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

NCT ID: NCT00259727

Last Updated: 2009-09-30

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Total Enrollment

80 participants

Study Classification

OBSERVATIONAL

Study Start Date

2006-01-31

Study Completion Date

2008-09-30

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Diabetes HIV Infections Insulin Resistance

Keywords

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Amprenavir Glucagon HIV Protease inhibitors Indinavir Lopinavir Ritonavir

Study Groups

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1

No interventions assigned to this group

Eligibility Criteria

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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.
Minimum Eligible Age

18 Years

Maximum Eligible Age

72 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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US Department of Veterans Affairs

FED

Sponsor Role lead

Responsible Party

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Department of Veterans Affairs

Principal Investigators

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Grace Lee, MD

Role: PRINCIPAL_INVESTIGATOR

VA Medical Center, San Francisco

Locations

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VA Medical Center, San Francisco

San Francisco, California, United States

Site Status

Countries

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United States

References

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Noor MA, Lo JC, Mulligan K, Schwarz JM, Halvorsen RA, Schambelan M, Grunfeld C. Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS. 2001 May 4;15(7):F11-8. doi: 10.1097/00002030-200105040-00001.

Reference Type RESULT
PMID: 11399973 (View on PubMed)

Noor MA, Seneviratne T, Aweeka FT, Lo JC, Schwarz JM, Mulligan K, Schambelan M, Grunfeld C. Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a randomized, placebo-controlled study. AIDS. 2002 Mar 29;16(5):F1-8. doi: 10.1097/00002030-200203290-00002.

Reference Type RESULT
PMID: 11964551 (View on PubMed)

Woerle HJ, Mariuz PR, Meyer C, Reichman RC, Popa EM, Dostou JM, Welle SL, Gerich JE. Mechanisms for the deterioration in glucose tolerance associated with HIV protease inhibitor regimens. Diabetes. 2003 Apr;52(4):918-25. doi: 10.2337/diabetes.52.4.918.

Reference Type RESULT
PMID: 12663461 (View on PubMed)

Lee GA, Seneviratne T, Noor MA, Lo JC, Schwarz JM, Aweeka FT, Mulligan K, Schambelan M, Grunfeld C. The metabolic effects of lopinavir/ritonavir in HIV-negative men. AIDS. 2004 Mar 5;18(4):641-9. doi: 10.1097/00002030-200403050-00008.

Reference Type RESULT
PMID: 15090769 (View on PubMed)

Lee GA, Mafong DD, Noor MA, Lo JC, Mulligan K, Schwarz JM, Schambelan M, Grunfeld C. HIV protease inhibitors increase adiponectin levels in HIV-negative men. J Acquir Immune Defic Syndr. 2004 May 1;36(1):645-7. doi: 10.1097/00126334-200405010-00017. No abstract available.

Reference Type RESULT
PMID: 15097312 (View on PubMed)

Schwarz JM, Lee GA, Park S, Noor MA, Lee J, Wen M, Lo JC, Mulligan K, Schambelan M, Grunfeld C. Indinavir increases glucose production in healthy HIV-negative men. AIDS. 2004 Sep 3;18(13):1852-4. doi: 10.1097/00002030-200409030-00017.

Reference Type RESULT
PMID: 15316349 (View on PubMed)

Other Identifiers

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RCD-005-05S

Identifier Type: -

Identifier Source: org_study_id