Human Models of Selective Insulin Resistance: Alpelisib, Part I

Prior treatment

• 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)
• 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
• 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
• 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.

Other illness

• 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)
• Clinical concern for increased risk of volume overload, including due to medications and/or heart/liver/kidney problems, as listed above
• 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
• History of or ongoing febrile illness within 30 days of screening
• 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.

Lab values

• 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
• 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)
• 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.

Other

• Inability to provide informed consent in English or Spanish
• Reproductive concerns i. Positive qualitative β-hCG (i.e., pregnancy test) in women of childbearing potential ii. Women currently pregnant iii. Women currently breastfeeding
• 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 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
• Dietary restrictions (e.g., vegan, kosher, halal) on gelatin present in overencapsulation

• Adults aged 18-70 years
• Able to understand written and spoken English and/or Spanish
• Body mass index of:
  • For Group IS: BMI 18-25 kg/m2
  • For Group IR: BMI 30-45 kg/m2
• 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