Effect of Insulin Lowering on Lipogenesis

NCT07403604 | Recruiting Phase 1 DMC FDA Drug FDA Device

• 2 other identifiers: AAAV7588K23DK140614
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to compare a one-week course of diazoxide (2 mg/kg per dose x 14 doses) and placebo in people with obesity and insulin resistance (IR) with metabolic dysfunction-associated steatotic liver disease (MASLD). The main question it aims to answer are how mitigation of compensatory hyperinsulinemia with diazoxide affects hepatic de novo lipogenesis, a major contributor to MASLD pathophysiology. Participants will:

• Take 14 doses of placebo over 7 days, followed 4-12 weeks later by either 14 doses of diazoxide (at 2 mg per kg of body weight per dose \[mpk\]) or another 14 doses of placebo, over 7 days
• Take 18 doses of heavy (deuterated) water (50 mL each) over 7 days, twice
• Have blood drawn and saliva collected after an overnight fast on four mornings over the course of the study
• Undergo insulin suppression tests (IST) to assess the degree of insulin resistance at the end of each 1-week study period
• Consume their total calculated daily caloric needs as divided into three meals per day Researchers will compare blood tests at the beginning and end of each 1-week study period in participants randomized (like the flip of a coin) to receive either placebo followed by diazoxide or placebo followed by placebo, to see how the drug treatment affects de novo lipogenesis, serum insulin, plasma glucose, and other serum lipid parameters (triglycerides, free fatty acids), among others.

Conditions

Hyperinsulinemia; Insulin Resistance; Non-Alcoholic Fatty Liver Disease; Prediabetic State; Obesity

Keywords

Hyperinsulinemia; Insulin Resistance; Metabolic Dysfunction-Associated Steatotic Liver Disease; Non-Alcoholic Fatty Liver Disease; Triglycerides

Outcome Measures

Primary Outcomes (2)

• Hepatic de novo lipogenesis (absolute values)

  Percent incorporation of newly synthesized fatty acids into serum or very low-density lipoprotein (VLDL) triglyceride (TG) (units: %)

  Study Days 8 and 16

• Hepatic de novo lipogenesis (relative/change)

  Percent incorporation of newly synthesized fatty acids into serum or VLDL TG (units: fold difference and/or ∆%)

  Study Days 8 and 16

Secondary Outcomes (6)

• Fasting plasma/serum insulin (absolute values)

  Study Days 8 and 16

• Fasting plasma/serum insulin (relative/change)

  Study Days 8 and 16

• Fasting plasma glucose

  Study Days 8 and 16

• Fasting serum or plasma triglycerides

  Study Days 8 and 16

• Fasting plasma free fatty acids

  Study Days 8 and 16

Other Outcomes (4)

• Skin de novo lipogenesis

  3 hours

• Deuterium tracer enrichment in body water (measured in blood)

  Study Days 8 and 16

• Deuterium tracer enrichment in body water (measured in saliva)

  Study Days 8 and 16

Study Arms (2)

Placebo first, then Diazoxide

EXPERIMENTAL

During the first 1-week study period, participants will ingest a placebo solution at 14 doses over 7 days. During the second 1-week study period, 4-12 weeks later, participants will ingest diazoxide oral suspension at 2 mg per kg body weight per dose (14 doses over 7 days). Blinding will occur by completely covering single-dose oral syringes with labels. 80% of participants will be randomized to this arm.

Drug: Placebo; Drug: Diazoxide Oral Suspension, 2 mg per kg per dose; Drug: Deuterated water (2H2O/D2O), 70%; Diagnostic Test: Insulin Suppression Test (IST)

Placebo / Placebo

PLACEBO COMPARATOR

During the first 1-week study period, participants will ingest a placebo solution at 14 doses over 7 days. During the second 1-week study period, 4-12 weeks later, participants will again ingest placebo solution (14 doses over 7 days). Blinding will occur by completely covering single-dose oral syringes with labels. 20% of participants will be randomized to this arm.

Drug: Placebo; Drug: Deuterated water (2H2O/D2O), 70%; Diagnostic Test: Insulin Suppression Test (IST)

Interventions

Placebo DRUG

Flavor-approximate placebo consisting of peppermint extract in diet tonic water, thickened with xanthan gum, provided in label-obscured single-use oral syringes at 40 µL per kg per dose. 80% of participants will receive placebo (14 doses over 7 days) during the first 1-week study period, while 20% of participants will receive an additional 14 doses of placebo over 7 days during the second study period, 4-12 weeks later.

Also known as: Placebo solution

Placebo / Placebo; Placebo first, then Diazoxide

Diazoxide Oral Suspension, 2 mg per kg per dose DRUG

Eighty percent of participants will ingest diazoxide oral suspension at 2 mg per kg body weight per dose (14 doses over 7 days) during the study's second 1-week treatment period. Blinding will occur by completely covering single-dose oral syringes with labels.

Also known as: Proglycem

Placebo first, then Diazoxide

Deuterated water (2H2O/D2O), 70% DRUG

All participants will consume 18 aliquots of deuterated water (2H2O/D2O) 50 mL over 7 days during both study periods to assess hepatic de novo lipogenesis. Tracer enrichment will be determined in blood and saliva.

Also known as: Heavy water

Placebo / Placebo; Placebo first, then Diazoxide

Insulin Suppression Test (IST) DIAGNOSTIC_TEST

Participants receive intravenous infusions of regular insulin (32 milliunits \[mU\] per square meter \[m2\] per minute \[min\]), octreotide acetate (25 µg bolus + 0.27 µg/m2/min continuous infusion), and dextrose 20% in water (267 mg/m2/min continuous infusion) for 3 hours. Insulin resistance is reflected as the steady-state plasma glucose (SSPG) during the final 30 minutes of the procedure. IST is performed at the end of both study periods to determine the impact of placebo versus diazoxide on insulin sensitivity.

Placebo / Placebo; Placebo first, then Diazoxide

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults aged 18-65 years
• Body mass index of 30-45 kg/m2
• Able to understand written and spoken English and/or Spanish
• Able to have pre-randomization screening labs drawn and study protocol initiated within 60 days of eligibility determination
• Presence of uncomplicated metabolic dysfunction-associated steatotic liver disease (MASLD) by vibration-controlled transient elastography (VCTE)
• Steatosis score of S1-S3
• Fibrosis score of F0-F2 (Note that if VCTE result is available from within past 6 months, then do not have to repeat VCTE for study purposes)
• Evidence of insulin resistance, represented by any or all of the following criteria:
• Meeting either of the American Diabetes Association's definitions for prediabetes or impaired fasting glucose (IFG) on screening labs:
• Prediabetes: Hemoglobin A1c 5.7-6.4%
• IFG: plasma glucose of 100-125 mg dL-1 after ≥ 8-h fast
• Homeostasis Model of Insulin Resistance (HOMA-IR) score ≥ 2.73
• Fasting hyperinsulinemia (fasting insulin level ≥ 13 μU/mL) on screening labs
• Written informed consent (in English or Spanish) and any locally required authorization (e.g., Health Insurance Portability and Accountability Act) obtained from the participant prior to performing any protocol-related procedures, including screening evaluations.

You may not qualify if:

• Unable to provide informed consent in English or Spanish
• Concerns arising at screening visit (any of the following):
• Documented weight loss of ≥ 5.0% of baseline within the previous 3 months
• Abnormal blood pressure (including on treatment, if prescribed)
• Systolic blood pressure (SBP) \< 90 mm Hg or \> 160 mm Hg, and/or
• Diastolic blood pressure (DBP) \< 60 mm Hg or \> 100 mm Hg
• Resting heart rate \< 55 bpm or ≥ 110 bpm
• Abnormal screening electrocardiogram (or if on file, performed within previous 90 days)
• Laboratory evidence of diabetes mellitus:
• Hemoglobin A1c ≥ 6.5%, and/or
• Fasting plasma glucose ≥ 126 mg/dL
• Positive qualitative serum β-human chorionic gonadotropin (β-hCG, i.e., pregnancy test) in women of childbearing potential
• Liver function abnormalities: transaminases (aspartate aminotransferase or alanine aminotransferase) \> 3.0 x the upper limit of normal, and/or total bilirubin \> 1.25 x the upper limit of normal
• Abnormal screening fasting triglycerides \> 500 mg/dL
• Abnormal screening serum electrolytes that are considered clinically significant according to the clinical judgment of the PI

Sponsors & Collaborators

• Columbia University: lead
• University of California, Berkeley: collaborator
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Columbia University Irving Medical Center

New York, New York, 10032, United States

RECRUITING

MeSH Terms

Conditions

Hyperinsulinism; Insulin Resistance; Non-alcoholic Fatty Liver Disease; Prediabetic State; Obesity

Interventions

Diazoxide; Deuterium Oxide

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Fatty Liver; Liver Diseases; Digestive System Diseases; Diabetes Mellitus; Endocrine System Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Benzothiadiazines; Sulfonamides; Sulfones; Sulfur Compounds; Organic Chemicals; Thiazides; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Water; Hydroxides; Alkalies; Inorganic Chemicals; Anions; Ions; Electrolytes; Deuterium; Hydrogen; Elements; Gases

Study Officials

• Joshua R Cook, MD, PhD

  Columbia University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ishwari Nagnur, BA

CONTACT

2123059336; imn2113@cumc.columbia.edu

Joshua Cook

CONTACT

2123056289; jrc2175@cumc.columbia.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Participants will be masked to treatment during both 1-week study periods, while investigators will be masked only during the second 1-week study period, when participants will receive either diazoxide or placebo. Routine unblinding will occur to investigators only after all of a participant's samples have been submitted for laboratory analysis. It should be noted that investigators may get a sense of group allocation based on changes in blood glucose. However, due to interindividual variability in extent of insulin resistance and body mass index, it will not be possible to assuredly decode the randomization prior to unblinding. The blinding of the study Principal Investigator (PI) will be repealed only in the case of early withdrawal and/or medical emergency (e.g., severe hyperglycemia), which in most cases will result in study termination anyway. Participants will be notified of their group assignment once all relevant data are collected and analyzed if opted in.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Model Details: Participants will be randomized into one of two study groups. All participants will receive a 1-week placebo treatment, while 4-12 weeks later, one group will receive diazoxide for 1 week while the other will receive a second week of placebo.

Study Record Dates

• First Submitted: February 4, 2026
• First Posted: February 11, 2026
• Study Start (Estimated): May 31, 2026
• Primary Completion (Estimated): September 30, 2029
• Study Completion (Estimated): September 30, 2029
• Last Updated: April 9, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL

Locations

US (1)