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CATIE News - Study links inflammation to increased risk of diabetes in HIV

18 August 2010 - Although anti-HIV therapy (called ART or HAART) helps to reduce the amount of HIV in the body and has greatly improved the survival of HIV-positive people, low levels of this virus persist despite many years of treatment. Persistent exposure to HIV and HIV-infected cells may eventually skew the immune system toward producing higher-than-normal levels of chemical signals-cytokines-that foster inflammation of many organs and tissues.

Some researchers worry that chronic inflammation associated with HIV may increase the risk for or accelerate the development of complications in HIV-positive people that are traditionally seen in older (HIV-negative) people, including cardiovascular disease, thinning bones, dysfunctional kidneys and diabetes.

Scientists at several research centres in the United States have collaborated in studying the impact of HIV infection, ART and the risk of developing diabetes. Their finding suggests that inflammation caused by HIV infection may accelerate the development of diabetes.

Study details

The research team reviewed a database of health information collected from participants in a large observational study called the ACTG Longitudinal Linked Randomized Trials (ALLRT). After participants entered ALLRT they received HAART because they entered other studies as well.

In the present sub-study of ALLRT that explored diabetes, researchers scanned the ALLRT database and selected 55 HIV-positive people who previously had not taken ART but once in ALLRT proceeded to do so. All 55 people subsequently developed diabetes. The researchers referred to these 55 people as "cases." Each case was compared to a group of 55 randomly selected HIV-positive people also from ALLRT who did not have diabetes, called "controls" by the researchers. This type of research is called a case-control study. All controls were of similar ethno-racial composition and body mass index (BMI-a measure of fatness) as the cases.

At the start of the study, the average profile of cases was as follows:

  • 24% females, 76% males
  • 47% White
  • 29% Hispanic
  • 24% Black
  • BMI - 25
  • fasting blood sugar - 5.67 mmol/l
  • family history of cardiovascular disease - 20%
  • history of tobacco smoking - 51%
  • high viral loads (more than 100,000 copies/ml) - 58%
  • CD4+ count less than 200 cells - 66%

In addition to blood tests routinely used in HIV care, technicians analysed levels of the following biomarkers, which have been associated with inflammation in other studies:

  • hsCRP (high-sensitivity C-reactive protein)
  • IL-6 (interleukin-6)
  • receptors for tumour necrosis factor-alpha (TNF) called sTNFR-1 and sTNFR-2

Researchers agreed that diabetes developed when one of the following occurred:

  • two consecutive non-fasting blood sugar levels of at least 7 mmol/l
  • two consecutive fasting blood sugar levels of at least 11 mmol/l

Results

Here are some key findings about the development of diabetes:

  • Cases developed diabetes about three years after they began taking ART.
  • People who developed diabetes tended to be a bit older (41 years) than people who did not (37 years). Although this difference in age seems small, it was highly statistically significant.
  • A year after starting ART, blood sugar levels were often at the high end of the normal range (5.7 mmol/l) in people who later developed diabetes compared to people who did not (4.6 mmol/l)-again a statistically significant difference.

Taking into account many factors, including age, CD4+ cell count, BMI, biomarker levels and blood sugar, researchers found that only levels of soluble TNF-alpha receptor-1 (sTNFR-1) in the blood were statistically linked to an increased risk for developing diabetes.

The insulin connection

An important question is: Why would soluble receptors for TNF-alpha have an impact on blood sugar levels? The team notes that previous research has found that TNF-alpha is produced in relatively large amounts in HIV-positive people whether or not they are taking ART. Cells of the immune system as well as fat cells make this chemical messenger. Experiments with animals suggest that TNF-alpha seems to interfere with the hormone insulin. This hormone is needed by cells to absorb sugar from the blood. By interfering with insulin, perhaps excessive TNF-alpha levels may play a role in the development of blood sugar problems that eventually lead to diabetes.

Putting it in perspective

The present diabetes sub-study of ALLRT is called a case-control study. Such studies can find associations between factors (such as biomarker levels) and events (such as diabetes). However, case-control studies can never prove that these biomarkers are the cause of diabetes or other events.

The value of case-control studies is that they are a relatively cheap and quick way of exploring an idea. The findings from such studies need to be confirmed in a clinical trial of a more robust design. Indeed, the diabetes researchers suggest such a course of action.

Future studies on biomarkers and diabetes should consider the following:

  • assess a broad range of inflammatory biomarkers to confirm or extend the present findings,
  • identify the source of excessive TNF-alpha in HIV-positive people taking ART,
  • explore possible differences in gender with TNF-alpha levels,
  • understand exactly how excessive TNF-alpha levels play a role in the development of diabetes.

- Sean R. Hosein

 

REFERENCES:

1. Hotamisligil GS, Peraldi P, Budavari A, et al. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science . 1996 Feb 2;271(5249):665-8.

2. Kalayjian RC, Machekano RN, Rizk N, et al. Pretreatment levels of soluble cellular receptors and interleukin-6 are associated with HIV disease progression in subjects treated with highly active antiretroviral therapy. Journal of Infectious Diseases . 2010 Jun 15;201(12):1796-805.

3. Dubé MP, Sattler FR. Inflammation and complications of HIV disease. Journal of Infectious Diseases. 2010 Jun 15;201(12):1783-5.

4. Neuhaus J, Jacobs DR Jr, Baker JV, et al. Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. Journal of Infectious Diseases. 2010 Jun 15;201(12):1788-95.

5. Brown TT, Tassiopoulos K, Bosch RJ, Shikuma C, McComsey GA. Association between systemic inflammation and incident diabetes mellitus in HIV-infected patients after initiation of antiretroviral therapy. Diabetes Care . 2010; in press.

 

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CATIE-News is written by Sean Hosein, with the collaboration of other members of the Canadian AIDS Treatment Information Exchange, in Toronto.

From Canadian AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca

Source: CATIE: CANADIAN AIDS TREATMENT INFORMATION EXCHANGE


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