In my first “fact check” of Dr. Ray
Peat, I had discussed the mechanisms by which insulin exerts its effects from
the conventional textbook point-of-view. I’ve gotten mostly good feedback
on that post, and some idiotic ones, from the people who obviously didn’t take
the time to read it, or if they did failed to understand it.
Briefly, the conventional view is
that insulin, upon being secreted by the β-cells of the pancreatic islets, acts on and activates the
insulin receptors, initiating the insulin-signaling cascade. This
activation of the insulin receptor then provides a docking site for the insulin
receptor substrate (IRS) proteins, which thereafter activate kinases in the
vicinity that contain a specific SH2 domain, namely the kinase that
phosphorylates the 3-position of the membrane lipid phosphatidylinositol
4,5-bisphosphate (PI 3,4 P2) to phosphatidylinositol 3,4,5-trisphosphate (PI 3,4,5 P3).
Figure 1 Insulin signaling
pathways in the cell.
GLUT =
glucose transporter (lower right)
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This lipid product, PI 3,4,5 P3 thereafter activates the
kinase, PDK1, and PDK1 phosphorylates and activates Akt, another kinase that
moves throughout the cell’s cytoplasm, executing most of insulin’s actions, the
most important of which for this post is the translocation of the glucose
transporters from the cytoplasm to the plasma membrane.
This complex insulin-signaling
cascade, which I’ve simplified a great deal, is obviously dependent on an
intact plasma membrane that’s impermeable (or semi-permeable) to glucose, as
well as glucose transporter proteins that are ready to be called into action at
a moment’s notice. (Others like Roden et al. have even gone as far as to
suggest that the passage of glucose through the plasma membrane is, inherently,
the rate limiting step in the use of glucose [Roden, 2004].) There are a
few issues with this scheme.
For one, in the absence of insulin,
glucose freely passes through the plasma membrane and into the cell’s
cytoplasm, such that at equilibrium, the glucose concentration inside the cell
is 20 to 30 percent of the glucose concentration in the blood (Randle &
Smith, 1958a, 1958b). Two, the evidence that there’s a defect of sorts in
the glucose transporters in diabetes is conspicuously sparse. And
three, glycogen tends to accumulate in insulin resistant tissues, indicating a
block on glucose use downstream of the glucose phosphorylation step upon
arrival into the cell by way of the previously mentioned glucose transporters
(Sakamoto & Holman, 2008).
So the impairment of glucose use is
taking place inside the cell, rather than at its border, in which the
glycolytic enzymes operate. Dr. Gilbert Ling believes, and has shown in a
series of experiments in the 1950s and 1960s, that the rate at which glucose
moves into the cell’s watery interior is governed by the availability of
glucose “adsorption sites” on certain proteins and enzymes. The plasma
membrane has little to nothing to do with this process.
Insulin, in Dr. Ling’s sense,
functions a an cardinal adsorbent, which is basically any substance (e.g.,
hormones and drugs) that interacts strongly with proteins at very low doses
(i.e., potent), changing the protein’s electronic state; this electronic
perturbation, so to speak, in turn is transmitted like dominoes to the rest of
the protein and other proteins. The proteins unfold a bit as a result,
exposing their glucose adsorption sites, which preferentially bind glucose over
other sugars, in a stereoselective manner.
In the resting living state where,
like in prepared Jello-O, water is structured in close association with
cellular proteins, as well as ions and other molecules (e.g., potassium and
ATP), and so glucose has a reduced solvency in the water inside the cell than
in the water outside the cell.
Figure 2 Ling's association-induction hypothesis. The figure on the right represents the
resting living state and the one on the left, the active living state. The squiggly lines are single protein
molecules, X+ is potassium, and Z could be insulin in this case.
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So in the resting living state, and
in the absence of insulin, in which the glucose adsorption sites become
unexposed, glucose is found at higher concentrations in the blood than in the
cell’s cytoplasm and adsorbed to intracellular proteins and enzymes. This
accounts for the unequal distribution of glucose across the plasma membrane (at
least 4.5-fold higher concentrations outside the cell than inside the
cell). No pumps or transporters are required.
Given the conventional model, how
does one account for this unequal distribution of glucose across the plasma
membrane in the absence of insulin? We could evoke the idea of a glucose
pump of sorts. Though this pump would have to operate bidirectionally;
that is, at high rates when the glucose concentration in the blood is low; and
at low rates when the glucose concentration in the blood is high, permitting
glucose to move into the cell in droves. Energy would be continuously
used to maintain these pumps, and membrane proteins would provide the channels
through which glucose could pass, via facilitated diffusion, into the
cell. (There are too many issues with this scheme to consider it further
at this point.)
When energy is used (for reasons
that will be discussed in another post) the cell, which operates cooperatively
as a unit, destabilizes a bit, and this allows glucose, as well as calcium, to
move into the cell in droves. Under the control of insulin, glucose
adsorption sites on proteins and enzymes become exposed, and glucose is burned
to replenish the ATP. At the same time, carbon dioxide is produced, which
functions to stabilize the resting living state and, via the Bohr effect,
increases the efficiency with which oxygen is unloaded from the red blood
cells, curtailing the production of lactate (and protons). In this highly
energized, resting living state, potassium is preferentially adsorbed to the
ionized carboxylate groups on intracellular proteins. (This satisfactorily
explains why the administration of glucose and insulin can uncomfortably lower
blood potassium levels.)
Insulin, glucose, and oxygen are at
the core of our resistance to stress,
as Danny Roddy
has pointed out, and now we have a firmer basis for understanding why this is.
Take for example what would happen,
in terms of Dr. Ling’s association-induction hypothesis, in ischemia (low
oxygen availability) of the heart, which represents an extreme case that offers
up a glimpse of the provision of support by oxygen, glucose, insulin, and
carbon dioxide.
Glycogen is a readily mobilizable
fuel source in the heart that’s increasingly called upon as the blood supply of
oxygen lessens. Almost instantly, glycogen provides free glucose
molecules, which is oxidized to generate ATP, and, once more, in an all-or-none
manner, this electronically shifts proteins in a way that maintains the highly
energized, resting living state in the face of stress. (Glycogen is replenished
by fructose more efficiently than any other single nutrient.)
Over time, or if glucose and
oxygen are not available, or available in inadequate amounts, the cell
destabilizes, and as a result calcium, which is normally excluded due to its
reduced solvency in structured cellular water, is permitted to move into the
cell in droves (i.e., calcium overloading). Cellular water is
structured, to some extent—somewhere between the states of liquid water and
solid ice—by the presence of ATP.1
Calcium overloading, via excessive
excitation or from ATP depletion, over time, irreversibly transitions the cell
into the so-called “dead state,” which is a concept—that is, being dead or
alive—the conventional model (i.e., membrane-pump theory) has failed to
adequately explain. (As I’ve said before ATP is synonymous with life.)
Oxygen is depleted as the cell
becomes increasingly reliant on the use of fatty acids to generate ATP, accelerating
the build up of lactate. At the same
time, the flux of glucose through the pyruvate dehydrogenase enzyme (PDH)
complex, which carries out a key step in the metabolism of carbohydrates,
essentially linking glycolysis to the citric acid cycle, 2 slows, and ultimately
comes to a stop, further contributing to lactate buildup.
Figure 3 PDH complex (blue) regulation via reversible phosphorylation
(inactive, right) and dephosphorylation (active, left) by kinases (PDK 1,2,3,
or 4) and phosphatases (PDP 1 or 2). Recall that fructose is one of the
activators of the PDH complex.
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The buildup of toxic metabolites
and the loss in cell structure leads to an impaired functioning of tissues and
their death quickly ensues. The provision of glucose, oxygen, and
insulin, however, can short-circuit and reverse this vicious cycle.
The oral hypoglycemic drugs, like
glipizide, are associated with an increased risk of cardiovascular death. This
warning was first made based on a long-term prospective study which was set up
to evaluate the efficacy of four different (non-insulin) classes of oral
diabetes drugs in the 1970s that included over 800 diabetics. The persistent
warped view of diabetes—that is, it is a disease of excessive blood sugar—has
made it possible to continue the practice of treating diabetics for the sole
purpose of "controlling blood glucose levels."
I’ve for the purpose of keeping
this discussion as reader friendly and short as possible, simplified concepts
as much as I could and left out the details, calculations, experiments that
have led to some of the assumptions made herein. I’ve also in this
discussion left out the role of hormones, which adds another layer of
complexity to the entire picture.
Thinking about physiology in terms
of Dr. Ling’s conception of everything is hard to do (at least for me) and I’ve
seen others try, but whether they realize it or not, they’ve oscillated back
and forth between Dr. Ling’s model and the conventional model.
Nonetheless the argument of
"context" is not applicable to my first "fact check" where
I challenged Dr. Peat's position regarding the role insulin assumes in the
blood glucose regulation. Much of the work cited in defense of Dr. Peat
is not only difficult to track down, but they can also by difficult to grasp
and can be, at times, obscure to my conventionally-educated scientific mind.
Yet, my position regarding Dr. Peat's quote on the role of insulin in the
post I've been alluding to hasn't been successfully refuted, even given Dr.
Ling's conception of cell physiology, but I'm still interested in having a
thoughtful discussion about it in the comments section.
References
Randle, P. J., & Smith, G. H. (1958a). Regulation of
glucose uptake by muscle. 1. The effects of insulin, anaerobiosis and cell
poisons on the uptake of glucose and release of potassium by isolated rat
diaphragm. The Biochemical journal, 70(3), 490–500. Retrieved
from
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1196696&tool=pmcentrez&rendertype=abstract
Randle, P. J.,
& Smith, G. H. (1958b). Regulation of glucose uptake by muscle. 2. The
effects of insulin, anaerobiosis and cell poisons on the penetration of
isolated rat diaphragm by sugars. The Biochemical journal, 70(3),
501–8. Retrieved from
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1196697&tool=pmcentrez&rendertype=abstract
Roden, M.
(2004). How free fatty acids inhibit glucose utilization in human skeletal
muscle. News in physiological sciences : an international journal of
physiology produced jointly by the International Union of Physiological
Sciences and the American Physiological Society, 19, 92–6. Retrieved
from http://www.ncbi.nlm.nih.gov/pubmed/15143200
Sakamoto, K.,
& Holman, G. D. (2008). Emerging role for AS160/TBC1D4 and TBC1D1 in the
regulation of GLUT4 traffic. American journal of physiology. Endocrinology
and metabolism, 295(1), E29–37. doi:10.1152/ajpendo.90331.2008
1 others in the field have confirmed this quality of cellular
water.
2 PDH complex carries out the metabolism of pyruvate to acetyl
CoA, a central point in all of metabolism that intertwines the oxidation of
protein, fat, and carbohydrate.
