Zn-Fe primary battery-enabled controlled hydrogen release in stomach for improving insulin resistance in obesity-associated type 2 diabetes.

Chronic systemic inflammation in obesity-associated type 2 diabetes (T2D) is a key inducing factor of insulin resistance (IR). Hydrogen molecule (H2 ) has been proved to be a safe and effective anti-inflammatory agent, but conventional H2 administration methods cannot provide a high dosage and a long duration of H2 treatment in IR-related tissues and thus lead to limited therapeutic efficacies. We here propose a new strategy of controlled H2 release to match the time window of gastric emptying for maximizing the bioavailability and therapeutic outcome of H2 . This work enhances the hydrolysis rate of Zn by constructing a Zn-Fe primary-battery micro-/nano-structure, and the H2 -releasing rate is adjusted by tuning the ratio of Zn to Fe. The Zn-Fe micro-/nano-structure is orally administrated once daily to alleviate obesity-associated T2D in a leptin-deficient ( ob/ob ) mouse model. The H2 generation time of the Zn-Fe primary-battery micro-/nano-structure with the Fe/Zn ratio of 1:100 in gastric acid is about 3 h, just matching with the time window of gastric emptying in mice. In vivo monitoring results show that H2 generated by Zn-Fe micro-/nano-structure in stomach can effectively accumulate in major IR-sited tissues including liver, adipose tissue, and skeletal muscle at a high dose for a relatively long time compared to H2 -rich water drinking. Oral administration of Zn-Fe micro-/nano-structure at 200 mg/kg body weight has realized an efficient IR improvement and remarkably ameliorated systemic inflammation in ob/ob mice. In addition, a high-dose administration of Zn-Fe shows no visible toxicity in mice. This work provides a new strategy to maximize the outcome of hydrogen therapy.