Transcriptional Profiling and Biological Pathway(s) Analysis of Type 2 Diabetes Mellitus in a Pakistani Population.

Zarish Noreen,Christopher A Loffredo,Attya Bhatti,Jyothirmai J Simhadri,Gail Nunlee-Bland,Somiranjan Ghosh,Peter John,Thomas Nnanabu,Jahangir S Khan

doi:10.3390/ijerph17165866

Abstract

The epidemic of type 2 diabetes mellitus (T2DM) is an important global health concern. Our earlier epidemiological investigation in Pakistan prompted us to conduct a molecular investigation to decipher the differential genetic pathways of this health condition in relation to non-diabetic controls. Our microarray studies of global gene expression were conducted on the Affymetrix platform using Human Genome U133 Plus 2.0 Array along with Ingenuity Pathway Analysis (IPA) to associate the affected genes with their canonical pathways. High-throughput qRT-PCR TaqMan Low Density Array (TLDA) was performed to validate the selected differentially expressed genes of our interest, viz., ARNT, LEPR, MYC, RRAD, CYP2D6, TP53, APOC1, APOC2, CYP1B1, SLC2A13, and SLC33A1 using a small population validation sample (n = 15 cases and their corresponding matched controls). Overall, our small pilot study revealed a discrete gene expression profile in cases compared to controls. The disease pathways included: Insulin Receptor Signaling, Type II Diabetes Mellitus Signaling, Apoptosis Signaling, Aryl Hydrocarbon Receptor Signaling, p53 Signaling, Mitochondrial Dysfunction, Chronic Myeloid Leukemia Signaling, Parkinson’s Signaling, Molecular Mechanism of Cancer, and Cell Cycle G1/S Checkpoint Regulation, GABA Receptor Signaling, Neuroinflammation Signaling Pathway, Dopamine Receptor Signaling, Sirtuin Signaling Pathway, Oxidative Phosphorylation, LXR/RXR Activation, and Mitochondrial Dysfunction, strongly consistent with the evidence from epidemiological studies. These gene fingerprints could lead to the development of biomarkers for the identification of subgroups at high risk for future disease well ahead of time, before the actual disease becomes visible.

Highlights

Type 2 Diabetes Mellitus (T2DM), the predominant form of diabetes, is a chronic, multifactorial, metabolic disorder characterized by hyperglycemia and has become a public health challenge Int
The present study extends those observations to investigate a pilot study of global gene expression patterns in the same patients, using microarrays coupled with Ingenuity Pathway Analysis (IPA) and followed by selective gene validation
The results showed that TP53 and MYC genes were mostly downregulated in our studied subjects (Figure 4), while expression of apolipoproteins C1 (APOC1), APOC2, CYP1B1, SLC2AB, and SLC33A1 genes was highly upregulated in all subjects (Figure 5)

Summary

Introduction

Type 2 Diabetes Mellitus (T2DM), the predominant form of diabetes, is a chronic, multifactorial, metabolic disorder characterized by hyperglycemia and has become a public health challenge Int. J. Res. Public Health 2020, 17, 5866; doi:10.3390/ijerph17165866 www.mdpi.com/journal/ijerph. Res. Public Health 2020, 17, 5866 worldwide [1,2,3]. T2DM accounts for 90% to 95% of all diabetes cases with the heritability ranging between 40% and 70% [4,5]. Beta cell dysfunction, impaired insulin secretion, and increased insulin resistance cause the chronic dysregulation of the hyperglycemia state and are critical in pathophysiological determinants of the disease’s progression and pathogenesis [6,7]. T2DM can lead to life-threatening complications, viz., neuropathy, cerebrovascular disease, nephropathy, peripheral vascular disease, coronary artery disease, and retinopathy [8,9]

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Conclusion