Introduction
The exponential growth in the incidence of Type 2 diabetes (T2D) is
largely due to sedentary lifestyles and changes in dietary preferences,
which adversely affects metabolism, immune system etc.(Daryabor,
Atashzar, Kabelitz, Meri, & Kalantar, 2020; Fahed, El-Hage-Sleiman,
Farhat, & Nemer, 2012; Leroith & Accili, 2008). The duo viz. obesity
and T2D are known for their unfavorable consequences on adipose tissue,
muscle, liver, and pancreatic islets which further results in altered
levels of chemokines and cytokines among others, leading to insulin
resistance syndrome (Nikolajczyk, Jagannathan-Bogdan, Shin, & Gyurko,
2011; Tsalamandris et al., 2019). Hence, inflammatory conditions such as
metabolic inflammation is linked to obesity and contributes downstream
to the pathogenesis of T2D and its clusters of characteristics
manifestations (Walker & Colledge, 2013).
Further, adiponectin (Adipoq), an antidiabetic adipokine (Karamian,
Moossavi, & Hemmati, 2021) has been well documented for its possible
therapeutic potentials (Choi, Doss, & Kim, 2020; Karamian et al., 2021;
J. Y. Kim, Barua, Jeong, & Lee, 2020). Recent understanding of
adiponectin receptors (AdipoR1 and AdipoR2) has paved the way forward in
understanding the development of insulin resistance and progressive
obesity linked diseases such as T2D (Whitehead, Richards, Hickman,
Macdonald, & Prins, 2006). Moreover, reduction in adiponectin hormone
secretion from adipose tissue is linked to insulin resistance in T2D as
reported in animal trials where adiponectin improved insulin resistance
(Okada-Iwabu et al., 2013). Interestingly, a recent orally active small
molecule AdipoR agonist (AdipoRON) has exhibited favorable anti-diabetic
features such as ability to bind AdipoR1/R2, activation of AMPK and
PPAR-α pathways, decreasing insulin resistance and glucose tolerance in
mice models in high fat diet (Okada-Iwabu et al., 2013).
Besides these, T2D also results in uncontrolled hepatic glucose
production, which leads to hyperglycemia as noted in diabetic
pathologies. Studies also revealed that activation of peroxisome
proliferator-activated receptors (PPARs) involves cascading effects on
various signaling pathways which results in suppressing hepatic glucose
production (Awazawa et al., 2011).Moreover, reports on animal and human
trials suggests that adiponectin can decrease hepatic gluconeogenesis
and stimulation of fatty acid oxidation in liver (Choi et al., 2020;
Howlader, Sultana, Akter, & Hossain, 2021). Furthermore, adiponectin
signaling in liver is linked to AdipoR2 which activates peroxisome
proliferator-activated alpha (PPARa) (Achari & Jain, 2017) suggesting
its therapeutic role in T2D. Additionally, the insulin sensitizing
properties of adiponectin is through increase in fatty-acid oxidation
via activation of AMPK (AMP-activated protein kinase) and regulation of
peroxisome proliferator-activated receptor (PPAR)-a (Tomas et al., 2002;
Yamauchi et al., 2002).
We previously reported the anti-inflammatory properties of AdipoAI (Qiu
et al., 2021; Wu et al., 2022). AdipoAI attenuated NF-κB (nuclear factor
kappa B), MAPK (mytogen activated protein kinase) and c-MAF (Qiu et al.,
2021) signaling pathways through activation of Adiponectin signaling
subunits AdipoR1 and APPL1 in Lipopolysaccharide (LPS)- induced
macrophages and decreased the production of cytokines. Furthermore,
AdipoAI was found to inhibit osteoclastogenesis at lower dose and
inhibited the expression of proinflammatory mediators in periodontal
tissues (Wu et al., 2022) indicating its potential candidature towards
activation of adiponectin receptor against development of T2D pathology.
In this investigation, we hypothesized that our chemically designed and
characterized AdipoAI small molecule have potent anti-diabetic
therapeutic potential similar to Adiponectin and thereby we evaluated
its in-vitro and in-vivo effects in comparison to a known
anti-diabetic small molecule agonist AdipoRON (Okada-Iwabu et al., 2013)
for further scientific affirmation.