Joan Khoo

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 × 104 and +5.8 × 104 copies, respectively) but decreased in healthy subjects during hyperglycemia (−1.4 × 104 copies). T1R2 levels increased significantly in type 2 diabetic patients under the same conditions (+6.9 × 105 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.

Gastrointestinal hormonal dysfunction in gastroparesis and functional dyspepsia

Background  Numerous hormones secreted by the gut, during both the fasted state and in response to a meal, influence gastrointestinal motor and/or sensory function, and appear to contribute to the pathogenesis of delayed gastric emptying associated with gastroparesis, functional dyspepsia (FD) and feed intolerance in critical illness. Gut hormones are, accordingly, potential targets for the management of these patients.

Pathophysiology and management of gastroparesis

Gastroparesis is characterized by upper gastrointestinal symptoms associated with delayed gastric emptying, without mechanical obstruction. However, symptoms do not correlate well with the magnitude of delay in gastric emptying. Diabetes mellitus and surgery are the most common causes, although more than 30% of cases are idiopathic. Coordination of insulin action with nutrient delivery is important in diabetics, as postprandial blood glucose levels and gastric emptying are interdependent, and gastroparesis probably represents a major cause of poor glycemic control. Scintigraphy is the gold standard for measuring gastric emptying. Current treatment mainly involves the use of prokinetic drugs. Pyloric botulinum toxin injection and gastric electrical stimulation require more evidence from controlled studies before their use can be recommended. Surgical options remain inadequately studied.

The Glucagon-Like Peptide 1 Receptor Agonist Exenatide Inhibits Small Intestinal Motility, Flow, Transit, and Absorption of Glucose in Healthy Subjects and Patients With Type 2 Diabetes: A Randomized Controlled Trial

The short-acting glucagon-like peptide 1 receptor agonist exenatide reduces postprandial glycemia, partly by slowing gastric emptying, although its impact on small intestinal function is unknown. In this study, 10 healthy subjects and 10 patients with type 2 diabetes received intravenous exenatide (7.5 μg) or saline (−30 to 240 min) in a double-blind randomized crossover design. Glucose (45 g), together with 5 g 3-O-methylglucose (3-OMG) and 20 MBq 99mTc-sulfur colloid (total volume 200 mL), was given intraduodenally (t = 0–60 min; 3 kcal/min). Duodenal motility and flow were measured using a combined manometry-impedance catheter and small intestinal transit using scintigraphy. In both groups, duodenal pressure waves and antegrade flow events were fewer, and transit was slower with exenatide, as were the areas under the curves for serum 3-OMG and blood glucose concentrations. Insulin concentrations were initially lower with exenatide than with saline and subsequently higher. Nausea was greater in both groups with exenatide, but suppression of small intestinal motility and flow was observed even in subjects with little or no nausea. The inhibition of small intestinal motor function represents a novel mechanism by which exenatide can attenuate postprandial glycemia.

Incretin-based therapies: new treatments for type 2 diabetes in the new millennium.

The advent of ‘incretin-based therapies’ – GLP-1 agonists and dipeptidyl-peptidase-4 inhibitors – which result in improvements in glycemic control comparable to those with existing oral hypoglycemic agents, and potentially improve cardiovascular and pancreatic β-cell function, represents a major therapeutic advance in the management of type 2 diabetes. Gastrointestinal adverse effects occur commonly with GLP-1 agonists, and rarely with DPP-4 inhibitors, but are dose-dependent and usually transient. The low risk of hypoglycemia, and beneficial or neutral effects on body weight, render GLP-1 agonists and DPP-4 inhibitors suitable alternatives to insulin secretagogues and insulin in overweight and elderly patients. Incretin-based therapies also improve quality of life in patients with type 2 diabetes, and may be cost-effective in the long term.

Acute effects of the glucagon-like peptide-1 receptor agonist, exenatide, on blood pressure and heart rate responses to intraduodenal glucose infusion in type 2 diabetes

Aim: To evaluate the effects of the glucagon-like peptide-1 receptor agonist, exenatide, on blood pressure and heart rate during an intraduodenal glucose infusion in type 2 diabetes. Methods: Nine subjects with type 2 diabetes were randomised to receive intravenous exenatide or saline control in a crossover design. Glucose (3 kcal min−1) was infused via an intraduodenal manometry catheter for 60 min. Blood pressure, heart rate, and the frequency and amplitude of duodenal pressure waves were measured at regular intervals. Gastrointestinal symptoms were monitored using 100 mm visual analogue scales. Results: During intraduodenal glucose infusion (0–60 min), diastolic (p(0–60) = 0.03) and mean arterial (p(0–60) = 0.03) blood pressures and heart rate (p(0–60) = 0.06; p(0–120) = 0.03)) were higher with exenatide compared to placebo. The increase in the area under the curve for diastolic blood pressure and mean arterial blood pressure was related directly to the suppression of the duodenal motility index with exenatide compared to control (p = 0.007 and 0.04, respectively). Conclusion: In type 2 diabetes, intravenous exenatide increases mean arterial blood pressure and heart rate during an intraduodenal glucose infusion, supporting the need for further research with exenatide for its potential use in postprandial hypotension.

Role of the Gastrointestinal Tract in Peptide Hormone Release and Appetite

Far from being a passive reservoir for digestion and absorption of food, the gastrointestinal tract is a dynamic participant in the regulation of appetite and energy homeostasis. During meals, distension of the stomach and delivery of the products of carbohydrate, lipid, and protein digestion to the small intestine act synergistically to limit food intake. Satiation is induced by the activation of vagal afferent nerves terminals in gastric and intestinal walls, and the secretion of peptide hormones such as cholecystokinin, leptin, glucagon-like peptide-1, oxyntomodulin, and peptide YY from specialized mucosal cells in the stomach and small intestine. These gut peptides exert their effects by endocrine and paracrine actions, the latter via vagal afferents. The vagus interacts with the enteric nervous system and the central nervous system to coordinate satiation signaling. In addition to inhibiting appetite centers in the hypothalamus and brainstem, gut hormones prolong the exposure of the gastrointestinal tract to nutrients by slowing gastric emptying and intestinal transit. The mechanisms by which nutrients stimulate the release of gut hormones are now known to include activation of mucosal “taste” receptors and G-protein coupled receptors in the small intestine by carbohydrates, proteins, and fatty acids. Pharmacological agonists and antagonists of gut peptides are potentially useful for the management of obesity, type 2 diabetes, gastrointestinal motility disorders, and cachexia of critical illness.

Disordered Control of Intestinal Sweet Taste Receptor Expression in Type 2 Diabetes

5,619,926.58 person years in our analysis. During a median of 3 years, ~ 10% of our cohort of first cancer patients (n: 135,725/1,391,490) developed a second primary cancer. Of them, 2,214 (1.6%) had a second esophageal cancer. Cancer patients had a 1.7 higher risk of developing any esophageal cancer (SIR: 1.7 (95% CI: 1.6-1.7)) and a 2.2 higher risk of developing ESCC (SIR: 2.2 (95% CI: 2.1-2.4)) as compared to the general population. The SIR for a second ESCC after lung cancer was 3.70 (95% CI: 3.0-4.5). There was a remarkably high risk for developing a second ESCC in patients diagnosed with head-and-neck cancer with a SIR of 22.4 (95% CI: 20.0-25.0). In male patients the SIR for head-and-neck cancer was 19.3 (95% CI: 16.9-22.0) and 36.9 (95% CI: 29.8-45.4) for female patients. Of the 9,584 female patients with a first head-and-neck cancer 92 developed a second ESCC with a Number Needed to Screen of 96. Conclusions This first nationwide, population-based study in the Western world on the incidence of ESCC in head-and-neck cancer survivors shows that these patients have a 22 times higher risk of developing ESCC. This observation is even more pronounced in female patients. These data suggest that that head-and-neck cancer survivors may benefit from periodical screening for ESCC.