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RE: [IP] good A1Cs without frequent lows possible? (Brain damage)



First, some historical perspective from 20 years ago:

[Stroke. 1986 Jul-Aug;17(4):699-708.]

Progress review: hypoglycemic brain damage.

Auer RN.

 The central question to be addressed in this review can be stated as "How does
hypoglycemia kill
 neurons?" Initial research on hypoglycemic brain damage in the 1930s was aimed
at demonstrating the
 existence of any brain damage whatsoever due to insulin. Recent results
indicate that uncomplicated
 hypoglycemia is capable of killing neurons in the brain. However, the mechanism
does not appear to
 be simply glucose starvation of the neuron resulting in neuronal breakdown.
Rather than such an
 "internal catabolic death" current evidence suggests that in hypoglycemia,
neurons are killed from
 without, i.e. from the extracellular space. Around the time the EEG becomes
isoelectric, an
 endogenous neurotoxin is produced, and is released by the brain into tissue and
cerebrospinal fluid.
 The distribution of necrotic neurons is unlike that in ischemia, being related
to white matter and
 cerebrospinal fluid pathways. The toxin acts by first disrupting dendritic
trees, sparing
 intermediate axons, indicating it to be an excitotoxin. Exact mechanisms of
excitotoxic neuronal
 necrosis are not yet clear, but neuronal death involves hyperexcitation, and
culminates in cell
 membrane rupture. Endogenous excitotoxins produced during hypoglycemia may
explain the tendency
 toward seizure activity often seen clinically. The recent research results on
which these findings
are based are reviewed, and clinical implications are discussed.

-----------------
 Of course, 20 years later, we know a lot more. Here's some of the very latest
research, indicating
changes non-lethal changes in neural activity:

[Regul Pept. 2006 May 4]; [Epub ahead of print]
<http://tinyurl.com/njqbb>

 Habituation of insulin-induced hypoglycemic transcription activation of lateral
hypothalamic
orexin-A-containing neurons to recurring exposure.

Paranjape SA, Vavaiya KK, Kale AY, Briski KP.

 Department of Basic Pharmaceutical Sciences, School of Pharmacy, College of
Health Sciences, The
University of Louisiana at Monroe, Monroe, LA 71209, United States.

 A CNS component of glucose counterregulatory collapse is supported by evidence
for nonuniform
 genomic responsiveness of neurons in characterized central autonomic loci
during recurring
 insulin-induced hypoglycemia (IIH). We have reported that exacerbated
hypoglycemia and attenuated
 patterns of glucagon and epinephrine secretion in rats treated by daily sc
injection of the
 intermediate-acting insulin formulation, Humulin NPH (NPH), are correlated with
diminished
 immunodemonstrability of the AP-1 transcription factor, Fos, in several
components of the central
 metabolic regulatory circuitry, including the lateral hypothalamic area (LHA).
Neurons that
 synthesize the potent orexigenic peptide neurotransmitter, orexin-A, are
restricted to the LHA and
 adjacent hypothalamic loci, and project throughout the central neuroaxis to
structures that govern
 autonomic and behavioral motor output. Dual-label immunocytochemical and
real-time RT-PCR techniques
 were utilized here to evaluate the functional status of this LHA phenotype
during a single versus
 repetitive exposure to prolonged IIH. Tissue sections were collected at
predetermined rostrocaudal
 levels of the LHA after acute or repeated NPH administration, and processed for
nuclear Fos- and
 cytoplasmic orexin-A-immunoreactivity (-ir). Mean numbers of orexin-A-ir
neurons were not different
 between treatment groups. Colabeling of these cells for Fos was increased
relative to controls
 following a single injection of insulin, but numbers of Fos-ir-positive
orexin-A neurons were
 significantly reduced after treatment with four versus one dose of insulin.
Prepro-orexin mRNA
 levels in microdissected LHA tissue were upregulated during acute hypoglycemia,
but were returned to
 control levels by repeated IIH. These data corroborate previous evidence that
IIH is an activational
 stimulus for orexin-A-synthesizing neurons in the LHA, and further demonstrate
that induction of
 cfos and prepro-orexin gene expression by acute hypoglycemia is attenuated by
precedent exposure to
 hypoglycemia. The current results thus provide unique evidence for
neurotransmitter-specific
habituation of LHA neuronal sensitivity to IIH.

-------------------

(Maybe the second one is reversible; I don't know).

 There are many mechanisms of damage involved. One not mentioned above is damage
to the mitochondria
 due to free radicals released when the supply of pyruvate (derived from glucose
via the citric
 acid/Krebs cycle) runs out. The effect is very similar to that of hypoxia or
carbon monoxide
poisoning.

 The damage continues AFTER restoration of the supply of glucose and recovery of
conciousness! At
 some point the PARP-1 DNA repair mechanisms kick in, and they consume a lot of
energy, depriving the
 cell of pyruvate for a time even after glucose is supplied. There's ongoing
research at the San
 Francisco VA Medical Center, aimed at addressing this either through
administration of high levels
of pyruvate, or inhibiting the PARP-1 enzyme activity.

 Reversible damage vs permanent damage -- I really don't care. I don't want
brain damage either way.
 While you often see 30 mg/dl as a dividing line, I have not seen ANY evidence
to support the
 existance of a threshold effect. I think it most unwise to even approach 30
mg/dl. And I think it
 unwise to accept temporary brain damage -- especially repeated, as in the
second article above.

 Somewhere below 60 mg/dl, brain damage starts. The exact level depends on time
-- the lower the
 quicker, and the more serious. And meters aren't exact. I try to avoid even
approaching 60 mg/dl.

 The rest of the body isn't spared either. The counter-regulatory hormones,
glucagon, cortisol,
 growth hormone, and epinepherine (adrenaline) each have their deleterious
side-effects. Glucagon
 consumes the body's stores of glycogen, leaving you susceptible to a more
serious low from which you
 may not recover. Cortisol excess has wide-ranging effects from immune-system
suppression to skin
 thining and bruising to bone loss, protein breakdown, hunger, weight gain...
Epinepherine rasises
 your blood pressure, stresses the heart, and is responsible for many of the
unpleasant effects.

I think some of you folk are too blase about hypoglycemia!
.
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