-CoA carboxylase (ACC) [l]. It is now becoming clear that different signalling pathways are involved although, as with other metabolic actions of insulin, important gaps in our knowledge remain. Temporal regulation of lipid homoeostasis is effected at several levels. Rapid modulation of cellular rates of lipolysis, fatty acid oxidation and lipogenesis occurs by changes in t h e activities of Abbreviations used: PPAR, peroxisomal proliferatoractivated receptor; PPRE, peroxisomal proliferator-key enzymes in the pathways of lipid metabolism. response element; DR, direct repeat; aP,, adipocyte activities may be allosterically, fatty acid-binding protein; LPI,, lipoprotein lipase; or by hormone-or catecholamine-induced NIDDM, non-insulin-dependent diabetes. changes in phosphorylation state. In the longer Volume 25

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“…Since in both cell groups activation takes only 15 min, the difficulties with phosphatase suggested above should not imply a quantitative enzyme defect. PDHP phosphatase is considered to be the insulin target [15][16][17][27][28][29][30] and patients insulin alone [8,22,24,25,32], or in reported evidence [16,17,28,[35][36][37][38][39][40][41].…”

Section: Drug Effect (E) In Terms Ofmentioning

confidence: 99%

“…At the end of preparation, cells forms, active dephosphorylated (PDHa) and inactive phosphorylated (PDHb). The balance between the two forms is were suspended in 110 mm NaCl buffered in 40 mm phosphate buffer pH 7.4 (PBS A) and identified by controlled by PDH kinase and PDHP phosphatase.The latter is activated by mm Ca ++ and mm Mg ++ and inhibited morphological, biochemical and immunological techniques [32]; in all preparations, the cell suspension consisted of by mm fluoride [26] and there is evidence that it constitutes the actual insulin target [15][16][17][27][28][29][30].…”

mentioning

confidence: 99%

Molecular effects of sulphonylurea agents in circulating lymphocytes of patients with non‐insulin‐dependent diabetes mellitus

Rabbone¹,

Piccinini²,

Curto³

et al. 1998

Brit J Clinical Pharma

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Aims In circulating lymphocytes of NIDDM patients pyruvate dehydrogenase (PDH), the major determinant in glucose consumption through oxidative pathways, is poorly active. The aim of this study is to examine whether sulphonylurea drug treatment revives PDH activity in circulating lymphocytes from NIDDM patients. Methods Twenty normal-weight individuals with NIDDM were enrolled in this study. They had maintained their glycaemic levels close to normal by means of a restricted diet that had no longer been successful in the proceeding 2 months. The treatment protocol consisted in 160 mg gliclazide daily for 5 weeks. Twenty healthy subjects, matched for age, body mass index and gender, were enrolled as a control group. Patients, before and after treatment, as well as controls were tested for PDH activity in their circulating lymphocytes. Nine other untreated patients and nine healthy subjects, with the above mentioned characteristics, were recruited for the assay of PDH activity in their circulating lymphocytes before and after exposure, in vitro, to gliclazide, to insulin, and to gliclazide and insulin in combination. Results In gliclazide-treated NIDDM patients, PDH activity in circulating lymphocytes recovered. In vitro, in circulating lymphocytes of untreated patients and controls insulin at 5 mU ml −1 was ineffective and highly effective, respectively, in raising enzyme activity; gliclazide at 10 ng ml −1 was ineffective on PDH in both groups, but in combination with insulin at 5 mU ml −1 in both groups PDH was as active as in cells of controls exposed to insulin only. In cells of controls, gliclazide alone at 25-50 ng ml −1 caused enzyme activation, whereas above 50 ng ml −1 it caused inhibition; in cells of patients below 50 ng ml −1 it had no effects, but at 50 ng mland above raised enzyme activity to the basal level of controls. Conclusions This study suggests that free gliclazide concentrations determine recovery of PDH activity in circulating lymphocytes of treated patients through drug-mediated enhanced insulin control over PDH or through the drug alone.Keywords: NIDDM, sulphonylureas, pyruvate dehydrogenase, circulating lymphocytescells. An understanding of the mechanisms underlying this Introduction benefit might throw new light on the mechanisms through which sulphonylureas behave as hypoglycaemic agents. Sulphonylurea drugs are largely employed to lower hyperglycaemia in patients with NIDDM. The mechanism In NIDDM patients systemic glucose consumption through oxidative pathways is abnormal and in tissues underlying this effect is still debated. Evidence indicates these drugs improve cell responsiveness to insulin or even actively involved in preserving glucose homeostasis, such as skeletal muscle [9][10][11], this alteration is accompanied by mimic some of the effects of insulin [1][2][3][4][5][6][7]. In a previous study it was observed that in circulating lymphocytes of poorly active PDH [12,13]. Further, in adipocytes from these patients [14] enzyme response to insulin is impaired. NIDDM patients the...

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Regulation of pyruvate dehydrogenase by insulin and polyamines within electropermeabilized fat-cells and isolated mitochondria

Cited by 21 publications

References 40 publications

Enhanced blood insulin overcomes pyruvate dehydrogenase derangements that reflect systemic insulin resistance in obese adolescents

Enhanced blood insulin overcomes pyruvate dehydrogenase derangements that reflect systemic insulin resistance in obese adolescents

Signalling pathways involved in the stimulation of fatty acid synthesis by insulin

Molecular effects of sulphonylurea agents in circulating lymphocytes of patients with non‐insulin‐dependent diabetes mellitus

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