Vitamin K2 supplementation lowers risk in Type 2 Diabetes Mellitus: Review

Published On 2021-01-02 07:15 GMT   |   Update On 2021-01-05 09:44 GMT

Studies on Vitamin K2 have witnessed a boom in the last few years owing to its multitude of beneficial effect on cardiovascular risk and vascular calcification. Besides these well- documented actions of Vitamin K2 on the human body, recent clinical trials have shown that the biological benefits of this vitamin extend much beyond. Recent studies have pointed out the possible novel effect of vitamin K2 on insulin resistance and glucose metabolism in type 2 diabetics.

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As the prevalence of type 2 DM continues to rise worldwide, it has now been accepted as a public health challenge. (1) Besides being complicated with microvascular and macrovascular effects (2), T2DM is also coupled with multiorgan failure (3), raising the mortality and morbidity risk associated with it.

Accumulating evidence in recent times have pointed out that vitamin K2 supplementation can lower the risk of T2DM. It has been highlighted from clinical trials as well as studies that optimum dietary Vitamin K2 helps to improve insulin sensitivity (4,5) commonly associated with T2DM.
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Vitamin K has been documented to help in the conversion of uncarboxylated Osteocalcin to carboxylated osteocalcin (cOC), which helps to regulate glucose metabolism by modulating osteocalcin and/or proinflammatory pathway. (6,7) Also, vitamin K dependent proteins like prothrombin and protein S have been identified in the pancreas and liver, organs responsible for glucose metabolism.
Though previous studies have repeatedly proved that improvement in glucose intolerance or relief of insulin resistance occurs by treatment with vitamin K1 (8) or vitamin K2 (9), respectively; a thorough review on its potential mechanism of action had been lagging.
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With this background, in 2017, a team of researchers under Yan Li et al, from the Department of Physiology, Dalian Medical University, Dalian, Liaoning, P.R. China, provided an overview (10) of currently available studies to assess the effect of vitamin K2 supplementation on insulin sensitivity, glycaemic control while reviewing the underlying mechanisms. The review has been published in Diabetes Research and Clinical Practice.
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Addressing how vitamin K2 helps in T2DM with an elaborate discussion on the various mechanisms involved in the same as well as highlighting the previous reviews on this topic, the reviewers put together a very detailed analysis. Some of the important excerpts are being pointed out below.
1. The action of Vitamin K2 on osteocalcin-Citing notable previous studies put forward by Lee et al(11), Pittas et al.(12), the reviewers focused on the fact that Osteocalcin favors β- cell proliferation, insulin secretion, and sensitivity; via stimulating the expression of adiponectin. This further confirms that serum osteocalcin is involved in the regulation of glucose metabolism.
Addressing the fact that most of the previous studies had been based on the measurement of the different forms of osteocalcin, including cOC, undercarboxylated osteocalcin, and uncarboxylated OC, the team opined that more studies specifically based on the role of the different variants of OC on glucose metabolism are needed.
The review paper further went on to explore the effect of adiponectin in T2DM, confirming it to enhance insulin sensitivity through increased fatty acid oxidation and inhibition of hepatic glucose production.
2. Vitamin K2 improves insulin sensitivity via anti-inflammatory effect-
 It is well known that Low-grade inflammation releases inflammatory mediators which in turn can downregulate glucose metabolism.
 Growing evidence now points out that Vitamin K2 plays a major role in reversing this mechanism and improving the glycemic index in diabetics. Inactivation of the NF-κB signaling pathway is one of the identified mechanism of action of Vitamin K2 which was supported in another study by Ohsaki et al. (2010) suggesting that vitamin K (MK-4) suppressed lipopolysaccharide-induced expression of inflammatory cytokines by inhibiting the activation of NF-κB via the repression of IKKα/β phosphorylation.(13)
3. Vitamin K2 improves insulin resistance via Lipid-lowering efficacy-Increased fat deposition in non-lipid tissues leads to the inactivation of glucose transporter proteins, causing a further imbalance in insulin sensitivity.
In this context, notable studies by Sogabe et al.(14) and Nagasawa et al.(15) had proved that regular Vitamin K2 supplementation significantly decreased the total fat accumulation and serum triglycerides.
"Based on the emerging new insights into the regulation of lipid metabolism, vitamin K2 supplementation is one of the potentially novel therapeutic strategies to treat IR and reduce the risk of T2DM.," the reviewers wrote.
Observing the findings, the authors concluded that "We proposed that vitamin K2 improved insulin sensitivity through the involvement of vitamin K-dependent-protein osteocalcin, anti-inflammatory properties, and lipid-lowering effects. Vitamin K2 had a better effect than vitamin K1 on T2DM. The interpretation of this review will promote the development of a potential therapeutic strategy to prevent and treat T2DM."

The above article has been published by Medical Dialogues under the MD Brand Connect Initiative. For more details on Vitamin K, click here

References
1. Tabish S. A. (2007). Is Diabetes Becoming the Biggest Epidemic of the Twenty-first Century?. International journal of health sciences, 1(2), V–VIII.
2. Chawla, A., Chawla, R., & Jaggi, S. (2016). Microvascular and macrovascular complications in diabetes mellitus: Distinct or continuum?. Indian journal of endocrinology and metabolism, 20(4), 546–551.
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3. Lin, Y., & Sun, Z. (2010). Current views on type 2 diabetes. The Journal of endocrinology, 204(1), 1–11. https://doi.org/10.1677/JOE-09-0260
4. Manna P, Kalita J. Beneficial role of vitamin K supplementation on insulin sensitivity, glucose metabolism, and the reduced risk of type 2 diabetes: A review. Nutrition. 2016 Jul-Aug;32(7-8):732-9. doi: 10.1016/j.nut.2016.01.011. Epub 2016 Jan 25. PMID: 27133809.
5. Yoshida, M., Jacques, P. F., Meigs, J. B., Saltzman, E., Shea, M. K., Gundberg, C., Dawson-Hughes, B., Dallal, G., & Booth, S. L. (2008). Effect of vitamin K supplementation on insulin resistance in older men and women. Diabetes care, 31(11), 2092–2096. https://doi.org/10.2337/dc08-1204
6. Gundberg, C. M., Lian, J. B., & Booth, S. L. (2012). Vitamin K-dependent carboxylation of osteocalcin: friend or foe?. Advances in nutrition (Bethesda, Md.), 3(2), 149–157. https://doi.org/10.3945/an.112.001834
7. Booth, S. L., Centi, A., Smith, S. R., & Gundberg, C. (2013). The role of osteocalcin in human glucose metabolism: marker or mediator?. Nature reviews. Endocrinology, 9(1), 43–55. https://doi.org/10.1038/nrendo.2012.201
8. Wilcox G. (2005). Insulin and insulin resistance. The Clinical biochemist. Reviews, 26(2), 19–39.
9. Dihingia A, Ozah D, Ghosh S, Sarkar A, Baruah PK, Kalita J, Sil PC, Manna P. Vitamin K1 inversely correlates with glycemia and insulin resistance in patients with type 2 diabetes (T2D) and positively regulates SIRT1/AMPK pathway of glucose metabolism in liver of T2D mice and hepatocytes cultured in high glucose. J Nutr Biochem. 2018 Feb;52:103-114. doi: 10.1016/j.jnutbio.2017.09.022. Epub 2017 Oct 12. PMID: 29175667.
10. Y. Li, J. peng Chen, L. Duan, S. Li, Effect of Vitamin K2 on Type 2 Diabetes Mellitus: A Review, Diabetes Research and Clinical Practice (2017), doi: https://doi.org/10.1016/j.diabres.2017.11.020
11. Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, et al. Endocrine regulation of energy metabolism by the skeleton. Cell. 2007;130:456-69.
12. Pittas AG, Harris SS, Eliades M, Stark P, Dawson-Hughes B. Association between serum osteocalcin and markers of metabolic phenotype. The Journal of clinical endocrinology and metabolism. 2009;94:827-32.
13. Saputra, W. D., Aoyama, N., Komai, M., & Shirakawa, H. (2019). Menaquinone- 4 Suppresses Lipopolysaccharide-Induced Inflammation in MG6 Mouse Microglia- Derived Cells by Inhibiting the NF-κB Signaling Pathway. International journal of molecular sciences, 20(9), 2317. https://doi.org/10.3390/ijms20092317
14. Kawashima H, Nakajima Y, Matubara Y, Nakanowatari J, Fukuta T,Mizuno S, et al. Effects of vitamin K2 (menatetrenone) on atherosclerosis and blood coagulation in hypercholesterolemic rabbits. Japanese journal of pharmacology. 1997;75:135-43.
15. Sogabe N, Maruyama R, Baba O, Hosoi T, Goseki-Sone M. Effects of long-term vitamin K(1) (phylloquinone) or vitamin K(2) (menaquinone-4) supplementation on body composition and serum parameters in rats. Bone.2011;48:1036-42.
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