Introduction. Danger of obesity lies in secondary pathogenesis, and Type II Diabetes (T2D) is a predominant, consequential issue.1 T2D is marked by insufficient insulin production; obesity is an energy imbalance, leading to chronic oxidative stress and overactivated mitochondrial ETC.1 This forms excess by-product ROS and reduces cyclin-dependent kinase (CDK) expression by halting G1/S and G2/M transition, leading to proliferative β-cell arrest, thus disrupted insulin signaling.2 Continued T2D progresses into malignant systemic complications, and currently 85% of T2D patients are obese.3 Current treatment options target BMI, or insulin directly. Understanding the molecular pathogenesis of obesity to T2D can open new doors to treatment, inhibiting certain progression points or involved molecules.3 The β-cell G1/S Cell Cycle Atlas notes the obstacle in inducing proliferation of human β-cells cell, as presumed nuclear proteins are cytoplasmic; thus, studying associated pancreatic cells and ROS/CDK related pathology aids in illustrating molecular pathway.2 Methods. In human cadaveric β-cells, nuclear abundance of p16INK4a, a tumor suppressor gene (TSG), increased from 2.7% to 8% between 24-72 hours when introduced overexpression of adenovirus CDK.4 When human dental pulp stem cells (hDPSCs) were cultured under physiological oxygen tension (3% O2) vs. 21% O2, mRNA expression of p16INK4a amplified 4 folds at the 15th passage, statistically significant p<0.0001, inducing premature senescence.5 Incubation of normal human epidermal keratinocytes (NHEK) in H2O2 additionally amplified in western blot intensity of mRNA from 0-72 hours, statistically significant p<0.01. Remarkably, co-expression and parallel intensity of DNA Methyl Transferase 1 (DMNT1) with p16INK4a was noted. Western blot furthermore presented larger intensity of p16 locus methylation in presence of H2O2.6 Results. The increased p16INK4a nuclear frequency with induction of proliferation supports the increase in inhibitory cell cycle tone in cells driven to proliferate; CDK altered mobilization of p16, supporting their dependent trafficking. ROS induces p16INK4a expression to trigger cellular premature senescence, reducing proliferation rate at the INK4/ARF locus that codes TSG. The NHEK study substantiates the effect of H2O2 to be upregulating p16INK4a through methylation in the promoter region.6 Methylation of promotor area represses gene transcription. Conclusions. Multiple studies illustrate the molecular pathway involving ROS, p16INK4a and CDK, and their linkage elucidates why obesity leads to T2D pathogenesis. It is through epigenetics, which ROS regulates activity of p16 that ultimately decreases expression of CDK and halts cell cycle. Reduction of inflammatory state by avoiding repeated fluctuation in blood glucose can help minimize to endow low level of pancreatic β-cell proliferation.7
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- Fiaschi-Taesch NM, Kleinberger JW, Salim FG, et al. Human Pancreatic -Cell G1/S Molecule Cell Cycle Atlas. Diabetes. 2013;62(7):2450-2459. doi:10.2337/db12-0777.
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- Fiaschi-Taesch N, Kleinberger J, Salim F, et al. Cytoplasmic-Nuclear Trafficking of G1/S Cell Cycle Molecules and Adult Human β-Cell Replication. Diabetes. 2013; 62(7): 2460-2470. doi:10.2337/db12-0778.
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- Mas-Bargues C, Vina-Almunia J, Ingles M, et al. Role of p16INK4a and BMI-1 in oxidative stress-induced premature senescence in human dental pulp stem cells. Redox Biology. 2017; 12(8): 690-698. doi: 10.1016/j.redox.2017.04.002.
- Zhang Z, Li J, Yang Lei, Chen R, et al. The Cytotoxic Role of Intermittent High Glucose on Apoptosis and Cell Viability in Pancreatic Beta Cells. Journal of Diabetes Research. 2014; 2014: 1-9. doi:10.1155/2014/712781.