Beyond the restriction of sugary, sweet foods, are ‘sugar-free’ pre-processed and highly cooked foods aggravating the diabetic condition? Sometimes the signaling of the ‘sweet tooth’ isn’t enough.
Informing a diabetic – or anyone for that matter – that consuming food high in sugar will elevate their blood sugar and exacerbate the diabetic condition or increase their risk for the disease diabetes is akin to declaring water is wet.
The multiple mechanisms responsible for sugar’s role in the development and progression of diabetes are tragically under-elucidated, one of which being glycation … the nonenzymatic bonding of a sugar molecule with a protein, lipid, or DNA. (1-2) Seemingly benign, this process is followed by oxidation and the creation of glycation end products, aptly acronymed ‘AGEs’.
Glycation products (AGEs) play a major role in the pathogenesis insulin resistance as inducers of beta cell death (3-4) and diabetic complications such as diabetic neuropathy, retinopathy and nephropathy. (5-7) AGEs promote cytotoxic effects not only on pancreatic beta cells but on other cells and tissues as well, thus making it a concern for the aforementioned indirect diabetic outcomes. (8-9). DNA glycation is currently less studied in diabetes, but it has been found to take place and is most likely responsible for more insidious complications in the disease, namely a diminution of genetic integrity followed by the development of cancer. (10-11) Once lasting hyperglycemia is established, the formation of endogenous AGEs occur – likely due to the acceleration of protein modification by excess serum glucose (12-13) . If renal insufficiency is an accompanying malady, which is often the case in diabetes, the accumulation of circulating AGEs is enhanced. (14) The clearance of AGEs lags behind that of creatinine, meaning even moderate degradation of the GFR (globular filtration rate) can lead to clinically meaningful deleterious outcomes. Simply stated, AGEs are both implicated in the etiology and in the worsening of AGE-initiated diabetic disease, an insidious vicious cycle (i.e., a cause and an effect).
The compliance to the request for fastidious restriction of high-sugar (high GI) foods only partially addresses the influx of exogenous (i.e., dietary) AGEs. Glycation can occur endogenously (within the body) or exogenously (outside the body). Besides the obvious culprits (e.g., chocolate, candies, sugar-sweetened beverages, refined grains, etc.) that contribute to endogenous glycation by spiking glucose, pre-processed foods and foods high in protein and fat can also be contributors of exogenous AGEs formed long before the digestion process that may be surreptitiously sabotaging control of the disease. As a matter of fact, fats and proteins – foods not normally associated with diabetes – contain the highest AGE content and are the major burden of dietary AGE absorption which is increased based on temperature, cooking time, and the amount of moisture during cooking. Broiling and frying produced the most AGEs, followed by roasting and then boiling. The most significant factor was not the time of cooking surprisingly but rather the temperature. Shorter cooking times with higher temperatures are proved to be stronger predictors of AGE generation. (15)
Among 250 foods and beverages were tested using an immunoassay that qualified CML (Nε-(carboxymethyl)lysine), an AGE product. Included in the food groups were unexpected foods and beverages that are not high in sugar or cooked before consumption. Carbohydrate foods were included for comparison as well. The results summarized are as follows:
Processed dairy foods such as butter, margarine, cream cheese, American cheese, Swiss cheese, and grated parmesan cheese were especially high in AGEs. Although dairy food is consumed cold, heat during the pasteurization process stimulates AGE formation. As an exception, nonfat yogurt was very low in AGEs. Mayonnaise contained among the highest amount of AGEs, once again owing to pasteurization to the eggs made with the mixture but moreso from its oil (usually soybean or canola oil) content. Heated cooking oils were indubitably high in AGEs, but uncooked oils were also fairly high. The heat-based extraction and purification procedures with light exposure and air (storage) could explain for this, which in turn also explains the high concentrations in mayonnaise and other high fat spreads that were tested. As expected, roasted nuts such as almonds and cashews were found to have high AGE levels due to the roasting process. Carbohydrate foods contained much lower amounts of AGEs, but by no means does that equate to this food group being invariably safe. Commercially prepared processed carbohydrate foods that are subjected to high-heat and/or high pressure extrusion where the product generates its own heat by friction beforehand had quite high levels of AGEs, particularly Rice Krispie’s, Corn Pops, ready-to-eat cereals, toasted frozen waffles and pancakes, biscotti, granola bars, and chips. Bread crusts were sources of high AGE content, too. Vegetables were very low in ages, but AGE content rose when vegetables were grilled. Starchy vegetables such as white potatoes were more vulnerable to develop high AGEs when fried, as they are usually consumed. Cooked white potatoes and fried eggs were, as predicted, significantly higher in AGEs than their boiled counterparts. Whole fruit and honey were very low in (pre-formed)AGEs compared to other food groups, but fruits naturally high in sugar still can produce marked endogenous AGEs by spiking serum glucose despite not being ingested as pre-formed AGE-carriers. The effect will be even more pronounced in juices which lack the fiber to slow digestion. Fruit juices were moderately low in AGEs against the highly cooked samples but their AGE content was not minimal as a result of pasteurization (frequently overlooked in fruit juices), so they could become troublesome if consumed often, also taking into account their very high sugar content. White rice, likewise, was low in AGEs but is problematic for the same reasons as a high glycemic index food. (16)
A separate study evaluated CML of foods using a more accurate method of measurement called liquid chromatography-mass spectrometry. Unlike relying on antibodies with an immunoassay, mixtures are physically separated where AGEs can be individually identified, reducing the risk of over- or underestimation. Similar to the study above, both white bread crust and whole wheat bread crust were notably high in AGEs, but unlike the other study that could not recover appreciable amounts of AGEs in milk products, whole fat milk and especially powdered milk contained AGE contents even higher than that of butter, which was likely incorrectly interpreted by the immunoassay used in the previous study. Pasteurization and evaporation can account for this, as raw full-fat milk showed negligible levels of CML. (17)
The presence of methylglyoxal in food and beverages is also harmful to the consumer, and thus should be avoided. Methylglyoxal is not (yet) an advanced glycation product or a marker of AGEs but it is a reactive metabolite and a potent glycating agent that modifies both protein and DNA to eventually form AGEs. It can occur endogenously (from hyperglycemia), but it is also formed in heat during the cooking of foods and thus can be ingested. (18-19) In that case, it is to be thought of as another source of AGE intake. Expectedly, it is associated with microvascular complications such as nephropathy, retinopathy, and neuropathy. (20)
Popular foods and beverages found to contain appreciable levels of methylglyoxal are potato chips, alcoholic drinks (wine, beer, whiskey, etc.), coffee, tea, carbonated, soy sauce, and soy paste. (19)(21-22) The content of methylgloxal tends to be less in teas – even with the same amount of added sugar as carbonated beverages due to the trapping and scavenging ability of tea polyphenols including catechins in green teas and theaflavins in black teas. (23) Thermal treatment followed by long-term storage (e.g., frying or microwaving over 2 minutes for potato chips (24), malting, brewing, fermentation, roasting, carbonation, etc.) is responsible for the glycating reactive compounds in these foodstuffs.
Apparently, only ~10% of exogenous (or dietary) AGEs are absorbed into circulation, but as little as one third is excreted after three days, leaving a significant portion remains in the body dispersed throughout tissues. (25-26)
Further, emerging evidence reveals not only can adherence to AGE-restrictive diets attenuate oxidative stress and inflammation – both predecessors of disease – in healthy subjects but in addition insulin resistance, markers of endothelial dysfunction, and cardiovascular risk are improved in diabetics as well. (27)
With the evidence that AGEs are a formidable threat in diabetes and that their restriction can halt disease progression, it is mandatory that precautions beyond a low GI diet are taken to reduce the amount of ingested AGEs. While the modern diet has become inextricably intertwined with heat-processing, simple substitution of harsh modes of cooking (e.g., frying, broiling, high-temperature baking, roasting, toasting, grilling, etc.) for gentler methods such as steaming, boiling, stewing, poaching, and even microwaving can result in drastically decreased amounts of AGEs in foods. For example, steamed or poached chicken contained less than one forth of AGEs as did roasted or broiled chicken. Rather than cooking beef until it is well done, it may be cooked rare to medium rare. ‘Undercooked’ meat may seem unpleasant where thoroughly cooked meat has become the norm, but rare meat alone is actually more palatable than cooked meat, which can be quite dry by itself. Marinating the meat in an acid, either lemon or vinegar, one hour before cooking can also decrease the AGE formation that occurs during the cooking process by over 50%. (28) Meat is enjoyed raw in traditional dishes and amongst raw dieters, although it must be noted that there is a risk of bacterial contamination and understandably, the USDA recommends against it. Importantly, the risk is highly variable and dependant on factors such as the cut of meat, the time it is kept frozen, and the source. With risk in mind, it is also recommended to seek a reliable, trusted source where quality is assumed. Ground meat eaten raw is highly discouraged against due to its higher surface area that predisposes a greater risk of contamination. The processing involved in store-bought meat ensures the presence of pathogens on the exterior, so lightly browning the outside of the meat is advised to mitigate risk. Of course, the meat should not be left out in warm temperatures when not in use where the replication of bacteria is expected. Microwaving has been unfairly vilified, mainly due to the failure to discriminate between ionizing radiation and non-ionizing radiation, with the only the former known to be capable of causing molecular damage. (29) Additionally and contrary to common belief, microwave-treated food suffer less nutrient loss than almost all other forms of heated cooking excluding steaming. (30-34) With cooking time maintained below six minutes, microwaving as a dry heat cooking methods produces the lowest amount of AGE formation compared to other forms of dry heating. Moisture cooking (e.g, boiling, poaching, etc) has its place depending upon the type of food, but it is to be kept in mind that cooking in moisture encourages the leaching of water soluble vitamins and minerals. (35-36)
Another source of exogenous AGEs that cannot be ignored is the cooking oil itself. When cooking does take place, oils that are least prone to oxidation are preferred. Oils highest in PUFAs (polyunsaturated fatty acids) undergo the most oxidation and produce the highest amount of lipid peroxidation products during high and also moderate heat cooking. (37) Light, including both natural sunlight and artificial sources (e.g., cold fluorescent light) accelerates the oxidation process, rendering many unprotected oils at least partially oxidized before cooking takes place. (38-39) Lipid peroxidation actually produces AGEs more efficiently than endogenous glycation (40), so it should be minimized as much as possible. Oils composed of mostly MUFAs (monounsaturated fatty acids) are less vulnerable but still pose a risk as oxidation continues to take place increasingly during heat, albeit less aggressively. Saturated fats are the most stable and undergo the least oxidation. (41) Therefore, any cooking should be done with oils containing the most saturated fats and the least amount of PUFAs such as coconut oil, butter, or red palm oil as opposed to sunflower oil or sesame oil for example. Keeping cooking temperature and time to a minimum is still paramount and re-heating of oils is never recommended.
Pre-cooked processed foods can be converted to homemade variants or replaced with raw alternatives. As an example, roasted nuts may be substituted for raw nuts and soaked for several hours to alter the texture to improve digestion. Jams can be made from mechanically pureeing fruits of choices with pectin or a pectin substitute such as chia seeds. Mayonnaise can be made within minutes with a low-PUFA oil of choice along with (favorably) pastured eggs for a fresher, lower-AGE variant less prone to oxidation. Likewise, spreads and dressings can be homemade with higher quality oils to control for the high lipid peroxide levels already formed in shelved mayonnaise and salad dressings. Due to the safety concerns and the need to pasteurize milk, milk substitutes can be made with fresh nuts or coconut as store-bought milk replacements are pre-treated with heat. There are orange juice brands that will state being unpasteurized, though blending juice from fresh oranges is a better option to retain the fiber. Even chocolate can be enjoyed both as an AGE-free and sugar-free dessert when it is prepared as a recipe using raw cocoa powder (warning: most cocoa powders are pre-roasted, unless stated otherwise).
An ‘anti-AGE’ diet need not feel restrictive. With gentler cooking and simple homemade substitutions for processed foods, most of the same foods can be enjoyed by non-diabetics and diabetes alike.
***Health supplements and food components that aid in minimizing endogenous and exogenous glycation will be outlined and discussed in Glycation: Part II.
1. Peppa M, Uribarri J, Vlassara H. Glucose, advanced glycation end products, and diabetes complications: What is new and what works. Clinical Diabetes. 2003
2. Dutta U, Cohenford MA, Dain JA. Nonenzymatic glycation of DNA nucleosides with reducing sugars. Anal Biochem. 2005 Oct 15;345(2):171-80.
3. Song F, Schmidt AM. Glycation and insulin resistance: novel mechanisms and unique targets? Arterioscler Thromb Vasc Biol. 2012 Aug;32(8):1760-5. doi: 10.1161/ATVBAHA.111.241877.
4. Coughlan MT, Yap FY, Tong DC, et al. Advanced glycation end products are direct modulators of β-cell function. Diabetes. 2011 Oct;60(10):2523-32. doi: 10.2337/db10-1033. Epub 2011 Sep 12.
5. Ahmed N. Advanced glycation endproducts–role in pathology of diabetic complications. Diabetes Res Clin Pract. 2005 Jan;67(1):3-21.
6. Jakus V, Rietbrock N. Advanced glycation end-products and the progress of diabetic vascular complications. Physiol Res. 2004;53(2):131-42.
7. Chilelli NC, Burlina S, Lapolla A. AGEs, rather than hyperglycemia, are responsible for microvascular complications in diabetes: a “glycoxidation-centric” point of view. Nutr Metab Cardiovasc Dis. 2013 Oct;23(10):913-9. doi: 10.1016/j.numecd.2013.04.004. Epub 2013 Jun 17.
8. Lim M, Park L, Shin G, et al. Induction of apoptosis of Beta cells of the pancreas by advanced glycation end-products, important mediatorsof chronic complications of diabetes mellitus. Ann N Y Acad Sci. 2008 Dec;1150:311-5. doi: 10.1196/annals.1447.011.
9. Ravelojaona V, Péterszegi G, Molinari J, et al. Demonstration of the cytotoxic effect of Advanced Glycation Endproducts (AGE-s). J Soc Biol. 2007;201(2):185-8.
10. Li H, Nakamura S, Miyazaki S, et al. N2-carboxyethyl-2′-deoxyguanosine, a DNA glycation marker, in kidneys and aortas of diabetic and uremicpatients. Kidney Int. 2006 Jan;69(2):388-92.
11. Rizwan Ahmad. Biochemical Studies of In Vitro Glycation of Human DNA. doi: 10.15272/ajbps.v2i13.100
12. Jakus V, Rietbrock N. Advanced glycation end-products and the progress of diabetic vascular complications. Physiol Res. 2004;53(2):131-42.
13. Ahmed N, Thornalley PJ. Advanced glycation endproducts: what is their relevance to diabetic complications?Diabetes Obes Metab. 2007 May;9(3):233-45.
14 .Bohlender JM, Franke S, Stein G, et al. Advanced glycation end products and the kidney. Am J Physiol Renal Physiol. 2005 Oct;289(4):F645-59.
15. Goldberg T, Cai W, Peppa M, et al. Advanced glycoxidation end products in commonly consumed foods. J Am Diet Assoc. 2004 Aug;104(8):1287-91.
17. Assar SH, Moloney C, Lima M, et al. Determination of Nepsilon-(carboxymethyl)lysine in food systems by ultra performance liquid chromatography-mass spectrometry. Amino Acids. 2009 Feb;36(2):317-26. doi: 10.1007/s00726-008-0071-4. Epub 2008 Apr 4.
18. Cantero AV, Portero-Otín M, Ayala V, et al. Methylglyoxal induces advanced glycation end product (AGEs) formation and dysfunction of PDGF receptor-beta: implications for diabetic atherosclerosis. FASEB J. 2007 Oct;21(12):3096-106. Epub 2007 May 15.
19. Nagoa M, Fujita Y, Sugimura T. Methylglyoxal in beverages and foods: its mutagenicity and carcinogenicity.1984. Presented at the IARC Meeting, Lyon, France.
20. Rabbani N, Thornalley PJ. The critical role of methylglyoxal and glyoxalase 1 in diabetic nephropathy. Diabetes. 2014 Jan;63(1):50-2. doi: 10.2337/db13-1606.
21. M Nagao, Y Fujita, K Wakabayashi, et al. Mutagens in coffee and other beverages. Environ Health Perspect. Aug 1986; 67: 89–91.
22. Tan D, Wang Y, Lo CY, et al. Methylglyoxal: its presence and potential scavengers. Asia Pac J Clin Nutr. 2008;17 Suppl 1:261-4.
24. Ye, H., Miao, Y., Zhao, C., et al. Acrylamide and methylglyoxal formation in potato chips by microwaving and frying heating. International Journal of Food Science & Technology, 46(9), 1921-1926.
25. He C, Sabol J, Mitsuhashi T, et al. Dietary glycotoxins: inhibition of reactive products by aminoguanidine facilitates renal clearance and reducestissue sequestration. Diabetes. 1999 Jun;48(6):1308-15.
26. Koschinsky T, He CJ, Mitsuhashi T, et al. Orally absorbed reactive glycation products (glycotoxins): an environmental risk factor in diabetic nephropathy. Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6474-9.
27. Kellow NJ, Savige GS. Dietary advanced glycation end-product restriction for the attenuation of insulin resistance, oxidative stressand endothelial dysfunction: a systematic review. Eur J Clin Nutr. 2013 Mar;67(3):239-48. doi: 10.1038/ejcn.2012.220. Epub 2013 Jan 30.
28. Uribarri J, Woodruff S, Goodman S, et al. Advanced glycation end products in foods and a practical guide to their reduction in the diet. J Am Diet Assoc. 2010 Jun;110(6):911-16.e12. doi: 10.1016/j.jada.2010.03.018.
29. Zamanian, A., Hardiman, C. Electromagnetic radiation and human health: A review of sources and effects. EMR & Human Health 16.2005: 16-26
30. Lassen, A., Ovesen, L. Nutritional effects of microwave cooking. Nutrition & Food Science 95.4 (1995): 8-10.
31. Selman, J. D. itamin retention during blanching of vegetables. Food Chemistry 49.2 (1994): 137-147.
32. Kumar, S., Aalbersberg, B. Nutrient retention in foods after earth-oven cooking compared to other forms of domestic cooking: 2. Vitamins. Journal of Food Composition and Analysis 19.4 (2006): 311-320.
33. Yuan GF, Sun B, Yuan J, et al. Effects of different cooking methods on health-promoting compounds of broccoli. J Zhejiang Univ Sci B. 2009 Aug;10(8):580-8. doi: 10.1631/jzus.B0920051.
34. Jiménez-Monreal AM, García-Diz L, Martínez-Tomé M, et al. Influence of cooking methods on antioxidant activity of vegetables. J Food Sci. 2009 Apr;74(3):H97-H103. doi: 10.1111/j.1750-3841.2009.01091.x.
35. Miller D. Minerals. In: Fennema OR, editor. Food Chemistry. 3rd edition. New York, NY, USA: Marcel Dekker; 1996.
36. Reddy, N. N., & Sistrunk, W. A. Effect of cultivar, size, storage, and cooking method on carbohydrates and some nutrients of sweet potatoes.
37. Claxson AW, Hawkes GE, Richardson DP, et al. Generation of lipid peroxidation products in culinary oils and fats during episodes of thermal stressing: a highfield 1H NMR study. FEBS Lett. 1994 Nov 21;355(1):81-90.
38. Anwar, F., Shahid Chatha, S. A., Ijaz Hussain, A. Assessment of oxidative deterioration of soybean oil at ambient and sunlight storage. Grasas y aceites 58.4 (2007): 390-395.
39. Pignitter M, Stolze K, Gartner S, et al. Cold fluorescent light as major inducer of lipid oxidation in soybean oil stored at household conditions foreight weeks. J Agric Food Chem. 2014 Mar 12;62(10):2297-305. doi: 10.1021/jf405736j. Epub 2014 Feb 26.
40. Schleicher, E. D., Gempel, K. E., Wagner, E., et al. Immunolocalization of the glycoxidation product N ϵ-carboxymethyllysine in normal and inflamed human intestinal tissues. Cambridge, UK: Royal Society of Chemistry (1998): 316-321.
41. Prabhu HR. Lipid peroxidation in culinary oils subjected to thermal stress. Indian J Clin Biochem. 2000 Aug;15(1):1-5. doi: 10.1007/BF02873539.