Conundrum of vitamin D on glucose and fuel homeostasis

Table 1 Vitamin D as a hormone: Comparison of the pituitary-thyroid and parathyroid hormone-vitamin D axes

	Pituitary-thyroid axis	Parathyroid-vitamin D axis
Organ(s)	Thyroid glands	Skin/liver/kidney
Source compound	Iodine, tyrosine	Cholecalciferol (cholesterol), ergocalciferol
Prehormone	Levothyroxine, T1/2 = 6-7 d	25-hydoxyvitamin D2/D3, T1/2 = 13-17 d
Active hormone	Triiodothyronine, T1/2 = 14-24 h	1,25-dihydroxyvitamin D2/D3, T1/2 = 10-20 h
Transportation	Thyroxine binding globulin	Vitamin D binding protein
Receptor	Thyroid hormone receptor	Vitamin D receptor
Stimulating factor	Thyroid stimulating hormone	Parathyroid hormone
Effect	Energy homeostasis	Calcium homeostasis

Table 2 Vitamin D content of selected foods

Food	Per serving		Percent DV
	IU	μg
Cod liver oil, 1 tablespoon	1360	34.00	170
Trout (rainbow), farmed, cooked, 3 ounces	645	16.13	81
Salmon (sockeye), cooked, 3 ounces	570	14.25	71
Mushrooms, white, raw, sliced, exposed to UV light, 1/2 cup	366	9.15	46
Milk, 2% milkfat, vitamin D fortified, 1 cup	120	3.00	15
Soy, almond, and oat milks, vitamin D fortified, various brands, 1 cup	100-144	2.50-3.60	13-18
Ready-to-eat cereal, fortified with 10% of the DV for vitamin D, 1 serving	80	2.00	10
Sardines (Atlantic), canned in oil, drained, 2 sardines	46	1.15	6
Egg, 1 large, scrambled (Vitamin D is in the yolk)	44	1.10	6
Liver, beef, braised, 3 ounces	42	1.05	5
Tuna fish (light), canned in water, drained, 3 ounces	40	1.00	5
Cheese, cheddar, 1 ounce	12	0.30	2
Mushrooms, portabella, raw, diced, ½ cup	4	0.10	1
Chicken breast, roasted, 3 ounces	4	0.10	1
Beef, ground, 90% lean, broiled, 3 ounces	1.7	0.04	0

Adapted from: https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/#en25. The Food and Drug Administration developed daily values (DVs) to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for vitamin D on the new Nutrition Facts and Supplement Facts labels used for the values in Table 2 is 20 μg (800 IU) for adults and children aged 4 years and older. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet. DV: Daily value.

Table 3 Comparison of transportation and metabolism of vitamin D₃ vs D₂

Ref.	Symbol	Name (chromosome location)	Function	D3/D2
Haddad et al[90], 1993	VBP	Vitamin D binding protein (4q12-q13)	Vitamin D transportation	1.14
Holmberg et al[91], 1986	CYP2R1	25-hydroxylase (11p15.2)	Conversion of vitamin D to 25-hydroxy vitamin D	5.0
Zarei et al[93], 2016	CYP27B1	1alpha-hydroxylase (12q13.1-q13.3)	Conversion of 25(OH)D to 1,25(OH)2D	2.4
Jones et al[94], 1980	VDR	Vitamin D receptor (7q36)	Receptor for vitamin D	1.3

Table 4 Recommended daily vitamin D intake as promulgated by selected organizations and agencies

Organization	Daily intake		Goal
	IU	μg	ng/mL	nmol/L
Institute of Medicine	600-800	15-20	> 20 (20-50)	> 50 (50-125)
Agency of Healthcare Research and Quality, Department of Health and Human Services	> 1000	> 25	> 30	> 75
Office of Dietary Supplements, NIH	600-800	15-20	20-50	50-125
National Osteoporosis Foundation	800-1000	20-25	> 30	> 75
American Association of Clinical Endocrinologists	1000-2000	25-50	30-60	75-150
Endocrine Society	1500-2000	37.5-50	30-100	75-250

Table 5 Diminished response of intestinal calcium absorption in response to increasing vitamin D supplementation

Daily vitamin D supplementation		Observed increase in calcium absorption	Estimated increase in calcium absorption per 1000 IU (25 μg)
IU	μg
800	20	3.90%	4.88%
2000	50	5.00%	2.50%
4000	100	6.70%	1.68%

Table 6 Major loci associated with changes in serum 25-hydroxyvitamin D concentration

Chromosome	SNP	Gene symbol	Protein	P value
4p12	rs2282679	GC	Vitamin D binding protein	1.9 × 10-109
11q12	rs12785878	DHCR7	7-dehydrocholsterol reductase	2.1 × 10-27
11p15	rs10741657	CYP2R1	1-alpha-hydroxylase	3.3 × 10-20
20q13	rs6013897	CYP24A1	1,25-dihydroxyvitamin D3 24-hydroxylase	6.0 × 10-10

Adapted from Wang et al[126]. SNP: Single nucleotide polymorphism.

Table 7 Vitamin D supplementation versus vitamin D replacement therapy

	Vitamin D supplement	Vitamin D replacement therapy
Target goal	Bone health	Beyond bone health
Target 25-hydroxyvitamin D level	> 20 ng/mL (50 nmol/L)	> 30 ng/mL (75 nmol/L)
Initial testing for 25-hydroxyvitamin D level	No	Yes
Concern of over-replacement	Yes	Yes
Follow-up testing for 25-hydroxyvitamin D level	No	Yes
Dose adjustment	No	Yes
Approach	Public health	Individualized

Table 8 Preventive trials of vitamin D supplementation to prevent the development of type 2 diabetes

Ref.	Country Race/ethnicity	Placebo control			Intervention			Dose	Frequency	Duration	Diabetes prevention
		n	25(OH)D nmol/L		n	25(OH)D nmol/L
			Initial	Final		Initial	Final
Dutta et al[134], 20141	IndiaAsian Indian	49	45	44	55	43	89	1500 μg	Weekly X 8, monthly	1 yr	Positive2
Niroomand et al[135], 2019	IranIranian	83	32	40	83	31	90	1250 μg	Weekly for 3 mo, monthly	6 mo	Positive3
Wagner et al[136], 20164	Sweden	22	47	46	21	42	83	750 μg	weekly	8 wk	Negative
Oosterwerff et al[137], 2014	HollandNon-Western	65	22	23	65	25	60	30 μg	daily	16 wk	Negative
Barengolts et al[141], 20155	United States African American	86	35	50	87	37	120	1250 μg	weekly	12 m	Negative
Davidson et al[139], 20136	United States Latino and African American	53	55	60	56	55	167	2222 μg	weekly	12 mo	Negative
Jorde et al[140], 2016	Norway	255	61	64	256	60	110	500 μg	weekly	5 yr	Negative
Pittas et al[138], 2019	United States mixed	1212	70	72	1211	69	136	100 μg	daily	24 mo	Negative

¹This study was an open label randomized design, instead of randomized placebo-control design as other studies.

²Intervention is associated with significantly lower progression to diabetes (11% vs 27%; P = 0.04) and higher reversal to normoglycemia (43% vs 20%; P = 0.02).

³The rate of progression toward diabetes was significantly lower in the intervention group (3% vs 28%; P = 0.002).

⁴Meadian 25-hydroxyvitamin was provided, rather than mean 25-hydroxyvitamin D as in other studies.

⁵Ergocalciferol was used, rather than cholecalciferol in other studies.

⁶Weekly dose of cholecalciferol was adjusted to titrate serum 25-hydroxyvitamin D between 162 nmol/L and 200 nmol/L.

Table 9 Calculated sample size requirement to detect an improvement in insulin sensitivity based on a baseline serum 25-hydroxyvitamin D concentration of 40 ng/mL (100 nmol/L) and a power of 0.80 and alpha of 0.05

Initial serum 25-hydroxy-vitamin D concentration		Estimated insulin sensitivity index(μM/min/m2/pM)	Improvement in insulin sensitivity index with postintervention Serum 25-hydroxyvitamin D concentration 40 ng/mL (100 nmol/L)	Diabetes reduction based on the Diabetes Prevention Program	Sample size
ng/mL	nmol/L
10	25	4.1326	0.8664	0.4361	340
15	37	5.4144	0.4246	0.2118	1602
20	50	6.2812	0.2280	0.1121	5934
25	62	6.8674	0.1232	0.0589	21878
30	75	7.2638	0.0619	0.0278	99260
35	87	7.5319	0.0241	0.0086	1041162