Javed A, Vella A, Balagopal PB, et al. Cholecalciferol supplementation does not influence β-cell function and insulin action in obese adolescents: a prospective double-blind randomized trial. J Nutr. 2015;145(2):284-290.
Randomized, prospective, double-blind study
Forty-six Caucasian adolescents (20 male, 26 female), mean age of 15 years (±1.9 y), were evaluable at the conclusion of the study. Participants were deemed obese if they had a body mass index (BMI) greater than or equal to the 95th percentile for age and gender according to the 2000 US Centers for Disease Control and Prevention growth charts. Excluded were those adolescents with high serum 25(OH)D (>100 ng/mL), high serum calcium (>10.8 mg/dL), hepatic or renal disorders, type 1 or 2 diabetes, or malabsorption syndromes (eg, celiac disease). Individuals taking glucocorticoids, antiseizure medications, multivitamins, insulin, metformin, or oral hypoglycemic medications were also excluded from the study.
Participants were randomly assigned to receive either 400 IU per day or 2,000 IU per day cholecalciferol supplementation (Biotech Pharmacal, Fayetteville, Arkansas) for 12 weeks.
Primary outcome measures included insulin sensitivity and pancreatic β-cell function as determined by the disposition index using data obtained through the 3-hour oral glucose tolerance test. Additional measures evaluated were insulin secretion rates as well as total cholesterol, high-density lipoprotein cholesterol, and triglyceride levels.
At 12 weeks, there was a slight but statistically significant increase in 25(OH)D levels from baseline noted in the group receiving 2,000 IU per day cholecalciferol (P=0.04), and this was not seen in the 400 IU per day (P=0.39) group. Insulin sensitivity, disposition index, insulin secretion rate, and lipid parameters observed remained unchanged in both groups and when compared to each other. BMI and weight remained unchanged in all participants throughout the study.
Vitamin D supplements do not appear to improve dysglycemia in this study; we should not assume that prescribing vitamin D will improve blood sugar control.
It has become common practice to prescribe vitamin D to patients who have metabolic syndrome (MetS), prediabetes, type-2 diabetes, and polycystic ovary syndrome (PCOS) with the justification that vitamin D will increase insulin sensitivity and decrease glucose dysregulation. This belief stems from ongoing studies that associate abnormal glucose tolerance profiles with low vitamin D levels.
Our assumption that supplementation will reverse these conditions and improve sugar regulation has not been consistently supported in recent clinical trials. A meta-analysis published in June 2015 assessed the association of serum vitamin D with metabolic and endocrine dysregulation in women with PCOS and determined the effects of cholecaliferol supplementation on metabolic and hormonal functions in these patients. In the 30 studies selected (N=3,182), vitamin D deficiency (VDD) was associated with metabolic and hormonal disorders: “PCOS patients with VDD were more likely to have dysglycemia (e.g., increased levels of fasting glucose and homeostatic model assessment-insulin resistance index (HOMA-IR)) compared to those without VDD.”1 But there was no evidence that vitamin D supplementation improved these conditions: “This meta-analysis found no evidence that vitamin D supplementation reduced or mitigated metabolic and hormonal dysregulations in PCOS. VDD may be a comorbid manifestation of PCOS or a minor pathway in PCOS associated metabolic and hormonal dysregulation”.1
Sun exposure also stimulates production of nitric oxide, and it is not implausible that this may be responsible for some of the cardiovascular protection that we commonly associate with higher vitamin D levels.
There are a few exceptions in which vitamin D does appear to improve glycemic control. A beneficial response was seen in a 2014 clinical trial conducted in Iran in which 50 obese adolescent participants were randomly assigned to receive cholecalciferol or a placebo over a 12-week trial. Those receiving vitamin D got 300,000 IU total during the trial (~25,000 IU/wk). Only 21 patients in the vitamin D arm completed the trial, but in those patients, “serum insulin and triglyceride concentrations, as well as HOMA -IR and C-MetS decreased significantly, both when compared with the baseline and with the placebo group.”2 Likewise, an April 2013 trial of cholecalciferol in 30 obese adolescents conducted in Missouri found mild benefits in subjects who received 4,000 IU per day. While there “were no significant differences in BMI, serum inflammatory markers, or plasma glucose concentrations between groups … Participants supplemented with vitamin D3 had [decreased] fasting insulin (‒6.5 compared with +1.2 μU/mL for placebo), [decreased] HOMA-IR (‒1.363 compared with +0.27 for placebo; P=0.033), and leptin-to-adiponectin ratio (‒1.41 compared with +0.10 for placebo; P=0.045).”3 These 2 small studies are the exception to the general pattern of vitamin D supplementation showing no benefit.
In a randomized placebo-controlled trial conducted in the Netherlands and published in July 2014, researchers gave 130 non-Western immigrants with prediabetes either cholecalciferol (1,200 IU/d) or a placebo for 16 weeks. While supplementation increased vitamin D serum levels, “There was no significant effect on insulin sensitivity and β cell function.”4 In September 2013, Wongwiwatthananukit et al reported that in a trial of 90 people who received either 20,000 IU or 40,000 IU of ergocalciferol per week vs placebo, supplementation with vitamin D had increased serum D levels but did not impact insulin sensitivity.5
Yet while most of these trials fail to find improved glycemic control, we continue to see studies published that contend that vitamin D deficiency is clearly associated with sugar problems. A study from June 2015 reported that low vitamin D is associated with an increased risk of MetS or its individual components, in particular elevated blood pressure and insulin resistance (IR).6 Another review published in June 2015 affirmed, “Most data show that insufficient vitamin D status is associated with increased prevalence of MetS or its individual components, mainly blood pressure and IR, often independent of overall obesity or abdominal adiposity.”7 These conclusions echo findings reported in a pair of studies from May 2015. The first reported that low vitamin D is associated with the hallmark characteristics of MetS in overweight or obese adults: high BMI and IR.8 The second reported that older working adults with vitamin D deficiency were at 2.5 times higher risk of developing diabetes.9
These incongruent findings—that vitamin D is associated with dysglycemia but that supplementation rarely improves the symptoms—bring up an important question that practitioners and the public tend to ignore. While alternate ideas have been suggested to explain these confusing findings in vitamin D studies, the simplest answer is that vitamin D levels are merely a marker of past sun exposure and not the active agent in providing benefit. Sun exposure may trigger some other changes in the body that provide the benefits we commonly associate with high vitamin D.
For example, sun exposure stimulates p53 production. This is the enzyme that regulates apoptosis and is key in protecting the body against cancer development.10 Sun exposure also stimulates production of nitric oxide (NO), and it is not implausible that this may be responsible for some of the cardiovascular protection that we commonly associate with higher vitamin D levels. In fact, according to an article published in the Journal of the American Heart Association, “Impaired generation and signaling of nitric oxide (NO) contribute substantially to cardiovascular (CV) risk (CVR) associated with hypertension, hyperlipidemia, and diabetes mellitus. . . .Many processes involved in aging are modulated by NO.”11 Could it be that sun exposure and the resultant increase in NO production are what limit all of these conditions that we often credit vitamin D for helping to prevent?
It is with these thoughts in mind that this summer, we have been strongly encouraging patients to depend less on vitamin D supplements and to instead rely on sun exposure to stimulate vitamin D production (accompanying this recommendation with the obligatory warnings against getting sunburned). Vitamin D’s benefits may not be as far reaching as we once thought; some of those benefits may be a result of sun exposure itself rather than sun-triggered generation of vitamin D.
Editor's note: Megan Chmelik wrote this article under the guidance of Jacob Schor, ND, FABNO, an associate editor of this journal.
- He C, Lin Z, Robb SW, Ezeamama AE. Serum vitamin D levels and polycystic ovary syndrome: a systematic review and meta-analysis. Nutrients. 2015;7(6):4555-4577.
- Kelishadi R, Salek S, Salek M, Hashemipour M, Movahedian M. Effects of vitamin D supplementation on insulin resistance and cardiometabolic risk factors in children with metabolic syndrome: a triple-masked controlled trial. J Pediatr (Rio J). 2014;90(1):28-34.
- Belenchia AM, Tosh AK, Hillman LS, Peterson CA. Correcting vitamin D insufficiency improves insulin sensitivity in obese adolescents: a randomized controlled trial. Am J Clin Nutr. 2013;97(4):774-781.
- Oosterwerff MM, Eekhoff EM, Van Schoor NM, et al. Effect of moderate-dose vitamin D supplementation on insulin sensitivity in vitamin D-deficient non-Western immigrants in the Netherlands: a randomized placebo-controlled trial. Am J Clin Nutr. 2014;100(1):152-160.
- Wongwiwatthananukit S, Sansanayudh N, Phetkrajaysang N, Krittiyanunt S. Effects of vitamin D(2) supplementation on insulin sensitivity and metabolic parameters in metabolic syndrome patients. J Endocrinol Invest. 2013;36(8):558-563.
- Challa AS, Makariou SE, Siomou EC. The relation of vitamin D status with metabolic syndrome in childhood and adolescence: an update. J Pediatr Endocrinol Metab. 2015 Jun 6. [Epub ahead of print]
- Kramkowska M, Grzelak T, Walczak M, Bogdanski P, Pupek-Musialik D, Czyzewska K. Relationship between deficiency of vitamin D and exponents of metabolic syndrome. Eur Rev Med Pharmacol Sci. 2015;19(12):2180-2187.
- Kavadar G, , Demircioğlu DT, Özgönenel L, Emre TY. The relationship between vitamin D status, physical activity and insulin resistance in overweight and obese subjects. Bosn J Basic Med Sci. 2015;20;15(2):62-66.
- Mauss D, Jarczok MN, Hoffmann K, Thomas GN, Fischer JE. Association of vitamin d levels with type 2 diabetes in older working adults. Int J Med Sci. 2015;12(5):362-368.
- Bermudez Y, Stratton SP, Curiel-Lewandrowski C, et al. Activation of the PI3K/Akt/mTOR and MAP kinase signaling pathways in response to acute solar simulated light exposure of human skin. Cancer Prev Res (Phila). 2015 Jun 1. [Epub ahead of print]
- Sverdlov AL, Ngo DT, Chan WP, Chirkov YY, Horowitz JD. Aging of the nitric oxide system: are we as old as our NO? J Am Heart Assoc. 2014 Aug 18;3(4).