Human Models of Selective Insulin Resistance: Alpelisib, Part I
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- Columbia University
- Enrollment
- 32
- Locations
- 1
- Primary Endpoint
- Hepatic de novo lipogenesis (DNL) (absolute value)
Overview
Brief Summary
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 overnight, while participants are asleep and fasting (not eating or drinking other than water) and while consuming a standardized diet of nutritional beverages during the following day.
The objective is to evaluate the effect of lowering insulin levels, while maintaining constant mild hyperglycemia, on plasma glucose and lipid levels.
Detailed Description
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an under-appreciated complication of lipid dysmetabolism in type 2 diabetes (T2DM). Although it appears that insulin resistance (IR) is a mechanism common to both, the mechanisms linking IR to unhealthy fat accumulation in liver remains unclear. "Pure" IR would be expected to disinhibit hepatic glucose production while dampening hepatic triglyceride (TG) biosynthesis, but the excessive hepatic de novo lipogenesis (DNL) of IR-associated MASLD suggests that hepatic IR is "selective." However, the concept of IR selectivity is controversial, and because of clinical heterogeneity, lead-time discrepancies, co-morbidities, and medication effects, parsing out this pathophysiologic conundrum in humans is challenging. The investigators plan to test whether the multifactorial IR in patients at risk of T2DM/MASLD is selective by determining if inducing a discrete, "pure" form of IR, via pharmacologic inhibition of phosphoinositide-3-kinase (PI3K) with alpelisib, versus placebo, attenuates excessive DNL. Investigators will also study this question in healthy, insulin-sensitive (IS) volunteers.
Participants in this randomized crossover trial will be admitted twice to the inpatient clinical research unit. During each admission, they will take a dose of either alpelisib or placebo (in randomized order) in the evening and receive infusions of [13C] sodium acetate and [2H] D-glucose to measure DNL and endogenous glucose production (EGP), respectively, during an overnight fast. DNL measurement will then continue during the following day during 8 hours of standardized mixed-meal feedings. Blood will be drawn at defined intervals for determining levels of glucose, insulin, lipids including triglycerides and free fatty acids, and tracer/tracee enrichments for the stable-isotope tracers. There will be a 2-8-week hiatus for drug washout between the two inpatient study admissions.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Basic Science
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 18 Years to 70 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •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
Exclusion Criteria
- •Inability to provide informed consent in English or Spanish
- •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
- •Reproductive concerns i. Positive qualitative β-hCG (i.e., pregnancy test) in women of childbearing potential ii. Women currently pregnant iii. Women currently breastfeeding
- •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)
Arms & Interventions
Placebo then alpelisib (Insulin Sensitive group)
On Study Visit 1, participants in the Insulin Sensitive (IS) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of placebo. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of alpelisib 300 mg.
Intervention: Alpelisib 300 mg (Drug)
Alpelisib then placebo (Insulin Sensitive group)
On Study Visit 1, participants in the Insulin Sensitive (IS) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of alpelisib 300 mg. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of placebo.
Intervention: Alpelisib 300 mg (Drug)
Alpelisib then placebo (Insulin Sensitive group)
On Study Visit 1, participants in the Insulin Sensitive (IS) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of alpelisib 300 mg. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of placebo.
Intervention: [1-13C] sodium acetate (Drug)
Placebo then alpelisib (Insulin Resistant group)
On Study Visit 1, participants in the Insulin Resistant (IR) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of placebo. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of alpelisib 300 mg.
Intervention: Alpelisib 300 mg (Drug)
Placebo then alpelisib (Insulin Resistant group)
On Study Visit 1, participants in the Insulin Resistant (IR) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of placebo. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of alpelisib 300 mg.
Intervention: Nestlé BOOST Plus (Dietary Supplement)
Alpelisib then placebo (Insulin Resistant group)
On Study Visit 1, participants in the Insulin Resistant (IR) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of alpelisib 300 mg. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of placebo.
Intervention: Alpelisib 300 mg (Drug)
Alpelisib then placebo (Insulin Resistant group)
On Study Visit 1, participants in the Insulin Resistant (IR) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of alpelisib 300 mg. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of placebo.
Intervention: Placebo (Drug)
Alpelisib then placebo (Insulin Sensitive group)
On Study Visit 1, participants in the Insulin Sensitive (IS) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of alpelisib 300 mg. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of placebo.
Intervention: Placebo (Drug)
Placebo then alpelisib (Insulin Sensitive group)
On Study Visit 1, participants in the Insulin Sensitive (IS) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of placebo. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of alpelisib 300 mg.
Intervention: Placebo (Drug)
Placebo then alpelisib (Insulin Sensitive group)
On Study Visit 1, participants in the Insulin Sensitive (IS) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of placebo. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of alpelisib 300 mg.
Intervention: [1-13C] sodium acetate (Drug)
Placebo then alpelisib (Insulin Sensitive group)
On Study Visit 1, participants in the Insulin Sensitive (IS) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of placebo. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of alpelisib 300 mg.
Intervention: [6,6-2H2] D-glucose (Drug)
Placebo then alpelisib (Insulin Sensitive group)
On Study Visit 1, participants in the Insulin Sensitive (IS) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of placebo. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of alpelisib 300 mg.
Intervention: Nestlé BOOST Plus (Dietary Supplement)
Alpelisib then placebo (Insulin Sensitive group)
On Study Visit 1, participants in the Insulin Sensitive (IS) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of alpelisib 300 mg. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of placebo.
Intervention: [6,6-2H2] D-glucose (Drug)
Alpelisib then placebo (Insulin Sensitive group)
On Study Visit 1, participants in the Insulin Sensitive (IS) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of alpelisib 300 mg. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of placebo.
Intervention: Nestlé BOOST Plus (Dietary Supplement)
Placebo then alpelisib (Insulin Resistant group)
On Study Visit 1, participants in the Insulin Resistant (IR) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of placebo. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of alpelisib 300 mg.
Intervention: Placebo (Drug)
Placebo then alpelisib (Insulin Resistant group)
On Study Visit 1, participants in the Insulin Resistant (IR) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of placebo. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of alpelisib 300 mg.
Intervention: [1-13C] sodium acetate (Drug)
Placebo then alpelisib (Insulin Resistant group)
On Study Visit 1, participants in the Insulin Resistant (IR) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of placebo. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of alpelisib 300 mg.
Intervention: [6,6-2H2] D-glucose (Drug)
Alpelisib then placebo (Insulin Resistant group)
On Study Visit 1, participants in the Insulin Resistant (IR) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of alpelisib 300 mg. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of placebo.
Intervention: [1-13C] sodium acetate (Drug)
Alpelisib then placebo (Insulin Resistant group)
On Study Visit 1, participants in the Insulin Resistant (IR) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of alpelisib 300 mg. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of placebo.
Intervention: [6,6-2H2] D-glucose (Drug)
Alpelisib then placebo (Insulin Resistant group)
On Study Visit 1, participants in the Insulin Resistant (IR) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of alpelisib 300 mg. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of placebo.
Intervention: Nestlé BOOST Plus (Dietary Supplement)
Outcomes
Primary Outcomes
Hepatic de novo lipogenesis (DNL) (absolute value)
Time Frame: Up to 24 hours after dosing
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)
Time Frame: Up to 24 hours after dosing
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)
Time Frame: Up to 15 hours after dosing
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)
Time Frame: Up to 15 hours after dosing
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
Secondary Outcomes
- Serum insulin level(Approximately 11-19 hours after dosing)
- Plasma glucose level(Approximately 11-19 hours after dosing)
- Triglycerides level(Approximately 11-19 hours after dosing)
- Free fatty acids level(Approximately 11-19 hours after dosing)
- Glucose kinetics: rate of appearance (absolute value)(Up to 15 hours after dosing)
- Glucose kinetics: rate of appearance (relative value)(Up to 15 hours after dosing)
- Glucose kinetics: rate of disappearance (absolute value)(Up to 15 hours after dosing)
- Glucose kinetics: rate of disappearance (relative value)(Up to 15 hours after dosing)
Investigators
Joshua Cook
Assistant Professor of Medicine
Columbia University