Intraduodenal calcium enhances the effects of L-tryptophan to stimulate gut hormone secretion and suppress energy intake in healthy males: a randomized, crossover, clinical trial.

BACKGROUND: In humans, intraduodenal infusion of L-tryptophan (Trp) increases plasma concentrations of gastrointestinal hormones and stimulates pyloric pressures, both key determinants of gastric emptying and associated with potent suppression of energy intake. The stimulation of gastrointestinal hormones by Trp has been shown, in preclinical studies, to be enhanced by extracellular calcium and mediated in part by the calcium-sensing receptor. OBJECTIVES: This study aim was to determine whether intraduodenal calcium can enhance the effects of Trp to stimulate gastrointestinal hormones and pyloric pressures and, if so, whether it is associated with greater suppression of energy intake, in healthy males. METHODS: Fifteen males with normal weight (mean ± standard deviation; age: 26 ± 7 years; body mass index: 22 ± 2 kg/m2), received on 3 separate occasions, 150-min intraduodenal infusions of 0, 500, or 1000 mg calcium (Ca), each combined with Trp (load: 0.1 kcal/min, with submaximal energy intake-suppressant effects) from t = 75-150 min, in a randomized, double-blind, crossover study. Plasma concentrations of GI hormones [gastrin, cholecystokinin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide (GLP)-1, and peptide tyrosine-tyrosine (PYY)], and Trp and antropyloroduodenal pressures were measured throughout. Immediately postinfusions (t = 150-180 min), energy intake at a standardized buffet-style meal was quantified. RESULTS: In response to calcium alone, both 500- and 1000-mg doses stimulated PYY, while only the 1000-mg dose stimulated GLP-1 and pyloric pressures (all P < 0.05). The 1000-mg dose also enhanced the effects of Trp to stimulate cholecystokinin and GLP-1, and both doses stimulated PYY but, surprisingly, reduced the stimulation of GIP (all P < 0.05). Both doses substantially and dose dependently enhanced the effects of Trp to suppress energy intake (Ca-0+Trp: 1108 ± 70 kcal; Ca-500+Trp: 961 ± 90 kcal; and Ca-1000+Trp: 922 ± 96 kcal; P < 0.05). CONCLUSIONS: Intraduodenal administration of calcium enhances the effect of Trp to stimulate plasma cholecystokinin, GLP-1, and PYY and suppress energy intake in healthy males. These findings have potential implications for novel nutrient-based approaches to energy intake regulation in obesity. The trial was registered at the Australian New Zealand Clinical Trial Registry (www.anzctr.org.au) as ACTRN12620001294943).

Association between total, animal, and plant protein intake and type 2 diabetes risk in adults: A systematic review and dose-response meta-analysis of prospective cohort studies.

BACKGROUND AND AIMS: While clinical studies indicate that dietary protein may benefit glucose homeostasis in type 2 diabetes (T2D), the impact of dietary protein, including whether the protein is of animal or plant origin, on the risk of T2D is uncertain. We conducted a systematic review and meta-analysis to evaluate the associations of total, animal, and plant protein intakes with the risk of T2D. METHODS: A systematic search was performed using multiple data sources, including PubMed/Medline, ISI Web of Science, Scopus, and Google Scholar, with the data cut-off in May 2023. Our selection criteria focused on prospective cohort studies that reported risk estimates for the association between protein intake and T2D risk. For data synthesis, we calculated summary relative risks and 95% confidence intervals for the highest versus lowest categories of protein intake using random-effects models. Furthermore, we conducted both linear and non-linear dose-response analyses to assess the dose-response associations between protein intake and T2D risk. RESULTS: Sixteen prospective cohort studies, involving 615,125 participants and 52,342 T2D cases, were identified, of which eleven studies reported data on intake of both animal and plant protein. Intakes of total (pooled effect size: 1.14, 95% CI: 1.04-1.24) and animal (pooled effect size: 1.18, 95% CI: 1.09-1.27) protein were associated with an increased risk of T2D. These effects were dose-related - each 20-g increase in total or animal protein intake increased the risk of T2D by ∼3% and ∼7%, respectively. In contrast, there was no association between intake of plant protein and T2D risk (pooled effect size: 0.98, 95% CI: 0.89-1.08), while replacing animal with plant protein intake (per each 20 g) was associated with a reduced risk of T2D (pooled effect size: 0.80, 95% CI: 0.76-0.84). CONCLUSIONS: Our findings indicate that long-term consumption of animal, but not plant, protein is associated with a significant and dose-dependent increase in the risk of T2D, with the implication that replacement of animal with plant protein intake may lower the risk of T2D.

The herbal preparation, STW5-II, reduces proximal gastric tone and stimulates antral pressures in healthy humans.

BACKGROUND: The herbal preparation, STW5-II, improves upper gastrointestinal symptoms, including abdominal fullness, early satiation, and epigastric pain, in patients with functional dyspepsia, and in preclinical models decreases fundic tone and increases antral contractility. The effects of STW5-II on esophago-gastric junction pressure, proximal gastric tone and antropyloroduodenal pressures, disturbances of which may contribute to symptoms associated with disorders of gut-brain interaction, including functional dyspepsia, in humans, have, hitherto, not been evaluated. METHODS: STW5-II or placebo (matched for color, aroma, and alcohol content) were each administered orally, at the recommended dose (20 drops), to healthy male and female volunteers (age: 27 ± 1 years) in a double-blind, randomized fashion, on two separate occasions, separated by 3-7 days, to evaluate effects on (i) esophago-gastric junction pressures following a standardized meal using solid-state high-resolution manometry (part 1, n = 16), (ii) proximal gastric volume using a barostat (part 2, n = 16), and (iii) antropyloroduodenal pressures assessed by high-resolution manometry (part 3, n = 18), for 120 min (part 1) or 180 min (parts 2, 3). KEY RESULTS: STW5-II increased maximum intrabag volume (ml; STW5-II: 340 ± 38, placebo: 251 ± 30; p = 0.007) and intrabag volume between t = 120 and 180 min (p = 0.011), and the motility index of antral pressure waves between t = 60 and 120 min (p = 0.032), but had no effect on esophago-gastric junction, pyloric, or duodenal pressures. CONCLUSIONS & INFERENCES: STW5-II has marked region-specific effects on gastric motility in humans, which may contribute to its therapeutic efficacy in functional dyspepsia.

Effects of Quinine on the Glycaemic Response to, and Gastric Emptying of, a Mixed-Nutrient Drink in Females and Males.

Intraduodenal quinine, in the dose of 600 mg, stimulates glucagon-like peptide-1 (GLP-1), cholecystokinin and insulin; slows gastric emptying (GE); and lowers post-meal glucose in men. Oral sensitivity to bitter substances may be greater in women than men. We, accordingly, evaluated the dose-related effects of quinine on GE, and the glycaemic responses to, a mixed-nutrient drink in females, and compared the effects of the higher dose with those in males. A total of 13 female and 13 male healthy volunteers received quinine-hydrochloride (600 mg ('QHCl-600') or 300 mg ('QHCl-300', females only) or control ('C'), intraduodenally (10 mL bolus) 30 min before a drink (500 kcal, 74 g carbohydrates). Plasma glucose, insulin, C-peptide, GLP-1, glucose-dependent insulinotropic polypeptide (GIP) and cholecystokinin were measured at baseline, for 30 min after quinine alone, and then for 2 h post-drink. GE was measured by 13C-acetate breath-test. QHCl-600 alone stimulated insulin, C-peptide and GLP-1 secretion compared to C. Post-drink, QHCl-600 reduced plasma glucose, stimulated C-peptide and GLP-1, and increased the C-peptide/glucose ratio and oral disposition index, while cholecystokinin and GIP were less, in females and males. QHCl-600 also slowed GE compared to C in males and compared to QHCl-300 in females (p < 0.05). QHCl-300 reduced post-meal glucose concentrations and increased the C-peptide/glucose ratio, compared to C (p < 0.05). Magnitudes of glucose lowering and increase in C-peptide/glucose ratio by QHCl-600 were greater in females than males (p < 0.05). We conclude that quinine modulates glucoregulatory functions, associated with glucose lowering in healthy males and females. However, glucose lowering appears to be greater in females than males, without apparent differential effects on GI functions.

Intermittent fasting plus early time-restricted eating versus calorie restriction and standard care in adults at risk of type 2 diabetes: a randomized controlled trial.

Intermittent fasting appears an equivalent alternative to calorie restriction (CR) to improve health in humans. However, few trials have considered applying meal timing during the 'fasting' day, which may be a limitation. We developed a novel intermittent fasting plus early time-restricted eating (iTRE) approach. Adults (N = 209, 58 ± 10 years, 34.8 ± 4.7 kg m-2) at increased risk of developing type 2 diabetes were randomized to one of three groups (2:2:1): iTRE (30% energy requirements between 0800 and 1200 hours and followed by a 20-h fasting period on three nonconsecutive days per week, and ad libitum eating on other days); CR (70% of energy requirements daily, without time prescription); or standard care (weight loss booklet). This open-label, parallel group, three-arm randomized controlled trial provided nutritional support to participants in the iTRE and CR arms for 6 months, with an additional 12-month follow-up. The primary outcome was change in glucose area under the curve in response to a mixed-meal tolerance test at month 6 in iTRE versus CR. Glucose tolerance was improved to a greater extent in iTRE compared with CR (-10.10 (95% confidence interval -14.08, -6.11) versus -3.57 (95% confidence interval -7.72, 0.57) mg dl-1 min-1; P = 0.03) at month 6, but these differences were lost at month 18. Adverse events were transient and generally mild. Reports of fatigue were higher in iTRE versus CR and standard care, whereas reports of constipation and headache were higher in iTRE and CR versus standard care. In conclusion, incorporating advice for meal timing with prolonged fasting led to greater improvements in postprandial glucose metabolism in adults at increased risk of developing type 2 diabetes. ClinicalTrials.gov identifier NCT03689608 .

Effect of gastric distension with concurrent small intestinal saline or glucose infusion on incretin hormone secretion in healthy individuals: A randomized, controlled, crossover study.

AIM: To evaluate the effect of gastric distension, induced using a gastric 'barostat', on the secretion of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in the presence and absence of small intestinal nutrients in healthy individuals. MATERIALS AND METHODS: Eight healthy participants (two females, six males, mean age 69.3 ± 1.2 years, body mass index 23.5 ± 0.8 kg/m2 ) were each studied on four occasions when they received an intraduodenal infusion of either (i) 0.9% saline or (ii) glucose delivered at a rate of 3 kcal/min both with, and without, an intragastric balloon with the pressure set to 8 mmHg above the intragastric minimum distending pressure. RESULTS: Following intraduodenal saline or glucose infusion, there was no difference in plasma GLP-1 with or without gastric distension (P = 1.00 for both saline and glucose infusions). There was also no difference in plasma GIP with or without gastric distension (P = 1.00 for saline infusion and P = .99 for glucose infusion). CONCLUSIONS: Gastric distension, either alone or during small intestinal glucose exposure, does not stimulate incretin hormone secretion significantly in healthy humans.

Effects of intraduodenal or intragastric administration of a bitter hop extract (Humulus lupulus L.), on upper gut motility, gut hormone secretion and energy intake in healthy-weight men.

Gastrointestinal functions, particularly pyloric motility and the gut hormones, cholecystokinin and peptide YY, contribute to the regulation of acute energy intake. Bitter tastants modulate these functions, but may, in higher doses, induce GI symptoms. The aim of this study was to evaluate the effects of both dose and delivery location of a bitter hop extract (BHE) on antropyloroduodenal pressures, plasma cholecystokinin and peptide YY, appetite perceptions, gastrointestinal symptoms and energy intake in healthy-weight men. The study consisted of two consecutive parts, with part A including n = 15, and part B n = 11, healthy, lean men (BMI 22.6 ± 1.1 kg/m2, aged 25 ± 3 years). In randomised, double-blind fashion, participants received in part A, BHE in doses of either 100 mg ("ID-BHE-100") or 250 mg ("ID-BHE-250"), or vehicle (canola oil; "ID-control") intraduodenally, or in part B, 250 mg BHE ("IG-BHE-250") or vehicle ("IG-control") intragastrically. Antropyloroduodenal pressures, hormones, appetite and symptoms were measured for 180 min, energy intake from a standardised buffet-meal was quantified subsequently. ID-BHE-250, but not ID-BHE-100, had modest, and transient, effects to stimulate pyloric pressures during the first 90 min (P < 0.05), and peptide YY from t = 60 min (P < 0.05), but did not affect antral or duodenal pressures, cholecystokinin, appetite, gastrointestinal symptoms or energy intake. IG-BHE-250 had no detectable effects. In conclusion, BHE, when administered intraduodenally, in the selected higher dose, modestly affected some appetite-related gastrointestinal functions, but had no detectable effects when given in the lower dose or intragastrically. Thus, BHE, at none of the doses or routes of administration tested, has appetite- or energy intake-suppressant effects.

Association between Dietary Macronutrient Intake and Symptoms in Uninvestigated Dyspepsia: Evidence from a Population-Based, Cross-Sectional Study.

(1) Background: Limited evidence from laboratory-based studies suggests that specific dietary macronutrients, particularly fat, can induce dyspeptic symptoms. Through a population-based study, we investigated the relationship between dietary macronutrients and dyspeptic symptoms and sought to determine macronutrient intake thresholds to predict or prevent dyspepsia and reduce symptoms in patients with dyspepsia. (2) Methods: A total of 4763 Iranian people were enrolled in this population-based, cross-sectional study. Uninvestigated dyspepsia (UD) and its symptoms, including postprandial fullness, early satiation, and epigastric pain, were evaluated using a modified Persian version of the Rome III criteria. The dietary intakes of participants were evaluated using a validated food−frequency questionnaire. Receiver operating characteristic (ROC) curve analysis was used to calculate threshold intakes of dietary macronutrients to prevent UD in the general population. The analysis was then repeated in those with UD to calculate intake thresholds for reducing UD symptoms. (3) Results: Early satiation occurred in 6.3% (n = 302), postprandial fullness in 8.0% (n = 384) and epigastric pain in 7.8% (n = 371) of participants. The prevalence of UD was 15.2%. Compared with individuals without UD, those with UD had a lower intake of carbohydrates (48.2% vs. 49.1%) and a higher intake of fats (38.3% vs. 37.4%), while protein and energy intakes did not differ. Higher dietary fat and protein intakes were associated with a higher prevalence of postprandial fullness and epigastric pain, respectively. Macronutrient intakes to predict UD in the general population were <49% of energy from carbohydrates, >14.7% from protein, and >37.7% from fats. Carbohydrate, protein, and fat intakes to prevent symptoms among those with UD were calculated to be >48.2%, <14.6%, and <38.6%, respectively. (4) Conclusion: Higher carbohydrate intake and lower fat or protein intakes were associated with a lower likelihood of UD. Prospective studies carefully manipulating dietary macronutrient composition are warranted to investigate the value of dietary changes to improve symptoms in people with UD.

Quinine Effects on Gut and Pancreatic Hormones and Antropyloroduodenal Pressures in Humans-Role of Delivery Site and Sex.

CONTEXT: The bitter substance quinine modulates the release of a number of gut and gluco-regulatory hormones and upper gut motility. As the density of bitter receptors may be higher in the duodenum than the stomach, direct delivery to the duodenum may be more potent in stimulating these functions. The gastrointestinal responses to bitter compounds may also be modified by sex. BACKGROUND: We have characterized the effects of intragastric (IG) versus intraduodenal (ID) administration of quinine hydrochloride (QHCl) on gut and pancreatic hormones and antropyloroduodenal pressures in healthy men and women. METHODS: 14 men (26 ±â€…2 years, BMI: 22.2 ±â€…0.5 kg/m2) and 14 women (28 ±â€…2 years, BMI: 22.5 ±â€…0.5 kg/m2) received 600 mg QHCl on 2 separate occasions, IG or ID as a 10-mL bolus, in randomized, double-blind fashion. Plasma ghrelin, cholecystokinin, peptide YY, glucagon-like peptide-1 (GLP-1), insulin, glucagon, and glucose concentrations and antropyloroduodenal pressures were measured at baseline and for 120 minutes following QHCl. RESULTS: Suppression of ghrelin (P = 0.006), stimulation of cholecystokinin (P = 0.030), peptide YY (P = 0.017), GLP-1 (P = 0.034), insulin (P = 0.024), glucagon (P = 0.030), and pyloric pressures (P = 0.050), and lowering of glucose (P = 0.001) were greater after ID-QHCl than IG-QHCl. Insulin stimulation (P = 0.021) and glucose reduction (P = 0.001) were greater in females than males, while no sex-associated effects were found for cholecystokinin, peptide YY, GLP-1, glucagon, or pyloric pressures. CONCLUSION: ID quinine has greater effects on plasma gut and pancreatic hormones and pyloric pressures than IG quinine in healthy subjects, consistent with the concept that stimulation of small intestinal bitter receptors is critical to these responses. Both insulin stimulation and glucose lowering were sex-dependent.

Appetite and Satiety Control-Contribution of Gut Mechanisms.

The prevalence of obesity, and its comorbidities, particularly type 2 diabetes, cardiovascular and hepatic disease and certain cancers, continues to rise at an alarming rate worldwide [...].

Suppression of Energy Intake by Intragastric l-Tryptophan in Lean and Obese Men: Relations with Appetite Perceptions and Circulating Cholecystokinin and Tryptophan.

BACKGROUND: l-Tryptophan reduces energy intake in healthy men. The underlying mechanisms, including appetite, plasma cholecystokinin (CCK), tryptophan (Trp), and the ratio of Trp to large neutral amino acids (Trp:LNAAs ratio), and whether responses differ in lean and obese individuals, are uncertain. OBJECTIVES: We evaluated the effects of intragastric Trp on energy intake (primary outcome) and their potential mechanisms, pre- and postmeal, in lean men and those with obesity. METHODS: Twelve lean men [mean ± SD age: 30 ± 3 y; BMI (in kg/m2): 23 ± 1] and 13 men with obesity (mean ± SD age: 31 ± 3 y; BMI: 33 ± 1) received, on 3 separate occasions, in double-blind, randomized order, 3 g ("Trp-3") or 1.5 g ("Trp-1.5") Trp, or control ("C"), intragastrically, 30 min before a buffet-meal. Energy intake from the buffet-meal, hunger, fullness, and plasma CCK and amino acid concentrations were measured in response to Trp alone and for 2 h postmeal. Data were analyzed using maximum likelihood mixed-effects models, with treatment, group, and treatment-by-group interaction as fixed effects. RESULTS: Trp alone increased plasma CCK, Trp, and the Trp:LNAAs ratio (all P < 0.001), with no difference between groups. Trp suppressed energy intake (P < 0.001), with no difference between groups (lean, C: 1085 ± 102 kcal, Trp-1.5: 1009 ± 92 kcal, Trp-3: 868 ± 104 kcal; obese, C: 1249 ± 98 kcal, Trp-1.5: 1217 ± 90 kcal, Trp-3: 1012 ± 100 kcal). Postmeal, fullness was greater after Trp-3 than after C and Trp-1.5 (all P < 0.05), and in men with obesity than in lean men (P < 0.05). Plasma Trp and the Trp:LNAAs ratio were greater after Trp-3 and Trp-1.5 than after C (all P < 0.001), and tended to be less in men with obesity than in the lean (P = 0.07) (Trp:LNAAs ratio: lean, C: 1.5 ± 0.2, Trp-1.5: 6.9 ± 0.7, Trp-3: 10.7 ± 1.4; obese, C: 1.4 ± 0.1, Trp-1.5: 4.6 ± 0.7, Trp-3: 7.8 ± 1.3). There were inverse correlations of energy intake with plasma Trp and the Trp:LNAAs ratio in both groups (lean, both r = -0.50, P < 0.01; obese, both r = -0.40, P < 0.05). CONCLUSIONS: Intragastric Trp has potent energy intake-suppressant effects, in both lean men and those with obesity, apparently related to the Trp:LNAAs ratio.

Comparative Effects of the Branched-Chain Amino Acids, Leucine, Isoleucine and Valine, on Gastric Emptying, Plasma Glucose, C-Peptide and Glucagon in Healthy Men.

(1) Background: Whey protein lowers postprandial blood glucose in health and type 2 diabetes, by stimulating insulin and incretin hormone secretion and slowing gastric emptying. The branched-chain amino acids, leucine, isoleucine and valine, abundant in whey, may mediate the glucoregulatory effects of whey. We investigated the comparative effects of intragastric administration of leucine, isoleucine and valine on the plasma glucose, C-peptide and glucagon responses to and gastric emptying of a mixed-nutrient drink in healthy men. (2) Methods: 15 healthy men (27 ± 3 y) received, on four separate occasions, in double-blind, randomised fashion, either 10 g of leucine, 10 g of isoleucine, 10 g of valine or control, intragastrically, 30 min before a mixed-nutrient drink. Plasma glucose, C-peptide and glucagon concentrations were measured before, and for 2 h following, the drink. Gastric emptying of the drink was quantified using 13C-acetate breath-testing. (3) Results: Amino acids alone did not affect plasma glucose or C-peptide, while isoleucine and valine, but not leucine, stimulated glucagon (p < 0.05), compared with control. After the drink, isoleucine and leucine reduced peak plasma glucose compared with both control and valine (all p < 0.05). Neither amino acid affected early (t = 0-30 min) postprandial C-peptide or glucagon. While there was no effect on overall gastric emptying, plasma glucose at t = 30 min correlated with early gastric emptying (p < 0.05). (4) Conclusion: In healthy individuals, leucine and isoleucine lower postprandial blood glucose, at least in part by slowing gastric emptying, while valine does not appear to have an effect, possibly due to glucagon stimulation.

Effects of Bitter Substances on GI Function, Energy Intake and Glycaemia-Do Preclinical Findings Translate to Outcomes in Humans?

Bitter substances are contained in many plants, are often toxic and can be present in spoiled food. Thus, the capacity to detect bitter taste has classically been viewed to have evolved primarily to signal the presence of toxins and thereby avoid their consumption. The recognition, based on preclinical studies (i.e., studies in cell cultures or experimental animals), that bitter substances may have potent effects to stimulate the secretion of gastrointestinal (GI) hormones and modulate gut motility, via activation of bitter taste receptors located in the GI tract, reduce food intake and lower postprandial blood glucose, has sparked considerable interest in their potential use in the management or prevention of obesity and/or type 2 diabetes. However, it remains to be established whether findings from preclinical studies can be translated to health outcomes, including weight loss and improved long-term glycaemic control. This review examines information relating to the effects of bitter substances on the secretion of key gut hormones, gastric motility, food intake and blood glucose in preclinical studies, as well as the evidence from clinical studies, as to whether findings from animal studies translate to humans. Finally, the evidence that bitter substances have the capacity to reduce body weight and/or improve glycaemic control in obesity and/or type 2 diabetes, and potentially represent a novel strategy for the management, or prevention, of obesity and type 2 diabetes, is explored.

Comparative Effects of Intragastric and Intraduodenal Administration of Quinine on the Plasma Glucose Response to a Mixed-Nutrient Drink in Healthy Men: Relations with Glucoregulatory Hormones and Gastric Emptying.

BACKGROUND: In preclinical studies, bitter compounds, including quinine, stimulate secretion of glucoregulatory hormones [e.g., glucagon-like peptide-1 (GLP-1)] and slow gastric emptying, both key determinants of postprandial glycemia. A greater density of bitter-taste receptors has been reported in the duodenum than the stomach. Thus, intraduodenal (ID) delivery may be more effective in stimulating GI functions to lower postprandial glucose. OBJECTIVE: We compared effects of intragastric (IG) and ID quinine [as quinine hydrochloride (QHCl)] administration on the plasma glucose response to a mixed-nutrient drink and relations with gastric emptying, plasma C-peptide (reflecting insulin secretion), and GLP-1. METHODS: Fourteen healthy men [mean ± SD age: 25 ± 3 y; BMI (in kg/m2): 22.5 ± 0.5] received, on 4 separate occasions, in double-blind, randomly assigned order, 600 mg QHCl or control, IG or ID, 60 min (IG conditions) or 30 min (IG conditions) before a mixed-nutrient drink. Plasma glucose (primary outcome) and hormones were measured before, and for 2 h following, the drink. Gastric emptying of the drink was measured using a 13C-acetate breath test. Data were analyzed using repeated-measures 2-way ANOVAs (factors: treatment and route of administration) to evaluate effects of QHCl alone and 3-way ANOVAs (factors: treatment, route-of-administration, and time) for responses to the drink. RESULTS: After QHCl alone, there were effects of treatment, but not route of administration, on C-peptide, GLP-1, and glucose (P < 0.05); QHCl stimulated C-peptide and GLP-1 and lowered glucose concentrations (IG control: 4.5 ± 0.1; IG-QHCl: 3.9 ± 0.1; ID-control: 4.6 ± 0.1; ID-QHCl: 4.2 ± 0.1 mmol/L) compared with control. Postdrink, there were treatment × time interactions for glucose, C-peptide, and gastric emptying, and a treatment effect for GLP-1 (all P < 0.05), but no route-of-administration effects. QHCl stimulated C-peptide and GLP-1, slowed gastric emptying, and reduced glucose (IG control: 7.2 ± 0.3; IG-QHCl: 6.2 ± 0.3; ID-control: 7.2 ± 0.3; ID-QHCl: 6.4 ± 0.4 mmol/L)  compared with control. CONCLUSIONS: In healthy men, IG and ID quinine administration similarly lowered plasma glucose, increased plasma insulin and GLP-1, and slowed gastric emptying. These findings have potential implications for lowering blood glucose in type 2 diabetes. This study was registered as a clinical trial with the Australian New Zealand Clinical Trials at www.anzctr.org.au as ACTRN12619001269123.

Effects of intragastric administration of L-tryptophan on the glycaemic response to a nutrient drink in men with type 2 diabetes - impacts on gastric emptying, glucoregulatory hormones and glucose absorption.

BACKGROUND: The rate of gastric emptying and glucoregulatory hormones are key determinants of postprandial glycaemia. Intragastric administration of L-tryptophan slows gastric emptying and reduces the glycaemic response to a nutrient drink in lean individuals and those with obesity. We investigated whether tryptophan decreases postprandial glycaemia and slows gastric emptying in type 2 diabetes (T2D). METHODS: Twelve men with T2D (age: 63 ± 2 years, HbA1c: 49.7 ± 2.5 mmol/mol, BMI: 30 ± 1 kg/m2) received, on three separate occasions, 3 g ('Trp-3') or 1.5 g ('Trp-1.5') tryptophan, or control (0.9% saline), intragastrically, in randomised, double-blind fashion, 30 min before a mixed-nutrient drink (500 kcal, 74 g carbohydrates), containing 3 g 3-O-methyl-D-glucose (3-OMG) to assess glucose absorption. Venous blood samples were obtained at baseline, after tryptophan, and for 2 h post-drink for measurements of plasma glucose, C-peptide, glucagon and 3-OMG. Gastric emptying of the drink was quantified using two-dimensional ultrasound. RESULTS: Tryptophan alone stimulated C-peptide (P = 0.002) and glucagon (P = 0.04), but did not affect fasting glucose. In response to the drink, Trp-3 lowered plasma glucose from t = 15-30 min and from t = 30-45 min compared with control and Trp-1.5, respectively (both P < 0.05), with no differences in peak glucose between treatments. Gastric emptying tended to be slower after Trp-3, but not Trp-1.5, than control (P = 0.06). Plasma C-peptide, glucagon and 3-OMG increased on all days, with no major differences between treatments. CONCLUSIONS: In people with T2D, intragastric administration of 3 g tryptophan modestly slows gastric emptying, associated with a delayed rise, but not an overall lowering of, postprandial glucose.

The regulation of gastric ghrelin secretion.

Ghrelin is a gastric hormone with multiple physiological functions, including the stimulation of food intake and adiposity. It is well established that circulating ghrelin levels are closely associated with feeding patterns, rising strongly before a meal and lowering upon food intake. However, the mechanisms underlying the modulation of ghrelin secretion are not fully understood. The purpose of this review is to discuss current knowledge on the circadian oscillation of circulating ghrelin levels, the neural mechanisms stimulating fasting ghrelin levels and peripheral mechanisms modulating postprandial ghrelin levels. Furthermore, the therapeutic potential of targeting the ghrelin pathway is discussed in the context of the treatment of various metabolic disorders, including obesity, type 2 diabetes, diabetic gastroparesis and Prader-Willi syndrome. Moreover, eating disorders including anorexia nervosa, bulimia nervosa and binge-eating disorder are also discussed.

Intragastric administration of leucine and isoleucine does not reduce the glycaemic response to, or slow gastric emptying of, a carbohydrate-containing drink in type 2 diabetes.

AIMS: In healthy individuals, intragastric administration of the branched-chain amino acids, leucine and isoleucine, diminishes the glycaemic response to a mixed-nutrient drink, apparently by stimulating insulin and slowing gastric emptying, respectively. This study aimed to evaluate the effects of leucine and isoleucine on postprandial glycaemia and gastric emptying in type-2 diabetes mellitus (T2D). METHODS: 14 males with T2D received, on 3 separate occasions, in double-blind, randomised fashion, either 10 g leucine, 10 g isoleucine or control, intragastrically 30 min before a mixed-nutrient drink (500 kcal; 74 g carbohydrates, 18 g protein, 15 g fat). Plasma glucose, insulin and glucagon were measured from 30 min pre- until 120 min post-drink. Gastric emptying of the drink was also measured. RESULTS: Leucine and isoleucine stimulated insulin, both before and after the drink (all P < 0.05; peak (mU/L): control: 70 ± 15; leucine: 88 ± 17; isoleucine: 74 ± 15). Isoleucine stimulated (P < 0.05), and leucine tended to stimulate (P = 0.078), glucagon before the drink, and isoleucine stimulated glucagon post-drink (P = 0.031; peak (pg/mL): control: 62 ± 5; leucine: 70 ± 9; isoleucine: 69 ± 6). Neither amino acid affected gastric emptying or plasma glucose (peak (mmol/L): control: 12.0 ± 0.5; leucine: 12.5 ± 0.7; isoleucine: 12.0 ± 0.6). CONCLUSIONS: In contrast to health, in T2D, leucine and isoleucine, administered intragastrically in a dose of 10 g, do not lower the glycaemic response to a mixed-nutrient drink. This finding argues against a role for 'preloads' of either leucine or isoleucine in the management of T2D.

The Effect of Isoleucine Supplementation on Body Weight Gain and Blood Glucose Response in Lean and Obese Mice.

Chronic isoleucine supplementation prevents diet-induced weight gain in rodents. Acute-isoleucine administration improves glucose tolerance in rodents and reduces postprandial glucose levels in humans. However, the effect of chronic-isoleucine supplementation on body weight and glucose tolerance in obesity is unknown. This study aimed to investigate the impact of chronic isoleucine on body weight gain and glucose tolerance in lean and high-fat-diet (HFD) induced-obese mice. Male C57BL/6-mice, fed a standard-laboratory-diet (SLD) or HFD for 12 weeks, were randomly allocated to: (1) Control: Drinking water; (2) Acute: Drinking water with a gavage of isoleucine (300 mg/kg) prior to the oral-glucose-tolerance-test (OGTT) or gastric-emptying-breath-test (GEBT); (3) Chronic: Drinking water with 1.5% isoleucine, for a further six weeks. At 16 weeks, an OGTT and GEBT was performed and at 17 weeks metabolic monitoring. In SLD- and HFD-mice, there was no difference in body weight, fat mass, and plasma lipid profiles between isoleucine treatment groups. Acute-isoleucine did not improve glucose tolerance in SLD- or HFD-mice. Chronic-isoleucine impaired glucose tolerance in SLD-mice. There was no difference in gastric emptying between any groups. Chronic-isoleucine did not alter energy intake, energy expenditure, or respiratory quotient in SLD- or HFD-mice. In conclusion, chronic isoleucine supplementation may not be an effective treatment for obesity or glucose intolerance.