A novel role of bone morphogenetic protein 6 (BMP6) in glucose homeostasis

Martina Pauk,Tatjana Bordukalo-Niksic,Slobodan Vukicevic,Lovorka Grgurevic,Ivo Dumic-Cule,Vishwas M Paralkar,Amy L Brault,Fran Borovecki,Jelena Brkljacic

doi:10.1007/s00592-018-1265-1

Martina Pauk, Tatjana Bordukalo-Niksic + Show 7 more

Open Access

https://doi.org/10.1007/s00592-018-1265-1

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Abstract

AimsBone morphogenetic proteins (BMPs) are involved in the development and homeostasis of multiple organs and tissues. There has been a significant focus on understanding the role of BMPs in pancreatic β-cell dysfunction associated with type 2 diabetes (T2D). Our objective was to investigate the relationship between BMP6 and glucose homeostasis.MethodsOb/ob mice were treated with BMP6 for 6 days and analyzed for insulin release, body weight, lipid parameters and glucose tolerance. Quantitative real-time PCR, chromatin immunoprecipitation and glucose output assays were used to assess BMP6 effect on gluconeogenesis in rat hepatoma H4IIE cells. Specificity of BMP6 receptors was characterized by the utilization of various receptor Fc fusion proteins in luciferase reporter gene and glucose output assays in INS1 and H4IIE cells.ResultsTreatment of ob/ob mice with BMP6 for 6 days resulted in a reduction of circulating glucose and lipid levels, followed by a significantly elevated plasma insulin level in a dose-dependent manner. In addition, BMP6 improved the glucose excursion during an oral glucose tolerance test, lowering the total glycemic response by 21%. In rat H4IIE hepatoma cells, BMP6 inhibited gluconeogenesis and glucose output via downregulation the PepCK expression. Moreover, BMP6 inhibited glucose production regardless of the presence of cAMP, antagonizing its glycogenolytic effect. BMP6 acted on pancreatic and liver cells utilizing Alk3, Alk6 and ActRIIA serine/threonine kinase receptors.ConclusionsCollectively, we demonstrate that BMP6 improves glycaemia in T2D mice and regulates glucose metabolism in hepatocytes representing an exciting prospect for future treatments of diabetes.

Highlights

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β (TGF-β) superfamily [1, 2]
There has been a significant focus on understanding the involvement of BMPs in β-cell dysfunction associated with type 2 diabetes (T2D), but there are many conflicting results regarding the effect of BMPs on glucose homeostasis and pancreatic cell function
We tested whether Bone morphogenetic protein 6 (BMP6) has beneficial effect on glucose homeostasis and insulin secretion using T2D mice model

Summary

Introduction

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β (TGF-β) superfamily [1, 2]. Involvement of BMPs in glucose metabolism has been demonstrated in mice with attenuated BMPR1A signaling in β-cells, which lead to decreased expression of key genes involved in insulin gene expression, glucose sensing and diabetes due to impaired insulin secretion [7]. BMP2 and 6 were proposed as new potent insulin sensitizers in adipocytes based on their ability to increase glucose uptake and to regulate genes involved in glucose and fatty acid metabolisms [10]. These results suggested that BMPs have essential roles in pancreas organogenesis and endocrine cell differentiation and are involved in regulating glucose metabolism in liver, pancreas, adipose tissue and muscle. There is no evidence of the bioavailability of BMPs and tissue-specific function of BMPs in diabetic animal models

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