Insulin Resistance Is Inversely Associated with the Intestinal Expression of Key Genes Involved in Chylomicron Assembly and Secretion

Abstract

BackgroundInsulin resistance is a chronic metabolic disorder associated with an overproduction of atherogenic intestinal triglyceride‐rich lipoproteins (TRLs). However, the mechanisms underlying this increased secretion of intestinal TRLs remain to be fully understood. The objective of the present study was to evaluate the association between the homeostasis model assessment of insulin‐resistance (HOMA‐IR) index and the intestinal expression of key genes involved in chylomicron assembly and secretion in a large sample of non‐diabetic men.MethodsDuodenal biopsies were obtained by gastroduodenoscopy in 105 non‐diabetic men. Gene expression was measured using quantitative PCR in duodenal biopsy samples. Anthropometric parameters and fasting plasma glucose and insulin concentrations were measured in all participants.ResultsParticipants' mean age (±SD) was 37.7 ± 11.1 years (range: 21.0 to 65.0 years). Mean BMI was 31.8 ± 4.3 kg/m2 (range: 20.4 to 43.8 kg/m2) and mean HOMA‐IR index was 4.10 ± 1.64 (range: 1.02 to 10.02).The HOMA‐IR index was inversely associated with the duodenal expression of microsomal triglyceride transfer protein (MTP) (r=‐0.23; P=0.02), acetyl‐coenzyme A synthetase 1 (ACS1) (r=−0.22; P=0.03), diacylglycerol O‐acyltransferase 1 (DGAT1) (r=−0.25; P=0.01) and DGAT2 (r=−0.24; P=0.02). These associations were independent of body mass index (BMI), waist circumference and age. There was no significant association between the HOMA‐IR index and the duodenal expression of apolipoprotein (apo) B (r=−0.15; P=0.15) and SAR1 gene homolog B (SAR1B) (r=−0.20; P=0.07).Duodenal expression of MTP was positively associated with the expression of apo B (r=0.60; P<0.0001), ACS1 (r=0.57; P<0.0001), DGAT1 (r=0.72; P<0.0001), DGAT2 (r=0.77; P<0.0001) and SAR1B (SAR1B) (r=0.66; P<0.0001).Using multiple linear regression models, the HOMA‐IR index was the only factor significantly associated with variations in the duodenal expression of MTP, DGAT1 and DGAT2, whereas BMI and the HOMA‐IR index both contributed significantly to the variance of ACS1 expression.ConclusionsThis study demonstrates that insulin‐resistance is inversely associated with expression of the key genes involved in chylomicron assembly in the duodenum, independent of variations in BMI, waist circumference and age. The downregulation of the expression of these genes may represent an adaptive response to the chronic insulin‐resistance to decrease chylomicron secretion.