Inflammatory markers associated with development of diabetes in people taking HIV therapy

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Low-level elevations in important markers of systemic inflammation are associated with the development of type-2 diabetes in people taking antiretroviral therapy (ART), investigators report in the online edition of the Journal of Acquired Immune Deficiency Syndromes. The authors examined the relationship between baseline levels of high sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) and incident type-2 diabetes among people in two large HIV treatment strategy trials – the SMART and ESPRIT studies. The study participants were taking continuous ART without any adjunct therapy. Higher baseline hsCRP and IL-6 were associated with diagnosis with type-2 diabetes during follow-up.

“Inflammatory markers provide independent information for predicting the development of diabetes,” comment the authors. “Experimental studies aimed at reducing inflammation are needed to establish a causal relationship.”

Improvements in treatment and care mean that many people with HIV now have an excellent life expectancy. However, HIV infection – even in the context of effective ART – is associated with a higher risk of metabolic complications, including the development of type-2 diabetes. The reasons for this are unclear, but possible causes include the side-effects of some anti-HIV drugs and the inflammatory effects of HIV infection, which can persist at low levels even in the context of ART.

Glossary

diabetes

A group of diseases characterized by high levels of blood sugar (glucose). Type 1 diabetes occurs when the body fails to produce insulin, which is a hormone that regulates blood sugar. Type 2 diabetes occurs when the body either does not produce enough insulin or does not use insulin normally (insulin resistance). Common symptoms of diabetes include frequent urination, unusual thirst and extreme hunger. Some antiretroviral drugs may increase the risk of type 2 diabetes.

inflammation

The general term for the body’s response to injury, including injury by an infection. The acute phase (with fever, swollen glands, sore throat, headaches, etc.) is a sign that the immune system has been triggered by a signal announcing the infection. But chronic (or persisting) inflammation, even at low grade, is problematic, as it is associated in the long term to many conditions such as heart disease or cancer. The best treatment of HIV-inflammation is antiretroviral therapy.

traditional risk factors

Risk factors for a disease which are well established from studies in the general population. For example, traditional risk factors for heart disease include older age, smoking, high blood pressure, cholesterol and diabetes. ‘Traditional’ risk factors may be contrasted with novel or HIV-related risk factors.

systemic

Acting throughout the body rather than in just one part of the body.

 

protein

A substance which forms the structure of most cells and enzymes.

Results of several studies in the general population suggest that higher levels of hsCRP and IL-6 are associated with incident type-2 diabetes. But it is unclear if this is also the case in people living with HIV.

Investigators therefore conducted a retrospective analysis of the relationship between baseline hsCRP and IL-6 and incident type-2 diabetes in approximately 3700 people enrolled in the SMART and ESPRIT studies.

These strategy studies explored the safety and efficacy of CD4-guided structured interruptions in ART (SMART) and the use of IL-2 adjunct therapy (ESPRIT). The present analysis was restricted to people taking continuous ART who were not randomised to receive IL-2.

Average CD4 count at baseline was 523 cells/mm3 and participants were followed for an average of 4.6 years (2.9 years in SMART and 6.8 years in ESPRIT). Type-2 diabetes was diagnosed in 137 people (3.5), a rate of 8.18 per 1000 person-years.

The proportion of people with a CD4 count above 500 cells/mm3 and virologic suppression remained unchanged during follow-up.

Median hsCRP and IL-6 levels were significantly higher among people who developed type-2 diabetes compared to people who did not (hsCRP = 4.91 vs 3.29 μg/ml, p < 0.001; IL-6 = 3.45 vs 2.50 pg/ml, p < 0.001).

A doubling of baseline hsCRP levels increased the risk of type-2 diabetes by approximately a fifth (HR = 1.22; 95% CI, 1.10-1.36, p < 0.001), whereas a doubling of baseline IL-6 increased the risk by almost a third (HR = 1.29; 95% CI, 1.08-1.55, p = 0.005).

A number of traditional risk factors were also associated with the diagnosis of diabetes. These included higher body mass index (p < 0.001), older age (p = 0.0.013), co-infection with hepatitis B or C virus (p = 0.03) and the use of lipid-lowering medication (p = 0.008).

The authors believe their findings offer “clues” as to why people living with HIV remain at increased risk of cardiovascular disease and other chronic illness even when they are taking effective ART, and conclude, “our findings support the hypothesis that low-grade systemic inflammation is an underlying factor in the pathogenesis of type-2 diabetes.”

References

Dooko CBA et al. Interleukin-6, high-sensitivity C-reactive protein, and the development of type 2 diabetes among HIV positive patients taking antiretroviral therapy. J Acquir Immune Defic Syndr. Online edition, 2014. DOI: 10:1097/QAI.0000000000000354