The HIV, Adipose Tissue Immunology, and Metabolism Study

Diabetes Mellitus, Type 2 Clinical Trial

— HATIM  

Official title:

The HIV, Adipose Tissue Immunology, and Metabolism Study

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04451980
• Other study ID #: 161254
• Status: Active, not recruiting
• Start date: August 31, 2017
• Est. completion date: January 31, 2025

Study information

• Verified date: March 2024
• Source: Vanderbilt University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

With the introduction of effective anti-retroviral therapy (ART), HIV-infected persons can now survive for decades, but this success has been accompanied by an increased risk of developing metabolic disease and diabetes in HIV-infected persons compared to the general population. Recent studies from HIV-negative subjects have identified several associations between circulating immune cell populations and impaired glucose tolerance, including increased activated CD4+ and CD8+ T cells, and reduced regulatory T cells. Of note, these same changes in peripheral T cell subsets are frequently observed in patients with chronic HIV infection. The goal of this study is to assess whether the circulating T cell distribution is reflective of the adipose tissue T cell distribution, and to understand whether chronic adipose tissue T cell activation may impair adipocyte (i.e., fat cell) function and insulin sensitivity. If the investigators' hypotheses are correct, this will demonstrate that chronic peripheral immune activation (i.e., high memory T cells, low naïve cells, and increased expression of activation surface markers) is associated with greater adipose-resident CD4+ and CD8+ T cell expression of activation markers, adipose tissue inflammation, and insulin resistance.

Description:

With the introduction of effective antiretroviral therapy (ART), HIV-infected persons can now survive for decades, but this success has been accompanied by an increased risk of developing metabolic disease compared HIV-negative persons. In the Multicenter AIDS Cohort Study, HIV-infected men had a greater than 4-fold increased incidence of a new diabetes diagnosis compared to HIV-negative men after adjusting for age and body mass index (BMI). Prevalence studies of diabetes in HIV-infected individuals on ART have reported incidence rates of 3.1 to 14 per 1000 patient-years. Furthermore, treated HIV infection appears to act synergistically with other risk factors, and diabetes prevalence is especially high among HIV-infected individuals with high BMI and advanced age.

Recent studies from HIV-negative subjects identified several associations between adaptive immune cell populations and impaired glucose tolerance. Peripheral T regulatory (Treg) cells are significantly lower in patients with type-2 diabetes , while the numbers activated T cells, CD4+ TH1 (pro-inflammatory) cells, and memory CD4+ T cells are higher in diabetics.

Immune cells translocate from the circulation into adipose tissue in a dynamic process, and T cells are present in the stromal fraction of adipose tissue and affect adipocyte function. The striking increase in adipose tissue CD4+ TH1 cells and CD8+ T cells, and a decrease in Treg cells, observed in obesity may have an important role in the development of insulin resistance. Secretion of the proinflammatory cytokines interferon-γ and interleukin (IL)-17 by TH1 and TH17 cells are implicated in the induction of proinflammatory M1 macrophages, which express IL-6 and tumor necrosis factor alpha, and inhibit adipocyte insulin signaling by promoting phosphorylation of insulin receptor substrate 1. The investigators hypothesize that the chronic, HIV-related activation of circulating CD4+ and CD8+ T cells may be accompanied by the accumulation of activated T cells in adipose tissue with adverse effects on metabolic activity.

In this study, the investigators will test the hypothesis that the oligoclonal expansion of chronically activated peripheral T cells in adipose tissue is a primary driver of macrophage inflammation and reduced adipocyte insulin sensitivity. Furthermore, the investigators propose that this represents a central mechanistic linkage underlying the association between circulating T cell activation and incident diabetes risk observed in HIV-infected and HIV-negative individuals.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 172
• Est. completion date: January 31, 2025
• Est. primary completion date: March 13, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

HIV+ Participants:

Inclusion Criteria:

• On antiretroviral therapy for at least 18 months

• HIV-1 RNA <400 copies/ml for the prior 12 months

• CD4+ count >350 cells/µl in the prior 12 months

• HbA1c in prior 6 months within specified limits (See Figure)

• Pre-menopausal by self-report or post-menopausal but not on hormone replacement therapy (HRT)

Exclusion Criteria:

• Known inflammatory or rheumatologic conditions

• Heavy alcohol (>11 drinks per week) or cocaine, amphetamine, or illicit (non-prescribed) opiate abuse by self-report

• Current use of DPP-4 inhibitors.

HIV-negative Participants:

Inclusion Criteria:

• A HbA1c >6.5% or a fasting glucose >126mg/dl, or on anti-diabetic medications for at least 6 months

• Pre-menopausal by self-report or post-menopausal but not on hormone replacement therapy (HRT)

Exclusion criteria:

• Known inflammatory or rheumatologic conditions

• Heavy alcohol (>11 drinks per week) or cocaine, amphetamine, or illicit (non-prescribed) opiate abuse by self-report

• Current use of DPP-4 inhibitors.

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Hiv

Intervention

Procedure:
• Subcutaneous adipose tissue biopsy
Percutaneous adipose tissue biopsy

Radiation:
• CT scan
CT scan of chest and abdomen without contrast

Diagnostic Test:
• Oral glucose tolerance test
Ingestion of 75g of oral glucose syrup and measurement of blood glucose and insulin at time 0, 15 min, 30 min, 60 min, 90 min, and 120 min.
• Blood collection
Fasting blood collection for plasma cytokines and T cell phenotypes.

Locations

Country	Name	City	State
United States	Vanderbilt University Medical Center	Nashville	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Vanderbilt University Medical Center

Country where clinical trial is conducted

United States, 

References & Publications (2)

Koethe JR, McDonnell W, Kennedy A, Abana CO, Pilkinton M, Setliff I, Georgiev I, Barnett L, Hager CC, Smith R, Kalams SA, Hasty A, Mallal S. Adipose Tissue is Enriched for Activated and Late-Differentiated CD8+ T Cells and Shows Distinct CD8+ Receptor Usa — View Citation

Wanjalla CN, McDonnell WJ, Barnett L, Simmons JD, Furch BD, Lima MC, Woodward BO, Fan R, Fei Y, Baker PG, Ram R, Pilkinton MA, Mashayekhi M, Brown NJ, Mallal SA, Kalams SA, Koethe JR. Adipose Tissue in Persons With HIV Is Enriched for CD4+ T Effector Memo — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adipose tissue T cell surface marker phenotype and antigen receptor sequence	Flow cytometry measurement of adipose tissue T cell surface marker phenotypes and sequencing of T cell receptors, compared by HIV and diabetes status	At study enrollment
Secondary	CT measurements of visceral, hepatic, and pericardial fat content	Quantification of visceral, hepatic, and pericardial adipose tissue content, compared by HIV and diabetes status	At study enrollment
Secondary	Circulating T cell surface marker phenotype	Flow cytometry measurement of circulating T cell surface marker phenotypes, compared by HIV and diabetes status	At study enrollment