الفهرس 
Insulin
Molecular mechanism of insulinOnly 14 pages are availabe for public view
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Abstract
Insulin resistance and metabolic disorders can result in prediabetes, which has been associated with obesity, cardiovascular diseases and a higher probability of developing diabetes. However, it is a transient stage, implying that avoiding it is an important step in preventing T2DM development. For decades, numerous techniques have been considered gold standards for detecting diabetes, including FBG levels, 2hr-PPG, and HbA1c levels. But, due to individual variation and test application, a certain probability of high deviation, low repeatability, and possible misinterpretation may exist. Clinical research is now focused on screening for and discovering novel biomarkers with high specificity and sensitivity for diagnosing prediabetes and T2DM, and determining their prognosis. MicroRNAs have significant effects in the progression and regulation of several diseases, including diabetes and obesity. Since their discovery, miRNAs also have critical roles in the regulation of insulin secretion, glucose homeostasis, lipid metabolism, and carbohydrate tolerance in pre- DM and T2DM. The miRNA 103 family comprises of two isoforms (miRNA 103a and miRNA 103b) and miRNA 107 that are highly conserved from mouse to human and both of which have been extensively studied in the pathophysiology of numerous disorders. Latest researches have informed that the miRNA 103 is elevated in the blood of patients with T2DM that contributes to maintaining the insulin sensitivity and glucose homeostasis. Accordingly, the goals of the current study are to estimate levels of miRNA 103 and miRNA 107 in obese patients with T2DM and obese individuals without, also, to analyze the correlations of miRNA 103 and miRNA 107 expression levels with insulin resistance and to elucidate the effect of metformin on levels of miRNA 103 and miRNA 107 in obese T2DM patients. In the present study, metformin was used as insulin sensitizer and antihyperglycemic agent. Metformin acts through its role on glucose transport via GLUT-4, AMPK activation, epigenetic variations, and improvements in GLUT-4 trafficking and translocation to the plasma membrane. The study included ninety subjects divided into an obese non-diabetic control group (OC, n=30), obese newly diagnosed diabetics (ONDD, n=30), and obese diabetics treated with metformin (MetD, n=30). All patients were included from those admitted to outpatient clinic of the Diabetes and Endocrinology Unit, Internal Medicine Department, Tanta University Hospital, Egypt. The research started in January 2019 and ended in December 2020. Full history was taken for all patients with particular importance on the period of diabetes and any other associated diseases and medications. Blood analysis and physical examination were used for the diagnosis of patients. miRNA 103 and miRNA 107 expression levels were assayed in serum with qRT-PCR technique. Human Dicer levels and insulin levels in serum were determined with ELISA technique. HOMA-IR model and lipid profiles were also determined. In the present study, the expressions levels of miRNA 103 and miRNA 107 showed significant increase in ONDD group in comparison with obese control group. However, their gene expressions were significantly decreased in metformin treated group in comparison with obese control group. Dicer level showed a significant decrease in ONDD group in comparison with obese control group; however, its level showed a significant increase in MetD group in comparison with obese control group. Also, a significant negative correlation between levels of miR-103, miR-107, and Dicer was found in all studied groups. The increased levels of miRNA 103 and miRNA 107 promote insulin resistance and feedback inhibition of Dicer enzyme activity so decreasing its levels. Regarding the relation of miRNA 103 and miRNA 107 as indicator parameters of insulin resistance; it was found that miRNA 103, miRNA 107 has significant positive relations with HOMA IR. This indicated that miRNA 103 and miRNA 107 may be prospective molecular indicators for insulin resistance and the onset of diabetes. Herein, HbA1c, FBG, insulin levels, and HOMA IR were improved after metformin consumption in the MetD group in comparison with ONDD and OC groups. As metformin acts by enhancing the response of peripheral tissues to insulin, it causes the reduction in the levels of insulin in the blood in addition; it could inhibit production of glucose in the liver, increases glucose uptake and utilization by the peripheral tissues, and reduces fatty acid oxidation. Levels of TCh, TG, LDL-C, and VLDL-C were reduced along with increased HDL-C after treatment with metformin in the MetD group compared to ONDD and OC groups. The impact of metformin on dyslipidemia and lipid profiles in people with T2DM occurs through triggering different pathways. After phosphorylating and activating AMPK, it may influence the transcription and production of many critical regulators of liver lipogenesis and hepatic gluconeogenesis. Moreover, ROC curve analyses showed that miRNA 103 and miRNA 107 are good biomarkers for insulin resistance and diabetes. The sensitivity of miRNA 103 and miRNA 107 in ONDD was 96.7% as indicated by AUC, and the specificity was 80% and 100% respectively (p˂0.0001). It was found miRNA 103 and miRNA 107 levels are increased in the pre-diabetic population with high sensitivity and specificity, therefore miRNA 103 and miRAN 107 could identify and predict T2DM with high diagnostic value.