Scientists block insulin to uncover blood sugar secrets

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

Inclusion Criteria: * 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).