The Study of HIV Protease Inhibitors and Their Effects on Glucose Metabolism

Sponsor

US Department of Veterans Affairs (U.S. Fed)

Overall Status

Completed

CT.gov ID

NCT00259727

Collaborator

(none)

Enrollment

Location

Duration (Months)

2.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the mechanisms by which HIV protease inhibitors contribute to the development of diabetes in HIV-infected patients. The investigators propose that some HIV protease inhibitors impair insulin secretion and increase the production of glucose by the liver.

Condition or Disease	Intervention/Treatment	Phase
Diabetes HIV Infections Insulin Resistance

Detailed Description

HIV protease inhibitors (PIs) have been associated with type 2 diabetes. To design future HIV drugs that have have the least adverse metabolic effects, it is necessary to identify the disorders of glucose metabolism with PI therapy. Previously PIs have been shown to acutely induce insulin resistance in the periphery. Preliminary data show that PIs also impair insulin secretion and increase hepatic glucose production in humans. These lesions are key contributors to the development of type 2 diabetes. Due to the difficulty in separating out factors related to HIV infection from the direct effect of PIs, an effective design is to study HIV-negative subjects to define the direct effects of PIs on the liver and pancreas on glucose metabolism:

Specific Aim 1: To determine which PIs acutely inhibit insulin secretion in humans; randomized, double-blind, placebo-controlled trials will be performed on healthy normal volunteers given either a single dose of PI or placebo using the hyperglycemic clamp to assess insulin secretion in relation to insulin sensitivity.

Specific Aim 2: To determine which PIs acutely increase hepatic glucose production, glycogenolysis, and gluconeogenesis; measurements will be assessed in the fasting and hyperinsulinemic states using stable isotope analysis techniques. Samples have already been collected from double-blind, placebo-controlled trials of the effects of a single dose of PI on insulin sensitivity during the euglycemic hyperinsulinemic clamp.

Specific Aim 3: To determine the mechanism by which certain PIs increase hepatic glucose production; an infusion of somatostatin during the fasting state and hyperinsulinemic state will be used to suppress the effects of glucagon. Subjects will undergo a randomized, double-blind, placebo-controlled trial of a single dose of PI or placebo on insulin sensitivity using the euglycemic hyperinsulinemic clamp. Somatostatin, glucagon, and growth hormone will be infused before and during the clamp study. Hepatic glucose production, glycogenolysis, and gluconeogenesis will be assessed using stable isotope tracer techniques. Results will be compared to PIs acutely given in the absence of somatostatin, as stated in Specific Aim 2.

Determination of the effects of PI therapy allows clinicians to identify patients who may be at particular risk for developing diabetes on certain PIs and treat them more effectively. In the future, drugs for the treatment of HIV can be developed that avoid these disorders of glucose metabolism.

Study Design

Study Type:

Observational

Anticipated Enrollment :

80 participants

Official Title:

The Effects of HIV Protease Inhibitors on Glucose Metabolism

Study Start Date :

Jan 1, 2006

Actual Study Completion Date :

Sep 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
1

Outcome Measures

Primary Outcome Measures

Insulin secretion after a single dose of HIV protease inhibitor versus placebo (insulin secretion assessed by using the hyperglycemic clamp technique) []

Secondary Outcome Measures

Hepatic glucose production, glycogenolysis, and gluconeogenesis after a single dose of HIV protease inhibitor versus placebo (stable isotope analysis with mass isotopic distribution analysis) []
Hepatic glucose production during a somatostatin infusion in the fasting and hyperinsulinemic state after a single dose of HIV protease inhibitor []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 72 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Healthy, HIV-negative volunteers between the ages of 18-72 years

Exclusion Criteria:

Any subject with states known to be associated with insulin resistance, such as impaired fasting glucose (glucose > 110 mg/dl), overweight (body mass index [BMI] > 27), dyslipidemia (triglycerides > 150 mg/dl), hypertension (blood pressure [BP] > 130/85 mmHg or on medication), renal disease, systemic use of glucocorticoids, growth hormone, niacin, or antipsychotics.
Women will be tested for pregnancy immediately prior to study and excluded if pregnant.