Genetic determinants of obesity heterogeneity in type II diabetes

Somayeh Alsadat Hosseini Khorami,Zulida Rejali,Mohd Sokhini Abd Mutalib,Mohammad Feili Shiraz,Razana Mohd Ali,Huzwah Khaza’Ai,Joseph Anthony Abdullah

doi:10.1186/s12986-020-00476-6

Somayeh Alsadat Hosseini Khorami, Zulida Rejali + Show 5 more

Open Access

https://doi.org/10.1186/s12986-020-00476-6

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Abstract

BackgroundAlthough obesity is considered as the main cause of Type II diabetes (T2DM), non-obese individuals may still develop T2DM and obese individuals may not.MethodThe mRNA expression of PI3K/AKT axis from 100 non-obese and obese participants with insulin sensitivity and insulin resistance states were compared in this study toward the understanding of obesity heterogeneity molecular mechanism.ResultIn present study, there was no statistically significant difference in gene expression levels of IRS1 and PTEN between groups, whereas PI3K, AKT2 and GLUT4 genes were expressed at a lower level in obese diabetic group compared to other groups and were statistically significant. PDK1 gene was expressed at a higher level in non-obese diabetic group compared to obese diabetic and non-obese non-diabetics groups. No statistically significant difference was identified in gene expression pattern of PI3K/AKT pathway between obese non-diabetics and non-obese non-diabetics.ConclusionThe components of PI3K/AKT pathway which is related to the fasting state, showed reduced expression in obese diabetic group due to the chronic over-nutrition which may induced insensitivity and reduced gene expression. The pathogenesis of insulin resistance in the absence of obesity in non-obese diabetic group could be due to disturbance in another pathway related to the non-fasting state like gluconeogenesis. Therefore, the molecular mechanism of insulin signalling in non-obese diabetic individuals is different from obese diabetics which more investigations are required to study insulin signalling pathways in greater depth, in order to assess nutritional factors, contribute to insulin resistance in obese diabetic and non-obese diabetic individuals.

Highlights

The relationship between insulin resistance and obesity is well recognised while the responsible mechanisms of obesity-related insulin resistance remain poorly understood [1,2,3]
Phosphatidylinositol 3-kinase (PI3K), AKT2 and Glucose Transporter 4 (GLUT4) expression levels were significantly lower in obese diabetic participants compared to obese non-diabetics
The gene expression levels of PI3K, AKT2 and GLUT4 were significantly lower in obese diabetic participants compared to non-obese diabetics whereas the gene expression level of PDK1 was significantly higher in non-obese diabetics compared to obese diabetics

Summary

Introduction

The relationship between insulin resistance and obesity is well recognised while the responsible mechanisms of obesity-related insulin resistance remain poorly understood [1,2,3]. PI3K phosphorylates membrane phospholipids and converts PIP2 (Phosphotidylinositol-4,5-bisphosphate) to PIP3 (Phosphotidylinositol-3,4,5-triphosphate) This complex phosphorylates/activates the PDK1 and PDK2 (PhosphoinositideDependent Kinase) leading to activation of AKT/PKB and PKC (Protein Kinase C) phosphorylation to translocate GLUT4 to the plasma membrane from intracellular vesicular compartment [9]. PI3K/AKT pathway can be reversely dephosphorylated by PTEN phosphatase (Phosphatase and TENsin homolog deleted on chromosome 10) through converting PIP3 back to PIP2 [10]. All these events are related to short-term post-translational regulation of protein functions and long-term transcriptional regulation [11]. Obesity is considered as the main cause of Type II diabetes (T2DM), non-obese individuals may still develop T2DM and obese individuals may not

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