Glyoxalase 1 inducer therapeutics for diabetes and diabetic vascular complications


The abnormal accumulation of methylglyoxal (MG) leading to increased glycation of protein and DNA has emerged as an important metabolic stress, dicarbonyl stress, linked to aging and disease. Increased MG glycation produces inactivation and misfolding of proteins, cell dysfunction, activation of the unfolded protein response and related low grade inflammation. Glyoxalase 1 (Glo1) of the glyoxalase system has a major role in the metabolism of MG. Small molecule inducers of Glo1, Glo1 inducers, have been developed to alleviate dicarbonyl stress as a prospective treatment for the prevention and early-stage reversal of type 2 diabetes and prevention of vascular complications of diabetes. The first clinical trial with the Glo1 inducer, trans-resveratrol and hesperetin combination (tRES-HESP) – a randomized, double-blind, placebo-controlled crossover phase 2A study for correction of insulin resistance in overweight and obese subjects, was completed successfully. tRES-HESP corrected insulin resistance, improved dysglycemia and low grade inflammation. These findings suggest tRES-HESP counters MG accumulation and protein glycation, decreasing activation of the unfolded protein response and expression of TXNIP and TNFα, producing reversal of insulin resistance. tRES-HESP is suitable for treatment of insulin resistance and related disorders.

Summary scheme

A diagram of a glycoprotein

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Principal publications

Xue, M., Weickert, M.O., Qureshi, S., Kandala, N.-B., Anwar, A., Waldron, M., Shafie, A., Messenger, D., Fowler, M., Jenkins, G., Rabbani, N. and Thornalley, P.J. (2016) Improved glycemic control and vascular function in overweight and obese subjects by glyoxalase 1 inducer formulation. Diabetes 65, 2282 – 2294.

Rabbani, N., Xue, M., Weickert, M.O. and Thornalley, P.J. (2021) Reversal of insulin resistance in overweight and obese subjects by trans-resveratrol and hesperetin combination – link to dysglycemia, blood pressure, dyslipidemia and low-grade inflammation.  Nutrients 13, 237.

Rabbani, N. and Thornalley, P.J. (2022) Emerging glycation-based therapeutics – glyoxalase 1 inducers and glyoxalase 1 inhibitors. Internat J. Molec. Sci. 23, 2453.

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