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ART - Lipodystrophy/Diabetes/Fat Tissue/Mitochondrial damage/Heart Disease: Relationships Between Adipose Mitochondrial Function, Serum Adiponectin, and Insulin Resistance in Persons With HIV After 96 Weeks of Antiretroviral Therapy
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"Our findings, in combination with results from the previous studies and in vitro data, support the hypothesis that impaired adipose tissue mitochondrial function in ART-treated persons with HIV decreases serum adiponectin and worsens IR [insulin resistance/diabetes risk]. We also found that the m.10398G mtDNA SNP was associated with lower serum adiponectin levels after starting ART,49 supporting a role for this variant in metabolic complications through an adiponectin-mediated pathway. Next steps will include more detailed mechanistic studies to characterize the mitochondria-adiponectin pathway and its metabolic effects in adipose tissue and peripherally. In addition, future clinical studies can be designed to test adiponectin-targeted and mtDNA genotype-guided therapeutics in HIV-seropositive persons initiating ART to prevent IR and diabetes.
Insulin resistance (IR) and type-2 diabetes mellitus (diabetes) are important problems in persons with HIV infection treated with antiretroviral therapy (ART).1,2 The pathophysiology of IR and diabetes in this setting is not well understood, but HIV infection does play a role independent of ART.. Mitochondrial function also influences metabolic diseases4,5 and is altered during HIV infection, both before and after ART initiation.6-8 Recent data have specifically highlighted the importance of mitochondrial dysfunction in the pathogenesis of IR and diabetes in HIV-uninfected persons.9-12 Although not considered traditional “mitochondrial toxicities,” diabetes and IR among persons with HIV may also be related to mitochondrial dysfunction.7,13,14 Older nucleoside reverse transcriptase inhibitors (NRTIs) with known adverse mitochondrial effects7,15,16 are associated with IR3,17-19 and diabetes20,21 in cohort and clinical studies. Importantly, even newer NRTIs can adversely impact mitochondrial function.. In AIDS Clinical Trials Group (ACTG) study A5224s, adipose tissue mitochondrial DNA (mtDNA) decreased in subjects treated with either tenofovir disoproxil fumarate (TDF), or abacavir (ABC), and mitochondrial complex I (CI) and complex IV (CIV) activity decreased significantly in persons randomized to TDF.22
Adiponectin is an adipose tissue-derived peptide mediator of energy balance and metabolism, including insulin sensitivity. In HIV-negative populations, low adiponectin is associated with low HDL cholesterol and high triglycerides,23 development of diabetes,24 and myocardial infarction.25 Adiponectin is typically decreased in HIV infection,26 with lean ART-treated men having levels similar to obese, insulin-resistant HIV-seronegative men.27 In untreated HIV infection, low adiponectin is associated with higher plasma HIV RNA levels,28 perhaps driven by increases in inflammatory cytokines such as tumor necrosis factor-α, which has been shown to suppress adiponectin in vitro.29 With ART initiation, adiponectin concentrations increase initially,30,31 but fall below baseline levels with the development of lipodystrophy.31,32 Indeed, lower adiponectin is associated with subcutaneous lipoatrophy,33 IR,34 and subclinical cardiovascular disease35 in ART-treated HIV-seropositive persons. These observations are consistent with reported connections between mitochondrial function and adiponectin,36-38 thus mitochondrial dysfunction may be an important contributor to the pathogenesis of hypoadiponectinemia, with downstream effects on IR and diabetes."
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Relationships Between Adipose Mitochondrial Function, Serum Adiponectin, and Insulin Resistance in Persons With HIV After 96 Weeks of Antiretroviral Therapy
Hulgan, Todd, MD, MPH*,; Ramsey, Benjamin S., BS‡; Koethe, John R., MD, MSCI*,; Samuels, David C., PhD; Gerschenson, Mariana, PhD; Libutti, Daniel E., PhD; Sax, Paul E., MD; Daar, Eric S., MD; McComsey, Grace A., MD#; Brown, Todd T., MD, PhD**
DISCUSSION
This study of ART-naive clinical trial participants with relatively low diabetes risk (median HOMA2-IR<1) identified associations between adipose mitochondrial function, adiponectin, and IR after 2 years of TDF/FTC or ABC/3TC-containing ART exposure and HIV suppression. These results suggest that decreased mitochondrial function on contemporary ART regimens corresponds to metabolic profiles associated with future diabetes risk: decreased adiponectin and IR. We also observed an association between serum adiponectin and an mtDNA variant that is highly consistent with that seen in a distinct ART-naive clinical trial population.60
In persons without HIV, low adiponectin is associated with cardiovascular disease risk factors23,71 and disease,25 and with risk of type 2 diabetes.72 Adipokines are dysregulated in persons with HIV.26,27,73 Lean ART-treated men with HIV had low adiponectin levels similar to obese, insulin-resistant men without HIV.27 Lower adiponectin was also seen in men with HIV compared with age-matched men without HIV in the Multicenter AIDS Cohort Study and was associated with coronary stenosis by CT angiography.35 We did not observe significant changes in adiponectin in the overall population after 96 weeks of ART. Some earlier studies reported significant increases in adiponectin on ART,30 but others did not.74 Differences in ART and/or population metabolic characteristics before ART could contribute to differences in adiponectin levels between studies. Data from cultured adipocytes suggest that adiponectinsynthesis is dependent on mitochondrial function, with induction of mitochondrial biogenesis and palmitate-induced mitochondrial dysfunction leading to increased and decreased adiponectin synthesis, respectively.36,37 Adiponectin also provides protection against mitochondrial dysfunction in multiple model systems,75-77 and obesity-associated adiponectin depletion in mice led to hepatic mitochondrial dysfunction.78 Thus, the direction of effects between adiponectin and mitochondrial function has not been fully elucidated yet.
With respect to mtDNA variation and adiponectin, a cross-sectional analysis of Spanish persons with HIV/HCV coinfection first reported an association between European mtDNA haplogroups and serum adiponectin.49 In that study, subjects belonging to the JT clade (including persons with both m.10398A and G alleles) had significantly lower adiponectin levels while on ART than those belonging to the HV clade (including only the m.10398A allele).49 A previous study in an earlier ACTG trial population examined short-term (24 week) changes in adiponectin and also found significant differences at baseline and after ART.60 Non-Hispanic white persons having the m.10398G variant had significantly higher baseline adiponectin and a significantly greater decrease in adiponectin on ART, the same pattern we observed in the present analysis. The m.10398G is a nonsynonymous variant that results in a threonine to alanine amino acid change in the NADH dehydrogenase subunit 3 of CI and alters in vitro mitochondrial measures including mitochondrial matrix pH and calcium concentration.61 It has also been studied in many human diseases and aging,79,80 but risk association studies have been complicated and inconsistent. Almost all African-ancestry persons have the m.10398G allele,62 since the A allele arose on the N mtDNA branch at the time of the out-of-Africa migration of modern European and Asian populations. In persons of European ancestry, ∼19% carry the G allele, and these are distributed across several major haplogroups as noted above.62 As a result of the lack of variation of m.10398 in Africans, association analyses are not possible within African-ancestry populations. It is not known whether m.10398 allele frequency contributes to ancestry-specific disease risk, whether the variant has different de novo functional implications in African-ancestry populations, or whether interactions with other ancestral variants in mtDNA or nuclear DNA interact to modify its expression or function.
The small sample size of our study precluded haplogroup analyses, limited our capacity to adjust for potential confounders, and may have led to false or missed associations. The m.10398G allele is present in European haplogroups I, J, and K, thus a careful analysis in a larger population might better characterize whether m.10398G is a marker for other variant(s) shared across multiple haplogroups or confined to a single haplogroup. Additional limitations of this study include the fact that most of the participants were male, limiting generalizability of the findings, and the use of self-reported race/ethnicity as the basis of stratification; genetic ancestry was not determined for these analyses. Diabetes was an exclusion from A5224s, and the overall baseline HOMA2-IR values suggest a low risk of overt diabetes. We did not account for ART changes or interruptions in our analyses, but since we only included data for participants with HIV RNA suppression at week 96, we believe this would have had minimal impact in this subgroup. We cannot yet determine causality between mitochondrial enzyme activity, adiponectin, and IR. Indeed, although correlations between changes in mitochondrial function in fat and adiponectin and IR in the periphery are compelling, the lack of direct correlation between adiponectin and HOMA2-IR or HOMA2-%B in this population suggests alternative or additional mechanisms may be contributing. These data cannot definitively answer this question.
In summary, we show for the first time associations between adipose tissue mitochondrial function, adiponectin, and insulin sensitivity in ART-treated persons with HIV, which is biologically plausible. Our findings, in combination with results from the previous studies and in vitro data, support the hypothesis that impaired adipose tissue mitochondrial function in ART-treated persons with HIV decreases serum adiponectin and worsens IR. We also found that the m.10398G mtDNA SNP was associated with lower serum adiponectin levels after starting ART,49 supporting a role for this variant in metabolic complications through an adiponectin-mediated pathway. Next steps will include more detailed mechanistic studies to characterize the mitochondria-adiponectin pathway and its metabolic effects in adipose tissue and peripherally. In addition, future clinical studies can be designed to test adiponectin-targeted and mtDNA genotype-guided therapeutics in HIV-seropositive persons initiating ART to prevent IR and diabetes.
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