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.
The central question to be addressed in this review can be stated as "How does
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
endogenous neurotoxin is produced, and is released by the brain into tissue and
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
intermediate axons, indicating it to be an excitotoxin. Exact mechanisms of
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
changes non-lethal changes in neural activity:
[Regul Pept. 2006 May 4]; [Epub ahead of print]
Habituation of insulin-induced hypoglycemic transcription activation of lateral
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
genomic responsiveness of neurons in characterized central autonomic loci
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
immunodemonstrability of the AP-1 transcription factor, Fos, in several
components of the central
metabolic regulatory circuitry, including the lateral hypothalamic area (LHA).
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
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.
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
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
The damage continues AFTER restoration of the supply of glucose and recovery of
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,
growth hormone, and epinepherine (adrenaline) each have their deleterious
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...
your blood pressure, stresses the heart, and is responsible for many of the
I think some of you folk are too blase about hypoglycemia!
for HELP or to subscribe/unsubscribe/change list versions,