Insulin-mimicking bioactivities of acylated inositol glycans in several mouse models of diabetes with or without obesity.

Yoshinori Hinokio,Viatcheslav N. Azev,Yasushi Ishigaki,Nilanjana Chakraborty,Hideki Katagiri,Yanqiao Zhang,Susumu Suzuki,Chitose Suzuki,Makoto Kanzaki,Marc d'Alarcao

doi:10.1371/journal.pone.0100466

Abstract

Insulin-mimetic species of low molecular weight are speculated to mediate some intracellular insulin actions. These inositol glycans, which are generated upon insulin stimulation from glycosylphosphatidylinositols, might control the activity of a multitude of insulin effector enzymes. Acylated inositol glycans (AIGs) are generated by cleavage of protein-free GPI precursors through the action of GPI-specific phospholipase C (GPI-PLC) and D (GPI-PLD). We synthesized AIGs (IG-1, IG-2, IG-13, IG-14, and IG-15) and then evaluated their insulin-mimicking bioactivities. IG-1 significantly stimulated glycogen synthesis and lipogenesis in 3T3-L1 adipocytes and rat isolated adipocytes dose-dependently. IG-2 significantly stimulated lipogenesis in rat isolated adipocytes dose-dependently. IG-15 also enhanced glycogen synthesis and lipogenesis in 3T3-L1 adipocytes. The administration of IG-1 decreased plasma glucose, increased glycogen content in liver and skeletal muscles and improved glucose tolerance in C57B6N mice with normal diets. The administration of IG-1 decreased plasma glucose in STZ-diabetic C57B6N mice. The treatment of IG-1 decreased plasma glucose, increased glycogen content in liver and skeletal muscles and improved glucose tolerance in C57B6N mice with high fat-diets and db/db mice. The long-term treatment of IG-1 decreased plasma glucose and reduced food intake and body weight in C57B6N mice with high fat-diets and ob/ob mice. Thus, IG-1 has insulin-mimicking bioactivities and improves glucose tolerance in mice models of diabetes with or without obesity.

Highlights

The peptide hormone insulin regulates glucose homeostasis by modulating the action of a multitude of metabolic enzymes in the liver, adipose tissue, and skeletal muscle
On the day after one-shoot intravenous injection, fasting plasma glucose levels showed no significant difference between the IG-1 and DMSO groups
Some intracellular insulin actions might be mediated by insulinmimetic species of low molecular weight, such as inositol phosphoglycans (IPGs), generated from the hydrolysis of GPI

Summary

Introduction

The peptide hormone insulin regulates glucose homeostasis by modulating the action of a multitude of metabolic enzymes in the liver, adipose tissue, and skeletal muscle. Glucose metabolism by activation of glycogen synthase, mitochondrial pyruvate dehydrogenase, and other regulatory enzymes through protein dephosphorylation, remain incompletely explained by these models for insulin action. Second messengers referred to as inositol phosphoglycans (IPGs) are generated upon insulin stimulation from glycosylphosphatidylinositol (GPI) and control the activity of a multitude of insulin effector enzymes [4]. IPGs are involved in mitogenic signaling via type I cytokine receptors [8,9], suggesting a broader role of IPGs as second messengers in the signaling network of hormones and cytokines. The mechanistic details of IPG action remain largely unknown

Methods

Results

Conclusion