Graded Insulin Suppression Test P&F

NCT ID: NCT06592261

Last Updated: 2025-12-09

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 15 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-09-16
• Study Completion Date: 2026-08-31

Brief Summary

The goal of this study is to learn about how the hormone insulin controls blood sugar in a variety of people. The main question it aims to answer is about how much insulin the body actually needs to maintain a normal blood sugar level. Participants will be asked to come in for a one-day study visit in which they will undergo a "graded insulin suppression test" ("GIST"). The GIST involves intravenous (into the vein) infusions of octreotide, a medication that turns off the body's own production of insulin, as well as replacement of insulin at two different levels (low and high), with or without replacement of glucagon, and glucose (sugar). The study investigators will check blood sugar levels every few minutes during the procedure to determine the effect of the two different insulin levels. This study will evaluate the GIST in both healthy volunteers and those at higher risk for type 2 diabetes.

Detailed Description

This study aims to determine to what extent the hyperinsulinemia commonly associated with insulin resistance (IR) in those at risk for type 2 diabetes (T2D) is a primary phenomenon, rather than merely a secondary, compensatory response to IR. The hypothesis is that some people with obesity and hyperinsulinemia exhibit a primary, non-compensatory hyperinsulinemia that may foment IR and its dysmetabolic sequelae. If this were the case, lowering insulin levels should not result in a proportional rise in blood glucose as might be expected if the hyperinsulinemia truly were purely compensatory. This hypothesis has been difficult to prove, however, because of the tight feedback mechanism between blood glucose and insulin secretion; under normal circumstances insulin secretion declines only alongside blood glucose. As such, an attempt to lower insulin levels independently of blood glucose will raise blood glucose and trigger further insulin secretion, negating the purpose of the experiment. In order to circumvent this feedback regulation of glucose-stimulated insulin secretion, this study will adapt the existing insulin suppression test (IST) technique, which employs the somatostatin receptor ligand octreotide to suppress endogenous insulin secretion and then replaces insulin and dextrose exogenously as a measure of insulin action. In addition to employing the current standard hyperinsulinemic IST protocol to assess insulin sensitivity, this study will introduce a preceding, euinsulinemic step, in which insulin is lowered toward a healthy fasting serum insulin while assessing the resultant steady-state glucose, potentially with replacement of basal glucagon. The primary endpoints in this study are the steady-state plasma glucose and serum insulin levels during low- and high-dose insulin infusions meant to induce euinsulinemia and hyperinsulinemia, respectively. The study investigators will carefully monitor plasma glucose levels every 5-15 min, drawing from an indwelling peripheral IV catheter and performing the analysis using a dedicated bedside glucose analyzer. These glucose values will be used to detect and arrest any trends toward hypo or hyperglycemia and will also serve as the readout of the primary outcome - the euinsulinemic steady-state glucose (E-SSG) and hyperinsulinemic steady-state glucose (H-SSG). Serum insulin, C-peptide, growth hormone, and glucagon levels will be measured periodically during the procedure, but these results will not be available until several days later.

Conditions

Insulin Resistance; Hyperinsulinemia; Obesity; Healthy

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Reference (healthy control) group

Healthy volunteers with body mass index of 18-25 kg/m2, fasting serum insulin \< 10 mU/L, hemoglobin A1c \< 5.7%, and fasting plasma glucose \< 100 mg/dL

Group Type: EXPERIMENTAL

Insulin regular, 2.0-3.2 mU/m2/min (euinsulinemia)

Intervention Type: DRUG

Insulin infusion to recapitulate euinsulinemia (normal basal insulin)

Insulin regular, 32 mU/m2/min (hyperinsulinemia)

Intervention Type: DRUG

Insulin infusion to induce hyperinsulinemia for assessment of insulin sensitivity

Octreotide Acetate, 6-45 ng/kg/min

Intervention Type: DRUG

Suppression of endogenous insulin secretion

Dextrose 20 % in Water

Intervention Type: DRUG

Production of steady-state plasma glucose (SSPG) reflective of insulin sensitivity at hyperinsulinemia

Glucagon, 0-0.5 ng/kg/min

Intervention Type: DRUG

Replacement of endogenous glucagon suppressed by octreotide. (Use is optional at the PI's discretion.)

Euinsulinemic group

Volunteers with body mass index of 30-45 kg/m2, fasting serum insulin \< 10 mU/L, hemoglobin A1c \< 5.7%, and fasting plasma glucose \< 100 mg/dL

Group Type: EXPERIMENTAL

Insulin regular, 2.0-3.2 mU/m2/min (euinsulinemia)

Intervention Type: DRUG

Insulin infusion to recapitulate euinsulinemia (normal basal insulin)

Insulin regular, 32 mU/m2/min (hyperinsulinemia)

Intervention Type: DRUG

Insulin infusion to induce hyperinsulinemia for assessment of insulin sensitivity

Octreotide Acetate, 6-45 ng/kg/min

Intervention Type: DRUG

Suppression of endogenous insulin secretion

Dextrose 20 % in Water

Intervention Type: DRUG

Production of steady-state plasma glucose (SSPG) reflective of insulin sensitivity at hyperinsulinemia

Glucagon, 0-0.5 ng/kg/min

Intervention Type: DRUG

Replacement of endogenous glucagon suppressed by octreotide. (Use is optional at the PI's discretion.)

Hyperinsulinemic group

Volunteers with body mass index of 30-45 kg/m2, fasting serum insulin \>= 13 mU/L, hemoglobin A1c \< 5.7%, and fasting plasma glucose \< 100 mg/dL

Group Type: EXPERIMENTAL

Insulin regular, 2.0-3.2 mU/m2/min (euinsulinemia)

Intervention Type: DRUG

Insulin infusion to recapitulate euinsulinemia (normal basal insulin)

Insulin regular, 32 mU/m2/min (hyperinsulinemia)

Intervention Type: DRUG

Insulin infusion to induce hyperinsulinemia for assessment of insulin sensitivity

Octreotide Acetate, 6-45 ng/kg/min

Intervention Type: DRUG

Suppression of endogenous insulin secretion

Dextrose 20 % in Water

Intervention Type: DRUG

Production of steady-state plasma glucose (SSPG) reflective of insulin sensitivity at hyperinsulinemia

Glucagon, 0-0.5 ng/kg/min

Intervention Type: DRUG

Replacement of endogenous glucagon suppressed by octreotide. (Use is optional at the PI's discretion.)

Interventions

Insulin regular, 2.0-3.2 mU/m2/min (euinsulinemia)

Insulin infusion to recapitulate euinsulinemia (normal basal insulin)

Intervention Type: DRUG

Insulin regular, 32 mU/m2/min (hyperinsulinemia)

Insulin infusion to induce hyperinsulinemia for assessment of insulin sensitivity

Intervention Type: DRUG

Octreotide Acetate, 6-45 ng/kg/min

Suppression of endogenous insulin secretion

Intervention Type: DRUG

Dextrose 20 % in Water

Production of steady-state plasma glucose (SSPG) reflective of insulin sensitivity at hyperinsulinemia

Intervention Type: DRUG

Glucagon, 0-0.5 ng/kg/min

Replacement of endogenous glucagon suppressed by octreotide. (Use is optional at the PI's discretion.)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Body mass index of 18-25 and 30-45 kg/m2
• Able to understand written and spoken English and/or Spanish
• Fasting euinsulinemia (fasting serum insulin of 4-10 μU/mL) for reference group or hyperinsulinemia (fasting serum insulin ≥ 13 μU/mL) for hyperinsulinemic group on screening labs
• 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.

• Known, documented history, at the time of screening, of any of the following medical conditions:

• Pancreatic pathology, including but not limited to: Pancreatic neoplasia (unless appropriately evaluated and considered benign and not producing hormones), Chronic pancreatitis, History of acute pancreatitis within the past 5 years
• Cardiovascular diseases (N.B. uncomplicated hypertension is not exclusionary)
• Atherosclerotic cardiovascular disease
• Stable or unstable angina
• Myocardial infarction
• Ischaemic or hemorrhagic stroke
• Peripheral arterial disease (claudication)
• Use of dual antiplatelet therapy (aspirin + P2Y12 inhibitor)
• History of percutaneous coronary intervention
• Heart rhythm abnormalities (non-sinus)
• Congestive heart failure of any New York Heart Association class
• Severe valvular heart disease (e.g., aortic stenosis)
• Pulmonary hypertension
• Chronic kidney disease, Stage 3 or higher (estimated glomerular filtration rate < 60 mL/min/1.73 m2), of any cause
• Advanced or severe liver disease, including but not limited to:

• Advanced liver fibrosis, as determined by non-invasive testing
• Cirrhosis of any etiology
• Autoimmune hepatitis or other rheumatologic disorder affecting the liver
• Biliopathy (e.g., progressive sclerosing cholangitis, primary biliary cholangitis)
• Hepatocellular carcinoma
• Infiltrative disorders (e.g., sarcoidosis, hemochromatosis, Wilson disease)
• Gallstone disease, including:

• Biliary colic (active)
• History of acute cholecystitis not treated with cholecystectomy
• History of other gallstone complications (e.g., pancreatitis, cholangitis)
• Chronic viral illness (N.B. diagnosis based only on medical history and not by laboratory confirmation)
• Hepatitis B virus (HBV), unless previously successfully eradicated with antiviral drugs that have been discontinued for at least 30 d prior to screening
• Hepatitis C virus (HCV) infection, unless previously successfully eradicated with antiviral drugs that have been discontinued for at least 30 d prior to screening
• Human immunodeficiency virus (HIV) infection
• Active seizure disorder (including controlled with antiepileptic drugs)
• Psychiatric diseases causing functional impairment that:

• Are or have been decompensated within 1 year of screening, and/or
• Require use of anti-dopaminergic antipsychotic drugs associated with significant weight gain/metabolic dysfunction (e.g., clozapine, olanzapine), monoamine oxidase inhibitors, tricyclic antidepressants, or lithium
• Other endocrinopathies:

• Cushing syndrome (okay if considered in remission after treatment, provided that no exogenous corticosteroids or other ongoing treatment are required)
• Adrenal insufficiency
• Primary aldosteronism
• 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
• Active malignancy, or hormonally active benign neoplasm, except allowances for:

• Non-melanoma skin cancer
• Differentiated thyroid cancer (AJCC Stage I only)
• 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 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/ARB used for uncomplicated hypertension rather than for congestive heart failure, etc.). Note, as above, that antidiabetic drugs except metformin within 30 d of screening are excluded.
• 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.
• 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.
• 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, 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.

Exclusion Criteria

• 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 GIST
• Documented weight loss of ≥ 5% of baseline within the previous 6 months
• 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 d):

• Non-sinus rhythm
• Heart conduction blocks
• Previously unknown ischaemic changes that persist on repeat EKG:
• ST elevations
• T-wave inversions in a vascular distribution
• Hemoglobin A1c ≥ 5.7%, and/or
• Fasting plasma glucose ≥ 100 mg/dL
• Positive qualitative β-hCG (i.e., pregnancy test) in women of childbearing potential
• Positive urine drug screen, except for lawfully prescribed medications and/or marijuana, provided that participant agrees to refrain from marijuana use during the period that they refrain from alcohol.
• Transaminases (AST or ALT) > 3.0 x the upper limit of normal
• Total bilirubin > 1.25 x the upper limit of normal
• Abnormal sodium, potassium, chloride, or bicarbonate levels that are considered potentially significant according to the clinical judgment of the PI.
• Creatinine equating to estimated glomerular filtration rate < 60 mL min-1 1.73 m-2
• Hemoglobin < 10 g/dL or hematocrit < 30%
• Platelet count < 100,000/μL
• Women currently pregnant, measured by serum and/or urine β-hCG
• Women currently breastfeeding
• History of having met any of the American Diabetes Association's definitions of prediabetic state during adulthood or diabetes mellitus (i.e., overt diabetes) at any time:

• Hemoglobin A1c ≥ 5.7%, or rapid rise in documented HbA1c values causing clinical concern for evolving insulin deficiency
• Plasma glucose ≥ 100 mg/dL after 8-h fast
• Plasma glucose of ≥ 140 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

University of Pisa

OTHER

Sponsor Role: collaborator

Columbia University

OTHER

Sponsor Role: lead

Responsible Party

Joshua Cook

Assistant Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Joshua R Cook, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Columbia University

Locations

Columbia University Irving Medical Center

New York, New York, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Joshua R Cook, MD, PhD

Role: CONTACT

jrc2175@cumc.columbia.edu

2123056289

Ishwari Nagnur

Role: CONTACT

imn2113@cumc.columbia.edu

2123059336

Facility Contacts

Joshua R Cook, MD, PhD

Role: primary

jrc2175@cumc.columbia.edu

212-305-9336

Role: backup

joshua.robert.cook@gmail.com

Other Identifiers

3P30DK063608-21

Identifier Type: NIH

Identifier Source: secondary_id

View Link

K12DK133995

Identifier Type: NIH

Identifier Source: secondary_id

View Link

K23DK140614

Identifier Type: NIH

Identifier Source: secondary_id

View Link

AAAV2481

Identifier Type: -

Identifier Source: org_study_id