Augmented capacity for peripheral serotonin release in human obesity.

BACKGROUND/OBJECTIVES: Evidence from animal studies highlights an important role for serotonin (5-HT), derived from gut enterochromaffin (EC) cells, in regulating hepatic glucose production, lipolysis and thermogenesis, and promoting obesity and dysglycemia. Evidence in humans is limited, although elevated plasma 5-HT concentrations are linked to obesity. SUBJECTS/METHODS: We assessed (i) plasma 5-HT concentrations before and during intraduodenal glucose infusion (4 kcal/min for 30 min) in non-diabetic obese (BMI 44 ± 4 kg/m2, N = 14) and control (BMI 24 ± 1 kg/m2, N = 10) subjects, (ii) functional activation of duodenal EC cells (immunodetection of phospho-extracellular related-kinase, pERK) in response to glucose, and in separate subjects, (iii) expression of tryptophan hydroxylase-1 (TPH1) in duodenum and colon (N = 39), and (iv) 5-HT content in primary EC cells from these regions (N = 85). RESULTS: Plasma 5-HT was twofold higher in obese than control responders prior to (P = 0.025), and during (iAUC, P = 0.009), intraduodenal glucose infusion, and related positively to BMI (R2 = 0.334, P = 0.003) and HbA1c (R2 = 0.508, P = 0.009). The density of EC cells in the duodenum was twofold higher at baseline in obese subjects than controls (P = 0.023), with twofold more EC cells activated by glucose infusion in the obese (EC cells co-expressing 5-HT and pERK, P = 0.001), while the 5-HT content of EC cells in duodenum and colon was similar; TPH1 expression was 1.4-fold higher in the duodenum of obese subjects (P = 0.044), and related positively to BMI (R2 = 0.310, P = 0.031). CONCLUSIONS: Human obesity is characterized by an increased capacity to produce and release 5-HT from the proximal small intestine, which is strongly linked to higher body mass, and glycemic control. Gut-derived 5-HT is likely to be an important driver of pathogenesis in human obesity and dysglycemia.

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.

Effects of intraduodenal hydroxycitrate on glucose absorption, incretin release, and glycemia in response to intraduodenal glucose infusion in health and type 2 diabetes: A randomised controlled trial.

OBJECTIVE: Hydroxycitric acid (HCA), derived from the fruit Garcinia cambogia, reduces the rate of glucose absorption and lowers postprandial glycemia in rodents, but its effect in humans is unknown. The aim of this study was to investigate the effects of small intestinal perfusion with HCA on glucose absorption, as well as the incretin and glycemic responses to a subsequent intraduodenal glucose infusion, in both healthy individuals and patients with type 2 diabetes. METHODS: Twelve healthy participants and 8 patients with type 2 diabetes received an intraduodenal infusion of HCA (2800 mg in water) or control (water) over 60 min, followed by an intraduodenal infusion of 60 g glucose over 120 min, in a double-blind, randomized crossover design. In healthy individuals, 5 g 3-O-methylglucose (3-OMG) was co-infused with glucose as a marker of glucose absorption. Blood was sampled frequently. RESULTS: In healthy individuals, blood glucose was lower with HCA than control, both before and during the intraduodenal glucose infusion (P < 0.05 for each). Plasma glucose-dependent insulinotropic polypeptide (GIP; P = 0.01) and glucagon (P = 0.06) were higher with HCA, but there were no differences in plasma glucagon-like peptide (GLP)-1, insulin, or serum 3-OMG concentrations. In patients with type 2 diabetes, blood glucose, and plasma GIP, GLP-1, and insulin did not differ between HCA and control either before or after intraduodenal glucose, but during glucose infusion, plasma glucagon was higher with HCA (P = 0.04). CONCLUSION: In healthy individuals, small intestinal exposure to HCA resulted in a modest reduction in glycemia and stimulation of plasma GIP and glucagon, but no effect on plasma GLP-1 or insulin, or on glucose absorption. HCA had no effect on glycemia in patients with type 2 diabetes.

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 (99m)Tc-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.

Administration of resveratrol for 5 wk has no effect on glucagon-like peptide 1 secretion, gastric emptying, or glycemic control in type 2 diabetes: a randomized controlled trial.

BACKGROUND: Resveratrol has been reported to lower glycemia in rodent models of type 2 diabetes associated with the stimulation of glucagon-like peptide 1 (GLP-1), which is known to slow gastric emptying, stimulate insulin secretion, and suppress glucagon secretion and energy intake. OBJECTIVE: We evaluated the effects of 5 wk of resveratrol treatment on GLP-1 secretion, gastric emptying, and glycemic control in type 2 diabetes. DESIGN: Fourteen patients with diet-controlled type-2 diabetes [mean ± SEM glycated hemoglobin (HbA1c): 6.4 ± 0.2% (46.4 ± 2.2 mmol/mol)] received resveratrol (500 mg twice daily) or a placebo over two 5-wk intervention periods with a 5-wk washout period in between in a double-blind, randomized, crossover design. Before and after each intervention period (4 visits), body weight and HbA1c were measured, and patients were evaluated after an overnight fast with a standardized mashed-potato meal labeled with 100 µg (13)C-octanoic acid to measure blood glucose and plasma GLP-1 concentrations and gastric emptying (breath test) over 240 min. Daily energy intake was estimated from 3-d food diaries during the week before each visit. RESULTS: Fasting and postprandial blood glucose and plasma total GLP-1 as well as gastric emptying were similar at each assessment, and the change in each variable from weeks 0 to 5 did not differ between resveratrol and placebo groups. Similarly, changes in HbA1c, daily energy intake, and body weight after 5 wk did not differ between the 2 treatments. CONCLUSIONS: In patients with diet-controlled type 2 diabetes, 5 wk of twice-daily 500 mg-resveratrol supplementation had no effect on GLP-1 secretion, glycemic control, gastric emptying, body weight, or energy intake. Our observations do not support the use of resveratrol for improving glycemic control. This trial was registered at www.anzctr.org.au as ACTRN12613000717752.

Changes in meal composition and duration affect postprandial endothelial function in healthy humans.

Endothelial function, measured by flow-mediated dilatation (FMD), predicts cardiovascular events and is impaired postprandially. The objective of this study was to evaluate the effects of changes in composition or duration of ingestion of a meal, which slows gastric emptying and/or small intestinal nutrient exposure, on postprandial endothelial function. Twelve healthy subjects (6 male, 6 female; 33 ± 6 yr) were each studied on three occasions, in a randomized crossover design. After an overnight fast, subjects consumed a [(13)C]octanoic acid-labeled mashed potato meal ("meal 1"), or meal 1 mixed with 9 g guar ("meal 2") within 10 min, or meal 1 divided into 12 equal portions over 60 min ("meal 3"). Brachial artery FMD was measured every 30 min for 120 min. Blood glucose, serum insulin, and gastric emptying (breath test) were evaluated for 240 min. Data are means ± SE. Compared with meal 1, meal 2 was associated with slower gastric emptying (half-emptying time 285 ± 27 vs. 208 ± 15 min, P < 0.05), lower postprandial blood glucose and insulin (P < 0.001 for both), and a delayed, but more sustained, suppression of FMD (P < 0.001). After meal 3, both glycemic increment and reduction in FMD were less than after meal 2 (P < 0.05 for both). The decrement in FMD was directly related to the increment in blood glucose (r = 0.46, P = 0.02). We conclude that, in health, postprandial FMD is influenced by perturbation of gastric emptying and the duration of meal consumption, which also impact on glycemia.

Mechanism of increase in plasma intact GLP-1 by metformin in type 2 diabetes: stimulation of GLP-1 secretion or reduction in plasma DPP-4 activity?

Metformin was reported to increase plasma intact glucagon-like peptide-1 (GLP-1) concentrations in type 2 diabetes. This is, at least partly, attributable to stimulation of GLP-1 secretion. A reduction in soluble dipeptidyl peptidase-4 activity may also make a modest contribution.

Glucose absorption in small intestinal diseases.

Recent developments in the field of diabetes and obesity management have established the central role of the gut in glucose homeostasis; not only is the gut the primary absorptive site, but it also triggers neurohumoral feedback responses that regulate the pre- and post-absorptive phases of glucose metabolism. Structural and/or functional disorders of the intestine have the capacity to enhance (e.g.: diabetes) or inhibit (e.g.: short-gut syndrome, critical illness) glucose absorption, with potentially detrimental outcomes. In this review, we first describe the normal physiology of glucose absorption and outline the methods by which it can be quantified. Then we focus on the structural and functional changes in the small intestine associated with obesity, critical illness, short gut syndrome and other malabsorptive states, and particularly Type 2 diabetes, which can impact upon carbohydrate absorption and overall glucose homeostasis.

Oral bismuth for chronic intractable diarrheal conditions?

OBJECTIVE: Bismuth has antidiarrheal, antibacterial, and anti-inflammatory properties. We report our single-center experience with oral colloidal bismuth subcitrate (CBS) treatment for patients with chronic intractable diarrhea. METHOD: We interrogated our web-based Inflammatory Bowel Disease Clinical and Research database to ascertain clinical details on all patients in our tertiary hospital gastroenterology service treated with CBS between 2000 and 2010. Treatment responses were based on prospective scoring of daily number of liquid stools. Responses were recorded prior to commencement of CBS and at follow-up visits over 12 months. RESULTS: Thirty-one patients, mean age 47 years (range 17-79 years) and a mean duration of diarrhea of 22 weeks (range 6-104 weeks), were prescribed CBS at doses ranging from 120 mg to 480 mg/day for ≥1 month. Of these, 23 patients (74%) had an initial clinical response and 12 (39%) who continued with this treatment had a sustained clinical response at 1 year. Twelve patients with pouchitis and four patients with indeterminate colitis had initial responses of 92% and 75%, respectively, and sustained responses of 50% and 75%, respectively. Ulcerative colitis patients (n = 5) responded poorly with respect to both initial and sustained responses. Three patients with microscopic colitis showed encouraging initial response of 100% but did not have any sustained benefit. Three of four patients with diarrhea-predominant irritable bowel syndrome (dIBS) had an initial response and two (50%) had good sustained responses. There were no serious adverse events. One patient stopped therapy because of nausea. CONCLUSION: This is the largest report of oral bismuth treatment in chronic intractable diarrhea. CBS is cheap and appears to have the potential to be effective for ameliorating diarrheal symptoms in indeterminate colitis, pouchitis, and dIBS. An appropriately powered, blinded, randomized, controlled study appears warranted to establish the position of oral bismuth in routine practice.

Diabetic gastroparesis: recent insights into pathophysiology and implications for management.

Delayed gastric emptying affects a substantial proportion of patients with long-standing diabetes, and when associated with symptoms and/or disordered glycemic control, affects quality of life adversely. Important clinicopathological insights have recently been gained by the systematic analysis of gastric biopsies from patients with severe diabetic gastroparesis, which may stimulate the development of new therapies in the coming decade. Experience with prokinetic therapies and treatments, such as pyloric botulinum toxin injection and gastric electrical stimulation, has established that relief of symptoms does not correlate closely with acceleration of delayed gastric emptying, and that well-designed controlled trials are essential to determine the efficacy of emerging therapies.

Toxic thyroid adenoma and acromegaly: an unusual association.

Hyperthyroidism is seen in 3.5-26% of acromegalic subjects, and can occur through TSH-dependent or independent mechanisms. Thyrotoxicosis as the first presenting illness in acromegaly is particularly uncommon, as described in this patient who had both acromegaly and a toxic thyroid adenoma.