Glycemic Effect of Diazoxide in NAFLD

Inclusion Criteria: 1. Adults aged 18-70 years (using highly effective contraception if of childbearing potential) 2. Body mass index of 27-50 kg/m2 3. Able to understand written and spoken English and/or Spanish 4. Able to have pre-randomization screening labs drawn and study protocol initiated within 30 days of informed consent 5. Diagnosed with, or clinically judged to be at high risk for, non-alcoholic fatty liver disease (NAFLD), also known as metabolic-associated fatty liver disease (MAFLD), by hepatologist or other qualified physician 6. Evidence of insulin resistance, represented by any or all of the following criteria: i. Meeting either of the American Diabetes Association's definitions for prediabetes or IFG on screening labs: 1. Prediabetes: Hemoglobin A1c 5.7-6.4% 2. IFG: plasma glucose of 100-125 mg dL-1 after ≥ 8-h fast and/or ii. Homeostasis Model of Insulin Resistance (HOMA-IR) score ≥ 2.73 7. Fasting hyperinsulinemia (fasting insulin level ≥ 13 µIU/mL) on screening labs 8. 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. Exclusion Criteria: 1. Unable to provide informed consent in English or Spanish 2. Concerns arising at screening visit (any of the following): i. Documented weight loss of ≥ 5.0% of baseline within the previous 6 months ii. Abnormal blood pressure (including on treatment, if prescribed) • Systolic blood pressure \< 95 mm Hg or \> 160 mm Hg, and/or • Diastolic blood pressure \< 65 mm Hg or \> 100 mm Hg iii. Abnormal resting heart rate \< 60 bpm or ≥ 100 bpm • Sinus brady- or tachycardia that has been appropriately evaluated and considered benign by the recruit's personal physician may be permitted at PI's discretion iv. Abnormal screening electrocardiogram (or if on file, performed within previous 90 d): * Non-sinus rhythm * Significant corrected QT segment (QTc) prolongation (≥ 480 ms) * New or previously unknown ischaemic changes that persist on repeat EKG: •• ST segment elevations •• T-wave inversions v. Laboratory evidence of diabetes mellitus: * Hemoglobin A1c ≥ 6.5%, and/or * Fasting plasma glucose ≥ 126 mg/dL vi. Positive qualitative serum β-hCG (human chorionic gonadotropin, beta subunit; i.e., pregnancy test) in women of childbearing potential vii. Liver function abnormalities * Transaminases (AST or ALT) \> 3.0 x the upper limit of normal, and/or * Total bilirubin \> 1.25 x the upper limit of normal viii. Abnormal screening triglycerides \> 500 mg/dL ix. Abnormal screening serum electrolytes (any of the following) • Sodium, potassium, chloride, or bicarbonate levels that are considered clinically significant according to the clinical judgment of the PI • Creatinine equating to estimated glomerular filtration rate \< 60 mL/min/1.73 m2 x. Uric acid level above the upper limit of normal xi. Glucose-6-phosphate dehydrogenase below the lower limit of normal 3. COVID-19 precautions i. Unwillingness to comply with masking requirements per hospital policy ii. Active, documented COVID-19 at any time after screening 4. Reproductive concerns i. Women of childbearing potential not using highly effective contraception, defined as: * Surgical sterilization (e.g., bilateral tubal occlusion, bilateral oophorectomy and/or salpingectomy, hysterectomy) * Combined oral contraceptive pills taken daily, including during the study * Intrauterine device (levonorgestrel-eluting or copper) active at the time of the study * Medroxyprogesterone acetate (Depo-Provera®) injection active at the time of the study * Etonogestrel implants (e.g., Implanon®, etc.) active at the time of the study * Etonogestrel/ethinyl estradiol vaginal rings (e.g., Nuvaring®, etc.) active at the time of the study * Norelgestromin/ethinyl estradiol transdermal system (e.g., Ortho-Evra®) active at the time of the study ii. Women currently pregnant (tested by serum and/or urine β-hCG) iii. Women currently breastfeeding 5. Concerns related to glucose metabolism i. History of having met any of the American Diabetes Association's definitions of diabetes mellitus (i.e., overt diabetes): * Hemoglobin A1c ≥ 6.5%, or rapid rise in documented HbA1c values causing clinical concern for evolving insulin deficiency * Plasma glucose ≥ 126 mg/dL after 8-h fast * Plasma glucose of ≥ 200 mg/dL at 2 h after ingestion of a 75-g glucose load * Random plasma glucose ≥ 200 mg/dL associated with typical hyperglycemic symptoms, diabetic ketoacidosis, or hyperglycemic-hyperosmolar state ii. History of gestational diabetes mellitus within the previous 5 years iii. Use of most antidiabetic medications within the 90 days prior to screening * Excluded: thiazolidinediones, sulfonylureas, meglitinides, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors, amylin mimetics, acarbose, insulin * Metformin is acceptable provided that recruits meet all of the inclusion criteria at screening iv. Clinical concern for absolute insulin deficiency (e.g., type 1 diabetes, pancreatic disease) 6. Concerns related to lipid metabolism i. Known diagnoses of familial hypercholesterolemia, familial combined hyperlipidemia, or familial hyperchylomicronemia ii. Use of certain lipid-lowering drugs within the 90 days prior to screening: * Statins or PCSK9 inhibitors for secondary prevention or for treatment of familial hypercholesterolemia. Statins or PCSK9 inhibitors for primary prevention of ASCVD are acceptable. * Fibrates (e.g., fenofibrate, clofibrate, gemfibrozil) * High-dose niacin (\>100 mg daily) 7. Known, documented history (i.e., not to be newly screened/tested for study purposes), at the time of screening, of any of the following medical conditions: i. Pancreatic pathology, including but not limited to: * Pancreatic neoplasia, unless appropriately evaluated and considered benign and not producing hormones * Chronic pancreatitis * Acute pancreatitis within the previous 5 years * Autoimmune pancreatitis * Surgical removal of any portion of the pancreas ii. Cardiovascular disease (N.B. uncomplicated hypertension is not exclusionary) * Atherosclerotic cardiovascular disease * Stable or unstable angina * Myocardial infarction * Ischaemic or hemorrhagic stroke, or transient ischaemic attack * Peripheral arterial disease (claudication) * Use of dual antiplatelet therapy (aspirin + P2Y12 inhibitor) * History of percutaneous coronary intervention * Heart rhythm abnormalities * Congestive heart failure of any New York Heart Association class * Symptomatic valvular heart disease (e.g., aortic stenosis) * Pulmonary hypertension iii. Chronic kidney disease, Stage 3 or higher (estimated glomerular filtration rate \< 60 mL/min/1.73 m2), of any cause iv. Chronic liver disease other than uncomplicated NAFLD, including but not limited to: * Advanced liver fibrosis, as determined by non-invasive testing * Cirrhosis of any etiology * Autoimmune hepatitis or other rheumatologic disorder affecting the liver * Biliopathy (e.g., progressive sclerosing cholangitis, primary biliary cholangitis) * Chronic liver infection (e.g., viral hepatitis, parasitic infestation) * Hepatocellular carcinoma * Infiltrative disorders (e.g., sarcoidosis, hemochromatosis, Wilson disease) v. Gout vi. Chronic viral illness (N.B. diagnosis based only on medical history; the investigators will not test for any of these viruses at any point in this study) * Hepatitis B virus (HBV), unless previously successfully eradicated with antiviral drugs that have been discontinued for at least 90 days prior to screening * Hepatitis C virus (HCV) infection, unless previously successfully eradicated with antiviral drugs that have been discontinued for at least 90 d prior to screening * Human immunodeficiency virus (HIV) infection vii. Malabsorptive conditions * Active inflammatory bowel disease (quiescent and off medication is acceptable) * Celiac disease (in remission on gluten-free diet is acceptable) * Surgical removal of a significant length of intestine viii. Active seizure disorder (including controlled with antiepileptic drugs) ix. Psychiatric diseases that: * Are or have been decompensated within 1 year of screening, and/or * Require use of anti-dopaminergic antipsychotic drugs associated with significant weight gain/metabolic dysfunction (e.g., clozapine, olanzapine), monoamine oxidase inhibitors, tricyclic antidepressants, or lithium x. Glucose-6-phosphate dehydrogenase (G6PD) deficiency * Due to presence of quinine in tonic water placebo xi. Other endocrinopathies: * Cushing syndrome (okay if considered in remission after treatment, provided that no exogenous corticosteroids are required) * Adrenal insufficiency * Primary aldosteronism xii. Venous thromboembolic disease (deep vein thrombosis or pulmonary embolism) or any required use of therapeutic anticoagulation xiii. Active malignancy, or hormonally active benign neoplasm, except allowances for: * Non-melanoma skin cancer * Differentiated thyroid cancer (AJCC Stage I only) 8. Clinical concern for increased risk of volume overload or hypotension (systolic blood pressure \<95 and/or diastolic blood pressure \<65 mm Hg), including due to medications and/or heart/liver/kidney problems, as listed above 9. Use of certain medications currently or within 90 d prior to screening: i. Prescribed medications used for any of the indications in the preceding list of excluded conditions, or their use within 90 d prior to screening, except allowances for: * Statins for primary prevention of cardiovascular disease * Use of drugs prescribed for indications other than the exclusionary diagnoses/purposes listed above (e.g., non-hydantoin antiepileptic drugs used for non-seizure indications, angiotensin converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) used for uncomplicated hypertension rather than for congestive heart failure, etc.) •• Note, as above, that antidiabetic drugs for any indication (except metformin) within 90 d of screening are excluded ii. Vasodilating drugs for any indication: hydralazine, nitrates, phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil), minoxidil (oral) iii. Phenytoin or fosphenytoin for any indication iv. Oral or parenteral corticosteroids (at greater than prednisone 5 mg daily, or equivalent) for more than 3 days within the previous 90 days; topical and inhaled formulations are permitted v. Fludrocortisone vi. Opioids 10. History of certain weight-loss (bariatric) surgeries, including: i. Roux-en-Y gastric bypass ii. Biliopancreatic diversion iii. Restrictive procedures (lap band, sleeve gastrectomy) performed within past 6 months 11. Clinical concern for alcohol overuse, including based on chart review and/or by participant's report of consuming more than 14 standard drinks per week for males or more than 7 standard drinks per week for females 12. Positive urine drug screen, except for: * Lawfully prescribed medication * Marijuana/THC positivity is okay, provided that the participant agrees not to use it during the same period that they will abstain from alcohol 13. History of severe infection or ongoing febrile illness within 30 days of screening 14. Any other disease or condition or laboratory value that, in the opinion of the investigator, would place the participant at an unacceptable risk and/or interfere with the analysis of study data. 15. Known allergy/hypersensitivity to any component of the medicinal product formulations (including sulfa drugs), other biologics, IV infusion equipment, plastics, adhesive or silicone, history of infusion site reactions with IV administration of other medicines, or ongoing clinically important allergy/hypersensitivity as judged by the investigator. 16. Concurrent enrollment in another clinical study of any investigational drug therapy or use of any biologicals within 6 months prior to screening or within 5 half-lives of an investigational agent or biologic, whichever is longer.