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 (H(2)) has been proved to be a safe and effective anti-inflammatory agent, but conventional H(2) administration methods cannot provide a high dosage and a long duration of H(2) treatment in IR-related tissues and thus lead to limited therapeutic efficacies. We here propose a new strategy of controlled H(2) release to match the time window of gastric emptying for maximizing the bioavailability and therapeutic outcome of H(2). This work enhances the hydrolysis rate of Zn by constructing a Zn-Fe primary-battery micro-/nano-structure, and the H(2)-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 H(2) 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 H(2) 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 H(2)-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.