Experimental Endotoxemia Induces Adipose Inflammation and Insulin Resistance in Humans

Abstract

OBJECTIVE-An emerging model of metabolic syndrome and type 2 diabetes is of adipose dysfunction with leukocyte recruitment into adipose leading to chronic inflammation and insulin resistance (IR). This study sought to explore potential mechanisms of inflammatory-induced IR in humans with a focus on adipose tissue. RESEARCH DESIGN AND METHODS-We performed a 60-h endotoxemia protocol (3 ng/kg intravenous bolus) in healthy adults (n ϭ 20, 50% male, 80% Caucasian, aged 27.3 Ϯ 4.8 years). Before and after endotoxin, whole-blood sampling, subcutaneous adipose biopsies, and frequently sampled intravenous glucose tolerance (FSIGT) testing were performed. The primary outcome was the FSIGT insulin sensitivity index (S i ). Secondary measures included inflammatory and metabolic markers and whole-blood and adipose mRNA and protein expression. RESULTS-Endotoxemia induced systemic IR as demonstratedby a 35% decrease in S i (3.17 Ϯ 1.66 to 2.06 Ϯ 0.73 ϫ 10 Ϫ4 [U ⅐ ml Ϫ1 ⅐ min Ϫ1 ], P Ͻ 0.005), while there was no effect on pancreatic ␤-cell function. In adipose, endotoxemia suppressed insulin receptor substrate-1 and markedly induced suppressor of cytokine signaling proteins (1 and 3) coincident with local activation of innate (interleukin-6, tumor necrosis factor) and adaptive (monocyte chemoattractant protein-1 and CXCL10 chemokines) inflammation. These changes are known to attenuate insulin receptor signaling in model systems.CONCLUSIONS-We demonstrate, for the first time in humans, that acute inflammation induces systemic IR following modulation of specific adipose inflammatory and insulin signaling pathways. It also provides a rationale for focused mechanistic studies and a model for human proof-of-concept trials of novel therapeutics targeting adipose inflammation in IR and related consequences in humans.

PBMCs reflect the immune component of the WAT transcriptome—Implications as biomarkers of metabolic health in the postprandial state

“…PBMCs have also been used as surrogate markers of gene expression in other tissues [8,52]. PBMCs have been used as a proxy for skeletal muscle [9], liver [10], and also in addition to adipose tissue transcriptomics [11,20]. The agreement between PBMC and skeletal muscle transcriptomes is high although key differences in the expression of immune-related genes were demonstrated, with much tissue function specific expression of genes described [9].…”

“…While existing studies have examined both PBMC and WAT transcriptomes concurrently [11,20], to the best of our knowledge, the direct relationship between the transcriptomes of these two tissue types remains largely unexplored or remains unpublished. With a growth in the use of transcriptomics as a tool for determining the metabolic phenotype, an understanding of if or how the PBMC transcriptome reflects that of SAT is warranted.…”

Double diabetes: A distinct high‐risk group?

“…63 Moreover, systemic cytokine leakage into the circulation contributes to a low-grade generalized inflammatory milieu, which, in turn, promotes endothelial dysfunction, the earliest abnormality in the atherosclerotic process. 64 Insulin resistance also increases lipolysis, leading to non-esterified free fatty acid flux into the systemic circulation, where triglyceride deposition in muscle and liver tissues augments insulin resistance. 65 Insulin resistance also leads to hyperglycaemia through unsuppressed hepatic gluconeogenesis and decreased muscular glucose uptake, 66,67 thus resulting in higher insulin requirements.…”

The association of admission hyperglycaemia and adverse clinical outcome in medical emergencies: the multinational, prospective, observational TRIAGE study

“…Nevertheless, after adjustment for demographics and acuity, residual confounding of our results cannot be definitively excluded because glucose is a well-known stress marker, that increases in response to endogenous stress hormone secretion such as cortisol [24]. Also, insulin resistance due to the acute inflammatory response further leads to hyperglycaemia in this population [25,26]. Initial triage prioritya score for disease severitywas higher in people with diabetes, which would argue against a bias regarding disease severity.…”