Abstract
BackgroundDietary glucose consumption has increased worldwide. Long-term high glucose intake contributes to the development of obesity and type 2 diabetes mellitus (T2DM). Obese people tend to eat glucose-containing foods, which can lead to an addiction to glucose, increased glucose levels in the blood and intestine lumen, and exposure of intestinal enterocytes to high dietary glucose. Recent studies have documented a role for enterocytes in glucose sensing. However, the molecular and genetic relationship between high glucose levels and intestinal enterocytes has not been determined. We aimed to identify relevant target genes and molecular pathways regulated by high glucose in a well-established in vitro epithelial cell culture model of the human intestinal system (Caco-2 cells).MethodsCells were grown in a medium containing 5.5 and 25 mM glucose in a bicameral culture system for 21 days to mimic the human intestine. Transepithelial electrical resistance was used to control monolayer formation and polarization of the cells. Total RNA was isolated, and genome-wide mRNA expression profiles were determined. Molecular pathways were analyzed using the DAVID bioinformatics program. Gene expression levels were confirmed by quantitative reverse transcription polymerase chain reaction (RT-qPCR).ResultsMicroarray gene expression data demonstrated that 679 genes (297 upregulated, 382 downregulated) were affected by high glucose treatment. Bioinformatics analysis indicated that intracellular protein export (p = 0.0069) and ubiquitin-mediated proteolysis (p = 0.024) pathways were induced, whereas glycolysis/gluconeogenesis (p < 0.0001), pentose phosphate (p = 0.0043), and fructose-mannose metabolism (p = 0.013) pathways were downregulated, in response to high glucose. Microarray analysis of gene expression showed that high glucose significantly induced mRNA expression levels of thioredoxin-interacting protein (TXNIP, p = 0.0001) and lipocalin 15 (LCN15, p = 0.0016) and reduced those of ATP-binding cassette, sub-family A member 1 (ABCA1, p = 0.0004), and iroquois homeobox 3 (IRX3, p = 0.0001).ConclusionsTo our knowledge, this is the first investigation of high glucose-regulated molecular responses in an intestinal enterocyte model. Our findings identify new target genes that may be important in the intestinal glucose absorption and metabolism during high glucose consumption.
Highlights
IntroductionLong-term high glucose intake contributes to the development of obesity and type 2 diabetes mellitus (T2DM)
Glucose efflux was significantly increased in the glucose-treated group relative to the controls at the 90-min (p = 0.0031; 1.4-fold), 120-min (p = 0.01; 1.4-fold), and 240-min (p = 0.0049; 1.9-fold) time points (Table 2), suggesting that Colorectal adenocarcinoma epithelial cell (Caco-2) cells mimic the human intestine in terms of glucose efflux in our experimental model
Our results demonstrate that high glucose can reduce ATP-binding cassette (ABCA1) mRNA expression levels in intestinal enterocytes, and levels of cholesterol efflux from the cells in our experimental model should be measured to allow definitive conclusions to be drawn from our results
Summary
Long-term high glucose intake contributes to the development of obesity and type 2 diabetes mellitus (T2DM). Consumption of high dietary glucose is a risk factor for the development of obesity and type 2 diabetes mellitus (T2DM) in humans [1, 2]. Recent studies have focused on the mechanisms controlling blood glucose turnover during obesity and T2DM. Hepatic glucose production from glycogen has been studied as a therapeutic target molecular pathway in the development of T2DM [7]. Glucose-dependent molecular mechanisms contributing to obesity and T2DM have been extensively studied in the adipose tissue, liver, pancreas, and brain. The small intestine may be an important tissue to investigate glucose metabolism during obesity and T2DM, as it can contribute to systemic glucose production in fasted and diabetic states [8]. The rate of interaction between nutrients and enterocytes varies depending on the eating habits of individuals
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