Pioglitazone Synthetic Analogue Ameliorates Streptozotocin-Induced Diabetes Mellitus through Modulation of ACE 2/Angiotensin 1–7 via PI3K/AKT/mTOR Signaling Pathway

Abstract

The renin angiotensin aldosterone system has a localized key regulatory action, especially in liver and body circulation. Furthermore, it accomplishes a significant role in the downregulation of the PI3K/AKT/mTOR signaling pathway that is involved in type II diabetes mellitus pathogenesis. The current study aimed to evaluate the effect of a synthetic pioglitazone analogue (benzenesulfonamide derivative) compared to the standard pioglitazone hypoglycemic drug on enhancing liver insulin sensitivity via ACE 2/Ang (1–7)/PI3K/AKT/mTOR in experimental STZ-induced diabetes. After the model was established, rats were distributed into the normal control group, diabetic group, pioglitazone group (20 mg/kg), and a benzenesulfonamide derivative group (20 mg/kg), with the last 2 groups receiving oral treatment for 14 consecutive days. Our results suggested enhancing liver insulin sensitivity against the ACE2/Ang (1–7)/PI3K/AKT/mTOR pathway. Moreover, the synthetic compound produced a reduction in blood glucose levels, restored hyperinsulinemia back to normal, and enhanced liver glycogen deposition. In addition, it up regulated the ACE2/Ang (1–7)/PI3K/AKT/mTOR signaling pathway via increasing insulin receptor substrate 1 and 2 sensitivity to insulin, while it increased glucose transporter 2 expression in the rat pancreas. The study findings imply that the hypoglycemic effect of the benzenesulfonamide derivative is due to enhancing liver sensitivity to regulate blood glucose level via the ACE2/Ang (1–7)/PI3K/AKT/mTOR pathway.

Genetic algorithm-optimized backpropagation neural network establishes a diagnostic prediction model for diabetic nephropathy: Combined machine learning and experimental validation in mice

“…Previous clinical studies have shown that siRNA-CYP4A14 can inhibit the proliferation and fibrosis of mesangial cells, which can be considered a therapeutic target for DN. Ahmed et al (2022) found that the reninangiotensin-aldosterone system has a key regulatory role locally, particularly in the liver and body circulation, and is also involved in the pathogenesis of type II diabetes by downregulating the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/ mTOR) signaling pathway. The hypoglycemic effect of benzenesulfonamide derivatives is to enhance the sensitivity of the liver to regulate blood glucose levels through the PI3K/AKT/mTOR pathway (Ahmed et al, 2022).…”

“…Ahmed et al (2022) found that the reninangiotensin-aldosterone system has a key regulatory role locally, particularly in the liver and body circulation, and is also involved in the pathogenesis of type II diabetes by downregulating the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/ mTOR) signaling pathway. The hypoglycemic effect of benzenesulfonamide derivatives is to enhance the sensitivity of the liver to regulate blood glucose levels through the PI3K/AKT/mTOR pathway (Ahmed et al, 2022). Taken together, these studies indicate that the five genes we identified may provide new therapeutic targets for the treatment of DN.…”

Partial Synthetic PPARƳ Derivative Ameliorates Aorta Injury in Experimental Diabetic Rats Mediated by Activation of miR-126-5p Pi3k/AKT/PDK 1/mTOR Expression

“…STZ (T2D) positive control group: receiving intraperitoneal STZ injection (45 mg/kg) [ 120 ] after being subjected to three consecutive weeks of HFD feeding [ 77 ];…”

“…Indeed, PPARƳ enhances nitric oxide (NO) production in the endothelium and retracts ET-1 expression, promoting endothelial relaxation [ 75 , 76 ]. Ahmet et al [ 77 ] reported that pioglitazone analogue significantly regulates Streptozotocin-Induced T2D through stimulating local angiotensin-converting enzyme 2/angiotensin 1-7 axis with the aid of PI3K/AKT/mTOR Signaling pathway in the hepatic tissues, thereby regulating glycogen deposition and enhancing lipolysis. However, Molavi et al [ 78 ] found that PPARƳ ligand rosiglitazone protects against myocardial ischemia/reperfusion injury via an effect on AT2 receptor upregulation and p42/44 MAPK inhibition.…”