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Vitamin K status and indices of energy metabolism in experimental and clinical conditions

Project leader: Assoc. Prof. Maria Zhelyazkova-Savova, MD, PhD

Recent research has revealed that vitamin K is involved in many other activities in addition to coagulation. Thus vitamin K may have a therapeutic potential in variety of conditions – osteoporosis, vascular calcification, cancer, for neuroprotection. Most of the effects of vitamin K are mediated by vitamin K-dependent proteins such as osteocalcin, matrix-GLA protein (MGP), gas-6 and others which are activated by gamma-glutamic carboxylation. There is evidence that both vitamin K and the under-carboxylated form of osteocalcin have beneficial effects in energy disorders. This discrepancy was of interest to us and we designed an experiment in which rats fed high fat high fructose diet to develop metabolic syndrome were treated with vitamin K1 and K2. The primary objective was to determine whether metabolic syndrome itself was associated with changes in carboxylated and/or under-carboxylated osteocalcin and if these changes occur, whether they correlated with other clinical and laboratory features of metabolic syndrome. The second aim was to check if vitamin K itself is capable to favorably affect the metabolic changes. We were also interested in the potential behavioral differences that accompany the metabolic syndrome, as well as the possible effects of vitamin K on such behavioral changes. Our first results revealed that in the rat model of metabolic syndrome the level of the under-carboxylated osteocalcin was reduced. It was also reduced in the diet manipulated animals treated with vitamin K but there was no difference between these groups. Vitamin K treatment did not improve most of the features of the metabolic syndrome, actually some symptoms were deteriorated. This was also confirmed by the morphological results which showed liver steatosis and lipomatosis of the pancreas in all the groups receiving high fat high fructose diet. An exception was the effect of vitamin K1 in the insulin-tolerance test, where the sensitivity to insulin was somewhat enhanced. This effect was associated with decrease in the oxidative stress found in the rats with metabolic syndrome. Since insulin resistance is thought to result at least partly from the generation of reactive oxygen species, the effect of vitamin K1 can be explained by its antioxidant action. We also found out that in this model of metabolic syndrome, the rats exhibited anxiety- and depression-like behavior and these changes were antagonized by vitamin K. However, the memory deficits associated with the metabolic syndrome, were not alleviated by vitamin K. Results that are still awaited include examination of the levels of serum leptin and adiponectin and their correlation with osteocalcin.

The clinical part of the study involves a 6 month follow up of children with metabolic syndrome. They will be examined routinely for the symptoms of the disorder and the level of carboxylated and under-carboxylated osteocalcin will be determined at the beginning and at the end of the treatment (by diet and exercise) period. Osteocalcin levels will be correlated with the routine measures as well as with the levels of insulin, leptin and adiponectin.

The results were presented at the 7th National Congress of Pharmacology held in Pleven on October 17-19 2014 in the form of 2 posters and 1 oral presentation. These will be transformed in papers in the near future.

  1. Gancheva S, Zhelyazkova-Savova M, Galunska B, Chervenkov T. Rat models of metabolic syndrome. J Biomed Clin Res 2014, 7(1); Suppl. 1, p. 65
  2. Gancheva S, Zhelyazkova-Savova M. Behavioral tests in rat models of metabolic syndrome. J Biomed Clin Res 2014, 7(1); Suppl. 1, p. 24
  3. Zhelyazkova-Savova M, Galunska B, Gancheva S,Popov H, Kitanova M, Genev P. Effects of vitamin K on rats fed high-fat high-fructose diet. J Biomed Clin Res 2014, 7(1); Suppl. 1, p. 62 

Presentations on vitamin K in cardiometabolic and other disorders have been presented at scientific meetings:

  1. Gancheva S, Zhelyazkova-Savova M, Galunska B. Vitamin K: the multiple faces of an old vitamin. Scripta Scientifica Pharmaceutica, 2014 (1), suppl. 1, p.35
  2. Galunska, B., M. Zhelyazkova-Savova, S. Gancheva. Vitamin K and Cardiometabolic syndrome - ISORD 2011. 9-ти Международен симпозиум по затлъстяване и съпътстващи заболявания, 21-23. 09. 2011, Гранд  хотел "Фламинго", кк. "Албена".
  3. Галунска, Б., М. Желязкова-Савова, С. Ганчева. Калциев парадокс и роля на витамин К. Балкански медицински дни, 16-18.09. 2011 Варна, кк. "Св. Константин и Елена".

The preliminary work on the generation of a suitable model of metabolic syndrome in rat has also been presented at scientific meetings:

  1. Gancheva S, Zhelyazkova-Savova M, Galunska B. Comparative biochemical and behavioral indices in rat models of metabolic syndrome and type 2 diabetes. 32nd Balkan Medical Week, University of Nis, Serbia, 21-23 September 2012. Abstract: P.164
  2. Gancheva S., Zhelyazkova-Savova M., Galunska B. Our experience with experimental models of metabolic syndrome in rats. XII International Congress of Medical Sciences 09-12 May 2013, Sofia. Abstract: p.89