The goal of this clinical trial is to understand how the blood sugar-lowering hormone insulin works in healthy adults versus those who are at risk for type 2 diabetes. The study will use a drug called alpelisib, which interferes with insulin's actions in the body, to answer the study's main question: does the liver continue to respond to insulin's stimulation of fat production even when it loses the ability to stop making glucose (sugar) in response to insulin. Researchers will compare the impact of single doses of both alpelisib and placebo (inert non-drug) in random order (like flipping a coin) in study participants. Participants will be asked to stay twice overnight in the hospital, take single doses of alpelisib and placebo (one or the other on each of the two hospital stays), and receive intravenous (into the vein) infusions of non-radioactive "tracer" molecules that allow researchers to measure the production of glucose (sugar) and fats by the liver. Measurements will be done both while participants are fasting (not eating or drinking other than water) and while consuming a standardized diet of nutritional beverages.
The objective is to evaluate the effect of lowering insulin levels, while maintaining constant mild hyperglycemia, on plasma glucose and lipid levels.
Adults aged 18-70 years
Able to understand written and spoken English and/or Spanish
For Group IS: BMI 18-25 kg/m2
For Group IR: BMI 30-45 kg/m2
Inability to provide informed consent in English or Spanish
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
Crossover
Alpelisib 300 mg
DrugAll participants will ingest one dose of alpelisib 300 mg (2 x 150-mg overencapsulated tablets) on one of two study admissions.
Placebo
DrugAll participants will ingest one dose of placebo (2 overencapuslated doses of microcrystalline cellulose) on one of two study admissions.
[1-13C] sodium acetate
DrugAll participants will receive continuous infusions of \[1-13C\] sodium acetate for up to 23 hours on both study visits in order to quantify de novo lipogenesis (DNL). (non-experimental)
[6,6-2H2] D-glucose
DrugAll participants will receive continuous infusions of \[6,6-2H2\] D-glucose for up to 15 hours on both study visits in order to quantify de novo lipogenesis (DNL). (non-experimental)
Mixed Meal Tolerance Test
Diagnostic testAll participants will undergo two serial standardized meals of Nestlé BOOST Plus on Study Day 2 over 8 hours. (Non-experimental.)
Nestlé BOOST Plus
Dietary supplementParticipants will consume standardized portions of Nestlé BOOST Plus as meal replacements on Study Day 1 and as two serial mixed meal tolerance tests on Study Day 2. (Non-experimental.)
Hepatic de novo lipogenesis (DNL) (absolute value)
Percent incorporation of newly synthesized fatty acids into plasma or VLDL TG. During both inpatient (overnight) study visits, starting after investigational agent dose. units: %
Hepatic de novo lipogenesis (DNL) (relative value)
Percent incorporation of newly synthesized fatty acids into plasma or VLDL TG. During both inpatient (overnight) study visits, starting after investigational agent dose. unit: fold difference and/or ∆% versus other group
Endogenous glucose production (EGP) (absolute value)
Calculated from D2G tracer enrichment by the Steele equations. During both inpatient (overnight) study visits, starting after investigational agent dose. units: mg/kg/min
Endogenous glucose production (EGP) (relative value)
Calculated from D2G tracer enrichment by the Steele equations. During both inpatient (overnight) study visits, starting after investigational agent dose. units: fold difference and/or ∆% versus other group
Serum insulin level
Serum insulin levels in response to placebo vs alpelisib following an overnight fast and then hourly during refeeding. During Study Day 2 of both study visits, starting after investigational agent dose. units: µIU/mL
Plasma glucose level
Plasma glucose levels in response to placebo vs alpelisib following an overnight fast and then hourly during refeeding. During Study Day 2 of both study visits, starting after investigational agent dose. units: mg/dL
Triglycerides level
(Serum or plasma) triglyceride levels in response to placebo vs alpelisib following an overnight fast and then hourly during refeeding. During Study Day 2 of both study visits, starting after investigational agent dose. units: mg/dL
Free fatty acids level
(Serum or plasma) triglyceride levels in response to placebo vs alpelisib following an overnight fast and then periodically during refeeding. During Study Day 2 of both study visits, starting after investigational agent dose. units: mmol/L
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Columbia University
Lead sponsor
University of California, Berkeley
Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborator
Stanford University
Collaborator
