Endocrine Abstracts

Diabetes remains a major public health burden worldwide. The causes of Diabetes have not been fully understood and there is to date no cure for Diabetes. Accumulating evidence, however, supports the notion that interplay between HC-gp39 and adipocytes could be fundamental in understanding the pathobiology of type 2 Diabetes and help to develop novel therapeutic strategies to arrest metabolic dysfunction. HC-gp39 is an inflammation-associated chitinase-like protein, found in vertebrates as well as invertebrates. HC-gp39 has been reported to implicated in almost all human pathological conditions. It is believed to play particularly critical role in both the genesis and the clinical outcome of diabetes, respectively. HC-gp39 working in concert with Toll-like receptor 4 and a set of adaptor proteins may impact on the activity of the DNA-binding components with concomitant perturbation of mitochondrial activity leading to impairment of age-related insulin production in human Islets. Additionally, HC-gp39 has been suggested to impact upon autophagy execution machinery. Autophagy is controlled by complex signaling pathways, including that used by insulin, whereby phosphatidyl-inositol 3 kinase (PI3K) plays important role. Hence, high serum levels of HC-gp39 resulting from disordered expression of HC-gp39 migh lead to the destruction of the beta-cells of the pancreas. Furthermore, Pannexin1 has been reported to contribute significantly to metabolic homeostasis through its role in controlled ATP-release from the adipocytes, suggesting that factors in a position to regulate Pannexin 1 channel activity may be of enormous importance for the management of type 2 diabetes. Src Kinase phpsphorylation of Pannexin1 was suggested to mediate NMDA-receptor activation of the channel. Now, high srum levels of HC-gp39 resulting in perturbation of the activation of Src Kinase(via disruption of the binding activity of 85 KDa regulatory subunit of PI3K) would negatively impact on the Src Kinase phosphorylation of Pannexin1 mediated NmDA-receptor activation of the channel resulting in preventing ATP release and eventually leading to disruption of insulin metabolism.

The above considerations, coupled with recently emerging notion that HC-gp39 may interact with tumor Suppressor Candidate 5 (TUSC5)-an important regulator of insulin action in adipocytes, make a case suggesting an exceptionally clinically relevant mechanism for HC-gp39 in this pathology and implies an important role for HC-gp39in controlling metabolic hormeostasis.