High-fat feeding stimulates endocrine, glucose-dependent insulinotropic polypeptide (GIP)-expressing cell hyperplasia in the duodenum of Wistar rats

Abstract

Aims/hypothesis Incretins are hormones released by enteroendocrine cells in response to meals, depending upon absorption of nutrients. The present study aimed to elucidate the mechanisms through which a high-fat diet (HFD) induces insulin resistance and insulin hypersecretion by focusing on the effects on enteroendocrine cells, especially those secreting glucose-dependent insulinotropic polypeptide (GIP). Methods Forty male Wistar rats, 4 months old, were randomised into two groups; one group received a chow diet and the other one received a purified tripalmitin-based HFD ad libitum. An OGTT was performed every 10 days and histological and immunofluorescence evaluations of the duodenum were obtained at 60 days from the beginning of the diets. Plasma glucose, insulin, GIP and glucagon-like peptide-1 (GLP-1) levels were measured. Immunofluorescence analysis of duodenal sections for pancreatic duodenal homeobox-1 (PDX-1), KI67, GLP-1, GIP and insulin were performed. Results Compared with chow diet, HFD induced a progressive significant increase of the glucose, insulin and GIP responses to OGTT, whereas GLP-1 circulating levels were reduced over time. After 60 days of HFD, cellular agglomerates of KI67 and PDX-1 positive cells, negative for insulin and GLP-1 but positive for GIP staining, were found inside the duodenal mucosa, and apoptosis was significantly increased. Conclusions/interpretation With the limitation that we could not establish a causal relationship between events, our study shows that HFD stimulates duodenal proliferation of endocrine cells differentiating towards K cells and oversecreting GIP. The progressive increment of GIP levels might represent the stimulus for insulin hypersecretion and insulin resistance.Keywords Duodenum . Glucose-dependent insulinotropic polypeptide . Glucagon-like peptide-1 . Endocrine cell hyperplasia . High-fat diet . Insulin Abbreviations GIPGlucose-dependent insulinotropic polypeptide GLP-1 Glucagon-like peptide-1 HFD High-fat diet PDX-1 Pancreatic duodenal homeobox-1

Endoscopic Duodenal Mucosal Resurfacing for the Treatment of Type 2 Diabetes: 6-Month Interim Analysis From the First-in-Human Proof-of-Concept Study

“…The duodenal mucosa becomes abnormal with high fat/hexose feeding (10,(21)(22)(23)(24)(25), which in turn disturbs local nutrient absorption (26) and neuronal and hormonal signaling (24,25,27). This appears to also involve the overgrowth of certain mucosal cell types, including the K cell (10,23), which is recognized for its glucoregulatory role in secreting the incretin hormone GIP. Duodenal biopsy from humans with diabetes also shows hypertrophy, thickening, and an overgrowth of entero-endocrine cell types (22).…”

“…Anatomically, the duodenum is the first site of fuel recognition at the time of nutrient intake. Observations in animal models and humans reveal that the duodenal mucosa exhibits abnormal hypertrophy and endocrine hyperplasia in the presence of diabetes (10). Moreover, gastrointestinal bypass procedures or device-based interventions (i.e., the endoluminal sleeve) that prevent contact between duodenal mucosa, bile, and nutrients improve insulin sensitivity (11) and b-cell function (12).…”

Dietary 1-monoolein decreases postprandial GIP release by reducing jejunal transport of glucose and fatty acid in rodents

“…Several studies have shown that postprandial GIP secretion was increased after chronic HF feeding (10) and in obese subjects (7). To examine the effect of 1-MO on GIP hypersecretion, mice were maintained on a semipurified HF diet for 23 wk to induce obesity, and we conducted glucose and fat loading tests.…”

Increased GIP signaling induces adipose inflammation via a HIF-1α-dependent pathway and impairs insulin sensitivity in mice

“…A high-fat diet dramatically increases GIP secretion (6). The blood concentration of GIP is elevated in obesity (1,5,19).…”