Alpelisib for Insulin Resistance and Type 2 Diabetes

Inclusion Criteria: * Adults aged 18-70 years * Able to understand wrifen and spoken English and/or Spanish * Body mass index of 18-45 kg/m2 (or 18-42 kg/m2 for those of Asian ancestry) * For Lean group: BMI 18.0-24.9 kg/m2 (or 18.0-22.9 kg/m2 for those of Asian ancestry) * For Overweight group: BMI 25.0-29.9 kg/m2 (or 23.0-27.4 kg/m2 for those of Asian ancestry) * For Obesity group: BMI 30.0-45.0 kg/m2 (or 27.5-42 kg/m2 for those of Asian ancestry) Exclusion Criteria: * Inability to provide informed consent in English or Spanish * Unwillingness to fast (except water) for up to 18 hours * Unwillingness not to get out of bed and to use bedpan/urinal to void for up to 15 hours * Documented weight change of ≥ 5.0% of baseline within the previous 3 months * Abnormal blood pressure * Systolic blood pressure \< 90 mm Hg or \> 160 mm Hg, and/or * Diastolic blood pressure \< 55 mm Hg or \> 100 mm Hg * Abnormal resting heart rate \< 55 bpm or ≥ 110 bpm * Sinus tachycardia that has been extensively worked up and considered benign by the recruit's personal physician may be permitted at the PI's discretion * Sinus bradycardia between heart rates of 45 and 54 bpm may be permitted at the PI's discretion if in a clinically appropriate setting (e.g., toned athlete, taking beta blockers) * Abnormal (i.e., non-regular) heart rhythm detected on physical exam * Abnormal screening serum electrolytes judged by the PI to be potentially clinically significant * Liver function abnormalities (either of the following) * Transaminases (AST or ALT) \> 3.0 x the upper limit of normal * Total bilirubin \> 1.25 x the upper limit of normal * Laboratory evidence of diabetes mellitus: * Hemoglobin A1c ≥ 6.5%, and/or * Fasting plasma glucose ≥ 126 mg dL-1 * Positive qualitative β-hCG (i.e., pregnancy test) in women of childbearing potential * Women currently pregnant * Women currently breastfeeding * 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 * History of gestational diabetes mellitus within the previous 5 years * Use of most antidiabetic medications within the 90 days prior to screening * Exceptions: thiazolidinediones, sulfonylureas, meglitinides, DPP4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, amylin mimetics, acarbose, insulin * Metformin is acceptable provided that recruits meet all of the inclusion criteria at screening * Clinical concern for absolute insulin deficiency (e.g., type 1 diabetes, pancreatic disease) * 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 (aspirin + P2Y12 inhibitor) * History of percutaneous coronary intervention * Congestive heart failure (NYHA Class ≥ 2) * Severe valvular heart disease (e.g., aortic stenosis) * Pulmonary hypertension * 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) * Chronic liver infection (e.g., viral hepatitis, parasitic infestation) * Hepatocellular carcinoma * Infiltrative disorders (e.g., sarcoidosis, hemochromatosis, Wilson disease) * 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) * Venous thromboembolic disease (deep vein thrombosis or pulmonary embolism) or any required use of therapeutic anticoagulation * Bleeding disorders, including due to anticoagulation, or significant anemia (see above) * 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 days 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., ACEi/ARB used for uncomplicated hypertension rather than for congestive heart failure, etc.) * Note, as above, that antidiabetic drugs except metformin within 30 d of screening are excluded * 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 based on chart review and/or by recruit's report of more than 14 standard drinks per week for males or more than 7 standard drinks per week for females * Regular tobacco use (smoking more than 1 cigarette per week) or regular nicotine vaping (daily) * Clinical concern for use of illicit drugs other than marijuana or lawfully prescribed medications based on recruit's report, chart review, and point-of-care urine drug test at screening * History of or ongoing febrile illness within 14 days of screening * 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. * Known allergy/hypersensitivity to any component of the medicinal product formulations (including soy, cow dairy, or gluten), other biologics, venipuncture materials, plastics, adhesive or silicone, or ongoing clinically important allergy/hypersensitivity as judged by the investigator. * Concurrent enrollment in another clinical study of any investigational drug/biologic therapy within 5 half-lives of an investigational agent or biologic.