Basic nutritional investigationVitamin 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
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.
References (74)
- et al.
Phylloquinone intake, insulin sensitivity, and glycemic status in men and women
Am J Clin Nutr
(2008) - et al.
Is vitamin K consumption associated with cardio-metabolic disorders? A systematic review
Maturitas
(2010) - et al.
Antinociceptive effect of vitamin K2 (menatetrenone) in diabetic mice
Jpn J Pharmacol
(2001) - et al.
Vitamin K intake and calcifications in breast arteries
Maturitas
(2007) - et al.
Menatetrenone prevents osteoblast dysfunctionbin unilateral sciatic neurectomized rats
Jpn J Pharmacol
(2002) - et al.
Curcumin prevents free radical-mediated cataractogenesis through modulations in lens calcium
Free Radic Biol Med
(2010) - et al.
Purification and characterization of two forms of low-affinity of Ca2+-ATPases from erythrocyte membrane
Biochim Biophys Acta
(1983) - et al.
Studies on sodium-potassium-activated adenosine triphosphatases. VI. Its role in cation transport in the lens of cat, calf and rabbit
Arch Biochem Biophys
(1963) - et al.
Curcumin prevents streptozotocin-induced damage by scavenging free radicals: a prophylactic and protective role
Eur J Phar
(2007) - et al.
Anticataractogenic effect of curcumin and aminoguanidine against selenium-induced oxidative stress in the eye lens of Wistar rat pups: an in vitro study using isolated lens
Chem Biol Interact
(2009)
Involvement of inducible nitric oxide synthase in hydroxyl radical-mediated lipid peroxidation in streptozotocin-induced diabetes
Free Radic Biol Med
Sequential inactivation of reactive oxygen species by combined overexpression of SOD isoforms and catalase in insulin-producing cells
Free Radic Biol Med
Impaired antioxidant status in diabetic rat liver: Effect of vanadate
Biochem Pharmacol
Experimental diabetes impairs function of the retinal pigmented epithelium
Metab Clin Exp
Animal and human tissue Na, K-ATPase in obesity and diabetes: a new proposed enzyme regulation
Am J Med Sci
Activation of transcription factor NF-κB is suppressed by curcumin (diferulolylmethane)
J Biol Chem
Vitamin K3 attenuates lipopolysaccharide-induced acute lung injury through inhibition of nuclear factor-kB activation
Clin Exp Immunol
Regulation of the protein C anticoagulant and antiinflammatory pathways
Curr Med Chem
Vitamin K2 stimulates osteoblastogenesis and suppresses osteoclastogenesis by suppressing NF-κB activation
Int J Mol Med
The potent antioxidant activity of the vitamin K cycle in microsomal lipid peroxidation
Biochem Pharmacol
Compilation of a provisional UK database for the phylloquinone (vitamin K1) content of foods
Br J Nutr
Comparative effects of vitamin K2 and estradiol on experimental arteriosclerosis with diabetes mellitus
Int J Vitam Nutr Res
Dietary phylloquinone intakes and metabolic syndrome in US young adults
J Am Coll Nutr
Effect of vitamin K supplementation on insulin resistance in older men and women
Diabetes Care
Association between dietary phylloquinone intake and peripheral metabolic risk markers related to insulin resistance and diabetes in elderly subjects at high cardiovascular risk
Cardiovasc Diabetol
Matrix gla protein species and risk of cardiovascular events in type 2 diabetic patients
Diabetes Care
Osteocalcin differentially regulates cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice
Proc Natl Acad Sci USA
Diabetes mellitus and osteoporosis. Dietary therapy of diabetes related osteoporosis
Clin Calcium
Bone quality and vitamin K2 in type 2 diabetes: Review of preclinical and clinical studies
Nutr Rev
Is ucOC a novel bone-derived antidiabetogenic hormone in humans?
Clin Calcium
Diabetic osteopathy and vitamin K
Clin Calcium
Impaired gamma carboxylation of osteocalcin in elderly women with type II diabetes mellitus: Relationship between increase in undercarboxylated osteocalcin levels and low bone mineral density
J Bone Miner Metab
Evaluation of genetic factors for warfarin dose prediction
Clin Med Res
Associations between vitamin K status and haemostatic and inflammatory biomarkers in community-dwelling adults. The Multi-Ethnic Study of Atherosclerosis
Thromb Haemost
Role of vitamin K and vitamin K-dependent proteins in vascular calcification
Z Kardiol
Atherosclerosis and matrix dystrophy
J Atheroscler Thromb
Regression of hepatocellular carcinoma during vitamin K administration
World J Gastroenterol
Cited by (33)
Hexacosylidenecyclohexane inhibits enzymatic breakdown of dietary sugars and modulates glucose homeostasis
2022, Phytomedicine PlusCitation Excerpt :The resulting supernatant was stored at −20 °C for further use as a source of aldose reductase (AR) enzyme (Suryanarayana et al., 2004). Lens aldose reductase activity was estimated according to Varsha et al. (2015) with slight modifications. Briefly, The assay mixture (1 mL) composed of 50 µM potassium phosphate buffer (pH 6.2), 0.4 mM lithium sulfate, 5 µM 2-mercaptoethanol, 10 µM DL-glyceraldehyde, 0.1 µM NADPH.
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
2018, Journal of Nutritional BiochemistryCitation Excerpt :Recent studies demonstrate a potentially significant role of dietary VK intake or VK supplementation in improving glycemic status and reducing the T2D risk factors and the prevalence of metabolic syndrome among normal subjects including both young and elderly volunteers [2]. Animal studies have also demonstrated the hypoglycemic action of VK supplementation in streptozotocin-induced diabetic rats [24–26]. However, the information on circulating VK level and its relationship with the glycemic status among T2D patients is lacking.
Curcumin attenuates oxidative stress induced NFκB mediated inflammation and endoplasmic reticulum dependent apoptosis of splenocytes in diabetes
2017, Biochemical PharmacologyCitation Excerpt :Polyol pathway is a hyperglycemia induced salvage pathway. Aldose reductase (ALR) is the rate limiting enzyme which leads to diabetic complications [36]. The next enzyme in the pathway, sorbitol dehydrogenase is responsible for the conversion of sorbitol, obtained from the initial reaction with aldose reductase, to fructose.
Interaction of AR and iNOS in lens epithelial cell: A new pathogenesis and potential therapeutic targets of diabetic cataract
2017, Archives of Biochemistry and BiophysicsBeneficial role of vitamin K supplementation on insulin sensitivity, glucose metabolism, and the reduced risk of type 2 diabetes: A review
2016, NutritionCitation Excerpt :Limited animal studies examined the role of vitamin K on glucose metabolism. Varsha et al. demonstrated the beneficial role of phylloquinone against streptozotocin (STZ)-induced type 1 diabetes in male albino Wistar rats [25]. Phylloquinone administration (5, 25, and 50 mg/kg body weight [bw], 2.5 mo, subcutaneously) decreased the free radicals formation and restored the antioxidant enzymes activities in the pancreatic tissues of the STZ-treated rats.
Hypoglycemic action of vitamin K1 protects against early-onset diabetic nephropathy in streptozotocin-induced rats
2015, NutritionCitation Excerpt :Because all three doses provided similar results during preliminary analyses, we selected 5 mg/kg, sc, for 3 mo for all further studies. In previous studies, 5 mg/kg vitamin K1 was used in treating diabetes by restoring the pancreatic β cells [12] and in the prevention of diabetic cataract [13]. Blood was collected from the tail vein once a month to monitor glucose levels after overnight starvation of the animal and when the animals were in a calm state.