Pancreatic Clamp in NAFLD

• Status: Recruiting
• Trial end date: 2025-01-01
• Target enrollment: 0
• Participant gender: All

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 prediabetic state (i.e., prediabetes or impaired fasting glucose, with fasting hyperinsulinemia), 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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Columbia University
• Collaborator: Albert Einstein College of Medicine
• Treatments: Glucagon; Hormones; Insulin; Insulin, Globin Zinc; Octreotide

Criteria

Inclusion Criteria:

1. Any gender, aged 18-65 years

2. Body mass index of 27.0-35.0 kg/m2

3. Able to understand written and spoken English and/or Spanish

4. Meeting either of the American Diabetes Association's (ADA) definitions for prediabetes or impaired fasting glucose (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 after 8-h fast

• Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) may be used to identify potential recruits, but recruits must meet at least one of the ADA definitions of prediabetic state on screening labs to be included

5. Fasting hyperinsulinemia (fasting insulin level ≥ 15 µIU/mL) on screening labs

6. 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

7. 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:

1. Unable to provide informed consent in English or Spanish

2. 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 ≥ 3% 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 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:

• ST segment elevations

• T-wave inversions vii. Laboratory evidence of diabetes mellitus:

• Hemoglobin A1c ≥ 6.5%, and/or

• Fasting plasma glucose ≥ 126 mg/dL

viii. Positive qualitative β-hCG (i.e., pregnancy test) in women of childbearing potential

ix. Positive urine drug screen

x. Liver function abnormalities (either of the following)

• Transaminases (AST or ALT) > 2.0 x the upper limit of normal

• Total bilirubin > 1.25 x the upper limit of normal

xi. Abnormal fasting lipids at screening (either of the following)

• Triglycerides ≥ 400 mg/dL

• LDL-cholesterol ≥ 190 mg/dL

xii. Abnormal screening serum electrolytes (any of the following)

• Sodium, potassium, or bicarbonate outside of the reference range

• Creatinine equating to estimated glomerular filtration rate < 60 mL min-1 1.73 m-2

xiii. Abnormal complete blood count (CBC) (any of the following)

• Hemoglobin < 10 g dL-1 or hematocrit < 30%

• Platelet count < 100,000 µL-1

• Exempt from CBC requirement if previously obtained value within 2 months of screening is available

xiv. Abnormal screening TSH (≥10 mIU L-1 or < LLN)

• Exempt from TSH requirement if previously obtained value within 2 months of screening is available

3. COVID-19 precautions

i. Not fully vaccinated against COVID-19 (4 doses if ages 50-65, 3 doses if ages 18-49)

ii. Unwillingness to comply with masking requirements per hospital policy

iii. Active, documented COVID-19 at any time after screening

4. Reproductive concerns

i. Women of childbearing potential not using highly effective contraception, defined as:

• Surgical sterilization (e.g., bilateral tubal occlusion, bilateral oophorectomy and/or salpingectomy, hysterectomy)

• Combined oral contraceptive pills taken daily, including during the study

• Intrauterine device (levonorgestrel-eluting or copper) active at the time of study

• Medroxyprogesterone acetate (Depo-Provera®) injection active at the time of study

• Etonogestrel implants (e.g., Implanon®, etc.) active at the time of the study

• Norelgestromin/ethinyl estradiol transdermal system (e.g., Ortho-Evra®) active at the time of the study

ii. Women currently pregnant, measured by serum and/or urine human chorionic gonadotropin, beta subunit (β-hCG)

iii. Women currently breastfeeding

5. Concerns related to glucose metabolism i. 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 ii. History of gestational diabetes mellitus iii. Use of antidiabetic medications within the 90 days prior to screening, including those prescribed for other indications (e.g., weight control, restoration of ovulation in of polycystic ovarian syndrome), including:

• Metformin, thiazolidinediones, sulfonylureas, meglitinides, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors, amylin mimetics, acarbose, insulin iv. Clinical concern for absolute insulin deficiency (e.g., type 1 diabetes, pancreatic disease) v. Fasting plasma glucose < 89 mg/dL at screening

6. Concerns related to lipid metabolism i. Known diagnoses of familial hypercholesterolemia, familial combined hyperlipidemia, or familial hyperchylomicronemia in the participant or a first-degree relative ii. Use of lipid-lowering drugs other than statins for primary prevention within 90 d prior to screening visit, including:

• PCSK9 inhibitors (alirocumab, evolocumab, inclisiran) (for inclisiran, use within the previous year is exclusionary)

• Fibrates (e.g., fenofibrate, clofibrate, gemfibrozil)

• High-dose niacin (>100 mg daily)

• Fish oils or purified supplements of omega-3 fatty acids

• Vitamin E supplements

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

i. Pancreatic pathology, including but not limited to:

• Pancreatic neoplasia

• Chronic pancreatitis

• Acute pancreatitis (history of)

• Autoimmune pancreatitis

• Surgical removal of any portion of the pancreas

ii. Cardiovascular diseases (N.B. uncomplicated hypertension is not exclusionary)

• Atherosclerotic cardiovascular disease

• Stable or unstable angina

• Myocardial infarction

• Ischaemic or hemorrhagic stroke, or transient ischaemic attack

• Carotid artery stenosis on imaging

• Peripheral arterial disease (claudication)

• Use of dual antiplatelet therapy (aspirin + P2Y12 inhibitor)

• History of percutaneous coronary intervention

• Heart rhythm abnormalities

• Congestive heart failure of any New York Heart Association class

• Severe valvular heart disease (e.g., aortic stenosis)

• Pulmonary hypertension

iii. Chronic kidney disease, Stage 2 or higher (estimated glomerular filtration rate < 60 mL / min / 1.73 m2), of any cause

iv. 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)

• Chronic liver infection (e.g., viral hepatitis, parasitic infestation)

• Hepatocellular carcinoma

• Infiltrative disorders (e.g., sarcoidosis, hemochromatosis, Wilson disease)

v. Gallstone disease, including:

• Biliary colic (active)

• History of acute cholecystitis not treated with cholecystectomy

• History of other gallstone complications (e.g., pancreatitis, cholangitis)

vi. Chronic viral illness (N.B. diagnosis based only on medical history; we will not test for any of these viruses at any point in this study)

• Hepatitis B virus (HBV), unless previously successfully eradicated with antiviral drugs that have been discontinued for at least 90 d prior to screening

• Hepatitis C virus (HCV) infection, unless previously successfully eradicated with antiviral drugs that have been discontinued for at least 90 d prior to screening

• Human immunodeficiency virus (HIV) infection

vii. Malabsorptive conditions (active)

• Active inflammatory bowel disease (quiescent and off medication is acceptable)

• Celiac disease (in remission with gluten-free diet is acceptable)

• Surgical removal of a significant length of intestine

viii. Active seizure disorder (including controlled with antiepileptic drugs)

ix. 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, monoamine oxidase inhibitors, tricyclic antidepressants, or lithium

x. 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

• Thyroid disease

• Hypothyroidism if TSH ≥ 10 mIU/L, with or without treatment

• Hyperthyroidism (TSH < LLN), with or without treatment

xi. Venous thromboembolic disease (deep vein thrombosis or pulmonary embolism) or any required use of therapeutic anticoagulation

xii. Bleeding disorders, including due to anticoagulation, or significant anemia (see above)

xiii. Dysautonomia, including post-vagotomy

xiv. Active malignancy, or hormonally active benign neoplasm, except allowances for:

• Non-melanoma skin cancer

• Differentiated thyroid cancer (AJCC Stage I only)

8. Clinical concern for increased risk of volume overload, including due to medications and/or heart/liver/kidney problems, as listed above

9. 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

10. Use of certain medications currently or within 90 d prior to screening:

i. Prescribed medications used for any of the indications in the preceding list (§5.3.7) of excluded conditions, or their use within 90 d prior to screening, except allowances for:

• Levothyroxine treatment of hypothyroidism, if TSH < 10 mIU L-1 at screening

• Use of drugs prescribed for indications other than the exclusionary diagnoses/purposes listed above (e.g., antiepileptic drugs used for non-seizure indications, angiotensin converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB) used for uncomplicated hypertension rather than for congestive heart failure, etc.)

•• Note, as above, that antidiabetic drugs for any indication within 90 d of screening are excluded ii. Thiazide diuretics, loop diuretics, or beta blockers for any indication

• Note, as above, that other antihypertensive drugs (e.g., ACEi/ARB, calcium channel blockers, pure alpha blockers) iii. Oral or parenteral corticosteroids (at greater than prednisone 5 mg daily, or equivalent) for more than 3 days within the previous 90 days; topical and inhaled formulations are permitted iv. Fludrocortisone v. Opioids other than dextromethorphan for cough

11. History of weight-loss (bariatric) surgery, including:

i. Adjustable lap banding ii. Vertical sleeve gastrectomy iii. Roux-en-Y gastric bypass iv. Biliopancreatic diversion

12. Clinical concern for alcohol overuse, including recent documented history or phosphatidylethanol ≥ 0.05 µmol/L at screening and/or participant report of regularly consuming more than 2 drinks per day for males or 1 drink per day for females.

13. Positive urine drug screen

14. History of severe infection or ongoing febrile illness within 30 days of screening

15. 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.

16. Known allergy/hypersensitivity to any component of the medicinal product formulations (including soy or dairy), 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.

17. Concurrent enrollment in another clinical study of any investigational drug therapy within 6 months prior to screening or within 5 half-lives of an investigational agent, whichever is longer.