Effects of Dihydroberberine (DHB) on GLP-1, Glycemic Control, Appetite, and Mood in Adults With Pre-Diabetes

Nanjing Nutrabuilding Bio-tech Co., Ltd.54 enrolled

Overview

The goal of this clinical trial is to learn if Dihydroberberine (DHB) supplementation affects adults with pre-diabetes. The main questions it aims to answer are: Does DHB supplementation increase the concentration of GLP-1 in the blood? Does DHB supplementation affect appetite, mood, and energy levels? Does DHB supplementation affect body weight, blood sugar control and insulin? Researchers will compare DHB supplementation to a placebo (a look-alike substance that contains no drug) to see if DHB has any effect. Participants will: Take DHB or a placebo every day for 6 weeks. Participate in tests to measure GLP-1 levels, blood glucose, insulin and other markers. Have their continuous blood sugar profiles (with CGMs) monitored to see how much time their blood sugar spends in a healthy range. Rate their appetite, mood, and energy levels using a visual analog scale.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

OTHER

Masking

QUADRUPLE

Enrollment

Conditions

Prediabetes

Interventions

Eligibility

Sex: ALLMin age: 35 YearsMax age: 65 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1.35 - 65 years of age (inclusive). 2.BMI 25.0 - 35.0 kg/m2 (inclusive). 3.HbA1c 5.7% - 6.4% (39 - 47 mmol/mol, inclusive) measured at visit 1. 4.Participant has a score of 7 - 10 on the Vein Access Scale Assessment at visit 1. 5.Non-user or former user (daily use; cessation ≥12 months) of tobacco or nicotine products (e.g., cigarette smoking, vaping, chewing tobacco) within 12 months of visit 1, and has no plans to begin use during the study period. 6.Non-habitual users (i.e., daily or almost daily) of marijuana or hemp products, including CBD/THC products, and willing to abstain from use throughout the study period (topical creams/lotions are allowed). 7.Willing to wear a CGM sensor throughout study period and willing to adhere to instructions/ restrictions associated with the proper use and care of the CGM. 8.Willing to use personal smart phone with operating system capable of downloading and operating the Cronometer and Dexcom CGM apps for diet records and blood glucose, respectively. 9.Willing to adhere to all study procedures, including lifestyle considerations, and sign forms providing informed consent to participate in the study and authorization to release relevant protected health information to the Clinical Investigator. Exclusion Criteria: 1. Extreme Diets: Extreme dietary habits (e.g., ketogenic, vegan/vegetarian) at investigator's discretion. 2. Intense Exercise: Moderate-to-intense physical training (≥5 hours/week). 3. Weight Instability/Program: Recent weight changes (\>4.5 kg≤90 d) or current/planned weight change program. 4. Abnormal Labs: Abnormal lab test results of clinical significance at Visit 1 (one re-test allowed). 5. Uncontrolled Chronic Illness: Uncontrolled or clinically important pulmonary, cardiac, hepatic, renal, endocrine (T1D/T2D excluded), hematologic, immunologic, neurologic, psychiatric, or biliary disorders. 6. Clinically Important GI: Clinically important GI condition interfering with study product (e.g., IBD, celiac, weight loss surgery history). 7. Uncontrolled HTN: Uncontrolled hypertension (SBP≥160 mmHg and/or DBP≥100 mmHg). 8. Cancer History: History or presence of cancer in the prior 2 years (except non-melanoma skin cancer). 9. Active Infection: Signs/symptoms of active infection ≤5 d of Visit 1. 10. Anti-Hyperglycemics: Recent use (≤6 mo) of any prescription anti-hyperglycemic medication. 11. Other Supplements: Use of dietary supplements (other than approved multivitamin) ≤14 d of Visit 1. 12. Alcohol/Substance Abuse: History (≤12 months) of alcohol (\>14 drinks/week) or substance abuse. 13. Antibiotics: Antibiotic use ≤90 d of Visit 1. 14. Regular NSAIDs: Regular use (≥3 days/week≤30 d) of anti-inflammatory medications. 15. Steroid Use: Recent use (≤30 d) of oral/injectable steroids, or high-dose topical/inhaled steroids. 16. Unregistered Drug: Exposure to any non-registered drug product ≤30 d prior to Visit 1 17. Medication Instability: Unstable dose (≤90 d) of any other prescription medications (PRN excluded). 18. Psychiatric Hospitalization: Major affective/psychiatric disorder requiring hospitalization ≤12 months prior to Visit 1. 19. Recent Trauma/Surgery: Major trauma or any surgical event ≤30 d of Visit 1. 20. Recent GI Prep: Endoscopy or colonoscopy preparation ≤90 d prior to Visit 1. 21. Planned Surgery: Scheduled or planning elective surgical procedures during the study. 22. Female Status: Pregnancy, lactation, planning pregnancy, or unwillingness to use approved contraception. 23. Allergies: Known sensitivity or allergy to any study products or foods. 24. Investigator Discretion: Any condition that interferes with compliance, confounds results, or presents undue risk.

Outcomes

Primary Outcomes

Change in Postprandial Total GLP-1 Cmax After Single Dose of DHB

Change in postprandial total glucagon-like peptide-1 (GLP-1) maximum concentration (Cmax) following a single dose of 200 mg DHB compared to placebo, measured at visit 3, day 0.

Time frame: Visit 3, Day 0 (after single dose administration)

Change in GLP-1 Cmax From Baseline to End of Study After 6 Weeks of DHB

Change in postprandial total GLP-1 maximum concentration (Cmax) from baseline to end of study after 6 weeks of daily supplementation with 400 mg DHB vs. placebo.

Time frame: Baseline to End of Study , approximately Week 6

Secondary Outcomes

Change in Postprandial GLP-1 AUC (piAUC0-120min) After Single Dose of DHB

Positive incremental AUC (piAUC0-120min) as calculated by the linear trapezoid method where the fasting levels will be subtracted from post-product consumption time points and levels lower than baseline will be truncated at 0

Time frame: 0-120 minutes post-meal at Baseline and Acute Visit 3, Day 0

Change in Time to Maximum Concentration (Tmax) of Postprandial GLP-1 After Single Dose of DHB

Time frame: 0-120 minutes post-meal at Baseline and Acute Visit 3, Day 0

Change in Fasting Total GLP-1 Levels from Baseline (day -7) to the Acute Visit 3 (day 0)

Time frame: From Baseline (Visit 2, Day -7) to Acute Visit (Visit 3, Day 0)

Postprandial Glucose and insulin Responses After Single Dose

Postprandial responses of plasma glucose and insulin during MTT at visit 3, day 0 after single-dose DHB (200 mg) vs. placebo, including: 1. maximum concentration (Cmax)； 2. time to peak (Tmax)； 3. positive incremental AUC (piAUC0-120min)； 4. fasting levels.

Time frame: 0-120 minutes post-meal at Visit 3, Day 0

Change in Subjective Appetite Perceptions After Single Dose of DHB

Appetite VAS ratings quantified by the following metrics：（1）0-120 min net incremental AUC (niAUC0-120min) as calculated by the linear trapezoid method where the baseline values (measured at t = -45 min) will be subtracted from post product consumption time points； 1. Composite appetite score (\[desire to eat + hunger + (100 - fullness) + prospective consumption\]/4)； 2. Individual VAS ratings: Hunger; Desire to eat; Fullness; Prospective food consumption ；（2）Positive maximum response (i.e., change from the fasted value t = -45 min) appetite for composite and individual VAS ratings；（3）Fasting (t = -45 min) appetite for composite and individual VAS ratings；

Time frame: 0-120 minutes post-meal at Visit 3, Day 0

Time In/Out of Range of 24-Hour Continuous Glucose Monitoring (CGM) Glycemic Health Endpoints

1. Time In Range (TIR) and percentage of TIR where the target range is 70 - 180 mg/dL； 2. Time In Tight Range (TITR) and percentage of TITR where the tight target range is 70 - 140 mg/dL ； 3. Time above range and the percentage of readings \>180 mg/dL ； 4. Time below range and the percentage of readings \< 70 mg/dL.

Time frame: 24 hours following product intake (Visit 3, Day 0)

Mean Glucose and Variability of 24-Hour Continuous Glucose Monitoring (CGM) Glycemic Health Endpoints

1. Change in Mean 24-Hour Glucose: Mean glucose averaged over the 24 collection period； 2. Glycemic Variability (Coefficient of Variation (CV) ): Glycemic variability defined by the Standard Deviation (SD) and CV over the 24 h collection period.

Time frame: 24 hours following product intake (Visit 3, Day 0)

Change in Postprandial GLP-1 (piAUC0-120min) After 6 Weeks of Supplementation

Change in positive incremental area under the curve (piAUC0-120min) for plasma total GLP-1 during the Meal Tolerance Test (MTT) from baseline (Visit 2, Day -7) to end of study (Visit 4, Day 42) following 6 weeks of daily DHB supplementation (400 mg/day) vs. placebo, calculated using the linear trapezoidal method.

Time frame: Baseline (Visit 2, Day -7) to End of Study (Visit 4, Day 42), approximately Week 6

Change in Postprandial Total GLP-1 Time to Maximum Concentration (Tmax) from Baseline to Week 6

Change in the Time to Tmax of plasma total GLP-1 during the MTT from baseline (Visit 2, Day -7) to end of study (Visit 4, Day 42) following 6 weeks of daily DHB supplementation (400 mg/day) vs. placebo

Time frame: Baseline (Visit 2, Day -7) to End of Study (Visit 4, Day 42), approximately Week 6

Change in Fasting Plasma Total GLP-1 Levels from Baseline to Week 6

Change in fasting plasma total GLP-1 levels from baseline (Visit 2, Day -7) to end of study (Visit 4, Day 42) following 6 weeks of daily DHB supplementation (400 mg/day) vs. placebo.

Time frame: Baseline (Visit 2, Day -7) to End of Study (Visit 4, Day 42), approximately Week 6

Change in Postprandial Plasma Glucose Maximum Concentration (Cmax) from Baseline After 6 Weeks of Supplementation

Change in plasma glucose dynamics from baseline (Visit 2, day 0) to end of study (Visit 4, Day 42) following 6 weeks of daily DHB supplementation (400 mg/day) vs. placebo, assessed during the MTT.