Human Models of Selective Insulin Resistance: Alpelisib, Part I

Inclusion Criteria: 1. Adults aged 18-70 years, using highly effective contraception if of childbearing potential 2. Able to understand written and spoken English and/or Spanish 3. Body mass index of: * For Group IS: BMI 18-25 kg/m2 * For Group IR: BMI 30-45 kg/m2 4. Evidence of insulin sensitivity or insulin resistance: * Insulin sensitive (for Group IS) defined as all of the following: (1) Fasting serum insulin ≤ 10 µIU/mL, (2) Absence of dysglycemia (fasting plasma glucose \< 100 mg/dL and hemoglobin A1c \< 5.7%), (3) Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) score \< 2.5, and (4) Fibrosis-4 (FIB-4) score \< 1.3 * Insulin resistant (for Group IR) defined as fasting serum insulin ≥ 13 µIU/mL plus at least one of the following: (1) Presence of prediabetic state (fasting plasma glucose 100-125 mg/dL and/or hemoglobin A1c 5.7-6.4%), and/or HOMA-IR ≥ 2.5 Exclusion Criteria: 1. Inability to provide informed consent in English or Spanish 2. Concerns arising at screening visit: * Abnormal vital signs: (1) Systolic blood pressure \< 90 mm Hg or \> 160 mm Hg and/or (2) Diastolic blood pressure \< 55 mm Hg or \> 100 mm Hg and/or (3) Abnormal resting heart rate \< 55 bpm (except at PI's discretion) or ≥ 110 bpm * Abnormal screening serum electrolytes judged by the PI to be potentially clinically significant, including liver function abnormalities (either of the following): (1) Transaminases (AST or ALT) \> 3.0 x the upper limit of normal and/or (2) Total bilirubin \> 1.25 x the upper limit of normal * Laboratory evidence of diabetes mellitus: (1) Hemoglobin A1c ≥ 6.5%, and/or (2) Fasting plasma glucose ≥ 126 mg/dL 3. Reproductive concerns i. Positive qualitative β-hCG (i.e., pregnancy test) in women of childbearing potential ii. Women currently pregnant iii. Women currently breastfeeding 4. Concerns related to glucose metabolism * History of having met any of the American Diabetes Association's definitions of diabetes mellitus (i.e., overt diabetes) * History of gestational diabetes mellitus within the previous 5 years * Use of most antidiabetic medications (other than metformin) within the 90 days prior to screening: 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 iv. Clinical concern for absolute insulin deficiency (e.g., type 1 diabetes, pancreatic disease) 5. Concerns related to lipid metabolism * Known diagnoses of familial hypercholesterolemia, familial combined hyperlipidemia, or familial hyperchylomicronemia in the participant or a first-degree relative * Use of certain lipid-lowering drugs within 14 d prior to screening visit: fibrates (e.g., fenofibrate, gemfibrozil), prescription-strength omega-3 fatty acids (e.g., icosapent ethyl), high-dose niacin (\>100 mg daily) 6. Known, documented history, at the time of screening, of any of the following medical conditions: * Significant cardiovascular diseases (N.B. uncomplicated hypertension is not exclusionary) * Severe liver disease, including advanced fibrosis (e.g., fibrosis score F3-F4 by vibration-controlled transient elastography) and cirrhosis * Psychiatric diseases causing functional impairment that: (1) Are or have been decompensated within 1 year of screening, and/or (2) 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 and differentiated thyroid cancer (Stage I only) 7. Clinical concern for increased risk of volume overload, including due to medications and/or heart/liver/kidney problems, as listed above 8. Use of 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 9. 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 10. 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 11. Regular use of tobacco, either daily or an average of at least 1 cigarette per day, and/or nicotine vaping more than 1 day per week 12. 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 13. History of 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 soy, cow dairy, or gluten), other biologics, venipuncture materials, plastics, adhesive or silicone, or ongoing clinically important allergy/hypersensitivity as judged by the investigator. 16. Dietary restrictions (e.g., vegan, kosher, halal) on gelatin present in overencapsulation 17. Concurrent enrollment in another clinical study of any investigational drug/biologic therapy within 6 months prior to screening or within 5 half-lives of an investigational agent or biologic, whichever is longer. * Prior participation in other studies led by Dr. Cook (PI) is excluded from this prohibition according to his medical/scientific judgment.