Glycemic Effect of Diazoxide in NAFLD

Summary

The goal of this clinical trial is to compare a two-week course of diazoxide (at two different doses) and placebo in people with overweight/obesity and insulin resistance (IR) with, or at high risk for, non-alcoholic fatty liver disease (NAFLD). The main questions it aims to answer are how mitigation of compensatory hyperinsulinemia with diazoxide affects parameters of glucose and lipid metabolism (how people with IR and NAFLD respond to lowering high insulin levels so that the investigators can see what happens to how the liver handles fat and sugar).

Participants will:

* Take 27 doses of diazoxide (at 1 mg per kg of body weight per dose \[mpk\] or 2 mpk) or of placebo, over 14 days
* Take 32 doses of heavy (deuterated) water (50 mL each) over 14 days
* Have blood drawn and saliva collected after an overnight fast on four mornings over the two-week study period
* Consume their total calculated daily caloric needs as divided into three meals per day
* Wear a continuous glucose monitor for the two-week study period

Researchers will compare fasting blood tests at intervals during the study period in participants randomized (like the flip of a coin) to diazoxide 1 mpk, diazoxide 2 mpk, or placebo, to see how the drug treatment affects plasma glucose, serum insulin, and serum lipid parameters (triglycerides, free fatty acids, and apolipoprotein B). They will also consume heavy (deuterated) water to assess de novo lipogenesis (building of new fatty acids by the liver).

Conditions

• Hyperinsulinemia
• Insulin Resistance
• Non-Alcoholic Fatty Liver Disease
• Prediabetic State

Interventions

DRUG

Diazoxide oral suspension, 1 mg per kg per dose

Diazoxide oral suspension provided in label-obscured single-use oral syringes at 1 mg per kg per dose (total of 27 doses over 14 days).

DRUG

Diazoxide oral suspension, 2 mg per kg per dose

Diazoxide oral suspension provided in label-obscured single-use oral syringes at 2 mg per kg per dose (total of 27 doses over 14 days).

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 2 mg per kg per dose (total of 27 doses over 14 days).

DEVICE

FreeStyle Libre Pro

All participants will wear a FreeStyle Libre Pro continuous glucose monitor (CGM) to track glycemic trends in response to study treatments. Investigators and participants will be blinded to CGM readings until after each participant has completed the trial.

DRUG

Deuterated water (2H2O/D2O)

All participants will consume 32 aliquots of deuterated water (2H2O/D2O) 50 mL over 14 days to assess hepatic de novo lipogenesis. Tracer enrichment will be determined in blood and saliva.

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

PARALLEL

Eligibility

Min Age

18 Years

Max Age

70 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2023-08-01

Primary Completion

2025-09-10

Completion

2025-09-10

FDA Drug

Yes

FDA Device

Yes

Countries

• United States

Study Locations