Research ArticleMetabolism

SMOC1 is a glucose-responsive hepatokine and therapeutic target for glycemic control

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Science Translational Medicine  02 Sep 2020:
Vol. 12, Issue 559, eaaz8048
DOI: 10.1126/scitranslmed.aaz8048

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Liver-led glycemic control

Hepatokines are liver-secreted proteins that regulate whole-body metabolism. Montgomery et al. identified sparc-related modular calcium-binding protein 1 (SMOC1) as a glucose-responsive hepatokine involved in the regulation of glucose homeostasis in mice. Both fasted lean mice and db/db mice injected with recombinant SMOC1 showed improved glycemic control, and a stabilized version of the SMOC1 protein injected into the diabetic mice once a week for 4 weeks also resulted in improved insulin sensitivity and glucose tolerance. Future work will need to confirm whether SMOC1 has potential as a therapeutic target in type 2 diabetes in humans.

Abstract

Intertissue communication is a fundamental feature of metabolic regulation, and the liver is central to this process. We have identified sparc-related modular calcium-binding protein 1 (SMOC1) as a glucose-responsive hepatokine and regulator of glucose homeostasis. Acute intraperitoneal administration of SMOC1 improved glycemic control and insulin sensitivity in mice without changes in insulin secretion. SMOC1 exerted its favorable glycemic effects by inhibiting adenosine 3′,5′-cyclic monophosphate (cAMP)–cAMP-dependent protein kinase (PKA)–cAMP response element–binding protein (CREB) signaling in the liver, leading to decreased gluconeogenic gene expression and suppression of hepatic glucose output. Overexpression of SMOC1 in the liver or once-weekly intraperitoneal injections of a stabilized SMOC1-FC fusion protein induced durable improvements in glucose tolerance and insulin sensitivity in db/db mice, without adverse effects on adiposity, liver histopathology, or inflammation. Furthermore, circulating SMOC1 correlated with hepatic and systemic insulin sensitivity and was decreased in obese, insulin-resistant humans. Together, these findings identify SMOC1 as a potential pharmacological target for the management of glycemic control in type 2 diabetes.

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