Diazoxide Suppression Test P&F Study

• Men and women, aged 18-65 years
• Body mass index of 30-45 kg/m2
• Able to understand written and spoken English and/or Spanish
• Fasting hyperinsulinemia (fasting serum insulin ≥ 13 μU/mL)
• Completion of the graded insulin suppression test (GIST) protocol (Group H)
• 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:

• Unable to provide informed consent in English or Spanish
• Documented weight loss of ≥ 5% of baseline within the previous 3 months
• Abnormal blood pressure (including on treatment, if prescribed): Systolic blood pressure \< 90 mm Hg or > 160 mm Hg, and/or Diastolic blood pressure \< 60 mm Hg or > 100 mm Hg
• Abnormal resting heart rate: \< 60 or ≥ 110 bpm
• Sinus brady- or tachycardia that has been worked up and considered benign by the recruit's personal physician may be permitted at the PI's discretion

• Abnormal screening electrocardiogram on GIST screening (or if on file, performed within previous 90 d):

  • Non-sinus rhythm
  • Heart conduction blocks
  • Previously unknown ischaemic changes that persist on repeat EKG:
  • ST elevations
  • T-wave inversions in a vascular distribution

• Laboratory evidence of dysglycemia on GIST screening:

  • Hemoglobin A1c ≥ 5.7%, and/or
  • Fasting plasma glucose ≥ 100 mg/dL
• Positive qualitative β-hCG (i.e., pregnancy test) in women of childbearing potential (both on the day of screening and on the first day of the DzST, prior to receipt of diazoxide doses)
• Positive urine drug screen during GIST screening or on first day of DzST, except for lawfully prescribed medications and/or marijuana, provided that participant agrees to refrain from marijuana use during the period that they refrain from alcohol.

• Liver function abnormalities (either of the following) on GIST screening:

  • Transaminases (AST or ALT) > 3.0 x the upper limit of normal
  • Total bilirubin > 1.25 x the upper limit of normal
  • These exclusion criteria may be waived if the recruit's personal hepatologist approves an exception

• Abnormal screening serum electrolytes (any of the following) on GIST screening:

  • Abnormal sodium, potassium, chloride, or bicarbonate levels that are considered potentially significant according to the clinical judgment of the PI.
  • Creatinine equating to estimated glomerular filtration rate \< 60 mL/min/1.73 m2
• Uric acid level above the upper limit of normal
• Women currently pregnant, measured by serum and/or urine β-hCG at DzST screening (and on first study visit of DzST)
• Women currently breastfeeding

• History of having met any of the American Diabetes Association's definitions of prediabetic state or diabetes mellitus (i.e., overt diabetes):

  • Hemoglobin A1c ≥ 5.7%, or rapid rise in documented HbA1c values causing clinical concern for evolving insulin deficiency
  • Plasma glucose ≥ 100 mg/dL after 8-h fast
  • Plasma glucose of ≥ 140 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
• History of gestational diabetes mellitus within the previous 5 years

• Use of most antidiabetic medications within the 30 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

• Pancreatic pathology, including but not limited to:

  • Pancreatic neoplasia, unless appropriately evaluated and considered benign and not producing hormones
  • Chronic pancreatitis
  • History of acute pancreatitis within the past 5 years
• Cardiovascular diseases (N.B. uncomplicated hypertension is not exclusionary)
• Atherosclerotic cardiovascular disease
• Stable or unstable angina
• Myocardial infarction
• Ischaemic or hemorrhagic stroke
• Peripheral arterial disease (claudication)
• Use of dual antiplatelet therapy
• History of percutaneous coronary intervention
• Heart rhythm abnormalities (non-sinus)
• Congestive heart failure of any New York Heart Association class
• Severe valvular heart disease (e.g., aortic stenosis)
• Pulmonary hypertension
• Chronic kidney disease, Stage 3 or higher (estimated glomerular filtration rate \< 60 mL/min/1.73 m2), of any cause

• Advanced or severe liver disease, 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)
  • Hepatocellular carcinoma
  • Infiltrative disorders (e.g., sarcoidosis, hemochromatosis, Wilson disease)
  • Gout
  • Chronic viral illness (N.B. diagnosis based only on medical history; 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 30 d prior to screening
  • Hepatitis C virus (HCV) infection, unless previously successfully eradicated with antiviral drugs that have been discontinued for at least 30 d prior to screening
  • Human immunodeficiency virus (HIV) infection
• Active seizure disorder (including controlled with antiepileptic drugs)

• Psychiatric diseases causing functional impairment 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
• Cushing syndrome (okay if considered in remission after treatment, provided that no exogenous corticosteroids or other ongoing treatment are required)
• Adrenal insufficiency

• Active malignancy, or hormonally active benign neoplasm, except allowances for:

  • Non-melanoma skin cancer
  • Differentiated thyroid cancer (AJCC Stage I only)
• Clinical concern for increased risk of volume overload, including due to medications and/or heart/liver/kidney problems, as listed above

• Use of certain medications currently or within 30 d prior to screening:

  • Prescribed medications used for any of the indications in the preceding list of excluded conditions, or their use within 30 d prior to screening, except allowances for use of drugs prescribed for indications other than the exclusionary diagnoses/purposes listed above (e.g., antiepileptic drugs used for non-seizure indications, angiotensin converting enzyme inhibitors or angiotensin receptor blockers used for uncomplicated hypertension rather than for congestive heart failure, etc.)
  • Oral or parenteral corticosteroids (at greater than prednisone 5 mg daily, or equivalent) for more than 3 days within the previous 30 days; topical and inhaled formulations are permitted

• History of certain weight-loss (bariatric) surgery, including:

  • Roux-en-Y gastric bypass
  • Biliopancreatic diversion
  • Restrictive procedures (lap band, sleeve gastrectomy) performed within the past 6 months
• Clinical concern for alcohol overuse, including recent documented history during screening and/or participant report of regularly consuming more than 2 drinks per day for males or 1 drink per day for females.

• Positive urine drug screen, with exceptions for:

  • Lawfully prescribed medications
  • Marijuana/THC positivity, provided that the participant agrees not to use it during the same period that they will abstain from alcohol
• History of severe infection or ongoing febrile illness within 14 days of screening
• Any other disease, 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.
• Known allergy/hypersensitivity to any component of the medicinal product formulations (including sulfa drugs) or ongoing clinically important allergy/hypersensitivity as judged by the investigator.
• Concurrent enrollment in another clinical study of any investigational drug therapy within 30 days prior to screening or within 5 half-lives of an investigational agent, whichever is longer. This restriction does not apply to participants who have participated in other studies performed by the PI (Dr. Cook).