Accelerated intestinal glucose absorption in morbidly obese humans: relationship to glucose transporters, incretin hormones, and glycemia.

CONTEXT: Intestinal glucose absorption is mediated by sodium-dependent glucose transporter 1 (SGLT-1) and glucose transporter 2 (GLUT2), which are linked to sweet taste receptor (STR) signaling and incretin responses. OBJECTIVE: This study aimed to examine intestinal glucose absorption in morbidly obese humans and its relationship to the expression of STR and glucose transporters, glycemia, and incretin responses. DESIGN/SETTING/PARTICIPANTS: Seventeen nondiabetic, morbidly obese subjects (body mass index [BMI], 48 ± 4 kg/m(2)) and 11 lean controls (BMI, 25 ± 1 kg/m(2)) underwent endoscopic duodenal biopsies before and after a 30-minute intraduodenal glucose infusion (30 g glucose and 3 g 3-O-methylglucose [3-OMG]). MAIN OUTCOME MEASURES: Blood glucose and plasma concentrations of 3-OMG, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), insulin, and glucagon were measured over 270 minutes. Expression of duodenal SGLT-1, GLUT2, and STR (T1R2) was quantified by PCR. RESULTS: The increase in plasma 3-OMG (P < .001) and blood glucose (P < .0001) were greater in obese than lean subjects. Plasma 3-OMG correlated directly with blood glucose (r = 0.78, P < .01). In response to intraduodenal glucose, plasma GIP (P < .001), glucagon (P < .001), and insulin (P < .001) were higher, but GLP-1 (P < .001) was less in the obese compared with lean. Expression of SGLT-1 (P = .035), but not GLUT2 or T1R2, was higher in the obese, and related to peak plasma 3-OMG (r = 0.60, P = .01), GIP (r = 0.67, P = .003), and insulin (r = 0.58, P = .02). CONCLUSIONS: In morbid obesity, proximal intestine glucose absorption is accelerated and related to increased SGLT-1 expression, leading to an incretin-glucagon profile promoting hyperinsulinemia and hyperglycemia. These findings are consistent with the concept that accelerated glucose absorption in the proximal gut underlies the foregut theory of obesity and type 2 diabetes.

Mechanisms of activation of mouse and human enteroendocrine cells by nutrients.

OBJECTIVE: Inhibition of food intake and glucose homeostasis are both promoted when nutrients stimulate enteroendocrine cells (EEC) to release gut hormones. Several specific nutrient receptors may be located on EEC that respond to dietary sugars, amino acids and fatty acids. Bypass surgery for obesity and type II diabetes works by shunting nutrients to the distal gut, where it increases activation of nutrient receptors and mediator release, but cellular mechanisms of activation are largely unknown. We determined which nutrient receptors are expressed in which gut regions and in which cells in mouse and human, how they are associated with different types of EEC, how they are activated leading to hormone and 5-HT release. DESIGN AND RESULTS: mRNA expression of 17 nutrient receptors and EEC mediators was assessed by quantitative PCR and found throughout mouse and human gut epithelium. Many species similarities emerged, in particular the dense expression of several receptors in the distal gut. Immunolabelling showed specific colocalisation of receptors with EEC mediators PYY and GLP-1 (L-cells) or 5-HT (enterochromaffin cells). We exposed isolated proximal colonic mucosa to specific nutrients, which recruited signalling pathways within specific EEC extracellular receptor-regulated kinase (p-ERK) and calmodulin kinase II (pCAMKII), as shown by subsequent immunolabelling, and activated release of these mediators. Aromatic amino acids activated both pathways in mouse, but in humans they induced only pCAMKII, which was colocalised mainly with 5-HT expression. Activation was pertussis toxin-sensitive. Fatty acid (C12) potently activated p-ERK in human in all EEC types and evoked potent release of all three mediators. CONCLUSIONS: Specific nutrient receptors associate with distinct activation pathways within EEC. These may provide discrete, complementary pharmacological targets for intervention in obesity and type II diabetes.

Upregulation of intestinal glucose transporters after Roux-en-Y gastric bypass to prevent carbohydrate malabsorption.

OBJECTIVE: To determine the effect of Roux-en-Y gastric bypass (RYGB) on the expression of intestinal sweet taste receptors (STRs), glucose transporters (GTs), glucose absorption, and glycemia. METHODS: Intestinal biopsies were collected for mRNA expression of STR (T1R2) and GTs (SGLT-1 and GLUT2) from 11 non-diabetic RYGB, 13 non-diabetic obese, and 11 healthy subjects, at baseline and following a 30 min small intestinal (SI) glucose infusion (30 g/150 ml water with 3 g 3-O-methyl-d-glucopyranose (3-OMG)). Blood glucose, plasma 3-OMG, and insulin were measured for 270 min. RESULTS: In RYGB patients, expression of both GTs was ∼2-fold higher at baseline and after glucose infusion than those of morbidly obese or healthy subjects (P < 0.001). STR expressions were comparable amongst the groups. Peak plasma 3-OMG in both RYGB (r = 0.69, P = 0.01) and obese (r = 0.72, P = 0.005) correlated with baseline expression of SGLT-1, as was the case with peak blood glucose in RYGB subjects (r = 0.69, P = 0.02). CONCLUSIONS: The upregulated intestinal GTs in RYGB patients are associated with increased glucose absorption when glucose is delivered at a physiological rate, suggesting a molecular adaptation to prevent carbohydrate malabsorption from rapid intestinal transit after RYGB.

The effects of critical illness on intestinal glucose sensing, transporters, and absorption.

OBJECTIVES: Providing effective enteral nutrition is important during critical illness. In health, glucose is absorbed from the small intestine via sodium-dependent glucose transporter-1 and glucose transporter-2, which may both be regulated by intestinal sweet taste receptors. We evaluated the effect of critical illness on glucose absorption and expression of intestinal sodium-dependent glucose transporter-1, glucose transporter-2, and sweet taste receptors in humans and mice. DESIGN: Prospective observational study in humans and mice. SETTING: ICU and university-affiliated research laboratory. SUBJECTS: Human subjects were 12 critically ill patients and 12 healthy controls. In the laboratory 16-week-old mice were studied. INTERVENTIONS: Human subjects underwent endoscopy. Glucose (30 g) and 3-O-methylglucose (3 g), used to estimate glucose absorption, were infused intraduodenally over 30 minutes. Duodenal mucosa was biopsied before and after infusion. Mice were randomized to cecal ligation and puncture to model critical illness (n = 16) or sham laparotomy (control) (n = 8). At day 5, mice received glucose (100 mg) and 3-O-methylglucose (10 mg) infused intraduodenally prior to mucosal tissue collection. MEASUREMENTS AND MAIN RESULTS: Quantitative polymerase chain reaction was performed to measure absolute (human) and relative levels of sodium-dependent glucose transporter-1, glucose transporter-2, and taste receptor type 1 member 2 (T1R2) transcripts. Blood samples were assayed for 3-O-methylglucose to estimate glucose absorption. Glucose absorption was three-fold lower in critically ill humans than in controls (p = 0.002) and reduced by a similar proportion in cecal ligation and puncture mice (p = 0.004). In critically ill patients, duodenal levels of sodium-dependent glucose transporter-1, glucose transporter-2, and T1R2 transcript were reduced 49% (p < 0.001), 50% (p = 0.009), and 85% (p = 0.007), whereas in the jejunum of cecal ligation and puncture mice sodium-dependent glucose transporter-1, glucose transporter-2, and T1R2 transcripts were reduced by 55% (p < 0.001), 50% (p = 0.002), and 69% (p = 0.004). CONCLUSIONS: Critical illness is characterized by markedly diminished glucose absorption, associated with reduced intestinal expression of glucose transporters (sodium-dependent glucose transporter-1 and glucose transporter-2) and sweet taste receptor transcripts. These changes are paralleled in cecal ligation and puncture mice.

Disordered control of intestinal sweet taste receptor expression and glucose absorption in type 2 diabetes.

We previously established that the intestinal sweet taste receptors (STRs), T1R2 and T1R3, were expressed in distinct epithelial cells in the human proximal intestine and that their transcript levels varied with glycemic status in patients with type 2 diabetes. Here we determined whether STR expression was 1) acutely regulated by changes in luminal and systemic glucose levels, 2) disordered in type 2 diabetes, and 3) linked to glucose absorption. Fourteen healthy subjects and 13 patients with type 2 diabetes were studied twice, at euglycemia (5.2 ± 0.2 mmol/L) or hyperglycemia (12.3 ± 0.2 mmol/L). Endoscopic biopsy specimens were collected from the duodenum at baseline and after a 30-min intraduodenal glucose infusion of 30 g/150 mL water plus 3 g 3-O-methylglucose (3-OMG). STR transcripts were quantified by RT-PCR, and plasma was assayed for 3-OMG concentration. Intestinal STR transcript levels at baseline were unaffected by acute variations in glycemia in healthy subjects and in type 2 diabetic patients. T1R2 transcript levels increased after luminal glucose infusion in both groups during euglycemia (+5.8 × 10(4) and +5.8 × 10(4) copies, respectively) but decreased in healthy subjects during hyperglycemia (-1.4 × 10(4) copies). T1R2 levels increased significantly in type 2 diabetic patients under the same conditions (+6.9 × 10(5) copies). Plasma 3-OMG concentrations were significantly higher in type 2 diabetic patients than in healthy control subjects during acute hyperglycemia. Intestinal T1R2 expression is reciprocally regulated by luminal glucose in health according to glycemic status but is disordered in type 2 diabetes during acute hyperglycemia. This defect may enhance glucose absorption in type 2 diabetic patients and exacerbate postprandial hyperglycemia.