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International audience; Objective: This study evaluated gastric emptying (GE) and small intestinal (SI) transit in people with morbid obesity and their relationships to glycaemia, incretin hormones, and glucose absorption Methods: GE and caecal arrival time (CAT) of a mixed meal were assessed in 22 morbidly obese (50.2 +/- 2.5 years; 13 F:9 M; BMI: 48.6 +/- 1.8 kg/m(2)) and 10 lean (38.6 +/- 8.4 years; 5 F:5 M; BMI: 23.9 +/- 0.7 kg/m(2)) subjects, using scintigraphy. Blood glucose, plasma 3-O-methylglucose, insulin, glucagon, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were measured. Insulin sensitivity and resistance were also quantified Results: When compared with lean subjects, GE (t50: 60.7 +/- 6.5 vs. 41.1 +/- 7.3 min; P = 0.04) and CAT (221.5 +/- 9.8 vs. 148.0 +/- 7.1 min; P = 0.001) of solids were prolonged in morbid obesity. Postprandial rises in GIP (P = 0.001), insulin (P = 0.02), glucose (P = 0.03) and 3-O-methylglucose (P = 0.001) were less. Whereas GLP-1 increased at 45 mins postprandially in lean subjects, there was no increase in the obese (P = 0.04). Both fasting (P = 0.045) and postprandial (P = 0.012) plasma glucagon concentrations were higher in the obese Conclusions: GE and SI transit are slower in the morbidly obese, and associated with reductions in postprandial glucose absorption, and glycaemic excursions, as well as plasma GIP and GLP-1

Context: The early glycemic response during a 75-g oral glucose tolerance test (OGTT) is directly related to the rate of gastric emptying (GE). There is little information about the effect of GE on the blood glucose at either 60 min (a predictor of diabetes) or 120 min (used diagnostically). Objective: This study aimed to evaluate the relationships between glycemic responses at 30, 60, and 120 min and GE following a 75-g OGTT in subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes (T2D). Design, Setting, and Subjects: Eighty-two subjects in the general community without diabetes (57 NGT, 25 IGT) and 16 with T2D consumed a 75-g glucose drink labeled with 99mTc-sulfur colloid. GE (by scintigraphy) and glycemia were measured from t = 0-120 min and relationships between blood glucose (absolute, change from baseline, and area under the curve) and GE at 30, 60, and 120 min determined. Results: There were no differences in GE. There were relationships between the blood glucose at 30 min and GE (NGT: r = 0.40; P < .01; IGT: r = 0.49; P = .02; T2D: r = 0.62; P = .01). There was also a relationship between the blood glucose at 60 min and GE in IGT (r = 0.52; P = .02) and T2D (r = 0.77; P < .01), but not NGT (r = 0.16; P = .24). In NGT, there was an inverse relationship between blood glucose at 120 min and GE (r=-0.30; P = .02), but not in IGT (r = 0.05; P = .82) or T2D (r = 0.37; P = .16). Conclusions: GE is a determinant of the glycemic response to an OGTT in NGT, IGT, and T2D but these relationships differ and are time dependent. Refereed/Peer-reviewed

The aim was to determine the effects of fat and protein preloads on pouch emptying (PE), caecal arrival time (CAT), glucose absorption, blood glucose (BSL), gut hormones, haemodynamics and gastrointestinal (GI) symptoms in subjects who had undergone Roux-en-Y gastric bypass (RYGB) >12 months previously. Ten RYGB subjects were studied on three occasions, in randomised order, receiving 200-ml preloads of either water, fat (30 ml olive oil) or whey protein (55 g), 30 min before a mixed meal. PE, CAT, BSL, plasma 3-O-methyl-D-glucopyranose (3-OMG), insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1) and glucagon, blood pressure (BP), heart rate (HR) and GI symptoms were assessed over 270 min. Although fat and protein preloads did not alter PE of either solids or liquids, the CAT of solids, but not liquids, was longer than that after the water preload (fat 68 ± 5 min and protein 71 ± 6 min vs. water 46 ± 5 min; P = 0.02). BSL elevated promptly after the meal on all days (P

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.

The purpose of this study is to determine the effects of posture and drink volume on gastric/pouch emptying (G/PE), intestinal transit, hormones, absorption, glycaemia, blood pressure and gastrointestinal (GI) symptoms after gastric bypass (Roux-en-Y gastric bypass (RYGB)). Ten RYGB subjects were studied on four occasions in randomized order (sitting vs. supine posture; 50 vs. 150 ml of labelled water mixed with 3 g 3-O-methyl-d-glucose (3-OMG) and 50 g glucose). G/PE, caecal arrival time (CAT), blood glucose, plasma insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), peptide YY (PYY), 3-OMG, blood pressure, heart rate and GI symptoms were assessed over 240 min. Controls were ten volunteers with no medical condition or previous abdominal surgery, who were studied with the 150-ml drink in the sitting position. Compared to controls, PE (P

Objective To evaluate the effect of modulating pouch emptying (PE) and SI transit of glucose after Roux-en-Y gastric bypass (RYGB) on blood glucose, incretin hormones, glucose absorption and gastrointestinal (GI) symptoms. Methods Ten RYGB patients were studied twice in random order, receiving either a 150 ml glucose drink (200 kcal) or the same solution infused into the proximal Roux-limb at 4 kcal/min. Data were compared with 10 healthy volunteers who received a 4 kcal/min duodenal infusion. PE, cecal arrival time (CAT), blood glucose, plasma 3-O-methylglucose (3-OMG), insulin, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1), and GI symptoms were measured. Results In RYGB subjects, the glucose drink emptied very rapidly (PE t50 = 3 ± 1 min) and intestinal glucose infusion was associated with higher blood glucose and plasma 3-OMG, but lower plasma GLP-1, GIP, insulin, and GI symptoms than oral glucose (all P

Glucagon-like peptide-1 (GLP-1), an important mediator of postprandial glycaemia, could potentially be stimulated by delivering small quantities of nutrient to a long length of distal gut. We aimed to determine whether enteric-coated pellets, releasing small amounts of lauric acid throughout the ileum and colon, could reduce glycaemic responses to meals in type 2 diabetes, associated with stimulation of GLP-1.Eligible patients, who had type 2 diabetes controlled by diet or metformin, were each studied on two occasions in a hospital setting. After an overnight fast, patients consumed 5 g active pellets (47% lauric acid by weight) or placebo with breakfast (T = 0 min) and lunch (T = 240 min), in a crossover design with order randomised by the hospital pharmacy and allocation concealed by numbered containers. Patients and investigators making measurements were blinded to the intervention. Blood was sampled frequently for blood glucose (the primary outcome) and hormone assays.Eight patients were randomised (four to receive either intervention first), and all completed the study without adverse effects. Blood glucose was lower after breakfast (T = 0-240 min, area under the curve (AUC) 2,075 ± 368 vs 2,216 ± 163 mmol/l × min) and lunch (T = 240-480 min, AUC 1,916 ± 115 vs 2,088 ± 151 mmol/l × min) (p = 0.02 for each) after active pellets than after placebo. Plasma GLP-1 concentrations were higher after breakfast (p = 0.08) and lunch (p = 0.04) for active pellets. While there were no differences in insulin or glucose-dependent insulinotropic polypeptide concentrations, glucagon concentrations were higher after breakfast and lunch (p = 0.002 for each) for active pellets.Delivering small amounts of nutrient to the ileum and colon can stimulate substantial endogenous GLP-1 release and attenuate postprandial glycaemia. This novel approach has therapeutic potential in type 2 diabetes.Australian New Zealand Clinical Trials Registry ACTRN12612000600842.The study was funded by Meyer Nutriceuticals.

Background: Intraduodenal fat and carbohydrate modulate. antropyloroduodenal motility and hormone release and suppress appetite and energy intake in a load-dependent manner. Protein also suppresses energy intake, but its effects on these gastrointestinal factors and their role in the appetite-suppressive effects of protein remain unclear. Objective: We aimed to characterize the effects of different intra-duodenal protein loads on antropyloroduodenal pressures, gastrointestinal hormone release, glucose and insulin concentrations, appetite perceptions, and energy intake. Design: Sixteen lean, healthy men were studied on 4 occasions in a randomized, double-blind fashion. Antropyloroduodenal pressures, plasma glucagon-like peptide 1 (GLP-1), cholecystokinin, peptide YY, ghrelin, blood glucose, serum insulin, and appetite were measured during 60-min, 4-mL/min intraduodenal infusions of protein at 0.5, 1.5, or 3 kca/min or saline (control). Energy intakes at a buffet lunch consumed immediately after the infusion were quantified. Results: Increases in the load of protein resulted in greater suppression of antral motility, greater stimulation of basal and isolated pyloric pressures and plasma cholecystokinin and GLP-1 concentrations, and greater suppression of energy intake. However, energy intake was reduced only after a protein load of 3 kcal/min compared with after all other treatments (P < 0.05). The suppression of energy intake after adjustment for cholecystokinin, GLP-1, and insulin was related inversely with basal pyloric pressure (r = -0.51, P < 0.001). Conclusion: The acute effects of intraduodenal protein on antropyloroduodenal motility, gastrointestinal hormone release, glucose, and insulin are load dependent and contribute to the suppression of energy intake. This trial was registered at www.anzetr.org.au as 12610000376044. Am J Clin Nutr 2012;96:474-82. Refereed/Peer-reviewed

Diabet. Med. 29, 604–608 (2012) Abstract Aims Postprandial glucagon-like peptide-1 (GLP-1) secretion and the ‘incretin effect’ have been reported to be deficient in Type 2 diabetes, but most studies have not controlled for variations in the rate of gastric emptying. We evaluated blood glucose, and plasma insulin, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) responses to intraduodenal glucose in Type 2 diabetes, and compared these with data from healthy controls. Methods Eight males with well-controlled Type 2 diabetes, managed by diet alone, were studied on four occasions in single-blind, randomized order. Blood glucose, and plasma insulin, GLP-1, and GIP were measured during 120-min intraduodenal glucose infusions at 1 kcal/min (G1), 2 kcal/min (G2) and 4 kcal/min (G4) or saline control. Results Type 2 patients had higher basal (P

Context: Aging is associated with deteriorating glucose tolerance. Studies assessing glucose tolerance and subsequent insulin and incretin hormone release often fail to take into account the rate of gastric emptying when evaluating these responses. Objective: Our objective was to determine the comparative effects of variations in the small intestinal glucose load on the glycemic, insulinemic, and incretin responses in healthy young and older subjects. Materials and Methods: Twelve healthy young (six males, six females; age 22.2 ± 2.3 yr) and 12 older (six males, six females; age 68.7 ± 1.0 yr) subjects had measurements of blood glucose, serum insulin and plasma incretin hormones [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] and calculations of insulin resistance (homeostatic model assessment) and -cell function corrected for insulin sensitivity, before and during intraduodenal infusions of glucose at 1, 2, or 3 kcal/min or saline for 60 minutes. The study was double-blinded and randomized, and performed in the Discipline of Medicine at the Royal Adelaide Hospital. Results: At baseline, blood glucose and serum insulin were slightly higher in the older subjects (P < 0.001), whereas GLP-1 and GIP were comparable between groups. In both groups, the glycemic, insulinemic, and GLP-1 responses were dependent on the duodenal glucose load in a nonlinear fashion (P < 0.001). The glycemic response was greater (P < 0.001) in the older subjects, whereas GLP-1 and GIP responses were comparable between groups. The older subjects were more insulin resistant (P < 0.001) and had impaired beta-cell function, particularly at higher glucose loads (P < 0.05). Conclusion: When glucose is infused into the small intestine at equal rates in healthy young and older subjects, GLP-1 and GIP responses are comparable, indicating that impaired incretin secretion does not account for age-related glucose intolerance. Refereed/Peer-reviewed

Postprandial hypotension is an important problem, particularly in the elderly. The fall in blood pressure is dependent on small intestinal glucose delivery and, possibly, changes in splanchnic blood flow, the release of glucagon-like peptide-1 (GLP-1), and sympathetic nerve activity. We aimed to determine in healthy older subjects, the effects of variations in small intestinal glucose load on blood pressure, superior mesenteric artery flow, GLP-1, and noradrenaline. Twelve subjects (6 male, 6 female; ages 65–76 yr) were studied on four separate occasions, in double-blind, randomized order. On each day, subjects were intubated via an anesthetized nostril, with a nasoduodenal catheter, and received an intraduodenal infusion of either saline (0.9%) or glucose at a rate of 1, 2, or 3 kcal/min (G1, G2, G3, respectively), for 60 min ( t = 0–60 min). Between t = 0 and 60 min, there were falls in systolic and diastolic blood pressure following G2 and G3 ( P = 0.003 and P < 0.001, respectively), but no change during saline or G1. Superior mesenteric artery flow increased slightly during G1 ( P = 0.01) and substantially during G2 ( P < 0.001) and G3 ( P < 0.001), but not during saline. The GLP-1 response to G3 was much greater ( P < 0.001) than to G2 and G1. Noradrenaline increased ( P < 0.05) only during G3. In conclusion, in healthy older subjects the duodenal glucose load needs to be > 1 kcal/min to elicit a significant fall in blood pressure, while the response may be maximal when the rate is 2 kcal/min. These observations have implications for the therapeutic strategies to manage postprandial hypotension by modulating gastric emptying.

It is uncertain whether the postprandial suppression of ghrelin is dependent on digestion and absorption of nutrients or whether the presence of nutrients in the small intestine is sufficient. Twenty-four healthy young adults with a mean age of 23 ± 0.6 years were examined on 3 separate days after an overnight fast. Twelve subjects participated in Part A, and the other 12 subjects in Part B. In Part A, subjects consumed, in random order, one of three study drinks: 300 mL water; 300 mL high-fat drink, with and without, 120 mg orlistat. In Part B, subjects received, in random order, one of three drinks: 300 mL water; 300 mL sucrose, with and without, 100 mg acarbose. In both parts gastric emptying as measured by 2-D ultrasound. In Part A, plasma ghrelin concentrations decreased following ingestion of the high-fat drink, but did not change with the high-fat–orlistat drink or water. In Part B, the suppression of plasma ghrelin following the sucrose drink, was attenuated by acarbose. Orlistat accelerated gastric emptying of the high-fat drink, while acarbose delayed gastric emptying of the sucrose drink. In conclusion, fat and carbohydrate digestion is required for maximal suppression of ghrelin secretion.

Human aging is associated with a reduction in appetite and food intake. Increased activity of the satiety hormone, cholecystokinin (CCK), may be partly responsible. This study aimed to determine whether an increase in fat and energy intake modifies the suppressive effects of CCK-8 on appetite and energy intake. Fourteen healthy older adults completed three separate dietary periods, a 14-day and a 7-day normal diet (ND; 8272 ± 480 kJ/day; 35% fat), and a 14-day high-fat diet (HFD; 11,642 ± 414 kJ/day; 43% fat), in randomised order. Immediately following each diet, subjects received, in single-blinded fashion, a 30-min intravenous infusion of either CCK-8 (1.5 ng/kg/min) (ND-CCK, HFD-CCK) or 0.9% saline (ND-SAL), the latter following only ND. Plasma CCK concentrations, appetite responses and energy intake at a buffet meal were determined. Energy intake at the buffet meal was higher on the ND-SAL study day (3349 ± 224 kJ), when compared with either ND-CCK (3023 ± 317 kJ) or HFD-CCK (2905 ± 316 kJ). The suppression of energy intake by CCK-8 infusion did not differ between the two diets. We conclude that suppression of energy intake by exogenous CCK-8 does not appear to be attenuated by incorporation of supplemental high-energy, high-fat drinks in the diet of healthy older adults.

Context: Acute hyperglycemia slows gastric emptying, but its effects on small intestinal motor activity and glucose absorption are unknown. In type 2 diabetes, the postprandial secretion of glucose-dependent insulinotropic polypeptide (GIP) is preserved, but that of glucagon-like peptide-1 (GLP-1) ispossibly reduced; whether the latter is secondary to hyperglycemia or diabetes per se is unknown. Aim: The aim was to investigate the effects of acute hyperglycemia on duodenal motility and flowevents, glucose absorption, and incretin hormone secretion. Methods: Nine healthy volunteers were studied on two occasions. A combined manometry/impedance catheter was positioned in the duodenum. Blood glucose was clamped at either 9 mmol/liter (hyperglycemia) or 5 mmol/liter (euglycemia) throughout the study. Manometry and impedance recordings continued between T 10 min and T 180 min. Between T 0 and 60 min, an intraduodenal glucose infusion was given (3 kcal/min), together with 14C-labeled 3-O-methylglucose (3-OMG) to evaluate glucose absorption. Results: Hyperglycemia had no effect on duodenal pressure waves or flow events during the 60 min of intraduodenal glucose infusion, when compared to euglycemia. During hyperglycemia, there was an increase in plasma GIP (P 0.05) and 14C-3-OMG (P 0.05) but no effect on GLP-1 concentrations in response to the intraduodenal infusion, compared to euglycemia. Conclusion: Acute hyperglycemia in the physiological range has no effect on duodenal pressurewaves and flow events but is associated with increased GIP secretion and rate of glucose absorptionin response to intraduodenal glucose. Refereed/Peer-reviewed

Postprandial ghrelin suppression arises from the interaction of meal contents with the small intestine and may relate to elevations in blood glucose and/or plasma insulin. We sought to determine whether the suppression of ghrelin by small intestinal glucose is dependent on the glucose load and can be accounted for by changes in blood glucose and/or plasma insulin. Blood glucose, plasma insulin, and plasma ghrelin levels were measured in 10 healthy males (aged 32 ± 4 yr; body mass index: 25.1 ± 0.4 kg/m2) during intraduodenal glucose infusions at 1 kcal/min (G1), 2 kcal/min (G2), and 4 kcal/min (G4), as well as intraduodenal hypertonic saline (control) for 120 min. There was a progressive decrease in ghrelin with all treatments, control at 45 min and between 90 and 120 min ( P < 0.05) and G1 ( P < 0.05), G2 ( P < 0.0001), and G4 ( P < 0.0001) between 30 and 120 min to reach a plateau at ∼90 min. There was no difference in plasma ghrelin between G1, G2, or G4. Control suppressed ghrelin to a lesser extent than intraduodenal glucose ( P < 0.05). The suppression of ghrelin was not related to rises in blood glucose or plasma insulin. Suppression of ghrelin by intraduodenal glucose in healthy males is apparently independent of the glucose load and unrelated to blood glucose or insulin levels.

Background: The regulation of gastrointestinal function and energy intake by fatty acids depends on their chain length. Animal studies suggest that lauric acid (C12) may have more potent suppressive effects on energy intake than does oleic acid (C18). Objective: We compared the effects of equicaloric loads of C 12 and C 18 on antropyloroduodenal (APD) motility, plasma concentrations of cholecystokinin (CCK) and peptide YY (PYY), appetite, and energy intake. Design: Thirteen healthy men (aged 20-46 y) were studied on 3 occasions in double-blind, randomized fashion. APD pressure waves, plasma hormones, and appetite perceptions were measured during 60-min intraduodenal infusions of 1) C 12,2) C 18, or 3)0.9% saline as control (rate: 4 mL/min; energy load for C12 and C18: 0.4 kcal/min); between 60 and 90 min, the subjects consumed a meal. Energy intake at a buffet meal was quantified. Results: C 12 and C 18 both reduced antral (P < 0.001) and duodenal (P < 0.01) pressure waves and stimulated isolated pyloric pressure waves (P < 0.01) and plasma CCK (P < 0.001), with no differences between them. Although C12 and C18 both increased basal pyloric pressure (P < 0.05), C12 had a greater effect than did C18 (P < 0.01). In contrast, although both C12 and C 18 increased plasma PYY (P < 0.001), C18 had a greater effect than C12. C12, but not C18, suppressed energy intake (P < 0.05). Conclusions: At the load administered, C12, but not C18, suppressed energy intake, and C12 was a more potent stimulant of basal pyloric pressure. These discrepant effects are not apparently accounted for by changes in CCK or PYY secretion.

There is evidence from studies in animals that the effects of both fat and CCK on gastrointestinal function and energy intake are attenuated by consumption of a high-fat diet. In humans, the effects of exogenous CCK-8 on antropyloroduodenal motility, plasma CCK, peptide YY (PYY), and ghrelin concentrations, appetite, and energy intake are attenuated by a high-fat diet. Ten healthy lean males consumed isocaloric diets (∼15,400 kJ per day), containing either 44% (high-fat, HF) or 9% (low-fat, LF) fat, for 21 days in single-blind, randomized, cross-over fashion. Immediately following each diet (i.e., on day 22), subjects received a 45-min intravenous infusion of CCK-8 (2 ng·kg−1·min−1), and effects on antropyloroduodenal motility, plasma CCK, PYY, ghrelin concentrations, hunger, and fullness were determined. Thirty minutes after commencement of the infusion, subjects were offered a buffet-style meal, from which energy intake (in kilojoules) was quantified. Body weight was unaffected by the diets. Fasting CCK ( P < 0.05), but not PYY and ghrelin, concentrations were greater following the HF, compared with the LF, diet. Infusion of CCK-8 stimulated pyloric pressures ( P < 0.01) and suppressed antral and duodenal pressures ( P < 0.05), with no difference between the diets. Energy intake also did not differ between the diets. Short-term consumption of a HF diet increases fasting plasma CCK concentrations but does not affect upper gut motility, PYY and ghrelin, or energy intake during CCK-8 infusion, in a dose of 2 ng·kg−1·min−1, in healthy males.

Background: Dietary interventions represent a promising therapeutic strategy to optimize postprandial glycemia. The addition of protein to oral glucose has been reported to improve the glycemic profile. Objective: The aim of the current study was to evaluate the mechanisms by which protein supplementation lowers the blood glucose response to oral glucose. Design: Nine healthy men were studied on 3 d each in a random order. Subjects consumed 300-mL drinks containing either 50 g glucose (Glucose), 30 g gelatin (Protein), or 50 g glucose with 30 g gelatin (Glucose + Protein) in water labeled with 150 mg [ 13 C]acetate. Blood and breath samples were subsequently collected for 3 h to measure blood glucose and plasma insulin, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) concentrations and gastric half-emptying time, which was calculated from 13 CO 2 excretion. Results: The blood glucose response was less after Glucose + Protein than after Glucose (P < 0.005); GIP was lower (P < 0.005), and there were no significant differences in plasma insulin or GLP-1. Protein alone stimulated insulin, GLP-1, and GIP (P < 0.05 for each) without elevating blood glucose. The gastric half-emptying time was greater after Glucose + Protein than after Glucose (P < 0.05) and tended to be greater for Glucose than for Protein (P = 0.06). Conclusions: In healthy humans, the addition of protein to oral glucose lowers postprandial blood glucose concentrations acutely, predominantly by slowing gastric emptying, although protein also stimulates incretin hormones and non-glucose-dependent insulin release.

The effects of fat on gastric emptying (GE), gut hormones, and energy intake are dependent on digestion to free fatty acids (FFAs). In animals, small intestinal oleic acid inhibits energy intake more potently than the triacylglyceride (TG) triolein, but there is limited information about the comparative effects of FFA and TG in human beings. We compared the effects of FFA and TG on GE, gut hormone secretion, appetite, and energy intake in healthy males.Nine men (age, 23 +/- 2 y; body mass index, 22 +/- 1 kg/m(2)) were studied on 3 occasions to evaluate the effects of (1) 40 g oleic acid (FFA, 1830 kJ), (2) 40 g macadamia oil (TG, 1856 kJ; both 600-mL oil-in-water emulsions stabilized with 4% milk protein and labeled with 15 MBq (123)I), or (3) 600 mL 4% milk protein (control, 352 kJ), administered intragastrically, on GE, plasma cholecystokinin (CCK) and peptide-YY (PYY) levels, appetite perceptions, and subsequent energy intake.GE of FFA was much slower than that of TG (P.05), with greater retention of FFA, than TG, in the proximal stomach (P.001). Hunger was less (P.05), and fullness was greater (P.05), after FFA when compared with control and TG. Increases in plasma CCK and PYY levels were greater after FFA than TG or control (P.05). Energy intake tended to be less after FFA compared with TG (control, 4754 +/- 610 kJ; TG, 5463 +/- 662 kJ; FFA, 4199 +/- 410 kJ).FFAs empty from the stomach more slowly, but stimulate CCK and PYY and suppress appetite more potently than TG in healthy human beings.

Gastric emptying is a major determinant of glycemia, gastrointestinal hormone release, and appetite. We determined the effects of different intraduodenal glucose loads on glycemia, insulinemia, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and cholecystokinin (CCK), antropyloroduodenal motility, and energy intake in healthy subjects. Blood glucose, plasma hormone, and antropyloroduodenal motor responses to 120-min intraduodenal infusions of glucose at 1) 1 (“G1”), 2) 2 (“G2”), and 3) 4 (“G4”) kcal/min or of 4) saline (“control”) were measured in 10 healthy males in double-blind, randomized fashion. Immediately after each infusion, energy intake at a buffet meal was quantified. Blood glucose rose in response to all glucose infusions ( P < 0.05 vs. control), with the effect of G4 and G2 being greater than that of G1 ( P < 0.05) but with no difference between G2 and G4. The rises in insulin, GLP-1, GIP, and CCK were related to the glucose load ( r > 0.82, P < 0.05). All glucose infusions suppressed antral ( P < 0.05), but only G4 decreased duodenal, pressure waves ( P < 0.01), resulted in a sustained stimulation of basal pyloric pressure ( P < 0.01), and decreased energy intake ( P < 0.05). In conclusion, variations in duodenal glucose loads have differential effects on blood glucose, plasma insulin, GLP-1, GIP and CCK, antropyloroduodenal motility, and energy intake in healthy subjects. These observations have implications for strategies to minimize postprandial glycemic excursions in type 2 diabetes.

Summary Objective To determine the effects of menopause on bone-related variables in Indonesian women and to compare them with corresponding data in Caucasian Australian women. Design A study of bone-related variables in women aged 45 ‐55 years in Jakarta compared with corresponding historical data from Caucasian Australian women. Measurements Dietary intakes, bone mineral density (BMD) and calcium-related variables in blood and urine. Results Dietary calcium, phosphorus and protein intakes were significantly lower in the women from Jakarta than in those from Adelaide (all P < 0·001), probably because of lower milk consumption, but energy intake was similar in the two cities. Indonesian women were shorter and lighter than Australian women ( P < 0·001) but had a comparable body mass index (BMI). The Indonesians also had a lower spinal BMD than the Australians but this was accounted for by the differences in height and weight between the two populations. The differences in serum and urinary calcium and phosphate and serum alkaline phosphatase across the menopause were comparable in Indonesian and Australian women but creatinine excretion was 25% lower in Jakarta than in Adelaide ( P < 0·001) and this was probably sufficient to account for higher ratios of some urinary solutes to urinary creatinine in the Indonesians. Serum 25-hydroxyvitamin D (25OHD) levels were significantly lower ( P < 0·001) and serum PTH levels significantly higher ( P = 0·0045) in Jakarta than in Adelaide. Conclusions The differences in bone-related biochemical variables across the menopause were similar in the two populations, but calcium and protein intake and urine creatinine were lower in Indonesian than in Australian women. Serum 25OHD was lower and PTH higher in the Indonesian women, probably because of their darker skin, their practice of avoiding direct sunlight and the heavy atmospheric pollution in Jakarta.

Animal studies suggest that the effects of fatty acids on gastric emptying and pancreatic secretion are both concentration and load dependent, while their suppressive effect on energy intake is only load dependent. We postulated that, in humans, the modulation of antropyloroduodenal pressure waves, plasma cholecystokinin (CCK) and peptide YY (PYY) concentrations and energy intake by intraduodenal lauric acid, a fatty acid with 12 carbon atoms (‘C12’) would be load, but not concentration, dependent. Two groups of 12 healthy males were each studied on three separate occasions in double-blind randomized fashion. Antropyloroduodenal pressure waves, plasma CCK and PYY, and appetite perceptions were measured during intraduodenal infusions of C12 at (1) different loads of (i) 0.2, (ii) 0.3 and (iii) 0.4 kcal min−1 (all 56 mm) for 90 min, and (2) different concentrations of (i) 40, (ii) 56 and (iii) 72 mm (all 0.4 kcal min−1) for 60 min. Energy intake at a buffet meal consumed immediately following each infusion was quantified. Suppression of antral and duodenal pressure waves, stimulation of pyloric pressure waves, stimulation of plasma CCK and PYY, and suppression of energy intake, were related to the load of C12 administered (r > 0.65, P < 0.05). In contrast, there were no concentration-dependent effects of C12 on any of these parameters. In conclusion, in humans, the effects of intraduodenal C12 on antropyloroduodenal motility, plasma CCK and PYY and energy intake appear to be related to load, but not concentration, at least at the loads and concentrations evaluated.

Objective: We previously reported that a single preprandial injection (120 μg) of pramlintide, an analog of the β-cell hormone amylin, reduced ad libitum food intake in obese subjects. To further characterize the meal-related effects of amylin signaling in humans, we studied a lower pramlintide dose (30 μg) in normal-weight subjects. Research Methods and Procedures: In a randomized, double-blind, placebo-controlled, cross-over study, 15 healthy men (age, 24 ± 7 years; BMI, 22.2 ± 1.8 kg/m2) underwent a standardized buffet meal test on two occasions. After an overnight fast, subjects received a single subcutaneous injection of pramlintide (30 μg) or placebo, followed immediately by a standardized pre-load meal. After 1 hour, subjects were offered an ad libitum buffet meal, and total caloric intake and meal duration were measured. Results: Compared with placebo, pramlintide reduced total caloric intake (1411 ± 94 vs. 1190 ± 117 kcal; Δ, −221 ± 101 kcal; −14 ± 9%; p = 0.05) and meal duration (36 ± 2 vs. 31 ± 3 minutes; Δ, −5.1 ± 1.4 minutes; p < 0.005). Visual analog scale profiles of hunger trended lower and fullness higher during the first hour after pramlintide administration. In response to the buffet, hunger and fullness changed to a similar degree after pramlintide and placebo, despite subjects on pramlintide consuming 14% fewer kilocalories. Visual analog scale nausea ratings remained near baseline, without differences between treatments. Plasma peptide YY, cholecystokinin, and ghrelin concentrations did not differ with treatment, whereas glucagon-like peptide-1 concentrations after meals were lower in response to pramlintide than to placebo. Discussion: These observations add support to the concept that amylin agonism may have a role in human appetite control.

Delayed gastric emptying and intolerance to gastric feeding occur frequently in the critically ill. In these patients, gastric motor responses to nutrients are disturbed. Cholecystokinin (CCK) slows gastric emptying. The aim of this study was to determine plasma CCK concentrations during fasting and in response to small-intestine nutrient infusion in critically ill patients.Randomized, controlled trial.Level 3, mixed medical and surgical intensive care unit.A total of 31 mechanically ventilated, critically ill patients (23 men, 51 +/- 3 yrs) and 28 healthy subjects (21 men, 43 +/- 2 yrs).Subjects received two 60-min duodenal infusions of Ensure (complete balanced nutrition), at 1 and 2 kcal/min, in a randomized, single-blind fashion. The nutrient infusions were separated by a 2-hr "washout" period. Blood samples for measurement of plasma CCK concentrations were obtained immediately before and every 20 mins during nutrient infusion.Baseline and nutrient-stimulated plasma CCK concentrations were higher in critically ill patients compared with healthy subjects (p.001). The magnitude of the rise in plasma CCK in response to nutrients was also greater in the critically ill (p.01). Of the 23 patients who received enteral nutrition before the study, nine were intolerant of gastric feeding. In these patients, both the baseline plasma CCK concentration and the magnitude of CCK increase during nutrient infusions were greater than in patients with feed tolerance (p.002). Impaired renal function was associated with an increased baseline CCK concentration but had no effect on the CCK response to nutrients.Both fasting and nutrient-stimulated plasma CCK concentrations are increased in critically ill patients, particularly in those with feed intolerance. This may provide a humoral mechanism for delayed gastric emptying seen in critical illness.

Enterally administered lipid modulates antropyloroduodenal motility, gut hormone release, appetite, and energy intake. We hypothesized that these effects would be dependent on both the load, and duration, of small intestinal exposure to lipid. Eleven healthy men were studied on four occasions in a double-blind, randomized, fashion. Antropyloroduodenal motility, plasma CCK and peptide YY (PYY) concentrations, and appetite perceptions were measured during intraduodenal infusion of lipid (Intralipid) at 1) 1.33 kcal/min for 50 min, 2) 4 kcal/min for 50 min, and 3) 1.33 kcal/min for 150 min, or 4) saline for 150 min. Immediately after the infusions, energy intake was quantified. Pressure wave sequences (PWSs) were suppressed, and basal pyloric pressure, isolated pyloric pressure waves (IPPWs), plasma CCK and PYY stimulated (all P < 0.05), during the first 50 min of lipid infusion, in a load-dependent fashion. The effect of the 4 kcal/min infusion was sustained so that the suppression of antral pressure waves (PWs) and PWSs and increase in PYY remained evident after cessation of the infusion (all P < 0.05). The prolonged lipid infusion (1.33 kcal/min for 150 min) suppressed antral PWs, stimulated CCK and PYY and basal pyloric pressure (all P < 0.05), and tended to stimulate IPPWs when compared with saline throughout the entire infusion period. There was no significant effect of any of the lipid infusions on appetite or energy intake, although nausea was slightly higher ( P < 0.05) with the 4 kcal/min infusion. In conclusion, both the load, and duration, of small intestinal lipid influence antropyloroduodenal motility and patterns of CCK and PYY release.

Objectives. Postprandial hypotension occurs frequently in older people and may result in syncope and falls. It has recently been established that the magnitude of the fall in blood pressure is related to the rate at whichglucose enters the small intestine. We addressed the hypothesis that the fall in blood pressure induced by an intraduodenal glucose infusion is influenced by the interaction of glucose with the small intestinal absorptive epithelium. Methods. Eight healthy older participants (four male, four female, age 70.3 ′ 3.4 years) were studied on two separate occasions, in single-blind, randomized order. Participants received an intraduodenal glucose infusion (3 kcal/min) with or without guar gum (4 g) for 60 minutes (0-60 minutes), followed by 0.9% saline intraduodenally for a further 60 minutes (60-120 minutes). Blood pressure and heart rate were measured every 3 minutes. Levels of blood glucose, plasma insulin, glucagon-like peptide-1 (GLP-1), and glucose-dependant insulinotropic-polypeptide (GIP) were also determined. Results. Between t = 0 and t = 30 minutes, the magnitude of the fall in systolic blood pressure (p =.03) and increase in heart rate (p =.027) were lower after guar. The blood glucose (p =.009), plasma insulin (p =.027), plasma GLP-1 (p = .018), and GIP (p

There is evidence that CCK and glucagon-like peptide-1 (GLP-1) mediate the effects of nutrients on appetite and gastrointestinal function and that their interaction may be synergistic. We hypothesized that intravenous CCK-8 and GLP-1 would have synergistic effects on appetite, energy intake, and antropyloroduodenal (APD) motility. Nine healthy males (age 22 ± 1 yr) were studied on four separate days in a double-blind, randomized fashion. Appetite and APD pressures were measured during 150-min intravenous infusions of 1) isotonic saline (control), 2) CCK-8 (1.8 pmol·kg−1·min−1), 3) GLP-1 (0.9 pmol·kg−1·min−1), or 4) both CCK-8 (1.8 pmol·kg−1·min−1) and GLP-1 (0.9 pmol·kg−1·min−1). At 120 min, energy intake at a buffet meal was quantified. CCK-8, but not GLP-1, increased fullness, decreased desire to eat and subsequent energy intake, and increased the number and amplitude of isolated pyloric pressure waves and basal pyloric pressure ( P < 0.05). Both CCK-8 and GLP-1 decreased the number of antral and duodenal pressure waves (PWs) ( P < 0.05), and CCK-8+GLP-1 decreased the number of duodenal PWs more than either CCK-8 or GLP-1 alone ( P < 0.02). This was not the case for appetite or isolated pyloric PWs. In conclusion, at the doses evaluated, exogenously administered CCK-8 and GLP-1 had discrepant effects on appetite, energy intake, and APD pressures, and the effects of CCK-8+GLP-1, in combination, did not exceed the sum of the effects of CCK-8 and GLP-1, providing no evidence of synergism.

Long-term trials in insulin-treated subjects with type 2 diabetes have shown that adjunctive treatment with the amylin analogue pramlintide reduces HbA(1)c levels and elicits weight loss. While amylin reduces food intake in rodents, pramlintide's effect on satiety and food intake in humans has not yet been assessed.In this randomised, double-blind, placebo-controlled crossover study, 11 insulin-treated men with type 2 diabetes (age 60+/-9 years, BMI 28.9+/-4.8 kg/m(2)) and 15 non-diabetic obese men (age 41+/-21 years, BMI 34.4+/-4.5 kg/m(2)) underwent two standardised meal tests. After fasting overnight, subjects received single subcutaneous injections of either pramlintide (120 microg) or placebo, followed by a preload meal. After 1 h, subjects ate an ad libitum buffet meal. Energy intake and meal duration were measured, as were hunger ratings (using visual analogue scales), and plasma cholecystokinin, glucagon-like peptide-1 and peptide YY concentrations over time.Compared with placebo, pramlintide reduced energy intake in both the type 2 diabetes (Delta-202+/-64 kcal, -23+/-8%, p0.01) and obese (Delta-170+/-68 kcal, -16+/-6%, p0.02) groups, without affecting meal duration. Hunger and hormonal analyte profiles provided evidence that pramlintide may exert a primary satiogenic effect, independently of other anorexigenic gut peptides.The results indicate that enhanced satiety and reduced food intake may explain the weight loss observed in long-term pramlintide trials.

We recently reported that intraduodenal infusion of lauric acid (C12) (0.375 kcal/min, 106 mM) stimulates isolated pyloric pressure waves (IPPWs), inhibits antral and duodenal pressure waves (PWs), stimulates release of cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1), and suppresses energy intake and that these effects are much greater than those seen in response to isocaloric decanoic acid (C10) infusion. Administration of C12 was, however, associated with nausea, confounding interpretation of the results. The aim of this study was to evaluate the effects of different intraduodenal doses of C12 on antropyloroduodenal (APD) motility, plasma CCK and GLP-1 concentrations, appetite, and energy intake. Thirteen healthy males were studied on 4 days in double-blind, randomized fashion. APD pressures, plasma CCK and GLP-1 concentrations, and appetite perceptions were measured during 90-min ID infusion of C12 at 0.1 (14 mM), 0.2 (28 mM), or 0.4 (56 mM) kcal/min or saline (control; rate 4 ml/min). Energy intake was determined at a buffet meal immediately following infusion. C12 dose-dependently stimulated IPPWs, decreased antral and duodenal motility, and stimulated secretion of CCK and GLP-1 ( r > 0.4, P < 0.05 for all). C12 (0.4 kcal/min) suppressed energy intake compared with control, C12 (0.1 kcal/min), and C12 (0.2 kcal/min) ( P < 0.05). These effects were observed in the absence of nausea. In conclusion, intraduodenal C12 dose-dependently modulated APD motility and gastrointestinal hormone release in healthy male subjects, whereas effects on energy intake were only apparent with the highest dose infused (0.4 kcal/min), possibly because only at this dose was modulation of APD motility and gastrointestinal hormone secretion sufficient for a suppressant effect on energy intake.

We examined the effects of lipase inhibition with orlistat on (i) gastric emptying of, and (ii) the glycaemic, glucagon-like peptide-1 (GLP-1) and cardiovascular responses to, a high-fat/carbohydrate meal in type 2 diabetic patients.Eight type 2 diabetic patients, who were aged 62 years (median range: 49-68 years) and managed by diet alone, consumed a meal containing 65 g powdered potato, 20 g glucose reconstituted with 200 ml water (labelled with 20 MBq (99m)Tc-sulphur-colloid) and 45 g margarine. They did this on two separate occasions, with and without 120 mg orlistat, and while in the seated position with their back against a gamma camera. Venous blood samples for measurement of blood glucose, plasma insulin and GLP-1 were obtained immediately before the meal and at regular intervals afterwards. Blood pressure (systolic and diastolic) and heart rate were measured using an automated device.Gastric emptying of the meal was faster after orlistat than without orlistat (50% emptying time [mean +/- SEM], 61+/-8 min vs 98+/-5 min; p=0.0001). In the first 60 min after the meal blood glucose (p=0.001) and plasma insulin (p=0.01) concentrations were higher in patients who had taken orlistat; between 60 and 180 min plasma GLP-1 (p=0.02) concentrations were lower after orlistat than without orlistat. Between 0 and 30 min systolic blood pressure (p=0.003) was lower, and heart rate (p=0.03) greater in subjects who had taken orlistat than in those who had not.Inhibition of fat digestion by orlistat may-as a result of more rapid gastric emptying-exacerbate postprandial glycaemia and the postprandial fall in blood pressure in patients with type 2 diabetes after ingestion of meals containing fat and carbohydrate.

The determinants of postprandial blood glycemia are controversial. We assessed the effects of variations in the initial rate of small intestinal glucose delivery on blood glucose, plasma insulin, and incretin responses in both health and type 2 diabetes. Eight controls and eight patients with type 2 diabetes managed by diet alone underwent paired studies. On both days subjects received an intraduodenal glucose infusion (t = 0-120 min); on one day the infusion rate was variable, being more rapid initially (3 kcal/min) between t = 0 and 15 min and slower (0.71 kcal/min) subsequently (t = 15-120 min), whereas on the other day, the infusion rate was constant (1 kcal/min) from t = 0 to 120 min (i.e. on both days 120 kcal of glucose were administered). Between t = 0-180 min blood glucose, plasma insulin and plasma glucose-dependent insulin-releasing polypeptide were greater with the variable, compared with the constant, infusion. Between t = 0 and 30 min the magnitude of the rise in plasma glucagon-like peptide-1 was greater with the variable, compared with the constant infusion (P < 0.01, both groups). We conclude that modest variations in the initial rate of duodenal glucose entry may have profound effects on subsequent glycemic, insulin, and incretin responses.

BACKGROUND: Abnormal nutrient-related small-intestinal feedback may contribute to disordered gastric motility and upper gastrointestinal symptoms in patients with diabetes. AIM: To evaluate the motor, sensory and incretin responses to intraduodenal nutrients in patients with type 1 diabetes and in controls. METHODS: Eight type 1 diabetes patients (two with autonomic neuropathy) and nine controls were studied during euglycaemia. A manometric catheter was positioned across the pylorus, and nutrient was infused intraduodenally (90 kcal over 30 min). Blood glucose and plasma glucagon-like peptide 1 and gastric inhibitory polypeptide were measured, and sensations were assessed with visual analogue questionnaires. RESULTS: During nutrient infusion, neither the number of antral waves nor the stimulation of phasic or basal pyloric pressures differed between patients and controls. Upper gut sensations and areas under the plasma incretin peptide curves did not differ between the groups. CONCLUSIONS: During euglycaemia, the upper gastrointestinal motor, sensory and incretin peptide responses to small-intestinal nutrient are comparable in patients with relatively uncomplicated type 1 diabetes and in healthy subjects

OBJECTIVE: To obtain information on the causes of age-related bone loss in men and the concomitant decline in calcium absorption. DESIGN: Cross-sectional study. SETTING: Adelaide, South Australia, Australia. SUBJECTS: A total of 95 healthy, Caucasian men (age range 27-87 y). RESULTS: Calcium absorption declined with age (r=-0.46, P-0.21, P0.41, P

The presence of nutrients in the small intestine slows gastric emptying and suppresses appetite and food intake; these effects are partly mediated by the release of gut hormones, including CCK. We investigated the hypothesis that the modulation of antropyloroduodenal motility, suppression of appetite, and stimulation of CCK and glucagon-like peptide-1 secretion by intraduodenal fat are dependent on triglyceride hydrolysis by lipase. Sixteen healthy, young, lean men were studied twice in double-blind, randomized, crossover fashion. Ratings for appetite-related sensations, antropyloroduodenal motility, and plasma CCK and glucagon-like peptide-1 concentrations were measured during a 120-min duodenal infusion of a triglyceride emulsion (2.8 kcal/min) on one day with, on the other day without, 120 mg tetrahydrolipstatin, a potent lipase inhibitor. Immediately after the duodenal fat infusion, food intake at a buffet lunch was quantified. Lipase inhibition with tetrahydrolipstatin was associated with reductions in tonic and phasic pyloric pressures, increased numbers of isolated antral and duodenal pressure waves, and stimulation of antropyloroduodenal pressure-wave sequences (all P < 0.05). Scores for prospective consumption and food intake at lunch were greater, and nausea scores were slightly less, and the rises in plasma CCK and glucagon-like peptide-1 were abolished (all P < 0.05). In conclusion, lipase inhibition attenuates the effects of duodenal fat on antropyloroduodenal motility, appetite, and CCK and glucagon-like peptide-1 secretion.

There is evidence that gastrointestinal function adapts in response to a high-fat (HF) diet. This study investigated the hypothesis that an HF diet modifies the acute effects of duodenal lipid on appetite, antropyloroduodenal pressures, plasma CCK and plasma glucagon-like peptide-1 (GLP-1) levels in humans. Twelve healthy men were studied twice in randomized, crossover fashion. The effects of a 90-min duodenal lipid infusion (6.3 kJ/min) on the above parameters were assessed immediately following 14-day periods on either an HF or a low-fat (LF) diet. After the HF diet, pyloric tonic and phasic pressures were attenuated, and the number of antropyloroduodenal pressure-wave sequences was increased when compared with the LF diet. Plasma CCK and GLP-1 levels did not differ between the two diets. Hunger was greater during the lipid infusion following the HF diet, but there was no difference in food intake. Therefore, exposure to an HF diet for 14 days attenuates the effects of duodenal lipid on antropyloroduodenal pressures and hunger without affecting food intake or plasma hormone levels.

Purpose To evaluate the natural history of gastric emptying and upper gastrointestinal symptoms in patients with diabetes mellitus. Subjects and methods We enrolled 20 patients (6 men, 14 women) with diabetes mellitus (16 with type 1 diabetes, 4 with type 2 diabetes). Each had measurements of gastric emptying of a solid (100 g of ground beef) and liquid (150 mL of 10% dextrose) meal using scintigraphy, glycemic control (glycosylated hemoglobin [HbA 1c ] and mean blood glucose levels), upper gastrointestinal symptoms, and autonomic nerve function at baseline and after a mean (± SD) of 12.3 ± 3.1 years of follow-up. Results There were no differences in mean gastric emptying of the solid component (retention at 100 minutes at baseline: 56% ± 19% vs. follow-up: 51% ± 21%, P = 0.23) or the liquid component (time for 50% to empty at baseline: 33 ± 11 minutes vs. follow-up: 31 ± 12 minutes, P = 0.71) during follow-up. Mean blood glucose (17.0 ± 5.6 mmol/L vs. 13.8 ± 4.9 mmol/L, P = 0.007) and HbA 1c (8.4% ± 2.3% vs. 7.6% ± 1.3%, P = 0.03) levels were lower at follow-up. There was no difference in symptom score (baseline: 3.9 ± 2.7 vs. follow-up: 4.2 ± 4.0, P = 0.78). There was evidence of autonomic neuropathy in 7 patients (35%) at baseline and 16 (80%) at follow-up. Conclusion In patients with diabetes mellitus, we did not observe any marked changes in either gastric emptying or upper gastrointestinal symptoms during a 12-year period.

Background. The objective of this study was to determine the pattern of forearm bone loss and its relationship to markers of bone turnover and sex steroids in normal men. This was a longitudinal study over a median interval of 41 months. The study was conducted in Adelaide, Australia. Study participants were 123 healthy male subjects, between the ages of 20 and 83 years. Methods. Fat-corrected forearm bone mineral content (fcBMC), markers of bone formation (alkaline phosphatase, osteocalcin, procollagen type 1 C-terminal extension peptide) and bone resorption (collagen type I cross-linked telopeptide, hydroxyproline/creatinine, pyridinoline/creatinine, and deoxypyridinoline/creatinine), calculated serum bioavailable testosterone, and serum estradiol were measured. Results. The mean time-weighted rate of change in forearm fcBMC was � 0.33% � 0.72 ( SD ) per year. Bone loss commenced after 30 years of age and increased with age ( p � .001), particularly after age 70 years. There was no relationship between the rate of change in fcBMC and either markers of bone turnover or serum sex steroids. Conclusions. In normal men, bone loss increases with age; there does not appear to be any relationship between this loss and either markers of bone turnover or levels of free androgen or estrogen.

This study evaluated the relationship between gastric emptying and upper gastrointestinal symptoms with H. pylori status in patients with diabetes mellitus. Sixty-three outpatients (44 type 1, 19 type 2, age 45 +/- 1.5 years) underwent measurements of gastric emptying of a mixed solid and liquid meal, gastrointestinal symptoms (gastric and esophageal), glycemic control (HbA1c), and autonomic nerve function. Anti-H. pylori IgG antibodies were quantified using a validated kit. Gastric emptying of solid and/or liquid was delayed in 47 (75%) patients, and 31 (49%) had autonomic neuropathy. Fifteen (24%) of the patients were H. pylori positive. There were no differences in gastric emptying (solid retention at 100 min: 67.5 +/- 5.7% vs 63.2 +/- 3.6%; P = 0.63, liquid T50: 35.5 +/- 2.9 min vs 42.5 +/- 3.4 min; P = 0.42), upper gastrointestinal symptoms (gastric 3.9 +/- 0.7 vs 4.0 +/- 0.4; P = 0.94 or esophageal 1.7 +/- 0.5 vs 1.3 +/- 0.2; P = 0.42) or HbA1c (8.8 +/- 0.4% vs 8.6 +/- 0.2%; P = 0.89) between H. pylori-positive and -negative patients. We conclude that H. pylori infection is not associated with delayed gastric emptying or upper gastrointestinal symptoms in diabetes.

The oral disposition index, the product of the early insulin secretory response during an oral glucose tolerance test and insulin sensitivity, is used widely for both the prediction of, and evaluation of the response to interventions, in type 2 diabetes. Gastric emptying, which determines small intestinal exposure of nutrients, modulates postprandial glycemia. The aim of this study was to determine whether the insulin secretory response and the disposition index (DI) related to gastric emptying in subjects with normal glucose tolerance. Thirty‐nine subjects consumed a 350 mL drink containing 75 g glucose labeled with 99m Tc‐sulfur colloid. Gastric emptying (by scintigraphy), blood glucose (G) and plasma insulin (I) were measured between t = 0–120 min. The rate of gastric emptying was derived from the time taken for 50% emptying ( T 50 ) and expressed as kcal/min. The early insulin secretory response was estimated by the ratio of the change in insulin (∆I 0–30 ) to that of glucose at 30 min (∆G 0–30 ) represented as ∆I 0–30 /∆G 0–30 . Insulin sensitivity was estimated as 1/fasting insulin and the DI was then calculated as ∆I 0–30 /∆G 0–30 × 1/fasting insulin. There was a direct relationship between ∆G 0–30 and gastric emptying ( r = 0.47, P = 0.003). While there was no association of either ∆I 0–30 ( r = −0.16, P = 0.34) or fasting insulin ( r = 0.21, P = 0.20), there were inverse relationships between the early insulin secretory response ( r = −0.45, P = 0.004) and the DI ( r = −0.33, P = 0.041), with gastric emptying. We conclude that gastric emptying is associated with both insulin secretion and the disposition index in subjects with normal glucose tolerance, such that when gastric emptying is relatively more rapid, both the early insulin secretory response and the disposition index are less. These findings should be interpreted as “hypothesis generating” and provide the rationale for longitudinal studies to examine the impact of baseline rate of gastric emptying on the prospective risk of type 2 diabetes.

The potential influence of gastric emptying on the "incretin effect," mediated by glucose-dependent insu-linotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), is unknown. The objectives of this study were to determine the effects of intraduodenal (ID) glucose infusions at 2 (ID2) and 4 (ID4) kcal/min (equating to two rates of gastric emptying within the physiological range) on the size of the incretin effect, gastrointestinal glucose disposal (GIGD), plasma GIP, GLP-1, and gluca-gon secretion in health and type 2 diabetes. We studied 10 male BMI-matched controls and 11 male type 2 patients managed by diet or metformin only. In both groups, GIP, GLP-1, and the magnitude of incretin effect were greater with ID4 than ID2, as was GIGD; plasma glucagon was suppressed by ID2, but not ID4. There was no difference in the incretin effect between the two groups. Based on these data, we conclude that the rate of small intestinal glucose exposure (i.e., glucose load) is a major determinant of the comparative secretion of GIP and GLP-1, as well as the magnitude of the incretin effect and GIGD in health and type 2 diabetes. Refereed/Peer-reviewed

The mechanisms responsible for the reduction in appetite and slowing of gastric emptying in older persons are poorly understood. The aim of this study was to evaluate the effects of aging on small intestinal regulation of appetite, GI hormone release, and gastric myoelectrical activity.Thirteen older (65-84 yr) and 13 young (18-32 yr) healthy men received isovolumetric, intraduodenal (i.d.) infusions of saline (control), lipid, and glucose for 120 min, on separate days. The energy content of the lipid and glucose infusions was identical at 2.86 kcal/min. Immediately after the i.d. infusions, each subject was offered a buffet meal, and ad libitum food intake was quantified. Blood glucose and plasma insulin, glucagon-like peptide 1, and glucose-dependent insulinotropic peptide were measured. Gastric myoelectrical activity was measured by surface electrogastrography (EGG).I.d. lipid suppressed food intake in both the young and older men (p0.05), whereas i.d. glucose suppressed food intake only in the older men (p0.05). The blood glucose (p0.01) and insulin (p0.05) responses to i.d. glucose were greater in older than young men. However, there were no differences in glucagon-like peptide 1 or glucose-dependent insulinotropic peptide responses to any of the infusions. There was a greater increase in the EGG power ratio both during and after i.d. glucose infusion in the young (p0.05) than the older men, and an attenuation of EGG frequency by nutrient infusions in older, but not young, men.Our findings indicate that aging is associated with nutrient-specific changes in appetite, hormonal, and gastric myoelectrical (EGG) responses to i.d. nutrients. An enhanced satiating effect of small intestinal carbohydrates may potentially contribute to the anorexia of aging.

The cause of age-related bone loss in men is poorly understood. Previous studies of the relationship between bone density and serum androgens have yielded inconsistent results, perhaps partly because age is a determinant of both. Recent studies suggest that serum estrogen levels influence bone density in adult men. In order to determine whether bone mineral density (BMD) and bone turnover are associated with serum sex steroids, we investigated 37 normal men within a narrow age range (60-70 years). Bone mineral density at the forearm, hip, and spine, testosterone, sex hormone binding globulin (SHBG), free androgen index (FAI:T/SHBG), estradiol (E), free estradiol index (FEI:E/SHBG), and markers of bone formation (alkaline phosphatase, osteocalcin, procollagen type I C-terminal extension peptide) and bone resorption (hydroxyproline/creatinine [OHPr/Cr], deoxypyridinoline/creatinine [Dpd/Cr], pyridinoline/creatinine, collagen type I cross-linked telopeptide) were measured. Bone mineral density was positively related (r0.35, p0.05 at all sites) to log FAI, whereas there was no significant relationship between BMD and either serum total testosterone, serum E, or FEI. Bone density at the spine and hip were inversely related to both OHPr/Cr (r-0.41, p0.05 for all sites) and Dpd/Cr (r-0.36, p0.05 for all sites). OHPr/Cr (r = -0.41, p0.05) and Dpd/Cr (r = -0.41, p0.05) were both inversely related to log FAI. We conclude that BMD and bone turnover in adult men are related to plasma free androgens.

Oral glucose is a potent stimulant of glucagon-like peptide-1 (GLP-1) secretion. The effect of oral fructose on GLP-1 secretion in humans is unknown. The aims of this study were to determine (i) whether oral fructose stimulates GLP-1 secretion and (ii) the comparative effects of oral glucose and fructose on appetite. On 3 separate days, 8 fasting healthy males received, in single-blind randomized order (i) 75 g glucose, (ii) 75 fructose, or (iii) 75 g glucose followed by 75 g fructose I h later. Venous glucose, insulin and GLP-1 were measured. Appetite was assessed by visual analog questionnaires and intake of a buffet meal. Whereas glucose and fructose both increased plasma glucose, insulin and GLP-1 (P < 0.000)] for all), the response to glucose was much greater (P < 0.005 for all). There was no increase in plasma GLP-1 when fructose was given after glucose. There was no difference in food intake after oral glucose or fructose. We conclude that oral fructose (75 g) stimulates GLP-1 (and insulin) secretion, but the response is less than that to 75 g glucose. These observations suggest that neither GLP-1 nor insulin play a major role in the regulation of satiation.

Background: Aging is associated with a decrease in appetite and a slowing of gastric emptying. The gastrointestinal hormones cholecystokinin (CCK), glucagon-like peptide I (GLP-I), and peptide YY (PYY) may mediate these changes. Objective: We investigated whether aging influenced the secretion of CCK, GLP-1, and PYY and their effects on appetite and pyloric motility. Design: Eight healthy older (65-80 y) and 7 younger (20-34 y) men received isoenergetic (12.1 kJ/min) intraduodenal infusions of lipid and glucose for 120 min on separate days. Plasma CCK, GLP-1, and PYY concentrations were measured. Results: Plasma CCK concentrations were higher in older than in younger subjects (P = 0.004) as a result of higher baseline values (4.7 ± 0.2 compared with 3.2 ± 0.2 pmol/L; P < 0.0001) and a greater rise during lipid infusion (increase from baseline: 7.1 ± 0.5 compared with 5.3 ± 0.6 pmol/L; P = 0.048). Plasma GLP-I and PYY concentrations were not significantly different between groups. The decrease in hunger during intraduodenal lipid infusion was inversely related to the increase in CCK, GLP-I, and PYY in younger but not older subjects. During intraduodenal lipid infusion, the increase in isolated pyloric pressure wave (IPPW) frequency was positively related to GLP-1 and PYY and the increase in IPPW amplitude was positively related to CCK in older but not younger subjects, whereas the increase in IPPW amplitude and pyloric tone was negatively related to GLP-1 and PYY in younger subjects. Conclusions: Human aging is associated with increased CCK concentrations, which may contribute to the slowing of gastric emptying, mediated by increased pyloric motility. The role of increased plasma CCK concentrations in mediating the age-related decrease in appetite remains to be established.

OBJECTIVE: The major aim of this study was to evaluate the prognosis of diabetic gastroparesis. RESEARCH DESIGN AND METHODS: Between 1984 and 1989, 86 outpatients with diabetes (66 type 1, 20 type 2; 40 male, 46 female) underwent assessment of solid and liquid gastric emptying and esophageal transit (by scintigraphy), gastrointestinal symptoms (by questionnaire), autonomic nerve function (by cardiovascular reflex tests), and glycemic control (by HbAlc and blood glucose concentrations during gastric emptying measurement). These patients were followed up in 1998. RESULTS: Of the 86 patients, solid gastric emptying (percentage of retention at 100 min) was delayed in 48 (56%) patients and liquid emptying (50% emptying time) was delayed in 24 (28%) patients. At follow-up in 1998, 62 patients were known to be alive, 21 had died, and 3 were lost to follow-up. In the group who had died, duration of diabetes (P = 0.048), score for autonomic neuropathy (P = 0.046), and esophageal transit (P = 0.032) were greater than in those patients who were alive, but there were no differences in gastric emptying between the two groups. Of the 83 patients who could be followed up, 32 of the 45 patients (71%) with delayed solid emptying and 18 of the 24 patients (75%) with delay in liquid emptying were alive. After adjustment for the effects of other factors that showed a relationship with the risk of dying, there was no significant relationship between either gastric emptying or esophageal transit and death. CONCLUSIONS: In this relatively large cohort of outpatients with diabetes, there was no evidence that gastroparesis was associated with a poor prognosis.

Background: dehydro-epiandrosterone sulphate (DHEAS) has been reported to ameliorate diabetes mellitus in rats. we investigated the relationships between plasma glucose, age, serum DHEAS and weight in healthy men. Methods: we measured the serum DHEAS, fasting plasma glucose, plasma cortisol and body mass index in 169 subjects (mean age 46.5 years). Results: there was a significant decline in serum DHEAS with age (P < 0.0001). Multiple linear regression showed significant relationships with plasma glucose for all measured variables. Age was not a significant determinant of plasma glucose after adjusting for log serum DHEAS, body mass index and log serum cortisol. Conclusions: a lowered serum DHEAS is paralleled by an elevated plasma glucose within the normal reference interval, and this may contribute to the rise in fasting plasma glucose which occurs with ageing.

Glucagon-like peptide-1 (GLP-1) may play a role in regulating gastric emptying. The aim of this study was to determine the relationship between gastric emptying of glucose and plasma concentrations of GLP-1. Gastric emptying of 75 g of glucose dissolved in 350 ml of water was measured by the use of scintigraphy in 12 normal volunteers. Venous blood samples for measurement of GLP-1 were obtained immediately before and for 180 min after ingestion of glucose. Plasma GLP-1 rose rapidly from a baseline of 8.5 +/- 1.2 pmol/l to 14.3 +/- 1.3 pmol/l at 10 min (p = 0.024), with a peak of 19.2 +/- 3.0 pmol/l at 30 min (p = 0.0006) after the glucose drink. The rate of gastric emptying was inversely related to the early rise in GLP-1, e.g., the 50% emptying time was related to the change in GLP-1 from baseline at 10 min (r = 0.57; p < 0.05). We conclude that there is an inverse relationship between gastric emptying of glucose and plasma GLP-1. This observation is consistent with the concept that GLP-1 is a determinant of, rather than determined by, the rate of gastric emptying.

In order to establish whether calcium supplementation suppresses bone resorption in early postmenopausal women and whether any response is related to calcium absorption status, we studied 22 healthy women (median age 52 years) all within 5 years of the menopause. Urine was collected between 9.00 p.m. and 9.00 a.m., and 9.00 a.m. and 9.00 p.m., (2 days) and a fasting blood and spot urine sample was obtained at 9 a.m. On the first day, 5 microCi of 45Ca in 250 ml water with 20 mg calcium carrier as the chloride was given at 9.00 a.m. and a further blood sample was obtained at 10.00 a.m. to measure calcium absorption. A 1 g calcium load was given at 9.00 p.m., immediately before the second 24-hour urine collection. There was a rise in plasma ionized calcium (1.18 +/- 0.010 mmol/liter versus 1. 21 +/- 0.011 mmol/liter, P0.01) and a fall in plasma PTH (4.2 +/- 0.34 pmol/liter versus 3.5 +/- 0.31 pmol/liter, P0.01) from baseline after the calcium load, and a trend for the magnitude of the change in PTH to be inversely related to calcium absorption (r = -0.33, P = 0.13). In the fasting spot urine samples, there were falls in hydroxyproline (OHPr/Cr; 14.6 +/- 0.71 versus 12.6 +/- 0.83, P0.001), pyridinoline (Pyr/Cr; 75 +/- 2.8 versus 70 +/- 3.5, P0.05), and deoxypyridinoline (Dpd/Cr; 22.7 +/- 1.2 versus 19.5 +/- 1. 1, P0.005) after the calcium load. The calcium load suppressed urinary Dpd/Cr between 9.00 p.m. and 9.00 a.m. (P0.005), but not between 9.00 a.m. and 9.00 p.m. We conclude that acute administration of a 1 g calcium load suppresses bone resorption in early postmenopausal women, probably by decreasing PTH secretion.