Partial CD36 deficiency in African Americans was associated with a 1.9-fold higher glucose infusion rate during hyperinsulinaemic clamps compared to non-carriers, despite an unresponsive microvascular blood volume.
Observational (n=21)
Open-label
No
Does CD36 deficiency alter microvascular insulin resistance and muscle glucose disposal in mice and humans?
CD36 deficiency causes microvascular insulin resistance but paradoxically enhances muscle glucose disposal, suggesting a compensatory metabolic adaptation to reduced oxygen and nutrient delivery.
Effect estimate: 1.9-fold higher
AIMS/HYPOTHESIS: Microvascular dysfunction contributes to insulin resistance. CD36, a fatty acid transporter and modulator of insulin signalling, is abundant in microvascular endothelial cells. Humans carrying the minor allele (G) of CD36 coding variant rs3211938 have 50% reduced CD36 expression and show endothelial dysfunction. We aimed to determine whether G allele carriers have microvascular resistance to insulin and, if so, how this affects glucose disposal. METHODS: and wild-type mice, and in individuals with 50% CD36 deficiency, together with control counterparts, in addition to primary human-derived microvascular endothelial cells with/without CD36 depletion. RESULTS: mice have enhanced insulin-stimulated glucose disposal but reduced vascular compliance and capillary perfusion. Intravital microscopy of the gastrocnemius showed unaltered transcapillary insulin flux. CD36-deficient humans had better insulin-stimulated glucose disposal but insulin-unresponsive microvascular blood volume (MBV). Human microvascular cells depleted of CD36 showed impaired insulin activation of Akt, endothelial NO synthase and NO generation. Thus, in CD36 deficiency, microvascular insulin resistance paradoxically associated with enhanced insulin sensitivity of glucose disposal. CONCLUSIONS/INTERPRETATION: CD36 deficiency was previously shown to reduce muscle/heart fatty acid uptake, whereas here we showed that it reduced vascular compliance and the ability of insulin to increase MBV for optimising glucose and oxygen delivery. The muscle and heart respond to these energy challenges by transcriptional remodelling priming the tissue for insulin-stimulated glycolytic flux. Reduced oxygen delivery activating hypoxia-induced factors, endothelial release of growth factors or small intracellular vesicles might mediate this adaptation. Targeting NO bioavailability in CD36 deficiency could benefit the microvasculature and muscle/heart metabolism. TRIAL REGISTRATION: Clinicaltrials.gov NCT03012386 DATA AVAILABILITY: The RNAseq data generated in this study have been deposited in the NCBI Gene Expression Omnibus ( www.ncbi.nlm.nih.gov/geo/ ) under accession code GSE235988 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235988 ).
Shibao et al. (Wed,) conducted a observational in Healthy individuals with or without partial CD36 deficiency (n=21). Partial CD36 deficiency (G allele carriers of rs3211938) vs. Normal CD36 expression (T/T non-carriers) was evaluated on Glucose infusion rate (GIR) during hyperinsulinaemic-euglycaemic clamp (1.9-fold higher). Partial CD36 deficiency in African Americans was associated with a 1.9-fold higher glucose infusion rate during hyperinsulinaemic clamps compared to non-carriers, despite an unresponsive microvascular blood volume.