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Vitamin K2 Supplementation Improves Insulin Sensitivity via Osteocalcin Metabolism: A Placebo-Controlled Trial

  1. Hyung Jin Choi, MD,
  2. Juyoun Yu, BS,
  3. Hosanna Choi, BS,
  4. Jee Hyun An, MD,
  5. Sang Wan Kim, MD, PHD,
  6. Kyong Soo Park, MD, PHD,
  7. Hak C. Jang, MD, PHD,
  8. Seong Yeon Kim, MD, PHD and
  9. Chan Soo Shin, MD, PHD
  1. From the Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
  1. Corresponding author: Chan Soo Shin, csshin{at}snu.ac.kr.
Diabetes Care 2011 Sep; 34(9): e147-e147. https://doi.org/10.2337/dc11-0551
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Undercarboxylated osteocalcin (ucOC) is reported to function as an endocrine hormone, affecting glucose metabolism in mice (1,2). Vitamin K, which converts ucOC to carboxylated osteocalcin (cOC), has been suggested to regulate glucose metabolism by modulating osteocalcin and/or proinflammatory pathway (3–5).

We studied whether modulation of ucOC via vitamin K2 supplementation for 4 weeks affects β-cell function and/or insulin sensitivity in healthy young male subjects. Forty-two healthy young male volunteers received vitamin K2 (menatetrenone; 30 mg; Eisai Co., Japan) or placebo t.i.d. for 4 weeks. Frequently sampled intravenous glucose tolerance test was performed to determine insulin sensitivity index (Si), acute insulin response to glucose (AIRg), and disposition index (DI) before and after treatment. Adiponectin, interleukin (IL)-6, C-reactive protein (CRP), ucOC, and cOC were measured before and after treatment.

After excluding frequently sampled intravenous glucose tolerance test failures (n = 4) and extreme outliers (n = 5), 18 subjects in the treatment group and 15 subjects in the control group were finally analyzed. The institutional review board of Seoul National University Hospital approved this study.

The age (29 [24–31] vs. 29 [25.5–31.5] years, median [interquartile range]) and BMI (24.9 [22.9–26.8] vs. 25.3 [21.9–27.0] kg/cm2) of the control and treatment groups were not significantly different. Vitamin K2 supplementation significantly increased Si (4.4 [3.2–5.6] vs. 6.6 [4.3–9.6]; P = 0.01) and DI (2,266 [1,536–2,785] vs. 3,025 [2,441–4,835]; P < 0.01), but these indices were not affected by placebo treatment. The percent increase in DI was significantly higher in the vitamin K2 group compared with the placebo group (50.9 [20.8–87.3] vs. 2.7 [-10.0 to 39.2]%; P = 0.03) resulting in higher posttreatment DI (3,025 [2,441–4,835] vs. 1,838 [1,320–2,741]; P = 0.01). These differences persisted even after adjusting for baseline Si, AIRg, DI, ucOC, cOC, IL-6, adiponectin, and CRP (P = 0.008 for percent increase in DI and P = 0.001 for posttreatment DI). Treatment with vitamin K2 decreased ucOC (0.9 [0.5–1.8] vs. 0.4 [0.4–0.6] ng/mL; P = 0.02) and increased cOC (9.6 [7.1–15.1] vs. 16.0 [12.4–16.0] ng/mL; P = 0.01). However, no significant changes were observed in AIRg, fasting plasma glucose, weight, IL-6, CRP, or adiponectin (data not shown). Si fold change was significantly associated with baseline cOC, baseline ucOC, and cOC fold change even after adjusting for age and weight fold change (all P < 0.05).

To summarize, we have demonstrated for the first time that vitamin K2 supplementation for 4 weeks increased insulin sensitivity in healthy young men, which seems to be related to increased cOC rather than modulation of inflammation. Small sample size limits firm interpretation on β-cell function. Our results are consistent with previous studies that demonstrated improved glucose intolerance or relieved insulin resistance by treatment with vitamin K1 (3) or vitamin K2 (4), respectively. We conclude that unlike in rodents, cOC rather than ucOC may be the endocrine hormone that increases insulin sensitivity in humans. Although our study could not provide the underlying mechanism, we speculate that cOC or vitamin K could modulate adipokines or inflammatory pathways other than the IL-6 pathways. Alternatively, cOC can directly regulate glucose disposal at skeletal muscle or adipose tissues. Further studies to elucidate the mechanism of action are warranted.

Acknowledgments

No potential conflicts of interest relevant to this article were reported.

H.J.C. researched data, contributed to discussion, wrote the manuscript, and reviewed and edited the manuscript. J.Y. researched data and contributed to discussion. H.C. researched data. J.H.A., S.W.K., K.S.P., H.C.J., and S.Y.K. contributed to discussion. C.S.S. had the original idea, contributed to discussion, and reviewed and edited the manuscript.

Footnotes

  • Clinical trial reg. no. NCT00960973, clinicaltrials.gov.

  • © 2011 by the American Diabetes Association.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

References

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    1. Lee NK,
    2. Sowa H,
    3. Hinoi E,
    4. et al
    . Endocrine regulation of energy metabolism by the skeleton. Cell 2007;130:456–469
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    1. Ferron M,
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    3. Karsenty G,
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    . Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci USA 2008;105:5266–5270
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    . Possible effects of one week vitamin K (menaquinone-4) tablets intake on glucose tolerance in healthy young male volunteers with different descarboxy prothrombin levels. Clin Nutr 2000;19:259–263
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    . Effect of vitamin K supplementation on insulin resistance in older men and women. Diabetes Care 2008;31:2092–2096
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    4. et al
    . Vitamin K and vitamin D status: associations with inflammatory markers in the Framingham Offspring Study. Am J Epidemiol 2008;167:313–320
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Vitamin K2 Supplementation Improves Insulin Sensitivity via Osteocalcin Metabolism: A Placebo-Controlled Trial
Hyung Jin Choi, Juyoun Yu, Hosanna Choi, Jee Hyun An, Sang Wan Kim, Kyong Soo Park, Hak C. Jang, Seong Yeon Kim, Chan Soo Shin
Diabetes Care Sep 2011, 34 (9) e147; DOI: 10.2337/dc11-0551

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Vitamin K2 Supplementation Improves Insulin Sensitivity via Osteocalcin Metabolism: A Placebo-Controlled Trial
Hyung Jin Choi, Juyoun Yu, Hosanna Choi, Jee Hyun An, Sang Wan Kim, Kyong Soo Park, Hak C. Jang, Seong Yeon Kim, Chan Soo Shin
Diabetes Care Sep 2011, 34 (9) e147; DOI: 10.2337/dc11-0551
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  • Comment on: Kromhout et al. n-3 Fatty Acids, Ventricular Arrhythmia–Related Events, and Fatal Myocardial Infarction in Postmyocardial Infarction Patients With Diabetes. Diabetes Care 2011;34:2515–2520
  • Comment on: Leeds et al. High Prevalence of Microvascular Complications in Adults With Type 1 Diabetes and Newly Diagnosed Celiac Disease. Diabetes Care 2011;34:2158–2163
  • Response to Comment on: Wheeler et al. Macronutrients, Food Groups, and Eating Patterns in the Management of Diabetes: A Systematic Review of the Literature, 2010. Diabetes Care 2012;35:434–445
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  • Comment on: Kromhout et al. n-3 Fatty Acids, Ventricular Arrhythmia–Related Events, and Fatal Myocardial Infarction in Postmyocardial Infarction Patients With Diabetes. Diabetes Care 2011;34:2515–2520
  • Comment on: Leeds et al. High Prevalence of Microvascular Complications in Adults With Type 1 Diabetes and Newly Diagnosed Celiac Disease. Diabetes Care 2011;34:2158–2163
  • Response to Comment on: Wheeler et al. Macronutrients, Food Groups, and Eating Patterns in the Management of Diabetes: A Systematic Review of the Literature, 2010. Diabetes Care 2012;35:434–445
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