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

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.

Fat mass largely contributes to insulin mediated glucose uptake in morbidly obese subjects.

OBJECTIVE: The aim of this study is to investigate the effect of body size on insulin-mediated, whole-body glucose uptake (M-value) in morbidly obese (MO) subjects, who have large amounts of fat mass. Furthermore, we aimed at verifying which surrogate insulin-sensitivity index can better substitute the euglycemic clamp values and whether the insulin secretion/insulin resistance index is meaningful also in MO subjects. DESIGN: The study design is cross-sectional, case-control study of insulin sensitivity--assessed by different methods--and insulin secretion. SUBJECTS: One-hundred and sixty-eight subjects ca. 39 years old, with a body mass index (BMI) between 17 and 64 kg m⁻², underwent euglycemic hyperinsulinemic clamp and oral glucose tolerance test (OGTT) with surrogate measures of insulin sensitivity together with body composition by ³H2O dilution. Insulin secretion rate (ISR) was measured at fast and after OGTT by C-peptide deconvolution. RESULTS: The population was divided into quartiles of BMI. In the fourth quartile, the best insulin-sensitivity variable between M/I/kg(FFM) and M/I/kg(bw) was the latter, as shown by area under the receiver-operator characteristic (ROC) curve (0.85 vs 0.89). The best index to identify insulin-resistant individuals (lowest distribution quartile: M/I/kg(bw)≤ 29.3 µmol min⁻¹ kg⁻¹ nmol l⁻¹) were Matsuda index and oral glucose insulin sensitivity (OGIS), whereas fasting insulin concentration, QUICKI, and HOMA failed (ROC analysis). M-value declined exponentially as the BMI increased, whereas ISR linearly increased. The insulin secretion/insulin resistance index well applied to MO. CONCLUSION: In MO subjects, in which the fat mass is highly represented, fat-free mass cannot be considered the only determinant of insulin sensitivity, thus M-value should be normalized by total body weight. The best surrogates of insulin sensitivity measured by euglycemic clamp are Matsuda index and OGIS. BMI directly affects both insulin sensitivity and ISR and the insulin secretion/insulin resistance index is a valid model to correlate ISR with insulin sensitivity also in MO.

Circadian rhythms of GIP and GLP1 in glucose-tolerant and in type 2 diabetic patients after biliopancreatic diversion.

AIMS/HYPOTHESIS: We tested the hypothesis that the reversibility of insulin resistance and diabetes observed after biliopancreatic diversion (BPD) is related to changes in circadian rhythms of gastrointestinal hormones. METHODS: Ten morbidly obese participants, five with normal glucose tolerance (NGT) and five with type 2 diabetes, were studied before and within 2 weeks after BPD. Within-day variations in glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP1) levels were assessed using a single cosinor model. Insulin sensitivity was assessed by euglycaemic-hyperinsulinaemic clamp. RESULTS: Basal GLP1 relative amplitude (amplitude/mesor x 100) was 25.82-4.06% in NGT; it increased to 41.38-4.32% after BPD but was unchanged in diabetic patients. GLP1 and GIP mesor were shifted in time after surgery in diabetic patients but not in NGT participants. After BPD, the GLP1 AUC significantly increased from 775 +/- 94 to 846 +/- 161 pmol l(-1) min in NGT, whereas GIP AUC decreased significantly from 1,373 +/- 565 to 513 +/- 186 pmol l(-1) min in diabetic patients. Two-way ANOVA showed a strong influence of BPD on both GIP (p = 0.010) and GLP1 AUCs (p = 0.033), which was potentiated by the presence of diabetes, particularly for GIP (BPD x diabetes, p = 0.003). Insulin sensitivity was markedly improved (p < 0.01) in NGT (from 9.14 +/- 3.63 to 36.04 +/- 8.55 micromol [kg fat-free mass](-1) min(-1)) and diabetic patients (from 9.49 +/- 3.56 to 38.57 +/- 4.62 micromol [kg fat-free mass](-1) min(-1)). CONCLUSIONS/INTERPRETATION: An incretin circadian rhythm was shown for the first time in morbid obesity. The effect of BPD on the 24 h pattern of incretin differed between NGT and diabetic patients. GLP1 secretion impairment was reversed in NGT and could not be overcome by surgery in diabetes. On the other hand, GIP secretion was blunted after the operation only in diabetic patients, suggesting a role in insulin resistance and diabetes.