Chronic β-carotene, magnesium, and zinc supplementation together with metformin attenuates diabetes-related complications in aged rats

Aged type 2 diabetes mellitus (T2DM) patients are linked with lower serum levels of total antioxidant activity, magnesium and zinc, particularly under uncontrolled hyperglycemia. Uncontrolled oxidative stress is an established contributor to diabetic complications. Magnesium is a cofactor for ∼600 enzymes, while zinc is a part of ∼3000 human proteins, essential for intermediary metabolism. A multi-targeted approach combining β-carotene, Magnesium and Zinc (BMZ) with metformin or vitamin E, Magnesium and Zinc (EMZ) with metformin for daily use in aged rats with T2DM identified astonishing findings compared to metformin monotherapy. Over three months, compared to metformin monotherapy, BMZ with metformin provided excellent glycemic control, outstanding protection against potential neuropathy and sensorimotor coordination, maintained robust retinal integrity and provided significant control for diabetic nephropathy. Mechanistically, the significant improvement in BMZ with metformin in controlling retinopathy, nephropathy, and neuropathy are directly linked to (1) Increased glycemic control (antihyperglycemic effect), (2) increased insulin sensitivity as evidenced by reduced HOMA-IR levels, (3) reduced oxidative stress (4) increased antioxidant activity through increased glutathione levels and increased GSH/GSSG ratio, and (5) improved regulation of carbohydrate and lipid metabolism as evidenced by metabolomic data. This study provides robust and direct evidence to support the use of affordable, proven antioxidant and mineral combinations with metformin to reduce diabetes-related complications in aging.