Effect of Nesiritide Infusion on Insulin Sensitivity in Healthy Obese Insulin Resistant Subjects

Study Overview
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Brief Summary
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The purpose of the study is to compare the effects of nesiritide to placebo administered by a continuous IV infusion over 48 hours for the treatment of insulin resistance in healthy, obese, insulin resistant individuals.

Official Title
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Effect of Nesiritide Infusion on Insulin Sensitivity in Healthy Obese Insulin Resistant Subjects

Conditions
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Diabetes

Intervention / Treatment
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* Drug: Continous IV infusion of Nesiritide
* Drug: Hyperinsulinemic euglycemic clamp
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 40-65 years inclusive Men and women Able to provide written, informed consent Weight stable (± 3 kg) during the 3 months prior to enrollment BMI ≥ 30 kg/m2; body weight ≤ 106 kg Resting blood pressure ≥ 110/60 mmHg and ≤ 150/100 mmHg Exclusion Criteria: Known coronary artery disease, angina or heart failure Type 1 or Type 2 Diabetes (A1c ≥ 6.5% and/or fasting plasma glucose >125mg/dL) Bleeding disorders Hemoglobin level < 12.5 g/dL for women; < 13.0 g/dL for men Acute or chronic infections Hepatitis and/or cirrhosis (AST or Alanine Aminotransferase 2.5 times upper limit of normal) Severe asthma or chronic obstructive pulmonary disease Renal insufficiency (creatinine > 1.6 mg/dL) Prior bariatric surgery Inflammatory bowel disease or malabsorption Cancer within the last 3 years (except non-melanoma skin cancer or treated cervical carcinoma in situ) Psychiatric or eating disorders Untreated or inadequately controlled thyroid (abnormal TSH) or other endocrine disorders Active rheumatoid arthritis or other inflammatory rheumatic disorder Pregnant or nursing women Presence of clinically significant abnormalities on electrocardiogram Smoking (within the last 3 months) Known hypersensitivity to nesiritide or any of its excipients Poor intravenous access Use of medications: a) nitrates, b) beta-blockers, c) digoxin, d) anti-diabetic agents, e) oral, injected or chronic topical steroids (inhaled steroids for mild asthma are acceptable), f) chronic use of aspirin or other non-steroidal anti-inflammatory drugs, including cyclooxygenase-2 inhibitors, g) other drugs known to affect immune or metabolic function and h) orlistat, phenteramine or other weight loss or anorectic agents.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This study is prospective randomized, double masked, 2-period cross over design, proof of concept study of the effects of intravenously administered rhBNP (nesiritide) on insulin sensitivity in otherwise healthy obese nondiabetic insulin resistant subjects.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Obese nondiabetic insulin resistant subjects- Panel A<br>IV nesiritide 3 pmol/kg/min or placebo for nesiritide | Drug: Continous IV infusion of Nesiritide<br>* Nesiritide (fhBNP) administered by continuous IV infusion during 48 hours.<br>Drug: Hyperinsulinemic euglycemic clamp<br>* 48 hours IV infusion of nesiritide on insulin sensitivity (IS) measured by two-step hyperinsulinemic euglycemic clamp in obese nondiabetic insulin resistant subjects.<br>Drug: Placebo<br>* 48 hours of placebo.<br>|
| Active Comparator: Obese nondiabetic insulin resistant subjects- Panel B<br>IV nesiritide 2 pmol/kg/min or placebo for nesiritide | Drug: Continous IV infusion of Nesiritide<br>* Nesiritide (fhBNP) administered by continuous IV infusion during 48 hours.<br>Drug: Hyperinsulinemic euglycemic clamp<br>* 48 hours IV infusion of nesiritide on insulin sensitivity (IS) measured by two-step hyperinsulinemic euglycemic clamp in obese nondiabetic insulin resistant subjects.<br>Drug: Placebo<br>* 48 hours of placebo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IV infusion of nesiritide at a 3pmol/kg rate | Average changes in glucose disposal rates (GDR) and endogenous glucose production (EGP) from baseline corrected for body weight at steady state of the clamp during the high- and low-dose portions. | 48 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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human B-type natriuretic peptide