Circulating cathepsin S improves glycaemic control in mice. Issue 2 (February 2021)

• Record Type: Journal Article
• Authors: Karimkhanloo, Hamzeh; Keenan, Stacey N; Sun, Emily W; Wattchow, David A; Keating, Damien J; Montgomery, Magdalene K; Watt, Matthew J
• Is Part Of: Journal of endocrinology. Volume 248:Issue 2(2021)
• Page Start: 167
• Page End: 179
• Publication Date: 2021-02
• Subjects: CTSS -- glucose metabolism -- liver -- insulin sensitivity -- lipid metabolism; Endocrinology -- Periodicals; 616.4005
• DOI: 10.1530/JOE-20-0408
• Languages: English
• ISSNs: 0022-0795

Abstract

Abstract : Cathepsin S (CTSS) is a cysteine protease that regulates many physiological processes and is increased in obesity and type 2 diabetes. While previous studies show that deletion of CTSS improves glycaemic control through suppression of hepatic glucose output, little is known about the role of circulating CTSS in regulating glucose and energy metabolism. We assessed the effects of recombinant CTSS on metabolism in cultured hepatocytes, myotubes and adipocytes, and in mice following acute CTSS administration. CTSS improved glucose tolerance in lean mice and this coincided with increased plasma insulin. CTSS reduced G6pc and Pck1 mRNA expression and glucose output from hepatocytes but did not affect glucose metabolism in myotubes or adipocytes. CTSS did not affect insulin secretion from pancreatic β-cells, rather CTSS stimulated glucagon-like peptide (GLP)-1 secretion from intestinal mucosal tissues. CTSS retained its positive effects on glycaemic control in mice injected with the GLP1 receptor antagonist Exendin (9–39) amide. The effects of CTSS on glycaemic control were not retained in high-fat-fed mice or db/db mice, despite the preservation of CTSS' inhibitory actions on hepatic glucose output in isolated primary hepatocytes. In conclusion, we unveil a role for CTSS in the regulation of glycaemic control via direct effects on hepatocytes, and that these effects on glycaemic control are abrogated in insulin resistant states.