الفهرس 
Aim of the WorkOnly 14 pages are availabe for public view
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Abstract
Diabetes mellitus (DM) is one of the most prevalent medical conditions, affecting over 415 million people worldwide with estimated increase in
prevalence by 2040 to 642 million adults. Traditional risk factors for the
development of tpye 2 diabetes mellitus (T2DM), represented by obesity,
age, physical inactivity and genetics (Trinh et al., 2021). Type 2 diabetes
mellitus, an eterogeneous metabolic disorder, has characteristics of
insulin resistance or insufficient secretion (Xinyun et al., 2020).
Diabetic kidney disease (DKD) is a worldwide danger because it
causes end stage renal disease (ESRD) and affects mortality in diabetic
patients. So, slowing down its onset and progression is an urgent issue,
and the development of therapeutic approaches against DKD is required.
Furthermore, DKD is an established risk factor for cardiovascular disease
(CVD) (Yasuda-Yamahara et al., 2021).
Understanding the mechanisms of diabetic complications
constitutes the cornerstone of the evaluation of drug regimens used for the
treatment of T2DM (Jingyi et al., 2021). Until now, there is no definite
theory on its pathological mechanism. Inflammation is thought to be the
most likely pathogenesis of diabetes. This theory holds that inflammatory
factors can inhibit glucose transporters on cell membranes and therefore
causes hyperinsulinemia, excessive inflammatory factors could directly
inhibit insulin signal transduction and cause insulin resistance. The
inflammatory cytokines involved are tumour necrosis factor α (TNF-α),
interleukin 6 ,8 (IL-6, 8), C-reactive protein (CRP), adiponectin, type-I
interferons (IFN) and transforming growth factor- β-1 (TGF-β1),
Introduction
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improvement of these inflammatory cytokines are an important strategy
for treatment of T2DM (Xu et al., 2017; Chen et al., 2020).
On the other hand, Hyperglycemia, the hallmark of DM, is
accompanied by significant changes in glucose and lipid metabolism as
well as the induction of oxidative stress (Othman et al., 2020), which is
involved to a great extent in the development of DM complications as it
promote the activation of NF-κB, which leads to inflammatory cytokines
such as TNF-α and IL-6 (Khan et al., 2017), apoptosis is another theory
(Kim et al., 2021). Treatments with better control of blood glucose, more
reduction of oxidative stress and modulation of pro-inflammatory
cytokines are beneficial for controlling diabetic complications.
To date, kidney dialysis and renal transplantation are the only final
options for the management of end-stage kidney disease that leads to a
significant burden on the health organizations. Hence new strategies are
needed for prevention and treatment of CKD.
Metformin is the most widely accepted first-line treatment to lower
blood glucose levels in patients who have type 2 diabetes mellitus. In
addition to its role in lowing blood glucose levels, recent reports
suggested it has anti-oncogenic (Leone et al., 2020), cardio-protective
and anti-inflammatory effects. Metformin can attenuate cyclosporine A-
induced renal fibrosis in rats (Lin et al., 2019), modulate immune cell
infiltration into the kidney during unilateral ureteral obstruction in mice
(Christensen et al., 2019), significantly ameliorates diabetic nephropathy
in a rat model of low-dose streptozotocin-induced diabetes (Zhang et al.,
2017), which suggest an antifibrotic effect. However, Metformin use is
currently limited to patients with Type 2 diabetes mellitus and normal
Introduction
16
renal function or stage 1–3 CKD, as its administration is not
recommended in patients with advanced renal impairment because it may
increase the risk of lactic acidosis. However, the potential efficacy of
metformin on reducing the cardiovascular disease (CVD) risk in T2D
patients with moderate chronic kidney disease (CKD) has also been
suggested (Hao Yi et al.,2021).
Thus, the world is waiting for anti-diabetic agents that can
attenuate both DKD and CVD. Like glucagon-like 1 receptor agonists
(GLP-1RAs) which have favorable effects on the cardiorenal outcomes in
(T2D) (Giugliano et al., 2019; Kristensen et al., 2019).
GLP-1RAs improve glucose metabolism by stimulating glucose-
dependent insulin secretion and inhibiting the release of glucagon. They
have also beneficial effects on cardiovascular risk factors by improving
obesity, hypertension, and the lipid profile. Recent CV outcome trials
utilizing GLP-1RAs have also investigated renal outcomes (Drucker,
2018). In addition, the elucidation of basic mechanisms underlying the
renoprotective effect of GLP-1RAs is progressing. In this work, we hope
to understand more the renoprotective effects of GLP-1RAs from clinical
and mechanistic standpoints.