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Background Gastrointestinal (GI) dysmotility impedes nutrient delivery in critically ill patients with major burns. We aimed to quantify the incidence, timing, and factors associated with GI dysmotility and subsequent nutrition delivery. Methods A 10-year retrospective observational study included mechanically ventilated, adult, critically ill patients with ≥15% total body surface area (TBSA) burns receiving nutrition support. Patients with a single gastric residual volume ≥250 mL were categorized as having GI dysmotility. Daily medical and nutrition data were extracted for ≤14 days in the intensive care unit (ICU). Data are mean (SD) or median (interquartile range). Factors associated with GI dysmotility and the effect on nutrition and clinical outcomes were assessed. Results Fifty-nine patients were eligible; 51% (n = 30) with GI dysmotility and 49% (n = 29) without. Baseline characteristics (dysmotility vs no dysmotility) were age (48 [33-60] vs 34 [26-46] years); Acute Physiology and Chronic Health Evaluation II score (16 [12-17] vs 13 [10-16]); sex ([men] 80% vs 86%); and TBSA (49% [35%-59%] vs 38% [26%-55%]). Older age was associated with increased probability of dysmotility (P = .049). GI dysmotility occurred 32 (19-63) hours after ICU admission but was not associated with reduced nutrient delivery. Postpyloric tube insertions were attempted in 83% (n = 25) of patients, with 72% (n = 18) being successful. Postpyloric feeding achieved higher nutrition adequacy than gastric feeding (energy: 82% [95% CI, 70-94] vs 68% [95% CI, 63-74], P = .036; protein: 75% [95% CI, 65-86] vs 61% [95% CI, 56-65], P = .009). Conclusion GI dysmotility occurs early in critically ill burn patients, and postpyloric feeding improves nutrition delivery.

Background Intermittent fasting (IF) is proposed as a viable alternative to moderate calorie restriction (CR) for weight loss and metabolic health, but few long term randomized trials have been conducted. This protocol paper describes the rationale and detailed protocol for DIRECT study ( D aily versus I ntermittent R estriction of E nergy: C ontrolled T rial to Reduce Diabetes Risk), comparing long term effectiveness of IF versus CR on metabolic health in individuals who are at increased risk of developing type 2 diabetes. Methods Anticipated 260 non-diabetic men and women aged 35–75 years, BMI 25−50 kg/m2 with score ≥12 on the Australian Diabetes Risk (AUSDRISK) calculator will be recruited into this open-label, multi-arm, parallel group sequential randomized controlled trial. Participants will be randomized to one of three groups for 18 months: IF (30% of energy needs on fast days), CR (70% of energy needs daily), or standard care (SC) group. All participants will visit the clinic fortnightly for weight assessments during active intervention phase (6 months), followed by a 12-month follow-up phase. IF and CR groups will receive further diet counselling by dietitian. Two primary outcomes are the changes in glycated haemoglobin (HbA1c) and postprandial glucose area under the curve (AUC) at week 24 post-randomization. Secondary outcomes include changes in weight, body composition via dual-energy X-ray absorptiometry, gastro-intestinal hormones, cardiovascular risk factors, and dietary record by a smartphone-based application. Discussion This study will provide substantial evidence as to whether IF is an effective nutrition intervention for glycaemic control in a population at risk of developing type 2 diabetes.

Summary 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.

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. usc Refereed/Peer-reviewed

BACKGROUND l-Tryptophan reduces energy intake in healthy men. The underlying mechanisms, including appetite, plasma cholecystokinin (CCK), tryptophan (Trp), and the ratio of Trp to large neutral amino acids (Trp:LNAAs ratio), and whether responses differ in lean and obese individuals, are uncertain. OBJECTIVES We evaluated the effects of intragastric Trp on energy intake (primary outcome) and their potential mechanisms, pre- and postmeal, in lean men and those with obesity. METHODS Twelve lean men [mean ± SD age: 30 ± 3 y; BMI (in kg/m2): 23 ± 1] and 13 men with obesity (mean ± SD age: 31 ± 3 y; BMI: 33 ± 1) received, on 3 separate occasions, in double-blind, randomized order, 3 g ("Trp-3") or 1.5 g ("Trp-1.5") Trp, or control ("C"), intragastrically, 30 min before a buffet-meal. Energy intake from the buffet-meal, hunger, fullness, and plasma CCK and amino acid concentrations were measured in response to Trp alone and for 2 h postmeal. Data were analyzed using maximum likelihood mixed-effects models, with treatment, group, and treatment-by-group interaction as fixed effects. RESULTS Trp alone increased plasma CCK, Trp, and the Trp:LNAAs ratio (all P

Background Energy-dense formulae are often provided to critically ill patients with enteral feed intolerance with the aim of increasing energy delivery, yet the effect on gastric emptying is unknown. The rate of gastric emptying of a standard compared with an energy-dense formula was quantified in critically ill patients. Methods Mechanically ventilated adults were randomized to receive radiolabeled intragastric infusions of 200 mL standard (1 kcal/mL) or 100 mL energy-dense (2 kcal/mL) enteral formulae on consecutive days in this noninferiority, blinded, crossover trial. The primary outcome was scintigraphic measurement of gastric retention (percentage at 120 minutes). Other measures included area under the curve (AUC) for gastric retention and intestinal energy delivery (calculated from gastric retention of formulae over time), blood glucose (peak and AUC), and intestinal glucose absorption (using 3-O-methyl-D-gluco-pyranose [3-OMG] concentrations). Comparisons were undertaken using paired mixed-effects models. Data presented are mean ± SE. Results Eighteen patients were studied (male/female, 14:4; age, 55.2 ± 5.3 years). Gastric retention at 120 minutes was greater with the energy-dense formula (standard, 17.0 ± 5.9 vs energy-dense, 32.5 ± 7.1; difference, 12.7% [90% confidence interval, 0.8%-30.1%]). Energy delivery (AUC120 , 13,038 ± 1119 vs 9763 ± 1346 kcal/120 minutes; P = 0.057), glucose control (peak glucose, 10.1 ± 0.3 vs 9.7 ± 0.3 mmol/L, P = 0.362; and glucose AUC120 8.7 ± 0.3 vs 8.5 ± 0.3 mmol/L.120 minutes, P = 0.661), and absorption (3-OMG AUC120 , 38.5 ± 4.0 vs 35.7 ± 4.0 mmol/L.120 minutes; P = .508) were not improved with the energy-dense formula. Conclusion In critical illness, administration of an energy-dense formula does not reduce gastric retention, increase energy delivery to the small intestine, or improve glucose absorption or glucose control; instead, there is a signal for delayed gastric emptying.

The authors wish to correct some minor errors in this article: 1. The fasting insulin secretion rate was correctly shown in Table 1 to be slightly increased after lixisenatide treatment, whereas the text of the Results and Conclusions sections incorrectly reported that it was decreased. 2. Change …

Background International guidelines recommend critically ill adults receive more protein than most receive. We aimed to establish the feasibility of a trial to evaluate whether feeding protein to international recommendations would improve outcomes, in which 1 group received protein doses representative of international guideline recommendations (high protein) and the other received doses similar to usual practice. Methods We conducted a prospective, randomized, blinded, parallel-group, feasibility trial across 6 intensive care units. Critically ill, mechanically ventilated adults expected to receive enteral nutrition (EN) for ≥2 days were randomized to receive EN containing 63 or 100 g/L protein for ≤28 days. Data are mean (SD) or median (interquartile range). Results The recruitment rate was 0.35 (0.13) patients per day, with 120 patients randomized and data available for 116 (n = 58 per group). Protein delivery was greater in the high-protein group (1.52 [0.52] vs 0.99 [0.27] grams of protein per kilogram of ideal body weight per day; difference, 0.53 [95% CI, 0.38-0.69] g/kg/d protein), with no difference in energy delivery (difference, -26 [95% CI, -190 to 137] kcal/kg/d). There were no between-group differences in the duration of feeding (8.7 [7.3] vs 8.1 [6.3] days), and blinding of the intervention was confirmed. There were no differences in clinical outcomes, including 90-day mortality (14/55 [26%] vs 15/56 [27%]; risk difference, -1.3% [95% CI, -17.7% to 15.0%]). Conclusion Conducting a multicenter blinded trial is feasible to compare protein delivery at international guideline-recommended levels with doses similar to usual care during critical illness.

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

Aim To determine the prevalence of malnutrition on admission to the intensive care unit (ICU) and the relationship between nutritional status on admission and clinical outcomes in adult critically ill patients. Methods This was a prospective study in an adult ICU. Patients with expected length of stay (LOS) >48 hours in ICU were assessed for nutritional status using the patient generated-subjective global assessment (PG-SGA) within 48 hours of admission to ICU. Results Primary outcomes were ICU and hospital mortality, ICU and hospital LOS and length of mechanical ventilation. A total of 166 patients were enrolled in this study. Patients were aged 59 ± 17 years on average with a mean BMI of 29 ± 7 kg/m2 and a mean Acute Physiology and Chronic Health Evaluation II score of 19 ± 7. The prevalence of malnutrition in critically ill patients was 36% (n = 60). Mortality rate of malnourished patients was 9% (n = 15) compared to 7.8% (n = 13) in well-nourished patients (adjusted odds ratio, 2.17; 95% confidence interval, 0.9-5.03, P = .069). There was no difference in hospital mortality between malnourished patients and well-nourished patients (10.2% vs 10.2% adjusted odds ratio, 1.93; 95% confidence interval, 0.89-4.19, P = .096). There was no relationship between nutritional status and length of mechanical ventilation (3.0 vs 1.0 days, P = .382)or ICU LOS (4.7 vs 4.8 days, P = .59). Malnourished patients had a longer LOS in hospital than well-nourished patients (24 vs 17 days, P = .03). Conclusion Malnutrition is an independent risk factor for increased hospital LOS.

ContextImpaired lipid metabolism is linked with obesity-associated insulin resistance, which may be reversed by caloric restriction (CR).ObjectiveIn a secondary analysis of a randomized controlled trial, we compared the effects of intermittent fasting (IF) and CR on markers of lipid metabolism in muscle.DesignSeventy-six women (body mass index, 25-40 kg/m2) were randomly assigned to 1 of 3 diets for 8 weeks and provided foods at 70% (CR70 and IF70) or 100% (IF100) of energy requirements. IF groups ate breakfast prior to a 24-hour fast on 3 nonconsecutive days per week. On nonfasting days, IF70 ate at 100% and IF100 ate at 145% of energy requirements to achieve the prescribed target. Weight, body composition, insulin sensitivity by clamp, nonesterified fatty acids (NEFAs), β-hydroxybutyrate (BHB), and markers of lipid metabolism and oxidative stress in muscle by quantitative polymerase chain reaction were measured at baseline and week 8 following a 12-hour overnight fast (all groups) and 24-hour fast (IF groups).ResultsIF70 resulted in greater weight and fat loss and reduced NEFAs vs CR70 and IF100 after an overnight fast. IF70 and IF100 induced a greater reduction only in mRNA levels of antioxidant enzymes glutathione peroxidase 1 (GPX1), superoxide dismutase 1, soluble (SOD1), and SOD2 vs CR70. Fasting for 24 hours increased NEFAs and BHB in IF groups, but impaired insulin sensitivity and increased PLIN5 mRNA levels.ConclusionsIn comparison to CR, IF did not increase markers of lipid metabolism in muscle, but reduced expression of antioxidant enzymes. However, fasting-induced insulin resistance was detected, alongside increased PLIN5 expression, potentially reflecting transient lipid storage.

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 β-cell function (assessed by β-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.

Background Obesity is becoming more prevalent in older people. A management strategy in obese, young adults is to increase dietary protein relative to other macronutrients. It is not clear if this is effective in obese, older individuals. Obesity may be associated with diminished sensitivity to nutrients. We have reported that a 30-g whey protein drink slows gastric emptying more, and suppresses energy intake less, in older, than younger, non-obese men. The aim of this study was to determine the effect of a 30 g whey protein drink on energy intake, GE and glycaemia in obese, older and younger men. Methods In randomized, double-blind order, 10 younger (age: 27 ± 2 years; BMI: 36 ± 2 kg/m²), and 10 older (72 ± 1 years; 33 ± 1 kg/m²), obese men were studied twice. After an overnight fast, subjects ingested a test drink containing 30 g whey protein (120 kcal) or control (2 kcal). Postprandial gastric emptying (antral area, 2D Ultrasound) and blood glucose concentrations were measured for 180 min. At t = 180 min subjects were given a buffet meal and ad libitum energy intake was assessed. Results Older subjects ate non-significantly less (~20%) that the younger subjects (effect of age, P = 0.16). Whey protein had no effect on subsequent energy intake (kcal) compared to control in either the younger (decrease 3 ± 8%) or older (decrease 2 ± 8%) obese men (age effect P > 0.05, protein effect P = 0.46, age × protein interaction effect P = 0.84). Whey protein slowed gastric emptying, to a similar degree in both age groups (50% emptying time: control vs. protein young men: 255 ± 5 min vs. 40 ± 7 min; older men: 16 ± 5 min vs. 50 ± 8 min; protein effect P = 0.001, age effect P = 0.93, age × protein interaction effect P = 0.13). Conclusions Our data suggest that obesity may blunt/abolish the age-related effect of whey protein on suppression of energy intake.

Aims: To determine the effects of the dipeptidyl peptidase-4 inhibitor, sitagliptin, ongastric emptying (GE) of a high-carbohydrate meal and associated glycaemic and blood pressure (BP) responses in type 2 diabetes mellitus (T2DM). Materials and Methods: Fourteen patients with T2DM (nine men, five women; age67.8 ± 1.5 years; body mass index 31.2 ± 0.9 kg/m2; T2DM duration: 4.2 ± 0.9 years; glycated haemoglobin: 46 ± 1.8 mmol/mol [6.4% ± 0.2%]), managed by diet and/or metformin, underwent concurrent measurements of GE, BP and plasma glucose for240 minutes after ingestion of a radio labelled mashed potato meal after receiving sitagliptin (100 mg) or placebo in randomized, double-blind, crossover fashion on2 consecutive days Results: Sitagliptin reduced postprandial plasma glucose (P< .005) without affecting GE (P= .88). The magnitude of the glucose-lowering effect (change in incremental area under the curve 0–240 min from placebo to sitagliptin) was related to GE (kcal/min)on placebo (r= 0.68,P= .008) There was a comparable fall in systolic BP (P= .80) following the meal, with no difference between the 2 days Conclusions: In T2DM, while sitagliptin has no effect on either GE or postprandial BP, its ability to lower postprandial glucose are dependent on the basal rate of GE usc Refereed/Peer-reviewed

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 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 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.

BACKGROUND The Augmented Versus Routine Approach to Giving Energy Trial (TARGET) is the largest blinded enteral nutrition (EN) intervention trial evaluating energy delivery to be conducted in the critically ill. To determine the external validity of TARGET results, nutrition practices in intensive care units (ICUs) in Australia and New Zealand (ANZ) are described and compared with international practices. METHODS This was a retrospective analysis of prospectively collected data for the International Nutrition Surveys, 2007-2013. Data are presented as mean (SD). RESULTS A total of 17,154 patients (ANZ: n = 2776 vs international n = 14,378) from 923 ICUs (146 and 777, respectively) were included. EN was the most common route of feeding (ANZ: 85%, n = 2365 patients vs international: 84%, n = 12,034; P = .258), and EN concentration was also similar (

Objective This study aimed to examine the effects of intermittent fasting (IF) on mRNA levels of peripheral clock genes in skeletal muscle and subcutaneous adipose tissue (SAT) in women with obesity. Methods Women were randomized to one of two IF protocols and provided with all foods at 100% or 70% of calculated weekly energy requirements for 8 weeks. Breakfast was consumed before a 24-hour fast, which was initiated on three nonconsecutive days per week. Muscle and SAT biopsies were performed at 8 am after an overnight fast at baseline and at week 8 on a refed day and again following a 24-hour fast at week 8 for analysis of the mRNA levels of key genes involved in circadian regulation. Results A group-by-time interaction was observed in Per2 in muscle (F = 3.497, P = 0.044) and SAT (F = 6.686, P = 0.008), but significance was lost upon post hoc adjustment. A time effect was observed in Rorα in muscle, which was decreased by refeeding in both groups (F = 7.225, P = 0.003). Conclusions There was no universal effect of IF to alter peripheral clocks, which may be partly because of the alignment of the fasting/feeding cycle with the biological clock. Optimizing intermittent fasting protocols could be important to prevent circadian misalignment in humans.

International audience; Aims: To evaluate the effects of 8 weeks’ administration of exenatide (EXE) once weekly on gastric emptying of solids and liquids (using the “gold standard” technique, scintigraphy), glucose absorption and postprandial glycaemia in healthy people.Material and methods: A total of 32 healthy participants were randomized to receive either EXE once weekly (2 mg/wk subcutaneously; six men, 10 women, mean age 59.9 ± 0.9 years, mean body mass index [BMI] 29.6 ± 0.6 kg/m2) or matching placebo (PBO; six men, 10 women, mean age 60.6 ± 1.2 years, mean BMI 29.5 ± 1.0 kg/m2) for 8 weeks. Gastric emptying, nausea (visual analogue scale), and plasma glucose, insulin, C-peptide and glucagon were measured for 120 min after a solid/liquid meal, comprising 100 g ground beef (radiolabelled with 20 MBq 99mTc-sulphur colloid) and 150 mL 10% glucose (radiolabelled with 7 MBq 67Ga-EDTA), and containing 5 g 3-O-methyl-glucose (3-OMG) as a marker of glucose absorption, at baseline and after 8 weeks’ treatment.Results: The study treatments were well tolerated. Scores for nausea were consistently low, with no difference between the EXE once weekly and PBO groups. EXE once weekly slowed gastric emptying of solids (area under the curve [AUC]0–120min: P

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 &lt, 0.05). The strongest correlations were with the branched-chain AAs as well as lysine, tyrosine, methionine, tryptophan, and aspartic acid (all R2 &gt, 0.52, p &lt, 0.05). Blood glucose did not correlate with any AA (all p &gt, 0.05). Ghrelin and energy intake correlated inversely, but only weakly, with 15/20 AAs (all R2 &lt, 0.34, p &lt, 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.

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.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).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 (CD40Unlike 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.

Background People with type 2 diabetes are advised to consume an even meal distribution of carbohydrate. Whether this distribution is optimal is unknown. Objective Our objective was to show that omitting carbohydrate in the first meal after a fast would lead to an augmented lunch response. Design Two diets of 1-d duration that differed only in the breakfast-meal composition (carbohydrate or no carbohydrate) were consumed on sequential days in a randomized crossover study. The procedure was repeated in the alternate order 1 wk later. Blood glucose concentrations were tested with the use of continuous glucose monitoring. The primary endpoints were the percentage of time spent with a blood glucose concentration >10 mmol/L (%T >10) and peak blood glucose (Gmax). The following 45 adults with type 2 diabetes were recruited: subjects with glycated hemoglobin (HbA1c) ≤7% and subjects with HbA1c ≥8%. Twenty-eight adults completed the study. Results The daily Gmax was significantly lower after the no-carbohydrate breakfast than after the carbohydrate breakfast (11.0 ± 0.4 and 12.1 ± 0.4 mmol/L, respectively; P = 0.003) whereas the %T >10 throughout the day was a nonsignificant 22% less after the no-carbohydrate breakfast than after the carbohydrate breakfast (13% ± 10% compared with 10% ± 8%; P = 0.09). Gmax over 5 h after breakfast was significantly lower after the no-carbohydrate meal (by 1.9 ± 0.4 mmol/L; P 10 was lower after the no-carbohydrate meal than after the carbohydrate meal (11% ± 3% compared with 26% ± 4%, respectively; P Conclusions The withholding of carbohydrate in the first meal results in significantly decreased Gmax after the meal, but the lunch response is not affected. Overall daily control is not significantly improved. This trial was registered at the Australian New Zealand Clinical Trials Registry as ACTRN12609000331235.

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 &lt, 0.001) and distal (p &lt, 0.001) stomach and decreased EI (p &lt, 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 = &minus, 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.

Protein-rich supplements are used commonly to increase energy intake in undernourished older people. This study aimed to establish age effects on energy intake, appetite, gastric emptying, blood glucose, and gut hormones in response to protein-rich drinks. In a randomized double-blind, order, 13 older men (age: 75 &plusmn, 2 yrs, body mass index (BMI): 26 &plusmn, 1 kg/m2) and 13 younger (23 &plusmn, 1 yrs, 24 &plusmn, 1 kg/m2) men consumed (i) a control drink (~2 kcal) or drinks (450 mL) containing protein/fat/carbohydrate: (ii) 70 g/0 g/0 g (280 kcal/&lsquo, P280&prime, ), (iii) 14 g/12.4 g/28 g (280 kcal/&lsquo, M280&prime, ), (iv) 70 g/12.4 g/28 g (504 kcal/&lsquo, M504&prime, ), on four separate days. Appetite (visual analog scales), gastric emptying (3D ultrasonography), blood glucose, plasma insulin, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1) concentrations (0&ndash, 180 min), and ad-libitum energy intake (180&ndash, 210 min) were determined. Older men, compared to younger men, had higher fasting glucose and CCK concentrations and lower fasting GLP-1 concentrations (all p &lt, 0.05). Energy intake by P280 compared to control was less suppressed in older men (increase: 49 &plusmn, 42 kcal) than it was in younger men (suppression: 100 &plusmn, 54 kcal, p = 0.038). After the caloric drinks, the suppression of hunger and the desire to eat, and the stimulation of fullness was less (p &lt, 0.05), and the stimulation of plasma GLP-1 was higher (p &lt, 0.05) in older men compared to younger men. Gastric emptying, glucose, insulin, ghrelin, and CCK responses were similar between age groups. In conclusion, ageing reduces the responses of caloric drinks on hunger, the desire to eat, fullness, and energy intake, and protein-rich nutrition supplements may be an effective strategy to increase energy intake in undernourished older people.

Background The effect of delivering nutrition at different calorie levels during critical illness is uncertain, and patients typically receive less than the recommended amount. Methods We conducted a multicenter, double-blind, randomized trial, involving adults undergoing mechanical ventilation in 46 Australian and New Zealand intensive care units (ICUs), to evaluate energy-dense (1.5 kcal per milliliter) as compared with routine (1.0 kcal per milliliter) enteral nutrition at a dose of 1 ml per kilogram of ideal body weight per hour, commencing at or within 12 hours of the initiation of nutrition support and continuing for up to 28 days while the patient was in the ICU. The primary outcome was all-cause mortality within 90 days. Results There were 3957 patients included in the modified intention-to-treat analysis (1971 in the 1.5-kcal group and 1986 in the 1.0-kcal group). The volume of enteral nutrition delivered during the trial was similar in the two groups; however, patients in the 1.5-kcal group received a mean (±SD) of 1863±478 kcal per day as compared with 1262±313 kcal per day in the 1.0-kcal group (mean difference, 601 kcal per day; 95% confidence interval [CI], 576 to 626). By day 90, a total of 523 of 1948 patients (26.8%) in the 1.5-kcal group and 505 of 1966 patients (25.7%) in the 1.0-kcal group had died (relative risk, 1.05; 95% CI, 0.94 to 1.16; P=0.41). The results were similar in seven predefined subgroups. Higher calorie delivery did not affect survival time, receipt of organ support, number of days alive and out of the ICU and hospital or free of organ support, or the incidence of infective complications or adverse events. Conclusions In patients undergoing mechanical ventilation, the rate of survival at 90 days associated with the use of an energy-dense formulation for enteral delivery of nutrition was not higher than that with routine enteral nutrition. (Funded by National Health and Medical Research Institute of Australia and the Health Research Council of New Zealand; TARGET ClinicalTrials.gov number, NCT02306746 .).

Whey protein, when ingested on its own, load-dependently slows gastric emptying and stimulates gut hormone concentrations in healthy young men. The aim of this study was to determine the effects of substitution, and addition, of carbohydrate (dextrose) and fat (olive oil) to whey protein. In randomized, double-blind order, 13 healthy young men (age: 23 &plusmn, 1 years, body mass index: 24 &plusmn, 1 kg/m2) ingested a control drink (450 mL, ~2 kcal/&lsquo, control&rsquo, ) or iso-volumetric drinks containing protein/carbohydrate/fat: (i) 14 g/28 g/12.4 g (280 kcal/&lsquo, M280&prime, ), (ii) 70 g/28 g/12.4 g (504kcal/&lsquo, M504&prime, ), and (iii) 70 g/0 g/0 g (280 kcal/&lsquo, P280&prime, ), on 4 separate study days. Gastric emptying (n = 11, 3D-ultrasonography), blood glucose, plasma insulin, ghrelin, cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) concentrations (0&ndash, 180 min), appetite (visual analogue scales), and ad-libitum buffet-meal energy intake (180&ndash, 210 min) were determined. Substitution of protein with carbohydrate and fat was associated with faster gastric emptying (lower 50% emptying time (T50)), reduced suppression of ghrelin, and stimulation of GLP-1 (all P &lt, 0.001), while the addition of carbohydrate and fat to protein did not affect gastric emptying or gut hormone responses significantly. Total energy intake (i.e., drink plus meal) was greater after all caloric drinks than control (P &lt, 0.001). In conclusion, substitution of whey protein with dextrose and olive oil accelerated gastric emptying. Higher protein content of a mixed macronutrient drink increased gut hormone and insulin responses.

Protein-rich supplements are used widely for the management of malnutrition in the elderly.We reported previously that the suppression of energy intake by whey protein is less in older than younger adults. The aim was to determine the effects of substitution, and adding of carbohydrate and fat to whey protein, on ad libitum energy intake from a buffet meal (180–210 min), gastric emptying(3D-ultrasonography), plasma gut hormone concentrations (0–180 min) and appetite (visual analogue scales), in healthy older men. In a randomized, double-blind order, 13 older men (75 ± 2 years) ingested drinks (~450 mL) containing: (i) 70 g whey protein (280 kcal; ‘P₂₈₀’); (ii) 14 g protein,28 g carbohydrate, 12.4 g fat (280 kcal; ‘M₂₈₀’); (iii) 70 g protein, 28 g carbohydrate, 12.4 g fat(504 kcal; ‘M₅₀₄’); or (iv) control (~2 kcal). The caloric drinks, compared to a control, did not suppress appetite or energy intake; there was an increase in total energy intake (drink + meal, p < 0.05),which was increased most by the M₅₀₄₋drink. P₂₈₀₋ and M₅₀₄₋drink ingestion were associated with slower a gastric-emptying time (n = 9), lower ghrelin, and higher cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) than M₂₈₀ (p < 0.05). Glucose and insulin were increased most by the mixed-macronutrient drinks (p < 0.05). In conclusion, energy intake was not suppressed, compared to a control, and particularly whey protein, affected gastric emptying and gut hormone responses. usc Refereed/Peer-reviewed

Summary Background & aims Oral intake is diminished immediately after ICU discharge, yet factors affecting nutritional intake after hospital discharge have not been evaluated. The aim of this study was to evaluate dietary intake and factors which may influence intake - appetite and gastric emptying - 3-months after ICU discharge. Methods Inception cohort study with ICU survivors compared to healthy subjects. Following an overnight fast, all participants consumed a standardized carbohydrate drink, containing 13C-octanoic acid, to measure gastric emptying. Dietary intake was assessed by recall of the preceding day and a standard weighed buffet meal 4-h post-drink. Appetite was assessed pre-drink (fasting) and pre- and post-buffet using visual analogue scales. Results Fifty-one ICU survivors (82% male; 70 ± 9 y; BMI 28 ± 6 kg/m2) and 25 healthy subjects (60% male; 67 ± 12 y; BMI 27 ± 4 kg/m2) were evaluated. From the 24-h recall ICU survivors consumed less calories (ICU 1876 (708) vs. healthy subjects 2291 (834) kcal; p = 0.025) with no difference in macronutrient intake, however reported a lower preference for fat (p Conclusions ICU survivors reported less preference for fat and less calorie consumption than healthy subjects. However, intake of calories and macronutrients at a weighed meal was similar in the two groups, as was the rate of gastric emptying. ICU survivors reported being less full after the test meal, suggesting factors other than appetite may influence intake.

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

Aim In healthy subjects, the oral disposition index (ratio of insulin response to insulin sensitivity) is predictive of the development of Type 2 diabetes. Gastric emptying, which exhibits a substantial interindividual variation, is a major determinant of postprandial glycaemia in health and diabetes. We sought to determine whether the rate of intraduodenal glucose delivery affects the disposition index in people without diabetes. Methods Nineteen Caucasian males received glucose infusions via an intraduodenal catheter at either 2 kcal/min (ID2) or 4 kcal/min (ID4) for 120 min, on two separate days with measurements of blood glucose (G) and plasma insulin (I) at frequent intervals. The insulin response was estimated by the ratio of the change in insulin to that of change in glucose at 30 min (∆I0–30/∆G0–30) and 60 min (∆I0–60/∆G0–60). Insulin sensitivity was estimated as 1/fasting insulin. The oral disposition index (DI) was calculated as ∆I0–30/∆G0–30 × 1/fasting insulin and ∆I0–60/∆G0–60 × 1/fasting insulin. Results The overall glycaemic response was comparable on both days, but the insulin response was much greater at ID4 when calculated at either 30 or 60 min (P

Introduction It has been proposed that nutritional therapy in critically ill patients after major burn reduces mortality. However, the actual practice of nutrient delivery, and the effect on outcome, has not been described. Study objectives To evaluate international practices related to nutritional support and outcomes in mechanically ventilated patients with burn injury. Methods Data from the International Nutrition Surveys (2007–2011) for patients with a primary diagnosis of burn were extracted and analysed. Results Eighty-eight of 90 patients (aged 16–84 years) received enteral nutrition. The median time for initiation of enteral feeding was 17 h [range 0–65]. Fifty patients (57%) had interruptions to nutrient delivery, most often these interruptions were fasting for operative procedures. There were substantive energy and protein deficits [943 (654) kcal/day and 49 (41) g/day, respectively; mean (SD)]. Nineteen (21%) patients died within 60 days of admission, and the energy and protein deficits were greater in those that died compared with survivors [died vs. survived, energy: 1251 (742) vs. 861 (607) kcal/d; p = 0.02; and protein 67(42) vs. 44(39) g/d; p = 0.03]. Energy and protein deficits were associated with increased mortality with the greater the deficit, the stronger the association with death (odds ratio for death: energy deficit/100 kcal 1.10 (1.01, 1.19); p = 0.028 and protein/10 g 1.16 (1.01, 1.33); p = 0.037). Results were similar and remained significant after adjusting for severity of illness. Conclusions Mechanically ventilated patients following burn develop substantial energy and protein deficits, with lesser deficits observed in survivors.

usc Postprandial hypotension occurs frequently in diabetes. We show in 9 type 2 patients, that the fall in systolic blood pressure is greater in response to intraduodenal glucose infused at 4 kcal/min than 2 kcal/min, implying that strategies to slow gastric emptying may be effective in the management of postprandial hypotension. Refereed/Peer-reviewed

Objectives While chronic obesity is associated with alterations in circulating glycerolipids, sphingolipids and plasmalogens, the effects of short-term overfeeding in humans are unclear. Design and Methods Healthy individuals (n = 40) were overfed by 1,250 kcal day−1 for 28 days. Insulin sensitivity (hyperinsulinemic-euglycemic clamp), abdominal fat distribution and serum lipidomics (mass spectrometry) were assessed. Results Overfeeding increased liver fat, insulin resistance, serum C-reactive protein and urinary F2-isoprostanes. HDL increased (11% ± 2%, P < 0.001) while LDL, triglycerides and nonesterified fatty acids were unchanged. Three hundred and thirty three serum lipids were detected, of which 13% increased and 20% decreased with overfeeding. Total diacylglycerol and lysoalkylphosphatidylcholine (LPC(O)) concentrations decreased (P < 0.01), while total ceramide, Cer22:0 and Cer24:0 increased (P ≤ 0.01). The most notable increases were observed in the HDL-associated phosphatidylethanolamine-based plasmalogens and their precursors alkylhosphatidylethanolamine (18 ± 5% and 38 ± 8% respectively, P ≤ 0.01). Conclusions Overfeeding led to weight gain and changes in the serum lipid profile. Increases in ceramides were noted, which left unchecked may promote systemic insulin resistance. Uniform increases were observed in plasmalogens and their precursors. Because plasmalogens are powerful antioxidants, this may be an appropriate response against increased oxidative stress generated by over-nutrition. The metabolic consequences of changes in concentrations of many circulating lipid species with overfeeding require further study. Copyright © 2013 The Obesity Society

We have previously identified pyloric pressures and plasma cholecystokinin (CCK) concentrations as independent determinants of energy intake following administration of intraduodenal lipid and intravenous CCK. We evaluated in healthy men whether these parameters also determine energy intake in response to intraduodenal protein, and whether, across the nutrients, any predominant gastrointestinal (GI) factors exist, or many factors make small contributions. Data from nine published studies, in which antropyloroduodenal pressures, GI hormones, and GI /appetite perceptions were measured during intraduodenal lipid or protein infusions, were pooled. In all studies energy intake was quantified immediately after the infusions. Specific variables for inclusion in a mixed‐effects multivariable model for determination of independent predictors of energy intake were chosen following assessment for collinearity, and within‐subject correlations between energy intake and these variables were determined using bivariate analyses adjusted for repeated measures. In models based on all studies, or lipid studies, there were significant effects for amplitude of antral pressure waves, premeal glucagon‐like peptide‐1 (GLP‐1) and time‐to‐peak GLP‐1 concentrations, GLP‐1 AUC and bloating scores (P

Objective: To quantify gallbladder dysfunction during critical illness. Design: Prospective observational comparison study of nutrient-stimulated gallbladder emptying in health and critical illness. Setting: Single-centre mixed medical/surgical ICU. Patients: Twenty-four mechanically ventilated critically ill patients suitable to receive enteral nutrition were compared with 12 healthy subjects. Interventions: Participants were studied after an 8-hour fast. Between 0 and 120 minutes, high-fat nutrient (20% intralipid) was infused via a postpyloric catheter into the duodenum at 2 kcal/min. Measurements and Main Results: Three-dimensional images of the gallbladder were acquired at 30-minute intervals from-30 to 180 minutes. Ejection fraction (%) was calculated as changes between 0 and 120 minutes. Blood samples were obtained at 30-minute intervals for plasma cholecystokinin. Data are mean (sd) or median [interquartile range]. In the critically ill, fasting gallbladder volumes (critically ill, 61 mL [36-100 mL] vs healthy, 22 mL [15-25] mL; p < 0.001] and wall thickness (0.45 mm [0.15 mm] vs 0.26 mm [0.08 mm]; p < 0.001] were substantially greater, and sludge was evident in the majority of patients (71% vs 0%). Nutrient-stimulated emptying was incomplete in the critically ill after 120 minutes but was essentially complete in the healthy individuals (22 mL [9-66 mL] vs 4 mL [3-5 mL]; p < 0.01]. In five critically ill patients (21%), there was no change in gallbladder volume in response to nutrient, and overall ejection fraction was reduced in the critically ill (50% [8-83%] vs 77 [72-84%]; p = 0.01]. There were no differences in fasting or incremental cholecystokinin concentrations. Conclusions: Fasted critically ill patients have larger, thicker-walled gallbladders than healthy subjects and nutrient-stimulated gallbladder emptying is impaired with "gallbladder paresis" occurring in approximately 20%. usc Refereed/Peer-reviewed

Background: Enteral feed intolerance occurs frequently in critically ill patients and can be associated with adverse outcomes. “Energy‐dense formulae” (ie, >1 kcal/mL) are often prescribed to critically ill patients to reduce administered volume and are presumed to maintain or increase calorie delivery. The aim of this study was to compare gastric emptying of standard and energy‐dense formulae in critically ill patients. Methods: In a retrospective comparison of 2 studies, data were analyzed from 2 groups of patients that received a radiolabeled 100‐mL “meal” containing either standard calories (1 kcal/mL) or concentrated calories (energy‐dense formulae; 2 kcal/mL). Gastric emptying was measured using a scintigraphic technique. Radioisotope data were collected for 4 hours and gastric emptying quantified. Data are presented as mean ± SE or median [interquartile range] as appropriate. Results: Forty patients were studied (n = 18, energy‐dense formulae; n = 22, standard). Groups were well matched in terms of demographics. However, patients in the energy‐dense formula group were studied earlier in their intensive care unit admission (P = .02) and had a greater proportion requiring inotropes (P = .002). A similar amount of calories emptied out of the stomach per unit time (P = .57), but in patients receiving energy‐dense formulae, a greater volume of meal was retained in the stomach (P = .045), consistent with slower gastric emptying. Conclusions: In critically ill patients, the administration of the same volume of a concentrated enteral nutrition formula may not result in the delivery of more calories to the small intestine over time because gastric emptying is slowed. usc Refereed/Peer-reviewed

Background: Inflammatory bowel disease (IBD) is a chronic disease requiring long-term management. General practitioners (GPs) are often the first point of contact for initial symptoms and flares. Thus we assessed GPs' attitudes to and knowledge of IBD. Methods: A state-wide postal survey of GPs was performed collecting demographic details, practice and attitudes in IBD-specific management and knowledge. Results: Of 1800 GPs surveyed in South Australia, 409 responded; 58% were male, 80% Australian trained and 73% practised in metropolitan areas. Most GPs (92%) reported seeing zero to five IBD patients per month. Overall, 37% of the GPs reported being generally ‘uncomfortable’ with IBD management. Specifically, they were only somewhat comfortable in providing/using maintenance therapy, steroid therapy or unspecified therapy for an acute flare. They were uncomfortable with the use of immunomodulators and biologicals (71 and 91% respectively). No GP reported never referring, referring sometimes (12%), often (34%) or always (55%). Most (87%) GPs rated their communication with private specialists positively; while only 32% were satisfied with support from public hospitals. Of concern, most (70%) monitored patients on immunosuppression on a case-by-case basis rather than by protocol. In multivariable analyses, GPs' IBD-specific knowledge did not influence comfort with overall management, nor did knowledge influence GP comfort with any particular therapy. Conclusion: Individual GPs care for few IBD patients and have variable attitudes in their practice. Whether improvement can realistically be achieved given individual GP's paucity of patients is questionable. These data support the provision of better support and specific action plans for IBD patients.

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

The postprandial reduction in blood pressure (BP) is triggered by the interaction of nutrients with the small intestine and associated with an increase in splanchnic blood flow. Gastric distension may attenuate the postprandial fall in BP. The aim of this study was to determine the effects of differences in intragastric volume, including distension at a low (100 ml) volume, on BP and superior mesenteric artery (SMA) blood flow responses to intraduodenal glucose in healthy older subjects. BP and heart rate (HR; automated device), SMA blood flow (Doppler ultrasound), mesenteric vascular resistance (MVR), and plasma norepinephrine of nine male subjects (65–75 yr old) were measured after an overnight fast on 4 separate days in random order. On each day, subjects were intubated with a nasoduodenal catheter, incorporating a duodenal infusion port, and orally with a second catheter, incorporating a barostat bag, positioned in the fundus. Each subject received a 60-min ( t = 0–60 min) intraduodenal glucose infusion (3 kcal/min) and gastric distension at a volume of 1) 0 ml (V0), 2) 100 ml (V100), 3) 300 ml (V300), or 4) 500 ml (V500). Systolic BP fell ( P < 0.05) during V0, but not during V100, V300, or V500. In contrast, HR ( P < 0.01) and SMA blood flow ( P < 0.001) increased and MVR decreased ( P < 0.05) comparably on all 4 days. Plasma norepinephrine rose ( P < 0.01) in response to intraduodenal glucose, with no difference between the four treatments. There was a relationship between the areas under the curve for the change in systolic BP from baseline with intragastric volume ( r = 0.60, P < 0.001). In conclusion, low-volume (≤100 ml) gastric distension has the capacity to abolish the fall in BP induced by intraduodenal glucose in healthy older subjects without affecting SMA blood flow or MVR. These observations support the concept that nonnutrient gastric distension prior to a meal has potential therapeutic applications in the management of postprandial hypotension.

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/m2, 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.

East Asians appear to secrete less insulin than Caucasians following oral glucose suggesting that impaired insulin secretion is fundamental to the pathogenesis of type 2 diabetes [1]. Information about the secretion of the incretin hormones, GIP and GLP-1, dependent on duodenal glucose load [2], in East Asians is limited [3]. We have evaluated glycemic, insulinemic and incretin hormone responses to intraduodenal glucose in healthy Han Chinese. We studied eleven Han Chinese (HC) and eight Caucasian (C) healthy men; the latter included in a previous study [2]. Each subject attended following an overnight fast. A catheter, incorporating an infusion channel opening 12 cm beyond the pylorus, was inserted intranasally [2]. An IV cannula was placed in an antecubital vein. Intraduodenal (ID) glucose (25 g/100 mL) was infused at 4 kcal/min from t = 0 to 120 min. Blood was collected at t = 0, 15, 30, 45, 60, 90, 105 and 120 min for measurements of blood glucose, plasma insulin, GIP and GLP-1. Insulin secretion was estimated as the change in insulin divided by the change in glucose at 30 min (∆I0–30/∆G0–30). Insulin sensitivity was estimated as 1/fasting insulin. The disposition index (DIO) was calculated as ∆I0–30/∆G0–30X 1/fasting insulin. Unpaired Student’s t test was used in analysis. Han Chinese younger than Caucasians (24.8 ± 1.3 HC vs. 45.3 ± 3.8 C years, P

Purpose: To define specific medical conditions associated with clinically significant depressive symptoms in men. Methods: A cross-sectional study was conducted in a community-based sample of Australian men (N = 1,195, aged 35–80 years; for 2002–2005). Depression was defined by: (1) symptomatic depression (current symptoms) or (2) current prescription for antidepressant(s) or (3) previously diagnosed depression. Logistic regression was used to determine prevalence odds ratios (OR) for depression independently associated with an extensive range of demographic, lifestyle, and clinical factors. Adjusted population attributable risk (PAR%) estimates were also computed. Results: Depression was significantly (ORs at P < 0.05) associated with previously diagnosed anxiety (12.0) and insomnia (4.4), not married (1.7), current smoker (1.7), low muscle strength tertile (1.7, P = 0.059), high triglycerides (1.6), high storage lower urinary tract symptoms (LUTS) tertile (1.8), past year general practitioner visits 5–9 (1.9), middle energy density tertile (0.4), and high systolic blood pressure (0.5). Significant PAR% estimates (at P < 0.05) were for previous anxiety (27.0%) and insomnia (16.1%), middle energy density tertile (−17.2%), high SBP (−23.5%), high triglycerides (15.2%), and high storage LUTS tertile (12.6%). Results strengthened when depression-related factors (previous anxiety and insomnia, psycholeptics, and cognition) were omitted, and became significant for CVD (OR 1.6; PAR 13.9%). Conclusions: Medical conditions associated with depression in men include high triglycerides, low muscle strength, CVD, and LUTS. Depressed men are likely to use health services frequently, be current smokers, not be married, eat unhealthily, and report previous diagnosis of anxiety and insomnia; which has important implications for clinicians managing male patients. Refereed/Peer-reviewed

Summary Background and aims Isotope breath tests are increasingly used to evaluate the effects of prokinetic drugs on gastric emptying. The aim was to assess intrasubject variability in gastric emptying, when using an isotope breath test in the critically ill. Methods A retrospective analysis of data was undertaken in 12 patients who had gastric emptying measurements on consecutive days using a 13 C-octanoic acid breath test. The gastric emptying coefficient – GEC (a global index for the gastric emptying rate), and the t 50 (calculated time for 50% of meal to empty) were calculated, together with the coefficient of variability for these parameters. Data are mean (SD). Results Neither GEC (day 1: 3.3 (0.8) vs. day 2: 3.1 (0.6); P = 0.31) nor t 50 (day 1: 127 (43) min vs. day 2: 141 (48) min; P = 0.46) were significantly different between the two days. Intrasubject variability was less for GEC (15.6%) than for t 50 (31.8%). Conclusion There is only modest intrasubject variability in GEC measurements using the 13 C-octanoic acid breath test in critically ill patients. As such, it may be an acceptable measurement tool to assess the effects of prokinetic drugs in this group.

Background and Aim: A significant proportion with inflammatory bowel disease (IBD) exhibit an adverse clinical phenotype reflected in endpoints like surgery and hospitalizations. We sought to identify clinico-demographic factors associated with these adverse consequences that may be amenable to change. Methods: Over 6 months IBD patients visiting a metropolitan center were prospectively identified and given a comprehensive survey addressing patient knowledge, mental health and satisfaction with medical care along with other clinical data. Logistic regression analyses assessed for associations between clinico-demographic variables and adverse clinical endpoints (previous surgery [ever] and/or recent inpatient admission over a 16 month observation period). Results: Of 256 IBD patients, 162 responded (response rate 63%); 95 (59%) had Crohn's disease (CD), 63 (40%) ulcerative colitis (UC), four indeterminate colitis; 53% were female. Factors associated with a greater likelihood of hospitalization included moderate/severe disease activity, psychological co-morbidity, numbers of medications and outpatient visits (odds ratio [OR] 7.09 [2.83–17.76], 4.13 [1.25–13.61], 1.26 [1.03–1.54], 1.17 [1.00–1.37] respectively; all P

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.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.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.In healthy individuals, pulsatile and continuous administration of i.v. GLP-1 appears to have comparable insulinotropic effects.ACTRN12612001040853 FUNDING: This study was supported by the National Health and Medical Research Council (NHMRC) of Australia.

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.

BACKGROUND Critically ill patients typically receive ∼60% of estimated calorie requirements. OBJECTIVES We aimed to determine whether the substitution of a 1.5-kcal/mL enteral nutrition solution for a 1.0-kcal/mL solution resulted in greater calorie delivery to critically ill patients and establish the feasibility of conducting a multicenter, double-blind, randomized trial to evaluate the effect of an increased calorie delivery on clinical outcomes. DESIGN A prospective, randomized, double-blind, parallel-group, multicenter study was conducted in 5 Australian intensive care units. One hundred twelve mechanically ventilated patients expected to receive enteral nutrition for ≥2 d were randomly assigned to receive 1.5 (n = 57) or 1.0 (n = 55) kcal/mL enteral nutrition solution at a rate of 1 mL/kg ideal body weight per hour for 10 d. Protein and fiber contents in the 2 solutions were equivalent. RESULTS The 2 groups had similar baseline characteristics (1.5 compared with 1.0 kcal/mL). The mean (±SD) age was 56.4 ± 16.8 compared with 56.5 ± 16.1 y, 74% compared with 75% were men, and the Acute Physiology and Chronic Health Evaluation II score was 23 ± 9.1 compared with 22 ± 8.9. The groups received similar volumes of enteral nutrition solution [1221 mL/d (95% CI: 1120, 1322 mL/d) compared with 1259 mL/d (95% CI: 1143, 1374 mL/d); P = 0.628], which led to a 46% increase in daily calories in the group given the 1.5-kcal/mL solution [1832 kcal/d (95% CI: 1681, 1984 kcal/d) compared with 1259 kcal/d (95% CI: 1143, 1374 kcal/d); P < 0.001]. The 1.5-kcal/mL solution was not associated with larger gastric residual volumes or diarrhea. In this feasibility study, there was a trend to a reduced 90-d mortality in patients given 1.5 kcal/mL [11 patients (20%) compared with 20 patients (37%); P = 0.057]. CONCLUSIONS The substitution of a 1.0- with a 1.5-kcal/mL enteral nutrition solution administered at the same rate resulted in a 46% greater calorie delivery without adverse effects. The results support the conduct of a large-scale trial to evaluate the effect of increased calorie delivery on clinically important outcomes in the critically ill.

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