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

Yasmin M Ahmed,Nada S Abdelwahab,Hossam M Hassan,Mohammed M Ghoneim,Asmaa M Othman,Khaled Shalaby,Asmaa M Aboulmagd,Mohamed A Abdelgawad

doi:10.3390/ph15030341

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.

Highlights

IntroductionHyperglycemia is a term used to describe a spectrum of metabolic disorders characterized by elevated blood glucose levels caused by abnormalities in insulin secretion, Pharmaceuticals 2022, 15, 341
To further explore the role ofcompared to increase liver insulin sensitivity and glucose uptake, we investigated the liver tissue levels of insulin receptor substrate 1 (IRS 1) protein which are responsible for glucose metabolism, and we found that in normal rats the insulin receptor substrate 1 (IRS-1) and insulin receptor substrate 2 (IRS 2) activities were 4.20 ± 0.19 ng/g and 5.72 ± 0.15 ng/g, respectively
Our work revealed the effect of the thiazolidinedione’s pioglitazone and benzosulfonamide derivative that were investigated against STZ- and High-Fat Diet (HFD)-induced type 2 diabetes mellitus in rats

Summary

Introduction

Hyperglycemia is a term used to describe a spectrum of metabolic disorders characterized by elevated blood glucose levels caused by abnormalities in insulin secretion, Pharmaceuticals 2022, 15, 341. Pharmaceuticals 2022, 15, 341 insulin sensitivity, or both [1]. Insulin resistance is a diagnostic sign for obesity-related diabetes mellitus, and it is regarded as the main risk factor for physiological phenomena in which organs such as the liver, skeletal muscle, and adipose tissue are less receptive to insulin [4,5]. Liver and white adipose tissues are the most abundant source of angiotensinogen and leptin in which both are insulin-sensitive regulators [7,8]. The oligopeptide hormone angiotensin II, one of the main regulatory RAS components, was implicated in the etiology of diabetes and its co-morbidities [10].

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Discussion

Conclusion