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BACKGROUND In preclinical studies, bitter compounds, including quinine, stimulate secretion of glucoregulatory hormones [e.g., glucagon-like peptide-1 (GLP-1)] and slow gastric emptying, both key determinants of postprandial glycemia. A greater density of bitter-taste receptors has been reported in the duodenum than the stomach. Thus, intraduodenal (ID) delivery may be more effective in stimulating GI functions to lower postprandial glucose. OBJECTIVE We compared effects of intragastric (IG) and ID quinine [as quinine hydrochloride (QHCl)] administration on the plasma glucose response to a mixed-nutrient drink and relations with gastric emptying, plasma C-peptide (reflecting insulin secretion), and GLP-1. METHODS Fourteen healthy men [mean ± SD age: 25 ± 3 y; BMI (in kg/m2): 22.5 ± 0.5] received, on 4 separate occasions, in double-blind, randomly assigned order, 600 mg QHCl or control, IG or ID, 60 min (IG conditions) or 30 min (IG conditions) before a mixed-nutrient drink. Plasma glucose (primary outcome) and hormones were measured before, and for 2 h following, the drink. Gastric emptying of the drink was measured using a 13C-acetate breath test. Data were analyzed using repeated-measures 2-way ANOVAs (factors: treatment and route of administration) to evaluate effects of QHCl alone and 3-way ANOVAs (factors: treatment, route-of-administration, and time) for responses to the drink. RESULTS After QHCl alone, there were effects of treatment, but not route of administration, on C-peptide, GLP-1, and glucose (P

BACKGROUND Postprandial falls in blood pressure (BP) are more common in older compared to younger individuals. The effects of protein compared to carbohydrates and fat on postprandial BP, and the relation to gastric emptying rates, are poorly studied. OBJECTIVES To determine the effects of a whey protein compared to a control drink on systolic BP (SBP) and diastolic BP (DBP), and heart rate (HR) in healthy younger and older men, and to relate these effects to gastric emptying. DESIGN A pooled analyses of two randomized, double-blind, cross-over studies. SETTING Two acute clinical intervention studies with identical study design. PARTICIPANTS Nineteen older (age: 74 ± 1 years, body mass index: 26 ± 1 kg/m2 ) and 13 younger (23 ± 1 years, 24 ± 1 kg/m2 ) healthy men. INTERVENTION A 70 g/280 kcal whey-protein or control (water with diet cordial, ~2 kcal) drink (450 ml). MEASUREMENTS BP and HR were assessed with an automated device immediately before and at 3-min intervals after drink ingestion (0-180 min). Gastric emptying of the drinks was measured using 3D ultrasonography (0-180 min). RESULTS Older versus younger men exhibited a greater fall in SBP (-23 ± 2 vs -15 ± 2 mmHg, p = 0.001) after whey-protein versus control, as BP did not change after the two drinks in younger men (p > 0.05). The nadir in SBP occurred later in the older than younger men (114 ± 11 vs 62 ± 14 min; p

OBJECTIVES: There is very limited information about glycemic control after discharge from the ICU. The aims of this study were to evaluate the prevalence of hypoglycemia in ICU survivors with type-2 diabetes and determine whether hypoglycemia is associated with cardiac arrhythmias. DESIGN: Prospective, observational, two-center study. Participants underwent up to 5 days of simultaneous blinded continuous interstitial glucose monitoring and ambulatory 12-lead electrocardiogram monitoring immediately after ICU discharge during ward-based care. Frequency of arrhythmias, heart rate variability, and cardiac repolarization markers were compared between hypoglycemia (interstitial glucose ≤ 3.5 mmol/L) and euglycemia (5-10 mmol/L) matched for time of day. SETTING: Mixed medical-surgical ICUs in two geographically distinct university-affiliated hospitals. PATIENTS: Patients with type-2 diabetes who were discharged from ICU after greater than or equal to 24 hours with greater than or equal to one organ failure and were prescribed subcutaneous insulin were eligible. MEASUREMENTS AND MAIN RESULTS: Thirty-one participants (mean ± sd, age 65 ± 13 yr, glycated hemoglobin 64 ± 22 mmol/mol) were monitored for 101 ± 32 hours post-ICU (total 3,117 hr). Hypoglycemia occurred in 12 participants (39%; 95% CI, 22-56%) and was predominantly nocturnal (40/51 hr) and asymptomatic (25/29 episodes). Participants experiencing hypoglycemia had 2.4 ± 0.7 discrete episodes lasting 45 minutes (interquartile range, 25-140 min). Glucose nadir was less than or equal to 2.2 mmol/L in 34% of episodes. The longest episode of nocturnal hypoglycemia was 585 minutes with glucose nadir less than 2.2 mmol/L. Simultaneous electrocardiogram and continuous interstitial glucose monitoring recordings were obtained during 44 hours of hypoglycemia and 991 hours of euglycemia. Hypoglycemia was associated with greater risk of bradycardia but did not affect atrial or ventricular ectopics, heart rate variability, or cardiac repolarization. CONCLUSIONS: In ICU survivors with insulin-treated type-2 diabetes, hypoglycemia occurs frequently and is predominantly nocturnal, asymptomatic, and prolonged.

Background Follow-up clinics after ICU admission have demonstrated limited benefit. However, existing trials have evaluated heterogeneous cohorts and used physicians who had limited training in outpatient care. Research Question What are the effects of a “shared-care” intensivist-endocrinologist clinic for ICU survivors with type 2 diabetes on process measures and clinical outcomes 6 months after hospital discharge, and is it feasible to conduct a larger trial? Study Design and Methods This was a prospective, randomized, single-center pilot study with blinded outcome assessment. Patients with type 2 diabetes, who required ≥ 5 days of ICU care (mixed medical-surgical ICU) and survived to ICU discharge, were eligible. Participants were randomized to attendance at the shared-care clinic 1 month after hospital discharge or usual care. Six months after hospital discharge, participants were assessed for outcomes including glycated hemoglobin, neuropathy, nephropathy, quality of life, return to employment, frailty, and health-care use. The primary outcome was participant recruitment and retention. Results During an 18-month period, 42 of 82 eligible patients (51%) were recruited. Four participants (10%) withdrew before assessment at 6 months and 11 (26%) died. At 6 months, only 18 of 38 participants who did not withdraw (47%) were living independently without support, and 24 (63%) required at least one subsequent hospital admission. In the intervention group (n = 21), 16 (76%) attended the clinic. Point estimates did not indicate that the intervention improved glycated hemoglobin (+5.6 mmol/mol; 95% CI, –6.3 to 17; P = .36) or quality of life (36-Item Short Form Survey physical summary score, 32 [9] vs. 32 [7]; P = 1.0). Interpretation Outcomes for ICU survivors with type 2 diabetes are poor. Because of low participation and high mortality, a larger trial of a shared-care follow-up clinic in this cohort, using the present design, does not appear feasible. Trial Registry Australian New Zealand Clinical Trials Registry (ANZCTR); No.: ACTRN12616000206426; URL: www.anzctr.org.au

Purpose To assess the potential of a transfer learning strategy leveraging radiologist supervision to enhance convolutional neural network-based (CNN) localization of pneumonia on radiographs and to further assess the prognostic value of CNN severity quantification on patients evaluated for COVID-19 pneumonia, for whom severity on the presenting radiograph is a known predictor of mortality and intubation. Materials and methods We obtained an initial CNN previously trained to localize pneumonia along with 25,684 radiographs used for its training. We additionally curated 1466 radiographs from patients who had a computed tomography (CT) performed on the same day. Regional likelihoods of pneumonia were then annotated by cardiothoracic radiologists, referencing these CTs. Combining data, a preexisting CNN was fine-tuned using transfer learning. Whole-image and regional performance of the updated CNN was assessed using receiver-operating characteristic area under the curve and Dice. Finally, the value of CNN measurements was assessed with survival analysis on 203 patients with COVID-19 and compared against modified radiographic assessment of lung edema (mRALE) score. Results Pneumonia detection area under the curve improved on both internal (0.756 to 0.841) and external (0.864 to 0.876) validation data. Dice overlap also improved, particularly in the lung bases (R: 0.121 to 0.433, L: 0.111 to 0.486). There was strong correlation between radiologist mRALE score and CNN fractional area of involvement (ρ=0.85). Survival analysis showed similar, strong prognostic ability of the CNN and mRALE for mortality, likelihood of intubation, and duration of hospitalization among patients with COVID-19. Conclusions Radiologist-supervised transfer learning can enhance the ability of CNNs to localize and quantify the severity of disease. Closed-loop systems incorporating radiologists may be beneficial for continued improvement of artificial intelligence algorithms.

What determines whether countries pursue and obtain armed drones? Using an original time-series dataset, we conduct the first comprehensive analysis of armed drone proliferation from 1994 to 2019. We theorize and find evidence that security threats—like terrorism—are not the only factors driving proliferation. Regime type also has a significant effect, but it varies over time. From 1994 to 2010 regime type had no significant effect. However, non-democracies became significantly more likely to pursue and obtain armed drones from 2011 to 2019 owing to China’s entrance into the drone export market, which asymmetrically eased supply-side constraints for non-democracies. We also find that status-seeking states are more likely to pursue armed drones. Our results contribute to the broader academic literature on proliferation by demonstrating how supply shocks can lead to changes in proliferation trends over time and lending further credence to the importance of prestige in international politics.

Aims Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are the recommended first injectable therapy in type 2 diabetes. However, long-term persistence is suboptimal, and partly attributable to gastrointestinal tolerability, particularly during initiation/escalation. Gradual titration of fixed-ratio combination GLP-1 RA/insulin therapies may improve GLP-1 RA gastrointestinal tolerability. We compared gastrointestinal adverse event (AE) rates for iGlarLixi versus GLP-1 RAs during the first 12 weeks of therapy, including a sensitivity analysis with IDegLira. Materials and methods The PICO framework was used to identify studies from MEDLINE, Embase, and CENTRAL searches using a proprietary, web-based, standardised tool with single data extraction. Gastrointestinal AEs were modelled using a Bayesian network meta-analysis (NMA), using fixed and random effects for each recommended dose (treatment-specific NMA) and class (drug-class NMA). Results Treatment-specific NMA included 17 trials (n=9030; 3665 event-weeks). Nausea rates were significantly lower with iGlarLixi versus exenatide 10 mcg twice-daily (rate ratio: 0.32; 95% credible interval: 0.15, 0.66), once-daily lixisenatide 20 mcg (0.35; 0.24, 0.50), and liraglutide 1.8 mg once-daily (0.48; 0.23, 0.98). Rates were numerically, but not statistically, lower versus once-weekly semaglutide 1 mg (0.60; 0.30, 1.23) and dulaglutide 1.5 mg (0.60; 0.29, 1.26), and numerically, but not statistically, higher versus once-weekly exenatide (1.91; 0.91, 4.03). Sensitivity analysis results were similar. In a naive pooled analysis, vomiting was lower with iGlarLixi versus other GLP-1 RAs. Conclusions During the first 12 weeks of treatment, iGlarLixi was generally associated with less nausea and vomiting than single-agent GLP-1 RAs. Enhanced gastrointestinal tolerability with fixed-ratio combinations may favour treatment persistence. This article is protected by copyright. All rights reserved.

BACKGROUND: Contemporary glucose management of intensive care unit (ICU) patients with type 2 diabetes is based on trial data derived predominantly from patients without type 2 diabetes. This is despite the recognition that patients with type 2 diabetes may be relatively more tolerant of hyperglycaemia and more susceptible to hypoglycaemia. It is uncertain whether glucose targets should be more liberal in patients with type 2 diabetes. OBJECTIVE: To detail the protocol, analysis and reporting plans for a randomised clinical trial — the Liberal Glucose Control in Critically Ill Patients with Pre-existing Type 2 Diabetes (LUCID) trial — which will evaluate the risks and benefits of targeting a higher blood glucose range in patients with type 2 diabetes. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: A multicentre, parallel group, open label phase 2B randomised controlled clinical trial of 450 critically ill patients with type 2 diabetes. Patients will be randomised 1:1 to liberal blood glucose (target 10.0–14.0 mmol/L) or usual care (target 6.0–10.0 mmol/L). MAIN OUTCOME MEASURES: The primary endpoint is incident hypoglycaemia (< 4.0 mmol/L) during the study intervention. Secondary endpoints include biochemical and feasibility outcomes. RESULTS AND CONCLUSION: The study protocol and statistical analysis plan described will delineate conduct and analysis of the trial, such that analytical and reporting bias are minimised. TRIAL REGISTRATION: This trial has been registered on the Australian New Zealand Clinical Trials Registry (ACTRN No. 12616001135404) and has been endorsed by the Australian and New Zealand Intensive Care Society Clinical Trials Group.

Rationale: The long-term effects of delivering approximately 100% of recommended calorie intake via the enteral route during critical illness compared with a lesser amount of calories are unknown.O...

OBJECTIVE: Postprandial hypotension occurs frequently in older survivors of critical illness at 3 months after discharge. We aimed to determine whether postprandial hypotension and its predictors — gastric dysmotility and cardiovascular autonomic dysfunction — persist or resolve as older survivors of critical illness recover, and whether postprandial hypotension after intensive care unit (ICU) discharge is associated with adverse outcomes at 12 months. DESIGN: Prospective observational study. SETTING: Tertiary medical–surgical ICU. PARTICIPANTS: Older adults (aged > 65 years) who had been studied 3 months after ICU discharge and who returned for a follow-up study at 12 months after discharge. MAIN OUTCOME MEASURES: On both occasions after fasting overnight, participants consumed a 300 mL drink containing 75 g glucose, radiolabelled with 20 MBq 99mTcphytate. Blood pressure, heart rate, blood glucose concentration and gastric emptying rate were measured concurrently before and after ingestion of the drink. Falls, quality of life, hospitalisation and mortality rates were also quantified. RESULTS: Out of 35 older adults studied at 3 months, 22 returned for the follow-up study at 12 months. Postprandial hypotension was evident in 29% of participants (95% CI, 14–44%) at 3 months and 10% of participants (95% CI, 1–30%) at 12 months. Postprandial hypotension at 3 months was associated with a more than threefold increase in the risk of falls in the year after ICU discharge (relative risk, 3.7 [95% CI, 1.6–8.8]; P = 0.003). At 12 months, gastric emptying was normal (mean time taken for 50% of gastric contents to empty, 101.6 [SD, 33.3] min) and cardiovascular autonomic dysfunction prevalence was low (9% [95% CI, 1–29%]). CONCLUSIONS: In older adults who were evaluated 3 and 12 months after ICU discharge, postprandial hypotension at 3 months was associated with an increased risk of subsequent falls, but the prevalence of postprandial hypotension decreased with time.

Glucose-dependent insulinotropic polypeptide (GIP) is released primarily from the proximal small intestine and glucagon-like peptide-1 (GLP-1) from the more distal small intestine and colon. Their relative importance to the incretin effect in health has been contentious in the past, although it now appears that GIP has the dominant role. It is uncertain whether there is a relationship between GIP and GLP-1 secretion. We aimed to evaluate the relationship between plasma GIP and GLP-1 responses to a 75-g oral glucose load in individuals with normal (NGT) and impaired glucose tolerance (IGT). One hundred healthy subjects had measurements of blood glucose, serum insulin, plasma GIP and GLP-1 concentrations for 240 min after a 300 mL drink containing 75 g glucose. Fifty had NGT and 41 IGT; 9 had type 2 diabetes and were excluded from analysis. In both groups, there were increases in plasma GIP and GLP-1 following the glucose drink, with no difference in the magnitude of the responses between t = 0–240 min. There was a weak relationship between the iAUC0–240 min for GIP and GLP-1 in the combined (r = 0.23, P = 0.015) and in the IGT (r = 0.34, P = 0.01), but not in the NGT (r = 0.15, P = 0.14) group. There is a weak relationship between oral glucose-induced GIP and GLP-1 secretions in non-diabetic subjects.

Background and aims: Whey protein and guar gum have both been reported to reduce postprandial glycemia in health and type 2 diabetes, associated with stimulation of glucagon-like peptide-1 (GLP-1) and/or slowing of gastric emptying. Our aim was to evaluate, in type 2 diabetes, the acute effects of low dose “preloads” of whey and guar, given alone or in combination before a meal, on postprandial glycemia, insulin, GLP-1, and gastric emptying. Methods: 21 patients with type 2 diabetes, managed by diet or metformin alone, were each studied on 4 days. They received a preload “shake” 15min before a mashed potato meal (368.5 kcal) labeled with 13C-octanoic-acid. The preloads comprised either (i) 17 g whey (W), (ii) 5 g guar (G), (iii) 17 g whey + 5 g guar (WG) each sweetened with 60 mg sucralose, and (iv) 60 mg sucralose alone (control; C), all dissolved in 150 mL water. Venous blood was sampled frequently for measurements of glucose, insulin, and GLP-1 concentrations. Gastric half-emptying time (T50) was calculated from breath 13CO2 excretion over 240 min. Results: Postprandial blood glucose concentrations were lower with W and WG compared to C (each P < 0.0001, treatment × time interaction), and lower after G than C only at 30min. Insulin, GLP-1, and glucagon concentrations were higher after W than WG, G, or C (P < 0.05, treatment × time interaction), without differences between the latter three. Gastric emptying was slower with W (T50: 179.6 ± 6.1 min, P < 0.05) and WG (T50: 197.6 ± 9.7 min, P < 0.0001) when compared to C (T50: 162.9 ± 6.2 min), but did not differ between G (T50: 171.3 ± 7.0) and C (P > 0.99). Conclusion: Both whey and whey/guar preloads reduced postprandial glycemia, associated with slowing of gastric emptying. Low dose guar was less effective as a preload for glucose-lowering and did not slow gastric emptying usc Refereed/Peer-reviewed

We read with interest the study by Rosenstock et al. (1), which demonstrates that in patients with type 2 diabetes managed on a basal-bolus insulin regimen, switching three prandial insulin injections for a long-acting glucagon-like peptide 1 receptor agonist (GLP-1RA), albiglutide, while maintaining the basal insulin, represents an effective strategy for optimizing glycemic control with reduced risks of hypoglycemia and weight gain along with increased convenience. In the cohort studied, baseline glycated hemoglobin levels were 7.8 ± 0.6% (albiglutide group) and 7.7 ± 0.6% (placebo group), indicating that in many participants, postprandial glycemic excursions were the dominant contributor of hyperglycemia. Achieving good glycemic control in those patients would, …

Context Both gastric emptying and the secretion of glucagon-like peptide-1 (GLP-1) are major determinants of postprandial glycemia in health and type 2 diabetes (T2D). GLP-1 secretion after a meal is dependent on the entry of nutrients into the small intestine, which, in turn, slows gastric emptying. Objective To define the relationship between gastric emptying and the GLP-1 response to both oral and small intestinal nutrients in subjects with and without T2D. Methods We evaluated: (i) the relationship between gastric emptying (breath test) and postprandial GLP-1 levels after a mashed potato meal in 73 individuals with T2D; (ii) inter-individual variations in GLP-1 response to (a) intraduodenal glucose (4 kcal/min) during euglycemia and hyperglycemia in 11 healthy and 12 T2D, subjects, (b) intraduodenal fat (2 kcal/min) in 15 T2D subjects, and (c) intraduodenal protein (3 kcal/min) in 10 healthy subjects; and (iii) the relationship between gastric emptying (breath test) of 75 g oral glucose and the GLP-1 response to intraduodenal glucose (4 kcal/min) in 21 subjects (9 healthy, 12 T2D). Results The GLP-1 response to the mashed potato meal was unrelated to the gastric half-emptying time (T50). The GLP-1 responses to intraduodenal glucose, fat, and protein varied substantially between individuals, but intra-individual variation to glucose was modest. The T50 of oral glucose was related directly to the GLP-1 response to intraduodenal glucose (r = 0.65, P = 0.002). Conclusion In a given individual, gastric emptying is not a determinant of the postprandial GLP-1 response. However, the intrinsic gastric emptying rate is determined in part by the responsiveness of GLP-1 to intestinal nutrients.

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

Machine learning (ML) and artificial intelligence (AI) researchers play an important role in the ethics and governance of AI, including taking action against what they perceive to be unethical uses of AI (Belfield, 2020; Van Noorden, 2020). Nevertheless, this influential group's attitudes are not well understood, which undermines our ability to discern consensuses or disagreements between AI/ML researchers. To examine these researchers' views, we conducted a survey of those who published in the top AI/ML conferences (N = 524). We compare these results with those from a 2016 survey of AI/ML researchers (Grace, Salvatier, Dafoe, Zhang, & Evans, 2018) and a 2018 survey of the US public (Zhang & Dafoe, 2020). We find that AI/ML researchers place high levels of trust in international organizations and scientific organizations to shape the development and use of AI in the public interest; moderate trust in most Western tech companies; and low trust in national militaries, Chinese tech companies, and Facebook. While the respondents were overwhelmingly opposed to AI/ML researchers working on lethal autonomous weapons, they are less opposed to researchers working on other military applications of AI, particularly logistics algorithms. A strong majority of respondents think that AI safety research should be prioritized and that ML institutions should conduct pre-publication review to assess potential harms. Being closer to the technology itself, AI/ML re-searchers are well placed to highlight new risks and develop technical solutions, so this novel attempt to measure their attitudes has broad relevance. The findings should help to improve how researchers, private sector executives, and policymakers think about regulations, governance frameworks, guiding principles, and national and international governance strategies for AI.

MRI is an essential diagnostic tool in the anatomic and functional evaluation of cardiovascular disease. In many practices, 2D phase-contrast (2D-PC) MRI has been used for blood flow quantification. Four-dimensional flow MRI is a time-resolved volumetric acquisition that captures the vector field of blood flow along with anatomic images. It also provides a simpler acquisition compared with 2D-PC and facilitates a more accurate and comprehensive hemodynamic assessment. Advancements in accelerated imaging have significantly shortened scanning times for 4D flow MRI while preserving image quality, enabling this technology to transition from the research arena to routine clinical practice. In this article, we review technical optimization based on our more than 10 years of clinical experience with 4D flow MRI. We also present pearls and pitfalls in the practical application of 4D flow MRI, including how to quantify cardiovascular shunts, valvular or vascular stenosis, and valvular regurgitation. As experience increases, and as 4D flow sequences and postprocessing software become more broadly available, 4D flow MRI will likely become an essential component of cardiac imaging in practices involved in the management of congenital and acquired structural heart disease.

While the applications of artificial intelligence (AI) for militaries are broad, lethal autonomous weapon systems (LAWS) represent one possible usage of narrow AI by militaries. Research an...

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

OBJECTIVES: Stress hyperglycemia occurs in critically ill patients and may be a risk factor for subsequent diabetes. The aims of this study were to determine incident diabetes and prevalent prediabetes in survivors of critical illness experiencing stress hyperglycemia and to explore underlying mechanisms. DESIGN: This was a prospective, single center, cohort study. At admission to ICU, hemoglobin A1c was measured in eligible patients. Participants returned at 3 and 12 months after ICU admission and underwent hemoglobin A1c testing and an oral glucose tolerance test. Blood was also collected for hormone concentrations, whereas gastric emptying was measured via an isotope breath test. β-cell function was modeled using standard techniques. SETTING: Tertiary-referral, mixed medical-surgical ICU. PATIENTS: Consecutively admitted patients who developed stress hyperglycemia and survived to hospital discharge were eligible. MEASUREMENTS AND MAIN RESULTS: Consent was obtained from 40 patients (mean age, 58 yr [SD, 10], hemoglobin A1c 36.8 mmol/mol [4.9 mmol/mol]) with 35 attending the 3-month and 26 the 12-month visits. At 3 months, 13 (37%) had diabetes and 15 (43%) had prediabetes. At 12 months, seven (27%) participants had diabetes, whereas 11 (42%) had prediabetes. Mean hemoglobin A1c increased from baseline during the study: +0.7 mmol/mol (-1.2 to 2.5 mmol/mol) at 3 months and +3.3 mmol/mol (0.98-5.59 mmol/mol) at 12 months (p = 0.02). Gastric emptying was not significantly different across groups at either 3 or 12 months. CONCLUSIONS: Diabetes and prediabetes occur frequently in survivors of ICU experiencing stress hyperglycemia. Based on the occurrence rate observed in this cohort, structured screening and intervention programs appear warranted. usc Refereed/Peer-reviewed

Metformin has been shown to modulate the cardiovascular response to intraduodenal glucose in patients with type 2 diabetes (T2DM), and may have the capacity to regulate postprandial blood pressure (BP), which is often inadequately compensated in T2DM, resulting in postprandial hypotension. In the present study, we evaluated the acute effects of metformin on the BP and heart rate (HR) responses to oral glucose in patients with T2DM. Ten diet-controlled T2DM patients were evaluated on two occasions in a double-blind, randomized, crossover design. Participants received either metformin 1 g or saline (control) intraduodenally 60 minutes before ingesting a 50 g glucose drink labelled with 150 mg 13C-acetate. BP, HR, plasma glucagon-like peptide-1 (GLP-1) and gastric emptying (breath test) were evaluated over 180 minutes. Systolic and diastolic BP decreased and HR increased after oral glucose (P < 0.001 for all) on both days. Metformin attenuated the fall in systolic BP (P < 0.001), increased plasma GLP-1 concentrations (P < 0.05) and slowed gastric emptying (P < 0.05) without significantly affecting diastolic BP or HR. In conclusion, metformin acutely attenuates the hypotensive response to oral glucose, associated with augmented GLP-1 secretion and delayed gastric emptying, effects potentially relevant to its favourable cardiovascular profile. usc Refereed/Peer-reviewed

Hypoglycaemia is arguably the most important complication of insulin therapy in type 1 and type 2 diabetes. Counter-regulation of hypoglycaemia is dependent on autonomic function and frequent hypoglycaemia may lead to reductions in both autonomic warning signals and the catecholamine response, the so-called “impaired awareness of hypoglycaemia”. It is now appreciated that gastric emptying is a major determinant of the glycaemic response to carbohydrate-containing meals in both health and diabetes, that disordered (especially delayed) gastric emptying occurs frequently in diabetes, and that acute hypoglycaemia accelerates gastric emptying substantially. However, the potential relevance of gastric emptying to the predisposition to, and counter-regulation of, hypoglycaemia has received little attention. In insulin-treated patients, the rate of gastric emptying influences the timing of the postprandial insulin requirement, and gastroparesis is likely to predispose to postprandial hypoglycaemia. Conversely, the marked acceleration of gastric emptying induced by hypoglycaemia probably represents an important counter-regulatory response to increase the rate of carbohydrate absorption. This review summarizes the current knowledge of the inter-relationships between hypoglycaemia and gastric emptying, with a focus on clinical implications usc Refereed/Peer-reviewed

BACKGROUND. The aim of this study was to clarify the pathophysiology of functional dyspepsia (FD), a highly prevalent gastrointestinal syndrome, and its relationship with the better understood syndrome of gastroparesis. METHODS. Adult patients with chronic upper gastrointestinal symptoms were followed prospectively for 48 weeks in multi-center registry studies. Patients were classified as gastroparesis if gastric emptying was delayed; if not, they were labeled as FD if they met Rome III criteria. Study analysis was conducted using ANCOVA and regression models. RESULTS. Of 944 patients enrolled over a 12-year period, 720 (76%) were in the gastroparesis group and 224 (24%) in the FD group. Baseline clinical characteristics and severity of upper gastrointestinal symptoms were highly similar. 48-week clinical outcome was also similar but at this time 42% of patients with an initial diagnosis of gastroparesis were reclassified as FD based on gastric emptying results at this time point, conversely, 37% of FD patients were reclassified as gastroparesis. Change in either direction was not associated with any difference in symptom severity changes. Full thickness biopsies of the stomach showed loss of interstitial cells of Cajal and CD206(+) macrophages in both groups compared to obese controls. CONCLUSIONS. A year after initial classification, patients with FD and gastroparesis, as seen in tertiary referral centers at least, are not distinguishable by clinical and pathological features or by assessment of gastric emptying. Gastric emptying results are labile and do not reliably capture the pathophysiology of clinical symptoms in either condition. FD and gastroparesis are unified by characteristic pathological features and should be considered as part of the same spectrum of truly “organic” gastric neuromuscular disorders. CLINICALTRIALS.GOV IDENTIFIER: NCT00398801, NCT01696747

Rapid advances in machine learning and related techniques have increased optimism about self-driving cars, autonomous surgery, and other uses of artificial intelligence (AI). But adoption of these technologies is not simply a matter of breakthroughs in the design and training of algorithms. Regulators around the world will have to make a litany of choices about law and policy surrounding AI. To advance knowledge of how they will make these choices, we draw on a unique survey pool—690 local officials in the United States—a representative sample of U.S. local officials. These officials will make many of the decisions about AI adoption, from government use to regulation, given the decentralized structure of the United States. The results show larger levels of support for autonomous vehicles than autonomous surgery. Moreover, those that used ridesharing apps prior to the COVID-19 pandemic are significantly more supportive of autonomous vehicles. We also find that self-reported familiarity with AI is correlated with increased approval of AI uses in a variety of areas, including facial recognition, natural disaster impact planning, and even military surveillance. Related, those who expressed greater opposition to AI adoption also appear more concerned about trade-offs between privacy and information and bias in algorithms. Finally, the explanatory logic used by respondents varies based on gender and prior experience with AI, which we demonstrate with quantitative text analysis.

Countries, companies, and universities are increasingly competing over top-tier artificial intelligence (AI) researchers. Where are these researchers likely to immigrate and what affects their immigration decisions? We conducted a survey $(n = 524)$ of the immigration preferences and motivations of researchers that had papers accepted at one of two prestigious AI conferences: the Conference on Neural Information Processing Systems (NeurIPS) and the International Conference on Machine Learning (ICML). We find that the U.S. is the most popular destination for AI researchers, followed by the U.K., Canada, Switzerland, and France. A country's professional opportunities stood out as the most common factor that influences immigration decisions of AI researchers, followed by lifestyle and culture, the political climate, and personal relations. The destination country's immigration policies were important to just under half of the researchers surveyed, while around a quarter noted current immigration difficulties to be a deciding factor. Visa and immigration difficulties were perceived to be a particular impediment to conducting AI research in the U.S., the U.K., and Canada. Implications of the findings for the future of AI talent policies and governance are discussed., Accepted for poster presentation at the 2021 AAAI/ACM Conference on AI, Ethics, and Society

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

Postprandial glycemic control is an important target for optimal type 2 diabetes management, but is often difficult to achieve. The gastrointestinal tract plays a major role in modulating postprandial glycaemia in both health and diabetes. The various strategies that have been proposed to modulate gastrointestinal function, particularly by slowing gastric emptying and/or stimulating incretin hormone GLP-1, are summarized in this review.

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

Context Dietary fat and protein impact postprandial hyperglycemia in people with type 1 diabetes, but the underlying mechanisms are poorly understood. Glucoregulatory hormones are also known to modulate gastric emptying and may contribute to this effect. Objective Investigate the effects of fat and protein on glucagon-like peptide (GLP-1), glucagon-dependent insulinotropic polypeptide (GIP) and glucagon secretion. Methods 2 crossover euglycemic insulin clamp clinical trials at 2 Australian pediatric diabetes centers. Participants were 12-21 years (n = 21) with type 1 diabetes for ≥1 year. Participants consumed a low-protein (LP) or high-protein (HP) meal in Study 1, and low-protein/low-fat (LPLF) or high-protein/high-fat (HPHF) meal in Study 2, all containing 30 g of carbohydrate. An insulin clamp was used to maintain postprandial euglycemia and plasma glucoregulatory hormones were measured every 30 minutes for 5 hours. Data from both cohorts (n = 11, 10) were analyzed separately. The main outcome measure was area under the curve of GLP-1, GIP, and glucagon. Results Meals low in fat and protein had minimal effect on GLP-1, while there was sustained elevation after HP (80.3 ± 16.8 pmol/L) vs LP (56.9 ± 18.6), P = .016, and HPHF (103.0 ± 26.9) vs LPLF (69.5 ± 31.9) meals, P = .002. The prompt rise in GIP after all meals was greater after HP (190.2 ± 35.7 pmol/L) vs LP (152.3 ± 23.3), P = .003, and HPHF (258.6 ± 31.0) vs LPLF (151.7 ± 29.4), P < .001. A rise in glucagon was also seen in response to protein, and HP (292.5 ± 88.1 pg/mL) vs LP (182.8 ± 48.5), P = .010. Conclusion The impact of fat and protein on postprandial glucose excursions may be mediated by the differential secretion of glucoregulatory hormones. Further studies to better understand these mechanisms may lead to improved personalized postprandial glucose management.

PURPOSE: To compare invasive right heart catheterization with four-dimensional (4D) flow MRI for estimating shunt fraction in patients with intracardiac and extracardiac shunts. MATERIALS AND METHODS: In this retrospective study, patients who underwent 4D flow MRI and invasive right heart catheterization with a shunt run between August 2015 and November 2018 were included. The primary objective was comparison of estimated shunt fraction (ratio of pulmonary-to-systemic flow, Q(p)/Q(s)) at 4D flow and catheterization. Secondary objectives included comparison of the right ventricular–to–left ventricular stroke volume ratio (RVSV/LVSV) to shunt fraction (for those with applicable shunts) and comparison of cardiac output between 4D flow and catheterization. Statistical analysis included Pearson correlation and Bland-Altman plots. RESULTS: A total of 33 patients met inclusion criteria (mean age, 49 years ± 16 [standard deviation]; 24 women). 4D flow measurements of Q(p)/Q(s) strongly correlated with those at catheterization (r = 0.938), and there was no bias. RVSV/LVSV correlated strongly with Q(p)/Q(s) from 4D flow (r = 0.852) and catheterization (r = 0.842). Measurements of left ventricle (Q(s)) and right ventricle (Q(P)) cardiac output from 4D flow and catheterization (Fick) correlated moderately overall (r = 0.673 [Q(p)] and r = 0.750 [Q(s)]). CONCLUSION: Shunt fraction measurement using 4D flow MRI compares well with that using invasive cardiac catheterization. Supplemental material is available for this article. © RSNA, 2021

During the last 30 years, there has been a paradigm shift in knowledge relating to gastric emptying in diabetes, reflecting the application of novel investigative techniques. Scintigraphy, which utilizes radiolabeled solid and/or liquid meals and a γ-camera, remains the gold standard for quantifying gastric emptying (1,2). More recently, stable isotope breath tests, involving measurement of 13CO2 in breath samples after ingestion of a 13C-labeled meal, have been validated against scintigraphy with inherent advantages of simplicity, point-of-care sampling, and avoidance of radiation exposure (1). Key insights in diabetes include the recognition that solids and liquids empty from the stomach differentially and that interindividual variation—already substantial in health (1–4 kcal/min) (2)—is increased in diabetes because emptying is delayed in ∼30–40% of complicated, suboptimally controlled patients attending tertiary centers (2–4), while often modestly accelerated in well-controlled patients with type 1 or type 2 diabetes (2). Upper gastrointestinal symptoms, such as nausea and fullness, occur frequently and impact quality of life adversely, but their relationship to gastric emptying is weak (1–3). Rather than simply being a manifestation of autonomic neuropathy, the pathogenesis of gastroparesis is heterogeneous, involving loss of interstitial cells of Cajal (“pacemaker” cells), an immune infiltrate, and muscle atrophy in addition to changes in intrinsic and extrinsic (vagal) innervation (1). There is a relatively weak relationship between gastroparesis and autonomic dysfunction, as assessed by standardized cardiovascular reflexes (3). Finally, and perhaps most importantly, gastric emptying influences postprandial glycemic excursions, the dominant determinant of HbA1c when the latter is less than ∼64 mmol/mol (8.0%) (5), and emptying can be modulated by dietary or pharmacological approaches (e.g., short-acting glucagon-like peptide 1 receptor agonists or pramlintide) for therapeutic gain (2). Accordingly, gastric emptying is central to the pathogenesis and personalized management of diabetes (6). …

Context Hypoglycemia is a major barrier to optimal glycemic control in insulin-treated diabetes. Recent guidelines from the American Diabetes Association have subcategorized “non-severe” hypoglycemia into level 1 ( Objective To determine the effects of 2 levels of hypoglycemia, 2.6 mmol/L (“marked”) and 3.6 mmol/L (“mild”), on gastric emptying in health. Design, Setting, and Subjects Fourteen healthy male participants (mean age: 32.9 ± 8.3 years; body mass index: 24.5 ± 3.4 kg/m2) from the general community underwent measurement of gastric emptying of a radiolabeled solid meal (100 g beef) by scintigraphy over 120 minutes on 3 separate occasions, while blood glucose was maintained at either ~2.6 mmol/L, ~3.6 mmol/L, or ~6 mmol/L in random order from 15 minutes before until 60 minutes after meal ingestion using glucose-insulin clamp. Blood glucose was then maintained at 6 mmol/L from 60 to 120 minutes on all days. Results Gastric emptying was accelerated during both mild (P = 0.011) and marked (P = 0.001) hypoglycemia when compared to euglycemia, and was more rapid during marked compared with mild hypoglycemia (P = 0.008). Hypoglycemia-induced gastric emptying acceleration during mild (r = 0.57, P = 0.030) and marked (r = 0.76, P = 0.0014) hypoglycemia was related to gastric emptying during euglycemia. Conclusion In health, acceleration of gastric emptying by insulin-induced hypoglycemia is dependent on the degree of hypoglycemia and baseline rate of emptying.

Postprandial hypotension (PPH) is an important and under-recognised disorder resulting from inadequate compensatory cardiovascular responses to meal-induced splanchnic blood pooling. Current approaches to management are suboptimal. Recent studies have established that the cardiovascular response to a meal is modulated profoundly by gastrointestinal factors, including the type and caloric content of ingested meals, rate of gastric emptying, and small intestinal transit and absorption of nutrients. The small intestine represents the major site of nutrient-gut interactions and associated neurohormonal responses, including secretion of glucagon-like peptide-1, glucose-dependent insulinotropic peptide and somatostatin, which exert pleotropic actions relevant to the postprandial haemodynamic profile. This review summarises knowledge relating to the role of these gut peptides in the cardiovascular response to a meal and their potential application to the management of PPH. Refereed/Peer-reviewed

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 …

The interaction of nutrients with the small intestine modulates postprandial cardiovascular function. Rapid small intestinal nutrient delivery may reduce blood pressure markedly, particularly in patients with type 2 diabetes (T2DM). Postprandial hypotension occurs in ~30% of patients with longstanding T2DM, but there is little information about the cardiovascular effects of different macronutrients. We compared the blood pressure and heart rate responses to standardized intraduodenal glucose and fat infusions in T2DM. Two parallel groups, including 26 T2DM patients who received intraduodenal glucose infusion and 14 T2DM patients who received intraduodenal fat, both at 2 kcal/min over 120 min, were compared retrospectively. Blood pressure and heart rate were measured at regular intervals. Systolic blood pressure was stable initially and increased slightly thereafter in both groups, without any difference between them. Diastolic blood pressure decreased in response to intraduodenal glucose, but remained unchanged in response to lipid, with a significant difference between the two infusions (P = 0.04). Heart rate increased during both intraduodenal glucose and lipid infusions (P < 0.001 each), and the increment was greater in response to intraduodenal fat than glucose (P = 0.004). In patients with T2DM, intraduodenal fat induced a greater increase in heart rate, associated with a diminished reduction in blood pressure, when compared with isocaloric glucose. The macronutrient composition of meals may be an important consideration in T2DM patients with symptomatic postprandial hypotension.

Metformin, the most widely prescribed drug therapy for type 2 diabetes, has pleiotropic benefits, in addition to its capacity to lower elevated blood glucose levels, including mitigation of cardiovascular risk. The mechanisms underlying the latter remain unclear. Mechanistic studies have, hitherto, focused on the direct effects of metformin on the heart and vasculature. It is now appreciated that effects in the gastrointestinal tract are important to glucose-lowering by metformin. Gastrointestinal actions of metformin also have major implications for cardiovascular function. This review summarizes the gastrointestinal mechanisms underlying the action of metformin and their potential relevance to cardiovascular benefits. usc Refereed/Peer-reviewed

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

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 Gastric emptying is a major determinant of the glycaemic response to carbohydrate and is frequently abnormal in type 2 diabetes (T2DM). There is little information about how chronic glycaemic control affects gastric emptying in T2DM. We evaluated gastric emptying of a 75 g glucose drink in community-based patients with T2DM of short duration with good or poor glycaemic control, and compared this to young and older controls. Methods T2DM patients managed by diet and/or metformin, either well-controlled or poorly-controlled, together with young and age-matched older controls without diabetes, consumed a 75 g oral glucose drink containing 150 mg 13C-acetate for evaluation of gastric emptying (breath test) and blood glucose over 180 min. Results The gastric half-emptying time (T50) was longer in the older than the young non-diabetic subjects (P = 0.041), but shorter in well-controlled T2DM patients than age-matched older controls (P = 0.043). The T50 in poorly-controlled T2DM patients was shorter than in older controls (P = 0.006), but similar to young non-diabetic subjects. Conclusions Gastric emptying of a glucose drink is delayed with ageing, but more rapid in patients with T2DM of relatively short duration, regardless of their glycaemic status. These observations support interventions that slow gastric emptying to improve postprandial glycaemia in these patients with T2DM.

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.

In humans, phenylalanine stimulates plasma cholecystokinin (CCK) and pyloric pressures, both of which are important in the regulation of energy intake and gastric emptying. Gastric emptying is a key determinant of postprandial blood glucose. We evaluated the effects of intragastric phenylalanine on appetite perceptions and subsequent energy intake, and the glycaemic response to, and gastric emptying of, a mixed-nutrient drink. The study consisted of two parts, each including 16 healthy, lean males (age: 23 &plusmn, 1 years). In each part, participants received on three separate occasions, in randomised, double-blind fashion, 5 g (Phe-5 g) or 10g (&lsquo, Phe-10 g) L-phenylalanine, or control, intragastrically, 30 min before a standardised buffet-meal (part A), or a standardised mixed-nutrient drink (part B). In part A, plasma CCK and peptide-YY (PYY), and appetite perceptions, were measured at baseline, after phenylalanine alone, and following the buffet-meal, from which energy intake was assessed. In part B, plasma glucose, glucagon-like peptide-1 (GLP-1), insulin and glucagon were measured at baseline, after phenylalanine alone, and for 2 h following the drink. Gastric emptying of the drink was also measured by 13C-acetate breath-test. Phe-10 g, but not Phe-5 g, stimulated plasma CCK (P = 0.01) and suppressed energy intake (P = 0.012), energy intake was correlated with stimulation of CCK (r = &minus, 0.4, P = 0.027), and tended to be associated with stimulation of PYY (r = &minus, 0.31, P = 0.082). Both Phe-10 g and Phe-5 g stimulated insulin and glucagon (all P &lt, 0.05), but not GLP-1. Phe-10 g, but not Phe-5 g, reduced overall plasma glucose (P = 0.043) and peak plasma glucose (P = 0.017) in response to the mixed-nutrient drink. Phenylalanine had no effect on gastric emptying of the drink. In conclusion, our observations indicate that the energy intake-suppressant effect of phenylalanine is related to the stimulation of CCK and PYY, while the glucoregulatory effect may be independent of stimulation of plasma GLP-1 or slowing of gastric emptying.

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.

ContextExposure of the small intestine to nutrients frequently leads to marked reductions in blood pressure (BP) in type 2 diabetes (T2DM). It remains unclear whether the region of the gut exposed to nutrients influences postprandial cardiovascular responses.ObjectiveTo evaluate the cardiovascular responses to proximal and distal small intestinal glucose infusion in health and T2DM.DesignDouble-blind, randomized, crossover design.SettingSingle center in Australia.Patients10 healthy subjects and 10 T2DM patients.InterventionsVolunteers were studied on 2 occasions, when a transnasal catheter was positioned with infusion ports opening 13 cm and 190 cm beyond the pylorus. A 30-g bolus of glucose was infused into either site and 0.9% saline into the alternate site over 60 minutes.Main Outcome MeasuresBP, heart rate (HR), and superior mesenteric artery (SMA) blood flow were measured over 180 minutes.ResultsSystolic BP was unchanged in response to both infusions in health, but decreased in T2DM, with a greater reduction after proximal versus distal infusion (all P ≤ .01). The increment in HR did not differ between treatments in health, but was greater after distal versus proximal infusion in T2DM (P = .02). The increases in SMA blood flow were initially greater, but less sustained, with proximal versus distal infusion in health (P < .001), a pattern less evident in T2DM.ConclusionsIn T2DM, postprandial hypotension may be mitigated by diversion of nutrients from the proximal to the distal small intestine.