Omega-3 Nutrition Therapy for the Treatment of Diabetic Sensorimotor Polyneuropathy.

Despite advances in clinical and translational research, an effective therapeutic option for diabetic sensorimotor polyneuropathy (DSP) has remained elusive. The pathomechanisms of DSP are diverse, and along with hyperglycemia, the roles of inflammatory mediators and lipotoxicity in the development of microangiopathy have been well elucidated. Omega-3 (n-3) polyunsaturated fatty acids (PUFA) are essential fatty acids with a vital role in a number of physiological processes, including neural health, membrane structure integrity, anti-inflammatory processes, and lipid metabolism. Identification of n-3 PUFA derived specialised proresolving mediators (SPM), namely resolvins, neuroprotectin, and maresins which also favour nerve regeneration, have positioned n-3 PUFA as potential treatment options in DSP. Studies in n-3 PUFA treated animal models of DSP showed positive nerve benefits in functional, electrophysiological, and pathological indices. Clinical trials in humans are limited, but recent proof-of-concept evidence suggests n-3 PUFA has a positive effect on small nerve fibre regeneration with an increase in the small nerve fiber measure of corneal nerve fibre length (CNFL). Further randomized control trials with a longer duration of treatment, higher n-3 PUFA doses, and more rigorous neuropathy measures are needed to provide a definitive understanding of the benefits of n-3 PUFA supplementation in DSP.

Baseline omega-3 level is associated with nerve regeneration following 12-months of omega-3 nutrition therapy in patients with type 1 diabetes.

AIM: Omega-3 (n-3) polyunsaturated fatty-acids are essential for the development and maintenance of nerve function, but the relationship of plasma n-3 to the presence of diabetic distal-symmetric-polyneuropathy (DSP) and the effect of n-3 therapy on plasma levels and small nerve fibre morphology in T1D are unknown. METHODS: Participants with T1D (n = 40, 53% female, aged (mean ±â€¯SD) 48 ±â€¯14 years, BMI 28.1 ±â€¯5.8 kg/m2, diabetes duration 27 ±â€¯18 years), 23 of whom had DSP, took seal-oil (10 mL/day; 750 mg eicosapentaenoic acid (EPA), 560 mg docosapentaenoic acid (DPAn-3), and 1020 mg docosahexaenoic acid (DHA)) for 12-months in a single-arm open-label study. The improvement in corneal nerve fibre length (CNFL) (primary outcome) was previously reported. In this secondary analysis, plasma n-3s were measured at baseline, 4, 8 and 12-months. RESULTS: At baseline, participants with DSP had lower DHA than those without (1.73 ±â€¯0.89 vs. 2.27 ±â€¯0.70%, p = 0.049). Twelve-months seal-oil therapy increased mean plasma EPA by 185%, DPA by 29%, DHA by 79% (p < 0.001) and CNFL by 29% (p = 0.001). Change in CNFL was positively associated with higher baseline total n-3 (Spearman's correlation coefficient r = 0.41, p = 0.013), DPA (r = 0.33, p = 0.047) and DHA (r = 0.42, p = 0.012). CONCLUSION: In conclusion, low plasma DHA was associated with prevalent DSP, n-3 therapy increased blood n-3 levels and higher baseline n-3s were associated with greater nerve regeneration.

Effect of omega-3 supplementation on neuropathy in type 1 diabetes: A 12-month pilot trial.

OBJECTIVE: To test the hypothesis that 12 months of seal oil omega-3 polyunsaturated fatty acids (ω-3 PUFA) supplementation will stop the known progression of diabetic sensorimotor polyneuropathy (DSP) in type 1 diabetes mellitus (T1DM). METHODS: Individuals with T1DM and evidence of DSP as determined by a Toronto Clinical Neuropathy Score ≥1 were recruited to participate in a single-arm, open-label trial of seal oil ω-3 PUFA supplementation (10 mL·d-1; 750 mg eicosapentaenoic acid, 560 mg docosapentaenoic acid, and 1,020 mg docosahexaenoic acid) for 1 year. The primary outcome was the 1-year change in corneal nerve fiber length (CNFL) measured by in vivo corneal confocal microscopy, with sensory and nerve conduction measures as secondary outcomes. RESULTS: Forty participants (53% female), aged 48 ± 14 years, body mass index 28.1 ± 5.8 with diabetes duration of 27 ± 18 years, were enrolled. At baseline, 23 participants had clinical DSP and 17 did not. Baseline CNFL was 8.3 ± 2.9 mm/mm2 and increased 29% to 10.1 ± 3.7 mm/mm2 (p = 0.002) after 12 months of supplementation. There was no change in nerve conduction or sensory function. CONCLUSIONS: Twelve months of ω-3 supplementation was associated with increase in CNFL in T1DM. CLINICALTRIALSGOVIDENTIFIER: NCT02034266. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with T1DM and evidence of DSP, 12 months of seal oil omega-3 supplementation increases CNFL.

Prospective association of 25(OH)D with metabolic syndrome.

CONTEXT: Vitamin D may play a role in the aetiology of the metabolic syndrome (MetS), yet the majority of previous studies have been cross-sectional, and the limited number of prospective studies has yielded inconsistent results. OBJECTIVE: To examine the prospective association of vitamin D [25-hydroxyvitamin D, 25(OH)D] with MetS in a multi-ethnic cohort of adults in Ontario, Canada. DESIGN: Nondiabetic individuals with pre-existing MetS risk factors were recruited for participation in the PROspective Metabolism and ISlet cell Evaluation (PROMISE) cohort study, a longitudinal study of the determinants of insulin resistance and MetS. METHODS: Of the 654 participants enrolled at baseline, 489 attended a 3-year follow-up visit. There were 301 participants eligible for the analysis of 25(OH)D with incident MetS (age 49·2 ± 9·3 years old, 75·4% female), after excluding 188 (38·5%) prevalent MetS cases at baseline. Longitudinal change in MetS components was assessed in the entire follow-up cohort. RESULTS: There were 76 (15·5%) participants who developed MetS over the 3-years of follow-up. Multivariate logistic regression analyses indicated a decreased risk of MetS at follow-up per standard deviation increase in baseline 25(OH)D after adjustment for sociodemographics, season, baseline and change in supplement use and physical activity and insulin resistance (OR = 0·63, 95% CI 0·44-0·90). Multivariate linear regression analyses revealed a significant inverse association of baseline 25(OH)D with fasting glucose at follow-up (ß = -0·0005, P = 0·025). CONCLUSIONS: There was a significant inverse association of baseline 25(OH)D with incident MetS, which may be partly driven by its association with glucose homoeostasis.

Prospective associations of vitamin D with ß-cell function and glycemia: the PROspective Metabolism and ISlet cell Evaluation (PROMISE) cohort study.

OBJECTIVE: To examine the prospective associations of baseline vitamin D [25-hydroxyvitamin D; 25(OH)D] with insulin resistance (IR), ß-cell function, and glucose homeostasis in subjects at risk for type 2 diabetes. RESEARCH DESIGN AND METHODS: We followed 489 subjects, aged 50 ± 10 years, for 3 years. At baseline and follow-up, 75-g oral glucose tolerance tests (OGTTs) were administered. IR was measured using the Matsuda index (IS(OGTT)) and the homeostasis model assessment of IR (HOMA-IR), ß-cell function was determined using both the insulinogenic index divided by HOMA-IR (IGI/IR) and the insulin secretion sensitivity index-2 (ISSI-2), and glycemia was assessed using the area under the glucose curve (AUC(glucose)). Regression models were adjusted for age, sex, ethnicity, season, and baseline value of the outcome variable, as well as baseline and change in physical activity, vitamin D supplement use, and BMI. RESULTS: Multivariate linear regression analyses indicated no significant association of baseline 25(OH)D with follow-up IS(OGTT) or HOMA-IR. There were, however, significant positive associations of baseline 25(OH)D with follow-up IGI/IR (ß = 0.005, P = 0.015) and ISSI-2 (ß = 0.002, P = 0.023) and a significant inverse association of baseline 25(OH)D with follow-up AUC(glucose) (ß = -0.001, P = 0.007). Progression to dysglycemia (impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes) occurred in 116 subjects. Logistic regression analyses indicated a significant reduced risk of progression with higher baseline 25(OH)D (adjusted odds ratio 0.69 [95% CI 0.53-0.89]), but this association was not significant after additional adjustment for baseline and change in BMI (0.78 [0.59-1.02]). CONCLUSIONS: Higher baseline 25(OH)D independently predicted better ß-cell function and lower AUC(glucose) at follow-up, supporting a potential role for vitamin D in type 2 diabetes etiology.

Association of 25(OH)D and PTH with metabolic syndrome and its traditional and nontraditional components.

CONTEXT: Emerging evidence suggests that 25-hydroxy vitamin D [25(OH)D] and PTH may play a role in the etiology of the metabolic syndrome (MetS). However, evidence to date is limited and inconsistent, and few studies have examined associations with nontraditional MetS components. OBJECTIVE: The objective of the study was to examine the association of vitamin D and PTH with MetS and its traditional and nontraditional components in a large multiethnic sample. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, we examined 654 participants from London and Toronto, Ontario, Canada, aged 30 yr and older with risk factors for type 2 diabetes. MAIN OUTCOME MEASURES: Presence of MetS and its traditional and nontraditional components was measured. RESULTS: Approximately 43% of the study participants were classified as having MetS. Higher 25(OH)D was significantly associated with a reduced presence of MetS after adjustment for age, sex, season, ethnicity, supplement use, physical activity, and PTH (odds ratio 0.76, 95% confidence interval 0.62-0.93). PTH was not associated with the presence of MetS after multivariate adjustment. Multivariate linear regression analyses indicated significant adjusted inverse associations of 25(OH)D with waist circumference, triglyceride level, fasting insulin, and alanine transaminase (P < 0.041). Elevated PTH was positively associated with waist circumference and high-density lipoprotein cholesterol (P < 0.04). Other associations between PTH and MetS components were attenuated after adjustment for adiposity. CONCLUSIONS: Serum 25(OH)D, but not PTH, was significantly associated with MetS as well as a number of MetS components after multivariate adjustment. These results suggest that low 25(OH)D may play a role in the etiology of the MetS.

Association of vitamin D with insulin resistance and beta-cell dysfunction in subjects at risk for type 2 diabetes.

OBJECTIVE: To examine cross-sectional associations of serum vitamin D [25-hydroxyvitamin D, 25(OH)D] concentration with insulin resistance (IR) and beta-cell dysfunction in 712 subjects at risk for type 2 diabetes. RESEARCH DESIGN AND METHODS: Serum 25(OH)D was determined using a chemiluminescence immunoassay. Insulin sensitivity/resistance were measured using the Matsuda insulin sensitivity index for oral glucose tolerance tests (IS(OGTT)) and homeostasis model assessment of insulin resistance HOMA-IR. beta-Cell function was determined using both the insulinogenic index (IGI) divided by HOMA-IR (IGI/IR) and the insulin secretion sensitivity index-2 (ISSI-2). RESULTS Linear regression analyses indicated independent associations of 25(OH)D with IS(OGTT) and HOMA-IR (beta = 0.004, P = 0.0003, and beta = -0.003, P = 0.0072, respectively) and with IGI/IR and ISSI-2 (beta = 0.004, P = 0.0286, and beta = 0.003, P = 0.0011, respectively) after adjusting for sociodemographics, physical activity, supplement use, parathyroid hormone, and BMI. CONCLUSIONS: Vitamin D may play a role in the pathogenesis of type 2 diabetes, as 25(OH)D concentration was independently associated with both insulin sensitivity and beta-cell function among individuals at risk of type 2 diabetes.