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Mitochondrial Membranes , Mg++, Malate/Oxaloacetate Translocators, Gluconeogenesis, and, Ketoacidosis....

  Hypothesis #NDC2.00 - Gluconeogenic Hormones affect Malate/Oxaloacetate Translocators or Shuttles in the mitochondrial membranes to result in (1) Increased cytoplasmic levels of OAA and (2) Decreased mitochondrial levels of malic acid.
  • Hypothesis #NDC2.01 - Gluconeogenic hormones - particularly AVP - directly inhibit Malic Enzyme (malate dehydrogenase) in both mitochondrial matices and cytosol.
  • Hypothesis #NDC2.02 - Insulin enhances hepatic lipogenesis by increasing mitochondrial membrane permeability to citrate and over-riding inhibition of Malic Enzyme
  • Hypothesis #NDC2.03 - Lipolysis (FFA-CoA -oxidation) results in increased mitochondrial NADH(H+) to NAD+ ratios thus further inhibiting the already endergonic conversion of malate => oxaloacetate
  • Hypothesis #NDC2.04 - Malate/Oxaloacetate Translocators (MOT) are dependent on [Mg++]'s with lower levels resulting in (1) Increased cytoplasmic levels of OAA and (2) Decreased mitochondrial levels of malic acid

"Type 2 Diabetes in whites, but not blacks, is inversely associated with serum magnesium levels................";

"Mg2+ control of respiration in isolated rat liver mitochondria.....";

  • Hypothesis #NDC2.05 - Increased cytoplasmic levels of OAA are gluconeogenic and
  • Hypothesis #NDC2.06 - Mitochondrial levels of malic acid which are decreased
    can result in decreased mitochondrial respiration

"The role of malate in regulating the rate of mitochondrial respiration in vitro.....";

"The role of malate in hormone-induced enhancement of mitochondrial respiration.....";

"Sources of intramitochondrial malate.....";

"Pyruvate/malate antiporter in rat liver mitochondria.....";

"Fumarate permeation in rat liver mitochondria: fumarate/malate and fumarate/phosphate translocators.....";

"Oxaloacetate permeation in rat kidney mitochondria: pyruvate/oxaloacetate and malate/oxaloacetate translocators.....";

"Oxaloacetate uptake into rat brain mitochondria and reconstruction of the malate/oxaloacetate shuttle.....";

"Capacity of the malate/oxaloacetate shuttle for transfer of reducing equivalents across the envelope of leaf chloroplasts.....";

"Aminooxyacetic acid inhibits the malate-aspartate shuttle in isolated nerve terminals and prevents the mitochondria from utilizing glycolytic substrates.....";

"Suppression of the mitochondrial oxidation of (-)-palmitylcarnitine by the malate-aspartate and alpha-glycerophosphate shuttles.....";

"Dehydroepiandrosterone and related steroids inhibit mitochondrial respiration in vitro.....";

"Regulation of oxalacetate metabolism in liver mitochondria. Evidence for nicotinamide adenine dinucleotide-malate dehydrogenase equilibrium and the role of phosphoenolpyruvate carboxykinase in the control of oxalacetate metabolism in intact guinea pig and rat liver mitochondria.....";

"Gluconeogenesis in vitro. Formation of glucose 6-phosphate from malate by a cell-free rat-liver system consisting of cytosol and mitochondria.....";

"Effect of alloxan on the transport of dicarboxylate, tricarboxylate, pyruvate and glutamate in isolated mouse liver mitochondria.....";

"Transport of malate and citrate into rat brain mitochondria under hypoxia and anesthesia.....";

  • Hypothesis #NDC2.07 - Vasopressin is the most potent gluconeogenic hormone in this context and can -
    in the absence of sufficient insulin-induced compensation - virtually abolish mitochondrial levels of OAA.
    This results in inability to metabolize Acetyl-CoA-SH and severe ketosis with acidosis
  • Hypothesis #NDC2.08 - Dehydration (through vomiting and/or diarrhea and/or sweating and/or hypodipsia)
    is the major pathophysiologic cause of DKA
    (acting through significantly increased ADH-Vasopressin release)
  • Hypothesis #NDC2.09
    On one level, adaptation to ongoing maximal leptin-enhanced lipolysis may confer some degree of resistance to ketosis
    Hypothesis #NDC2.10
    On another level, leptin may compete with vasopressin to maintain mitochondrial levels of OAA

"Vasopressin increases cytosolic sodium concentration in hepatocytes and activates calcium influx through cation-selective channels.....";

"Ketogenesis in isolated rat-liver mitochondria. IV. Oxaloacetate decarboxylation: consequences for metabolic calculations.....";

"Type I and II models of diabetes produce different modifications of K+ currents in rat heart: role of insulin.....";

"DKA can occur in patients classified as Type 2 based on previous insulin dose or subsequent oral Rx (Hispanics were mainly type 2 (47%), with 34% type 1 and 19% unknown. Whites were predominantly type 1 (80%), with 17% type 2 and 3% unknown. African Americans showed a slight preponderance of type 1 (53%), with a large number of type 2 patients (44%) and 3% unknown).....";

"Feeding old rats high levels of key mitochondrial metabolites can ameliorate oxidative damage, enzyme activity, substrate-binding affinity, and mitochondrial dysfunction" (Proc. Natl. Acad. Sci. USA, [2002] 99:1876-1881)

Inositols and and Insulin Resistance

"Insulin resistance, a result of reduced synthesis of prostaglandylinositol cyclic phosphate, a mediator of insulin action?
Regulation of cyclic PIP synthetase activity by oral antidiabetic and antihypertensive drugs

"Phosphoinositides decrease ATP sensitivity of the cardiac ATP-sensitive K(+) channel. A molecular probe for the mechanism of atp-sensitive inhibition.....";

"D-chiro-inositol effective in reducing insulin resistance................";

"Insulin resistant subjects lack islet adaptation to short-term dexamethasone-induced reduction in insulin sensitivity.................";

Genetic Markers of Insulin Resistance

"Insulin resistance in Sicilians has been linked to the PC-1 region of Chromosome 6 [but in Mexican-Americans it has been variously linked to Chromosomes 2,6,10,15,the SUR-1 receptor, and TRP64ARG";

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