Glyoxalase 1 inducer

trans-Resveratrol and hesperetin combination (tRES+HESP)

Impaired glucose use and balance in the body develops after prolonged and frequent consumption of foods rich in simple sugars (glucose, fructose and sucrose) – such as table sugar, sweets and cakes – with and without fats. This may lead to increased levels of glucose in the blood – referred to as hyperglycemia. Poor glucose balance in the body leads to excessive loading of some organs with glucose. This is referred to as “glycolytic overload”. Uncorrected, this may become progressively worse with health decline to prediabetes and type 2 diabetes.

The body has a built-in mechanism to help counter and correct this. It’s called “Nrf2” – a master health protector. It regulates genes with regulatory antioxidant response elements (ARE). It regulates the basal and inducible expression of ca. 1,300 cytoprotective genes. Nrf2 needs often needs activation by exogenous compounds, or combinations thereof, for full and beneficial effect. Our vision is to achieve this with a science-based, clinically validated health-protective food supplement.

Major outcomes of the Healthy Aging Through Functional Food (HATFF) Study

The HATFF study was a randomized double blind, placebo-controlled crossover study evaluating tRES+HESP (GlucoRegulate) in subjects living with overweight and obesity. Treatment was by GlucoRegulate for 8 weeks with 6 weeks washout between crossover. There was no carry over and the treatment was highly tolerated. Treatment was by one capsule taken orally, once daily, before breakfast. GlucoRegulate contained 90 mg tRES and 120 mg HESP.

Target pharmacology validation

Target pharmacology was confirmed by assay of Glo1 activity in peripheral blood mononuclear cells (PBMCs) and assay of plasma methylglyoxal (MG). PBMC Glo1 activity was increased and plasma MG decreased by treatment with GlucoRegulate – see below.

Figure above: Changes in PBMC Glo1 activity and plasma MG in highly overweight and obese subjects. Data are mean ± SEM (n = 20). From Xue et al., Diabetes 65, 2282 – 2294, 2016.

Primary endpoint: effect of treatment on plasma glucose and insulin resistance

Primary endpoints were effect of GlucoRegulate on fasting plasma glucose (FPG), 2 h area-under-the-curve plasma glucose (AUCg) in a 75 g glucose oral glucose tolerance test (oGTT) and insulin resistance – as assessed by 2-h Oral Glucose Insulin Sensitivity Index (OGIS). Outcomes were:

FPG: Decreased 5% in highly overweight and obese (decreased 9% in obese subjects).

AUCg: Decreased 8% in highly overweight and obese.

OGIS (units mlmin^-1m^-2): Increased + 42 units in highly overweight and obese (+58 units in obese subjects). Maximum response: 41% increase from baseline OGIS. This is similar to improved insulin sensitivity achieved with pharmaceutical treatment of patients with type 2 diabetes with 1.7 g metformin per day (OGIS increase +54 units) or extreme weight loss (>20 kg) after bariatric surgery (+62 units), and better than after carbohydrate-restricted diet and high-intensity interval training (+19).

Figure above: Changes in FPG, PPG and OGIS in highly overweight and obese subjects in the HATFF study. Data are mean ± SEM (n = 20). From Xue et al., Diabetes 65, 2282 – 2294, 2016.

So, GlucoRegulate improved fasting and mealtime glucose spikes and corrected improved insulin sensitivity to that of healthy, physically active subjects – essentially correcting insulin resistance.

Secondary endpoints: effect on low grade inflammation

Low grade inflammation was assessed by PBMC expression of inflammatory markers. In all subjects, expression of interleukin-8 (IL8) and cyclo-oxygenase-2 (COX2) were decreased 39% and 30%, respectively. In highly overweight and obese subjects, IL8, COX2 and also monocyte chemoattractant protein-1 (MCP-1) and receptor for advanced glycation endproducts (RAGE) were decreased 31 – 49%.

Table above: Summary of change in gene expression of PBMC with tRES-HESP coformulation in the HATFF study. From Xue et al., Diabetes 65, 2282 – 2294, 2016.

So, GlucoRegulate decreased low grade inflammation – a powerful anti-inflammatory effect.

How GlucoRegulate improves control of plasma glucose and insulin resistance

Since the HATFF study, further advances have been made in understanding of how GlucoRegulate improves blood glucose control and insulin resistance.

Correction of hepatic insulin resistance to decrease fasting plasma glucose

Diets rich in simple sugars lead to overactivation of hepatic carbohydrate response element binding protein (ChREBP) which synergizes with fats to down regulate expression of insulin receptor substrate-2 (IRS-2) to produce hepatic insulin resistance, increasing FPG. GlucoRegulate increases the expression of glucose-6-phosphate dehydrogenase (G6PD), thereby decreasing glucose-6-phosphate (G6P) and G6P/ChREBP/Mlx transcriptional signalling downregulating IRS-2. It also decreases expression of sterol response element binding protein-1c which also counters decreased expression of IRS-2.

Figure: Mechanisms of hepatic insulin resistance, de novo lipogenesis and increased gluconeogenesis increasing fasting plasma glucose on a sugar-rich diet. From: Rabbani and Thornalley Clin Sci 139, 1405–1429, 2025.

Correction of peripheral insulin resistance and incretin effect to decrease mealtime glucose spikes

GlucoRegulate also increases expression of G6PD in muscle and adipose tissue, thereby decreasing G6P and G6P/Mondo A/Mlx transcriptional signalling – including decrease of expression of hexokinase-2 (HK2). Decreased expression of HK2 decreases glycolytic overload and prevents impairment of GLUT4 recruitment in the absorptive phase. This restores glucose disposal at peripheral sites in the absorptive phase, decreasing post-meal glucose spikes. contributes to prevention of peripheral insulin resistance. See Rabbani, N. and Thornalley, P.J. (2024) Hexokinase-linked glycolytic overload and unscheduled glycolysis in hyperglycemia-induced pathogenesis in insulin resistance, beta-cell glucotoxicity and diabetic vascular complications. Frontiers in Endocrinology 14, 1268308, 2024.

Glycolytic overload in the intestinal enteroendocrine K-cells and L-cells impairs the secretion of incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Glycolytic overload in pancreatic beta-cells impairs the insulinotropic activity of GIP and GLP-1. Decrease of FPG counters this and restores incretin secretion and incretin insulinotropic response in the postprandial period, restoring the insulin secretory response and mealtime increase in blood glucose to normal. This is the same abnormal control of blood glucose as addressed in treatment by glucagon-like peptide 1 (GLP-1) agonists – such as Semaglutide (brand names – Ozempic, Wegovy etc.). See Rabbani, N. and Thornalley, P.J. (2024) Unraveling the impaired incretin effect in obesity and type 2 diabetes: key role of hyperglycemia-induced unscheduled glycolysis and glycolytic overload. Diabetes Res. Clin. Pract., 217, 111905.

Correction of hepatic insulin resistance and peripheral insulin resistance normalizes insulin sensitivity and plasma glucose to that of a healthy physically active person. Thereby GlucoRegulate restores good glycemic health.

How GlucoRegulate decreases low grade inflammation

In glycolytic overload there is increased levels of triosephosphate glycolytic intermediates, glyceraldehyde-3-phosphate (GA3P) and dihydroxyacetonephosphate (DHAP). This increases the formation of reactive metabolite methylglyoxal (MG). There is consequently increased modification of proteins by MG which are unfolded. This activates the unfolded protein response (UPR) and downstream inflammatory signalling by activation of the NLRP3 inflammasome.

Figure: Pathways of the UPR – indicating interactions with methylglyoxal and methylglyoxal-modified proteins. Blue arrows are processes of UPR sensor activation and deactivation; yellow arrows are UPR signalling; and red arrows are PDI modification by MG. From: Xue at al. Redox Biology 69, 103025, 2024.

How GlucoRegulate may improve appetite control

We have proposed that glycolytic overload impairs the incretin effect also involved in appetite control through responses to GIP and GLP-1 in neurons of the dorsomedial hypothalamus (DMH) and dorsal vagal complex (DVC). Increased pre-ingestive satiation induced by GLP-1 agonists is thought to involve GLP-1R expressing neurons in the DMH with interplay of arcuate neuropeptide Y/agouti-related protein neurons to regulate food intake. GIP/GIPR signalling in DMH and DVC neurons suppressed food intake and in DVC neurons also increased conditioned taste avoidance which may contribute to control of energy take and development of adiposity. Glycolytic overload in these neurons may impair normal appetite control and GlucoRegulate restore this to normal. See Rabbani, N. and Thornalley, P.J. (2024) Unraveling the impaired incretin effect in obesity and type 2 diabetes: key role of hyperglycemia-induced unscheduled glycolysis and glycolytic overload. Diabetes Res. Clin. Pract., 217, 111905.

Main health benefits of Glo1 inducer (GlucoRegukate)

→ Improves fasting glucose and flattens post-meal glucose spikes

→ Corrects insulin resistance

→ Safe, effective and highly-tolerated

Overall, a strong boost to improve control of blood glucose and insulin sensitivity “glucose balance”

Combination of trans-resveratrol with hesperetin is more effective than trans-resveratrol alone because:

● trans-Resveratrol and hesperetin synergize together to activate master health protector Nrf2. The effect of hesperetin brings clinically achievable concentrations of trans-resveratrol to the “sweet spot” for health beneficial effect.

● Hesperetin temporarily inhibits intestinal modification “glucuronidation” of trans-resveratrol and likely improves its uptake and bioavailability

● Also note: trans-resveratrol is about 9-foldmore effective in activation of Nrf2 than cis-resveratrol. See Xue et al., Glyoxalase 1 Inducer, trans-Resveratrol and Hesperetin – Dietary Supplement with Multi- Modal Health Benefits. Antioxidants 14, 956, 2025

Quotes

“Glo1 inducer increased insulin sensitivity to that of lean, healthy subjects.  We know of no other supplement that has achieved this in robust, randomized placebo-controlled crossover studies in overweight and obese subjects”

“Glo1 inducer, brand name GlucoRegulate, is the first dietary supplement specifically optimized to increase gene expression protective of good blood glucose control“

“Recent research suggests that in countering hepatic insulin resistance, GlucoRegulate is likely also a treatment for early-stage metabolic dysfunction associated steatotic liver disease (MASLD)”

– Paul J Thornalley, Ph.D.

“Subsequent studies show Glo1 inducer also corrects abnormally high levels of glucose metabolism in hyperglycemia or glycolytic overload and unscheduled glycolysis that also contributes to health benefits”

“Recent research suggests that in countering glycolytic overload, GlucoRegulate likely corrects the impaired incretin effect in obesity and type 2 diabetes and may be a suitable adjunct or standalone after coming off treatment by GLP-1 and GLP-1/GIP co-agonists like Ozempic and Mounjaro”

– Naila Rabbani, Ph.D.

Glo1 inducer peer-reviewed publications