Insulin Resistance in HIV-Patients: Causes and Consequences

Abstract

Here we review how immune activation and insulin resistance contribute to the metabolic alterations observed in HIV-infected patients, and how these alterations increase the risk of developing CVD. The introduction and evolution of antiretroviral drugs over the past 25 years has completely changed the clinical prognosis of HIV-infected patients. The deaths of these individuals are now related to atherosclerotic CVDs, rather than from the viral infection itself. However, HIV infection, cART, and intestinal microbiota are associated with immune activation and insulin resistance, which can lead to the development of a variety of diseases and disorders, especially with regards to CVDs. The increase in LPS and proinflammatory cytokines circulating levels and intracellular mechanisms activate serine kinases, resulting in insulin receptor substrate-1 (IRS-1) serine phosphorylation and consequently a down regulation in insulin signaling. While lifestyle modifications and pharmaceutical interventions can be employed to treat these altered metabolic functions, the mechanisms involved in the development of these chronic complications remain largely unresolved. The elucidation and understanding of these mechanisms will give rise to new classes of drugs that will further improve the quality of life of HIV-infected patients, over the age of 50.

Keywords: CVD; HIV; LPS; cART; diabetes; insulin resistance.

Figure 1

(A) Tissue specific insulin resistance. In HIV untreated patients there is severe insulin resistance with increased LPS and cytokines that involves liver, hypothalamus, muscle, vessels and adipose tissue. After cART treatment the insulin resistance is mild/moderate, with reduced LPS and cytokines that probably spares adipose tissue. (B) Molecular mechanism of LPS-induced insulin resistance. The increase in LPS circulating levels in HIV patients will induce an increase in circulating inflammatory cytokines, and these increases will activate TLR4, IL-6, and TNFalpha receptors, which will induce ER stress, mitochondrial dysfunction, activation of inflammasome and an increase in intracellular lipid accumulation. Then, there will be activation of PKR, JNK, and IKKβ/NF-κB pathways in liver, muscle, adipose tissue, macrophages and also in other tissues. The activation of these serine kinases (PKR, JNK, and IKKβ) will induce serine phosphorylation of the IRS1/2 and consequently a down regulation in insulin signaling.

Figure 2

The triad HIV infection/inflammation, antiretroviral therapy (cART), and gut microbiota contribute to induce immune activation and insulin resistance. The clinical consequences of chronic immune activation and insulin resistance can contribute to increase Visceral Adipose Tissue (VAT), dyslipidemia, CVDs and non-alcoholic fat liver disease (NAFLD) as well as neurocognitive disorders, metabolic disorders, bone abnormalities and non-HIV associated cancers While the evolution of these complications depends on genetic and environmental factors, each condition has the potential of aggravating another, increasing the risk of CVD in HIV patients.