Human Models of Selective Insulin Resistance: Pancreatic Clamp

Plain English Summary

Human Models of Selective Insulin Resistance: Pancreatic Clamp is a Phase 1 clinical trial sponsored by Columbia University studying Insulin Resistance, Hyperinsulinemia, Metabolic Dysfunction Associated Steatotic Liver Disease, Non-Alcoholic Fatty Liver Disease, Prediabetic State, Obesity. Tests the impact of lowering insulin levels on liver metabolism in people with insulin resistance. For adults (18-65) with a history of overweight/obesity and insulin resistance. Participation involves two pancreatic clamp procedures and blood tests. Alternative treatments include lifestyle changes and medications. The trial aims to enroll 36 participants.

Official 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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Ages 18-65, BMI 27-50, able to speak English or Spanish, evidence of insulin resistance. Cannot have abnormal blood pressure, heart rate, or liver function. Women must not be pregnant or breastfeeding. No history of diabetes or severe liver disease. This trial is studying Insulin Resistance, Hyperinsulinemia, Metabolic Dysfunction Associated Steatotic Liver Disease, Non-Alcoholic Fatty Liver Disease, Prediabetic State, Obesity, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcome measures how insulin levels affect liver glucose and fat production, helping to tailor treatments for insulin resistance. The specific primary outcome measures are: Hepatic de novo lipogenesis (DNL) (absolute value) (Up to 6.5 hours of pancreatic clamp protocol); Hepatic de novo lipogenesis (DNL) (relative value) (Up to 6.5 hours of pancreatic clamp protocol); Endogenous glucose production (EGP) (absolute value) (Up to 6.5 hours of pancreatic clamp protocol); Endogenous glucose production (EGP) (relative value) (Up to 6.5 hours of pancreatic clamp protocol); Plasma glucose level (Up to 6.5 hours of pancreatic clamp protocol). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 1, the first major stage of clinical testing. Phase 1 trials typically involve 20-100 participants and focus on safety, dosage levels, and side effects. The primary goal is not to test whether the treatment works but to establish that it is safe enough for further testing. About 70% of Phase 1 drugs advance to Phase 2. If successful, the treatment will proceed to Phase 2 efficacy testing.

Why This Trial Matters

This trial aims to understand how lowering insulin affects liver metabolism in people with insulin resistance, filling a gap in treatment options. This research targets Insulin Resistance, Hyperinsulinemia, Metabolic Dysfunction Associated Steatotic Liver Disease, Non-Alcoholic Fatty Liver Disease, Prediabetic State, Obesity, where improved treatment options are needed.

Investor Insight

The market for diabetes and metabolic disorders is large, with this trial potentially leading to new treatments, making it an attractive investment opportunity. Phase 1 trials have approximately a 10% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about your BMI and insulin resistance levels. The study involves two procedures and blood tests over 6.5 hours. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: CROSSOVER
• Masking: SINGLE
• Enrollment: 36 participants

Interventions

• DRUG: Insulin human — 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).
• DRUG: Octreotide Acetate — Octreotide will be infused at 30 ng/kg/min to suppress endogenous insulin, glucagon, and growth hormone secretion. Co-administered with glucagon and rhGH.
• DRUG: Glucagon — 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.
• DRUG: Growth Hormone, Human — 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.
• DRUG: 20% D-glucose (aq) — 20% D-glucose (aq) (D20W) will be administered to counteract hypoglycemia or strongly downward blood glucose trends, as needed.

Primary Outcomes

• Hepatic de novo lipogenesis (DNL) (absolute value) (Up to 6.5 hours of pancreatic clamp protocol)
• Hepatic de novo lipogenesis (DNL) (relative value) (Up to 6.5 hours of pancreatic clamp protocol)
• Endogenous glucose production (EGP) (absolute value) (Up to 6.5 hours of pancreatic clamp protocol)
• Endogenous glucose production (EGP) (relative value) (Up to 6.5 hours of pancreatic clamp protocol)
• Plasma glucose level (Up to 6.5 hours of pancreatic clamp protocol)

Secondary Outcomes

• 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)

Full Eligibility Criteria

Inclusion Criteria:

* 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:

    1. Prediabetes: Hemoglobin A1c 5.7-6.4%
    2. 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.

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 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)

  * 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 dis

Trial Locations

• Columbia University Irving Medical Center, New York, New York, United States

Frequently Asked Questions

Related Conditions

• Diabetes, obesity, metabolic syndrome, non-alcoholic fatty liver disease, prediabetes.

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