Overview

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).

Eligibility

Inclusion Criteria:

1. Adults aged 18-70 years (using highly effective contraception if of childbearing potential)
2. Body mass index of 25.0-45.0 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:
7. 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 > 400 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.