Comparative Analysis of Pioglitazone and Tirzepatide on Body Weight, Glucose Levels, Neuroinflammation, and Oxidative Stress in Diabetic Rats

Abstract

Introduction: Type 2 diabetes mellitus (T2DM) is a widespread metabolic illness that compromises cognitive function by inducing inflammation and oxidative damage. Diabetes mellitus is treated with many types of medications, including tirzepatide (TZP) and pioglitazone (PIO), which have also been shown to enhance cognitive deficits associated with the condition. This study intends to investigate the neuroprotective effects of TZP and PIO on type 2 diabetic mellitus (T2DM) via mitigating neuroinflammation and oxidative stress, along with enhancing cognitive impairment in rats as models with T2DM.

Methods: A total of six distinct groups of sixty albino rat males (n = 10) were allocated at random: Saline, TZP, PIO, T2DM, T2DM+TZP, and T2DM+PIO. Intramuscular doses of streptozotocin (50 mg/kg) and nicotinamide (120 mg/kg) precipitated T2DM. The TZP and PIO therapies persisted for a duration of 15 days. The survival percentage, body weight, behavioral assessments (Y-maze, novel object recognition (NOR)), glucose concentrations, inflammatory mediators tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin-1 beta (IL-1β), as well as oxidative stress biomarkers superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA), and lipid peroxidation were evaluated following the conclusion of the treatments.

Results: The results demonstrate that diabetes decreased survival rates, body weight, cognitive function, increased glucose levels, neuroinflammation, and oxidative stress. The TZP and PIO increased survival rates and cognitive function as well as decreased glucose levels, neuroinflammation, and oxidative stress in diabetic rats, with PIO demonstrating a more pronounced effect on neuroinflammation and oxidative stress, contrasted with TZP.

Discussion: This study concluded that TZP and PIO enhanced cognitive impairment in diabetic rats, with PIO demonstrating superior efficacy in contrast to TZP.

Keywords: cognitive impairment; diabetes; inflammation; insulin; oxidative stress; pioglitazone; tirzepatide.

Figure 1

The design of the study and its results (schematic).

Figure 2

Effect of TZP and PIO on diabetic rats on the survival rate.

Figure 3

Impact of TZP and PIO on the body-weight in diabetic rats. The graphs illustrate the mean body weight for each group, tracked since the initial day through to the conclusion of the study. The findings indicated that there were no notable alterations in body weight throughout the study duration for the saline, TZP, or PIO groups, nor were there significant changes observed in the diabetic, T2DM+TZP, or T2DM+PIO cohorts. The data can be seen as the average divided by the standard error of the mean. (n=6).

Figure 4

Impact of TZP and PIO on diabetes-induced Y-maze regarding the frequency of entrances into the new arm (A), the total amount of time allocated in the new arm (B), and cumulative entries across all arms (C). Contrasted with the saline group, those in the T2DM group entered the new arm far less frequently (*p < 0.05) and for shorter periods of time (**p < 0.01), suggesting cognitive deficits. The administration of TZP and PIO led to improvements in cognitive deficits, with PIO demonstrating superior efficacy over TZP by significantly enhancing cognitive function. The data exist as the average ± standard error of the average. (n=6).

Figure 5

Impact of TZP and PIO on dementia caused by diabetes in rat models. The data is presented as SEM. Asterisks denote significant differences: * an apparent variance among the saline group and the one with diabetes (*p < 0.05, ***p < 0.001 vs saline group), and between the diabetic and PIO treated groups related to the group those with diabetes (*p < 0.05 in contrast to the diabetic group). (n=6).

Figure 6

Impact of TZP and PIO on glucose concentrations (A) and plasma insulin levels (B) in diabetic rats. The data point out the mean ± SEM of the amount of glucose recorded on days 1, 4, 7, 10, and 13, alongside the plasma insulin concentrations noticed in the saline group (**p < 0.01 against the diabetic groups). (n=6).

Figure 7

Impacts of TZP or PIO regarding expressed levels of TNF-α, IL-6, and IL-1β proteins in the brains of diabetic rats. (A–C) Rats with diabetic mellitus indicated a substantial increase in TNF-α, IL-6, and IL-1β levels, which were greatly dropped after delivered of PIO. The observed expressed volumes of (A) TNF-α, (B) IL-1β, and (C) IL-6 were identified to be higher than those in the saline group. Bars suggest the average ± the SEM (*p < 0.05, **p < 0.01, and ***p < 0.001). (n=6).

Figure 8

Impact of TZP or PIO on the concentrations of SOD, GPx, MDA, and lipid peroxidation in the cerebral tissue of diabetic rats. (A–D) T2DM rats exhibited markedly elevated levels of SOD, GPx, MDA, and lipid peroxidation, and this increase was significantly attenuated with PIO treatment but not with TZP. (A) SOD, (B) GPx, (C) MDA, and (D) lipid peroxidation were analyzed in comparison to the saline control. The bars point to the mean ± SEM (*p < 0.05 and **p < 0.01). (n=6).