Recently, research has underlined the pivotal role of adiponectin (ApN) in modulating insulin sensitivity, chronic inflammation, and pancreatic cancer (PDAC). ApN functions to regulate multiple signaling pathways such as AMPK (AMP-activated protein kinase) and peroxisome proliferator-activated receptor alpha (PPARα) with implications in glucose regulation, fatty acid oxidation, oxidative stress, and inflammation. Circulating levels of ApN are associated with tumor progression by affecting apoptosis and inhibiting β-catenin signaling (Begum et al., 2023). Despite increasing interest in ApN's therapeutic potential, a comprehensive understanding of its mechanistic roles in diabetes and PDAC is still required, along with its significance as a biomarker of the therapeutic target. Chronic inflammation in PDAC damages pancreatic β cells and islets of Langerhans, causing impaired insulin secretion and the onset of diabetes linked to PDAC (Abbruzzese et al., 2018). This bidirectional association is mediated by disruption of adipokine balance, especially low ApN levels, insulin resistance, oxidative stress, immune dysregulation, and altered signaling pathways such as PI3K/AKT and β-catenin. A small group of studies suggests higher levels of ApN in PDAC, contrary to a larger group of studies suggesting that low levels of ApN increase the aggressiveness of PDAC due to impaired apoptosis and unchecked β-catenin signaling (Booth et al., 2015). The variation in results may be due to context-specific effects. The EPIC (European Prospective Investigation into Cancer and Nutrition) and ATBC (Alpha-Tocopherol, Beta-Carotene Cancer Prevention) also supported the idea that a high level of ApN decreases the risk of PDAC (Gonzalez and Riboli, 2010). The review's objectives are to explore how ApN influences insulin signaling pathways and the relationship between ApN levels and chronic inflammation or oxidative stress in PDAC and diabetics, as ApN influences metabolic homeostasis. Also, to evaluate whether modulating ApN activity could be an effective therapeutic strategy for managing diabetes and PDAC.

Adiponectin is an innovative adipose tissue-specific collagen-like 30 kDa plasma protein extensively expressed in human adipose tissue. Encoded by gene Adipo Q it spans 17 kb on chromosome site 3q27 (Achari and Jain, 2017). It is an anti-diabetic adipokine with AdipoR1 and AdipoR2 receptors. The receptors belong to a superfamily of rhodopsin-like receptors and pumps which are members of the progesterone adipoQ receptor (PAQR) family (Ma et al., 2023). AdipoR1 is majorly expressed by skeleton muscle and AdipoR2 is expressed hepatocytes (Lee et al., 2008). The levels of ApN decrease in type II diabetes (insulin-resistant diabetes) to compensate for the pancreas producing more insulin but still, the glucose level is elevated causing a chronic increase in blood glucose levels as the body cannot use insulin efficiently. In contrast, the level of ApN increases in type I diabetes, which is an autoimmune condition where β cells of the pancreas are damaged by autoantibodies; the body, as a part of a defense mechanism, synthesizes more ApN to compensate for the levels of insulin (Galicia-Garcia et al., 2020). When ApN binds to the receptors, it activates two important signal pathways, AMPK and PPARα, signals that ameliorate glucose levels by increasing glucose uptake, reducing blood glucose, and enhancing the oxidation of fatty acids. It also controls inflammation, improves insulin sensitivity, and regulates oxidative stress, exhibiting antiatherogenic, proapoptotic, and antiproliferative properties (Begum et al., 2023). AdipoR1 and AdipoR2's crystal structures were determined at 2.9 Å and 2.4 Å resolution, respectively. The structure has a separate cytoplasmic and extracellular region and seven transmembrane helices arranged in a clockwise helical bundle as shown in Fig. 1 (Tanabe et al., 2015). Dissimilar to GPCRs, AdipoR1 and AdipoR2 hold a unique C-terminus-out, N-terminus-in topology, and their transmembrane helices lack the proline-induced twists, which is a characteristic of GPCRs (Tanabe et al., 2015). The zinc ion is bound within the transmembrane domain, a distinct feature from other known membrane proteins. The zinc ion coordinates in AdipoR1 and AdipoR2 are His191, His337, and His 341; His202, His348, and His352, respectively, and one aspartate residue (D219 in AdipoR2), forming a tetrahedral geometry (Fig. 1) (Tanabe et al., 2015; Namuswe and Berg, 2012). The mutational study showed that disrupting zinc coordination in AdipoR1 minimally affected ApN-stimulated AMPK phosphorylation, indicating its structural-stabilizing role compared to its functional role. However, in AdipoR2, zinc binding is critical for ApN-stimulated UCP2 upregulation, linking a more direct functional role in this signaling pathway (Tanabe et al., 2015). These results indicate that zinc coordination stabilizes the structural integrity of helices I, II, III, and VII, and may contribute to a hydrolytic mechanism where a water molecule coordinated with zinc facilitates substrate processing, potentially generating free fatty acids that activate PPARα to enhance target gene expression, including UCP2 (Kadowaki and Yamauchi, 2011). While AdipoRs show no structural homology with intramembrane metalloproteases, their zinc-binding motif shares similarities with certain globular zinc enzymes, hinting at possible hydrolytic activity akin to ceramidases proved experimentally (Tanabe et al., 2015; Kadowaki and Yamauchi, 2011). The large internal cavity formed from transmembrane helices of AdipoR1 and AdipoR2 is linked to substrate or product interactions in the hydrolytic functions of these receptors. ApN binds on the extracellular domain of receptors AdipoR1 and AdipoR2 (Yadav et al., 2013). Therefore, adiponectin contributes significantly to energy metabolism and controls a disease associated with metabolism. The AdipoRs are unique, with zinc ions maintaining structural stability, which may help in the hydrolytic processes important for controlling downstream signal pathways.

ApN, as a pleiotropic protein, controls pathological conditions like type II diabetes, obesity-related disease, hypercholesterolemia, hyperlipoproteinemia, lipid disorders, cardiovascular disease, metabolic syndrome, an immune system like CVID and cancers of the colon, breast, endometrial, oesophagus, leukaemia, and multiple myeloma, thyroid, pancreatic and high-grade prostate cancer (Lei et al., 2023) (Jorgensen et al., 2023). A non-canonical receptor for ApN is T-cadherin, a protein located on the surface of endothelial cells and smooth muscle, where it plays a crucial role in cell adhesion and calcium-dependent cell-to-cell communication and signaling (Parker-Duffen et al., 2013). It is also present in tumor-associated endothelial cells, suggesting that ApN could directly affect blood vessel function within tumors for angiogenesis (Yao and Zeng, 2023). Unlike AdipoR1 and AdipoR2, T-cadherin lacks an intracellular domain for transmitting signals into the cell, making it a coreceptor. It may bind high-molecular-weight (HMW) and hexameric forms of ApN, potentially competing with or modulating the signaling of AdipoR1 and AdipoR2 (Rubina et al., 2021).