Sanjay Kalra  ( Department of Endocrinology, Bharti Hospital, Karnal, India. )
Sameer Aggarwal  ( Department of Endocrinology, Apex Hospital, Rohtak, India )

Vitamin D insufficiency and diabetes mellitus are two important aspects of endocrine care. Both these conditions are prevalent across the world, and pose a significant challenge to public health. In this article, we explore the various interactions between vitamin D and glucose metabolism.

Keywords: Glucose, Osteomalacia, Type 1 diabetes, Type 2 diabetes.

 

Cause or connection?

 

Low levels of vitamin D have been found to be associated with a greater risk of developing type 2 diabetes. In a recently published case-cohort study of middle-aged Australians (Health et al) the odds ratio for the highest versus lowest serum 25- hydroxyvitamin D quartile for developing diabetes was 0.60 (95CI 0.44,0.81). This association did not seem to be due to reverse causality.¹

 

Potential for prevention?

 

Researchers have tried to assess the impact of vitamin D supplementation on prevention of diabetes. High dose vitamin D, however, has been found to improve insulin sensitivity, and reduce the risk of progression to diabetes, in persons with prediabetes and vitamin D deficiency. This was reported by Niroomand et al, who performed a double blind, placebo-controlled randomized controlled trial on 162 participants.² In a randomized controlled trial, Pittas et al administered 4000 IU daily of vitamin D to a cohort of 1211 adults with prediabetes, irrespective of their baseline serum 25- hydroxyvitamin D level. This supplementation was well tolerated, and was effective in increasing vitamin D concentration in serum, However, it did not reduce the risk of diabetes as compared to the control group of 1212 adults who did receive supplementation.³

In a similarly planned study, by Corcoy et al, antenatal women at high risk of developing gestational diabetes mellitus (GDM) were randomized to receive 1600 IU/day of vitamin D, or placebo. Vitamin D sufficiency was achieved in almost all participants of the intervention arm (-0.14mmol/l; CI 95 -0.28, -0.00) the authors felt that vitamin D has a limited potential for GDM prevention in women with vitamin D sufficiency.⁴

Vitamin D has also been explored in the development or progression of diabetes complications such as kidney disease. Boer et al reported the findings of a 5 years long 2x2 factorial randomized clinical trial on 1312 participants with type 2 diabetes. Their results do not support the use of vitamin D (or omega 3- fatty acid) supplementation to preserve estimated glomerular filtration rate.⁵

 

Research helps unravel

 

Researchers in basic science continue to add to our knowledge of vitamin D and glucose metabolism.^6,7 The first step in bioactivation of vitamin D is limited by both fasting and diabetes, as they suppress hepatic cytochrome P450 (Cyp) 2RI. This occurs through over- expression of coactivator peroxisome proliferator-activated receptor Y coactivator 1-a (PGC-1a) glucocorticoid receptor (GR) and estrogen-related receptor a (ERRa) are also involved in this homeostasis.⁸

Research has moved beyond classic forms of vitamin D. The hormone is present in various subtypes, including nonepimeric and epimeric 25-hydroxyvitamin D stereoisomers, as well as 25-hydroxy vitamin D2. The European Prospective Investigation in to Cancer and Nutrition (EPIC)-InterAct case-cohort study has revealed a positive association of epimeric 25 hydrovitamin D with incident type 2 diabetes.⁹ This suggests that more work is needed to unravel the link between vitamin D and glucose metabolism.

It is possible that monogenic forms of vitamin D related dysfunction may be linked to insulin resistance and reduced insulin secretion. Shaat et al have discovered that the A-allele of the VDR rs 1544410 polymorphism is associated with increased insulin secretion in women with a history of GDM in previous pregnancy.¹⁰

 

Pragmatic suggestions

 

Vitamin D affects both musculoskeletal and metabolic homeostasis of the body. The musculoskeletal benefits of vitamin D are proven beyond doubt. It is prudent, therefore, to supplement the vitamin in vitamin D- deficient populations. Whether this supplementation helps improve overall metabolic, and specifically gluco-metabolic health, is a matter of debate.

Evidence from basic science and epidemiological studies suggest a clear cut benefit of vitamin D and glucometabolic health. This can be explained by improvement in musculoskeletal function, which leads to increased physical activity and exercise. We thus recommend supplementation with vitamin D in all persons with dysglycaemia (including prediabetes, GDM, type 1 diabetes and type 2 diabetes), as per national or local guidelines. Intervention should also include motivation to improve vitamin D status through sunlight exposure and outdoor physical activity, as well as dietary intake.

It is doubtful if this intervention will prevent occurrence of diabetes in persons with prediabetes, or progression of complications in those with pre-existing diabetes. However, the musculoskeletal benefits that accrue with a healthy vitamin D level support the need for supplementation.

Overtreatment with vitamin D may be associated with vitamin D toxicity, and should be avoided. A close watch on red flag signs (headache, altered sensorium, constipation), and biomedical abnormalities (hypercalcaemia, hypercalciuria) should be kept. Monitoring of serum 25 hydroxy vitamin D should be performed as per local guidance.

 

Summary

 

The link between vitamin D and diabetes is an interesting facet of glucocrinology. This is continuously being explored by basic scientists and clinical researchers.  Maintenance of healthy vitamin D and glycaemic levels is needed to ensure comprehensive health in all persons with diabetes.

 

References

 

1.      Heath AK, Williamson EJ, Hodge AM, Ebeling PR, Eyles DW, Kvaskoff D et.al. Vitamin D status and the risk of type 2 diabetes: The Melbourne Collaborative Cohort Study. Diabetes Res. Clin. Pract. 2019;149:179-87.

2.      Niroomand M, Fotouhi A, Irannejad N, Hosseinpanah F. Does high-dose vitamin D supplementation impact insulin resistance and risk of development of diabetes in patients with pre-diabetes? A double-blind randomized clinical trial. Diabetes Res. Clin. Pract. 2019;148:1-9.

3.      Pittas AG, Dawson?Hughes B, Sheehan P, Ware JH, Knowler WC, Aroda VR, Brodsky I, Ceglia L, Chadha C, Chatterjee R, Desouza C. Vitamin D supplementation and prevention of type 2 diabetes. Available at:  https://digitalcommons.unl.edu/veterans/125/. Cited on 01 November, 2020

4.      Corcoy R, Mendoza LC, Simmons D, Desoye G, Adelantado JM, Chico A et.al. The DALI vitamin D randomized controlled trial for gestational diabetes mellitus prevention: no major benefit shown besides vitamin D sufficiency. Clin. Nutr. 2020;39:976-84.

5.      de Boer IH, Zelnick LR, Ruzinski J, Friedenberg G, Duszlak J, Bubes VY et.al. Effect of vitamin D and omega-3 fatty acid supplementation on kidney function in patients with type 2 diabetes: a randomized clinical trial. JAMA. 2019 ;322:1899-909.

6.      Yaribeygi H, Maleki M, Sathyapalan T, Iranpanah H, Orafai HM, Jamialahmadi T et.al. The molecular mechanisms by which vitamin D improve glucose homeostasis: A mechanistic review. Life Sciences. 2020:117305.

7.      Marquina C, Mousa A, Scragg R, de Courten B. Vitamin D and cardiometabolic disorders: a review of current evidence, genetic determinants and pathomechanisms. Obesity reviews. 2019;20:262-77.

8.      Aatsinki SM, Elkhwanky MS, Kummu O, Karpale M, Buler M, Viitala P, Rinne V, Mutikainen M, Tavi P, Franko A, Wiesner RJ. Fasting-induced transcription factors repress vitamin D bioactivation, a mechanism for vitamin D deficiency in diabetes. Diabetes. 2019;68:918-31.

9.      Zheng JS, Imamura F, Sharp SJ, Van Der Schouw YT, Sluijs I, Gundersen TE, et.al. Association of plasma vitamin D metabolites with incident type 2 diabetes: EPIC-InterAct case-cohort study. J. Clin. Endocrinol. Metab. 2019;104:1293-303.

10.    Shaat N, Katsarou A, Shahida B, Prasad RB, Kristensen K, Planck T. Association between the rs1544410 polymorphism in the vitamin D receptor (VDR) gene and insulin secretion after gestational diabetes mellitus. Plos one. 2020;15:e0232297.