Effect of Insulin Lowering on Lipogenesis

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

Interventions

DRUG

Placebo

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.

DRUG

Diazoxide Oral Suspension, 2 mg per kg per dose

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.

DRUG

Deuterated water (2H2O/D2O), 70%

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.

DIAGNOSTIC_TEST

Insulin Suppression Test (IST)

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.

Sponsors & Collaborators

• University of California, Berkeley

  collaborator OTHER

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  collaborator NIH

• Columbia University

  lead OTHER

Principal Investigators

• Joshua R Cook, MD, PhD · Columbia University

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

65 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2026-05-31

Primary Completion

2029-09-30

Completion

2029-09-30

FDA Drug

Yes

FDA Device

Yes

Countries

• United States

Study Locations