NCT07403604

Effect of Insulin Lowering on Lipogenesis

Human Models of Selective Insulin Resistance: Diazoxide, Part I

• Status: Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 25 (estimated)
• Sponsor: Columbia University · Academic / Other
• Sex: All
• Age: 18 Years – 65 Years
• Healthy volunteers: Not accepted

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.

Detailed description

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an under-appreciated complication of lipid dysmetabolism in type 2 diabetes (T2DM). Although it appears that insulin resistance (IR) is a mechanism common to both, the pathophysiology of its connection to unhealthy fat accumulation in the liver remains unclear. The investigators propose that the hyperinsulinemia that accompanies IR drives the excess hepatic de novo lipogenesis (DNL) that characterizes IR-associated MASLD. In other words, hepatic IR may be "selective," such that DNL is more sensitive to stimulation by insulin than is suppression of endogenous glucose production. As such, despite its potential impact on glucose metabolism, lowering insulin levels might attenuate the pro-steatotic drive in patients with IR. The investigators' objective, therefore, is to blunt endogenous insulin secretion using the insulin anti-secretagogue diazoxide in order to assess the impact on DNL. This is a single-center, randomized, double-blinded, placebo-controlled, crossover clinical trial to determine the lipogenic impact of hyperinsulinemia reduction with diazoxide oral suspension in participants with obesity and insulin resistance (prediabetic state or elevated Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) score, + fasting hyperinsulinemia) who are diagnosed with MASLD. Participants will be randomized to one of two groups. Both groups will receive 14 doses of placebo over 7 days. Then, 4-12 weeks later, one group will cross over to receive 14 doses of diazoxide 2 mg per kg of body weight for 7 days, while the other group will receive a second 1-week course of placebo. Participants will consume heavy (deuterated) water for a total of 18 doses of 50 ml over each 1-week study period to measure de novo lipogenesis. They will present for outpatient blood draws and saliva collections after an overnight fast at the start and conclusion of each study period (Study Days 1, 8, 9 and 16), and will undergo formal assessment of insulin resistance by the insulin suppression test (IST) at the end of each study period (Days 8 and 16).

Conditions

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

Interventions

Type	Name	Description
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.

Timeline

• Start date: 2026-05-31
• Primary completion: 2029-09-30
• Completion: 2029-09-30
• First posted: 2026-02-11
• Last updated: 2026-04-09

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study
• FDA-regulated device study