Pancreatic Clamp in NAFLD

NCT05724134 | Completed Phase 1 FDA Drug FDA Device

• 2 other identifiers: AAAU30143P30DK063608
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

This is a single-center, prospective, randomized, controlled (crossover) clinical study designed to investigate the specific dose-response impact of insulin infusion rate (IIR) on blood glucose levels during a pancreatic clamp study. 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, or clinically judged to be at high risk for, uncomplicated non-alcoholic fatty liver disease (NAFLD). Participants will undergo two pancreatic clamp procedures in which individualized basal IIR are identified, followed in one by maintenance of basal IIR (maintenance hyperinsulinemia, MH) and in the other by a stepped decline in IIR (reduction toward euinsulinemia, RE). In both clamps the investigators will closely monitor plasma glucose and various metabolic parameters. The primary outcome will be the absolute and relative changes in steady-state plasma glucose levels at each stepped decline in IIR.

Conditions

Insulin Resistance; Prediabetic State; Hyperinsulinemia; Non-Alcoholic Fatty Liver Disease; Obesity

Keywords

Insulin resistance; Hyperinsulinemia; Diabetes; Non-alcoholic fatty liver disease

Outcome Measures

Primary Outcomes (6)

• Plasma glucose (absolute values) (units: mg/dL)

  Goal is first to clamp insulin infusion rate to maintain mean basal fasting plasma glucose during the basal titration phase, and then during the intervention phase to observe the glucose levels that result from altering the basal IIR.

  Up to 425 minutes from the start of the procedure.

• Plasma glucose (relative/change) (units: fold difference and/or ∆mg/dL relative to previous time points)

  Goal is first to clamp insulin infusion rate to maintain mean basal fasting plasma glucose during the basal titration phase, and then during the intervention phase to observe the impact of altering the basal IIR on glycemia.

  Up to 425 minutes from the start of the procedure.

• Serum insulin (absolute values) (units: micro-international units per milliliter (µIU/mL))

  Investigators will assess the insulin levels attained at the basal IIR, and at each stepwise reduction in IIR during the intervention phase.

  Up to 425 minutes from the start of the procedure.

• Serum insulin (relative/change) (units: fold difference and/or ∆ µIU/mL relative to previous time points)

  Investigators will compare the baseline insulin level to that attained at the basal IIR, as well as comparing to the change in insulin level that occurs with alterations in the IIR during the intervention phase.

  Up to 425 minutes from the start of the procedure.

• Serum C-peptide (absolute values) (units: ng/mL)

  Suppression of endogenous insulin by octreotide during pancreatic clamp is expected to result in a fall in C-peptide levels to near zero.

  Up to 425 minutes from the start of the procedure

• Serum C-peptide (relative/change) (units: fold difference and/or ∆ µIU/mL relative to previous time points)

  Suppression of endogenous insulin by octreotide during pancreatic clamp is expected to result in a fall in C-peptide levels to near zero.

  Up to 425 minutes from the start of the procedure

Secondary Outcomes (9)

• Serum or plasma triglyceride (TG) (absolute values) (units: mg/dL)

  Up to 425 minutes from the start of the procedure

• Serum or plasma triglyceride (TG) (relative/change) (units: fold difference and/or ∆mg/dL relative to previous time points)

  Up to 425 minutes from the start of the procedure

• Serum or plasma free fatty acid (FFA) (absolute values) (units: mg/dL)

  Up to 425 minutes from the start of the procedure

• Serum or plasma free fatty acid (FFA) (relative/change) (units: fold difference and/or ∆mg/dL relative to previous time points)

  Up to 425 minutes from the start of the procedure

• Serum or plasma apolipoprotein B (ApoB) (absolute values) (units: mg/dL)

  Up to 425 minutes from the start of the procedure

Other Outcomes (4)

• Serum/plasma glucagon (absolute values) (units: ng/L)

  Up to 425 minutes from the start of the procedure

• Serum or plasma glucagon (relative/change) (units: fold difference and/or ∆ng/L relative to previous time points)

  Up to 425 minutes from the start of the procedure

• Serum or plasma growth hormone (absolute values) (units: ng/mL)

  Up to 425 minutes from the start of the procedure

Study Arms (2)

Maintenance hyperinsulinemia (MH) protocol

ACTIVE COMPARATOR

The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will remain at 100% of basal for the full duration (225 min). The IIR and resulting insulin levels are expected to be relatively high (cf. hyperinsulinemia) because of underlying insulin resistance.

Drug: Insulin human; Drug: Octreotide Acetate; Drug: Glucagon; Drug: Growth Hormone, Human; Other: [6,6-2H2] D-glucose; Drug: 20% D-glucose (aq); Dietary Supplement: BOOST Plus; Dietary Supplement: CORE Bar; Device: Harvard Apparatus PHD ULTRA CP syringe pump; Device: Yellow Springs Instruments (YSI) 2500 Biochemistry Glucose/Lactate Analyzer

Reduction toward euinsulinemia (RE) protocol

EXPERIMENTAL

The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the basal IIR will be reduced by up to 50%. Thus, the basal hyperinsulinemia expected due to underlying insulin resistance will be reduced toward euinsulinemia.

Drug: Insulin human; Drug: Octreotide Acetate; Drug: Glucagon; Drug: Growth Hormone, Human; Other: [6,6-2H2] D-glucose; Drug: 20% D-glucose (aq); Dietary Supplement: BOOST Plus; Dietary Supplement: CORE Bar; Device: Harvard Apparatus PHD ULTRA CP syringe pump; Device: Yellow Springs Instruments (YSI) 2500 Biochemistry Glucose/Lactate Analyzer

Interventions

Insulin human DRUG

Insulin infusion rate (IIR) will be determined empirically first to maintain mean basal fasting plasma glucose, and then either maintained at the basal rate (MH protocol) or be reduced stepwise toward euinsulinemia (RE protocol).

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

Octreotide Acetate DRUG

Octreotide will be infused at 30 ng/kg/min to suppress endogenous insulin, glucagon, and growth hormone secretion. Co-administered with glucagon and rhGH.

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

Glucagon DRUG

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.

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

Growth Hormone, Human DRUG

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.

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

[6,6-2H2] D-glucose OTHER

Stable isotope tracer administered to calculate glucose kinetics during pancreatic clamp.

Also known as: D2-glucose, D2G

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

20% D-glucose (aq) DRUG

20% D-glucose (aq) (D20W) will be administered to counteract hypoglycemia or strongly downward blood glucose trends, as needed.

Also known as: D20W

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

BOOST Plus DIETARY_SUPPLEMENT

Nutritional supplement will be administered to provide three standardized "mixed meals" on the day before the pancreatic clamp.

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

CORE Bar DIETARY_SUPPLEMENT

Energy bar used as a standardized snack on the day before the pancreatic clamp.

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

Harvard Apparatus PHD ULTRA CP syringe pump DEVICE

Syringe pump used for highly precise administration of insulin, octreotide/glucagon/rhGH, and D20W (as needed) even at low infusion rates.

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

Yellow Springs Instruments (YSI) 2500 Biochemistry Glucose/Lactate Analyzer DEVICE

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.

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women (using highly effective contraception if of childbearing potential, aged 18-65 years
• Body mass index of 25-45 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:
• a. Meeting either of the American Diabetes Association's definitions for prediabetes or IFG within the previous year\* and on screening labs: i. Prediabetes: Hemoglobin A1c 5.7-6.4% ii. IFG: plasma glucose of 100-125 mg dL-1 after 8-h fast b. Homeostasis Model of Insulin Resistance (HOMA-IR) score ≥ 2.73
• Fasting hyperinsulinemia (fasting insulin level ≥ 13 µIU/mL) on screening labs
• Diagnosed with, or clinically judged to be at high risk for, non-alcoholic fatty liver disease (NAFLD), also known as metabolic-associated fatty liver disease (MAFLD), by hepatologist or other qualified specialist physician and the condition is listed as an active problem in the electronic medical record
• 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
• Concerns arising at screening visit (any of the following):
• i. Unwillingness to use only bedpan or urinal to void during the clamp
• ii. Unwillingness to fast (except water) for up to 22 hours
• iii. Documented weight loss of ≥ 5% of baseline within the previous 6 months
• iv. 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
• v. Abnormal resting heart rate: \<60 or ≥100 bpm
• Sinus brady- or tachycardia that has been extensively worked up and considered benign by the recruit's personal physician may be permitted at the Principal Investigator's discretion
• vi. Abnormal screening electrocardiogram (or if on file, performed within previous 90 d)
• Non-sinus rhythm
• Significant corrected QT segment (QTc) prolongation (≥ 480 ms)
• New or previously unknown ischemic changes that persist on repeat EKG: 1. ST segment elevations; 2. T-wave inversions
• vii. Laboratory evidence of diabetes mellitus:

Sponsors & Collaborators

• Columbia University: lead
• Albert Einstein College of Medicine: collaborator
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Columbia University Irving Medical Center

New York, New York, 10032, United States

Location

MeSH Terms

Conditions

Insulin Resistance; Prediabetic State; Hyperinsulinism; Non-alcoholic Fatty Liver Disease; Obesity; Diabetes Mellitus

Interventions

Insulin; Octreotide; Glucagon; Human Growth Hormone; Glucose

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Fatty Liver; Liver Diseases; Digestive System Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Proglucagon; Growth Hormone; Pituitary Hormones, Anterior; Pituitary Hormones; Hexoses; Monosaccharides; Sugars; Carbohydrates

Study Officials

• Joshua R. Cook, MD, PhD

  Columbia University

  PRINCIPAL INVESTIGATOR

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

Model Details: All participants will undergo (i.e., cross over between) both pancreatic clamp protocols (MH, RE) separated by 2-8 weeks. The order of the clamp protocols (i.e., MH \> RE, RE \> MH) will be randomized.

Study Record Dates

• First Submitted: February 2, 2023
• First Posted: February 13, 2023
• Study Start: August 29, 2023
• Primary Completion: September 24, 2025
• Study Completion: September 24, 2025
• Last Updated: January 12, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Indefinitely following study completion.
• Access Criteria: All requests will be reviewed by the PI for scientific merit and samples/data will be transferred only upon completion of a MTA or DUA, as appropriate. No PHI will be disclosed or shared.

Locations

US (1)