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 predominant substrate for glycation processes resides: 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 and degree of wrinkling, etc. – can serve as a (rough) barometer of the glycation processes occurring 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 – creating the conditions for high rates of AGE formation. And four, energy production is diminished because of the cumulative damages incurred to mitochondrial respiratory 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.
Collagen is not only found in the skin, but also in the arteries, cartilage, and bones. So, the health of the skin – its rigidness and degree of wrinkling, etc. – can serve as a (rough) barometer of the glycation processes occurring 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 – creating the conditions for high rates of AGE formation. And four, energy production is diminished because of the cumulative damages incurred to mitochondrial respiratory 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–mediated by positively charged calcium cations (interacting with the negative charges on glutamate's carboxylate)–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 (Schaefer, Gleason, & Dansinger, 2009; Tappy et al., 1986).
The permissive effect on glucose use that fructose has protects against glycation processes. For instance, fructose activates the enzyme complex, PDH, and this in turn prevents the accumulation of triose phosphates (substrates for glycation reactions) and allows for glucose to be metabolized oxidatively (Park et al., 1992). 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 (see for instance, Matarese et al., 2002). Fructose, as compared to glucose, also decreases insulin and blood fatty acid concentrations, indicating an enhanced sensitivity to the hormone insulin; these effects are more pronounced in insulin resistant people (Teff et al., 2009).
The largest benefit with regard to the main interest of this post concerns the carbon dioxide increasing effect of fructose. A high concentration of carbon dioxide, via carboxylation, protects glycation liable 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, compared to some of the oxidative products from polyunsaturated fats, fructose is much less reactive. Fructose is also found in the blood and in cells at very low concentrations–orders of magnitude less than glucose in fact, which is because fructose is rapidly used or converted to other substrates. For instance, on the ingestion of fructose, 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 (Chan et al., 2001; Zhang et al., 2001).
Finally, a concern raised by the reader of this blog about ingesting fructose-containing foods is fructose malabsorption. Briefly, fructose malabsorption is greatly attenuated when glucose is co-ingested with fructose, as in fruit & sucrose (Riby, Fujisawa, & Kretchmer, 1993). Also tolerance should develop to fructose over time, on the order of days, such that progressively more could be taken without experiencing adverse digestive effects (Beyer, Caviar, & McCallum, 2005); though the evidence for this 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.
Beyer, P. L., Caviar, E. M., & McCallum, R. W. (2005). Fructose intake at current levels in the United States may cause gastrointestinal distress in normal adults. Journal of the American Dietetic Association, 105(10), 1559–66. doi:10.1016/j.jada.2005.07.002
Chan, C. B., De Leo, D., Joseph, J. W., McQuaid, T. S., Ha, X. F., Xu, F., Tsushima, R. G., et al. (2001). Increased uncoupling protein-2 levels in beta-cells are associated with impaired glucose-stimulated insulin secretion: mechanism of action. Diabetes, 50(6), 1302–10. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11375330
Matarese, G., Sanna, V., Lechler, R. I., Sarvetnick, N., Fontana, S., Zappacosta, S., & La Cava, A. (2002). Leptin accelerates autoimmune diabetes in female NOD mice. Diabetes, 51(5), 1356–61. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11978630
Park, O. J., Cesar, D., Faix, D., Wu, K., Shackleton, C. H., & Hellerstein, M. K. (1992). 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. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1130852&tool=pmcentrez&rendertype=abstract
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Schaefer, E. J., Gleason, J. A., & Dansinger, M. L. (2009). Dietary Fructose and Glucose Differentially Affect Lipid and Glucose Homeostasis 1 – 3, 1257–1262. doi:10.3945/jn.108.098186.WHO
Tappy, L., Randin, J. P., Felber, J. P., Chiolero, R., Simonson, D. C., Jequier, E., & DeFronzo, R. A. (1986). Comparison of thermogenic effect of fructose and glucose in normal humans. The American journal of physiology, 250(6 Pt 1), E718–24. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3521319
Teff, K. L., Grudziak, J., Townsend, R. R., Dunn, T. N., Grant, R. W., Adams, S. H., Keim, N. L., et al. (2009). 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(5), 1562–9. doi:10.1210/jc.2008-2192
Zhang, C. Y., Baffy, G., Perret, P., Krauss, S., Peroni, O., Grujic, D., Hagen, T., et al. (2001). Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell, 105(6), 745–55. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11440717