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.