Abstract
There is no safe and effective prevention for insulin-dependent diabetes (IDDM) mellitus, which makes it highly dependent on its treatment. This systematic review with meta-analyses of randomized clinical trials investigated the overall effects of dietary supplements of vitamins, minerals, trace elements, and non-essential compounds with antioxidant properties, fatty acids, and amino acids in IDDM. Searches of MEDLINE, Embase, CENTRAL, LILACS, The Grey Literature Report, and ClinicaTrials.gov, and citations from previous reviews were used to identify reports published through July 2023. The Risk of Bias 2 (RoB2) tool was used to analyze the risk of bias and GRADE was used to assess the quality of the results. Fifty-eight studies (n=3,044) were included in qualitative analyses and seventeen (n=723) in meta-analyses. Qualitative analyses showed few positive effects on some metabolic function markers, such as endothelial and renal function and lipid profile. Meta-analyses showed a positive effect of omega-3 on glycated hemoglobin (HbA1c) (RMD=-0.33; 95%CI: -0.53, -0.12, P=0.002; I2=0%; GRADE: low quality; 4 studies) and of vitamin D on fasting C-peptide (FCP) (RMD=0.05; 95%CI: 0.01, 0.9, P=0.023; I2=0%; GRADE: very low quality; 4 studies). Most studies showed bias concern or high risk of bias. A recommendation for dietary supplementation in IDDM cannot be made because of the few positive results within different interventions and markers, the serious risk of bias in the included studies, and the low quality of evidence from meta-analyses. The positive result of vitamin D on FCP is preliminary, requiring further investigation.
Diabetes complications; Endocrine system diseases; Glycemic control; Biomarkers; Nutritional therapy
Introduction
Insulin-dependent diabetes mellitus (IDDM) is one of the types of diabetes mellitus (DM) that accounts for up to 10% of all cases of DM in adults, with the most common onset in children and adolescents (11. International Diabetes Federation (IDF). IDF Diabetes Atlas. 10th ed. Brussels, Belgium: International Diabetes Federation; 2021.). The global prevalence is about 1.21 million patients younger than 20 years, with an incidence of 149,000 new cases annually in this age group (22. International Diabetes Federation (IDF). IDF Diabetes Atlas. 9th ed. Brussels, Belgium: International Diabetes Federation; 2019.). The autoimmune etiology is present in 90% of cases, with the destruction of pancreatic β-cells, which are responsible for producing insulin, in a process of apoptosis via humoral and cellular autoimmunity induced by inflammatory reactions with high levels of cytokines (33. Lind M, Svensson AM, Rosengren A. Glycemic control and excess mortality in type 1 diabetes. N Engl J Med 2015; 372: 880-881, doi: 10.10.1056/NEJMc1415677.
https://doi.org/10.10.1056/NEJMc1415677...
). As a result, the body is unable to produce this hormone and there is a consequent increase in blood glucose, since insulin reduces blood glucose by signaling the translocation of GLUT4 in the membranes of cells that capture glucose (44. Tokarz VL, MacDonald PE, Klip A. The cell biology of systemic insulin function. J Cell Biol 2018; 2: 2273-2289, doi: 10.1083/jcb.201802095.
https://doi.org/10.1083/jcb.201802095...
). It is a chronic disease characterized by increased blood glucose, which can lead to damage to various organs and systems if long-term uncontrolled high plasma glucose levels persist for a long period of time. Early discovery and appropriate treatment management are the best way to delay or even prevent the onset of these complications (22. International Diabetes Federation (IDF). IDF Diabetes Atlas. 9th ed. Brussels, Belgium: International Diabetes Federation; 2019.,55. Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet 2014; 383: 69-82, doi: 10.1016/S0140-6736(13)60591-7.
https://doi.org/10.1016/S0140-6736(13)60...
).
Despite the progress of research to better understand IDDM, there is still no safe and effective way for its prevention (33. Lind M, Svensson AM, Rosengren A. Glycemic control and excess mortality in type 1 diabetes. N Engl J Med 2015; 372: 880-881, doi: 10.10.1056/NEJMc1415677.
https://doi.org/10.10.1056/NEJMc1415677...
), making it a disease highly dependent on its treatment, which is mainly based on the administration of exogenous insulin, making it a costly therapy with limited access, in addition to dietary control and exercise (44. Tokarz VL, MacDonald PE, Klip A. The cell biology of systemic insulin function. J Cell Biol 2018; 2: 2273-2289, doi: 10.1083/jcb.201802095.
https://doi.org/10.1083/jcb.201802095...
). Nutritional treatment aims at glycemic control, with studies and nutritional recommendations focusing on the distribution of macronutrients, especially the consumption of carbohydrates, in addition to the carbohydrate counting technique, which optimizes the use of insulin according to the amount of ingested carbohydrate (66. Smart CE, Annan F, Higgins LA, Jelleryd E, Lopez M, Acerini CL. ISPAD Clinical Practice Consensus Guidelines 2018: nutritional management in children and adolescents with diabetes. Pediatri Diabetes 2018; 19: 136-154, doi: 10.1111/pedi.12738.
https://doi.org/10.1111/pedi.12738...
).
There is no recommendation for the intake of micronutrients or specific compounds other than values recommended for the healthy population (66. Smart CE, Annan F, Higgins LA, Jelleryd E, Lopez M, Acerini CL. ISPAD Clinical Practice Consensus Guidelines 2018: nutritional management in children and adolescents with diabetes. Pediatri Diabetes 2018; 19: 136-154, doi: 10.1111/pedi.12738.
https://doi.org/10.1111/pedi.12738...
). The need to adjust micronutrients in type 1 diabetic patients is crucial, because their deficiency and low consumption has already been reported in patients with uncontrolled diabetes, who are more susceptible due to high levels of oxidative stress and inflammation, which can increase the demand for micronutrients (77. Pancheva R, Zhelyazkova D, Ahmed F, Gillon-Keren M, Usheva N, Bocheva Y, et al. Dietary intake and adherence to the recommendations for healthy eating in patients with type 1 diabetes: a narrative review. Front Nutr 2021; 8: 782670, doi: 10.3389/fnut.2021.782670.
https://doi.org/10.3389/fnut.2021.782670...
-8. Rosyid FN. Micronutrient deficiency in type 1 and 2 diabetes mellitus: diagnosis and therapy. Int J Res Med Sci 2022; 4: 973, doi: 10.18203/2320-6012.ijrms20220997.
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99. Mooradian AD, Morley JE. Micronutrient status in diabetes mellitus. Am J Clin Nutr 1987; 45: 877-895, doi: 10.1093/ajcn/45.5.877.
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). Despite this, only reviews without quantitative analysis and only using vitamin D supplementation have been carried out on IDDM (1010. Nascimento BF, Moreira CFF, da Fonseca ER, Fedeszen PMK, de Paula TP, de Sena ASS, et al. Effects of vitamin D supplementation on glycemic control of children and adolescents with type 1 diabetes mellitus: a systematic review. J Pediatr Endocrinol Metab 2022; 35: 973-988, doi: 10.1515/jpem-2022-0044.
https://doi.org/10.1515/jpem-2022-0044...
,1111. Yu J, Sharma P, Girgis CM, Gunton JE. Vitamin D and beta cells in type 1 diabetes: a systematic review. Int J Mol Sci 2022; 23: 14434, doi: 10.3390/ijms232214434.
https://doi.org/10.3390/ijms232214434...
).
Hence, this systematic review with meta-analyses aimed to compile the results of randomized clinical trials (RCTs) with nutritional supplementation interventions, especially of vitamins, minerals, trace elements, non-essential compounds with antioxidant properties, fatty acids, and amino acids, to summarize the effects of these interventions in individuals with IDDM, guiding intake recommendations and future research on this topic.
Material and Methods
Data availability and transparency statement
This research followed the recommendations of the Cochrane Collaboration Handbook for Systematic Reviews of Interventions (1212. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane Handbook for systematic reviews of interventions version 6.3, Cochrane Library. Chichester (UK): John Wiley & Sons; 2019.) and is reported according to Preferred Reporting Items for Systematic Reviews and Meta-analyses PRISMA 2020 (1313. Page MJ, Mckenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372: n71, doi: 10.1136/bmj.n71.
https://doi.org/10.1136/bmj.n71...
) (Supplementary Figure S1). The protocol was published and approved by the International Prospective Register of Systematic Reviews (PROSPERO) under the registration code CRD42021266766.
Search strategies
Searches were performed in the main electronic bibliographic databases MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), in the Latin American regional database LILACS, in the Gray Literature database Gray Literature Report (https://www.greylit.org), and in the Clinical Trials Registry ClinicalTrials.gov. In addition, studies cited by previous systematic reviews on this topic were manually included for screening. For the search strategy in the main databases, the following terms were used: “insulin-dependent diabetes mellitus”, “vitamin”, “trace element”, “mineral”, “antioxidant”, “amino acid”, and “fatty acid”, with slight changes for the other databases (Supplementary Table S1).
In the MEDLINE database, a highly sensitive strategy to identify RCTs proposed by Cochrane was used (1212. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane Handbook for systematic reviews of interventions version 6.3, Cochrane Library. Chichester (UK): John Wiley & Sons; 2019.). For the Embase and CENTRAL databases, the filters of the platforms were used to identify this type of study, while in ClinicalTrials.gov, a filter was used to locate only studies with results. For LILACS, filters for RCTs were not used due to the low number of reports found and to avoid the loss of possible eligible studies. The searches had no restrictions on time or language of publication, and the last update was performed in July 2023.
Eligibility assessment
This study included RCTs with two groups of people with IDDM with or without other associated diseases: one group receiving oral dietary supplements of vitamins, minerals, trace elements, non-essential compounds with antioxidant properties, amino acids, and fatty acids and one group receiving a placebo supplementation. The supplemented compounds needed to be in the natural form or as corresponding synthetic metabolites, have a defined concentration, and be taken alone or combined with another substance of the same or different nature. Individuals with other DM types, food extracts, except for concentrated oils used as fatty acid supplementation (e.g., fish oil), and compounds associated with medications as an intervention were excluded.
Furthermore, other dietary supplements or therapies and studies with subgroups diagnosed with IDDM that did not present the results separately from other subgroups were also excluded. There was no restriction on age, sex, and ethnicity of the participants of the studies.
Data extraction
Two independent reviewers were involved in study selection, data extraction, risk of bias assessment, and quality of evidence assessment, following the Cochrane guidelines for systematic reviews (1212. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane Handbook for systematic reviews of interventions version 6.3, Cochrane Library. Chichester (UK): John Wiley & Sons; 2019.), acting in parallel in all stages of the selection of studies eligible for inclusion and data extraction, with a third independent researcher available to resolve conflicts between the two reviewers. Relevant studies identified by title and abstract screening were selected for full-text review and included or excluded according to the eligibility criteria. Qualitative and quantitative data from the final reports were compiled into tables in Excel software (Microsoft, USA) for further organization and analyses. The following data were extracted from each selected trial: first author, publication year, location (country), study design, duration of intervention, sex, number of participants, age of participants, intervention, dose and frequency of the intervention, main analyzed outcomes, and effect data (significant changes in intervention vs placebo values).
Criteria for inclusion in the systematic review
Following the eligibility criteria, the remaining reports that analyzed the effects of supplementation on different biomarkers were included in the qualitative assessment of the data. The primary endpoints to this review were changes in glycated hemoglobin (HbA1c) and fasting glucose. Insulin requirement, fasting C-peptide (FCP), hypoglycemia events, regulatory T-lymphocyte activity, lipid profile, body composition, inflammatory cytokines, platelet reactivity, thromboxane production, flow-mediated dilation, residual β-cell activity markers, antioxidant profile, and disease progression endpoints (neurological, macrovascular, microvascular, and metabolic disorders) were secondary endpoints.
Risk of bias and quality of evidence assessment
The Cochrane RCTs Risk of Bias tool version 2 (RoB 2) was used to assess the quality of the included studies. The risk of bias is assessed in 5 domains: randomization of participants, loss of participants from the intervention group, missing outcome data, measurement of outcomes, and selection of reported outcomes. An algorithmically generated result based on the answers to the specific questions is obtained, categorizing each domain, giving the study an overall rating of “low risk”, “high risk”, or “some concern” (1414. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: l4898, doi: 10.1136/bmj.l4898.
https://doi.org/10.1136/bmj.l4898...
).
Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool was used to assess the quality of evidence and the strength of health recommendations for the results obtained in the meta-analyses, classifying them into “very low”, “low”, “moderate”, or “high” quality of evidence on the basis of the design of the studies, risk of bias, inconsistency, indirect evidence, imprecision, and publication bias (1515. Schünemann H, Brożek J, Guyatt G, Oxman A (Editors). GRADE handbook for grading quality of evidence and strength of recommendations, The GRADE Working Group. Ontario (CN): Evidence Prime; 2013).
Criteria for inclusion in the meta-analyses
Meta-analyses were performed on outcomes that were analyzed by three or more reports included on the systematic review when their data were presented in an extractable form, i.e. in mean and standard deviation or mean and standard error of the mean for both groups, with the standard deviation value converted from the sample data. Outcome data from studies with an adult, adolescent, or child sample were included, and studies with pregnant women were not.
Statistical analyses
The analyses of the raw mean difference (RMD) were used when the data of the reports were presented in the same unit or units with direct conversion into percentage (e.g., HbA1c, in percentage (%) and mmol/mol; FCP, in ng/mL, pmol/mL, and nmol/L) for HbA1c and nmol/L for FCP. Standardized mean difference (SMD) analysis was used for outcomes with different measurement units without the possibility of direct conversion (e.g., insulin dose requirement, in IU/kg/day and IU/day).
The weights for each study were assigned using the inverse of variance, performing a random effects analysis by the DerSimonian & Laird method. Tau2 statistic was used to identify heterogeneity, considering P<0.10 as significant, and inconsistency was determined by the I2 statistic, considering ≤40% a low value (1616. Deeks JJ, Julian PT, Higgins DG, Altman CSM. Analysing data and undertaking meta-analyses. Cochrane handbook for systematic reviews of interventions; 2019. p 241-284, doi: 10.1002/9781119536604.
https://doi.org/10.1002/9781119536604...
). Subgroup, publication bias, and meta-regression analyses could not be performed due to the low number of studies included in each meta-analysis. All statistical analyses and graph plotting were performed in Jamovi software version 1.6.23 (The Jamovi Project, Australia).
Results
Characteristics of the included studies
The screening process started with 6,229 records in the electronic databases and 27 reports of systematic reviews related to the topic, totaling 6,256 records. At the end, 65 reports belonging to 58 studies were included in the systematic review, and 17 were included in the meta-analyses. All steps of the search process and selection of studies and reports included in the analyses are shown in Figure 1.
The detailed characteristics of all 65 reports analyzed are presented in Supplementary Tables S2-S4 (1717. Alian Z, Hashemipour M, Dehkordi EH, Hovsepian S, Amini M, Moadab MH, et al. The effects of folic acid on markers of endothelial function in patients with type 1 diabetes mellitus. Med Arh 2012; 66: 12-15, doi: 10.5455/medarh.2012.66.12-15.
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56. Skyrme-Jones RA, Meredith IT. Soluble adhesion molecules, endothelial function and vitamin E in type 1 diabetes. Coron Artery Dis 2001; 12: 69-75, doi: 10.1097/00019501-200102000-00010.
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57. Beckman JA, Goldfine AB, Gordon MB, Garrett LA, Keaney Jr JF, Creager MA. Oral antioxidant therapy improves endothelial function in type 1 but not type 2 diabetes mellitus. Am J Physiol Heart Circ Physiol 2003; 285: H2392-H2398, doi: 10.1152/ajpheart.00403.2003.
https://doi.org/10.1152/ajpheart.00403.2...
58. Johnston PC, Powell LA, McCance DR, Pogue K, McMaster C, Gilchrist S, et al. Placental protein tyrosine nitration and MAPK in type 1 diabetic pre-eclampsia: Impact of antioxidant vitamin supplementation. J Diabetes Complications 2013; 27: 322-327, doi: 10.1016/j.jdiacomp.2013.02.001.
https://doi.org/10.1016/j.jdiacomp.2013....
59. Johnston PC, McCance DR, Holmes VA, Young IS, McGinty A. Placental antioxidant enzyme status and lipid peroxidation in pregnant women with type 1 diabetes: the effect of vitamin C and E supplementation. J Diabetes Complications 2016; 30: 109-114, doi: 10.1016/j.jdiacomp.2015.10.001.
https://doi.org/10.1016/j.jdiacomp.2015....
60. McCance DR, Holmes VA, Maresh MJA, Patterson CC, Walker JD, Pearson DWM, et al. Vitamins C and E for prevention of pre-eclampsia in women with type 1 diabetes (DAPIT): a randomised placebo-controlled trial. Lancet 2010; 376: 259-266, doi: 10.1016/S0140-6736(10)60630-7.
https://doi.org/10.1016/S0140-6736(10)60...
61. Weissgerber TL, Gandley RE, Roberts JM, Patterson CC, Holmes VA, Young IS, et al. Haptoglobin phenotype, pre-eclampsia, and response to supplementation with vitamins C and E in pregnant women with type-1 diabetes. BJOG 2013; 120: 1192-1199, doi: 10.1111/1471-0528.12288.
https://doi.org/10.1111/1471-0528.12288...
62. Jumaah LF, Alosy BD, Ibrahim HM, Al Hadeethi EM. Double-blind placebo? Controlled effectiveness of cholecalciferol (vitamin D3) plus magnesium and zinc in management of type 1 diabetes (T1d) in pediatric age group. System Rev Pharm 2020; 11: 543-548.
63. Ludvigsson J, Samuelsson U, Johansson C, Stenhammar L. Treatment with antioxidants at onset of type 1 diabetes in children: a randomized, double-blind placebo-controlled study. Diabetes Metab Res Rev 2001; 17: 131-136, doi: 10.1002/dmrr.176.
https://doi.org/10.1002/dmrr.176...
64. Shidfar F, Aghasi M, Vafa M, Heidary I, Hosseini S, Shidfar S. Effects of combination of zinc and vitamin A supplementation on serum fasting blood sugar, insulin, apoprotein B and apoprotein AI in patients with type I diabetes. Int J Food Sci Nutr 2010; 61: 182-191, doi: 10.3109/09637480903334171.
https://doi.org/10.3109/0963748090333417...
65. Andersen CB, Henriksen JE, Hother-Nielsen O, Vaag A, Mortensen SA, Beck-Nielsen H. The effect of coenzyme Q10 on blood glucose and insulin requirement in patients with insulin dependent diabetes mellitus. Mol Aspects Med 1997; 18: S307-S309, doi: 10.1016/S0098-2997(97)00010-1.
https://doi.org/10.1016/S0098-2997(97)00...
66. Huang EA, Gitelman SE. The effect of oral alpha-lipoic acid on oxidative stress in adolescents with type 1 diabetes mellitus. Pediatr Diabetes 2008; 9: 69-73, doi: 10.1111/j.1399-5448.2007.00342.x.
https://doi.org/10.1111/j.1399-5448.2007...
67. Mollo R, Zaccardi F, Scalone G, Scavone G, Rizzo P, Navarese EP, et al. Effect of α-lipoic acid on platelet reactivity in type 1 diabetic patients. Diabetes Care 2012; 35: 196-197, doi: 10.2337/dc11-1255.
https://doi.org/10.2337/dc11-1255...
68. Scaramuzza A, Giani E, Redaelli F, Ungheri S, Macedoni M, Giudici V, et al. Alpha-lipoic acid and antioxidant diet help to improve endothelial dysfunction in adolescents with type 1 diabetes: a pilot trial. J Diabetes Res 2015; 2015: 474561, doi: 10.1155/2015/474561.
https://doi.org/10.1155/2015/474561...
69. Mauras N, Xing D, Fox LA, Englert K, Darmaun D. Effects of glutamine on glycemic control during and after exercise in adolescents with type 1 diabetes: a pilot study. Diabetes Care 2010; 33: 1951-1953, doi: 10.2337/dc10-0275.
https://doi.org/10.2337/dc10-0275...
70. Rossetti P, Porcellati F, Ricci NB, Candeloro P, Cioli P, Nair KS, et al. Effect of oral amino acids on counterregulatory responses and cognitive function during insulin-induced hypoglycemia in nondiabetic and type 1 diabetic people. Diabetes 2008; 57: 1905-1917, doi: 10.2337/db08-0276.
https://doi.org/10.2337/db08-0276...
71. Torres-Santiago L, Mauras N, Hossain J, Weltman AL, Darmaun D. Does oral glutamine improve insulin sensitivity in adolescents with type 1 diabetes? Nutrition 2017; 34: 1-6, doi: 10.1016/j.nut.2016.09.003.
https://doi.org/10.1016/j.nut.2016.09.00...
72. Britten-Jones AC, Kamel JT, Roberts LJ, Braat S, Craig JP, MacIsaac RJ, et al. Investigating the neuroprotective effect of oral omega-3 fatty acid supplementation in type 1 diabetes (nPROOFS1): a randomized placebo-controlled trial. Diabetes 2021; 70: 1794-1806, doi: 10.2337/db21-0136.
https://doi.org/10.2337/db21-0136...
73. Haines AP, Sanders TA, Imeson JD, Mahler RF, Martin J, Mistry M, et al. Effects of a fish oil supplement on platelet function, haemostatic variables and albuminuria in insulin- dependent diabetics. Thromb Res 1986; 43: 643-655, doi: 10.1016/0049-3848(86)90101-5.
https://doi.org/10.1016/0049-3848(86)901...
74. Horvaticek M, Djelmis J, Ivanisevic M, Oreskovic S, Herman M. Effect of eicosapentaenoic acid and docosahexaenoic acid supplementation on C-peptide preservation in pregnant women with type-1 diabetes: randomized placebo controlled clinical trial. Eur J Clin Nutr 2017; 71: 968-972, doi: 10.1038/ejcn.2017.46.
https://doi.org/10.1038/ejcn.2017.46...
75. Ivanisevic M, Horvaticek M, Delmis K, Delmis J. Supplementation of EPA and DHA in pregnant women with type 1 diabetes mellitus. Ann Med 2021; 53: 848-859, doi: 10.1080/07853890.2021.1936151.
https://doi.org/10.1080/07853890.2021.19...
76. Khorshidi M, Sayyari A, Aryaeian N, Olang B, Alaei M, Khalili M, et al. Effects of omega-3 supplementation on endothelial function, vascular structure, and metabolic parameters in adolescents with type 1 diabetes mellitus: a randomized clinical trial. Front Nutr 2022; 9: 962773, doi: 10.3389/fnut.2022.962773.
https://doi.org/10.3389/fnut.2022.962773...
77. Mori TA, Vandongen R, Masarei JR, Rouse IL, Dunbar D. Comparison of diets supplemented with fish oil or olive oil on plasma lipoproteins in insulin-dependent diabetics. Metabolism 1991; 40: 241-246, doi: 10.1016/0026-0495(91)90104-5.
https://doi.org/10.1016/0026-0495(91)901...
78. Myrup B, Rossing P, Jensen T, Parving HH, Hølmer G, Gram J, et al. Lack of effect of fish oil supplementation on coagulation and transcapillary escape rate of albumin in insulin- dependent diabetic patients with diabetic nephropathy. Scand J Clin Lab Invest 2001; 61: 349-356, doi: 10.1080/003655101316911387.
https://doi.org/10.1080/0036551013169113...
79. O'Mahoney LL, Dunseath G, Churm R, Holmes M, Boesch C, Stavropoulos-Kalinoglou A, et al. Omega-3 polyunsaturated fatty acid supplementation versus placebo on vascular health, glycaemic control, and metabolic parameters in people with type 1 diabetes: a randomised controlled preliminary trial. Cardiovasc Diabetol 2020; 19: 127, doi: 10.1186/s12933-020-01094-5.
https://doi.org/10.1186/s12933-020-01094...
80. Page KA, Williamson A, Yu N, McNay EC, Dzuira J, McCrimmon RJ, et al. Medium-chain fatty acids improve cognitive function in intensively treated type 1 diabetic patients and support in vitro synaptic transmission during acute hypoglycemia. Diabetes 2009; 58: 1237-1244, doi: 10.2337/db08-1557.
https://doi.org/10.2337/db08-1557...
-8181. Rossing P, Hansen BV, Nielsen FS, Myrup B, Hølmer G, Parving HH. Fish oil in diabetic nephropathy. Diabetes Care 1996; 19: 1214-1219, doi: 10.2337/diacare.19.11.1214.
https://doi.org/10.2337/diacare.19.11.12...
). In total, 44 (75.9%) studies had a parallel design, and 14 (24.1%) had a crossover design. The studies included a total of 3,044 randomized subjects, with the adult population being the most common among samples. For the diabetes duration, 12 reports worked with the new-onset disease within a few days or months of diagnosis to observe the preservation of pancreatic function, glycemic control, insulin, initial symptoms, or immune response. The other 53 studies worked with chronically established IDDM, aiming to control metabolic changes and complications of the disease.
Systematic review
Vitamin B complex and vitamin D
On the glycemic control variable Hb1Ac, a significant difference was only reported with nicotinamide alone in one of five reports with this vitamin (2727. Vague P, Picq R, Bernal M, Lassmann-Vague V, Vialettes B. Effect of nicotinamide treatment on the residual insulin secretion in type 1 (insulin-dependent) diabetic patients. Diabetologia 1989; 32: 316-321, doi: 10.1007/BF00265549.
https://doi.org/10.1007/BF00265549...
) and with the combined supplementation of vitamin B1, B6, and B12 (1919. Elbarbary NS, Ismail EAR, Zaki MA, Darwish YW, Ibrahim MZ, El-Hamamsy M. Vitamin B complex supplementation as a homocysteine-lowering therapy for early stage diabetic nephropathy in pediatric patients with type 1 diabetes: a randomized controlled trial. Clin Nutr 2020; 39: 49-56, doi: 10.1016/j.clnu.2019.01.006.
https://doi.org/10.1016/j.clnu.2019.01.0...
). Nwosu et al. (3636. Nwosu BU, Parajuli S, Jasmin G, Fleshman J, Sharma RB, Alonso LC, et al. Ergocalciferol in new-onset type 1 diabetes: a randomized controlled trial. J Endocr Soc 2022; 6: bvab179, doi: 10.1210/jendso/bvab179.
https://doi.org/10.1210/jendso/bvab179...
) demonstrated a significant difference in the variable of insulin dose required per day in addition to A1c-adjusted insulin dose with vitamin D (ergocalciferol).
Significant improvement in flow-mediated dilation was shown with combined and isolated supplementation of vitamin B6 and folate for eight weeks (2323. MacKenzie KE, Wiltshire EJ, Gent R, Hirte C, Piotto L, Couper JJ. Folate and vitamin B6 rapidly normalize endothelial dysfunction in children with type 1 diabetes mellitus. Pediatrics 2006; 118: 242-253, doi: 10.1542/peds.2005-2143.
https://doi.org/10.1542/peds.2005-2143...
). Another important marker for endothelial function, homocysteine production showed a significant reduction in the study by Elbarbary et al. (1919. Elbarbary NS, Ismail EAR, Zaki MA, Darwish YW, Ibrahim MZ, El-Hamamsy M. Vitamin B complex supplementation as a homocysteine-lowering therapy for early stage diabetic nephropathy in pediatric patients with type 1 diabetes: a randomized controlled trial. Clin Nutr 2020; 39: 49-56, doi: 10.1016/j.clnu.2019.01.006.
https://doi.org/10.1016/j.clnu.2019.01.0...
) after supplementation of vitamins B1, B6, and B12.
Joergensen et al. (3434. Joergensen C, Tarnow L, Goetze JP, Rossing P. Vitamin D analogue therapy, cardiovascular risk and kidney function in people with type 1 diabetes mellitus and diabetic nephropathy: a randomized trial. Diabet Med 2015; 32: 374-381, doi: 10.1111/dme.12606.
https://doi.org/10.1111/dme.12606...
) was the only report with vitamin D supplementation present in this review that analyzed renal aspects between these compounds, having significant results in reduction of estimated glomerular filtration rate and albuminuria. The supplementation of vitamins B1, B6, and B12 also showed a significant reduction in urinary albumin/creatinine ratio and cystatin-C (2121. Lewis CM, Canafax DM, Sprafka JM, Barbosa JJ. Double-blind randomized trial of nicotinamide on early-onset diabetes. Diabetes Care 1992; 15: 121-123, doi: 10.2337/diacare.15.1.121.
https://doi.org/10.2337/diacare.15.1.121...
).
Cholecalciferol (vitamin D3) supplementation may improve the ability to suppress regulatory T lymphocytes in reducing the proliferation of effector T lymphocytes (3737. Treiber G, Prietl B, Fröhlich-Reiterer E. Cholecalciferol supplementation improves suppressive capacity of regulatory T-cells in young patients with new-onset type 1 diabetes mellitus - a randomized clinical trial. Clin Immunol 2015; 161: 217-224, doi: 10.1016/j.clim.2015.08.002.
https://doi.org/10.1016/j.clim.2015.08.0...
), in addition to the increase of chemokine ligand 2 (3838. Walter M, Kaupper T, Adler K, Foersch J, Bonifacio E, Ziegler AG. No effect of the 1α, 25-dihydroxyvitamin D3 on β-cell residual function and insulin requirement in adults with new-onset type 1 diabetes. Diabetes Care 2010; 33: 1443-1448, doi: 10.2337/dc09-2297.
https://doi.org/10.2337/dc09-2297...
). Additionally, tumor necrosis factor-α was reduced in the study by Nwosu et al. (3636. Nwosu BU, Parajuli S, Jasmin G, Fleshman J, Sharma RB, Alonso LC, et al. Ergocalciferol in new-onset type 1 diabetes: a randomized controlled trial. J Endocr Soc 2022; 6: bvab179, doi: 10.1210/jendso/bvab179.
https://doi.org/10.1210/jendso/bvab179...
) using ergocalciferol.
Vitamin C and vitamin E
Among the three reports with vitamin C supplementation included in this review, Juhl et al. (4040. Juhl B, Klein F, Christiansen JS. Vitamin C treatment reduces transcapillary escape rate of albumin in type 1 diabetes. Eur J Intern Med 2004; 15: 428-435, doi: 10.1016/j.ejim.2004.07.009.
https://doi.org/10.1016/j.ejim.2004.07.0...
) found a significant reduction in the transcapillary escape rate. With vitamin E, flow-mediated dilation was improved only in two reports (5454. Pinkney JH, Downs L, Hopton M, Mackness MI, Bolton CH. Endothelial dysfunction in type 1 diabetes mellitus: relationship with LDL oxidation and the effects of vitamin E. Diabet Med 1999; 16: 993-999, doi: 10.1046/j.1464-5491.1999.00191.x.
https://doi.org/10.1046/j.1464-5491.1999...
,5555. Skyrme-Jones RA, O'Brien RC, Berry KL, Meredith IT. Vitamin E supplementation improves endothelial function in type I diabetes mellitus: a randomized, placebo-controlled study. J Am Coll Cardiol 2000; 36: 94-102, doi: 10.1016/S0735-1097(00)00720-8.
https://doi.org/10.1016/S0735-1097(00)00...
), with no significant result on these markers in studies with joint vitamin C and vitamin E supplementation. Markers related to platelet activity and blood coagulation were analyzed by studies with vitamin E supplementation, with only a significant decrease in thromboxane B2 production in the report by Gisinger et al. (5151. Gisinger C, Jeremy J, Speiser P. Effect of vitamin E supplementation on platelet thromboxane A2 production in type I diabetic patients: double-blind crossover trial. Diabetes 1988; 37: 1260-1264, doi: 10.2337/diab.37.9.1260.
https://doi.org/10.2337/diab.37.9.1260...
).
Ascorbic acid as prophylactic pre-exercise supplementation decreased the production of free radicals and lipid hydroperoxides (3939. Davison GW, Ashton T, George L, Young IS, McEneny J, Davies B, et al. Molecular detection of exercise-induced free radicals following ascorbate prophylaxis in type 1 diabetes mellitus: a randomised controlled trial. Diabetologia 2008; 51: 2049-2059, doi: 10.1007/s00125-008-1101-1.
https://doi.org/10.1007/s00125-008-1101-...
), being the only study with vitamin C that analyzed these aspects. Decreased low-density lipoprotein (LDL) oxidation was significant in two reports (5050. Giannini C, Lombardo F, Currò F, Pomilio M, Bucciarelli T, Chiarelli F, et al. Effects of high-dose vitamin E supplementation on oxidative stress and microalbuminuria in young adult patients with childhood onset type 1 diabetes mellitus. Diabetes Metab Res Rev 2007; 23: 539-546, doi: 10.1002/dmrr.717.
https://doi.org/10.1002/dmrr.717...
,5555. Skyrme-Jones RA, O'Brien RC, Berry KL, Meredith IT. Vitamin E supplementation improves endothelial function in type I diabetes mellitus: a randomized, placebo-controlled study. J Am Coll Cardiol 2000; 36: 94-102, doi: 10.1016/S0735-1097(00)00720-8.
https://doi.org/10.1016/S0735-1097(00)00...
), and the malondialdehyde production significantly decreased in the study by Colette et al. (4646. Colette C, Pares-Herbute N, Monnier LH, Cartry E. Platelet function in type I diabetes: effects of supplementation with large doses of vitamin E. Am J Clin Nutr 1988; 47: 256-261, doi: 10.1093/ajcn/47.2.256.
https://doi.org/10.1093/ajcn/47.2.256...
). Also, with alpha-tocopherol, the decrease in lipid peroxides by a reduction in the production of thiobarbituric acid reactive substances was observed in the report by Engelen et al. (4949. Engelen W, Keenoy BM, Vertommen J, De Leeuw I. Effects of long-term supplementation with moderate pharmacologic doses of vitamin E are saturable and reversible in patients with type 1 diabetes. Am J Clin Nutr 2000; 72: 1142-1149, doi: 10.1093/ajcn/72.5.1142.
https://doi.org/10.1093/ajcn/72.5.1142...
). In a more specific analysis of different variables and haptoglobin genotypes, the report by Costacou et al. (4444. Costacou T, Levy AP, Miller RG, Snell-Bergeon J, Asleh R, Farbstein D, et al. Effect of vitamin E supplementation on HDL function by haptoglobin genotype in type 1 diabetes: results from the HapE randomized crossover pilot trial. Acta Diabetol 2016; 53: 243-250, doi: 10.1007/s00592-015-0770-8.
https://doi.org/10.1007/s00592-015-0770-...
) found higher HDL-mediated cholesterol efflux in the group with the Hp 2-2 genotype, but with worsening HDL particle size in the Hp 1-1 genotype.
Minerals, trace elements, and antioxidant compounds
Jumaah et al. (6262. Jumaah LF, Alosy BD, Ibrahim HM, Al Hadeethi EM. Double-blind placebo? Controlled effectiveness of cholecalciferol (vitamin D3) plus magnesium and zinc in management of type 1 diabetes (T1d) in pediatric age group. System Rev Pharm 2020; 11: 543-548.) observed a beneficial effect of the use of zinc, magnesium, and vitamin D on signs and symptoms of diabetes and diabetic ketoacidosis, and Shidfar et al. (6464. Shidfar F, Aghasi M, Vafa M, Heidary I, Hosseini S, Shidfar S. Effects of combination of zinc and vitamin A supplementation on serum fasting blood sugar, insulin, apoprotein B and apoprotein AI in patients with type I diabetes. Int J Food Sci Nutr 2010; 61: 182-191, doi: 10.3109/09637480903334171.
https://doi.org/10.3109/0963748090333417...
) reported an increase over placebo in apolipoprotein A-I and a decrease in the apolipoprotein B/apolipoprotein A-I ratio with zinc and vitamin A intervention. Mollo et al. (6767. Mollo R, Zaccardi F, Scalone G, Scavone G, Rizzo P, Navarese EP, et al. Effect of α-lipoic acid on platelet reactivity in type 1 diabetic patients. Diabetes Care 2012; 35: 196-197, doi: 10.2337/dc11-1255.
https://doi.org/10.2337/dc11-1255...
) was the only study that reported a positive effect with antioxidant supplementation, finding increased clotting time in patients who received alpha-lipoic acid (ALA) compared to those who received a placebo, in addition to lower expression of CD41 and CD62P lymphocytes, indicators of platelet activation.
Amino acid and fatty acids
Mauras et al. (6969. Mauras N, Xing D, Fox LA, Englert K, Darmaun D. Effects of glutamine on glycemic control during and after exercise in adolescents with type 1 diabetes: a pilot study. Diabetes Care 2010; 33: 1951-1953, doi: 10.2337/dc10-0275.
https://doi.org/10.2337/dc10-0275...
) and Torres-Santiago et al. (7171. Torres-Santiago L, Mauras N, Hossain J, Weltman AL, Darmaun D. Does oral glutamine improve insulin sensitivity in adolescents with type 1 diabetes? Nutrition 2017; 34: 1-6, doi: 10.1016/j.nut.2016.09.003.
https://doi.org/10.1016/j.nut.2016.09.00...
) found a higher occurrence of nocturnal hypoglycemia episodes in the group that received the treatment with glutamine compared to the placebo group, raising the hypothesis of a possible mechanism of increased insulin sensitivity by glutamine, which was not observed by the latter study, which also performed this analysis.
Reports by Horvaticek et al. (7474. Horvaticek M, Djelmis J, Ivanisevic M, Oreskovic S, Herman M. Effect of eicosapentaenoic acid and docosahexaenoic acid supplementation on C-peptide preservation in pregnant women with type-1 diabetes: randomized placebo controlled clinical trial. Eur J Clin Nutr 2017; 71: 968-972, doi: 10.1038/ejcn.2017.46.
https://doi.org/10.1038/ejcn.2017.46...
) and Ivanisevic et al. (7575. Ivanisevic M, Horvaticek M, Delmis K, Delmis J. Supplementation of EPA and DHA in pregnant women with type 1 diabetes mellitus. Ann Med 2021; 53: 848-859, doi: 10.1080/07853890.2021.1936151.
https://doi.org/10.1080/07853890.2021.19...
) are part of the same study conducted with pregnant women supplemented with omega-3 that analyzed glycemic control, C-peptide, and insulin dose variations. The results showed a higher FCP in the third semester in the group that received the supplementation compared to the placebo, in addition to a lower concentration of glucose and higher concentration of cord C-peptide in newborns and a significantly lower value of the IR-HOMA 2 parameter in children of mothers who received omega-3 supplementation. Analyzing endothelial and coagulation function variables, Khorshidi et al. (7676. Khorshidi M, Sayyari A, Aryaeian N, Olang B, Alaei M, Khalili M, et al. Effects of omega-3 supplementation on endothelial function, vascular structure, and metabolic parameters in adolescents with type 1 diabetes mellitus: a randomized clinical trial. Front Nutr 2022; 9: 962773, doi: 10.3389/fnut.2022.962773.
https://doi.org/10.3389/fnut.2022.962773...
) reported significantly improved flow-mediated dilation with omega-3 supplementation for 12 weeks. Haines et al. (7373. Haines AP, Sanders TA, Imeson JD, Mahler RF, Martin J, Mistry M, et al. Effects of a fish oil supplement on platelet function, haemostatic variables and albuminuria in insulin- dependent diabetics. Thromb Res 1986; 43: 643-655, doi: 10.1016/0049-3848(86)90101-5.
https://doi.org/10.1016/0049-3848(86)901...
) observed a significant reduction in thromboxane production and increased coagulation factor X and platelet aggregation.
The analysis of cognitive test performance during induced hypoglycemia was the central outcome of two studies included in this review, one with the supplementation of an amino acid mixture (7070. Rossetti P, Porcellati F, Ricci NB, Candeloro P, Cioli P, Nair KS, et al. Effect of oral amino acids on counterregulatory responses and cognitive function during insulin-induced hypoglycemia in nondiabetic and type 1 diabetic people. Diabetes 2008; 57: 1905-1917, doi: 10.2337/db08-0276.
https://doi.org/10.2337/db08-0276...
) and the other with medium-chain fatty acid (MCFA) (8080. Page KA, Williamson A, Yu N, McNay EC, Dzuira J, McCrimmon RJ, et al. Medium-chain fatty acids improve cognitive function in intensively treated type 1 diabetic patients and support in vitro synaptic transmission during acute hypoglycemia. Diabetes 2009; 58: 1237-1244, doi: 10.2337/db08-1557.
https://doi.org/10.2337/db08-1557...
). In both studies, the group that received the intervention had better results than the group that received the placebo for most of the tests. As for a change in lipid profile, Rossing et al. (8181. Rossing P, Hansen BV, Nielsen FS, Myrup B, Hølmer G, Parving HH. Fish oil in diabetic nephropathy. Diabetes Care 1996; 19: 1214-1219, doi: 10.2337/diacare.19.11.1214.
https://doi.org/10.2337/diacare.19.11.12...
) reported a significant decrease in very low-density lipoprotein (VLDL) and triglycerides (TGL), but an increase in total cholesterol after 12 months of treatment. Mori et al. (7777. Mori TA, Vandongen R, Masarei JR, Rouse IL, Dunbar D. Comparison of diets supplemented with fish oil or olive oil on plasma lipoproteins in insulin-dependent diabetics. Metabolism 1991; 40: 241-246, doi: 10.1016/0026-0495(91)90104-5.
https://doi.org/10.1016/0026-0495(91)901...
) reported favorable results in a 3-week intervention, with a significant decrease in HDL3 and TGL subfractions and an increase in HDL2 subfraction. A significant decrease in plasma triglyceride was also found by Khorshidi et al. (7676. Khorshidi M, Sayyari A, Aryaeian N, Olang B, Alaei M, Khalili M, et al. Effects of omega-3 supplementation on endothelial function, vascular structure, and metabolic parameters in adolescents with type 1 diabetes mellitus: a randomized clinical trial. Front Nutr 2022; 9: 962773, doi: 10.3389/fnut.2022.962773.
https://doi.org/10.3389/fnut.2022.962773...
), with no changes in total cholesterol and its fractions. Britten-Jones et al. (7272. Britten-Jones AC, Kamel JT, Roberts LJ, Braat S, Craig JP, MacIsaac RJ, et al. Investigating the neuroprotective effect of oral omega-3 fatty acid supplementation in type 1 diabetes (nPROOFS1): a randomized placebo-controlled trial. Diabetes 2021; 70: 1794-1806, doi: 10.2337/db21-0136.
https://doi.org/10.2337/db21-0136...
) showed a neuroprotective effect of omega-3 confirmed by significant positive results in central corneal nerve fiber length, central corneal nerve branch density, and central corneal nerve fiber density.
Meta-analyses
Effects of vitamin B3 supplementation
Three reports (n=117) (1818. Chase HP, Butler-Simon N, Garg S, McDuffie M, Hoops SL, O'Brien D. A trial of nicotinamide in newly diagnosed patients with type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1990; 33: 444-446, doi: 10.1007/BF00404097.
https://doi.org/10.1007/BF00404097...
,2626. Pozzilli P, Visalli N, Signore A, Baroni MG, Buzzetti R, Cavallo MG, et al. Double blind trial of nicotinamide in recent-onset IDDM (the IMDIAB III study). Diabetologia 1995; 38: 848-852, doi: 10.1007/s001250050362.
https://doi.org/10.1007/s001250050362...
,2727. Vague P, Picq R, Bernal M, Lassmann-Vague V, Vialettes B. Effect of nicotinamide treatment on the residual insulin secretion in type 1 (insulin-dependent) diabetic patients. Diabetologia 1989; 32: 316-321, doi: 10.1007/BF00265549.
https://doi.org/10.1007/BF00265549...
) with vitamin B3 supplementation had HbA1c data that was possible to extract for meta-analysis, showing a non-significant effect on improvement in glycated hemoglobin (RMD=-1.01; 95%CI: -2.57, 0.55; P=0.205), with high heterogeneity (I2=82.45%; P=0.003) (Figure 2A). Also, vitamin B3 supplementation (three reports, n=137) (1818. Chase HP, Butler-Simon N, Garg S, McDuffie M, Hoops SL, O'Brien D. A trial of nicotinamide in newly diagnosed patients with type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1990; 33: 444-446, doi: 10.1007/BF00404097.
https://doi.org/10.1007/BF00404097...
,2222. Mendola G, Casamitjana R, Gomis R. Effect of nicotinamide therapy upon B-cell function in newly diagnosed type 1 (insulin-dependent) diabetic patients. Diabetologia 1989; 32: 160-162, doi: 10.1007/BF00265087.
https://doi.org/10.1007/BF00265087...
,2626. Pozzilli P, Visalli N, Signore A, Baroni MG, Buzzetti R, Cavallo MG, et al. Double blind trial of nicotinamide in recent-onset IDDM (the IMDIAB III study). Diabetologia 1995; 38: 848-852, doi: 10.1007/s001250050362.
https://doi.org/10.1007/s001250050362...
) showed no significant effect on FCP secretion (RMD=0.04; 95%CI: -0.02, 0.10; P=0.224), with low heterogeneity of data (I2=0%; P=0.970) (Figure 3A). Finally, there was a meta-analysis of data from three reports (n=117) (1818. Chase HP, Butler-Simon N, Garg S, McDuffie M, Hoops SL, O'Brien D. A trial of nicotinamide in newly diagnosed patients with type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1990; 33: 444-446, doi: 10.1007/BF00404097.
https://doi.org/10.1007/BF00404097...
,2626. Pozzilli P, Visalli N, Signore A, Baroni MG, Buzzetti R, Cavallo MG, et al. Double blind trial of nicotinamide in recent-onset IDDM (the IMDIAB III study). Diabetologia 1995; 38: 848-852, doi: 10.1007/s001250050362.
https://doi.org/10.1007/s001250050362...
,2727. Vague P, Picq R, Bernal M, Lassmann-Vague V, Vialettes B. Effect of nicotinamide treatment on the residual insulin secretion in type 1 (insulin-dependent) diabetic patients. Diabetologia 1989; 32: 316-321, doi: 10.1007/BF00265549.
https://doi.org/10.1007/BF00265549...
) for the insulin dose required, which also showed no significant difference in results (SMD=-0.20; 95%CI: -0.57, 0.18; P=0.306) and low heterogeneity of the data (I2=0%; P=0.713) (Figure 3C).
Effects of dietary supplementations on glycated hemoglobin (HbA1c). A, Vitamin B3; B, Vitamin D; C, Vitamin E; D, Omega-3.
Effects of dietary supplementations on fasting C-peptide and insulin dose requirements. A, Vitamin B3 on fasting C-peptide; B, Vitamin D on fasting C-peptide; C, Vitamin B3 on insulin dose requirement.
Effects of vitamin D supplementation
Four reports (n=175) (3030. Ataie-Jafari A, Loke SC, Rahmat AB, Larijani B, Abbasi F, Leow MKS, et al. A randomized placebo-controlled trial of alphacalcidol on the preservation of beta cell function in children with recent onset type 1 diabetes. Clin Nutr 2013; 32: 911-917, doi: 10.1016/j.clnu.2013.01.012.
https://doi.org/10.1016/j.clnu.2013.01.0...
,3333. Gabbay MAL, Sato MN, Finazzo C, Duarte AJS, Dib SA. Effect of cholecalciferol as adjunctive therapy with insulin on protective immunologic profile and decline of residual β- cell function in new-onset type 1 diabetes mellitus. Arch Pediatr Adolesc Med 2012; 166: 601-607, doi: 10.1001/archpediatrics.2012.164.
https://doi.org/10.1001/archpediatrics.2...
,3636. Nwosu BU, Parajuli S, Jasmin G, Fleshman J, Sharma RB, Alonso LC, et al. Ergocalciferol in new-onset type 1 diabetes: a randomized controlled trial. J Endocr Soc 2022; 6: bvab179, doi: 10.1210/jendso/bvab179.
https://doi.org/10.1210/jendso/bvab179...
,3838. Walter M, Kaupper T, Adler K, Foersch J, Bonifacio E, Ziegler AG. No effect of the 1α, 25-dihydroxyvitamin D3 on β-cell residual function and insulin requirement in adults with new-onset type 1 diabetes. Diabetes Care 2010; 33: 1443-1448, doi: 10.2337/dc09-2297.
https://doi.org/10.2337/dc09-2297...
) with vitamin D supplementation on HbA1c showed no significant effect (RMD=-0.23; 95%CI: -0.53, 0.08; P=0.152), and low heterogeneity of data (I2=0%; P=0.751) (Figure 2B). However, FCP secretion data from four reports (n=144) (3333. Gabbay MAL, Sato MN, Finazzo C, Duarte AJS, Dib SA. Effect of cholecalciferol as adjunctive therapy with insulin on protective immunologic profile and decline of residual β- cell function in new-onset type 1 diabetes mellitus. Arch Pediatr Adolesc Med 2012; 166: 601-607, doi: 10.1001/archpediatrics.2012.164.
https://doi.org/10.1001/archpediatrics.2...
,3636. Nwosu BU, Parajuli S, Jasmin G, Fleshman J, Sharma RB, Alonso LC, et al. Ergocalciferol in new-onset type 1 diabetes: a randomized controlled trial. J Endocr Soc 2022; 6: bvab179, doi: 10.1210/jendso/bvab179.
https://doi.org/10.1210/jendso/bvab179...
-37. Treiber G, Prietl B, Fröhlich-Reiterer E. Cholecalciferol supplementation improves suppressive capacity of regulatory T-cells in young patients with new-onset type 1 diabetes mellitus - a randomized clinical trial. Clin Immunol 2015; 161: 217-224, doi: 10.1016/j.clim.2015.08.002.
https://doi.org/10.1016/j.clim.2015.08.0...
3838. Walter M, Kaupper T, Adler K, Foersch J, Bonifacio E, Ziegler AG. No effect of the 1α, 25-dihydroxyvitamin D3 on β-cell residual function and insulin requirement in adults with new-onset type 1 diabetes. Diabetes Care 2010; 33: 1443-1448, doi: 10.2337/dc09-2297.
https://doi.org/10.2337/dc09-2297...
) showed a C-peptide preservation effect with the intervention (RMD=0.05; 95%CI: 0.01, 0.9; P=0.023), with low data heterogeneity (I2=0%; P=0.391) (Figure 3B).
Effects of vitamin E supplementation
The only possible meta-analysis with vitamin E included four reports (n=113) (4343. Bursell SE, Clermont AC, Aiello LP, Aiello LM, Schlossman DK, Feener EP, et al. High-dose vitamin E supplementation normalizes retinal blood flow and creatinine clearance in patients with type 1 diabetes. Diabetes Care 1999; 22: 1245-1251, doi: 10.2337/diacare.22.8.1245.
https://doi.org/10.2337/diacare.22.8.124...
,4747. Duntas L, Kemmer TP, Vorberg B, Scherbaum W. Administration of d-alpha- tocopherol in patients with insulin-dependent diabetes mellitus. Curr Ther Res 1996; 57: 682-690, doi: 10.1016/S0011-393X(96)80073-7.
https://doi.org/10.1016/S0011-393X(96)80...
,4848. Economides PA, Khaodhiar L, Caselli A, Caballero AE, Keenan H, Bursell SE, et al. The effect of vitamin E on endothelial function of micro-and macrocirculation and left ventricular function in type 1 and type 2 diabetic patients. Diabetes 2005; 54: 204-211, doi: 10.2337/diabetes.54.1.204.
https://doi.org/10.2337/diabetes.54.1.20...
,5050. Giannini C, Lombardo F, Currò F, Pomilio M, Bucciarelli T, Chiarelli F, et al. Effects of high-dose vitamin E supplementation on oxidative stress and microalbuminuria in young adult patients with childhood onset type 1 diabetes mellitus. Diabetes Metab Res Rev 2007; 23: 539-546, doi: 10.1002/dmrr.717.
https://doi.org/10.1002/dmrr.717...
) that presented HbA1c, demonstrating no significant effect with the intervention (RMD=-0.19; 95%CI: -0.52, 0.14; P=0.253), with low data heterogeneity (I2=0%; P=0.809) (Figure 2C).
Effects of omega-3 supplementation
Four reports (n=140) (7272. Britten-Jones AC, Kamel JT, Roberts LJ, Braat S, Craig JP, MacIsaac RJ, et al. Investigating the neuroprotective effect of oral omega-3 fatty acid supplementation in type 1 diabetes (nPROOFS1): a randomized placebo-controlled trial. Diabetes 2021; 70: 1794-1806, doi: 10.2337/db21-0136.
https://doi.org/10.2337/db21-0136...
,7676. Khorshidi M, Sayyari A, Aryaeian N, Olang B, Alaei M, Khalili M, et al. Effects of omega-3 supplementation on endothelial function, vascular structure, and metabolic parameters in adolescents with type 1 diabetes mellitus: a randomized clinical trial. Front Nutr 2022; 9: 962773, doi: 10.3389/fnut.2022.962773.
https://doi.org/10.3389/fnut.2022.962773...
,7979. O'Mahoney LL, Dunseath G, Churm R, Holmes M, Boesch C, Stavropoulos-Kalinoglou A, et al. Omega-3 polyunsaturated fatty acid supplementation versus placebo on vascular health, glycaemic control, and metabolic parameters in people with type 1 diabetes: a randomised controlled preliminary trial. Cardiovasc Diabetol 2020; 19: 127, doi: 10.1186/s12933-020-01094-5.
https://doi.org/10.1186/s12933-020-01094...
,8181. Rossing P, Hansen BV, Nielsen FS, Myrup B, Hølmer G, Parving HH. Fish oil in diabetic nephropathy. Diabetes Care 1996; 19: 1214-1219, doi: 10.2337/diacare.19.11.1214.
https://doi.org/10.2337/diacare.19.11.12...
) were included for the meta-analysis of the effects of supplementation of omega-3 on HbA1c. The result showed a significant effect on HbA1c control (RMD=-0.33; 95%CI: -0.53, -0.12; P=0.002), presenting low heterogeneity in the data (I2=0%; P=0.758) (Figure 2D).
Risk of bias analysis
The overall risk of bias assessment of each included study is indicated in the final column of the respective tables with the interventions in this review (Supplementary Tables S2-S4). Altogether, 16 studies were classified as high risk of bias, 32 as some concern for risk of bias, and 10 as low risk of bias, with deviations from intended interventions and selection of the reported outcome being the leading causes of bias in these reports (Supplementary Figure S2).
Analysis of the overall quality of the evidence
The markers analyzed in the meta-analyses were defined as critically important (HbA1c) and important (FCP and required insulin dose) due to their direct relationship with the prognosis of IDDM. The meta-analyses were assessed as low or very low quality, with the serious risk of bias of the included studies being primarily responsible for the low quality of the results of the analyses, in addition to serious inconsistency, indirect evidence, and imprecision of some of them. Supplementary Table S5 shows the GRADE summary of findings for quality of evidence assessment for the effects of nutritional compounds supplementation in individuals with IDDM.
Discussion
This extensive systematic review with meta-analyses of intervention studies with supplementation of vitamins, minerals, trace elements, and non-essential compounds with antioxidant properties, amino acids, and fatty acids showed inconsistent results among most of the outcomes analyzed. The primary endpoint of this review, variables of glycemic control, had only a few isolated positive significant results in the qualitative analysis of reports. Instead of glycemic control, most of the included studies had as central endpoint markers of other biological functions that undergo changes throughout the disease, such as endothelial, renal, and antioxidant defense, which were the secondary endpoints analyzed in this review. However, as with the markers of glucose metabolism, it was only possible to observe significant effects on isolated variables and rarely with positive results in more than one study with the same intervention.
Nicotinamide was one of the interventions in studies that looked at the effect of these compounds in preserving pancreatic β-cell function in newly diagnosed individuals with IDDM, with the hypothesis of the action being the inhibition of poly (ADP-ribose) synthesis, an enzyme involved in the process of cell apoptosis and other mechanisms (8282. Pociot F, Reimers JI, Andersen HU. Nicotinamide-biological actions and therapeutic potential in diabetes prevention: IDIG Workshop, Copenhagen, Denmark, 4-5 December 1992. Diabetologia 1992; 36: 574-576, doi: 10.1007/BF02743277.
https://doi.org/10.1007/BF02743277...
). However, no effect was observed in the meta-analyses performed by this review on the preservation of C-peptide secretion or reduction of the required daily insulin dose (Figure 3), which are β-cell function markers.
In the same spectrum, the use of vitamin D supplementation in this context arises after the advancement of studies showing several interactions of the vitamin with different cells of the body, especially the immune system (8383. Hewison M. Vitamin D and the immune system: new perspectives on an old theme. Rheum Dis Clin North Am 2012; 38: 125-139, doi: 10.1016/j.rdc.2012.03.012.
https://doi.org/10.1016/j.rdc.2012.03.01...
). The qualitative analysis of vitamin D studies showed significant changes in immunological markers, glycemic control, and inflammatory markers (3333. Gabbay MAL, Sato MN, Finazzo C, Duarte AJS, Dib SA. Effect of cholecalciferol as adjunctive therapy with insulin on protective immunologic profile and decline of residual β- cell function in new-onset type 1 diabetes mellitus. Arch Pediatr Adolesc Med 2012; 166: 601-607, doi: 10.1001/archpediatrics.2012.164.
https://doi.org/10.1001/archpediatrics.2...
,3636. Nwosu BU, Parajuli S, Jasmin G, Fleshman J, Sharma RB, Alonso LC, et al. Ergocalciferol in new-onset type 1 diabetes: a randomized controlled trial. J Endocr Soc 2022; 6: bvab179, doi: 10.1210/jendso/bvab179.
https://doi.org/10.1210/jendso/bvab179...
,3737. Treiber G, Prietl B, Fröhlich-Reiterer E. Cholecalciferol supplementation improves suppressive capacity of regulatory T-cells in young patients with new-onset type 1 diabetes mellitus - a randomized clinical trial. Clin Immunol 2015; 161: 217-224, doi: 10.1016/j.clim.2015.08.002.
https://doi.org/10.1016/j.clim.2015.08.0...
). Additionally, the meta-analysis on the secretion of FCP with the use of vitamin D showed a statistically significant result, which would indicate a protective action of vitamin D in controlling the progression of IDDM in its early stages, in line with the results of meta-analyses of observational studies that suggest high circulating 25(OH)D concentration and vitamin D supplementation in early childhood protect against the development of IDDM (8484. Hou Y, Song A, Jin Y, Xia Q, Song G, Xing X. A dose-response meta-analysis between serum concentration of 25-hydroxy vitamin D and risk of type 1 diabetes mellitus. Eur J Clin Nutr 2021; 75: 1010-1023, doi: 10.1038/s41430-020-00813-1.
https://doi.org/10.1038/s41430-020-00813...
).
However, caution should be taken regarding the interpretation of these data before recommending vitamin D supplementation for the control of IDDM progression, primarily because this meta-analysis only included four studies with small samples and was rated by GRADE as ‘very-low' quality of evidence. Among the four studies included, three different formulations of vitamin D were used: calcitriol (3838. Walter M, Kaupper T, Adler K, Foersch J, Bonifacio E, Ziegler AG. No effect of the 1α, 25-dihydroxyvitamin D3 on β-cell residual function and insulin requirement in adults with new-onset type 1 diabetes. Diabetes Care 2010; 33: 1443-1448, doi: 10.2337/dc09-2297.
https://doi.org/10.2337/dc09-2297...
), ergocalciferol (3636. Nwosu BU, Parajuli S, Jasmin G, Fleshman J, Sharma RB, Alonso LC, et al. Ergocalciferol in new-onset type 1 diabetes: a randomized controlled trial. J Endocr Soc 2022; 6: bvab179, doi: 10.1210/jendso/bvab179.
https://doi.org/10.1210/jendso/bvab179...
), and cholecalciferol (3333. Gabbay MAL, Sato MN, Finazzo C, Duarte AJS, Dib SA. Effect of cholecalciferol as adjunctive therapy with insulin on protective immunologic profile and decline of residual β- cell function in new-onset type 1 diabetes mellitus. Arch Pediatr Adolesc Med 2012; 166: 601-607, doi: 10.1001/archpediatrics.2012.164.
https://doi.org/10.1001/archpediatrics.2...
,3737. Treiber G, Prietl B, Fröhlich-Reiterer E. Cholecalciferol supplementation improves suppressive capacity of regulatory T-cells in young patients with new-onset type 1 diabetes mellitus - a randomized clinical trial. Clin Immunol 2015; 161: 217-224, doi: 10.1016/j.clim.2015.08.002.
https://doi.org/10.1016/j.clim.2015.08.0...
), which have different metabolisms, so further research is needed to define the effects of vitamin D.
Vitamins of the B complex are related to endothelial function, and the use of folic acid has already been tested in other conditions, such as hypercholesterolemia, T2DM, coronary artery disease, and stroke, showing positive effects on endothelial function in these individuals (8585. Lee R, Channon KM, Antoniades C. Therapeutic strategies targeting endothelial function in humans: clinical implications. Curr Vasc Pharmacol 2012; 10: 77-93, doi: 10.2174/157016112798829751.
https://doi.org/10.2174/1570161127988297...
). However, our results indicated the need for more evidence for these compounds in IDDM, as only two studies with B vitamins have shown positive effects on these markers (1919. Elbarbary NS, Ismail EAR, Zaki MA, Darwish YW, Ibrahim MZ, El-Hamamsy M. Vitamin B complex supplementation as a homocysteine-lowering therapy for early stage diabetic nephropathy in pediatric patients with type 1 diabetes: a randomized controlled trial. Clin Nutr 2020; 39: 49-56, doi: 10.1016/j.clnu.2019.01.006.
https://doi.org/10.1016/j.clnu.2019.01.0...
,2323. MacKenzie KE, Wiltshire EJ, Gent R, Hirte C, Piotto L, Couper JJ. Folate and vitamin B6 rapidly normalize endothelial dysfunction in children with type 1 diabetes mellitus. Pediatrics 2006; 118: 242-253, doi: 10.1542/peds.2005-2143.
https://doi.org/10.1542/peds.2005-2143...
).
From studies using chronic vitamin C supplementation, it was only possible to observe a positive effect on renal function by reducing the transcapillary escape rate of albumin (4040. Juhl B, Klein F, Christiansen JS. Vitamin C treatment reduces transcapillary escape rate of albumin in type 1 diabetes. Eur J Intern Med 2004; 15: 428-435, doi: 10.1016/j.ejim.2004.07.009.
https://doi.org/10.1016/j.ejim.2004.07.0...
). Beyond that, Davison et al. (3939. Davison GW, Ashton T, George L, Young IS, McEneny J, Davies B, et al. Molecular detection of exercise-induced free radicals following ascorbate prophylaxis in type 1 diabetes mellitus: a randomised controlled trial. Diabetologia 2008; 51: 2049-2059, doi: 10.1007/s00125-008-1101-1.
https://doi.org/10.1007/s00125-008-1101-...
) showed that pre-exercise ascorbic acid can have a prophylactic effect with decreased vascular free radical generation in IDDM patients, but attention is needed to its use in this context since its antioxidant effect tends to block anabolic signaling pathways, impairing metabolic adaptations to training (8686. Higgins MR, Izadi A, Kaviani M. Antioxidants and exercise performance: With a focus on vitamin E and C supplementation. Int J Environ Res Public Health 2020; 17: 8452, doi: 10.3390/ijerph17228452.
https://doi.org/10.3390/ijerph17228452...
). Therefore, evidence is scarce to establish a recommendation about its supplementation.
The qualitative analysis of his review showed that vitamin E supplementation in IDDM may positively affect some markers of endothelial function, coagulation, and antioxidant defense (4343. Bursell SE, Clermont AC, Aiello LP, Aiello LM, Schlossman DK, Feener EP, et al. High-dose vitamin E supplementation normalizes retinal blood flow and creatinine clearance in patients with type 1 diabetes. Diabetes Care 1999; 22: 1245-1251, doi: 10.2337/diacare.22.8.1245.
https://doi.org/10.2337/diacare.22.8.124...
-44. Costacou T, Levy AP, Miller RG, Snell-Bergeon J, Asleh R, Farbstein D, et al. Effect of vitamin E supplementation on HDL function by haptoglobin genotype in type 1 diabetes: results from the HapE randomized crossover pilot trial. Acta Diabetol 2016; 53: 243-250, doi: 10.1007/s00592-015-0770-8.
https://doi.org/10.1007/s00592-015-0770-...
4545. Ceriello A, Giugliano D, Quatraro A, Donzella C, Dipalo G, Lefebvre PJ. Vitamin E reduction of protein glycosylation in diabetes. New prospect for prevention of diabetic complications? Diabetes Care 1991; 14: 68-72, doi: 10.2337/diacare.14.1.68.
https://doi.org/10.2337/diacare.14.1.68...
,4949. Engelen W, Keenoy BM, Vertommen J, De Leeuw I. Effects of long-term supplementation with moderate pharmacologic doses of vitamin E are saturable and reversible in patients with type 1 diabetes. Am J Clin Nutr 2000; 72: 1142-1149, doi: 10.1093/ajcn/72.5.1142.
https://doi.org/10.1093/ajcn/72.5.1142...
-50. Giannini C, Lombardo F, Currò F, Pomilio M, Bucciarelli T, Chiarelli F, et al. Effects of high-dose vitamin E supplementation on oxidative stress and microalbuminuria in young adult patients with childhood onset type 1 diabetes mellitus. Diabetes Metab Res Rev 2007; 23: 539-546, doi: 10.1002/dmrr.717.
https://doi.org/10.1002/dmrr.717...
5151. Gisinger C, Jeremy J, Speiser P. Effect of vitamin E supplementation on platelet thromboxane A2 production in type I diabetic patients: double-blind crossover trial. Diabetes 1988; 37: 1260-1264, doi: 10.2337/diab.37.9.1260.
https://doi.org/10.2337/diab.37.9.1260...
,5454. Pinkney JH, Downs L, Hopton M, Mackness MI, Bolton CH. Endothelial dysfunction in type 1 diabetes mellitus: relationship with LDL oxidation and the effects of vitamin E. Diabet Med 1999; 16: 993-999, doi: 10.1046/j.1464-5491.1999.00191.x.
https://doi.org/10.1046/j.1464-5491.1999...
,5555. Skyrme-Jones RA, O'Brien RC, Berry KL, Meredith IT. Vitamin E supplementation improves endothelial function in type I diabetes mellitus: a randomized, placebo-controlled study. J Am Coll Cardiol 2000; 36: 94-102, doi: 10.1016/S0735-1097(00)00720-8.
https://doi.org/10.1016/S0735-1097(00)00...
). Although vitamin E can be related to the reduction of lipoprotein oxidation, most observational studies could not find a relationship between tocopherol plasma values and cardiovascular disease reduction in other populations (8787. Shah S, Shiekh Y, Lawrence JA, Ezekwueme F, Alam M, Kunwar S, et al. A systematic review of effects of vitamin E on the cardiovascular system. Cureus 2021; 13: e15616, doi: 10.7759/cureus.15616.
https://doi.org/10.7759/cureus.15616...
).
In IDDM patients, glutamine supplementation should be used with caution, as the studies using this intervention observed increased nocturnal hypoglycemic events and the related mechanisms have not been elucidated (6969. Mauras N, Xing D, Fox LA, Englert K, Darmaun D. Effects of glutamine on glycemic control during and after exercise in adolescents with type 1 diabetes: a pilot study. Diabetes Care 2010; 33: 1951-1953, doi: 10.2337/dc10-0275.
https://doi.org/10.2337/dc10-0275...
,7171. Torres-Santiago L, Mauras N, Hossain J, Weltman AL, Darmaun D. Does oral glutamine improve insulin sensitivity in adolescents with type 1 diabetes? Nutrition 2017; 34: 1-6, doi: 10.1016/j.nut.2016.09.003.
https://doi.org/10.1016/j.nut.2016.09.00...
). On the other hand, the use of a multi-amino acid mixture (7070. Rossetti P, Porcellati F, Ricci NB, Candeloro P, Cioli P, Nair KS, et al. Effect of oral amino acids on counterregulatory responses and cognitive function during insulin-induced hypoglycemia in nondiabetic and type 1 diabetic people. Diabetes 2008; 57: 1905-1917, doi: 10.2337/db08-0276.
https://doi.org/10.2337/db08-0276...
) and MCFA concentrate (8080. Page KA, Williamson A, Yu N, McNay EC, Dzuira J, McCrimmon RJ, et al. Medium-chain fatty acids improve cognitive function in intensively treated type 1 diabetic patients and support in vitro synaptic transmission during acute hypoglycemia. Diabetes 2009; 58: 1237-1244, doi: 10.2337/db08-1557.
https://doi.org/10.2337/db08-1557...
) could improve cognitive function during acute hypoglycemic episodes and thus be recommended as a prophylactic use in preserving brain function during these events, such as sleeping or driving, without producing high peaks of hyperglycemia (7070. Rossetti P, Porcellati F, Ricci NB, Candeloro P, Cioli P, Nair KS, et al. Effect of oral amino acids on counterregulatory responses and cognitive function during insulin-induced hypoglycemia in nondiabetic and type 1 diabetic people. Diabetes 2008; 57: 1905-1917, doi: 10.2337/db08-0276.
https://doi.org/10.2337/db08-0276...
).
The decrease in triglyceride and minor changes in HDL found in studies with omega-3 intervention included in this review (7676. Khorshidi M, Sayyari A, Aryaeian N, Olang B, Alaei M, Khalili M, et al. Effects of omega-3 supplementation on endothelial function, vascular structure, and metabolic parameters in adolescents with type 1 diabetes mellitus: a randomized clinical trial. Front Nutr 2022; 9: 962773, doi: 10.3389/fnut.2022.962773.
https://doi.org/10.3389/fnut.2022.962773...
,7777. Mori TA, Vandongen R, Masarei JR, Rouse IL, Dunbar D. Comparison of diets supplemented with fish oil or olive oil on plasma lipoproteins in insulin-dependent diabetics. Metabolism 1991; 40: 241-246, doi: 10.1016/0026-0495(91)90104-5.
https://doi.org/10.1016/0026-0495(91)901...
,8181. Rossing P, Hansen BV, Nielsen FS, Myrup B, Hølmer G, Parving HH. Fish oil in diabetic nephropathy. Diabetes Care 1996; 19: 1214-1219, doi: 10.2337/diacare.19.11.1214.
https://doi.org/10.2337/diacare.19.11.12...
) is in accordance with the most recent evidence of the use of this supplement (8888. Skulas-Ray AC, Wilson PWF, Harris WS, Brinton EA, Kris-Etherton PM, Richter CK, et al. Omega-3 fatty acids for the management of hypertriglyceridemia: a science advisory from the American Heart Association. Circulation 2019; 140: e673-e691, doi: 10.1161/CIR.0000000000000709.
https://doi.org/10.1161/CIR.000000000000...
). Based on the fact that mean baseline values of plasma lipids and lipoproteins in the samples of these studies were in the normal range and on the pathogenesis of IDDM, people with IDDM with elevated TGL levels and low HDL may benefit from omega-3 supplementation. The only study that observed a positive effect of this fatty acid on corneal neuroregeneration with the use of omega-3 was by Britten-Jones et al. (7272. Britten-Jones AC, Kamel JT, Roberts LJ, Braat S, Craig JP, MacIsaac RJ, et al. Investigating the neuroprotective effect of oral omega-3 fatty acid supplementation in type 1 diabetes (nPROOFS1): a randomized placebo-controlled trial. Diabetes 2021; 70: 1794-1806, doi: 10.2337/db21-0136.
https://doi.org/10.2337/db21-0136...
). Additionally, the reports included in this review with a sample of pregnant women showed positive effects of omega-3 (7474. Horvaticek M, Djelmis J, Ivanisevic M, Oreskovic S, Herman M. Effect of eicosapentaenoic acid and docosahexaenoic acid supplementation on C-peptide preservation in pregnant women with type-1 diabetes: randomized placebo controlled clinical trial. Eur J Clin Nutr 2017; 71: 968-972, doi: 10.1038/ejcn.2017.46.
https://doi.org/10.1038/ejcn.2017.46...
,7575. Ivanisevic M, Horvaticek M, Delmis K, Delmis J. Supplementation of EPA and DHA in pregnant women with type 1 diabetes mellitus. Ann Med 2021; 53: 848-859, doi: 10.1080/07853890.2021.1936151.
https://doi.org/10.1080/07853890.2021.19...
).
The data analyses performed by this review showed a significant effect of omega-3 in controlling HbA1c, but this result had some points that deserve attention: only four studies were included in the analyses, all with small samples; despite the low heterogeneity, one of the studies had a weight of 92.37% in the analysis (7676. Khorshidi M, Sayyari A, Aryaeian N, Olang B, Alaei M, Khalili M, et al. Effects of omega-3 supplementation on endothelial function, vascular structure, and metabolic parameters in adolescents with type 1 diabetes mellitus: a randomized clinical trial. Front Nutr 2022; 9: 962773, doi: 10.3389/fnut.2022.962773.
https://doi.org/10.3389/fnut.2022.962773...
); and the quality of evidence is low, according to the GRADE assessment. Due to the particularities of this meta-analysis and the low quality of evidence, there is low support for the recommendation of omega-3 supplementation in the control of HbA1c in individuals with IDDM.
Regarding the risk of bias, most of the included reports presented some concern (55.1%) or high risk (27.6%), with only ten reports with a low risk of bias (17.3%), which negatively affects the quality of data of these publications. Moreover, the GRADE assessment of the overall quality of evidence showed a ‘low' or ‘very-low' quality for all analyses in this research. Considering the high importance of the analyzed variables, it is not possible to establish recommendations based on the results of the meta-analyses, especially positive results, with vitamin D for FCP and omega-3 for HbA1c.
To the best of our knowledge, this study is the largest and most comprehensive systematic review with meta-analysis of intervention studies with nutritional supplementation in IDDM, and the only one that compiled data from different compounds in this condition and performed statistical analyses of the data. The main limitation of this review was the small number of meta-analyses and small number of studies included in those meta-analyses. This was due mainly to the underreported information in the studies, precluding meta-analyses for some biological markers, such as for endothelial function, renal function, and other variables related to the disease progression.
Even though positive results were reported in some studies, there was no consistency in findings for an indication of these compounds as adjuvant therapy in the treatment and control of complications and progression of IDDM. The dietetic intake of these compounds should be maintained as recommended for the healthy population, and clinical practice should be focused on avoiding nutritional deficiency in this population.
The current state of vitamin D research involving the control of IDDM progression in its early stage needs to be highlighted. The positive result of the meta-analysis for FCP, even with a few low-quality studies included, shows a possible effect of this vitamin in slowing down the destruction of β-cells. These results are preliminary but corroborate epidemiological findings in this population, opening the horizon for further studies and methodological standardization for the actual recommendation of vitamin D as therapy in controlling the progression of IDDM.
Supplementary Material
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Acknowledgments
This research did not receive any funding. L.C. Ferraz received a fellowship (No. E: 60030.0000001056/2022) from the Alagoas state government through the agency FAPEAL (Foundation for Research Support of the State of Alagoas). N.B. Bueno is supported by a research productivity fellowship from the National Council for Scientific and Technological Development (CNPq, No. 311401/2022-8).
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Publication Dates
-
Publication in this collection
23 Aug 2024 -
Date of issue
2024
History
-
Received
07 Mar 2024 -
Accepted
19 June 2024