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

Abstract

Aims Bone 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. Methods Ob / 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. Results Treatment 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. Conclusions Collectively, we demonstrate that BMP6 improves glycaemia in T2D mice and regulates glucose metabolism in hepatocytes representing an exciting prospect for future treatments of diabetes.

Obesity-linked PPARγ S273 phosphorylation promotes insulin resistance through Growth Differentiation Factor 3

“…Heterozygous deletion of the type 1 BMP receptor, Bmpr1a causes impaired glucose tolerance [49], while adipocyte-specific receptor deletion does not [50]. Similar salutary effects of glucose homeostasis have been observed in mice treated with BMP6, BMP7, and BMP9 [28,30,31]. BMPs can drive cellular differentiation including potentiation of brown and beige fat activation [47,48,51].…”

“…Members of the TGF- superfamily, including BMPs, GDFs, and TGF- proteins can affect insulin sensitivity, cellular differentiation, and obesity [28][29][30][31]. These proteins typically work either through BMP-type receptors or TGF-−type receptors.…”

Bone Morphogenetic Protein-6 Attenuates Type 1 Diabetes Mellitus-Associated Bone Loss

“…In our study, we did not observe gross appearance of HO at the peritoneal injection site with the dose we selected. Moreover, given that previous studies investigating systemic treatment with doses of BMP6 ranging from 1 to 50 ng per gram of mouse weight reported no HO was found , the dose of 10 ng per gram of animal weight seems to be safe and we think there is still room for increasing the dose of injection before safety is compromised. The frequency of injection is another critical variable that should be considered for safety and effectiveness of BMP6 injection.…”

The Impact of Antiosteoporotic Drugs on Glucose Metabolism and Fracture Risk in Diabetes: Good or Bad News?

“…BMPs have recently been implicated in pancreas development, control of adult glucose homeostasis, energy expenditure by stimulation of brown adipose tissue formation [ 37 ], and the development of diabetic complications [ 38 ]. In particular, BMP-9 [ 39 ] and BMP-6 [ 40 ] improve glycemia and insulin resistance in T2DM mice and regulate glucose metabolism in hepatocytes. An in vivo human study confirmed that circulating BMP-9 levels are significantly higher in healthy subjects than in patients with newly diagnosed T2DM, and found a negative correlation with metabolic control, as assessed by HbA1c and fasting blood glucose [ 41 ].…”