Improved Metabolic and Vascular Health in Obese Patients Treated with Trans-Resveratrol and Hesperetin

A small new study suggests that a combination of compounds found in grapes and oranges could help treat diabetes and protect against cardiovascular disease in obese patients.

Previous efforts to use either trans-resveratrol (tRES) from grapes or hesperetin (HESP) from oranges had not succeeded in reducing blood glucose levels or insulin sensitivity in obese subjects, but investigators hypothesized that an optimized combination of the 2 compounds might increase expression of glyoxalase 1 (Glo1) enough to do both.

They tested their formulation on 29 overweight and obese subjects in a randomized, placebo-controlled crossover trial and found that — in highly overweight subjects (body mass index >27.5 kg/m²) — the tRES-HESP combination increased expression and activity of Glo1 (+ 27%; P < 0.05), decreased plasma methylglyoxal (-37%; P < 0.05) and decreased total body methylglyoxal-protein glycation (-14%; P < 0.01).

The combination also decreased fasting plasma glucose by 5% (P < 0.01) and postprandial plasma glucose by 6% (P < 0.03), increased scores on the Oral Glucose Insulin Sensitivity Index by 42 ml min^-1 m^-2 (P < 0.02) and improved arterial dilatation Δ flow mediated dilation/Δ glyceryl trinitrate-induced dilation (95% confidence interval, 0.13—2.11). In all subjects, it decreased the vascular inflammation marker sICAM-1 by 10% (P < 0.01).

Such results, the study authors wrote in Diabetes, suggest that the tRES-HESP combination may be a suitable treatment for improved metabolic and vascular health in a broad swath of overweight and obese populations.

“Glo1 deficiency has been identified as a driver of health problems in obesity, diabetes and cardiovascular disease… The key steps to discovery were to focus on increasing Glo1 and then to combine tRES and HESP together in the formulation for effective treatment,” said study team leader Paul Thornalley, PhD, speaking in a news release from the University of Warwick.

“Diabetic kidney disease will be the initial target to prove effective treatment for which we are currently seeking commercial investors and partners. Our new pharmaceutical is safe and expected to be an effective add-on treatment taken with current therapy.”

Glo1 helps control metabolism by neutralizing a sugar-derived compound called methylglyoxal (MG), which can drive insulin resistance and help create type 2 diabetes mellitus when too much of it accumulates in the body.

“MG is a highly potent glycating agent with specific reactivity ∼20,000-fold higher than that of glucose. This is tolerable in vivo because efficient detoxification of MG by Glo1 maintains the concentration of MG in plasma approximately 50,000-fold lower than that of glucose. In diabetes, however, MG concentrations and MG-derived AGEs increase in plasma and at sites of complications development,” Thornalley and a colleague wrote in a 2014 research review that was also published in Diabetes.

Methylglyoxal also damages blood vessels and impairs the body’s ability to deal with cholesterol, the authors of the new study wrote. A 2014 study that manipulated Glo1 levels in mice found not only that mice with too little Glo1 “had increased serum cholesterol and triglycerides and increased atherosclerosis at both times after diabetes induction.”

Some popular stories about the new trial in human patients suggested that the study indicated that fruit or fruit juice could help treat or prevent diabetes or vascular disease in obese people, but the investigators noted that the amounts of tRES and HESP in their formulation greater than people could ingest from food consumption. Subjects in the studies took the compounds via concentrated capsules.