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Circulating cathepsin S improves glycaemic control in mice
Hamzeh Karimkhanloo1,2, Stacey N Keenan1, Emily W Sun3
1Department of Physiology, University of Melbourne, Melbourne, Australia.
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.
Insights
Cathepsin S (CTSS) improves glucose tolerance by directly impacting liver glucose production and stimulating GLP-1 secretion. However, these benefits are lost in insulin-resistant states like obesity and type 2 diabetes.
Area of Science:
- Biochemistry
- Metabolic research
- Endocrinology
Background:
- Cathepsin S (CTSS), a cysteine protease, is implicated in metabolic dysregulation, with elevated levels observed in obesity and type 2 diabetes.
- Previous research indicates CTSS deficiency improves glycemic control by reducing hepatic glucose production, but its circulating role in metabolism remains unclear.
Purpose of the Study:
- To investigate the effects of recombinant CTSS on glucose and energy metabolism.
- To elucidate the mechanisms by which CTSS influences glycemic control, including its impact on hepatocytes, myotubes, adipocytes, and incretin secretion.
Main Methods:
- Administration of recombinant CTSS to cultured cells (hepatocytes, myotubes, adipocytes) and lean mice.
- Assessment of glucose tolerance, plasma insulin levels, hepatic glucose output, and gene expression (G6pc, Pck1).
- Evaluation of CTSS effects on pancreatic beta-cell insulin secretion and intestinal GLP-1 secretion, including experiments with GLP-1 receptor antagonists and in insulin-resistant mouse models (high-fat-fed and db/db mice).
Main Results:
- CTSS administration improved glucose tolerance and increased plasma insulin in lean mice.
- CTSS reduced hepatic glucose output by suppressing G6pc and Pck1 mRNA expression in hepatocytes but had no effect on myotubes or adipocytes.
- CTSS stimulated GLP-1 secretion from intestinal tissues and maintained glycemic benefits even with GLP-1 receptor blockade; however, these effects were abrogated in insulin-resistant mice.
Conclusions:
- CTSS plays a role in regulating glycemic control through direct effects on hepatocytes and GLP-1 secretion.
- The beneficial effects of CTSS on glycemic control are lost in states of insulin resistance, highlighting a potential therapeutic limitation.
