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.
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
Unable to provide informed consent in English or Spanish
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
Crossover
Placebo
DrugFlavor-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.
Diazoxide Oral Suspension, 2 mg per kg per dose
DrugEighty 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.
Deuterated water (2H2O/D2O), 70%
DrugAll 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.
Insulin Suppression Test (IST)
Diagnostic testParticipants 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.
Hepatic de novo lipogenesis (absolute values)
Percent incorporation of newly synthesized fatty acids into serum or very low-density lipoprotein (VLDL) triglyceride (TG) (units: %)
Hepatic de novo lipogenesis (relative/change)
Percent incorporation of newly synthesized fatty acids into serum or VLDL TG (units: fold difference and/or ∆%)
Fasting plasma/serum insulin (absolute values)
Measurement of fasting endogenous insulin levels during treatment with diazoxide 2 mpk vs. placebo (units: micro-international units \[µIU\] per mL).
Fasting plasma/serum insulin (relative/change)
Measurement of fasting endogenous insulin levels during treatment with diazoxide 2 mpk vs. placebo (units: fold difference and/or change in µIU/mL).
Fasting plasma glucose
Measurement of fasting plasma glucose levels during treatment with diazoxide 2 mpk vs. placebo (units: mg/dL).
Fasting serum or plasma triglycerides
Measurement of fasting plasma or serum triglyceride levels during treatment with diazoxide 2 mpk vs. placebo (units: mg/dL).
Skin de novo lipogenesis
Percent incorporation of newly synthesized fatty acids into sebum from healthy skin and, if present, skin from inflammatory skin lesions (units: %)
Deuterium tracer enrichment in body water (measured in blood)
Enrichment of total body water with deuterated water (2H2O/D2O) (units: %)
Deuterium tracer enrichment in body water (measured in saliva)
Enrichment of total body water with deuterated water (2H2O/D2O) (units: %)
Deuterium tracer enrichment in sebum
Enrichment of sebum with deuterated water (2H2O/D2O) (units: %)
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Columbia University
Lead sponsor
University of California, Berkeley
Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborator
Heidelberg University
Collaborator
