GP73 blockade alleviates abnormal glucose homeostasis in diabetic mice

Abstract

Golgi protein 73 (GP73) is a resident Golgi type II transmembrane protein and is considered as a serum marker for the detection of a variety of cancers. A recent work revealed the role of the secreted GP73 in stimulating liver glucose production and systemic glucose homeostasis. Since exaggerated hepatic glucose production plays a key role in the pathogenesis of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), GP73 may thus represent a potential therapeutic target for treating diabetic patients with pathologically elevated levels. Here in this study, we found that the circulating GP73 levels were significantly elevated in T2DM and positively correlated with hemoglobin A1C (HbA1c). Notably, the aberrantly up-regulated GP73 levels were indispensable for the enhanced PKA signaling pathway associated with diabetes. In diet-induced obese (DIO) mouse model, GP73 siRNA primarily targeting liver tissue was potently effective in alleviating abnormal glucose metabolism. Ablation of GP73 from whole animals also exerted a profound glucose-lowering effect. Importantly, neutralizing circulating GP73 improved glucose metabolism in STZ and HFD/STZ-induced diabetic mice. We thus concluded that GP73 was a feasible therapeutic target for the treatment of diabetes.

Unveiling the impact of GOLM1/GP73 on cytokine production in cancer and infectious disease

“…In mouse models of type 2 diabetes mellitus, it was shown that the glucose metabolism could be improved by neutralizing sGOLM1 with antibodies. 17 As explained in this review, neutralization of sGOLM1 and/or full-length GOLM1 by the same approach could also be a promising therapeutic strategy in cancer and infectious disease.…”

“…17 Circulating levels of sGOLM1 were increased in patients with type 2 diabetes mellitus, and this was found to stimulate liver glucose production and systemic glucose homeostasis. 17 Cleavage of GOLM1 is mediated by the endoprotease Furin, as it can be blocked by a Furin inhibitor. 18 The luminal coiled-coil domain of GOLM1 is essential for binding and interacting with the extracellular chaperone Clusterin, as found by a yeast two-hybrid screen and confirmed by co-immunoprecipitation.…”

“…33 Nevertheless, these mice might be more suspectable to disease, since both liver-specific and whole-animal ablation of GOLM1 alleviated abnormal glucose metabolism in diet-induced obese mice. 17 In addition, another study found that the complete GOLM1 knockout mice are more susceptible to septic death induced by the bacterial immune stimulus lipopolysaccharide (LPS), 33 suggesting that GOLM1 plays a role in infectious disease.…”

“…GOLM1 can be cleaved at R55, located within the luminal coiled‐coil domain (approximately residues 40–200), generating a soluble form of GOLM1, called sGOLM1, which is present in the sera of patients with liver and prostate cancer 9,10 . Recently, it was shown that GOLM1 also plays a role in type 2 diabetes mellitus (T2DM) 17 . Circulating levels of sGOLM1 were increased in patients with type 2 diabetes mellitus, and this was found to stimulate liver glucose production and systemic glucose homeostasis 17 .…”

“…Recently, it was shown that GOLM1 also plays a role in type 2 diabetes mellitus (T2DM) 17 . Circulating levels of sGOLM1 were increased in patients with type 2 diabetes mellitus, and this was found to stimulate liver glucose production and systemic glucose homeostasis 17 . Cleavage of GOLM1 is mediated by the endoprotease Furin, as it can be blocked by a Furin inhibitor 18 …”