Treatment of insulin resistance: straight from the gut

•The gastrointestinal (GI) system is involved in host regulation of insulin responses.•Targeting GI mechanisms is a promising route for reversing insulin resistance (IR).•Gut-targeted therapies can complement current therapeutics for IR.•Gut-restricted drugs for IR can have better safety profiles.

Insulin resistance (IR) is a key pathological hallmark of obesity and type 2 diabetes. Emerging evidence has uncovered the gastrointestinal (GI) system as a previously overlooked player in fine-tuning systemic glucose homeostasis and insulin responses, which involved a complex inter-organ crosstalk through metabolic, endocrine, immune and neural mechanisms. These facts raise the intriguing possibility to explore the GI system as a new territory for IR intervention and glycemic control. Here we provide an overview of recent findings illustrating GI signals in the control of systemic insulin sensitivity and glucose homeostasis, and discuss the therapeutic prospects of exploiting the GI mechanisms to reverse IR and treat metabolic diseases.