- Email: [email protected]
Diabetes – A man made disease
Medical Hypotheses (2006) 67, 388–391
http://intl.elsevierhealth.com/journals/mehy
Diabetes – A man made disease R.B. Elliott
*
Living Cell Technologies Limited, 19 Laureston Avenue, Papatoetoe, Auckland 1730, New Zealand Received 31 October 2005; accepted 4 November 2005
Summary The recent increase in both forms of diabetes must be caused by a modern change in the environment. Candidate agents must satisfy at least three criteria. Firstly, the agent must have increased in the environment recently, secondly that it causes diabetes in appropriate animal models, and thirdly that there is a plausible diabetogenic mechanism. Modern food processing can produce glycation end products, oxidised ascorbic acid and lipoic acid, all of which may cause diabetes. Infant formula in particular has high levels of glycation products, and added ascorbic acid. A casomorphin released from A1 b-casein (but not the A2 variant) can become glycated and have adverse immune effects. Food processing and additives can be posited as a man made cause of the increase in both forms of diabetes. This hypothesis does not exclude other environmental agents which meet the above three criteria. c 2006 Elsevier Ltd. All rights reserved.
Introduction Symptomatic diabetes has been recognised for millennia, but the documented increase in incidence of both Type 1 and Type 2 diabetes is a very recent phenomenon. Where reliable records are available, it appears that Type 1 diabetes incidence has doubled over the last two to three decades which is similar to Type 2 incidence [1,2]. This is far too rapid to be caused by genetic changes, so environmental causes need to be examined. In the context of islet beta cell damage, such environmental causes are likely to be of microbiological or ingested agent nature. The major environmental candidates suggested summarised in Table 1, are made more likely if they have become more prevalent over the last
* Tel.: +64 92762690; fax: +64 92762691. E-mail address: [email protected].
few decades. This candidacy is also enhanced if the agent is diabetogenic in either normal animals or diabetes prone strains, and a plausible mechanism for this diabetogenicity exists. It is not the purpose of this communication to review the evidence for a microbiological cause of the recent epidemic of diabetes. The excessive hygiene hypothesis meets all three criteria of secular trend congruity, animal model, and plausible diabetogenic mechanism, whilst the others listed in Table 1 lack one or more of these criteria, or have been disproved in other ways. Among the ingested agents, too much food, associated with obesity provides an attractive hypothesis for both Type 1 and Type 2 diabetes – the accelerator hypothesis [7], whereas the other specific agents listed do not fit with secular trend – i.e. consumption of the agent has not increased 2–3-fold in the last three decades. Some do not fit with ecological considerations, e.g. arsenic, to provide a holistic aetiology.
0306-9877/$ - see front matter c 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2005.11.047
Diabetes – A man made disease
389
Table 1 Previously suggested environmental diabetogenic agents Microbiological agents ‘Excessive’ hygiene [3] Specific viruses causing islet damage [4] Common vaccines [5,6] ‘Ingested’ agents Overweight/obesity associated with excess food/inadequate exercise [7] A1 b-casein containing cow milk [8] Gluten containing cereals [9] Coffee [10] Bafilomycin [11] Arsenic [12] Nitrites and nitrates [13]
Evidence that changes in modern food processing and storage techniques can provide potential diabetogens’ will be presented. This coupled with the ‘accelerator’ hypothesis provides a likely explanation for the recent epidemic of diabetes.
Glycation, Amadori rearrangement, and advanced glycation end products Heating in air of many foods in the presence of sugars (e.g. glucose, fructose, lactose, etc.), lipids or protein will produce a range of glycated products. Ascorbic acid behaves as a sugar in this context. An exemplar from the literature is shown in Table 2. The more extensive the heating, the longer the time, and the greater the concentration of reactants, the more formed and the more advanced these non-enzymatic products, e.g. UHT milk contains a thousand-fold higher amount of a glycation product than in-bottle sterilised milk [14]. Modern food processing often involves the
preservation of the product by heating, which then allows it to be stored long term before consumption, often with further reheating immediately before the meal. Antioxidants are often added. Ascorbic acid is increasingly added to foods as an antioxidant. The global production of this preservative is shown in Table 3. Most of this is used in modern food preservation processes. Ascorbic acid is added to bread dough as an improver, meat to prevent unattractive colouration on storage and exposure to air, potato chips as a fat antioxidant, bottled fruit drink head space to prevent oxidation, infant formulae and many other foods. The often prolonged reaction time implicit in the use of vitamin C in this way, will ensure interaction with proteins and lipids. Glycation products form, frequently in large amounts. This form of glycation fits with the secular trend of both forms of diabetes. Such glycation products have been shown to be diabetogenic in a mouse model of Type 1 diabetes [16], and also a Type 2 diabetes rodent model [17]. The second criterion has thus been met. Advanced glycation end products are neurotoxins and have been implicated in the aetiology of Alzheimer’s disease [18,19]. The islets of Langerhans have a profuse neural component. Additionally, glycation alters the reactivity of peptides derived from intestinal protein digestion. Short peptide chains
Table 3
Global production of ascorbic acid in tonnes Tonnes
1933
0
<1992
<20,000
Table 2 Amadori–phosphatidylethanolamine (PE) found in milk products
1997
97,000
Glucose-PE (nmol/g)
Lactose-PE (nmol/g)
2002
110,000
Human milk Cow milk
ND ND
ND 78
Infant formulae A B C
35 112 124
78 88 49
2004
130,000
Soy milk
268
128
Sourced from [15].
First chemical synthesis 1934 Estimated from amounts below and global market values for ascorbic and isoascorbic acid (Business Communications Company Inc.,www.Bccresearch.com) Leo Hepner ([email protected]) Viola R Development of a yeast based single step process for the manufacture of ascorbic acid (vitamin C) Scottish Enterprise Proof of Concept Fund, 2002 Leo Hepner ([email protected])
Estimated 72% used in food industry. Approximate annual per capita consumption in North America and Europe is 100 g (2005).
390 of dietary origin are quickly destroyed in the gut wall or blood by dipeptidyl peptidase 1 V. Morphiceptin derived from cow milk b-casein has different physiological and immunological properties when glycated [20] compared with the unglycated peptide. Dipeptidyl peptidase 1 V (DPP1V) is CD26, a T lymphocyte activation marker, important in immune responses [21]. Glycation of peptides which react with this immune marker (peptidase), but are not quickly destroyed has implication for the development of diabetes related autoimmunity. Beta casomorphin-7 a peptide from the same area of the molecule of b-casein as morphiceptin is released from the A1 variant of cow casein, but not the A2 variant, and consumption of the A1 variant, but not the A2 variant has been highly correlated with Type 1 diabetes incidence [8]. The addition of modern processing producing glycation products provides the secular trend link otherwise missing from this attractive hypothesis. Gliadomorphin derived from wheat gluten has also been proposed as a dietary diabetogen, but per capita hard wheat consumption has not increased in the past few decades. Nor is there an ecological association of wheat intake and Type 1 diabetes globally. However, modern food processing with glycation could account for the secular trend. Blockade of the receptors for advanced glycation products in general have been shown to inhibit autoimmune diabetes in the mouse [22]. Thus the third criterion of plausible mechanism(s) of action has been met.
Oxidation of antioxidants as a result of food processing
Elliott
Discussion Although many environmental agents have been implicated in the rising incidence of diabetes, only a handful of these satisfy the three criteria of increase in the environment of the past three decades, causing diabetes in animal models, and having a plausible mechanism of action. Modern food processing and storage through glycation and oxidation may confer adverse effects on some food components, and lead to the speculation that diabetes is a man made disease. The accelerating effect of elevated blood and tissue glucose found in overt diabetes on production of harmful glycation products has its mirror image in the production of harmful food contaminants resulting from many modern food preserving processes. Of particular concern is cow milk based infant formulae. The processing involved yields high levels of Amadori products [14], and consequently glycated peptides such as beta casomorphin-7, which has been implicated in the aetiology of Type 1 diabetes. Ascorbic acid is frequently added to the formulae, which will enhance the formation of Amadori products, as well as allowing the formation of diabetogenic oxidised ascorbic acid products. It is particularly likely that the introduction of dietary diabetogens in infancy may be harmful [26].
Acknowledgements Leo Hepner for providing vitamin C production data. Prof. Henryk Kostyra for provision of an English translation of the paper on glycated morphiceptin.
Vitamin C From the above it can be seen that ascorbic acid additions to food as an antioxidant have become increasingly widespread. (Table 3) Vitamin C is oxidised itself by food processing, and oxidation products of ascorbate are diabetogenic [23]. It is not clear that it is dehydro ascorbic acid itself or further degradation products that is responsible for this b-cell toxicity [24].
Lipoic acid This acid is widespread in foods and is a potent lipid antioxidant. As with vitamin C the oxidised form of lipoic acid may be pro-oxidant and cause tissue damage [25]. Prolonged heating in vitro in the presence of oxygen and subsequent storage increases the proportion of this pro-oxidant.
References [1] Onkamo P, Vaananen S, Karvonen M, Tuomilehto J. Worldwide increase in incidence of Type I diabetes – the analysis of the data on published incidence trends. Diabetologia 1999;42(12):1395–403. [2] Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27(5):1047–53. [3] Kolb H, Elliott RB. Increasing incidence of IDDM a consequence of improved hygiene? Diabetologia 1994;37(7):729. [4] Filippi C, von Herrath M. How viral infections affect the autoimmune process leading to Type 1 diabetes. Cell Immunol 2005;233(2):125–32. [5] Heijbel H, Chen RT, Dahlquist G. Cumulative incidence of childhood-onset IDDM is unaffected by pertussis immunization. Diabetes Care 1997;20(2):173–5. [6] Dahlquist G, Gothefors L. The cumulative incidence of childhood diabetes mellitus in Sweden unaffected by BCGvaccination. Diabetologia 1995;38(7):873–4.
Diabetes – A man made disease [7] Wilkin TJ. The accelerator hypothesis: weight gain as the missing link between Types I and II diabetes. Diabetologia 2001;44(7):914–22. [8] Elliott RB, Harris DP, Hill JP, Bibby NJ, Wasmuth HE. Type I (insulin-dependent) diabetes mellitus and cow milk: casein variant consumption. Diabetologia 1999;42(3):292–6. [9] Vaarala O. Environmental causes: dietary causes. Endocrinol Metab Clin North Am 2004;33(1):17–26 [vii]. [10] Virtanen SM, Rasanen L, Aro A, Ylonen K, Lounamaa R, Akerblom HK, et al. Is children’s or parents’ coffee or tea consumption associated with the risk for Type 1 diabetes. Eur J Clin Nutr 1994;48(4):279–85. [11] Myers MA, Hettiarachchi KD, Ludeman JP, Wilson AJ, Wilson CR, Zimmet PZ. Dietary microbial toxins and Type 1 diabetes. Ann N Y Acad Sci 2003;1005:418–22. [12] Tseng CH. The potential biological mechanisms of arsenicinduced diabetes mellitus. Toxicol Appl Pharmacol 2004;197(2):67–83. [13] Dahlquist GG, Blom LG, Persson LA, Sandstrom AI, Wall SG. Dietary factors and the risk of developing insulin dependent diabetes in childhood. BMJ 1990;300(6735):1302–6. [14] Pellegrino L, Cattaneo S. Occurrence of galactosyl isomaltol and galactosyl b-pyranone in commercial drinking milk. Nahrung 2001;45(3):195–200. [15] Oak JH, Nakagawa K, Miyazawa T. UV analysis of Amadoriglycated phosphatidylethanolamine in foods and biological samples. J Lipid Res 2002;43(3):523–9. [16] Peppa M, He C, Hattori M, McEvoy R, Zheng F, Vlassara H. Fetal or neonatal low-glycotoxin environment prevents autoimmune diabetes in NOD mice. Diabetes 2003;52(6): 1441–8. [17] Sandu O, Song K, Cai W, Zheng F, Uribarri J, Vlassara H. Insulin resistance and Type 2 diabetes in high-fat-fed mice
391
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
are linked to high glycotoxin intake. Diabetes 2005;54(8): 2314–9. Woltjer RL, Maezawa I, Ou JJ, Montine KS, Montine TJ. Advanced glycation endproduct precursor alters intracellular amyloid-b/A beta PP carboxy-terminal fragment aggregation and cytotoxicity. J Alzheimers Dis 2003;5(6): 467–76. Reddy VP, Obrenovich ME, Atwood CS, Perry G, Smith MA. Involvement of Maillard reactions in Alzheimer disease. Neurotox Res 2002;4(3):191–209. Krowczuk S, Kostyra E, Kostyra H, Fraczek J. Effect of nonenzymatic glycation on biological properties of morphiceptin. Pol J Food Nutr Sci 2000;50(1):39–42. Reinhold D, Kahne T, Steinbrecher A, Wrenger S, Neubert K, Ansorge S, et al. The role of dipeptidyl peptidase IV (DP IV) enzymatic activity in T cell activation and autoimmunity. Biol Chem 2002;383(7–8):1133–8. Chen Y, Yan SS, Colgan J, Zhang HP, Luban J, Schmidt AM, et al. Blockade of late stages of autoimmune diabetes by inhibition of the receptor for advanced glycation end products. J Immunol 2004;173(2):1399–405. Patterson JW. Course of diabetes and development of cataracts after injecting dehydroascorbic acid and related substances. Am J Physiol 1951;165(1):61–5. Domke I, Weis W. Reinvestigation of the diabetogenic effect of dehydroascorbic acid. Int J Vitam Nutr Res 1983;53(1):51–60. Scott BC, Aruoma OI, Evans PJ, O’Neill C, Van der Vliet A, Cross CE, et al. Lipoic and dihydrolipoic acids as antioxidants. A critical evaluation. Free Radic Res 1994; 20(2):119–33. Leslie RD, Elliott RB. Early environmental events as a cause of IDDM. Evidence and implications. Diabetes 1994;43(7): 843–50.
http://intl.elsevierhealth.com/journals/mehy
Diabetes – A man made disease R.B. Elliott
*
Living Cell Technologies Limited, 19 Laureston Avenue, Papatoetoe, Auckland 1730, New Zealand Received 31 October 2005; accepted 4 November 2005
Summary The recent increase in both forms of diabetes must be caused by a modern change in the environment. Candidate agents must satisfy at least three criteria. Firstly, the agent must have increased in the environment recently, secondly that it causes diabetes in appropriate animal models, and thirdly that there is a plausible diabetogenic mechanism. Modern food processing can produce glycation end products, oxidised ascorbic acid and lipoic acid, all of which may cause diabetes. Infant formula in particular has high levels of glycation products, and added ascorbic acid. A casomorphin released from A1 b-casein (but not the A2 variant) can become glycated and have adverse immune effects. Food processing and additives can be posited as a man made cause of the increase in both forms of diabetes. This hypothesis does not exclude other environmental agents which meet the above three criteria. c 2006 Elsevier Ltd. All rights reserved.
Introduction Symptomatic diabetes has been recognised for millennia, but the documented increase in incidence of both Type 1 and Type 2 diabetes is a very recent phenomenon. Where reliable records are available, it appears that Type 1 diabetes incidence has doubled over the last two to three decades which is similar to Type 2 incidence [1,2]. This is far too rapid to be caused by genetic changes, so environmental causes need to be examined. In the context of islet beta cell damage, such environmental causes are likely to be of microbiological or ingested agent nature. The major environmental candidates suggested summarised in Table 1, are made more likely if they have become more prevalent over the last
* Tel.: +64 92762690; fax: +64 92762691. E-mail address: [email protected].
few decades. This candidacy is also enhanced if the agent is diabetogenic in either normal animals or diabetes prone strains, and a plausible mechanism for this diabetogenicity exists. It is not the purpose of this communication to review the evidence for a microbiological cause of the recent epidemic of diabetes. The excessive hygiene hypothesis meets all three criteria of secular trend congruity, animal model, and plausible diabetogenic mechanism, whilst the others listed in Table 1 lack one or more of these criteria, or have been disproved in other ways. Among the ingested agents, too much food, associated with obesity provides an attractive hypothesis for both Type 1 and Type 2 diabetes – the accelerator hypothesis [7], whereas the other specific agents listed do not fit with secular trend – i.e. consumption of the agent has not increased 2–3-fold in the last three decades. Some do not fit with ecological considerations, e.g. arsenic, to provide a holistic aetiology.
0306-9877/$ - see front matter c 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2005.11.047
Diabetes – A man made disease
389
Table 1 Previously suggested environmental diabetogenic agents Microbiological agents ‘Excessive’ hygiene [3] Specific viruses causing islet damage [4] Common vaccines [5,6] ‘Ingested’ agents Overweight/obesity associated with excess food/inadequate exercise [7] A1 b-casein containing cow milk [8] Gluten containing cereals [9] Coffee [10] Bafilomycin [11] Arsenic [12] Nitrites and nitrates [13]
Evidence that changes in modern food processing and storage techniques can provide potential diabetogens’ will be presented. This coupled with the ‘accelerator’ hypothesis provides a likely explanation for the recent epidemic of diabetes.
Glycation, Amadori rearrangement, and advanced glycation end products Heating in air of many foods in the presence of sugars (e.g. glucose, fructose, lactose, etc.), lipids or protein will produce a range of glycated products. Ascorbic acid behaves as a sugar in this context. An exemplar from the literature is shown in Table 2. The more extensive the heating, the longer the time, and the greater the concentration of reactants, the more formed and the more advanced these non-enzymatic products, e.g. UHT milk contains a thousand-fold higher amount of a glycation product than in-bottle sterilised milk [14]. Modern food processing often involves the
preservation of the product by heating, which then allows it to be stored long term before consumption, often with further reheating immediately before the meal. Antioxidants are often added. Ascorbic acid is increasingly added to foods as an antioxidant. The global production of this preservative is shown in Table 3. Most of this is used in modern food preservation processes. Ascorbic acid is added to bread dough as an improver, meat to prevent unattractive colouration on storage and exposure to air, potato chips as a fat antioxidant, bottled fruit drink head space to prevent oxidation, infant formulae and many other foods. The often prolonged reaction time implicit in the use of vitamin C in this way, will ensure interaction with proteins and lipids. Glycation products form, frequently in large amounts. This form of glycation fits with the secular trend of both forms of diabetes. Such glycation products have been shown to be diabetogenic in a mouse model of Type 1 diabetes [16], and also a Type 2 diabetes rodent model [17]. The second criterion has thus been met. Advanced glycation end products are neurotoxins and have been implicated in the aetiology of Alzheimer’s disease [18,19]. The islets of Langerhans have a profuse neural component. Additionally, glycation alters the reactivity of peptides derived from intestinal protein digestion. Short peptide chains
Table 3
Global production of ascorbic acid in tonnes Tonnes
1933
0
<1992
<20,000
Table 2 Amadori–phosphatidylethanolamine (PE) found in milk products
1997
97,000
Glucose-PE (nmol/g)
Lactose-PE (nmol/g)
2002
110,000
Human milk Cow milk
ND ND
ND 78
Infant formulae A B C
35 112 124
78 88 49
2004
130,000
Soy milk
268
128
Sourced from [15].
First chemical synthesis 1934 Estimated from amounts below and global market values for ascorbic and isoascorbic acid (Business Communications Company Inc.,www.Bccresearch.com) Leo Hepner ([email protected]) Viola R Development of a yeast based single step process for the manufacture of ascorbic acid (vitamin C) Scottish Enterprise Proof of Concept Fund, 2002 Leo Hepner ([email protected])
Estimated 72% used in food industry. Approximate annual per capita consumption in North America and Europe is 100 g (2005).
390 of dietary origin are quickly destroyed in the gut wall or blood by dipeptidyl peptidase 1 V. Morphiceptin derived from cow milk b-casein has different physiological and immunological properties when glycated [20] compared with the unglycated peptide. Dipeptidyl peptidase 1 V (DPP1V) is CD26, a T lymphocyte activation marker, important in immune responses [21]. Glycation of peptides which react with this immune marker (peptidase), but are not quickly destroyed has implication for the development of diabetes related autoimmunity. Beta casomorphin-7 a peptide from the same area of the molecule of b-casein as morphiceptin is released from the A1 variant of cow casein, but not the A2 variant, and consumption of the A1 variant, but not the A2 variant has been highly correlated with Type 1 diabetes incidence [8]. The addition of modern processing producing glycation products provides the secular trend link otherwise missing from this attractive hypothesis. Gliadomorphin derived from wheat gluten has also been proposed as a dietary diabetogen, but per capita hard wheat consumption has not increased in the past few decades. Nor is there an ecological association of wheat intake and Type 1 diabetes globally. However, modern food processing with glycation could account for the secular trend. Blockade of the receptors for advanced glycation products in general have been shown to inhibit autoimmune diabetes in the mouse [22]. Thus the third criterion of plausible mechanism(s) of action has been met.
Oxidation of antioxidants as a result of food processing
Elliott
Discussion Although many environmental agents have been implicated in the rising incidence of diabetes, only a handful of these satisfy the three criteria of increase in the environment of the past three decades, causing diabetes in animal models, and having a plausible mechanism of action. Modern food processing and storage through glycation and oxidation may confer adverse effects on some food components, and lead to the speculation that diabetes is a man made disease. The accelerating effect of elevated blood and tissue glucose found in overt diabetes on production of harmful glycation products has its mirror image in the production of harmful food contaminants resulting from many modern food preserving processes. Of particular concern is cow milk based infant formulae. The processing involved yields high levels of Amadori products [14], and consequently glycated peptides such as beta casomorphin-7, which has been implicated in the aetiology of Type 1 diabetes. Ascorbic acid is frequently added to the formulae, which will enhance the formation of Amadori products, as well as allowing the formation of diabetogenic oxidised ascorbic acid products. It is particularly likely that the introduction of dietary diabetogens in infancy may be harmful [26].
Acknowledgements Leo Hepner for providing vitamin C production data. Prof. Henryk Kostyra for provision of an English translation of the paper on glycated morphiceptin.
Vitamin C From the above it can be seen that ascorbic acid additions to food as an antioxidant have become increasingly widespread. (Table 3) Vitamin C is oxidised itself by food processing, and oxidation products of ascorbate are diabetogenic [23]. It is not clear that it is dehydro ascorbic acid itself or further degradation products that is responsible for this b-cell toxicity [24].
Lipoic acid This acid is widespread in foods and is a potent lipid antioxidant. As with vitamin C the oxidised form of lipoic acid may be pro-oxidant and cause tissue damage [25]. Prolonged heating in vitro in the presence of oxygen and subsequent storage increases the proportion of this pro-oxidant.
References [1] Onkamo P, Vaananen S, Karvonen M, Tuomilehto J. Worldwide increase in incidence of Type I diabetes – the analysis of the data on published incidence trends. Diabetologia 1999;42(12):1395–403. [2] Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27(5):1047–53. [3] Kolb H, Elliott RB. Increasing incidence of IDDM a consequence of improved hygiene? Diabetologia 1994;37(7):729. [4] Filippi C, von Herrath M. How viral infections affect the autoimmune process leading to Type 1 diabetes. Cell Immunol 2005;233(2):125–32. [5] Heijbel H, Chen RT, Dahlquist G. Cumulative incidence of childhood-onset IDDM is unaffected by pertussis immunization. Diabetes Care 1997;20(2):173–5. [6] Dahlquist G, Gothefors L. The cumulative incidence of childhood diabetes mellitus in Sweden unaffected by BCGvaccination. Diabetologia 1995;38(7):873–4.
Diabetes – A man made disease [7] Wilkin TJ. The accelerator hypothesis: weight gain as the missing link between Types I and II diabetes. Diabetologia 2001;44(7):914–22. [8] Elliott RB, Harris DP, Hill JP, Bibby NJ, Wasmuth HE. Type I (insulin-dependent) diabetes mellitus and cow milk: casein variant consumption. Diabetologia 1999;42(3):292–6. [9] Vaarala O. Environmental causes: dietary causes. Endocrinol Metab Clin North Am 2004;33(1):17–26 [vii]. [10] Virtanen SM, Rasanen L, Aro A, Ylonen K, Lounamaa R, Akerblom HK, et al. Is children’s or parents’ coffee or tea consumption associated with the risk for Type 1 diabetes. Eur J Clin Nutr 1994;48(4):279–85. [11] Myers MA, Hettiarachchi KD, Ludeman JP, Wilson AJ, Wilson CR, Zimmet PZ. Dietary microbial toxins and Type 1 diabetes. Ann N Y Acad Sci 2003;1005:418–22. [12] Tseng CH. The potential biological mechanisms of arsenicinduced diabetes mellitus. Toxicol Appl Pharmacol 2004;197(2):67–83. [13] Dahlquist GG, Blom LG, Persson LA, Sandstrom AI, Wall SG. Dietary factors and the risk of developing insulin dependent diabetes in childhood. BMJ 1990;300(6735):1302–6. [14] Pellegrino L, Cattaneo S. Occurrence of galactosyl isomaltol and galactosyl b-pyranone in commercial drinking milk. Nahrung 2001;45(3):195–200. [15] Oak JH, Nakagawa K, Miyazawa T. UV analysis of Amadoriglycated phosphatidylethanolamine in foods and biological samples. J Lipid Res 2002;43(3):523–9. [16] Peppa M, He C, Hattori M, McEvoy R, Zheng F, Vlassara H. Fetal or neonatal low-glycotoxin environment prevents autoimmune diabetes in NOD mice. Diabetes 2003;52(6): 1441–8. [17] Sandu O, Song K, Cai W, Zheng F, Uribarri J, Vlassara H. Insulin resistance and Type 2 diabetes in high-fat-fed mice
391
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
are linked to high glycotoxin intake. Diabetes 2005;54(8): 2314–9. Woltjer RL, Maezawa I, Ou JJ, Montine KS, Montine TJ. Advanced glycation endproduct precursor alters intracellular amyloid-b/A beta PP carboxy-terminal fragment aggregation and cytotoxicity. J Alzheimers Dis 2003;5(6): 467–76. Reddy VP, Obrenovich ME, Atwood CS, Perry G, Smith MA. Involvement of Maillard reactions in Alzheimer disease. Neurotox Res 2002;4(3):191–209. Krowczuk S, Kostyra E, Kostyra H, Fraczek J. Effect of nonenzymatic glycation on biological properties of morphiceptin. Pol J Food Nutr Sci 2000;50(1):39–42. Reinhold D, Kahne T, Steinbrecher A, Wrenger S, Neubert K, Ansorge S, et al. The role of dipeptidyl peptidase IV (DP IV) enzymatic activity in T cell activation and autoimmunity. Biol Chem 2002;383(7–8):1133–8. Chen Y, Yan SS, Colgan J, Zhang HP, Luban J, Schmidt AM, et al. Blockade of late stages of autoimmune diabetes by inhibition of the receptor for advanced glycation end products. J Immunol 2004;173(2):1399–405. Patterson JW. Course of diabetes and development of cataracts after injecting dehydroascorbic acid and related substances. Am J Physiol 1951;165(1):61–5. Domke I, Weis W. Reinvestigation of the diabetogenic effect of dehydroascorbic acid. Int J Vitam Nutr Res 1983;53(1):51–60. Scott BC, Aruoma OI, Evans PJ, O’Neill C, Van der Vliet A, Cross CE, et al. Lipoic and dihydrolipoic acids as antioxidants. A critical evaluation. Free Radic Res 1994; 20(2):119–33. Leslie RD, Elliott RB. Early environmental events as a cause of IDDM. Evidence and implications. Diabetes 1994;43(7): 843–50.