With the increasing prevalence of type 2 diabetes and fatty liver disease, there is still an unmet need to better treat hyperglycemia and hyperlipidemia. Here, we identify isthmin-1 (Ism1) as an adipokine and one that has a dual role in increasing adipose glucose uptake while suppressing hepatic lipid synthesis. Ism1 ablation results in impaired glucose tolerance, reduced adipose glucose uptake, and reduced insulin sensitivity, demonstrating an endogenous function for Ism1 in glucose regulation. Mechanistically, Ism1 activates a PI3K-AKT signaling pathway independently of the insulin and insulin-like growth factor receptors. Notably, while the glucoregulatory function is shared with insulin, Ism1 counteracts lipid accumulation in the liver by switching hepatocytes from a lipogenic to a protein synthesis state. Furthermore, therapeutic dosing of recombinant Ism1 improves diabetes in diet-induced obese mice and ameliorates hepatic steatosis in a diet-induced fatty liver mouse model. These findings uncover an unexpected, bioactive protein hormone that might have simultaneous therapeutic potential for diabetes and fatty liver disease.

随着 2 型糖尿病和脂肪肝疾病患病率的增加，对更好地治疗高血糖和高脂血症的需求仍未得到满足。在这里，我们将 isthmin-1 (Ism1) 确定为一种脂肪因子，它在增加脂肪葡萄糖摄取和抑制肝脏脂质合成方面具有双重作用。Ism1 消融导致葡萄糖耐量受损、脂肪葡萄糖摄取减少和胰岛素敏感性降低，表明 Ism1 在葡萄糖调节中具有内源性功能。从机制上讲，Ism1 独立于胰岛素和胰岛素样生长因子受体激活 PI3K-AKT 信号通路。值得注意的是，虽然葡萄糖调节功能与胰岛素共享，但 Ism1 通过将肝细胞从脂肪生成状态转变为蛋白质合成状态来抵消肝脏中的脂质积累。此外，重组Ism1的治疗剂量可改善饮食诱导的肥胖小鼠的糖尿病，并改善饮食诱导的脂肪肝小鼠模型中的肝脂肪变性。这些发现揭示了一种意想不到的生物活性蛋白激素，它可能同时具有治疗糖尿病和脂肪肝的潜力。