Therapeutic Intervention of Eriomin Associated With Metformin in the Control of Hyperglycemia in Pre-Diabetic Patients

Pre-diabetes Clinical Trial

— Eriomin+Met  

Official title:

Therapeutic Intervention of Nutraceutical Eriomin Associated With Metformin to Improve the Control of Hyperglycemia in Patients With Prediabetes: A Double-blind, Randomized, Placebo-controlled Crossover Clinical Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT06005142
• Other study ID #: SaoPSU23
• Status: Active, not recruiting
• Phase: N/A
• Start date: July 15, 2023
• Est. completion date: December 30, 2024

Study information

• Verified date: January 2024
• Source: São Paulo State University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Citrus bioflavonoids, such as eriocitrin, hesperidin and naringin, have been shown improved hyperglycemia, insulin resistance and systemic inflammation, related to the development of type 2 diabetes. The nutraceutical Eriomin, a lemon flavonoid extract composed mainly by eriocitrin (70%) and other flavonoids (30%), improved the control of moderate hyperglycemia in pre-diabetic and diabetic patients without drug therapy. However, most patients with pre-diabetes are on oral biguanide (metformin) therapy, despite its limited efficacy (30-40%) on glycemic control and its undesirable gastrointestinal effects.

Therefore, in the current study, Eriomin will be administered at a dose of 250 mg/d to adults diagnosed with pre-diabetes and being treated with metformin (1,000 mg/d). This clinical trial was designed as a placebo-control, double-blind, two-arm, crossover design. Clinical characteristics, body composition, food consumption, metabolic and inflammatory biomarkers and the microbiota of all patients will be evaluated before, during and at the end of the 12-week period (arm). Biochemical and metabolic parameters associated with prediabetes are expected to improve or return to normal with Eriomin in combination with metformin. At the same time, an increase in beneficial intestinal bacteria is expected, reducing pre-diabetic dysbiosis, and perhaps a noticeable improvement in body composition.

Description:

Recent evidence shows that bioflavonoids from citrus fruits and herbs can reduce hyperglycemia, dyslipidemia, insulin resistance and the systemic inflammatory process related to type 2 diabetes (T2D). Although they can be found in fruits and herbs, bioflavonoid supplements and nutraceuticals can provide sufficient and safe amounts of bioactive compounds to prevent the development of metabolic disorders, such as metabolic syndrome, diabetes, obesity and others. Eriocitrin flavanone, present in lemons, limes and oranges, has demonstrated anti-inflammatory, anti-hyperglycemic and antioxidant properties and is an integral part of lemon bioflavonoid supplements that have been widely marketed.

Eriocitrin metabolism, similar to hesperidin, is resistant to pancreatic enzymes and are mostly deglycosylated by intestinal bacteria (Bacteroides distasonis or Bacteroides uniformis) to eriodictyol before absorption. A minimal amount can be absorbed as glycosylated in the upper intestine. Eriodictyol, the aglycon of eriocitrin, can be metabolized by intestinal bacteria (with 3,4-dihydroxycinnamic acid formation) to homoeriodictyol and hesperetin through methoxylation. In the liver, eriodictyol is metabolized into glucuronides and conjugated sulfates of eriodictyol, homoeriodictyol, and hesperitin, through sulfation, glucuronidation and methylation, and later released into the circulation to exert biological activity.

Eriocitrin can increase the total antioxidant capacity, leading to a decrease in inflammatory markers (IL-6, MCP-1 and us-CRP) in the blood and organs of mice supplemented with the flavonoid. Eriocitrin also increased catalase and glutathione enzymes in the liver of diabetic rats, and decreased lipid peroxidation in blood, liver and kidney. Furthermore, oral administration of eriodictyol to diabetic rats improved glucose metabolism in the blood, liver and kidney, and suppressed diabetes by upregulating PPARγ29 mRNA expression.

Based on this experimental evidence, the nutraceutical Eriomin, composed of lemon bioflavonoids, was tested as a dietary supplement to control mild to moderate hyperglycemia in pre-diabetic and diabetic patients. After three months of therapy, there was a decrease in hyperglycemia, improvement in insulin resistance and a decrease in HbA1c.

Thus, the hypothesis of the current study is to use the nutraceutical Eriomin as a co-adjuvant to oral biguanide (metformin) therapy, improving control of hyperglycemia and insulin resistance, while increasing efficacy with a low dosage (250 mg/d) of the nutraceutical. It is expected to improve the quality of the microbiota, the glucose metabolism and body composition, in addition to reducing the side effects associated with the continuous use of metformin.

Therefore, the main objective of this study is to evaluate the effects of Eriomin (250mg/day) associated with metformin on glycemic control, insulin resistance and other metabolic, inflammatory and clinical parameters. Furthermore, it will evaluate changes in the microbiota of pre-diabetic patients.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 80
• Est. completion date: December 30, 2024
• Est. primary completion date: April 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 35 Years to 65 Years

Eligibility

Inclusion Criteria:

• Glycemia of 6.1 to 7.0 mmol / L

• Glycated hemoglobin with values between 5.7 and 6.4%

Exclusion Criteria:

• use of drugs, vitamins and dietary supplements, alcohol consumption (> 20 g alcohol/d), and intense physical activity (> 5 hours/week).

• History of cardiovascular disease, diabetes mellitus, liver, kidney or pancreatic disease

Related Conditions & MeSH terms

• Hyperglycemia
• Pre-diabetes
• Prediabetic State

Intervention

Dietary Supplement:
• Eriomin
Pre-diabetic patients on oral biguanide (metformin) (1000 mg/day) will receive a 250 mg/day capsule of Eriomin for 12 weeks.
• Washout
After 12 weeks of treatment with the active component (Eriomin) or placebo, the participants will follow a washout for 2 weeks.
• Placebo
Pre-diabetic patients on oral biguanide (metformin) (1000 mg/day) will receive a 250 mg/day placebo capsule for 12 weeks.

Locations

Country	Name	City	State
Brazil	Centro de Estudos e Praticas em Nutrição (CEPRAN)	Botucatú	SP

Sponsors (2)

Lead Sponsor	Collaborator
Thais Cesar	Ingredients by Nature TM

Country where clinical trial is conducted

Brazil, 

References & Publications (9)

Cesar TB, Ramos FMM, Ribeiro CB. Nutraceutical Eriocitrin (Eriomin) Reduces Hyperglycemia by Increasing Glucagon-Like Peptide 1 and Downregulates Systemic Inflammation: A Crossover-Randomized Clinical Trial. J Med Food. 2022 Nov;25(11):1050-1058. doi: 10.1089/jmf.2021.0181. Epub 2022 Jul 7. — View Citation

Ferreira PS, Spolidorio LC, Manthey JA, Cesar TB. Citrus flavanones prevent systemic inflammation and ameliorate oxidative stress in C57BL/6J mice fed high-fat diet. Food Funct. 2016 Jun 15;7(6):2675-81. doi: 10.1039/c5fo01541c. Epub 2016 May 16. — View Citation

Flory J, Lipska K. Metformin in 2019. JAMA. 2019 May 21;321(19):1926-1927. doi: 10.1001/jama.2019.3805. — View Citation

Hiramitsu M, Shimada Y, Kuroyanagi J, Inoue T, Katagiri T, Zang L, Nishimura Y, Nishimura N, Tanaka T. Eriocitrin ameliorates diet-induced hepatic steatosis with activation of mitochondrial biogenesis. Sci Rep. 2014 Jan 15;4:3708. doi: 10.1038/srep03708. — View Citation

Minato K, Miyake Y, Fukumoto S, Yamamoto K, Kato Y, Shimomura Y, Osawa T. Lemon flavonoid, eriocitrin, suppresses exercise-induced oxidative damage in rat liver. Life Sci. 2003 Feb 21;72(14):1609-16. doi: 10.1016/s0024-3205(02)02443-8. — View Citation

Miyake Y, Shimoi K, Kumazawa S, Yamamoto K, Kinae N, Osawa T. Identification and antioxidant activity of flavonoid metabolites in plasma and urine of eriocitrin-treated rats. J Agric Food Chem. 2000 Aug;48(8):3217-24. doi: 10.1021/jf990994g. — View Citation

Ribeiro CB, Ramos FM, Manthey JA, Cesar TB. Effectiveness of Eriomin(R) in managing hyperglycemia and reversal of prediabetes condition: A double-blind, randomized, controlled study. Phytother Res. 2019 Jul;33(7):1921-1933. doi: 10.1002/ptr.6386. Epub 2019 Jun 11. — View Citation

Testa R, Bonfigli AR, Genovese S, De Nigris V, Ceriello A. The Possible Role of Flavonoids in the Prevention of Diabetic Complications. Nutrients. 2016 May 20;8(5):310. doi: 10.3390/nu8050310. — View Citation

Vinayagam R, Xu B. Antidiabetic properties of dietary flavonoids: a cellular mechanism review. Nutr Metab (Lond). 2015 Dec 23;12:60. doi: 10.1186/s12986-015-0057-7. eCollection 2015. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Fasting Glycemia	Dosages of glycemia concentration (mg/dL) before and after intervention with Eriomin/placebo	0-12-18-26 week
Secondary	Oral Glucose Tolerance Test (OGTT)	Changes in blood glucose 2 hours after the oral glucose tolerance test (mg/dL) before and after intervention with Eriomin/placebo	0-12-18-26 week
Secondary	HbA1c	Dosages of glycated hemoglobin (%) in the blood serum/plasma before and after intervention with Eriomin/placebo	0-12-18-26 week
Secondary	Insulin	Dosages of Insulin (µU/mL) in the blood serum/plasma before and after intervention with Eriomin/placebo	0-12-18-26 week
Secondary	Blood Lipids profile	Dosages of cholesterol (mg/dL), HDL-cholesterol (mg/dL) and triglycerides (mg/dL) in the blood serum/plasma before and after intervention with Eriomin/placebo	0-12-18-26 week
Secondary	Antioxidant Capacity	Dosages of Trolox equivalent antioxidant capacity (TEAC) (µM) in the blood serum/plasma before and after intervention with Eriomin/placebo	0-12-18-26 week
Secondary	Lipid Peroxidation	Dosages of Malondialdehyde (MDA) (mM) the blood serum/plasma before and after intervention with Eriomin/placebo	0-12-18-26 week
Secondary	Glucagon-like peptide-1 (GLP-1)	Dosages of GLP-1 (pmol/L) the blood serum/plasma before and after intervention with Eriomin/placebo	0-12-18-26 week
Secondary	Inflammatory parameters	Dosages of C Reactive Protein (CRP) (mg/dL), TNF-alpha (mg/dL), IL-6 (mg/dL) in the blood serum/plasma before and after intervention with Eriomin/placebo	0-12-18-26 week
Secondary	Hepatic Enzymes	dosages of alkaline phosphatase (U/L), gamma glutamyl transferase (U/L), aspartate aminotransferase (U/L), and alanine aminotransferase (U/L) in the blood serum/plasma before and after intervention with Eriomin/placebo	0-12-18-26 week
Secondary	Kidney Blood Parameters	Dosages of urea (mg/dL) and creatinine (mg/dL) in the blood serum/plasma before and after intervention with Eriomin/placebo	0-12-18-26 week
Secondary	Anthropometric Parameters	Measurements of body weight (kg), muscle mass (kg), fat mass (kg) before and after intervention with Eriomin/placebo	0-12-18-26 week
Secondary	Microbiota composition by 16S rRNA gene sequencing	Dosages of the main bacteria groups by Operational Taxonomic Units (OTU) and % of relative abundance by group	0-12-18-26 week