Abstract
Vitamin K2 is indispensable for blood coagulation and bone metabolism. Menaquinone-4 (MK-4) is the predominant homolog of vitamin K2, which is present in large amounts in the pancreas, although its function is unclear. Meanwhile, β-cell dysfunction following insulin secretion has been found to decrease in patients with type 2 diabetes mellitus. To elucidate the physiological function of MK-4 in pancreatic β-cells, we studied the effects of MK-4 treatment on isolated mouse pancreatic islets and rat INS-1 cells. Glucose-stimulated insulin secretion significantly increased in isolated islets and INS-1 cells treated with MK-4. It was further clarified that MK-4 enhanced cAMP levels, accompanied by the regulation of the exchange protein directly activated by the cAMP 2 (Epac2)-dependent pathway but not the protein kinase A (PKA)-dependent pathway. A novel function of MK-4 on glucose-stimulated insulin secretion was found, suggesting that MK-4 might act as a potent amplifier of the incretin effect. This study therefore presents a novel potential therapeutic approach for impaired insulinotropic effects.
Highlights
Vitamin K (VK) is a fat-soluble vitamin that functions as a cofactor for microsomal γ-glutamyl carboxylase and has a distinct role in the posttranslational carboxylation of glutamate to γ-carboxyglutamate (Gla) residues of VK-dependent proteins
To confirm the effect of MK-4 on Glucose-stimulated insulin secretion (GSIS), isolated islets and INS-1 cells were used in the present study
The isolated pancreatic islets were stimulated with 2.8 mM Glc and MK-4 for 1 h, and 20 μM MK-4 was found to enhance GSIS about two fold compared with the 0 μM MK-4 group; MK-4 amplified GSIS in the isolated mouse pancreatic islets of KK-Ay mice (Figure 2)
Summary
Vitamin K (VK) is a fat-soluble vitamin that functions as a cofactor for microsomal γ-glutamyl carboxylase and has a distinct role in the posttranslational carboxylation of glutamate to γ-carboxyglutamate (Gla) residues of VK-dependent proteins. VK exists in two natural forms, VK1 (phylloquinone, highly abundant in leafy greens) and VK2 (menaquinone, contained in dairy products and fermented foods). Certain functions of MK-4, besides its well-known roles in blood coagulation and bone metabolism via Gla modification, have been confirmed, including the induction of apoptosis in tumor cells [2,3,4,5], modulation of the nuclear receptor SXR/PXR [6,7,8], anti-inflammatory activity in lipopolysaccharide-induced models [9,10], and the enhancement of testosterone production [11]. We showed that MK-4 is widely present in the body, especially in the pancreas [16]; the role of MK-4 in the pancreas remains uncertain
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