Reversal of Insulin Resistance by Trans-Resveratrol and Hesperetin

Posted on by Jesse Santiano, M.D.

This article presents a study showing that combining two over-the-counter nutritional supplements, hesperidin and trans-resveratrol, could reverse insulin resistance.[1]

The study authors are from Qatar University, Hamad Bin Khalifa University, and the  Warwickshire Institute for the Study of Diabetes in the UK.

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 was published in the journal Nutrients in 2021.

The research Healthy Aging Through Functional Food (HATFF) is a randomized, placebo-controlled crossover trial.

Insulin Resistance

Insulin resistance is when the skeletal muscles and liver do not respond appropriately to insulin, resulting in high blood sugar. High blood sugar is seen in prediabetes and diabetes.

Besides high blood sugar, insulin resistance can lead to excessive fat deposits, resulting in obesity, hypertension, and high triglyceride levels.

Additional body weight can make it difficult for a person to move around or exercise and thus lead to a sedentary lifestyle and lower HDL or high-density lipoprotein.

If a person has three of either high blood sugar, high triglycerides (>150 mg/dl), hypertension, obesity, and low HDL, then they have metabolic syndrome.

Learn more about its details in my previous article, The Metabolic Syndrome.

Aside from heart attacks, strokes, and cancer, the Deadliest Diseases Associated with Metabolic Syndrome, there are many common diseases associated with metabolic syndrome.

Diseases that arise from metabolic syndrome include periodontitis, gallbladder stones, some kidney disease, fatty liver leading to liver failure or cirrhosis, fatty pancreas, pancreatic cancer, Polycystic Ovarian Syndrome, erectile dysfunction, loss of hair, vertigo, loss of hearing, dark patches on the skin, skin tags and many others.

I talked about them in Diseases Associated with the Metabolic Syndrome.

With all the conditions coming from insulin resistance, it makes sense to reverse it.

Ways to Reverse Insulin Resistance

Bariatric surgery is done to decrease the stomach size; low-calorie diets or carbohydrate restrictions have been shown to reverse insulin resistance.[3]

However, bariatric surgery is expensive, and there is a risk of complications. Many people regain the weight they lost after a few months or years. Among the people that I know who had bariatric surgery, all of them are still overweight or obese.

Dr. Jason Fung published 2018 a small study of three type 2 diabetes patients on insulin. They underwent intermittent fasting from 16 hours to several days.

At the end of the study, which lasted from seven to eleven months, all three could discontinue insulin therapy, lose significant body weight, reduce their waist circumference, and reduce their hemoglobin A1c level (HbA1C).[4]

Hemoglobin A1C or glycated hemoglobin is the average measure of blood sugar in the previous three months.

In another research, 30 obese patients with type 2 diabetes went through a very low-calorie ketogenic diet (VLCKD) for 12 months. They were instructed to stop all diabetes drugs except for metformin. At the end of the study, in the VLCKD group, 26.6% of patients had stopped all antidiabetic medications, and 73.3% were taking only metformin.[5]

Another way to improve insulin resistance is with the use of a prescription drug, metformin. One way that metformin acts is by decreasing the production of ATP in the liver and thus preventing sugar production by the liver (gluconeogenesis), which contributes to a high blood sugar level.

When I used metformin recently, I found that I had low energy levels, which could be related to lower ATP production. I don’t like to have low levels since I’m always on the go, so I stopped using it.

Other patients who use metformin typically complain of nausea. That is one way that metformin works. Who would like to eat if their stomach is off?

Why Trans-Resveratrol and Hesperitin?

Trans-resveratrol is not a cross-dressing polyphenol. Resveratrol is commonly found in grape skin and seeds. The trans-resveratrol form is more stable compared to its cis form.[6]

Source: Resveratrol: A Double-Edged Sword in Health Benefits. Biomedicines. 2018 Sep 9;6(3):91.

Baur et al. showed that resveratrol can improve mice’s metabolic health and survival on a high-calorie diet.[7]

In human studies, a meta-analysis by Liu et al. showed that resveratrol reduced fasting blood sugar, insulin, glycated hemoglobin, and insulin resistance among diabetic subjects but not among non-diabetics.[8]

Hesperitin or hesperidin is a flavonone present in oranges and other citrus fruits. A review article by Mas-Capdevila and colleagues featured the glucose-lowering and anti-inflammatory properties in diabetic models.[9]

Hesperidin can also improve dyslipidemia, atherosclerosis, and hypertension and prevent obesity. Thus reducing the risk of cardiovascular disease. [9]

Methylglyoxal

Methylglyoxal, or MG for short, is a metabolite in the body that plays a role in developing insulin resistance. The enzyme glyoxalase-1 or Glo-1 breaks down MG. Thus, increasing Glo-1 can decrease MG and improve or reverse insulin resistance.

Naila Rabbani, the principal author of the featured study, has published several papers about MG. In one research, they found a way to increase Glo-1, which led to a decrease in MG and reverse insulin resistance.[10]

When they screened compounds that can increase Glo-1, they found that combining hesperetin and trans-resveratrol was the most effective Glo-1 inducer and could reverse insulin resistance and increase insulin sensitivity.[11]

Testing for the Effects of Improved Insulin Sensitivity

If insulin resistance is reversed, then its effects should also go away.

This leads us to the aims of the featured study. 1] Reversal of insulin resistance should improve the lipid profile (HDL and triglycerides) and decrease inflammation, blood pressure, and blood sugar.

They also measured the mediators of insulin resistance, like the thioredoxin interacting protein (TXNIP) and tumor necrosis factor-α.

Study Design

Twenty-nine subjects with impaired metabolic health were included. Nine subjects have prediabetes.

Twenty participants were highly overweight and obese (BMI ≥ 27.5 kg/m2), and 11 were obese (BMI ≥ 30 kg/m2).

Treatment was by daily oral capsule before breakfast. The capsule contained 90 mg trans-resveratrol and 120 mg hesperetin for eight weeks. The control group got a placebo.

After eight weeks, there was a six-week washout period where the two groups did not take any tRES or hesperetin. Then, the other group took the trans-resveratrol-hesperidin, and the other became the placebo group.

It was a double-blind trial, so the people giving the capsules and the study and control groups knew what they were taking. This technique prevents bias.

Results

In the study group:

  1. There was a 27% increase in Glo-1, and that’s a good thing.
  2. A decrease of MG concentration in the blood by 37%. (Good)
  3. Fasting blood sugar decreased by 5% (Good)
  4. Insulin decreased by 8%. (Oh yeah)
  5. Insulin sensitivity, as measured by the Oral Glucose Insulin Sensitivity, increased. (Yay!)
  6. Levels of inflammatory molecules like MCP-1, IL-8, COX-2, and RAGE (Receptor for Advanced Glycation End-Products) in the blood cells decreased. (OMG!)
  7. Markers of inflammation in the blood vessels (MCP-1, sVCAM1, sICAM1, and endothelin) that lead to hypertension also decreased as the Glo-1 increased. (Great!)
  8. Systolic and diastolic blood pressure improved.
  9. The lipid profile improved. HDL, aka “good cholesterol,” increased while the”baddies,” LDL-VLDL, and triglyceride levels decreased. (Statin-like effects without the side effects)
  10. The mediators of insulin resistance, like the thioredoxin interacting protein (TXNIP) and tumor necrosis factor-α, also decreased. 

Many other tests were made, like correlations and measures of metabolites and expression of relevant genes, which were also done to add weight to the integrity of their results. I only included the results that are clinically useful to the readers.

Overall, the decrease in blood pressure, blood sugar, triglycerides, and markers of inflammation, which is the consequence of obesity, and an increase in the HDL tells us that the trans-resveratrol and hesperetin combination can reverse not only insulin resistance but also the metabolic syndrome. A grand slam.

Therefore, it is very probable that the use of trans-resveratrol and hesperetin could improve and possibly eliminate insulin resistance, type 2 diabetes and all its complications, cardiovascular diseases like heart attacks and strokes, and diseases related to metabolic syndrome.

Rant on.

Can improving the population’s health when trans-resveratrol and hesperidin are used save any country millions, if not billions, of dollars? Definitely!

Why are no government agencies or medical groups pushing for its use?

That’s because no large multi-country clinical trials have been done to show their effectiveness. And why is that?

Because both are nutritional supplements and cannot be patented separately, big pharma cannot recover or make millions, if not billions, of dollars if it sponsors that study.

Big pharma needs the money so they can lobby the corrupt politicians, government health agencies, and medical organizations and pay mainstream media who will push for their drugs.

That’s how it works. It’s not about health. Only money. Who suffers? We the people.

Rant off.

Trans-resveratrol and Hesperitin availability

After reading this study weeks ago, I bought these two products on Amazon.

Research Labs Trans-Resveratrol 600 mg and Hesperidin 500 mg. Unfortunately, that hesperidin brand is unavailable now, but there are others.

The capsule used in the study contained 90 mg trans-resveratrol and 120 mg hesperetin. I didn’t see any combined trans-resveratrol and hesperidin on Amazon. Still, you can save money by getting a powder form of hesperidin from Nootropics or a powdered trans-resveratrol one from Prohealth. 

The federal government wants me to remind you that I earn from qualifying purchases as an Amazon Associate. You can freely choose any product that you like. Make sure you read the reviews. 

Since I started using both, my fasting blood sugar has improved, and my one-hour-after-meal blood sugar has been less than 155 mg/dl, even if I ate more carbs than usual or did less exercise after the meal. So far, I’m impressed, and it has been less than a week since I started them.

Read about the possible side effects and precautions using hesperidin at this link and trans-resveratrol here. 

Let me know how it works out for you. Anecdotal evidence works.

Find out why blood sugar levels one hour after a meal is important below.

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Related:

  1. A Tool Box of Strategies to Prevent Blood Sugar Spikes When Eating High Glycemic Index Foods
  2. A High One-hour After-Meal Blood Sugar Test can Lead to Several Deadly Conditions
  3. The Blood Sugar Lowering and Metabolic Effects of Vinegar
  4. Ways to Lower After-Meal Blood Sugar when Eating White Bread
  5. A High-Protein Breakfast Can Lower Blood Sugar the Whole Day
  6. Eating rather than skipping breakfast results in lower blood sugars the whole day
  7. Pistachios improve insulin resistance and inflammatory markers
  8. Pistachios decrease after-meal blood sugar
  9. A surprising reason why people get heart attacks
  10. After-meal high blood sugar predicts Atherosclerosis better than Fasting blood sugar and HbA1c.
  11. How often do you do the post-prandial sugar test?
  12. Blood Glucose Spike and its Prevention
  13. Testing Post Prandial Glucose Level after a Feast
  14. After-meal blood sugar spikes as a cause of vascular failure
  15. Veggies Meat Carbohydrate Sequence Prevents After Meal Sugar Spike
  16. A Healthy Lifestyle is as effective as Voglibose and Nateglinide in Lowering 10-year Cardiac Mortality
  17. Intermittent fasting Reverses Endothelial Dysfunction
  18. Walk After Meals to Prevent Sky High Blood Sugars

References:

  1. Rabbani N, Xue M, Weickert MO, Thornalley PJ. 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. 2021 Jul 11;13(7):2374. doi: 10.3390/nu13072374. PMID: 34371884; PMCID: PMC8308792.
  2. Dobrowolski P, et al. Metabolic syndrome – a new definition and management guidelines. Arch Med Sci. 2022 Aug 30;18(5):1133-1156. doi: 10.5114/aoms/152921. PMID: 36160355; PMCID: PMC9479724.
  3. Hallberg SJ, Gershuni VM, Hazbun TL, Athinarayanan SJ. Reversing Type 2 Diabetes: A Narrative Review of the Evidence. Nutrients. 2019 Apr 1;11(4):766. doi: 10.3390/nu11040766. PMID: 30939855; PMCID: PMC6520897.
  4. Furmli S, Elmasry R, Ramos M, Fung J. Therapeutic use of intermittent fasting for people with type 2 diabetes as an alternative to insulin. BMJ Case Rep. 2018 Oct 9;2018:bcr2017221854. doi: 10.1136/bcr-2017-221854. PMID: 30301822; PMCID: PMC6194375.
  5. Moriconi E, Camajani E, Fabbri A, Lenzi A, Caprio M. Very-Low-Calorie Ketogenic Diet as a Safe and Valuable Tool for Long-Term Glycemic Management in Patients with Obesity and Type 2 Diabetes. Nutrients. 2021 Feb 26;13(3):758. doi: 10.3390/nu13030758. PMID: 33652834; PMCID: PMC7996853.
  6. Salehi B, Mishra AP, Nigam M, Sener B, Kilic M, Sharifi-Rad M, Fokou PVT, Martins N, Sharifi-Rad J. Resveratrol: A Double-Edged Sword in Health Benefits. Biomedicines. 2018 Sep 9;6(3):91. doi: 10.3390/biomedicines6030091. PMID: 30205595; PMCID: PMC6164842.
  7. Baur JA, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006 Nov 16;444(7117):337-42. doi: 10.1038/nature05354. Epub 2006 Nov 1. PMID: 17086191; PMCID: PMC4990206.
  8. Liu K, Zhou R, Wang B, Mi MT. Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis of 11 randomized controlled trials. Am J Clin Nutr. 2014 Jun;99(6):1510-9. doi: 10.3945/ajcn.113.082024. Epub 2014 Apr 2. PMID: 24695890.
  9. Mas-Capdevila A, Teichenne J, Domenech-Coca C, Caimari A, Del Bas JM, Escoté X, Crescenti A. Effect of Hesperidin on Cardiovascular Disease Risk Factors: The Role of Intestinal Microbiota on Hesperidin Bioavailability. Nutrients. 2020 May 20;12(5):1488. doi: 10.3390/nu12051488. PMID: 32443766; PMCID: PMC7284956.
  10. Xue M., Rabbani N., Momiji H., Imbasi P., Anwar M.M., Kitteringham N.R., Park B.K., Souma T., Moriguchi T., Yamamoto M., et al. Transcriptional control of glyoxalase 1 by Nrf2 provides a stress responsive defence against dicarbonyl glycation. Biochem. J. 2012;443:213–222. doi: 10.1042/BJ20111648
  11. Xue M., Weickert M.O., Qureshi S., Ngianga-Bakwin K., Anwar A., Waldron M., Shafie A., Messenger D., Fowler M., Jenkins G., et al. Improved glycemic control and vascular function in overweight and obese subjects by glyoxalase 1 inducer formulation. Diabetes. 2016;65:2282–2294. doi: 10.2337/db16-0153.

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