Insulin resistance in HIV-infected youth is associated with decreased mitochondrial respiration

Takemoto, Jody K.; Miller, Tracie L.; Wang, Jiajia; Jacobson, Denise L.; Geffner, Mitchell E.; Dyke, Russell B. Van; Gerschenson, Mariana

doi:10.1097/qad.0000000000001299

Cited by 33 publications

(28 citation statements)

References 19 publications

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“…The underlying reason for higher l ‐lactate concentrations in ponies compared to horses is still unknown. In people, increases in l ‐lactate concentrations are closely associated with fasting glucose and insulin concentrations, insulin resistance, and type 2 diabetes . Increases in l ‐lactate concentration are predictive of development of insulin resistance and might be an independent risk factor for the development of type 2 diabetes .…”

Section: Discussionmentioning

confidence: 99%

“…The origin of the increased l ‐lactate concentrations in people is still unknown, but a decreased aerobic capacity has been suggested . A low oxidative capacity due to impaired mitochondrial phosphorylation has been associated with subclinical or clinical insulin resistance . Although it is currently unknown whether the low oxidative capacity is a consequence or cause of insulin resistance, recent studies have suggested that a low oxidative capacity may precede insulin resistance and diabetes .…”

Section: Discussionmentioning

confidence: 99%

“…In people, increases in L-lactate concentrations are closely associated with fasting glucose and insulin concentrations, insulin resistance, and type 2 diabetes. [21][22][23][24] Increases in L-lactate concentration are predictive of development of insulin resistance and might be an independent risk factor for the development of type 2 diabetes. 25,26 In a mouse model, increased L-lactate production by adipose and muscle tissue was thought to be at least partially responsible for insulin resistance and diabetes.…”

Section: Discussionmentioning

confidence: 99%

“…27 A low oxidative capacity due to impaired mitochondrial phosphorylation has been associated with subclinical or clinical insulin resistance. 23 Although it is currently unknown whether the low oxidative capacity is a consequence or cause of insulin resistance, recent studies have suggested that a low oxidative capacity may precede insulin resistance and diabetes. 28,29 It is possible that an underlying lower oxidative capacity could contribute to the observed differences in L-lactate, glucose, and insulin metabolism between ponies and horses.…”

Section: Discussionmentioning

confidence: 99%

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Retrospective evaluation of the association between admission blood glucose and l‐lactate concentrations in ponies and horses with gastrointestinal disease (2008‐2016): 545 cases

Dunkel

Mason

Chang

2019

J Vet Emergen Crit Care

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Objectives A recent study described increased l‐lactate concentrations in ponies with gastrointestinal disease compared to horses, but blood glucose (BG) concentrations were not considered. The study tested the hypothesis that BG and l‐lactate concentrations are correlated in horses and ponies with gastrointestinal disease and that BG concentrations, not equid type (pony vs horse), are an independent predictor of L‐lactate concentrations. It was further hypothesized that equid type was an independent predictor of BG concentrations. Design Retrospective study 2008–2016. Setting University teaching hospital. Animals Admission data from 545 animals (384 horses and 161 ponies) with gastrointestinal disease. Interventions None. Measurements and Main Results Data collected included signalment, clinicopathological findings on admission, and nature and location of the gastrointestinal lesion (strangulating vs non‐strangulating and large vs small intestinal lesion). The association between admission blood l‐lactate concentrations, equid type (pony or horse) and BG concentrations was investigated in a multivariable model. Admission l‐lactate and BG concentrations were strongly correlated (n = 522; r = 0.63; P < 0.001). Ponies had significantly higher l‐lactate (2.7 mmol/L (0.5–18.0 mmol/L) vs 1.4 mmol/L (0.3–19 mmol/L); P < 0.001) and BG concentrations than horses (8.4 mmol/L (4.2–24.4 mmol/L); 151 mg/dL (76–439 mg/dL) vs 6.9 mmol/L (3.4–26.8 mmol/L); 124 mg/dL (61–482 mg/dL); P < 0.001). In the multivariable analysis, l‐lactate concentrations were significantly and positively associated with admission BG concentrations in all animals and also with equid type. For each millimole per liter (18 mg/dL) increase in BG, l‐lactate concentrations increased by 7.9% (5.9, 9.9); P < 0.001. In comparison to ponies, l‐lactate concentrations were decreased by 27.7% (37.4, 16.5); P < 0.001 in horses. Admission BG concentrations were significantly and positively associated with l‐lactate concentrations in all animals. For each millimole per liter increase in l‐lactate concentration, BG concentration increased by 6.2% (4.7, 7.6; P < 0.001). Admission BG concentrations were not associated with equid type. Conclusion Admission BG concentrations and equid type are independent predictors of blood l‐lactate concentrations in equids with gastrointestinal disease, but their relationship requires further investigation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Retrospective evaluation of the association between admission blood glucose and l‐lactate concentrations in ponies and horses with gastrointestinal disease (2008‐2016): 545 cases

Dunkel

Mason

Chang

2019

J Vet Emergen Crit Care

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“…The increase in non-mitochondrial respiration suggests mitochondria dysfunction leading to a compromised ETC. Takemoto et al recently reported that HIV-infected youth with insulin resistance had lower mitochondrial respiratory parameters and concluded that disordered mitochondrial respiration may be a potential mechanism of insulin resistant in HIV-infected youth (35).…”

Section: Discussionmentioning

confidence: 99%

Combination of tenofovir and emtricitabine with efavirenz does not moderate inhibitory effect of efavirenz on mitochondrial function and cholesterol biosynthesis in human T lymphoblastoid cell line

Li¹,

Sopeyin²,

Paintsil

2018

Preprint

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20Efavirenz (EFV), the most popular non-nucleoside reverse transcriptase inhibitor, has been 21 associated with mitochondrial dysfunction in most in vitro studies. However, in real life the 22 prevalence of EFV-induced mitochondrial toxicity is relatively low. We hypothesized that the 23 agents given in combination with EFV might moderate the effect of EFV on mitochondrial 24 function. To test this hypothesis, we cultured human T lymphoblastoid cell line (CEM cells) with 25 EFV alone and in combination with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) 26 to investigate the effects on mitochondrial respiration and function and cholesterol biosynthesis. 27 There was a statistically significant concentration-and time-dependent apoptosis, reduction in 28 mitochondrial membrane potential (ΔΨ), and increase production of reactive oxygen species 29 (ROS) in cells treated with either EVF alone or in combination with TDF/FTC. EFV treated 30 cells compared to DMSO treated cells had significant reduction in oxygen consumption rate 31 (OCR) contributed by mitochondrial respiration, ATP production-linked respiration, and spare 32 respiratory capacity (SRC). Treatment with EFV resulted in a decrease in mitochondrial DNA 33 content, and perturbation of more coding genes (n=13); among these were 11 genes associated 34 with lipid or cholesterol biosynthesis. Our findings support the growing body of knowledge on 35 the effects of EFV on mitochondrial respiration and function and cholesterol biosynthesis. 36Interestingly, combining TDF/FTC with EFV did not alter the effects of EFV on mitochondrial 37 respiration and function and cholesterol biosynthesis. The gap between the prevalence of EFV-38 induced mitochondrial toxicity in vitro and in vivo studies may be explained by individual 39 differences in the pharmacokinetic of EFV.40 41 42 3 INTRODUCTION: 43Combination antiretroviral therapy (ART) has resulted in a decrease in AIDS-related 44 morbidity and mortality (1), though the therapeutic benefit of ART is often limited by delayed 45 toxicity (2). Although contemporary ART regimens compared to early ART regimens are less 46 toxic(3, 4), toxicity is still pervasive and affects a significant number of people living with HIV 47 (4, 5). In vitro studies demonstrated that inhibition of polymerase gamma (Pol-γ), enzyme 48 responsible for mitochondrial DNA replication, by nucleoside reverse transcriptase inhibitors 49 (NRTIs) leads to depletion of mitochondrial DNA (mtDNA) and subsequent mitochondrial 50 dysfunction(6, 7); the "Pol-γ inhibition" hypothesis. However, there is a growing body of 51 knowledge to suggest that ART-associated mitochondrial dysfunction cannot be explained solely 52 by Pol-γ inhibition (8, 9). For instance, other classes of ART such as protease inhibitors (PIs) and 53 non-nucleoside reverse transcriptase inhibitors (NNRTIs) do not inhibit Pol-γ and yet they cause 54 side effects akin to mitochondrial dysfunction(8, 10). Taken together, there must be alternative or 55 additional mechanisms...

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Mitochondrial Toxicity in Children and Adolescents Exposed to Antiretroviral Therapy

Noguera-Julián

Velasco-Arnaiz

Fortuny

2018

Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants

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Insulin resistance in HIV-infected youth is associated with decreased mitochondrial respiration

Cited by 33 publications

References 19 publications

Retrospective evaluation of the association between admission blood glucose and l‐lactate concentrations in ponies and horses with gastrointestinal disease (2008‐2016): 545 cases

Retrospective evaluation of the association between admission blood glucose and l‐lactate concentrations in ponies and horses with gastrointestinal disease (2008‐2016): 545 cases

Combination of tenofovir and emtricitabine with efavirenz does not moderate inhibitory effect of efavirenz on mitochondrial function and cholesterol biosynthesis in human T lymphoblastoid cell line

Mitochondrial Toxicity in Children and Adolescents Exposed to Antiretroviral Therapy

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