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Insulin ResistancePhase 1NCT06558422

Human Models of Selective Insulin Resistance: Pancreatic Clamp

A Phase 1 study testing Insulin human, Octreotide Acetate and Glucagon in people with Insulin Resistance and Hyperinsulinemia, run by Columbia University at 1 site in United States.

Not yet recruiting

Opening soon. The study is approved but enrolment has not started yet. Sites may already take enquiries.

Sites and contacts
Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 to 65 years
What is being tested?
Insulin human, Octreotide Acetate and Glucagon
Could I receive a placebo?
No, everyone receives an active treatment
How many people
36 participants
Where
1 siteUnited States
Study dates
1 Jan 2027to 28 Feb 2029
Phase
Phase 1
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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%
Show all 11Show fewer
  • 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.

Who cannot join

  • 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
Show all 73Show fewer
  • 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)
  • Transaminases (AST or ALT) > 3.0 x the upper limit of normal
  • Total bilirubin > 1.25 x the upper limit of normal
  • Fasting serum triglycerides at screening ≥ 400 mg/dL
  • Abnormal screening serum electrolytes that are considered potentially significant according to the clinical judgment of the PI
  • Abnormal complete blood count (CBC) (any of the following)
  • Hemoglobin < 10 g/dL or hematocrit < 30%
  • Platelet count < 100,000/µL
  • Women currently pregnant, measured by serum and/or urine β-hCG, or trying to become pregnant
  • Women currently breastfeeding
  • History of having met any of the American Diabetes Association's definitions of diabetes mellitus (i.e., overt diabetes):
  • Hemoglobin A1c ≥ 6.5%, or rapid rise in documented HbA1c values causing clinical concern for evolving insulin deficiency
  • Plasma glucose ≥ 126 mg/dL after 8-h fast
  • Plasma glucose of ≥ 200 mg/dL at 2 h after ingestion of a 75-g glucose load
  • Random plasma glucose ≥ 200 mg/dL associated with typical hyperglycemic symptoms, diabetic ketoacidosis, or hyperglycemic-hyperosmolar state
  • History of gestational diabetes mellitus within the previous 5 years
  • Use of most antidiabetic medications within the 30 days prior to screening
  • Excluded: thiazolidinediones, sulfonylureas, meglitinides, DPP4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, amylin mimetics, acarbose, insulin
  • Metformin is acceptable provided that recruits meet all of the inclusion criteria at screening
  • Clinical concern for absolute insulin deficiency (e.g., type 1 diabetes, pancreatic disease)
  • Known diagnoses of familial combined hyperlipidemia or familial chylomicronemia syndrome
  • Use of certain lipid-lowering drugs within 30 d prior to screening visit:
  • Fibrates (e.g., fenofibrate, clofibrate, gemfibrozil)
  • Prescription-strength omega-3 fatty acids (e.g., Lovaza®, Vascepa®)
  • Known, documented history, at the time of screening, of any of the following medical conditions:
  • Pancreatic pathology
  • Cardiovascular diseases (N.B. uncomplicated hypertension is not exclusionary)
  • Chronic kidney disease, Stage 3 or higher (estimated glomerular filtration rate < 60 mL min-1 1.73 m-2), of any cause
  • Advanced or severe liver disease (including fibrosis scores of F3-F4 on screening VCTE)
  • Gallstone disease
  • Chronic viral illness
  • Malabsorptive conditions (active)
  • Active seizure disorder (including controlled with antiepileptic drugs)
  • Psychiatric diseases causing functional impairment and/or requiring use of anti-dopaminergic antipsychotic drugs associated with significant weight gain/metabolic dysfunction (e.g., clozapine, olanzapine), monoamine oxidase inhibitors, tricyclic antidepressants, or lithium
  • Known adrenal disease
  • Venous thromboembolic disease (deep vein thrombosis or pulmonary embolism) or any required use of therapeutic anticoagulation
  • Bleeding disorders, including due to anticoagulation, or significant anemia (see above)
  • Active malignancy, or hormonally active benign neoplasm
  • Clinical concern for increased risk of volume overload, including due to medications and/or heart/liver/kidney problems, as listed above
  • Clinical concern for increased risk of hypokalemia, including low potassium on screening labs (i.e., below lower limit of normal), use of certain medications, or any medical conditions listed above
  • Use of certain medications currently or within 30 d prior to screening:
  • Prescribed medications used for any of the indications in the preceding list of excluded conditions, or their use within 30 d prior to screening, except allowances for:
  • Use of drugs prescribed for indications other than the exclusionary diagnoses/purposes listed above, e.g., antiepileptic drugs used for non-seizure indications, ACEi (angiotensin-converting enzyme inhibitor) / ARB (angiotensin receptor blocker) used for uncomplicated hypertension rather than for congestive heart failure, etc. Note, as above, that antidiabetic drugs except metformin within 30 days of screening are excluded.
  • Loop diuretics (furosemide, torsemide, ethacrynic acid)
  • Oral or parenteral corticosteroids (at greater than prednisone 5 mg daily, or equivalent) for more than 3 days within the previous 30 days; topical and inhaled formulations are permitted
  • Fludrocortisone
  • Beta blockers or non-dihydropyridine calcium channel blockers (verapamil or diltiazem)
  • History of certain weight-loss (bariatric) surgery, including:
  • Roux-en-Y gastric bypass
  • Biliopancreatic diversion
  • Restrictive procedures (lap band, sleeve gastrectomy) performed within the past 6 months
  • Clinical concern for alcohol overuse, including recent documented history during screening and/or participant report of regularly consuming more than 2 drinks per day for males or 1 drink per day for females.
  • Positive urine drug screen, with exceptions for:
  • Lawfully prescribed medications
  • Marijuana/THC positivity, provided that the participant agrees not to use it during the same period that they will abstain from alcohol
  • History of severe infection or ongoing febrile illness within 14 days of screening
  • Any other disease, condition, or laboratory value that, in the opinion of the investigator, would place the participant at an unacceptable risk and/or interfere with the analysis of study data.
  • Known allergy/hypersensitivity to any component of the medicinal product formulations, foods (including soy, dairy, peanuts, tree nuts, or egg), IV infusion equipment, plastics, adhesive or silicone, history of infusion site reactions with IV administration of other medicines, or ongoing clinically important allergy/hypersensitivity as judged by the investigator.
  • Concurrent enrollment in another clinical study of any investigational drug therapy within 30 days prior to screening or within 5 half-lives of an investigational agent, whichever is longer.

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Joshua R Cook, MD, PhD contact

2123056289

jrc2175@cumc.columbia.edu

Ishwari Nagnur contact

2123059336

imn2113@cumc.columbia.edu

United States1 site

  • Columbia University Irving Medical Center

    New York, New York, 10032

    Joshua R. Cook, MD, PhD, 212-305-6289, jrc2175@cumc.columbia.edu

    Joshua R. Cook, MD, PhD

Other trials in United States

About this study

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.

Read the detailed description

Although high blood sugar and risk of heart disease are the most well-known health effects of type 2 diabetes (T2DM), metabolic dysfunction-associated steatotic liver disease (MASLD), in which too much fat accumulates in the liver, has come to be recognized as another important complication. Unchecked, MASLD can progress to severe liver inflammation, liver failure, and even liver cancer. The investigators suspect that high levels of the blood sugar-lowering hormone insulin leads to excessive fat production by the liver, and so lowering insulin levels might help to improve MASLD. In order to answer this question, the investigators will recruit people with MASLD at risk for T2DM to perform a "pancreatic clamp" - a procedure in which the body's production of insulin is temporarily shut off and then replaced at the same or lower levels. Again, the investigators expect that lowering insulin levels will lower fat production ("de novo lipogenesis" or DNL). Research participants in this prospective, randomized, controlled (crossover) study will therefore undergo two pancreatic clamps in random order: one roughly maintaining their own internal ("basal") insulin level ("MH Protocol") and one in which the investigators lower that basal insulin level by 50% ("RE Protocol"). In each case, the investigators will observe the absolute and relative changes in the liver's production of glucose (hepatic glucose production, HGP) and of triglycerides (de novo lipogenesis, DNL) using stable-isotope tracers.

Being tested
Insulin human, Octreotide Acetate, Glucagon, Growth Hormone, Human, 20% D-glucose (aq)
Keywords
Insulin resistance, Hyperinsulinemia, Diabetes, Non-alcoholic fatty liver disease, Metabolic dysfunction associated steatotic liver disease
Medical subject headings
Insulin Resistance, Hyperinsulinism, Non-alcoholic Fatty Liver Disease, Prediabetic State, Obesity, Diabetes Mellitus

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Insulin humanDrug

    Also called Novolin-R, Humulin-R

    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 AcetateDrug

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

  • GlucagonDrug

    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.

  • Growth Hormone, HumanDrug

    Also called Omnitrope, Zomacton

    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)Drug

    Also called D20W

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

  • [6,6-2H2] D-glucoseDiagnostic test

    Also called D2-glucose, D2G

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

  • [1-13C1] sodium acetateDiagnostic test

    Also called 13C-acetate, C13A

    Stable isotope tracer administered to calculate de novo lipogenesis during pancreatic clamp.

  • Nestle BOOST PlusDietary supplement

    Nutritional supplement will be administered to provide standardized "mixed meals" prior to the pancreatic clamp.

  • KIND BarDietary supplement

    Energy bar snack will be administered the evening before the pancreatic clamp.

  • Harvard Apparatus PHD ULTRA CP syringe pumpDevice

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

  • Yellow Springs Instruments (YSI) 2500 Biochemistry Glucose/Lactate AnalyzerDevice

    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.

Study groups in NCT06558422
Study groupRoleWhat they receive
Maintenance hyperinsulinemia (MH) Protocol then Reduction toward Euinsulinemia (RE) ProtocolExperimentalOn 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%.
Receives: Drug: Insulin human; Drug: Octreotide Acetate; Drug: Glucagon; Drug: Growth Hormone, Human; Drug: 20% D-glucose (aq); Diagnostic Test: [6,6-2H2] D-glucose; Diagnostic Test: [1-13C1] sodium acetate; Dietary Supplement: Nestle BOOST Plus; Dietary Supplement: KIND Bar; Device: Harvard Apparatus PHD ULTRA CP syringe pump; Device: Yellow Springs Instruments (YSI) 2500 Biochemistry Glucose/Lactate Analyzer
Reduction toward euinsulinemia (RE) protocolExperimentalOn 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%.
Receives: Drug: Insulin human; Drug: Octreotide Acetate; Drug: Glucagon; Drug: Growth Hormone, Human; Drug: 20% D-glucose (aq); Diagnostic Test: [6,6-2H2] D-glucose; Diagnostic Test: [1-13C1] sodium acetate; Dietary Supplement: Nestle BOOST Plus; Dietary Supplement: KIND Bar; Device: Harvard Apparatus PHD ULTRA CP syringe pump; Device: Yellow Springs Instruments (YSI) 2500 Biochemistry Glucose/Lactate Analyzer

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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: %)

    Measured: Up to 6.5 hours of pancreatic clamp protocol

  2. 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)

    Measured: Up to 6.5 hours of pancreatic clamp protocol

  3. Endogenous glucose production (EGP) (absolute value)

    Calculated from D2G tracer enrichment by the Steele equations during pancreatic clamp procedures. (Units: mg/kg/min)

    Measured: Up to 6.5 hours of pancreatic clamp protocol

  4. 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)

    Measured: Up to 6.5 hours of pancreatic clamp protocol

  5. Plasma glucose level

    Plasma glucose level during pancreatic clamp procedures. (Units: mg/dL)

    Measured: Up to 6.5 hours of pancreatic clamp protocol

  6. Serum insulin level

    Serum insulin level during pancreatic clamp procedures (Units: µU/mL)

    Measured: Up to 6.5 hours of pancreatic clamp protocol

Secondary outcomes (6)

  1. Serum or plasma triglyceride level

    Serum or plasma triglyceride level in response to pancreatic clamp procedures (Units: mg/dL)

    Measured: Up to 6.5 hours of pancreatic clamp protocol

  2. Plasma free fatty acids level

    Plasma free fatty acids level in response to pancreatic clamp procedures. (Units: mmol/L)

    Measured: Up to 6.5 hours of pancreatic clamp protocol

  3. Glucose kinetics: rate of appearance (absolute value)

    Calculated from D2G tracer enrichment by the Steele equations during pancreatic clamp procedures. (Units: mg/kg/min)

    Measured: Up to 6.5 hours of pancreatic clamp protocol

  4. Glucose kinetics: rate of appearance (relative value)

    Calculated from D2G tracer enrichment by the Steele equations during pancreatic clamp procedures. (Units: fold difference and/or ∆% versus other group)

    Measured: Up to 6.5 hours of pancreatic clamp protocol

  5. Glucose kinetics: rate of disappearance (absolute value)

    Calculated from D2G tracer enrichment by the Steele equations during pancreatic clamp procedures. (Units: mg/kg/min)

    Measured: Up to 6.5 hours of pancreatic clamp protocol

  6. Glucose kinetics: rate of disappearance (relative value)

    Calculated from D2G tracer enrichment by the Steele equations during pancreatic clamp procedures. (Units: fold difference and/or ∆% versus other group)

    Measured: Up to 6.5 hours of pancreatic clamp protocol

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Aug 2024
  2. Study start1 Jan 2027 (estimated)
  3. Primary completion31 Dec 2028 (estimated)
  4. Study completion28 Feb 2029 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Crossover
Model description
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.
Masking
Single blind
Who is masked
Participant
Enrolment
36 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06558422
Sponsor's protocol ID
AAAU9702
Other IDs
P30DK063608, K12DK133995
Status last verified
Feb 2026
First submitted
14 Aug 2024
Last updated
6 Feb 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
Yes
Individual data sharing
Yes: 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.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Insulin human, Octreotide Acetate and Glucagon in people with Insulin Resistance and Hyperinsulinemia, run by Columbia University at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 73 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: opening soon, as of the sponsor's last update on 6 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Joshua R Cook, MD, PhD (2123056289, jrc2175@cumc.columbia.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Hepatic de novo lipogenesis (DNL) (absolute value) (time frame: Up to 6.5 hours of pancreatic clamp protocol). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06558422.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Feb 2026.

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