Omega-3 fatty acids are a class of lipids with established biological properties. They become part of the constitution of the cell membrane in many types of both animal and human tissue, they are also widely represented in the plant kingdom and in microorganisms. Apart from fish and other marine organisms, omega-3 acids are found in the oils of various plants and are used as supplements for the correction of cardiovascular disease and imbalances in the metabolism of cholesterol and triglycerides. They are also essential for renal function and external integration has shown that omega-3s can improve or stabilize the natural evolution of chronic renal failure. Omega-3s are also recommended for diabetic patients, who due to their metabolic condition are more prone to silent inflammation and the effects of oxidative stress. These molecules act with different but apparently integrated molecular mechanisms.
To begin with, they are substrates of enzymes that process other fatty acids such as omega-6 (eg arachidonic acid) which are inflammatory due to the production of prostaglandins and leukotrienes; from their transformation, on the other hand, anti-inflammatory biolipids called lipoxins, resolvins and protectins originate. Omega-3 acids are also direct molecular regulators: it has been shown that they can bind cell proteins such as peroxisomal receptors (PPARs) and nuclear receptors of liver cells (HNF1-4). These transcription factors are important, if not central, regulators of carbohydrate and triglyceride metabolism. It is with this mechanism that scientists thought they could correct the dysmetabolism seen in obesity, diabetes and high cholesterol. Recently, it has been shown that omega-3 fatty acids can interact with surface receptors, such as the former orphan receptor GPR120 which sets in motion a cell cascade with an ultimately anti-inflammatory effect.
Another bioactive molecule is vitamin D, which is mainly known for regulating calcium metabolism and immune defenses. More and more evidence has been added over the past 20 years, indicating the role of vitamin D in maintaining homeostasis of the nervous system, bone marrow, kidney and cardiovascular system. Most of its actions are mediated by binding to the vitamin D receptor (VDR), initially found in intestinal mucosal cells but present in all tissues. The active vitamin D present in the plasma, bound to its carrier protein (DBP), enters the cytoplasm of the target cells and there binds the VDR. In turn, this recruits another transcription factor, the retinoid X receptor (RXR-alpha), forming a complex that is able to stimulate specific gene expression. Finally, more and more experimental evidence supports the role of vitamin D in maintaining the cellular functions of the pancreas.
Several scientific studies have suggested that the use of high doses of omega-3 and vitamin D, both with anti-inflammatory and immunomodulatory properties, may offer a potential beneficial effect on autoimmune conditions, such as type 1 diabetes. Vitamin D has been linked to different immunomodulatory effects. Studies on new-onset type 1 diabetes have shown that treatment with cholecalciferol (vitamin D3) results in both an increase in the percentage and suppressive capacity of regulatory T cells. A recent study in adults with vitamin D deficiency showed that daily treatment with 4,000 IU of vitamin D3 significantly reduced activation of CD4+ T cells compared to treatment with 400 IU. However, the role of vitamin D in maintaining beta cell function in new-onset T1D has been controversial.
Two studies showed no significant effect of calcitriol therapy (1,25-(OH)2-D3) while one study using 2,000 IU cholecalciferol per day showed a higher stimulated C-peptide at 18 months than placebo. Both vitamin D and omega-3 acids have been used experimentally against medical situations such as multiple sclerosis, rheumatoid arthritis, systemic lupus and other autoimmunities, with alleviation and control results. They have also found a place in the management of type 2 diabetes, but scientists from the Diabetes Research Institute (DRI) at the University of Miami Miller School of Medicine, led by Dr. Camillo Ricordi, are studying the impact of omega fatty acids. -3 at high doses and vitamin D supplementation on arresting the progression of genetic or type 1 diabetes (T1D).
Their studies began in 2016, starting from scientific data in the literature and the absence of clinical data on the effect of omega-3s on the onset and / or progression of diabetes on a genetic basis. A few years ago, researchers performed a phase I / IIa study, called the POSEIDON study (pilot study of high-dose omega-3 and vitamin D in T1D), to compare the effects of the proposed intervention in children and adults of newly diagnosed diabetes and in those with long-lasting T1D, to evaluate any benefit of early and late interventions. The DRI researchers speculate that treatment may delay or prevent the disease. The DRI plans to recruit 56 adults and children in the two-arm, open-label study. The investigators compared children and adults with type 1 diabetes, both newly diagnosed and those more than six months after diagnosis, who took both vitamin D alone and in combination with omega-3s.
Participants were treated for one year, followed by a one-year observation period to measure any long-term effects on blood glucose control, increased endogenous insulin production, and other parameters. Participants were randomized to 25-hydroxyvitamin D (cholecalciferol) alone or in combination with ultra-refined omega-3 (EPA / DHA) derived from fish oil. Although the initial dosage is based on factors such as age and body weight, investigators adjusted the dosage of vitamin D every four months, and that of omega-3s based on monthly monitoring of the ratio of arachidonic acid to eicosapentaenoic acid (ARA / EPA). A higher AA / EPA ratio is considered harmful as AA is believed to promote inflammation and decrease regulatory cells that may protect against autoimmunity, while EPA may be protective.
More EPA could improve other conditions where inflammation plays a key role; in fact, it is a precursor of recently discovered mediators (neuroprotectins, resolvins, etc.) which have an anti-inflammatory effect. All participants received standard diabetes treatment with insulin and dietary control. The use of a combination of high-dose omega-3 fatty acids and high-dose vitamin D3 therapy has been well tolerated and may have beneficial effects on beta cell function. In 2018, the team followed up on two pediatric cases of type 1 diabetes, which were enrolled for thorough study and experimental therapy. Both children were characterized by hormonal point of view, saturated / unsaturated fatty acid ratio, omega-3 / omega-6 ratio (ARA-EPA) vitamin D3 levels, plasma C peptide and blood glucose monitoring.
Both children were vitamin D deficient and far from the ARA / EPA goal of <3. Vitamin D (1000 IU / day) supplements started as soon as discharge and omega-3 (EPA + DHA 50-60 mg / kg / day, EnerZona ® Omega 3) within three months afterwards. After discharge, the clinical course of the disease for both children was initially characterized by repeated hypoglycemia, especially after meals, then the doses of Lys-pro insulin were progressively reduced; therefore, in case 2, an insulin dilution was included to use dose adjustment doses of 0.25 IU with the pen at meals. Both children showed fairly complete and persistent remission from the onset of T1D. Specifically, the supplements were administered near the start of insulin therapy, with vitamin D soon after and with omega 3 by the 3rd month.
The following year, the team enrolled type 1 diabetic patients to test supplementation with vitamin D, without omega-3 but in the context of a Mediterranean style diet (MED). Once again, 82% of the enrolled cases (all pediatric) had moderate vitamin D insufficiency and 12% severe insufficiency. Patients with supplementation vs non-integrated: at 12 months of supplementation with ω-3 (T12), cases (n = 22) showed a significantly lower insulin requirement than controls (n = 37). In particular, lower daily insulin requirements and pre-meal bolus were found, with no difference in HbA1c%. Analysis of the IDAA1c index at 12 months showed IDAA1c <9, consistent with a partial remission, in 12 of 22 cases versus 7 of 37 controls. Diet composition assessment was performed only in cases receiving ω-3 supplementation, comparing dietary intakes at T0 and T12.
Research has shown that within macronutrients, carbohydrate, fiber and protein intake was lower than T12 and therefore T0. The micronutrients in the diet were similar for vitamin D, EPA and DHA. However, dietary ARA intake was significantly lower at T12 than at the beginning. Calorie intake was similar at the beginning and end of the one-year ω-3 administration. The daily supplementation of ω-3 starting from clinical onset led, a year later, to a lower requirement for insulin without affecting glycemic control, since the subjects had a similar HbA1c%. Considering IDAA1c (HbA1c% adjusted insulin dose) as a surrogate index of residual beta cell function, and IDAA1c ≤9 is indicative of partial T1D remission, the data show that omega-3s can preserve beta cell secretion. The clinical outcome of a reduced insulin requirement, mainly at meals, is compatible with the hypothesis of inhibition of postprandial protein neoglucogenesis.
Unexpectedly, the team found a decreasing trend in fasting C peptide from the start of omega-3 supplementation (T0) to one year later (T12). A plausible explanation for similar metabolic control with lower insulin administration, despite a reduced C-peptide, is likely related to the contraction of ω-3 on gluconeogenesis, which limits the postmeal glucose rise and reduces insulin requirements for meals. Lowering glycemic excursions could in turn affect the beta cell death process, reducing glucotoxicity. This is in agreement with the recommendations of diabetologists, who require their patients to avoid sudden glycemic peaks and as many episodes of hypoglycemia, or a fluctuating trend. It is the high blood sugar peaks that exert a toxic effect on the tissues (glycation of proteins, oxidative stress) and determine the loss of beta cells. These can also be protected directly from glucotoxicity by EPA and DHA, as demonstrated by an independent team.
Considering that supplements based on vitamin D and omega-3 are widespread and can be well tolerated, they could find short-term use in the prevention of the onset of genetic diabetes in pediatric cases. It involves working on the dosage and coordination of the treatment plan. In addition, the possible adoption of a diet based on the Mediterranean diet is quite simple to accept and would allow young patients to adopt a healthy lifestyle from the very beginning.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Limonte CP, Zelnick LR et al. Diabetologia 2021 Feb; 64(2):437-447.
Ricordi C et al. CellR4 Repair Repl Regen Reprogram. 2019; 7:e2737.
Cadario F, Pozzi E et al. Nutrients. 2019 Sep 9; 11(9):2158.
Cadario F et al. Eur Rev Med Pharm Sci. 2018; 22(2):512-515.
Donlon CM et al. Contemp Clin Trials. 2018 Apr; 67:56-67.
Bi X, Li F, Liu S et al. J Clin Invest. 2017; 127(5):1757-1771.
Cadario F et al. Eur Rev Med Pharm Sci. 2017; 21(7):1604-09.
Baidal DA et al. Eur Rev Med Pharm Sci. 2016; 20(15):3313-18.