T1 Diabetes reduction by high Omega-3 and Vitamin D – GRH ongoing observation

Update: Nov 2022: added 3 tests of T1D Autoantibodies in 16 months for $315

Vitamin D and Omega 3 Field Study on Progression of Type 1 Diabetes

CellR4 2019; 7: e2737
C. RicordP, M. Clare-Salzler2, M. Infante1, C. Baggerly3, J. Aliano3, S. McDonnell3, S. Chritton4 sonia at soniachritton.com
1Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
2 department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, USA 3 GrassrootsHealth, Encinitas, CA, USA
4 Children With Diabetes Research Foundation, Superior, CO, USA

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Chronic inflammation has been linked to the progression of type 1 diabetes (T1D). Supplementation with vitamin D and omega-3 fatty acids, which have anti-inflammatory properties, may slow or stop the progression of T1D. A field study is underway to assess the relationship between these nutrients and T1D progression among auto-antibody positive individuals who have not been diagnosed with T1D.
The T1D Prevention Field Study is currently recruiting participants to complete online health surveys and home blood-spot tests for 25-hydroxyvitamin D [25(OH)D], Omega-3 Index, AA:EPA Ratio, high-sensitivity C-reactive protein, and HbA1c every three to four months for 5 years. Participants (or their parents/ guardians) are given information about the importance of achieving a 25(OH)D level between 40-60 ng/ml and an AA:EPA Ratio between 1.5-3.0 to reduce inflammation. However, participants are free to choose their own supplement or dietary regimens. Data analysis will focus on associations between vitamin D and omega-3 status and progression of T1D. Initial enrollment in the T1D Prevention Field Study includes 103 participants from fifteen countries; total enrollment is expected to reach at least 400 participants by the end of 2022.
The field study approach allows for cost- effective research that capitalizes on new technologies for recruitment, data collection, and blood level testing from home. However, some challenges have arisen. Many individuals are reading the open source protocols and some choose to supplement and test on their own so incentives may be needed to increase enrollment. Additionally, some participants do not have access to auto-antibody testing or are unable to get access to their test results; therefore, there is a need to provide blood spot autoantibody testing through the field study.

Introduction

Type 1 diabetes (T1D), which is a chronic autoimmune disease characterized by the destruction of insulin-producing pancreatic beta cells, affects approximately 1.25 million people in the U.S1. Almost 18,000 new cases of T1D are diagnosed each year among those aged less than 20 years1. Complications related to T1D include cardiovascular disease, blindness, and kidney failure2. The estimated yearly cost of T1D in the United States in terms of medical costs and lost income is $14.4 billion3.
Studies have linked vitamin D and omega-3 status with T1D risk. Incidence rates of T1D were found to be higher in countries further from the equator, which have lower UVB irradiance from the sun4. Vitamin D and omega-3 intake and increased nutrient levels have been associated with a lower risk of developing autoimmunity against insulin-producing (islet) cells of the pancreas, or islet autoimmunity, and T1D diagnosis5-11. Also, studies have shown that use of Cod Liver Oil, which contains both vitamin D and omega-3 fatty acids, is associated with a lower risk of T1D10,11. Therefore, improving both vitamin D and omega-3 status may prevent T1D.
Chronic inflammation has also been associated with the development and progression of many chronic diseases including T1D12-15. Therefore, the mechanism for the association of vitamin D and omega-3s with reduced risk of T1D may, in part, be related to the known anti-inflammatory properties of vitamin D and omega-3 fatty acids16-19. A recent randomized clinical trial demonstrated that co-supplementation with vitamin D and omega-3s has beneficial effects on inflammation biomarkers among those with diabetes20. The T1D Prevention Field Study was initiated to further evaluate the combined effect of vitamin D and omega-3 on inflammation and T1D prevention, with specific regard to nutrient levels rather than intake amount due to the significant variability in dose-response21,22. In accordance with the Open Source Movement, this paper describes the T1D Prevention Field Study in an effort to make participation as openly available as possible and allow protocol modifications if needed.

Type 1 Diabetes (T1D) Prevention Field Study

GrassrootsHealth, a non-profit public health research organization, has been running a field study on nutrient levels and health outcomes since 2008. This field study is a long-term (5+ years), real-world prospective cohort study with a large worldwide participant population (N=10,000+). Participation includes completing online health surveys and home blood-spot 25-hydroxyvitamin D [25(OH)D] test kits. This field study has no inclusion or exclusion criteria and participants are allowed to achieve the nutrient status of their choice.
In July 2018, a T1D prevention sub-study was initiated and is currently recruiting auto-antibody positive individuals who have not been diagnosed with T1D to assess the relationship between vitamin D and omega-3 status with T1D progression. Participants complete online health surveys, which collect demographics, auto-antibody status, T1D diagnosis, supplement intake, and other health-related information. Blood-spot tests for serum 25(OH) D and Omega-3 Index, the physiological measures of vitamin D and omega-3 status, are completed at home every three to four months for a duration of 5 years. The AA:EPA Ratio, which is a measure of the primary pro-inflammatory omega-6 (arachi- donic acid, AA) to the primary anti-inflammatory omega-3 (eicosapentaenoic acid, EPA), is also measured along with HbA1c levels and high-sensitivity C-reactive protein (hs-CRP), a biomarker of inflammation. Participants do not have any in-person visits with project staff or medical professionals as part of the field study. This study is neither designed nor intended to replace any communication or treatment from the participant’s physician(s).
Different from a clinical trial, participants in this field study are not assigned to treatment and control groups or required to take a specific dose or achieve a specific nutrient level. Participants (or their parents/guardians) receive their blood-spot test results and information about the importance of achieving 25(OH)D levels between 40-60 ng/ml, an Omega-3 Index at or above 8%, and an AA:EPA Ratio between 1.5-3.0 to reduce chronic inflammation and improve health. However, they are free to choose their own supplement or dietary regimens and nutrient status targets. Due to non-supplemen- tal inputs (e.g. diet, sun exposure) and inter-individual variability in dose response, participants are able to personalize their supplement doses based on their test results and desired nutrient status. Participants also receive information about islet autoantibodies, anti- and pro-inflammatory foods, and other T1D-related information. The dissemination of test results and information allows participants to take ownership over their health and creates a more interactive and dynamic study environment compared to other observational study designs.
Participants have been recruited via social media, websites, and conferences for T1D families. Initial enrollment in the T1D Prevention Field Study includes 103 participants from fifteen countries; total enrollment is expected to reach at least 400 participants by the end of 2022. Data analysis will focus on associations between vitamin D and omega-3 status and progression of T1D. Specifically, the individual and combined effects of 25(OH)D, Omega-3 Index, and AA:EPA Ratio on hs-CRP levels, HbA1c levels, auto-antibody status, and diagnosis of T1D will be assessed. All participants provide informed consent and this study was approved by the Western Institutional Review Board (Olympia, WA, USA).

Discussion

Families with children who have a high risk of developing T1D have asked for a less invasive, less expensive, and more convenient way of intervening in the progression of T1D. Vitamin D and omega-3 testing and supplementation are safe and affordable and could be a key tool to slow or stop T1D progression. Given the opportunities created by Open Source, such as through support groups and social media, many are aware of the possible benefits of vitamin D and omega-3 and have been supplementing for many years. Anecdotal evidence from these individuals indicates that the T1D status of some has been updated to “non-progressor” or “reverter.” The T1D Prevention Field Study allows for the collection of data from individuals across the vitamin D and O3 status ranges so that the relationship between nutrient status and T1D progression can be determined and quantified.
A field study approach allows for more cost-effective and generalizable research than most clinical trials. New technology can be utilized to increase research efficiency and participant involvement in the study. This includes internet-based recruitment, enrollment, and data collection; at home blood spot testing; and a personalized and interactive nutrient health system for participants. A field study with this new technology can easily collect measurements for multiple co-nutrients and data on many risk factors and health outcomes, which can be used to identify associations and synergistic effects between nutrients. Data collected from the field study may be used to help inform clinical trial hypotheses and promote collaborative research.
Some challenges have arisen during the first year of the T1D Prevention Field Study. Since many individuals are reading the open source protocols, some have chosen to supplement and test on their own. Incentives could be helpful to increase enrollment in the T1D Prevention Field Study. For example, providing supplements at no charge could increase enrollment and ensure supplement quality. Additionally, some participants do not have access to auto-antibody testing or are unable to get access to their test results. Providing blood spot auto-antibody testing through the field study could increase data completion and provide valuable information to participants about their status. Also, there has been concern that supplementation within or outside of the field study may interfere with pharmaceutical drug trials. However, we suggest that vitamin D and omega-3 supplementation and measurement may have an important role in any T1D clinical trial because the reduction of chronic inflammation and immuno- modulation could be critical to the success of any other clinical intervention strategy.
While the T1D Prevention Field Study focuses on individuals who are auto-antibody positive without a T1D diagnosis, additional sub-studies are being planned to also assess the effect of vitamin D and omega-3 status among those who have an increased genetic risk but are not yet auto-antibody positive and those who have already been diagnosed with T1D. Preliminary findings from other research studies suggest that this therapeutic approach may halt autoimmunity, preserve residual beta-cell function, and reduce exogenous insulin requirements in patients with T1D23-25. Importantly, even a partial level of beta-cell function is associated with reduced risk of chronic complications26, hypoglycemia, and diabetic ketoacidosis27. The relative contribution of vitamin D and omega-3s to reduce inflammation and autoimmune responses is being investigated by the ongoing POSEIDON trial, a phase I/II trial enrolling T1D children (6-17 years) and adults (18-65 years) with both new-onset (<6 months of disease duration) and established disease (>6 months and up to 10 years of disease duration)28,29. Participants are randomly assigned to receive vitamin D in a dose that achieves 40 ng/ ml and omega-3 fatty acids in a dose that achieves an AA:EPA Ratio of 1.5-3.0, or vitamin D alone. As the additional GrassrootsHealth sub-study for those already diagnosed with T1D is established, participants who are unable to participate in the POSEIDON trial may enroll this alternative study, which will focus on the potential benefit of vitamin D and omega-3s beyond prevention.

Funding: The T1D Prevention Field Study is funded by the Children With Diabetes Research Foundation and GrassrootsHealth, both non-profit entities.
Conflict of Interest: The Authors declare that they have no conflict of interests.

References

1. American Diabetes Association. Statistics About Diabetes. Available at: http://www.diabetes.org/diabetes-ba- sics/statistics. Accessed July 1, 2019.
2. World Health Organization. Diabetes Fact Sheet. Available at: https://www.who.int/news-room/fact-sheets/de- tail/diabetes. Accessed July 1, 2019.
3. Tao B, Pietropaolo M, Atkinson M, Schatz D, Taylor D. Estimating the cost of type 1 diabetes in the U.S.: a propensity score matching method. PLoS One 2010; 5: e11501.
4. Mohr SB, Garland CF, Gorham ED, Garland FC. The association between ultraviolet B irradiance, vitamin D status and incidence rates of type 1 diabetes in 51 regions worldwide. Diabetologia 2008; 51: 1391-1398.
5. Munger KL, Levin LI, Massa J, Horst R, Orban T, Asch- erio A. Preclinical serum 25-hydroxyvitamin D levels and risk of type 1 diabetes in a cohort of US military personnel. Am J Epidemiol 2013; 177: 411-419.
6. Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001; 358: 15001503.
7. Norris JM, Lee HS, Frederiksen B, Erlund I, Uusitalo U, Yang J, Lernmark A, Simell O, Toppari J, Rewers M, Ziegler AG, She JX, Onengut-Gumuscu S, Chen WM, Rich SS, Sundvall J, Akolkar B, Krischer J, Virtanen SM, Hagopian W; TEDDY Study Group. Plasma 25-hy- droxyvitamin D concentration and risk of islet autoimmunity. Diabetes 2018; 67: 146-154.
8. Norris JM, Yin X, Lamb MM, Barriga K, Seifert J, Hoffman M, Orton HD, Baron AE, Clare-Salzler M, Chase HP, Szabo NJ, Erlich H, Eisenbarth GS, Rewers M. Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at increased risk for type 1 diabetes. JAMA 2007; 298: 1420-1428.
9. Niinistö S, Takkinen HM, Erlund I, Ahonen S, Toppari J, Ilonen J, Veijola R, Knip M, Vaarala O, Virtanen SM. Fatty acid status in infancy is associated with the risk of type 1 diabetes-associated autoimmunity. Diabetologia 2017; 60: 1223-1233.
10. Stene LC, Joner G; Norwegian Childhood Diabetes Study Group. Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large, population-based, case-control study. Am J Clin Nutr 2003; 78: 1128-1134.
11. Stene LC, Ulriksen J, Magnus P, Joner G. Use of cod liver oil during pregnancy associated with lower risk of Type I diabetes in the offspring. Diabetologia 2000; 43: 1093-1098.
12. Hunter P. The inflammation theory of disease. EMBO Rep 2012; 13: 968-970.
13. Limbert C. Type 1 diabetes - an auto-inflammatory disease: a new concept, new therapeutical strategies. J Transl Med 2012; 10(Suppl 3): I12.
14. Bending D, Zaccone P, Cooke A. Inflammation and type one diabetes. Int Immunol 2012; 24: 339-346.
15. Chase HP, Cooper S, Osberg I, Stene LC, Barriga K, Norris J, Eisenbarth GS, Rewers M. Elevated C-reactive protein levels in the development of type 1 diabetes. Diabetes 2004; 53: 2569-2573.
16. Caprio M, Infante M, Calanchini M, Mammi C, Fabbri A. Vitamin D: not just the bone. Evidence for beneficial pleiotropic extraskeletal effects. Eat Weight Disord 2017; 22: 27-41.
17. Simopoulis AP. Evolutionary aspects of diet, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic diseases. Biomed Pharmacother 2006; 60: 502-507.
18. Riachy R, Vandewalle B, Moerman E, Belaich S, Luko- wiak B, Gmyr V, Muharram G, Kerr Conte J, Pattou F. 1,25-Dihydroxyvitamin D3 protects human pancreatic islets against cytokine-induced apoptosis via down-regulation of the Fas receptor. Apoptosis 2006; 11: 151-159.
19. Ergas D, Eilat E, Mendlovic S, Sthoeger ZM. n-3 fatty acids and the immune system in autoimmunity. Isr Med Assoc J 2002; 4: 34-38.
20. Razavi M, Jamilian M, Samimi M, Afshar Ebrahimi F, Taghizadeh M, Bekhradi R, Seyed Hosseini E, Haddad Kashani H, Karamali M, Asemi Z. The effects of vitamin D and omega-3 fatty acids co-supplementation on biomarkers of inflammation, oxidative stress and pregnancy outcomes in patients with gestational diabetes. Nutr Metab 2017; 14: 80.
21. Garland CF, French CB, Baggerly LL, Heaney RP. Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention. Anticancer Res 2011; 31: 607-611.
22. Infante M, Ricordi C, Baidal DA, Alejandro R, Lanzoni G, Sears B, Caprio M, Fabbri A. VITAL study: an incomplete picture? Eur Rev Med Pharmacol Sci 2019; 23: 3142-3147.
23. Baidal DA, Ricordi C, Garcia-Contreras M, Sonnino A, Fabbri A. Combination high-dose omega-3 fatty acids and high-dose cholecalciferol in new onset type 1 diabetes: a potential role in preservation of beta-cell mass. Eur Rev Med Pharmacol Sci 2016; 20: 3313-3318.
24. Cadario F, Savastio S, Rizzo AM, Carrera D, Bona G, Ricordi C. Can type 1 diabetes progression be halted? Possible role of high dose vitamin D and omega 3 fatty acids. Eur Rev Med Pharmacol Sci 2017; 21: 1604-1609.
25. Cadario F, Savastio S, Ricotti R, Rizzo AM, Carrera D, Maiuri L, Ricordi C. Administration of vitamin D and high dose of omega 3 to sustain remission of type 1 diabetes. Eur Rev Med Pharmacol Sci 2018; 22: 512-515.
26. Steffes MW, Sibley S, Jackson M, Thomas W. Beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial. Diabetes Care 2003; 26: 832-836.
27. Ludvigsson J. C-peptide in diabetes diagnosis and therapy. Front Biosci (Elite Ed) 2013; 5: 214-223.
28. Ricordi C, Lanzoni G. Can high-dose omega-3 fatty acids and high-dose vitamin D3 (cholecalciferol) prevent type 1 diabetes and sustain preservation of beta-cell function after disease onset? CellR4 2018; 6: e2493.
29. Baidal DA, Sanchez J, Alejandro R, Blaschke CE, Hir ani K, Matheson DL, Messinger S, Pugliese A, Rafkin LE, Roque LA, Ver a Ortiz JM, Ricordi C. POSEIDON study: a pilot, safety and feasibility trial of high-dose omega3 fatty acids and high-dose cholecalciferol supplementation in type 1 diabetes. CellR4 2018; 6: e2489.