1. Journal Club 亀田メディカルセンター 糖尿病内分泌内科 Diabetes and Endocrine Department, Kameda Medical Center 松田 昌文 Matsuda, Masafumi 2008 年 10 月 16 日 8:20-8:50 B 棟８階 カンファレンス室 Forouhi NG, Luan J, Cooper A, Boucher BJ, Wareham NJ. Baseline serum 25-hydroxy vitamin d is predictive of future glycemic status and insulin resistance: the Medical Research Council Ely Prospective Study 1990- 2000. Diabetes. 2008 Oct;57(10):2619-25. Epub 2008 Jun 30. Scragg R. Vitamin D and type 2 diabetes: are we ready for a prevention trial? Diabetes. 2008 Oct;57(10):2565-6.

2. Matsuda M, Sugaya K, Mandarino LJ, Marusawa H, DeFronzo RA: Abnormal vitamin D binding protein fragment in blood of first degree relatives of patients with type 2diabetes mellitus 16th International Diabetes Federation Congress (Helsinki, Finnland) 1997 7.20-25 Diabetologia 40 (suppl. 1): A169, 1997.

3. Diabetes 57:2619–2625, 2008 1 Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Cambridge, U.K. 2 Centre for Diabetes and Metabolic Medicine, Bart’s and the London School of Medicine and Dentistry, London, U.K.

4. Aim Accumulating epidemiological evidence suggests that hypo- vitaminosis D may be associated with type 2 diabetes and related metabolic risks. However, prospective data using the biomarker serum 25- hydroxyvitamin D [25(OH)D] are limited and therefore examined in the present study.

5. Methods A total of 524 randomly selected nondiabetic men and women, aged 40–69 years at baseline, with measurements for serum 25(OH)D and IGF-1 in the population-based Ely Study, had glycemic status (oral glucose tolerance), lipids, insulin, anthropometry, and blood pressure measured and metabolic syndrome risk (metabolic syndrome z score) derived at baseline and at 10 years of follow-up.

6. Age- and sex-adjusted baseline characteristics by categories of baseline 25(OH)D: the Ely Study 1990–2000

7. The distribution of serum 25(OH)D by month in men (solid line) and women (broken line) in the Ely study. Vertical lines are the 95% CIs around the mean values at each month point. Month 1 represents January, while month 12 represents December.

8. Association between baseline serum 25(OH)D and 10-year follow-up fasting glucose (A and B) and 2-h glucose (C and D). A and C: The association in the entire cohort. B and D: The association was modified in participants with below and above median values of IGFBP-1. B: □, lower IGFBP-1, P = 0.0028; ■, higher IGFBP-1, P = 0.6802; IGFBP-1–vitamin D interaction, P = 0.00047. C: □ lower IGFBP-1, P = 0.0031; ■, higher IGFBP-1, P = 0.4935; IGFBP-1–vitamin D interaction, P = 0.0286. The MRC Ely Study 1990–2000.

9. We also derived a continuous metabolic syndrome risk z score as the mean of the following five sex-specific standardized continuous indexes of obesity (BMI + waist circumference/2), hypertension (systolic blood pressure + diastolic blood pressure/2), insulin resistance (fasting insulin), hyperglycemia (2-h plasma glucose), and dyslipidemia (inverted fasting HDL + fasting triglycerides/2).

10. Results Age-adjusted baseline mean serum 25(OH)D was greater in men (64.5 nmol/l [95% CI 61.2– 67.9]) than women (57.2 nmol/l [54.4,60.0]) and varied with season (highest late summer). Baseline 25(OH)D was associated inversely with 10-year risk of hyperglycemia (fasting glucose: β= － 0.0023, P < 0.019; 2-h glucose: β= － 0.0097, P < 0.006), insulin resistance (fasting insulin β= － 0.1467, P < 0.010; homeostasis model assessment of insulin resistance [HOMA- IR]: β= － 0.0059, P < 0.005), and metabolic syndrome z score (β= － 0.0016, P < 0.048) after adjustment for age, sex, smoking, BMI, season, and baseline value of each metabolic outcome variable. Associations with 2-h glucose, insulin, and HOMA-IR remained significant after further adjustment for IGF-1, parathyroid hormone, calcium, physical activity, and social class.

11. Conclusion This prospective study reports inverse associations between baseline serum 25(OH)D and future glycemia and insulin resistance. These associations are potentially important in understanding the etiology of abnormal glucose metabolism and warrant investigation in larger, specifically designed prospective studies and randomized controlled trials of supplementation.

13. DIABETES 57: 2565-6, 2008 the School of Population Health, University of Auckland, Auckland, New Zealand.

14. Previous Observation Only three intervention studies had more than 100 participants and also administered vitamin D for long periods (2–3 years). One study did not find any effect from a vitamin D3 dose of 2,000 IU/day but had only 25 people on this dose. Nilas L, Christiansen C: Treatment with vitamin D or its analogues does not change body weight or blood glucose level in postmenopausal women. Int J Obes 8:407– 411, 1984 Another was a post hoc analysis of a trial designed for bone-related outcomes that found that 700 IU/day of vitamin D3 (combined with calcium) decreased homeostasis model assessment of insulin resistance in participants with impaired glucose tolerance but not in those with normal fasting glucose. Pittas AG, Harris SS, Stark PC, Dawson-Hughes B: The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults. Diabetes Care 30:980 –986, 2007 The largest sample to date of 33,951 women in the Women’s Health Initiative study did not observe any effect from vitamin D (15). Again, there are major limitations with this study due to the low vitamin D3 dose of 400 IU/day, which only increases blood 25(OH)D levels by about 7 nmol/l ; less-than-ideal compliance; and the presence of contamination, since control subjects were able to take vitamin D. de Boer IH, Tinker LF, Connelly S, Curb JD, Howard BV, Kestenbaum B, Larson JC, Manson JE, Margolis KL, Siscovick DS, Weiss NS: Calcium plus vitamin D supplementation and the risk of incident diabetes in the Women’s Health Initiative. Diabetes Care 31:701–707, 2008

15. Comments In the absence of well-designed clinical trials, the strongest evidence to date is provided by cohort studies comparing baseline measures of blood 25(OH)D (which reflect vitamin D status from both sun and dietary sources) and subsequent glycemic status. Forouhi NG, Luan J, Cooper A, Boucher BJ, Wareham NJ.: Baseline serum 25-hydroxy vitamin d is predictive of future glycemic status and insulin resistance: the Medical Research Council Ely Prospective Study 1990-2000. Diabetes. 2008 Oct;57(10):2619-25. Epub 2008 Jun 30. These findings confirm recent results from a Finnish cohort study showing an inverse association between baseline serum 25(OH)D and 17-year risk of type 2 diabetes, which was attenuated after adjustment for confounders. Mattila C, Knekt P, Mannisto S, Rissanen H, Laaksonen MA, Montonen J, Reunanen A: Serum 25- hydroxyvitamin D concentration and subsequent risk of type 2 diabetes. Diabetes Care 30:2569 –2570, 2007 The strengths of the Ely study, in addition to its prospective design and use of 25(OH)D to measure vitamin D status, include its community-based sampling, which increases the generalizability of the results, and the controlling of the most important confounders (obesity and physical activity) in statistical analyses. Its limitations are its relatively small sample size (n = 524) and the 50% loss to follow-up after 10 years.

16. Provision Most importantly, given that nearly three decades have passed since the first studies linking vitamin D with insulin metabolism, well-designed clinical trials of the effect of vitamin D supplementation on glycemia status and diabetes risk are urgently required to settle this question. And they need to prevent past mistakes. In particular, the vitamin D dose given in such trials needs to be high enough—above 2,000 IU per day—to raise blood 25(OH)D levels above 80 nmol/l because diabetes risk is lowest at this level. If well-designed trials are carried out and confirm a protective effect from vitamin D, it could be used by the general population as a simple and cheap solution to help prevent the diabetes epidemic.