Glycation processes and the
potentially protective effects of an intensely active metabolic rate are topics
that have been referenced on this blog frequently. Glycation and
cross-linking of molecules in the body contribute to the complications of diabetes
and the changes in tissues seen in aging. A salient consequence of these
processes is the stiffening and loss of functioning of tissues in the body—including
the skin, where a major substrate for glycation processes exists:
collagen.
Collagen is not only found in the
skin, but also in the arteries, cartilage, and bones. So, the health of
the skin (its rigidness, degree of wrinkling, etc.) can serve as a (rough)
barometer of the glycation processes that occur in the body.
With age cross-linked proteins
accumulate in tissues throughout the body. This is a consequence of a few
things. For one, the turnover of proteins is decreased. Two, the
synthesis of proteins, despite the availability of amino acids, is, to some
extent, impaired. Three, fat is oxidized in preference to glucose, and as
a result less carbon dioxide is produced and oxidative stress is promoted,
thereby creating the conditions for high rates of AGE formation. And
four, energy production is diminished due to the cumulative damages incurred to
mitochondrial respiratory protein complexes.
A protective factor lost as a
consequence of the processes listed above is carbon dioxide. Dissolved in
blood mainly as bicarbonate, carbon dioxide has a myriad of known functions in
the body, mainly by way of forming carboxylated adducts with other
macromolecules. Some of the reactions that carbon dioxide participates in
are listed below.
- As with other enzymes that employ biotin as a cofactor, pyruvate carboxylase (the first step of gluconeogenesis) uses carbon dioxide as a substrate– namely, its activated form carboxyphosphate–to carboxylate pyruvate to oxaloacetate.
- The enzyme catalyzing the first step in de novo synthesis of fats, acetyl CoA carboxylase, uses carbon dioxide, forming malonyl CoA. The formation of malonyl CoA inhibits fatty acid oxidation and promotes glucose oxidation and insulin sensitivity. The activity of acetyl CoA carboxylase is depressed in diabetic hearts (even in the presence of saturating concentrations of acetyl CoA) and insulin resistant animals.
- Blood clotting proteins, for activity, require carboxylation of their glutamate residues, otherwise, interactions between clotting proteins (that is mediated by positively charged calcium cations interacting with the negative charges on the carboxylate group of glutamate residues) could not occur and so the clotting cascade would not be able to move forward.
Carbon dioxide is produced in the
process of energy generating metabolism. The amount of carbon dioxide
produced in relation to the amount of oxygen consumed is the respiratory
quotient (RQ). Generally experimental evidence bears out the supposition
that sugar oxidation produces a higher RQ than fat oxidation. The stress
metabolism, in stark contrast, wastes carbon dioxide.
Total energy expenditure is the sum
total of the resting energy expenditure and activity energy expenditure.
The resting energy expenditure contributes about 60 to 80 percent of the total
energy expenditure.
Declining with age, activity energy
expenditure is the energy expended from volitional movements (i.e., exercise)
and diet-induced thermogenesis.
Aging, obesity, and diabetes are
all associated with a lower thermogenic response to food ingestion.
However, as mentioned previously on this blog, fructose can raise the energy
expended and carbon dioxide produced after eating to near normal in diabetics.
The thermogenic effect of sugars
can be estimated, theoretically, by the ratio of ATP synthesized to ATP
hydrolyzed. From this rough analysis alone, compared to an equal amount
of glucose, fructose generates more heat and produces more carbon dioxide in
the process.1,2
The permissive effect on glucose
use that fructose has protects against glycation processes. For instance,
fructose activates the enzyme complex PDH that in turn prevents the accumulation
of triose phosphates, substrates for glycation reactions, and allows for glucose
to be metabolized oxidatively.3 Fructose also supplies pyruvate, which is hypothesized to, via
competition, block glycation reactions.
Furthermore, fructose decreases the
levels of the proinflammatory peptide, leptin, which is, among other hormones,
secreted in excess in diabetes and obesity, and it’s clear that leptin is a
hormone of the immune system as much as it is a hormone of metabolism.4 Fructose, compared to glucose, also decreases insulin and
blood free fatty acid concentrations, indicating an enhanced sensitivity to the
hormone insulin; these effects are more pronounced in people who are insulin
resistant.5
The largest benefit with regard to
the main interest of this post concerns the carbon dioxide raising effect of
fructose. High levels of carbon dioxide, via carboxylation, protect
glycation labile amino acids and lipids. Thus, the equilibrium in
cells shifts to favor amine group carboxylation, rather than glycosylation,
staving off the initial step in AGE formation (i.e., Schiff base formation).
Even though it could glycate
proteins in the body, fructose is much less reactive than some of the oxidative
products derived from polyunsaturated fats.
Fructose is also found in the blood and in cells at very low
concentrations, orders of magnitude less than glucose, because fructose is
rapidly used or converted to other substrates by cells. Upon the
ingestion of fructose, for instance, about 10 percent of it is converted to
glucose by the intestinal cells, and the rest is converted to glucose, lactate,
glycogen, and carbon dioxide by the liver. Thus, fructose rarely rises by
more than 0.5 to 1 percent after ingesting even high doses of it.
Interestingly, high rates of fat
oxidation, by producing large amounts of mitochondrial reactive oxygen species
(e.g., superoxide), uncouple glucose oxidation from ATP formation, via UCP-2,
in the pancreas. ATP is depleted as a result, and this keeps the voltage-gated
calcium channels closed, the opening of which is required for the secretion of
insulin containing granules from β-cells of the pancreatic islets. By removing the inhibition
on fatty acid mobilization, this uncoupling effect reinforces the body wide
insulin resistant and inflammatory states.6,7
On a final note, there was a concern
raised by the reader about fructose malabsorption. Briefly, fructose
malabsorption is greatly attenuated when glucose is co-ingested with fructose,
as in fruit and sucrose.8 Also, tolerance should develop to fructose over time, on
the order of days, such that more and more fructose could be eaten without
experiencing adverse digestive effects.9 (The evidence for this is, however, is circumstantial.)
In a word fructose–or even better sucrose–could
be protective against the complications of diabetes, obesity, and aging.
A simple recipe of sugar and baking soda, dissolved in water, can
significantly, and rapidly, raise carbon dioxide levels.
References
1. Schaefer, E.
J., Gleason, J. A. & Dansinger, M. L. Dietary Fructose and Glucose
Differentially Affect Lipid and Glucose Homeostasis 1 – 3. 1257–1262
(2009).doi:10.3945/jn.108.098186.WHO
2. Tappy, L. et al. Comparison of
thermogenic effect of fructose and glucose in normal humans. The American
journal of physiology 250, E718–24 (1986).
3. Park, O. J. et al. Mechanisms of
fructose-induced hypertriglyceridaemia in the rat. Activation of hepatic
pyruvate dehydrogenase through inhibition of pyruvate dehydrogenase kinase. The
Biochemical journal 282 ( Pt 3, 753–7 (1992).
4. Matarese, G. et al. Leptin
accelerates autoimmune diabetes in female NOD mice. Diabetes 51,
1356–61 (2002).
5. Teff, K. L. et al. Endocrine and
metabolic effects of consuming fructose- and glucose-sweetened beverages with
meals in obese men and women: influence of insulin resistance on plasma
triglyceride responses. The Journal of clinical endocrinology and metabolism
94, 1562–9 (2009).
6. Chan, C. B. et al. Increased
uncoupling protein-2 levels in beta-cells are associated with impaired
glucose-stimulated insulin secretion: mechanism of action. Diabetes 50,
1302–10 (2001).
7. Zhang, C. Y. et al. Uncoupling
protein-2 negatively regulates insulin secretion and is a major link between
obesity, beta cell dysfunction, and type 2 diabetes. Cell 105,
745–55 (2001).
8. Riby, J. E., Fujisawa, T. &
Kretchmer, N. Fructose absorption. The American journal of clinical
nutrition 58, 748S–753S (1993).
9. Beyer, P. L., Caviar, E. M. &
McCallum, R. W. Fructose intake at current levels in the United States may
cause gastrointestinal distress in normal adults. Journal of the American
Dietetic Association 105, 1559–66 (2005).
