Human Models of Selective Insulin Resistance: Pancreatic Clamp
3 other identifiers
interventional
36
1 country
1
Brief Summary
This is a single-center, prospective, randomized, controlled (crossover) clinical study designed to investigate the impact of lowering insulin levels on hepatic glucose production (HGP) vs de novo lipogenesis (DNL) in people with insulin resistance. The investigators will recruit participants with a history of overweight/obesity and evidence of insulin resistance (i.e., fasting hyperinsulinemia plus prediabetes and/or impaired fasting glucose and/or Homeostasis Model Assessment of Insulin Resistance \[HOMA-IR\] score \>=2.73), and with evidence of metabolic dysfunction-associated steatotic liver disease (MASLD). Participants will undergo two pancreatic clamp procedures -- one in which serum insulin levels are maintained near hyperinsulinemic baseline (Maintenance Hyperinsulinemia or "MH" Protocol) and the other in which serum insulin levels are lowered by 50% (Reduction toward Euinsulinemia or "RE" Protocol). In both clamps the investigators will use stable-isotope tracers to monitor hepatic glucose and triglyceride metabolism. The primary outcome will be the impact of steady-state clamp insulinemia on HGP vs DNL.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_1
Started Jan 2027
Typical duration for phase_1
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
August 14, 2024
CompletedFirst Posted
Study publicly available on registry
August 16, 2024
CompletedStudy Start
First participant enrolled
January 1, 2027
ExpectedPrimary Completion
Last participant's last visit for primary outcome
December 31, 2028
Study Completion
Last participant's last visit for all outcomes
February 28, 2029
February 6, 2026
February 1, 2026
2 years
August 14, 2024
February 4, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (6)
Hepatic de novo lipogenesis (DNL) (absolute value)
Percent incorporation of newly synthesized fatty acids into plasma or very low-density lipoprotein (VLDL) triglyceride (TG) during pancreatic clamp procedures. (Unit: %)
Up to 6.5 hours of pancreatic clamp protocol
Hepatic de novo lipogenesis (DNL) (relative value)
Percent incorporation of newly synthesized fatty acids into plasma or VLDL TG during pancreatic clamp procedures. (Unit: fold difference and/or ∆% versus other group)
Up to 6.5 hours of pancreatic clamp protocol
Endogenous glucose production (EGP) (absolute value)
Calculated from D2G tracer enrichment by the Steele equations during pancreatic clamp procedures. (Units: mg/kg/min)
Up to 6.5 hours of pancreatic clamp protocol
Endogenous glucose production (EGP) (relative value)
Calculated from D2G tracer enrichment by the Steele equations during pancreatic clamp procedures. (Units: fold difference and/or ∆% versus other group)
Up to 6.5 hours of pancreatic clamp protocol
Plasma glucose level
Plasma glucose level during pancreatic clamp procedures. (Units: mg/dL)
Up to 6.5 hours of pancreatic clamp protocol
Serum insulin level
Serum insulin level during pancreatic clamp procedures (Units: µU/mL)
Up to 6.5 hours of pancreatic clamp protocol
Secondary Outcomes (6)
Serum or plasma triglyceride level
Up to 6.5 hours of pancreatic clamp protocol
Plasma free fatty acids level
Up to 6.5 hours of pancreatic clamp protocol
Glucose kinetics: rate of appearance (absolute value)
Up to 6.5 hours of pancreatic clamp protocol
Glucose kinetics: rate of appearance (relative value)
Up to 6.5 hours of pancreatic clamp protocol
Glucose kinetics: rate of disappearance (absolute value)
Up to 6.5 hours of pancreatic clamp protocol
- +1 more secondary outcomes
Other Outcomes (3)
Serum C-peptide level
Up to 6.5 hours of pancreatic clamp protocol
Plasma glucagon level
Up to 6.5 hours of pancreatic clamp protocol
Serum growth hormone level
Up to 6.5 hours of pancreatic clamp protocol
Study Arms (2)
Maintenance hyperinsulinemia (MH) Protocol then Reduction toward Euinsulinemia (RE) Protocol
EXPERIMENTALOn Pancreatic Clamp Visit 1 (MH Protocol), the insulin infusion rate (IIR) will be set to approximately replicate participants' endogenous fasting serum insulin levels based on screening visit data for the duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (RE Protocol), the IIR will be set to reduce serum insulin levels to roughly 50% of the screening fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
Reduction toward euinsulinemia (RE) protocol
EXPERIMENTALOn Pancreatic Clamp Visit 1 (RE Protocol), the insulin infusion rate (IIR) will be set to produce serum insulin levels of approximately 50% that of the screening fasting serum insulin level for the full duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (MH Protocol), the IIR will be set to approximately replicate the full fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
Interventions
Insulin infusion rate (IIR) will be determined either to maintain fasting serum insulin levels (MH protocol) or to reduce fasting serum insulin levels by approximately 50% toward euinsulinemia (RE protocol).
Octreotide will be infused at 30 ng/kg/min to suppress endogenous insulin, glucagon, and growth hormone secretion. Co-administered with glucagon and rhGH.
Glucagon will be replaced at a constant rate of up to 0.65 ng/kg/min to maintain baseline counterregulatory response. Co-administered with octreotide and rhGH.
Recombinant human growth hormone (rhGH) will be replaced at a constant rate of up to 3 ng/kg/min to maintain baseline counterregulatory response. Co-administered with octreotide and glucagon.
20% D-glucose (aq) (D20W) will be administered to counteract hypoglycemia or strongly downward blood glucose trends, as needed.
Stable isotope tracer administered to calculate glucose kinetics during pancreatic clamp.
Stable isotope tracer administered to calculate de novo lipogenesis during pancreatic clamp.
Nutritional supplement will be administered to provide standardized "mixed meals" prior to the pancreatic clamp.
Energy bar snack will be administered the evening before the pancreatic clamp.
Syringe pump used for highly precise administration of insulin, octreotide/glucagon/rhGH, and D20W (as needed) even at low infusion rates.
Glucose oxidase analyzer used to detect plasma glucose levels at the point of care. YSI have been the gold standard in clamp studies for many years. Two machines will run in parallel to ensure accuracy of results.
Eligibility Criteria
You may qualify if:
- Men and women, ages 18-65 years
- Body mass index of 27-50 kg/m2
- Able to understand written and spoken English and/or Spanish
- Evidence of insulin resistance, represented by any or all of the following criteria:
- Meeting either of the American Diabetes Association's definitions for prediabetes or Impaired fasting glucose (IFG) within the previous year and on screening labs:
- Prediabetes: Hemoglobin A1c 5.7-6.4%
- IFG: plasma glucose of 100-125 mg/dL after 8-h fast
- Homeostasis Model of Insulin Resistance (HOMA-IR) score ≥ 2.73
- Fasting hyperinsulinemia (fasting insulin level ≥ 13 µU/mL) on screening labs
- Presence of uncomplicated MASLD, defined by vibration-controlled transient elastography (VCTE) as a steatosis score S1-S3 + fibrosis score F0-F2
- Written informed consent (in English or Spanish) and any locally required authorization (e.g., Health Insurance Portability and Accountability Act) obtained from the participant prior to performing any protocol-related procedures, including screening evaluations.
You may not qualify if:
- Unable to provide informed consent in English or Spanish
- Unwillingness to use only bedpan or urinal to void or to refrain from non-emergent mobile device use during the clamp
- Documented weight loss of ≥ 5% of baseline within the previous 3 months
- Abnormal blood pressure (including on treatment, if prescribed)
- Systolic blood pressure \< 90 mm Hg or \> 160 mm Hg, and/or
- Diastolic blood pressure \< 60 mm Hg or \> 100 mm Hg
- Abnormal resting heart rate: \< 60 or ≥ 110 bpm
- Sinus brady- or tachycardia that has been worked up and considered benign by the recruit's personal physician may be permitted at the PI's discretion
- Abnormal screening electrocardiogram (or if on file, performed within previous 90 days)
- Laboratory evidence of diabetes mellitus:
- Hemoglobin A1c ≥ 6.5%, and/or
- Fasting plasma glucose ≥ 126 mg/dL
- Positive qualitative β-hCG (Human chorionic gonadotropin, β subunit) (i.e., pregnancy test) in women of childbearing potential
- Positive urine drug screen, except for lawfully prescribed medications and/or marijuana
- Liver function abnormalities (either of the following)
- +55 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (1)
Columbia University Irving Medical Center
New York, New York, 10032, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Joshua R Cook, MD, PhD
Columbia University
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- RANDOMIZED
- Masking
- SINGLE
- Who Masked
- PARTICIPANT
- Masking Details
- Participant will be blinded to study group assignment.
- Purpose
- BASIC SCIENCE
- Intervention Model
- CROSSOVER
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Assistant Professor of Medicine
Study Record Dates
First Submitted
August 14, 2024
First Posted
August 16, 2024
Study Start (Estimated)
January 1, 2027
Primary Completion (Estimated)
December 31, 2028
Study Completion (Estimated)
February 28, 2029
Last Updated
February 6, 2026
Record last verified: 2026-02
Data Sharing
- IPD Sharing
- Will share
- Time Frame
- Scientific data will be shared as soon as possible. Scientific data included in published manuscripts will be available at the time of publication; all other generated scientific data will be shared no later than the end of the award. The study data will be stored in the repository for at least 5 years.
- Access Criteria
- To request access of the data, researchers will use the standard processes at Dryad. Given that we seek the widest possible availability, in most cases all that is necessary is obtaining a Dryad account from the repository web site.
Participant-level clinical data will be preserved by depositing the deidentified data to Dryad, a generalist repository that is participating in the NIH Generalist Repository Ecosystem Initiative. The repository will provide metadata, persistent identifiers, and long-term access for open and controlled access. Each study created in Dryad is assigned a digital object identifier (DOI). This data DOI will be referenced in the publication to allow the research community easy access to the exact data used in the publication. To protect research participants' privacy and confidentiality, data submitted to the repository will not include personally identifiable information such as names or addresses. Additional protections, such as the approach for managing Health Insurance Portability and Accountability Act identifiers, will be used for de-identification and to provide a limited data set to minimize the risk of participant reidentification.