Bile Acids in Acute Insulin Resistance

Bile Acid and Lipid Metabolism in Patients With Drug-induced Acute Insulin Resistance

This is a prospective observational study with a primary goal of monitoring changes in circulating bile acid profiles and parameters of glucose and lipid metabolism prior, during, and after cancer treatment with agents that directly impair insulin action: PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. Patients will not receive any cancer treatment specifically for the purposes of this study. Rather, this study will be based on treatment decisions made independently by participants' oncologists according to standard of care or other clinical trial protocol. This study seeks to enroll at least 25 participants each for PI3K inhibitors, mTOR inhibitors and, once available for open-label treatment, AKT inhibitors.

Study Overview

• Status: Recruiting
• Conditions: Cancer; Insulin Resistance; MTOR Gene Mutation; PI3K Gene Mutation; AKT Gene Mutation
• Intervention / Treatment: Drug: Drug-induced acute insulin resistance due to PI3K inhibitor, AKT inhibitor, or mTOR inhibitor

Detailed Description

The primary objective of this study is to determine the effect of drug-induced acute insulin resistance (diaIR) on the ratio of 12α-hydroxylated bile acids (12-HBA) to 12α-hydroxylated bile acids (non-12-HBA) in cancer patients treated with phosphatidylinositol-4,5-bisphosphate kinase (PI3K) inhibitors (PI3Ki), mammalian target of rapamycin (mTOR) inhibitors (mTORi), and AKT inhibitors (AKTi) once possible. Specifically, this study will: (1) verify the induction of diaIR by monitoring changes in fasting ± postprandial blood glucose, insulin/c-peptide, and fructosamine; and (2) assess qualitative and quantitative changes in the circulating bile acid (BA) pool (including bile acid intermediary metabolites) by mass spectrometry in the fasting ± postprandial states prior to and then at 2 and 4 weeks after starting treatment. This study focuses in particular on determining changes in the 12α-hydroxylated bile acids to 12α-hydroxylated bile acids, as well as each of these subclasses and their individual substituents as a proportion of the overall BA pool.

• Study Type: Observational
• Enrollment (Estimated): 75

Contacts and Locations

• Study Contact: Name: Research Nurse Navigator; Phone Number: 212-342-5162; Email: cancerclinicaltrials@cumc.columbia.edu
• Study Contact Backup: Name: Dawn Hershman, MD; Phone Number: 212-305-1945; Email: dlh23@cumc.columbia.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Medical Center
      • Contact: Joshua Cook, MD; Phone Number: 609-694-7867; Email: jrc2175@cumc.columbia.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adult patients of any gender, without pre-existing diabetes, treated with PI3K/AKT/mTOR inhibitors for cancer according to standard of care.

Description

Inclusion Criteria:

• Age ≥ 18 years
• Speaks English and/ or Spanish
• Any cancer diagnosis

• Planned for treatment with:

  • PI3K inhibitors

    • Alpelisib
    • Inavolisib
    • Any experimental PI3K inhibitor

  • AKT inhibitors (if these become available for open-label use during the study course)

    • Afuresertib
    • Capivasertib
    • Ipatasertib
    • Miransertib
    • Uposertib

  • mTOR inhibitors

    • Everolimus
    • Sirolimus
    • Temsirolimus
• Signed informed consent

Exclusion Criteria:

• Known dysglycemia
• Known diagnosis of diabetes mellitus

• Treatment with glucose-lowering medications at baseline

  • Insulin
  • Sulfonylureas or meglitinides
  • Metformin >1000mg total daily dose
  • Thiazolidinediones
  • SGLT2 inhibitors
  • GLP-1 receptor agonists
  • DPP4 inhibitors
  • Amylin mimetics
  • Acarbose
• Significant biochemical evidence of liver dysfunction on lab tests within 30 days before starting drug that have not fallen to below the following thresholds prior to starting drug
• Significant functional or anatomical abnormalities of the small intestine
• Use of certain medications at baseline, within 7 days of starting cancer drug
• Allergy to cow dairy or soy (only excludes from MMTT, does not exclude from fasting blood draws)
• Inability to provide informed consent

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients treated with PI3K/AKT/mTOR inhibitors for cancer; Patients with cancer being treated with PI3K/AKT/mTOR inhibitors will be studied prospectively for the impact of treatment on bile acid metabolism as a function of drug-induced acute insulin resistance. Treatments will be selected by patients' treating oncologist based on standard of care.	Drug: Drug-induced acute insulin resistance due to PI3K inhibitor, AKT inhibitor, or mTOR inhibitor; Participants will be treated with PI3K/AKT/mTOR inhibitors by their treating oncologist based on standard of care. This study will prospectively monitor bile acids and parameters of insulin resistance before and during treatment with these drugs.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ratio of 12-HBA to non-12-HBA	Insulin resistance is expected to cause a rise in total bile acids, but with 12-alpha-hydroxylated bile acid (12-HBA) species outpacing non-12-alpha-hydroxylated bile acid (non-12-HBA) species, leading to a rise in the 12-HBA:non-12-HBA ratio. This would indicate that insulin resistance per se is sufficient to alter 12-HBA balance, and thus 12-HBA may be a useful therapeutic target for management of the macrovascular complications of insulin resistance. BA profile and levels of BA intermediates 7-HCO and 7,12-diHCO will be measured by LC-MS/MS when fasting +/- after 2-hour mixed meal tolerance test.	1-2 Months
Insulin resistance	Determine the timing and extent of PI3K/AKT/mTOR inhibitor treatment on parameters of insulin resistance: glucose, insulin, c-peptide, and adiponectin when fasting +/- following 2-hour mixed meal tolerance test	1-2 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lipid profile	The primary endpoint is the outcome of the secondary objective: namely, evaluation of the effect of PI3Ki/AKTi/mTORi-induced insulin resistance on the lipid profile (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, free fatty acids) when fasting +/- after 2-hour mixed meal tolerance test	1-2 months
Surrogate markers of BA signaling	Determine the timing and extent of PI3K/AKT/mTOR inhibitor treatment on parameters of bile acid signaling: fibroblast growth factor 19 (FGF-19) and glucagon-like peptide-1 (GLP-1). We expect that a shift in BA pool composition (especially as regards 12-HBA vs non-12-HBA) will impact differentially on FGF-19 and GLP-1 levels.	1-2 months

Collaborators and Investigators

• Sponsor: Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2022
• Primary Completion (Estimated): June 10, 2026
• Study Completion (Estimated): June 10, 2026

Study Registration Dates

• First Submitted: October 5, 2022
• First Submitted That Met QC Criteria: October 5, 2022
• First Posted (Actual): October 7, 2022

Study Record Updates

• Last Update Posted (Actual): December 29, 2023
• Last Update Submitted That Met QC Criteria: December 22, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Cardiovascular disease; Insulin resistance; Dyslipidemia; Bile acids
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Insulin Resistance; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Protein Kinase Inhibitors; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus; Temsirolimus; MTOR Inhibitors
• Other Study ID Numbers: AAAU0504

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No