الفهرس 
Introduction and Aim of the WorkOnly 14 pages are availabe for public view
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Abstract
Diabetes is a serious and long-term condition with a major effect on the lives of individuals, families and societies worldwide. The global diabetes prevalence in 2019 is estimated to be 463 million people, rising to 578 million by 2030 and 700 million by 2045. Diabetes prevalence in Egypt increases rapidly within a relatively short period from approximately 8.9 million in 2019 to 11.9 million in 2030. It is expected this number will jump up to 16.9 million by 2045.
Type 1 diabetes mellitus (T1DM) is caused by an autoimmune response against pancreatic β-cells. The autoimmune destruction of pancreatic -cells leads to the defective insulin secretion. Type 2 diabetes mellitus (T2DM) is a metabolic condition marked by insulin resistance and hyperglycemia that progresses over time. In T2DM, inadequate insulin levels fails to satisfy the increased demand brought on by insulin resistance.
Cell-based therapy is being explored as a potential treatment strategy for diabetes. Mesenchymal stem cells (MSCs) possess various properties, including differentiation into insulin producing cells (IPCs), promoting the regeneration of pancreatic islet beta cells, protection of endogenous pancreatic islet beta cells and amelioration of insulin resistance.
Therefore, the purpose of this study was to evaluate the ability of MSCs, either alone or in combination with pioglitazone or exendin-4 to ameliorate hyperglycemia in type 2 diabetes mellitus.
To achieve this goal, a total number of 56 male Sprague Dawley rats were randomly allocated into 7 equally-sized groups as follows:
group 1 (Control, C): Rats received a single intraperitoneal injection of 0.1 M citrate buffer (pH 4.5) (1 ml/kg bw).
group 2 (Diabetic, D): Rats were assigned to the high-fat diet for 3 consecutive weeks, fasted overnight and then injected with a single intraperitoneal dose of freshly prepared STZ (35 mg/kg bw).
group 3(D+MSC): Diabetic rats receiveda single ip injection of mesenchymal stem cells (1106 cells/ml) starting from the 7th day following STZ injection.
group 4 (D+Pz): Diabetic rats were orally injected with 10 mg/kg bw pioglitazone for 30 consecutive days starting from the 7th day following STZ injection.
group 5 (D+EX): Diabetic rats were injected ip with exendin-4 (1 nmol/kg bw/day) for one week starting from the 7th day following STZ injection.
group 6 (D+MSC+Pz): Diabetic rats were first injected ip with a single dose of mesenchymal stem cells (1.0106 cells/ml) starting from the 7th day following STZ injection, followed by oral administration of 10 mg/kg bw pioglitazone two hours latter for 30 consecutive days.
group 7 (D+MSC+EX): Diabetic rats were first injected ip with a single dose of mesenchymal stem cells (1.0106 cells /ml) starting from the 7th day following STZ injection, followed by an ip injection of 1 nmol/kg bw exendin-4 two hours latter for 7 consecutive.
At the end of the experiment, whole blood was withdrawn from animals for the analysis of serum glucose, insulin and TNF-α. Adipose tissue was excised for the analysis of oxidative stress biomarkers (MDA, TAC and NO). In addition, the expression of NF-B, PGC-1α, LC3, Beclin and caspase-3 mRNA was measured in adipose tissue using RT-PCR. A part of excised adipose tissue was used for estimation of JNKprotein expression. Histological examinations of pancreas were performed to confirm biochemical data.
The results obtained were statistically analyzed and can be summarized as follows:
Co-administration of either pioglitazone or exendin-4 along with MSCs injection in diabetic rats normalized serum glucose and insulin levels.
MSCs injection to diabetic rats in combination with pioglitazone or exendin-4 significantly reduced the oxidative stress in adipose tissues, as demonstrated by the significant decrease in NO and MDA levels, along with the significant enhancement of total antioxidant capacity (TAC), compared to untreated diabetic rats.
MSCs injection to diabetic rats in combination with pioglitazone or exendin-4 produced a significant down- regulation in the expression of caspase-3and NF-B genes in the adipose tissue, and by contrast the gene expression of the autophagy markers (PGC-1α, beclin and LC3) was significantly up regulated, compared to untreated diabetic rats.
A rebound to the normal level in the expression of JNK protein in the adipose tissue was noticed following injection of MSCs along with pioglitazone or exendin-4 treatment in T2DM rats.
The protective effects of the co-administration of pioglitazone or exendin-4 with mesenchymal stem cells (MSCs) were superior to that of MSCs alone and their effects were based on their ability to improve mitochondrial functions through targeting inflammatory and autophagy signaling.
Concomitant with the improvement of biochemical markers, the histological finding in the tissues of T2DM rats (pancreas) showed ameliorative effect of MSCs and pioglitazone or exendin-4 treatment.
According to the obtained results, it could be concluded that MSCs may be used as potential therapeutic agents for diabetes by reducing JNK production in order to decrease insulin resistance and increase glucose uptake via decreasing inflammatory mediators.