Abstract

Type 2 diabetes mellitus (T2DM), one of the most common metabolic diseases, is characterized by insulin resistance and inadequate insulin secretion of β cells. Glycogen phosphorylase (GP) is the key enzyme in glycogen breakdown, and contributes to hepatic glucose production during fasting or during insulin resistance. Pharmacological GP inhibitors are potential glucose lowering agents, which may be used in T2DM therapy. A natural product isolated from the cultured broth of the fungal strain No. 138354, called 2,3-bis(4-hydroxycinnamoyloxy)glutaric acid (FR258900), was discovered a decade ago. In vivo studies showed that FR258900 significantly reduced blood glucose levels in diabetic mice. We previously showed that GP inhibitors can potently enhance the function of β cells. The purpose of this study was to assess whether an analogue of FR258900 can influence β cell function. BF142 (Meso-Dimethyl 2,3‐bis[(E)‐3‐(4‐acetoxyphenyl)prop‐2‐enamido]butanedioate) treatment activated the glucose-stimulated insulin secretion pathway, as indicated by enhanced glycolysis, increased mitochondrial oxidation, significantly increased ATP production, and elevated calcium influx in MIN6 cells. Furthermore, BF142 induced mTORC1-specific phosphorylation of S6K, increased levels of PDX1 and insulin protein, and increased insulin secretion. Our data suggest that BF142 can influence β cell function and can support the insulin producing ability of β cells.

Highlights

  • Diabetes mellitus is the most common endocrine and metabolic disorder

  • We investigated BF142, a tartaric acid derived Glycogen phosphorylase (GP) inhibitor, which is an analogue of 3-bis(4-hydroxycinnamoyloxy)glutaric acid (FR258900)

  • We investigated the effects of BF142 in the MIN6 cell line, a well-established model for insulin producing β cells

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Summary

Introduction

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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