Elsevier

Nutrition

Volume 31, Issue 1, January 2015, Pages 214-222
Nutrition

Basic nutritional investigation
Vitamin K1 alleviates streptozotocin-induced type 1 diabetes by mitigating free radical stress, as well as inhibiting NF-κB activation and iNOS expression in rat pancreas

https://doi.org/10.1016/j.nut.2014.05.012Get rights and content

Abstract

Objective

The aim of this study was to understand the mechanism of action of vitamin K1 against streptozotocin (STZ)-induced diabetes.

Methods

Male Wistar rats were administered 35 mg/kg STZ and after 3 d were treated with vitamin K1 (5 mg/kg, twice a week) for 3 months. Blood glucose was monitored twice a month. At the end of the study, animals were sacrificed and pancreas dissected out and analyzed for free radicals, antioxidants, metabolic enzymes related to glucose, membrane ATPases, histopathological evaluation, and expression of nuclear factor (NF)-κB and inducible nitric oxide synthase (iNOS). Glycated hemoglobin, plasma insulin, and islet area were determined at the end of the study.

Results

Treatment of STZ-induced type 1 diabetic rats with vitamin K1 reduced oxidative stress, enhanced antioxidants, and inhibited aldose reductase in pancreas. Vitamin K1 administration rescued endocrine pancreas from STZ-induced cell death, resulting in enhanced insulin secretion and normal blood glucose and glycosylated hemoglobin levels. Histologic analyses also showed the antidiabetic potential of vitamin K1. Measure of pancreatic islet area showed an increase in the islet area upon vitamin K1 treatment when compared with the STZ-administered group, suggesting the possibility of regeneration. To understand the mechanism involved in vitamin K1 mediated changes, we performed immunohistochemical analyses for NF-κB and iNOS enzyme. Vitamin K1 was shown to suppress NF-κB activation and iNOS expression in the islets upon administration of STZ.

Conclusion

This work shows, to our knowledge for the first time, the mechanism of action of vitamin K1 against type 1 diabetes and the possible therapeutic use of this vitamin in stimulating islet cell proliferation/regeneration.

Introduction

Vitamin K is a fat-soluble compound and consists of two natural forms, phylloquinone (vitamin K1) and menaquinone (vitamin K2). Apart from its role in blood homeostasis, vitamin K is getting widespread attention for its anti-inflammatory [1], [2], bone recycling [3], antioxidant [4], and anticancer activities. Phylloquinone is the most common form of vitamin K and is abundant in green vegetables [5]. In diabetes, vitamin K has been shown to be important for acute insulin response [6], insulin sensitivity, and modulating glycemic status [7], [8], [9], blocking insulin resistance [10], inhibiting production of inflammatory cytokines associated with insulin response [11], and modulating dephosphorylated uncarboxylated protein [12]. It also has been reported that vitamin K is important for gamma-carboxylation of proteins such as osteocalcin, which is important in regulating insulin sensitivity and type 2 diabetes by controlling insulin expression and markers for pancreatic β-cell proliferation [13].

Vitamin K is also important in preventing bone loss in individuals with diabetes [14], [15], [16], [17], [18], coronary heart disease [19], [20], atherosclerosis [21], [22], [23], [24], and hepatocellular carcinoma [25]. Findings have unequivocally shown that administration of vitamin K has the potency to reduce risk of type 2 diabetes [26], [27]. In rodents, vitamin K deficiency has been shown to delay insulin response to glucose load [4]. Apart from its role in gamma-carboxylation of proteins, vitamin K functions are largely unclear. It is also not clear what effect vitamin K has on pathologic changes in the pancreas during diabetes, especially type 1 diabetes. To our knowledge, there is only one study that has shown the ability of vitamin K2 against type 1 diabetes [28]. However, this study was primarily concerned with the ability of vitamin K2 to prevent diabetes-induced loss of bone weight.

Human type 1 diabetes is known for its autoimmune disease pathology. Experimental models have been aimed at mimicking the characteristic autoimmune component of the spontaneously developing diabetes [29]. In human type 1 diabetes as well as in rodent models, the main objective is to selectively destroy pancreatic β cells. Cyclophospamide and streptozotocin (STZ) are used to induce diabetes in rodent models, which is a putative model for human type 1 diabetes [30]. STZ is a β-cell toxin that is transported to islets by glucose transporter-2 leading to β islet cell necrosis [30].

Thus, the objective of this study was to assess the effect of vitamin K1 on STZ-induced diabetic pancreas. We also investigated the effect of vitamin K1 on biochemical changes, oxidative stress levels, and proinflammatory markers in the pancreas to decipher probable mechanisms involved in its antidiabetic functions.

Section snippets

Materials and methods

1,1,3,3, tetramethoxy propane, dl-glyceraldehyde, vitamin K1, STZ, and dithiobis nitrobenzoic acid were from Sigma Aldrich. All other chemicals were of analytical grade.

Vitamin K1 administration led to reduction in blood glucose and a concomitant decrease in gHb

STZ led to hyperglycemia in group 2 (298.66 ± 25.4 mg/dL) and 3 rats compared with controls. However, in the case of group 3 rats treated with vitamin K1 after hyperglycemia, there was a significant reduction (186.5 ± 26.12 mg/dL) in blood glucose (Fig. 1A) and levels were slightly higher than control (86.4 ± 9.125 mg/dL). Hyperglycemia resulted in significantly elevated levels of gHb (Fig. 1B) in the case of group 2 rats (5.47 ± 0.08 mg/gHb) compared with control (3.28 ± 0.06 mg/gHb). However,

Discussion

The major findings of this study showed the antidiabetic mechanism of vitamin K1 that can prevent pathogenesis associated with β islet destruction as seen in type 1 diabetes. Additionally, we presented data that suggests that vitamin K1 probably has a therapeutic effect against type 1 diabetes.

In this study, STZ led to a significant increase in blood glucose indicating diabetes onset. This was also evident from a significant and comparable increase in gHb in the STZ-induced group. However,

Acknowledgment

TR would like to acknowledge the Vice Chancellor, SASTRA University, for financial and infrastructural support through R&M Fund. The authors have no competing financial interests to declare.

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