Abstract

Type 2 diabetes is a complex, heterogeneous, and polygenic disease. Currently, available drugs for treating type 2 diabetes predominantly include sulfonylureas, α-glucosidase inhibitors, and biguanides. However, long-term treatment with these therapeutic drugs is often accompanied by undesirable side effects, which have driven interest in the development of more effective and safer antidiabetic agents. To address the urgent need for new chemical solutions, we focused on the analysis of structurally novel and/or biologically new metabolites produced by insect-associated microbes as they have recently been recognized as a rich source of natural products. Comparative LC/MS-based analysis of Actinomadura sp. RB99, isolated from a fungus-growing termite, led to the identification of the type II polyketide synthase-derived fridamycin A. The structure of fridamycin A was confirmed by 1H NMR data and LC/MS analysis. The natural microbial product, fridamycin A, was examined for its antidiabetic properties in 3T3-L1 adipocytes, which demonstrated that fridamycin A induced glucose uptake in 3T3-L1 cells by activating the AMP-activated protein kinase (AMPK) signaling pathway but did not affect adipocyte differentiation, suggesting that the glucose uptake took place through activation of the AMPK signaling pathway without inducing adipogenesis. Our results suggest that fridamycin A has potential to induce fewer side effects such as weight gain compared to rosiglitazone, a commonly used antidiabetic drug, and that fridamycin A could be a novel potential therapeutic candidate for the management of type 2 diabetes.

Highlights

  • Type 2 diabetes is a metabolic disease characterized by abnormally high blood glucose levels and cellular insulin resistance despite normal insulin production by the pancreas [1]

  • We found that 10 μM fridamycin A treatment induced AMPK phosphorylation compared blotting was performed

  • We examined the effect of fridamycin A on lipid accumulation. 3T3-L1 preadipocytes were differentiated in the presence of fridamycin A or rosiglitazone

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Summary

Introduction

Type 2 diabetes is a metabolic disease characterized by abnormally high blood glucose levels and cellular insulin resistance despite normal insulin production by the pancreas [1]. In an insulin-resistant state, insulin cannot activate the insulin signaling pathway to stimulate glucose uptake in insulin-sensitive tissues such as adipose tissues, liver, and skeletal muscle [3,4]. Thiazolidinediones, such as rosiglitazone, metformin, and glyburide, have been used as insulin-sensitizing drugs for the treatment of type 2 diabetes [5,6]. Nutrients 2019, 11, 765 cardiovascular diseases, weight gain, and edema, the development of new antidiabetic agents from natural sources which have fewer side effects than commonly used drugs has become necessary. Natural products have been reported to improve insulin sensitivity via the activation of AMP-activated protein kinase (AMPK), which is believed to be a therapeutic target for the treatment of type 2 diabetes [4,7,8]

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