Combination therapy enhances efficacy and overcomes toxicity of metal‐based anti‐diabetic agent

Background and Purpose Metal‐based therapeutic agents are limited by the required concentration of metal‐based agents. Hereby, we determined if combination with 17β‐oestradiol (E2) could reduce such levels and the therapy still be effective in type 2 diabetes mellitus (T2DM). Experimental Approach The metal‐based agent (vanadyl acetylacetonate [VAC])– 17β‐oestradiol (E2) combination is administered using the membrane‐permeable graphene quantum dots (GQD), the vehicle, to form the active GQD–E2–VAC complexes, which was characterized by fluorescence spectra, infrared spectra and X‐ray photoelectron spectroscopy. In db/db type 2 diabetic mice, the anti‐diabetic effects of GQD–E2–VAC complexes were evaluated using blood glucose levels, oral glucose tolerance test (OGTT), serum insulin levels, homeostasis model assessment (homeostasis model assessment of insulin resistance [HOMA‐IR] and homeostasis model assessment of β‐cell function [HOMA‐β]), histochemical assays and western blot. Key Results In diabetic mice, GQD–E2–VAC complex had comprehensive anti‐diabetic effects, including control of hyperglycaemia, improved insulin sensitivity, correction of hyperinsulinaemia and prevention of β‐cell loss. Co‐regulation of thioredoxin interacting protein (TXNIP) activation by the combination of metal complex and 17β‐oestradiol contributed to the enhanced anti‐diabetic effects. Furthermore, a potent mitochondrial protective antioxidant, coniferaldehyde, significantly potentiates the protective effects of GQD–E2–VAC complexes. Conclusion and Implications A metal complex–E2 combinatorial approach achieved simultaneously the protection of β cells and insulin enhancement at an unprecedented low dose, similar to the daily intake of dietary metals in vitamin supplements. This study demonstrates the positive effects of combination and multi‐modal therapies towards type 2 diabetes treatment.