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.

Assessment of physiological barriers to nutrition following critical illness.

BACKGROUND & AIMS: Nutrition may be important for recovery from critical illness. Gastrointestinal dysfunction is a key barrier to nutrition delivery in the Intensive Care Unit (ICU) and metabolic rate is elevated exacerbating nutritional deficits. Whether these factors persist following ICU discharge is unknown. We assessed whether delayed gastric emptying (GE) and impaired glucose absorption persist post-ICU discharge. METHODS: A prospective observational study was conducted in mechanically ventilated adults at 3 time-points: in ICU (V1); on the post-ICU ward (V2); and 3-months after ICU discharge (V3); and compared to age-matched healthy volunteers. On each visit, all participants received a test-meal containing 100 ml of 1 kcal/ml liquid nutrient, labelled with 0.1 g 13C-octanoic acid and 3 g 3-O-Methyl-glucose (3-OMG), and breath and blood samples were collected over 240min to quantify GE (gastric emptying coefficient (GEC)), and glucose absorption (3-OMG concentration; area under the curve (AUC)). Data are mean ± standard error of the mean (SEM) and differences shown with 95% confidence intervals (95%CI). RESULTS: Twenty-six critically ill patients completed V1 (M:F 20:6; 62.0 ± 2.9 y; BMI 29.8 ± 1.2 kg/m2; APACHE II 19.7 ± 1.9), 15 completed V2 and eight completed V3; and were compared to 10 healthy volunteers (M:F 6:4; 60.5 ± 7.5 y; BMI 26.0 ± 1.0 kg/m2). GE was significantly slower on V1 compared to health (GEC difference: -0.96 (95%CI -1.61, -0.31); and compared to V2 (-0.73 (-1.16, -0.31) and V3 (-1.03 (-1.47, -0.59). GE at V2 and V3 were not different to that in health (V2: -0.23 (-0.61, 0.14); V3: 0.10 (-0.27, 0.46)). GEC: V1: 2.64 ± 0.19; V2: 3.37 ± 0.12; V3: 3.67 ± 0.10; health: 3.60 ± 0.13. Glucose absorption (3-OMG AUC0-240) was impaired on V1 compared to V2 (-37.9 (-64.2, -11.6)), and faster on V3 than in health (21.8 (0.14, 43.4) but absorption at V2 and V3 did not differ from health. Intestinal glucose absorption: V1: 63.8 ± 10.4; V2: 101.7 ± 7.0; V3: 111.9 ± 9.7; health: 90.7 ± 3.8. CONCLUSION: This study suggests that delayed GE and impaired intestinal glucose absorption recovers rapidly post-ICU. This requires further confirmation in a larger population. The REINSTATE trial was prospectively registered at www.anzctr.org.au. TRIAL ID: ACTRN12618000370202.

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.

Acute Effects of Lixisenatide on Energy Intake in Healthy Subjects and Patients with Type 2 Diabetes: Relationship to Gastric Emptying and Intragastric Distribution.

Glucagon-like peptide-1 receptor agonists induce weight loss, which has been suggested to relate to the slowing of gastric emptying (GE). In health, energy intake (EI) is more strongly related to the content of the distal, than the total, stomach. We evaluated the effects of lixisenatide on GE, intragastric distribution, and subsequent EI in 15 healthy participants and 15 patients with type 2 diabetes (T2D). Participants ingested a 75-g glucose drink on two separate occasions, 30 min after lixisenatide (10 mcg) or placebo subcutaneously, in a randomised, double-blind, crossover design. GE and intragastric distribution were measured for 180 min followed by a buffet-style meal, where EI was quantified. Relationships of EI with total, proximal, and distal stomach content were assessed. In both groups, lixisenatide slowed GE markedly, with increased retention in both the proximal (p < 0.001) and distal (p < 0.001) stomach and decreased EI (p < 0.001). EI was not related to the content of the total or proximal stomach but inversely related to the distal stomach at 180 min in health on placebo (r = -0.58, p = 0.03) but not in T2D nor after lixisenatide in either group. In healthy and T2D participants, the reduction in EI by lixisenatide is unrelated to changes in GE/intragastric distribution, consistent with a centrally mediated effect.

Effects of Sustained Treatment With Lixisenatide on Gastric Emptying and Postprandial Glucose Metabolism in Type 2 Diabetes: A Randomized Controlled Trial.

OBJECTIVE: Tachyphylaxis for slowing of gastric emptying is seen with continuous exposure to glucagon-like peptide 1 (GLP-1). We therefore aimed to establish whether prolonged use of a "short-acting" GLP-1 receptor agonist, lixisenatide, achieves sustained slowing of gastric emptying and reduction in postprandial glycemia. RESEARCH DESIGN AND METHODS: A total of 30 patients with metformin-treated type 2 diabetes underwent assessment of gastric emptying (scintigraphy) and glucose metabolism (dual tracer technique) after a 75-g glucose drink, before and after 8 weeks' treatment with lixisenatide (20 µg subcutaneously daily) or placebo, in a double-blind randomized parallel design. RESULTS: Gastric retention of the glucose drink was markedly increased after lixisenatide versus placebo (ratio of adjusted geometric means for area under the curve [AUC] over 240 min of 2.19 [95% CI 1.82, 2.64], P < 0.001), associated with substantial reductions in the rate of systemic appearance of oral glucose (P < 0.001) and incremental AUC for blood glucose (P < 0.001). Lixisenatide suppressed both glucagon (P = 0.003) and insulin (P = 0.032), but not endogenous glucose production, over 120 min after oral glucose intake. Postprandial glucose lowering over 240 min was strongly related to the magnitude of slowing of gastric emptying by lixisenatide (r = -0.74, P = 0.002) and to the baseline rate of emptying (r = 0.52, P = 0.048) but unrelated to ß-cell function (assessed by ß-cell glucose sensitivity). CONCLUSIONS: Eight weeks' treatment with lixisenatide is associated with sustained slowing of gastric emptying and marked reductions in postprandial glycemia and appearance of ingested glucose. Short-acting GLP-1 receptor agonists therefore potentially represent an effective long-term therapy for specifically targeting postprandial glucose excursions.

Plasma Free Amino Acid Responses to Whey Protein and Their Relationships with Gastric Emptying, Blood Glucose- and Appetite-Regulatory Hormones and Energy Intake in Lean Healthy Men.

This study determined the effects of increasing loads of whey protein on plasma amino acid (AA) concentrations, and their relationships with gastric emptying, blood glucose- and appetite-regulatory hormones, blood glucose and energy intake. Eighteen healthy lean men participated in a double-blinded study, in which they consumed, on 3 separate occasions, in randomised order, 450-mL drinks containing either 30 g (L) or 70 g (H) of pure whey protein isolate, or control with 0 g of protein (C). Gastric emptying, serum concentrations of AAs, ghrelin, cholecystokinin (CCK), glucagon-like-peptide 1 (GLP-1), insulin, glucagon and blood glucose were measured before and after the drinks over 180 min. Then energy intake was quantified. All AAs were increased, and 7/20 AAs were increased more by H than L. Incremental areas under the curve (iAUC0-180 min) for CCK, GLP-1, insulin and glucagon were correlated positively with iAUCs of 19/20 AAs (p < 0.05). The strongest correlations were with the branched-chain AAs as well as lysine, tyrosine, methionine, tryptophan, and aspartic acid (all R2 > 0.52, p < 0.05). Blood glucose did not correlate with any AA (all p > 0.05). Ghrelin and energy intake correlated inversely, but only weakly, with 15/20 AAs (all R2 < 0.34, p < 0.05). There is a strong relationship between gluco-regulatory hormones with a number of (predominantly essential) AAs. However, the factors mediating the effects of protein on blood glucose and energy intake are likely to be multifactorial.

Markers of adipose tissue inflammation are transiently elevated during intermittent fasting in women who are overweight or obese.

OBJECTIVE: This study compared the effects of daily calorie restriction (DR) versus intermittent fasting (IF) on markers of inflammation and extracellular matrix deposition in adipose tissue and skeletal muscle in a controlled feeding trial in women with overweight or obesity. METHODS: Women (N = 76) were randomised to one of three diets and provided with all foods at 100% (IF100) or 70% (IF70 and DR70) of calculated energy requirements for 8 weeks. IF groups ate breakfast prior to fasting for 24-h on 3 non-consecutive days/week. Weight, body composition, serum non-esterified fatty acids (NEFA), tumour necrosis factor-alpha (TNFα), interleukin-6 (IL-6), interleukin-10 (IL-10), M1- and M2-macrophage markers by qPCR and immunohistochemistry in adipose tissue and skeletal muscle were measured following a 12-h overnight fast (fed day, all groups) and a 24-h fast (IF groups only). RESULTS: IF70 resulted in greater weight and fat losses and reductions in serum NEFA versus DR70 and IF100 (P < 0.05) after fed days. Markers of inflammation in serum (TNFα, IL6 and IL10), subcutaneous adipose tissue and skeletal muscle (CD68, CD40 and CD163) were unchanged by DR or IF after fed days. After fasting, NEFA, M1-macrophages (CD40+) in adipose tissue, and M2-macrophages (CD163+) in muscle were increased in IF70 and IF100 (all P < 0.05) and the changes in NEFA and mRNA of pan-macrophage marker CD68 in adipose tissue were positively correlated (r = 0.56, P = 0.002). CONCLUSIONS: Unlike caloric restriction, IF transiently elevated markers of macrophage infiltration in adipose tissue and skeletal muscle, possibly in response to marked increases in adipose tissue lipolysis.

Effects of lixisenatide on postprandial blood pressure, gastric emptying and glycaemia in healthy people and people with type 2 diabetes.

AIM: To evaluate the effects of the prandial glucagon-like peptide-1 receptor agonist lixisenatide on gastric emptying and blood pressure (BP) and superior mesenteric artery (SMA) blood flow, and the glycaemic responses to a 75-g oral glucose load in healthy people and those with type 2 diabetes (T2DM). MATERIALS AND METHODS: Fifteen healthy participants (nine men, six women; mean ± SEM age 67.2 ± 2.3 years) and 15 participants with T2DM (nine men, six women; mean ± SEM age 61.9 ± 2.3 years) underwent measurement of gastric emptying, BP, SMA flow and plasma glucose 180 minutes after a radiolabelled 75-g glucose drink on two separate days. All participants received lixisenatide (10 µg subcutaneously) or placebo in a randomized, double-blind, crossover fashion 30 minutes before the glucose drink. RESULTS: Lixisenatide slowed gastric emptying (retention at 120 minutes, P < 0.01), attenuated the rise in SMA flow (P < 0.01) and markedly attenuated the decrease in systolic BP (area under the curve [AUC] 0-120 minutes, P < 0.001) compared to placebo in healthy participants and those with T2DM. Plasma glucose (incremental AUC 0-120 minutes) was greater in participants with T2DM (P < 0.005) than in healthy participants, and lower after lixisenatide in both groups (P < 0.001). CONCLUSIONS: In healthy participants and those with T2DM, the marked slowing of gastric emptying of glucose induced by lixisenatide was associated with attenuation of the increments in glycaemia and SMA flow and decrease in systolic BP. Accordingly, lixisenatide may be useful in the management of postprandial hypotension.

Effect of gender on the acute effects of whey protein ingestion on energy intake, appetite, gastric emptying and gut hormone responses in healthy young adults.

BACKGROUND/OBJECTIVES: Protein supplements, usually drinks rich in whey protein, are used widely for weight loss purposes in overweight adults. Information comparing the effects of whey protein on appetite and energy intake in men and women is limited. The objective was to compare the acute effects of whey-protein intake on energy intake, appetite, gastric emptying and gut hormones in healthy young men and women. SUBJECTS/METHODS: Gastric emptying (3D-ultrasonography), blood glucose and plasma insulin, glucagon, ghrelin, cholecystokinin (CCK), gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) concentrations (0-180 min), appetite (visual analogue scales), and ad libitum energy intake from a buffet meal (180-210 min) were determined after ingestion of 30 g (120 kcal) or 70 g (280 kcal) whey protein, or a flavoured-water control drink (~2 kcal) in 8 healthy young men (25 ± 2 y, 72 ± 3 kg, 23 ± 1 kg/m2) and 8 women (23 ± 1 y, 64 ± 2 kg, 24 ± 0.4 kg/m2). RESULTS: There was a protein-load effect on gastric emptying, blood glucose, plasma insulin, glucagon, ghrelin, CCK, GIP and GLP-1 concentrations, and perceptions of hunger, desire to eat and prospective food consumption (P < 0.05). Ad libitum energy intake (average decrease of 206 ± 39 kcal (15 ± 2%) for men and of 46 ± 54 kcal (0 ± 26%) for women for the mean of the intakes after the 30 and 70 g whey-protein loads) and hunger were suppressed more by whey-protein ingestion in men than women (P = 0.046). There was no difference in suppression of energy intake between the 30 and 70 g protein loads (P = 0.75, interaction effect P = 0.19). Consequently, total energy intake (protein drink plus buffet meal) increased more compared to control in women than men (P = 0.010). The drinks emptied more slowly, and plasma glucagon, CCK and GLP-1 increased less after the protein drinks, in women than men (P < 0.05). CONCLUSION: The acute effects of whey protein ingestion on appetite, energy intake, gastric emptying and gut hormone responses are influenced by gender in healthy young adults.

Effects of randomized whey-protein loads on energy intake, appetite, gastric emptying, and plasma gut-hormone concentrations in older men and women.

Background: Protein- and energy-rich supplements are used widely for the management of malnutrition in the elderly. Information about the effects of protein on energy intake and related gastrointestinal mechanisms and whether these differ between men and women is limited.Objective: We determined the effects of whey protein on energy intake, appetite, gastric emptying, and gut hormones in healthy older men and women.Design: Eight older women and 8 older men [mean ± SEM age: 72 ± 1 y; body mass index (in kg/m2): 25 ± 1] were studied on 3 occasions in which they received protein loads of 30 g (120 kcal) or 70 g (280 kcal) or a flavored water control drink (0 kcal). At regular intervals over 180 min, appetite (visual analog scales), gastric emptying (3-dimensional ultrasonography), and blood glucose and plasma gut-hormone concentrations [insulin, glucagon, ghrelin, cholecystokinin, gastric inhibitory polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and peptide tyrosine tyrosine (PYY)] were measured, and ad libitum energy intake was quantified from a buffet meal (180-210 min; energy intake, appetite, and gastric emptying in the men have been published previously).Results: Energy intake at the buffet meal was ∼80% higher in older men than in older women (P < 0.001). Energy intake was not suppressed by protein compared with the control in men or women (P > 0.05). There was no effect of sex on gastric emptying, appetite, gastrointestinal symptoms, glucose, or gut hormones (P > 0.05). There was a protein load-dependent slowing of gastric emptying, an increase in concentrations of insulin, glucagon, cholecystokinin, GIP, GLP-1, and PYY, and an increase in total energy intake (drink plus meal: 12% increase with 30 g and 32% increase with 70 g; P < 0.001). Energy intake at the buffet meal was inversely related to the stomach volume and area under the curve of hormone concentrations (P < 0.05).Conclusion: In older men and women, whey-protein drinks load-dependently slow gastric emptying and alter gut hormone secretion compared with a control but have no suppressive effect on subsequent ad libitum energy intake. This trial was registered at www.anzctr.org.au as ACTRN12612000941864.

Relationships of the early insulin secretory response and oral disposition index with gastric emptying in subjects with normal glucose tolerance.

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 99mTc-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 (T50) and expressed as kcal/min. The early insulin secretory response was estimated by the ratio of the change in insulin (∆I0-30) to that of glucose at 30 min (∆G0-30) represented as ∆I0-30/∆G0-30 Insulin sensitivity was estimated as 1/fasting insulin and the DI was then calculated as ∆I0-30/∆G0-30 × 1/fasting insulin. There was a direct relationship between ∆G0-30 and gastric emptying (r = 0.47, P = 0.003). While there was no association of either ∆I0-30 (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.

Energy and protein deficits throughout hospitalization in patients admitted with a traumatic brain injury.

BACKGROUND AND AIMS: Patients with traumatic brain injury (TBI) experience considerable energy and protein deficits in the intensive care unit (ICU) and these are associated with adverse outcomes. However, nutrition delivery after ICU discharge during ward-based care, particularly from oral diet, has not been measured. This study aimed to quantify energy and protein delivery and deficits over the entire hospitalization for critically ill TBI patients. METHODS: Consecutively admitted adult patients with a moderate-severe TBI (Glasgow Coma Scale 3-12) over 12 months were eligible. Observational data on energy and protein delivered from all routes were collected until hospital discharge or day 90 and compared to dietician prescriptions. Oral intake was quantified using weighed food records on three pre-specified days each week. Data are mean (SD) unless indicated. Cumulative deficit is the mean absolute difference between intake and estimated requirements. RESULTS: Thirty-seven patients [45.3 (15.8) years; 87% male; median APACHE II 18 (IQR: 14-22)] were studied for 1512 days. Median duration of ICU and ward-based stay was 13.4 (IQR: 6.4-17.9) and 19.9 (9.6-32.0) days, respectively. Over the entire hospitalization patients had a cumulative deficit of 18,242 (16,642) kcal and 1315 (1028) g protein. Energy and protein intakes were less in ICU than the ward (1798 (800) vs 1980 (915) kcal/day, p = 0.015; 79 (47) vs 89 (41) g/day protein, p = 0.001). Energy deficits were almost two-fold greater in patients exclusively receiving nutrition orally than tube-fed (806 (616) vs 445 (567) kcal/day, p = 0.016) while protein deficits were similar (40 (5) vs 37 (6) g/day, p = 0.616). Primary reasons for interruptions to enteral and oral nutrition were fasting for surgery/procedures and patient-related reasons, respectively. CONCLUSIONS: Patients admitted to ICU with a TBI have energy and protein deficits that persist after ICU discharge, leading to considerable shortfalls over the entire hospitalization. Patients ingesting nutrition orally are at particular risk of energy deficit.

The insulinotropic effect of pulsatile compared with continuous intravenous delivery of GLP-1.

AIMS/HYPOTHESIS: In healthy individuals, both insulin and glucagon-like peptide 1 (GLP-1) are secreted in a pulsatile fashion. Insulin has greater glucose-lowering properties when administered in pulses compared with a constant i.v. infusion. The primary aim of this randomised double-dummy cross-over study was to compare the insulinotropic response to pulsatile and continuous i.v. infusions of equivalent doses of GLP-1. METHODS: Twelve healthy participants aged 18-35 years were randomised to three different treatments on separate days: a continuous infusion day (GLP-1 at 0.6 pmol kg(-1) min(-1) [1 ml/min] and a 1 ml placebo bolus every 6 min); a pulsatile infusion day (placebo at 1 ml/min and a 3.6 pmol/kg GLP-1 bolus every 6 min); and a placebo day (placebo at 1 ml/min and a 1 ml placebo bolus every 6 min). Between 45 and 120 min, a hyperglycaemic clamp was used to maintain blood glucose at 9 mmol/l. Venous blood glucose and plasma insulin concentrations were measured every 5 min from 0 to 45 min and every 1 min from 45 to 120 min; plasma glucagon was measured every 15 min. The order of treatment was randomised by the Pharmacy Department and both study investigators and participants were blinded to the treatment arm. The dextrose requirement and glucagon data were analysed using repeated measures ANOVA and insulin data were analysed with a linear mixed effects maximum likelihood model. RESULTS: Continuous and pulsatile infusions of GLP-1 increased the dextrose requirement by ~threefold (p < 0.001) and increased insulin secretion by ~ninefold (p < 0.001). There was no difference in the effect of both treatments. Although hyperglycaemia reduced plasma glucagon concentrations, there was no difference between the treatment days. CONCLUSIONS/INTERPRETATION: In healthy individuals, pulsatile and continuous administration of i.v. GLP-1 appears to have comparable insulinotropic effects. TRIAL REGISTRATION: ACTRN12612001040853 FUNDING: This study was supported by the National Health and Medical Research Council (NHMRC) of Australia.

Small intestinal glucose exposure determines the magnitude of the incretin effect in health and type 2 diabetes.

The potential influence of gastric emptying on the "incretin effect," mediated by glucose-dependent insulinotropic 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 glucagon 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.

Risk factors for progression or improvement of lower urinary tract symptoms in a prospective cohort of men.

PURPOSE: We determined the metabolic, lifestyle and physical factors associated with progression or improvement of storage and voiding lower urinary tract symptoms in a population based cohort of men. MATERIALS AND METHODS: After the exclusion of men with prostate or bladder cancer and/or surgery from the study, progression and improvement of storage and voiding lower urinary tract symptoms was assessed using the AUA-SI (American Urological Association symptom index) in 780 men, age 35 to 80 years at baseline, who attended 5-year followup clinics. RESULTS: Storage and voiding lower urinary tract symptoms progressed in 39.8% (308) and 32.3% (250) of men, and improved in 33.1% (256) and 23.4% (181), respectively. In final adjusted regression models greater bother and physical activity at baseline predicted improvement in storage and voiding lower urinary tract symptoms, while greater income, high-density lipoprotein cholesterol and lower triglycerides predicted improvement of storage lower urinary tract symptoms only. Being widowed, higher plasma estradiol and depression at baseline predicted the progression of storage and voiding lower urinary tract symptoms, while greater abdominal fat mass and obstructive sleep apnea risk predicted the progression of storage lower urinary tract symptoms only. Older age, lower high-density lipoprotein cholesterol, testosterone, income, previous benign prostatic hyperplasia and erectile dysfunction at baseline predicted the progression of voiding lower urinary tract symptoms only. The initiation or continued use of α-blockers or anticholinergics (storage lower urinary tract symptoms), and 5α-reductase inhibitors (voiding lower urinary tract symptoms), were associated with symptom improvement. CONCLUSIONS: Lower urinary tract symptoms may progress or remit. Even accounting for medication use, progression may be associated with modifiable disease, or metabolic or behavioral factors, which are also risk factors for type 2 diabetes and cardiovascular disease. These factors should be looked for and managed.

Gastroesophageal reflux disease after diagnostic endoscopy in the clinical setting.

AIM: To investigate the outcome of patients with symptoms of gastroesophageal reflux disease (GERD) referred for endoscopy at 2 and 6 mo post endoscopy. METHODS: Consecutive patients referred for upper endoscopy for assessment of GERD symptoms at two large metropolitan hospitals were invited to participate in a 6-mo non-interventional (observational) study. The two institutions are situated in geographically and socially disparate areas. Data collection was by self-completion of questionnaires including the patient assessment of upper gastrointestinal disorders symptoms severity and from hospital records. Endoscopic finding using the Los-Angeles classification, symptom severity and it's clinically relevant improvement as change of at least 25%, therapy and socio-demographic factors were assessed. RESULTS: Baseline data were available for 266 patients and 2-mo and 6-mo follow-up data for 128 and 108 patients respectively. At baseline, 128 patients had erosive and 138 non-erosive reflux disease. Allmost all patient had proton pump inhibitor (PPI) therapy in the past. Overall, patients with non-erosive GERD at the index endoscopy had significantly more severe symptoms as compared to patients with erosive or even complicated GERD while there was no difference with regard to medication. After 2 and 6 mo there was a small, but statistically significant improvement in symptom severity (7.02 ± 5.5 vs 5.9 ± 5.4 and 5.5 ± 5.4 respectively); however, the majority of patients continued to have symptoms (i.e., after 6 mo 81% with GERD symptoms). Advantaged socioeconomic status as well as being unemployed was associated with greater improvement. CONCLUSION: The majority of GORD patients receive PPI therapy before being referred for endoscopy even though many have symptoms that do not sufficiently respond to PPI therapy.

Gastric emptying measurement of liquid nutrients using the (13)C-octanoate breath test in critically ill patients: a comparison with scintigraphy.

PURPOSE: Scintigraphy is considered the most accurate technique for the measurement of gastric emptying (GE) but, for patients in the intensive care unit, it is technically demanding, involves radiation and can interfere with care. The (13)C-octanoate breath test ((13)C-OBT) is a simple, non-invasive technique that does not involve radiation exposure. AIM: To evaluate the performance of the (13)C-OBT in the assessment of GE in critically ill patients. METHODS: The GE was assessed in 33 mechanically ventilated patients (23 M; 54.3 ± 3.0 yrs; APACHE II: 22.0 ± 1.1). Following test meal administration (100 ml Ensure(®)), concurrent scintigraphic measurement and breath samples ((13)C-OBT) were collected over 4 h. Scintigraphic meal retention was determined and the gastric emptying coefficient (GEC) and half emptying time [t50(BT)] were calculated for the (13)C-OBT. Delayed GE was defined as meal retention >13 % at 180 min. RESULTS: Delayed GE was identified in 27/33 patients. Meal retention correlated modestly with t50(BT) (r = 0.55-0.66; P < 0.001) and well with GEC (r = -0.63 to -0.74; P < 0.0001). The strength of agreement between the two techniques was highest between GEC and retention at 120 min. The best cut-off GEC for defining delayed GE was 3.25 (AUC = 0.75; 95 % CI = 0.52-0.99; P = 0.05), with 89 % sensitivity and 67 % specificity to detect delayed GE. The GE was delayed in all (23/23) patients with feed intolerance (GRV > 250 ml) on scintigraphy and 91 % (21/23) patients on (13)C-OBT. CONCLUSION: In critical illness, there was a correlation between (13)C-OBT and gastric scintigraphy, with GEC performing as a better and more sensitive marker of detecting delayed GE than t50. However the relatively wide 95 % confidence intervals suggest that (13)C-OBT is more suitable as a technique to assess GE in a group setting for research studies rather than for individual patients in clinical practice.

Comparative effects of variations in duodenal glucose load on glycemic, insulinemic, and incretin responses in healthy young and older subjects.

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 ß-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 ß-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.

Comparing effects of a low-energy diet and a high-protein low-fat diet on sexual and endothelial function, urinary tract symptoms, and inflammation in obese diabetic men.

INTRODUCTION: Abdominal obesity and type 2 diabetes mellitus are associated with sexual and endothelial dysfunction, lower urinary tract symptoms (LUTS), and chronic systemic inflammation. AIM: To determine the effects of diet-induced weight loss and maintenance on sexual and endothelial function, LUTS, and inflammatory markers in obese diabetic men. MAIN OUTCOME MEASURES: Weight, waist circumference (WC), International Index of Erectile Function (IIEF-5) score, Sexual Desire Inventory (SDI) score, International Prostate Symptom Scale (IPSS) score, plasma fasting glucose and lipids, testosterone, sex hormone binding globulin (SHBG), inflammatory markers (high-sensitivity C-reactive protein [CRP] and interleukin-6 [IL-6]) and soluble E-selectin, and brachial artery flow-mediated dilatation (FMD) were measured at baseline, 8 weeks, and 52 weeks. METHODS: Over 8 weeks, 31 abdominally obese (body mass index ≥ 30 kg/m(2) , WC ≥ 102 cm), type 2 diabetic men (mean age 59.7 years) received either a meal replacement-based low-calorie diet (LCD) ∼1,000 kcal/day (N = 19) or low-fat, high-protein, reduced-carbohydrate (HP) diet (N = 12) prescribed to decrease intake by ∼600 kcal/day. Subjects continued on, or were switched to, the HP diet for another 44 weeks. RESULTS: At 8 weeks, weight and WC decreased by ∼10% and ∼5% with the LCD and HP diet, respectively. Both diets significantly improved plasma glucose, low-density lipoprotein (LDL), SHBG, IIEF-5, SDI and IPSS scores, and endothelial function (increased FMD, reduced soluble E-selectin). Erectile function, sexual desire, and urinary symptoms improved by a similar degree with both diets. CRP and IL-6 decreased with the HP diet. At 52 weeks, reductions in weight, WC, and CRP were maintained. IIEF-5, SDI, and IPSS scores improved further. CONCLUSIONS: Diet-induced weight loss induces rapid improvement of sexual, urinary, and endothelial function in obese diabetic men. A high-protein, carbohydrate-reduced, low-fat diet also reduces systemic inflammation and sustains these beneficial effects to 1 year.