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Vitamin D Status, Vitamin D Receptor Polymorphisms, and Risk of Type 2 Diabetes
abstract
This abstract is available on the publisher's site.
Access this abstract nowCONTEXT
Vitamin D status has been associated with risk of type 2 diabetes (T2D), but evidence is scarce regarding whether such relation differs by glycemic status.
OBJECTIVE
To prospectively investigate the association between serum 25-hydroxyvitamin D [25(OH)D] and risk of incident T2D across the glycemic spectrum and the modification effect of genetic variants in vitamin D receptor (VDR).
METHODS
This prospective study included 379,699 participants without T2D at baseline from the UK Biobank. Analyses were performed according to glycemic status and HbA1c levels. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs.
RESULTS
During a median of 14.1 years of follow-up, 6,315 participants with normoglycemia and 9,085 prediabetes patients developed T2D. Compared to individuals with 25(OH)D <25 nmol/L, the multivariable-adjusted hazard ratios (95% CIs) of incident T2D for those with 25(OH)D ≥75 nmol/L was 0.62 (0.56, 0.70) among the normoglycemia and 0.64 (0.58, 0.70) among the prediabetes. A significant interaction was observed between 25(OH)D and VDR polymorphisms among participants with prediabetes (Pinteraction=0.017), whereby the reduced HR of T2D associated with higher 25(OH)D was more prominent in those carrying T allele of rs1544410. Triglycerides levels mediated 26% and 34% of the association between serum 25(OH)D and incident T2D among participants with normoglycemia and prediabetes.
CONCLUSIONS
Higher serum 25(OH)D concentrations were associated with lower T2D risk across the glycemic spectrum below the threshold for diabetes, and the relations in prediabetes were modified by VDR polymorphisms. Improving lipid profile, mainly triglycerides, accounted for part of the favorable associations.
Additional Info
Disclosure statements are available on the authors' profiles:
Vitamin D status, vitamin D receptor polymorphisms, and risk of type 2 diabetes: A prospective cohort study
J. Clin. Endocrinol. Metab. 2024 Apr 04;[EPub Ahead of Print], Y Fu, M Lu, K Zhang, Y Sun, X Tan, N Wang, F Xu, B Jiang, Y Lu, B WangFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Vitamin D levels and risk of diabetes
A good amount of research has correlated low vitamin D levels with the risk of metabolic dysfunction. In 2023, a systematic review and meta-analysis of three large studies showed that vitamin D supplementation to a level close to 50 ng/L in individuals with prediabetes reduced the risk of developing diabetes by 15% compared with that in individuals with prediabetes who did not supplement with vitamin D.1
However, this study of the UK Biobank data did not examine vitamin D supplementation. It focused on examining baseline vitamin D levels in individuals with normal blood glucose and those with prediabetes. The mainly White British cohort was followed for a median of 14 years to determine who would develop diabetes. The researchers also correlated vitamin D levels to vitamin D receptor genetic variants to determine whether the latter played a role in modifying the risk.
The findings showed that there was a correlation between low vitamin D levels and the risk of progression to diabetes among both individuals with normal blood sugar and prediabetes at baseline. The serum level that was the transition point from risk to protection was 50 nmol/L.
Please note that serum levels are measured in both nmol/L and ng/mL; 1.0 nmol/L = 0.4 ng/mL. Most of the world uses nmol/L but the United States uses ng/mL. Generally, vitamin D deficiency is considered as a level <50 nmol/L, which is equal to (50 x 0.4) 20 ng/mL. The therapeutic goal in replacing vitamin D is 120 nmol/L or about 50 ng/mL (120 x 0.4 = 48).
Individuals with vitamin D receptor genetic polymorphisms did not show a consistent trend. However, those with a T allele on the BsmI gene for the vitamin D receptor had a reduced risk of developing diabetes with high vitamin D levels. We may find out that genetic variants of the vitamin D receptor influence risk in the future, but it is too early to tell.
Lipid levels were also correlated. The highest association with the incidence of diabetes correlated with triglycerides. If an individual had both low vitamin D and high triglyceride levels, the risk of developing diabetes was elevated compared with having each alone.
Vitamin D is more a hormone than a vitamin and has been found to upregulate insulin sensitivity and improve pancreatic beta-cell function. We now have supporting evidence that low serum levels are associated with a higher risk of developing diabetes in the future among individuals with normal glucose and prediabetes at baseline.
Consider checking vitamin D levels and supplementing to bring serum levels to the mid-normal range (120 nmol/L or 50 ng/mL) in individuals at risk of metabolic dysfunction. And, remember, this study was in White Brits. The risk is higher among individuals with more pigment, particularly if they have moved away from the strong sun rays at the equator.
Reference
Despite a flurry of research on vitamin D in the last 2 decades, there remains no consensus regarding the optimal serum levels of vitamin D for skeletal health, let alone non-skeletal health. In 2011, the National Academy of Medicine1 suggested that a serum 25-hydroxyvitamin D (25[OH]D) concentration of ≥20 ng/mL (50 nmol/L) was sufficient for skeletal health, whereas the Endocrine Society recommended ≥30 ng/mL (75 nmol/L).2 There have been no updates to these recommendations, and, in 2021, the US Preventive Services Task Force concluded that there were no benefits to screening for vitamin D deficiency in asymptomatic adults.3
The current study by Fu et al evaluated the association between baseline serum 25(OH)D and a non-skeletal outcome, incident type 2 diabetes (T2D), in a large (N = 379,699) population enrolled in the UK Biobank. After a median follow-up of 14 years, the study found that 6315 (1.9%) participants with normoglycemia and 9085 (16.9%) with prediabetes developed T2D. A higher serum 25(OH)D concentration was significantly associated with a lower risk of incident T2D. Compared with individuals with serum 25(OH)D <10 ng/mL, those with 25(OH)D ≥30 ng/mL had a lower risk for incident T2D, with a multivariable-adjusted hazard ratios of 0.62 for normoglycemia and 0.64 for prediabetes.
As with all cohort studies, there are limitations to this study, including a study population that was mostly White and a T2D outcome that was defined by hospital admissions and death registry. Moreover, we must remember the old maxim that association does not equal causation, especially after a clinical trial, the D2d study, showed no overall benefit for vitamin D supplementation in reducing incident T2D in individual with prediabetes.4 How do we reconcile the findings from the current study and intervention trials like the D2d study? First, the D2d study may have been underpowered despite enrolling 2423 individuals with prediabetes, and there are some nuances that should be noted. In a post hoc analysis of the D2d study data, vitamin D supplementation significantly reduced incident T2D by 62% in those with baseline serum 25(OH)D <12 ng/mL; however, this subset of individuals represented only 4% of the study population, and 42% of the D2d population had serum 25(OH)D ≥30 ng/mL. Second, a meta-analysis of three prediabetes vitamin D intervention trials (N = 4190 participants), including D2d, showed that vitamin D supplementation significantly reduced risk for T2D by 15% — a degree of benefit none of the three individual trials were powered to detect. Relative to vitamin D supplementation, participants maintaining a serum 25(OH)D concentration ≥50 ng/mL had a lower risk for T2D by 76% compared with those with serum 25(OH)D concentrations between 20 and 29 ng/mL.
Taken together, including the new findings by Fu et al, we should consider screening and treating vitamin D deficiency in individuals at risk for T2D, aiming for a target serum 25(OH)D concentration of at least 30 ng/mL.
References