British journal of pharmacology · 2024
Combination therapy enhances efficacy and overcomes toxicity of metal-based anti-diabetic agent.
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Shang Bing, Dong Yaqiong, Feng Bo, Zhao Jingyan, Wang Zhi, Crans Debbie C, Yang Xiaoda
Аннотация
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.
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.