Insulin-Mimicking Bioactivities of Acylated Inositol Glycans in Several Mouse Models of Diabetes with or without Obesity

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.

The Biomedical Uses of Inositols: A Nutraceutical Approach to Metabolic Dysfunction in Aging and Neurodegenerative Diseases

“…In contrast, GPI-PLD may be cleaved when inositol groups are acylated, supposedly releasing acylated IPGs (A-IPGs) ( Figure 1 C) [ 92 ]. Synthetic A-IPGs also show a strong insulin-mimetic activity [ 93 ]. Non-protein linked GPIs are intermediate GPIs, as they quickly bind proteins when reaching the plasma membrane surface.…”

MASP1, THBS1, GPLD1 and ApoA-IV are novel biomarkers associated with prediabetes: the KORA F4 study

“…Comparable studies in humans are lacking and the potential role of GPLD1 in diabetes and prediabetes is currently unknown. GPLD1 cleavage generates second messengers that can act as insulin-mimetic low molecular mass species [33,34]. Suzuki et al demonstrated that treatment of mice with certain insulin-mimetic low molecular mass species led to decreased plasma glucose levels, increased glycogen content in the liver and skeletal muscles, and improved glucose tolerance in db/db mice and C57B6N mice on high-fat diets [34].…”

A review of the role of inositols in conditions of insulin dysregulation and in uncomplicated and pathological pregnancy

“…Synthetic GPIs and IPGs and the relationship between structure and function Since the isolation and structural elucidation of natural IPGs has been difficult, chemists have produced a range of synthetic GPIs, IPGs and inositol glycans in order to better understand structure-function relationships and identify possible drug candidates (Larner, Brautigan, and Thorner 2010;Goel and Azev 2009;Suzuki et al 2014). While many of these candidates showed insulin mimetic activity in various assays, the strength of the effect, and whether the effect was on glucose, glycogen or lipid metabolism varied by molecular structure (Larner, Brautigan, and Thorner 2010;Goel and Azev 2009;Suzuki et al 2014). These effects were reviewed by Goel et.al.…”