An Australian study led by University of Melbourne scientists has identified a previously unknown role for the hepatokine, sparc-related modular calcium-binding protein 1 (SMOC1), in suppressing hepatic glucose production.

The study also demonstrated that intervention with the stabilized SMOC1-FC (fragment crystallizable) fusion protein had durable effects on glycemic control and insulin action in mouse models of type 2 diabetes mellitus (T2DM). The investigators reported their results in the Sept. 2, 2020, edition of Science Translational Medicine.

“This is the first identification of SMOC1 as a potential new target for the therapeutic control of glycemia,” said study leader Matthew Watt, professor and head of the department of physiology at The University of Melbourne, noting the need for new anti-glycemic agents.

“There are several medications [such as metformin] that can be used alone, or increasingly, in combination, which help to maintain blood glucose levels in patients,” Watt told BioWorld. “However, all T2DM medications, without exception, have either limited effectiveness or have off-target effects that adversely affect the patient’s health, hence the need to develop new approaches.”

One such approach involves hepatokines, which are proteins regulating liver and systemic metabolism via signaling to induce changes in lipid metabolism, β-cell function, peripheral insulin action and glycemic control.

Hepatokine secretion changes occur in obesity and other conditions characterized by insulin resistance, such as nonalcoholic fatty liver disease (NAFLD), suggesting roles for hepatokines in normal physiology and in affecting metabolic dysregulation.

For example, “FGF-21 [fibroblast growth factor-21] is a well-known hepatokine, a thorough understanding of the biology of which has led to the development of FGF-21-targeted therapies [including FGF-21 analogues and receptor agonists] for obesity and NAFLD,” said Watt.

In order to understand the role of specific hepatokines in regulating metabolism, the roles of several such proteins and other secreted hepatokines of unknown metabolic function have been investigated, including SMOC1.

A member of the BM-40 family of extracellular proteins, SMOC1 is generally localized to the cell basement membrane, where it interacts with other metabolites to play a role in integrin-matrix interactions and cell adhesion.

However, while the role of SMOC1 in matrix remodeling has been well described, its function as a circulating protein remains unknown.

In their study, Watt and his team investigated the role of SMOC1 in regulating glycemic control and insulin in mice and in mouse primary hepatocytes, using acute intraperitoneal (IP) administration of recombinant SMOC1 or liver-specific gene editing with metabolic phenotyping.

They also examined the role of the SMOC1-FC fusion protein as a potential therapeutic agent for T2DM.

That identified SMOC1 as being a glucose-responsive hepatokine and regulator of glucose homeostasis, with acute IP SMOC1 injection improving glycemic control and insulin sensitivity in mice.

“SMOC1 administration improved glycemic control, as demonstrated by faster clearance of orally administered glucose from the bloodstream, while we assessed insulin sensitivity using a complex technique called euglycemic-hyperinsulinemic clamping,” Watt explained.

Moreover, those improvements were not accompanied by changes in insulin secretion, which is important as “this information provides us with information about how SMOC1 works,” noted Watt.

“By knowing that SMOC1 works by reducing hepatic glucose production, we can consider ways in which we might combine SMOC1 with other therapies for even greater benefit: for example, SMOC1 should work well with a sulfonylurea, that promotes insulin secretion.”

SMOC1 was shown to exert favorable glycemic effects by inhibiting adenosine 3′, 5′-cyclic monophosphate (cAMP)-dependent protein kinase-cAMP response element-binding (CREB) protein signaling in the liver, leading to decreased gluconeogenic gene expression and suppression of hepatic glucose output.

SMOC1-FC was found to induce rapid signaling in hepatocytes, which results in reduced activation of the CREB transcription factor, which then reduces the levels of proteins important for gluconeogenesis, resulting in reduced hepatic glucose production and release,” Watt said.

Overexpression of SMOC1 in liver or once-weekly IP administration stabilized SMOC1-FC fusion protein injections induced durable improvements in glucose tolerance and insulin sensitivity in diabetic mice.

Importantly, no adverse effects on adiposity, liver histopathology, or inflammation were observed in these widely used mouse models of obesity, T2DM and dyslipidemia.

“The [beneficial glycemic] effects of once weekly SMOC1-FC treatment in diabetic mouse models was greater than frontline metformin treatment, while our findings indicate that SMOC1 adeno-associated virus (AAV)-mediated overexpression works through the same pathways as SMOC1-FC,” said Watt.

Moreover, circulating SMOC1 levels were closely correlated with hepatic and systemic insulin sensitivity and were decreased in “28 obese individuals with insulin resistance, indicating a potential involvement in disease development,” he noted.

Together, those findings identify SMOC1 as a potential pharmacological target for the management of glycemic control in T2DM patients.

In that regard, “we envisage that SMOC1-FC would be a good option for individuals with early and late-stage T2DM, as it improves blood glucose control and does not cause hypoglycemia, which is a major problem of other current diabetes medications, while once-weekly injections would certainly appeal to many patients,” said Watt.

“We are now seeking to elucidate the SMOC1 receptor, which should provide important insights into how SMOC1 induces its effects on glucose control and potentially reveal new ways to treat T2DM.”

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