Human Models of Selective Insulin Resistance: Diazoxide, Part I
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
• 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.