Investigation of Molecular Mechanisms Underlying Type 2 Diabetes Mellitus and Alzheimer’s disease

Abstract

The type 2 diabetes mellitus (T2DM) is one of the serious health problems worldwide. The occurrence of T2DM and its role in the development of Alzheimer’s disease (AD) has become important health concern worldwide and in Pakistan. The current study was carried out to gain insights on the pathophysiology of these diseases and their risk factors with an intriguing molecular transcriptional investigation. This transcriptional profiling contributed in providing detailed information about differential gene expression and signaling pathways assosicated with these two diseases and helped in addressing their increased prevalence in Pakistan. A total number of 820 research participants were recruited that include 250 controls, 450 T2DM, 100 AD and 20 T2DM and AD both. The background information was recorded with their comprehensive epidemiological information, viz, age, gender, family history, education, residence, etc. The microarray experiment was carried out on Affymetrix platforms using Human Genome U133 plus 2.0 Array. The significant data sets which we got from microarray studies were uploaded in Ingenuity Pathway Analysis (IPA) software to reveal the global gene expression profile data, significant signaling pathways, and biological mechanisms associated with T2DM and AD subjects. High-throughput qRT-PCR TaqMan Low Density Array (TLDA) was carried out to validate the selected differentially expressed diseases specific (T2DM & AD) genes of our interest, including., APOC1, APOC2, RRAD,ARNT, LEPR, MYC, TP53, CYP2D6, and SLC2A13. Overall, our study comcluded a discrete gene expression profile in studied subjects as compared to our control subjects. The results concluded from our study suggested that T2DM and AD both were associated with socio-demographicand environmental factors in Pakistani population.Significant differences between T2DM and AD groups with their respective controls were observed between studied groups and age with p value < 0.0001 and studied groups with locality p value = 0.0472. The average HbA1c (%) level was 10.68 ± 2.34 in the T2DM group, and females had a lower level than males p = 0.003. iv The signling pathways revelaed from our results included: Neuroinflammation Signaling Pathway,Mitochondrial Dysfunction, Oxidative Phosphorylation, Type II Diabetes Mellitus Signaling, Molecular Mechanism of Cancer, Dopamine Receptor Signaling, Insulin Receptor Signaling, Apoptosis Signaling, GABA Receptor Signaling, p53 Signaling, Cell Cycle G1/S Checkpoint Regulation and LXR/RXR Activation. These pathways were strongly consistent with some of the validated genes including APOC1, APOC2, RRAD, ARNT, LEPR, MYC, TP53, CYP2D6, and SLC2A13 in T2DM and AD subjects. The study suggested that these genesmay have potential to be used in therapeutic approaches for the development of novel drug targets. This will also help in the identification of subgroups at high risk with chronic T2DM, for the future disease and disorder development, well ahead of time during their live course. Thus, the gene expression studies along with their signaling pathways provide insight knowledge of biological mechanisms and pathogenesis of T2DM and AD in the studied Pakistani population.