THE
Diabetes
DAILYNEWS© CONCEPTUAL INDEX
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Mitochondrial Membranes , Mg++, Malate/Oxaloacetate
Translocators, Gluconeogenesis, and, Ketoacidosis....
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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
ß-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
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"Type 2 Diabetes
in whites, but not blacks, is inversely associated with
serum magnesium levels................";
"Mg2+
control of respiration in isolated rat liver mitochondria.....";
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- Hypothesis
#NDC2.05
- Increased cytoplasmic
levels of OAA are gluconeogenic and
insulin-antagonistic
- Hypothesis
#NDC2.06
- Mitochondrial
levels of malic acid which are decreased
can result in
decreased mitochondrial respiration
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"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.....";
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- 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
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"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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