Linagliptin Ameliorates Hepatic Steatosis via Non-Canonical Mechanisms in Mice Treated with a Dual Inhibitor of Insulin Receptor and IGF-1 Receptor

Abstract

Abnormal hepatic insulin signaling is a cause or consequence of hepatic steatosis. DPP-4 inhibitors might be protective against fatty liver. We previously reported that the systemic inhibition of insulin receptor (IR) and IGF-1 receptor (IGF1R) by the administration of OSI-906 (linsitinib), a dual IR/IGF1R inhibitor, induced glucose intolerance, hepatic steatosis, and lipoatrophy in mice. In the present study, we investigated the effects of a DPP-4 inhibitor, linagliptin, on hepatic steatosis in OSI-906-treated mice. Unlike high-fat diet-induced hepatic steatosis, OSI-906-induced hepatic steatosis is not characterized by elevations in inflammatory responses or oxidative stress levels. Linagliptin improved OSI-906-induced hepatic steatosis via an insulin-signaling-independent pathway, without altering glucose levels, free fatty acid levels, gluconeogenic gene expressions in the liver, or visceral fat atrophy. Hepatic quantitative proteomic and phosphoproteomic analyses revealed that perilipin-2 (PLIN2), major urinary protein 20 (MUP20), cytochrome P450 2b10 (CYP2B10), and nicotinamide N-methyltransferase (NNMT) are possibly involved in the process of the amelioration of hepatic steatosis by linagliptin. Thus, linagliptin improved hepatic steatosis induced by IR and IGF1R inhibition via a previously unknown mechanism that did not involve gluconeogenesis, lipogenesis, or inflammation, suggesting the non-canonical actions of DPP-4 inhibitors in the treatment of hepatic steatosis under insulin-resistant conditions.

The Roles of the IGF Axis in the Regulation of the Metabolism: Interaction and Difference between Insulin Receptor Signaling and IGF-I Receptor Signaling

“…The liver weight, as well as both liver triglyceride and liver glycogen contents, were significantly increased by the administration of OSI-906. On the other hand, the gene expressions involved in lipogenesis, such as Srebp1c, Fas, and Scd1, were not altered by treatment with OSI-906 in the liver [14,16]. Notably, leptin supplementation on OSI-906-treated mice reduced hepatic triglyceride accumulation and improved steatosis without improving lipodystrophy.…”

“…To understand the roles of IGF-I/IGF-IR signaling in the regulation of metabolism and to distinguish the action of IGF-I/IGF-IR signaling from that of insulin/IR signaling, several reports have taken advantage of the Cre recombinase/loxP system to manipulate IGF-I and IGF-IR in a tissue-specific fashion (Table 1). In addition, we previously reported the role of IGF-IR and IR signaling in multiple metabolic organs, including the liver, adipose tissue, and pancreas, by using an orally bioavailable dual IGF-IR/IR inhibitor OSI-906 [13][14][15][16].…”

Insulin‐Like Growth Factor 1 Receptor Deficiency Alleviates Angiotensin II–Induced Cardiac Fibrosis Through the Protein Kinase B/Extracellular Signal‐Regulated Kinase/Nuclear Factor‐κB Pathway

“…OSI‐906 (linsitinib) is a potent selective inhibitor of the insulin receptor and IGF1R. 34 , 35 To investigate the role of IGF1R in cardiac fibrosis, we used 8‐week‐old male C57BL/6J mice subjected to the subcutaneous injection of Ang II (2 mg/kg per day) with or without vehicle PBS and with OSI‐906‐treatment (50 mg/kg per day) for 2 weeks. Mice (n=30) were randomly divided into 3 groups: (1) vehicle mice (PBS control); (2) Ang II mice (cardiac fibrosis mouse model); and (3) Ang II mice with OSI‐906 treatment.…”

Association of metabolic-dysfunction associated steatotic liver disease with polycystic ovary syndrome

“… 142 Furthermore, linagliptin has been demonstrated to lower the expression of SREBP1c and FAS, both associated with de novo lipogenesis, and increase the expression of PPARα, leading to an improvement in hepatic steatosis in mouse experiments. 143 In addition, in mouse PCOS models induced by letrozole, linagliptin treatment improved dyslipidemia and decreased inflammatory markers and free testosterone levels, in part by inhibiting the NF-κB pathway. 144 Therefore, DPP-4 inhibitors may alleviate symptoms associated with glucose and lipid metabolism and prevent the progression of MASLD.…”