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Diabetes

Med Hypotheses. 2008;70(6):1207-9. Epub 2008 Feb 4. Links
A unifying hypothesis on the development of type 1 diabetes and celiac disease: gluten consumption may be a shared causative factor.

Frisk G, Hansson T, Dahlbom I, Tuvemo T.
Department of Women's and Children's Health, Uppsala University, Akademiska Hospital, Uppsala, Sweden. Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den.

This paper presents a hypothesis of the aetiology of the increasing incidence of type 1 diabetes (T1D). This together with the global increased incidence of celiac disease (CD) and that these increases cannot be explained by genetic factors suggest a common environmental factor for these two diseases. Even though enterovirus (EV) infections are believed to trigger T1D and gluten is the trigger of CD, the increasing intake of gluten containing products all over the world could be the trigger for both diseases directly and indirectly. It has been shown that the duration of exposure to gluten is related to the prevalence of T1D. It has also been shown that T1D patients at onset have an inflammatory reaction in the gut. Hence, early diagnose of CD followed by elimination of dietary gluten will lead to a decreased incidence of T1D.
PMID: 18249499 [PubMed - indexed for MEDLINE]

J Appl Genet. 2007;48(3):189-98. Links
Polymorphism of bovine beta-casein and its potential effect on human health.Kaminski S, Cieslinska A, Kostyra E.
Department of Animal Genetics, University of Warmia and Mazury, M. Oczapowskiego 5, 10-718 Olsztyn, Poland.

Proteins in bovine milk are a common source of bioactive peptides. The peptides are released by the digestion of caseins and whey proteins. In vitro the bioactive peptide beta-casomorphin 7 (BCM-7) is yielded by the successive gastrointestinal proteolytic digestion of bovine beta-casein variants A1 and B, but this was not seen in variant A2. In hydrolysed milk with variant A1 of beta-casein, BCM-7 level is 4-fold higher than in A2 milk. Variants A1 and A2 of beta-casein are common among many dairy cattle breeds. A1 is the most frequent in Holstein-Friesian (0.310-0.660), Ayrshire (0.432-0.720) and Red (0.710) cattle. In contrast, a high frequency of A2 is observed in Guernsey (0.880-0.970) and Jersey (0.490-0.721) cattle. BCM-7 may play a role in the aetiology of human diseases. Epidemiological evidence from New Zealand claims that consumption of beta-casein A1 is associated with higher national mortality rates from ischaemic heart disease. It seems that the populations that consume milk containing high levels of beta-casein A2 have a lower incidence of cardiovascular disease and type 1 diabetes. BCM-7 has also been suggested as a possible cause of sudden infant death syndrome. In addition, neurological disorders, such as autism and schizophrenia, seem to be associated with milk consumption and a higher level of BCM-7. Therefore, careful attention should be paid to that protein polymorphism, and deeper research is needed to verify the range and nature of its interactions with the human gastrointestinal tract and whole organism.
PMID: 17666771 [PubMed - in process]

Ann Nutr Metab. 2006;50(3):177-83. Epub 2006 Jan 10. Links
Lower consumption of cow milk protein A1 beta-casein at 2 years of age, rather than consumption among 11- to 14-year-old adolescents, may explain the lower incidence of type 1 diabetes in Iceland than in Scandinavia.

Birgisdottir BE, Hill JP, Thorsson AV, Thorsdottir I.
Unit for Nutrition Research, Landspitali University Hospital & Department of Food Science, Reykjavik, Iceland.

AIM: To compare the consumption of the cow milk proteins A1 and B beta-casein among children and adolescents in Iceland and Scandinavia (Norway, Denmark, Sweden and Finland) as this might explain the lower incidence of type 1 diabetes (per 100,000/year, 0-14 years) in Iceland. METHODS: The consumption of A1 beta-casein in each country among 2- and 11- to 14-year-old children was calculated from results on food intake and on cow milk protein concentration. The consumption values were then compared and evaluated against the incidence of type 1 diabetes. RESULTS: There was a significant difference between the consumption of A1 (p = 0.034) as well as the sum of A1 and B (p = 0.021) beta-casein in Iceland and Scandinavia for 2-year-old children. In the same age group, consumption of A1 beta-casein correlated with the incidence of type 1 diabetes in the countries (r = 0.9; p = 0.037). No significant difference in consumption of A1 or the sum of A1 and B beta-casein was found for 11- to 14-year-old adolescents. CONCLUSION: This study supports that lower consumption of A1 beta-casein might be related to the lower incidence of type 1 diabetes in Iceland than in Scandinavia. Additionally it indicates that consumption in young childhood might be of more importance for the development of the disease incidence than consumption in adolescence. Copyright 2006 S. Karger AG, Basel.
PMID: 16407643 [PubMed - indexed for MEDLINE]

Med Hypotheses. 2006;67(2):388-91. Epub 2006 Mar 10.Links
Diabetes--a man made disease.
Elliott RB.
Living Cell Technologies Limited, 19 Laureston Avenue, Papatoetoe, Auckland 1730, New Zealand. Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den.

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 beta-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.
PMID: 16530335 [PubMed - indexed for MEDLINE]

Ischaemic heart disease, Type 1 diabetes, and cow milk A1 beta-casein.
Laugesen M, Elliott R.
Health New Zealand, Auckland, New Zealand. Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den.

AIM: To test the correlation of per capita A1 beta-casein (A1/capita) and milk protein with: 1) ischaemic heart disease (IHD) mortality; 2) Type 1 (insulin-dependent) diabetes mellitus (DM-1) incidence. METHODS: A1/capita was estimated as the product of per capita cow milk and cream supply and its A1 beta-casein content (A1/beta) (calculated from herd tests and breed distribution, or from tests of commercial milk), then tested for correlation with: 1) IHD five years later in 1980, 1985, 1990 and 1995, in 20 countries which spent at least US $1000 (purchasing power parities) per capita in 1995 on healthcare; 2) DM-1 at age 0-14 years in 1990-4 (51 were surveyed by WHO DiaMond Project; 19 had A1 data). For comparison, we also correlated 77 food, and 110 nutritive supply FAO (Food and Agriculture Organization)-based measures, against IHD and DM-1. RESULTS: For IHD, cow milk proteins (A1/capita, r = 0.76, p <0.001; A1/capita including cheese, r = 0.66; milk protein r = 0.60, p = 0.005) had stronger positive correlations with IHD five years later, than fat supply variables, such as the atherogenic index (r = 0.50), and myristic, the 14-carbon saturated fat (r = 0.48, p <0.05). The Hegsted scores for estimating serum cholesterol (r = 0.42); saturated fat (r = 0.37); and total dairy fat (r = 0.31) were not significant for IHD in 1995. Across the 20 countries, a 1% change in A1/capita in 1990 was associated with a 0.57% change in IHD in 1995. A1/capita correlations were stronger for male than female mortality. On multiple regression of A1/capita and other food supply variables in 1990, only A1/capita was significantly correlated with IHD in 1995. DM-1 was correlated with supply of: A1/capita in milk and cream (r = 0.92, p <0.00001); milk and cream protein excluding cheese (r = 0.68, p <0.0001); and with A1/beta in milk and cream (r = 0.47, p <0.05). Correlations were not significant for A2, B or C variants of milk beta-casein. DM-1 incidence at 0-4, 5-9 and 10-14 years was equally correlated (r = 0.80, 0.81, 0.81 respectively) with milk protein supply. A 1% change in A1/capita was associated with a 1.3% change in DM-1 in the same direction. CONCLUSIONS: Cow A1 beta-casein per capita supply in milk and cream (A1/capita) was significantly and positively correlated with IHD in 20 affluent countries five years later over a 20-year period--providing an alternative hypothesis to explain the high IHD mortality rates in northern compared to southern Europe. For DM-1, this study confirms Elliott's 1999 correlation on 10 countries for A1/capita,1 but not for B beta-casein/capita. Surveys of A1 beta-casein consumption in two-year-old Nordic children, and some casein animal feeding experiments, confirm the A1/capita and milk protein/capita correlations. They raise the possibility that intensive dairy cattle breeding may have emphasised a genetic variant in milk with adverse effects in humans. Further animal research and clinical trials would be needed to compare disease risks of A1-free versus 'ordinary' milk
PMID: 12601419 [PubMed - indexed for MEDLINE]

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Establishment of T cell lines to bovine beta-casein and beta-casein-derived epitopes in patients with type 1 diabetes.
Monetini L, Barone F, Stefanini L, Petrone A, Walk T, Jung G, Thorpe R, Pozzilli P, Cavallo MG.
Department of Endocrinology and Diabetes, University 'Campus Biomedico', Rome, Italy.

Enhanced cellular immune response to bovine beta-casein has been reported in patients with type 1 diabetes. In this study we aimed to establish beta-casein-specific T cell lines from newly diagnosed type 1 diabetic patients and to characterise these cell lines in terms of phenotype and epitope specificity. Furthermore, since sequence homologies exist between beta-casein and putative beta-cell autoantigens, reactivity to the latter was also investigated. T cell lines were generated from the peripheral blood of nine recent onset type 1 diabetic patients with different HLA-DQ and -DR genotypes, after stimulation with antigen pulsed autologous irradiated antigen presenting cells (APCs) and recombinant human interleukin-2 (rhIL-2). T cell line reactivity was evaluated in response to bovine beta-casein, to 18 overlapping peptides encompassing the whole sequence of beta-casein and to beta-cell antigens, including the human insulinoma cell line, CM, and a peptide from the beta-cell glucose transporter, GLUT-2. T cell lines specific to beta-casein could not be isolated from HLA-matched and -unmatched control subjects. beta-Casein T cell lines reacted to different sequences of the protein, however a higher frequency of T cell reactivity was observed towards the C-terminal portion (peptides B05-14, and B05-17 in 5/9 and 4/9 T cell lines respectively). Furthermore, we found that 1 out of 9 beta-casein-specific T cell lines reacted also to the homologous peptide from GLUT-2, and that 3 out of 4 of tested cell lines reacted also to extracts of the human insulinoma cell line, CM. We conclude that T cell lines specific to bovine beta-casein can be isolated from the peripheral blood of patients with type 1 diabetes; these cell lines react with multiple and different sequences of the protein particularly towards the C-terminal portion. In addition, reactivity of beta-casein T cell lines to human insulinoma extracts and GLUT-2 peptide was detected, suggesting that the potential cross-reactivity with beta-cell antigens deserves further investigation.
PMID: 12525258 [PubMed - indexed for MEDLINE]

Horm Metab Res. 2002 Aug;34(8):455-9.Links
Antibodies to bovine beta-casein in diabetes and other autoimmune diseases.
Monetini L, Cavallo MG, Manfrini S, Stefanini L, Picarelli A, Di Tola M, Petrone A, Bianchi M, La Presa M, Di Giulio C, Baroni MG, Thorpe R, Walker BK, Pozzilli P; IMDIAB Group.
Unit of Diabetes and Endocrinology, University Campus Bio-Medico, Rome, Italy.

Cow's milk is thought to be an environmental trigger for autoimmune response in Type 1 diabetes. In the present study, our aim was to investigate the antibody response to bovine beta-casein in different immune- and non-immune-mediated diseases and to establish whether such an antibody response is specific to Type 1 diabetes. We measured antibodies to bovine beta-casein using an enzyme-linked immunosorbent assay in a total of 519 sera from subjects as follows: 71 patients with Type 1 diabetes, 33 patients with coeliac disease, 100 patients with latent autoimmune diabetes in adults (LADA), 50 patients with autoimmune thyroid disease (ATD), 50 patients with Type 2 diabetes, 24 patients with multiple sclerosis (MS), and 3 different groups of controls (n = 191). Significantly increased levels of antibodies to beta-casein were found in patients with Type 1 diabetes, coeliac disease and in LADA compared to age-matched controls (p = 0.01, p = 0.02 and p = 0.01, respectively). No differences were observed in beta-casein antibody titres between patients with other disease conditions (MS, and ATD) and age-matched controls. The highest antibody response to beta-casein in Type 1 diabetic patients and in patients with coeliac disease could reflect the gut mucosal immune disorders common to Type 1 diabetes and coeliac disease. Furthermore, the elevated beta-casein antibody levels found in LADA patients suggest that the antibody response to this protein may be relevant in autoimmune diabetes.
PMID: 12198602 [PubMed - indexed for MEDLINE]

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