Showing papers by "Michael Horowitz published in 2017"

Ghrelin, CCK, GLP-1, and PYY(3-36): Secretory Controls and Physiological Roles in Eating and Glycemia in Health, Obesity, and After RYGB.

Abstract: The efficacy of Roux-en-Y gastric-bypass (RYGB) and other bariatric surgeries in the management of obesity and type 2 diabetes mellitus and novel developments in gastrointestinal (GI) endocrinology have renewed interest in the roles of GI hormones in the control of eating, meal-related glycemia, and obesity. Here we review the nutrient-sensing mechanisms that control the secretion of four of these hormones, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide tyrosine tyrosine [PYY(3-36)], and their contributions to the controls of GI motor function, food intake, and meal-related increases in glycemia in healthy-weight and obese persons, as well as in RYGB patients. Their physiological roles as classical endocrine and as locally acting signals are discussed. Gastric emptying, the detection of specific digestive products by small intestinal enteroendocrine cells, and synergistic interactions among different GI loci all contribute to the secretion of ghrelin, CCK, GLP-1, and PYY(3-36). While CCK has been fully established as an endogenous endocrine control of eating in healthy-weight persons, the roles of all four hormones in eating in obese persons and following RYGB are uncertain. Similarly, only GLP-1 clearly contributes to the endocrine control of meal-related glycemia. It is likely that local signaling is involved in these hormones' actions, but methods to determine the physiological status of local signaling effects are lacking. Further research and fresh approaches are required to better understand ghrelin, CCK, GLP-1, and PYY(3-36) physiology; their roles in obesity and bariatric surgery; and their therapeutic potentials.

Effect of Age on Blood Glucose and Plasma Insulin, Glucagon, Ghrelin, CCK, GIP, and GLP-1 Responses to Whey Protein Ingestion

Abstract: Protein-rich supplements are used widely to prevent and manage undernutrition in older people. We have previously shown that healthy older, compared to younger, adults have less suppression of energy intake by whey protein-although the effects of age on appetite-related gut hormones are largely unknown. The aim of this study was to determine and compare the acute effects of whey protein loads on blood glucose and plasma gut hormone concentrations in older and younger adults. Sixteen healthy older (eight men, eight women; mean ± SEM: age: 72 ± 1 years; body mass index: 25 ± 1 kg/m²) and 16 younger (eight men, eight women; 24 ± 1 years; 23 ± 0.4 kg/m²) adults were studied on three occasions in which they ingested 30 g (120 kcal) or 70 g (280 kcal) whey protein, or a flavored-water control drink (~2 kcal). At regular intervals over 180 min, blood glucose and plasma insulin, glucagon, ghrelin, cholecystokinin (CCK), gastric inhibitory peptide (GIP), and glucagon-like peptide-1 (GLP-1) concentrations were measured. Plasma ghrelin was dose-dependently suppressed and insulin, glucagon, CCK, GIP, and GLP-1 concentrations were dose-dependently increased by the whey protein ingestion, while blood glucose concentrations were comparable during all study days. The stimulation of plasma CCK and GIP concentrations was greater in older than younger adults. In conclusion, orally ingested whey protein resulted in load-dependent gut hormone responses, which were greater for plasma CCK and GIP in older compared to younger adults.

Obesity-Associated Alterations in Glucose Metabolism Are Reversed by Chronic Bilateral Stimulation of the Abdominal Vagus Nerve.

Abstract: Acute vagal stimulation modifies glucose and insulin metabolism, but the effect of chronic bilateral vagal stimulation is not known. Our aim was to quantify the changes in whole-body and organ-specific insulin sensitivities 12 weeks after permanent, bilateral, vagal stimulation performed at the abdominal level in adult mini-pigs. In 15 adult mini-pigs, stimulating electrodes were placed around the dorsal and ventral vagi using laparoscopy and connected to a dual-channel stimulator placed subcutaneously. Animals were divided into three groups based on stimulation and body weight (i.e., lean nonstimulated, obese nonstimulated, and obese stimulated). Twelve weeks after surgery, glucose uptake and insulin sensitivity were measured using positron emission tomography during an isoglycemic clamp. Mean whole-body insulin sensitivity was lower by 34% (P < 0.01) and the hepatic glucose uptake rate was lower by 33% (P < 0.01) in obese-nonstimulated mini-pigs but was no different in obese-stimulated compared with lean mini-pigs. An improvement in skeletal glucose uptake rate was also observed in obese-stimulated compared with obese-nonstimulated groups (P < 0.01). Vagal stimulation was associated with increased glucose metabolism in the cingulate and prefrontal brain areas. We conclude that chronic vagal stimulation improves insulin sensitivity substantially in diet-induced obesity by both peripheral and central mechanisms.

Droning On: Explaining the Proliferation of Unmanned Aerial Vehicles

Abstract: Unmanned Aerial Vehicles (UAVs), more popularly known as “drones,” have become emblematic of twenty-first century military technologies but scholars have yet to convincingly explain the drivers of UAV proliferation. Using the first systematic data set of UAV proliferation, this research note examines the spread of UAVs in the context of scholarly debates about interests versus capacity in explaining policy adoption. The results yield important insights for both IR scholarship and the policy-making community. While countries that experience security threats—including territorial disputes and terrorism—are more likely to seek UAVs, drone proliferation is not simply a function of the threat environment. We find evidence that democracies and autocracies are more likely than mixed regimes to develop armed UAV programs, and suggest that autocracies and democracies have their own unique incentives to acquire this technology. Moreover, supply-side factors play a role in the UAV proliferation process: a state's technological capacity is a strong predictor of whether it will obtain the most sophisticated UAVs. The theories and evidence we present challenge emerging views about UAV proliferation and shed useful light on how and why drones spread.

New insights into the anti-diabetic actions of metformin: from the liver to the gut.

Abstract: Metformin is established as the first-line therapy for type 2 diabetes (T2DM), but its mode of action remains elusive. Elucidation of the mechanisms underlying the anti-diabetic action of metformin may have the potential to optimise its glucose-lowering efficacy and lead to the development of agents acting on novel targets for the management of type 2 diabetes. Areas covered: This review highlights key pharmacokinetic features of metformin, summarises recent insights into its hepatic and gastrointestinal actions relevant to blood glucose homeostasis, and discusses the common gastrointestinal side effects of metformin. Literature concerning these areas was reviewed on PubMed. Expert commentary: The mechanisms by which metformin improves glycaemic control in type 2 diabetes are complex. Although novel hepatic pathways continue to be reported in preclinical studies, there is a lack of human evidence for most of these. Considering the fundamental role of the gastrointestinal tract in the regulation of blood glucose homeostasis and pleiotropic actions of metformin on several gastrointestinal targets relevant to glycaemic control, the gut is likely to represent at least as important a site of metformin action as the liver in the management of type 2 diabetes.

Upper and/or lower gastrointestinal adverse events with glucagon-like peptide-1 receptor agonists: Incidence and consequences.

Abstract: Aims To characterize gastrointestinal adverse events (AEs) with different glucagon-like peptide-1 receptor agonists (GLP-1RAs). Methods Two retrospective intention-to-treat analyses of 6-month patient-level data were conducted. Data from three studies comparing exenatide once weekly (n = 617) with exenatide twice daily (n = 606) were pooled, and one (DURATION-6) comparing exenatide once weekly (n = 461) with liraglutide (n = 450) was analysed separately. Patient-reported gastrointestinal AEs were classified as upper or lower, AE incidences and timing were determined, subgroups were analysed, and associations of gastrointestinal AEs with efficacy were examined. Results Nausea was the most common gastrointestinal AE for all treatments. Fewer exenatide once-weekly-treated vs exenatide twice-daily- or liraglutide-treated patients reported gastrointestinal AEs (34% vs 45% and 25% vs 41%, respectively; both P < .0001). Fewer exenatide once-weekly-treated patients reported upper plus lower events than liraglutide-treated patients ( P < .001); the difference between exenatide once weekly and twice daily was not significant. Within each group, more women than men reported gastrointestinal AEs. Events occurrred early and were predominantly mild. Glycated haemoglobin reductions were similar for patients with or without gastrointestinal AEs. Weight loss was greater for patients with gastrointestinal AEs with exenatide once weekly and exenatide twice daily ( P < .05); no difference was observed in DURATION-6. Conclusions Gastrointestinal AEs were less frequent with exenatide once weekly vs exenatide twice daily or liraglutide, and combined upper and lower events occurred less often. Gastrointestinal AEs were typically mild and occurred early. Gastrointestinal AEs did not affect glycaemic control but may be associated with greater weight loss.

Metformin reduces the rate of small intestinal glucose absorption in type 2 diabetes.

Abstract: In rodents, metformin slows intestinal glucose absorption, potentially increasing exposure of the distal gut to glucose to enhance postprandial glucagon-like peptide-1 (GLP-1) secretion. We evaluated the effects of metformin on serum 3-O-methylglucose (3-OMG; a marker of glucose absorption) and plasma total GLP-1 concentrations during a standardized intraduodenal infusion of glucose and 3-OMG in patients with type 2 diabetes. A total of 12 patients, treated with metformin 850 mg twice daily or placebo for 7 days each in a double-blind, randomized, crossover design (14 days' washout between treatments), were evaluated on days 5 or 8 of each treatment (6 subjects each). On each study day, 30 minutes after ingesting 850 mg metformin or placebo, patients received an infusion of glucose (60 g + 5 g 3-OMG, dissolved in water to 240 mL) via an intraduodenal catheter over the course of 120 minutes. Compared with placebo, metformin was associated with lower serum 3-OMG ( P < .001) and higher plasma total GLP-1 ( P = .003) concentrations. The increment in plasma GLP-1 after metformin vs placebo was related to the reduction in serum 3-OMG concentrations ( P = .019). Accordingly, metformin inhibits small intestinal glucose absorption, which may contribute to augmented GLP-1 secretion in type 2 diabetes.

Domestic Signaling of Commitment Credibility: Military Recruitment and Alliance Formation

Abstract: We provide a new perspective on how domestic factors shape the prospects for international cooperation. Internal arms, specifically conscription, signal a willingness and suitability to be a depend...

Exogenous glucagon-like peptide-1 attenuates glucose absorption and reduces blood glucose concentration after small intestinal glucose delivery in critical illness

Abstract: Objective To evaluate the effect of exogenous glucagonlike peptide-1 (GLP-1) on small intestinal glucose absorption and blood glucose concentrations during critical illness. Design, setting and participants A prospective, blinded, placebo-controlled, cross-over, randomised trial in a mixed medical-surgical adult intensive care unit, with 12 mechanically ventilated critically ill patients, who were suitable for receiving small intestinal nutrient. Interventions On consecutive days, in a randomised order, participants received intravenous GLP-1 (1.2 pmol/ kg/min) or placebo (0.9% saline) as a continuous infusion over 270 minutes. After 6 hours of fasting, intravenous infusions of GLP-1 or placebo began at T = -30 min (in which T = time), with the infusion maintained at a constant rate until study completion at T = 240 min. At T = 0 min, a 100 mL bolus of mixed liquid nutrient meal (1 kcal/mL) containing 3 g of 3-O-methyl-D-gluco-pyranose (3-OMG), a marker of glucose absorption, was administered directly into the small intestine, via a post-pyloric catheter, over 6 minutes. Main outcome measures Blood samples were taken at regular intervals for the measurement of plasma glucose and 3-OMG concentrations. Results Intravenous GLP-1 attenuated initial small intestinal glucose absorption (mean area under the curve [AUC]0-30 for 3-OMG: GLP-1 group, 4.4 mmol/L/min [SEM, 0.9 mmol/L/min] v placebo group, 6.5 mmol/L/min [SEM, 1.0 mmol/L/min]; P = 0.01), overall small intestinal glucose absorption (mean AUC0-240 for 3-OMG: GLP-1, 68.2 mmol/L/ min [SEM, 4.7 mmol/L/min] v placebo, 77.7 mmol/L/min [SEM, 4.4 mmol/lLmin]; P = 0.02), small intestinal glucose absorption and overall blood glucose concentration (mean AUC0-240 for blood glucose: GLP-1, 2062 mmol/L/min [SEM, 111 mmol/L/min] v placebo 2328 mmol/L/min [SEM, 145 mmol/L/min]; P = 0.005). Conclusions Short-term administration of exogenous GLP-1 reduces small intestinal glucose absorption for up to 4 hours during critical illness. This is likely to be an additional mechanism for the glucose-lowering effect of this agent.

Comparative effects of intraduodenal amino acid infusions on food intake and gut hormone release in healthy males

Abstract: In contrast to the many studies of the effects of individual amino acids (AAs) on eating, no studies have compared the effects of different AAs on eating and underlying preabsorptive gastrointestinal mechanisms. To compare the effects of intraduodenal infusions of l‐tryptophan (TRP), l‐leucine (LEU), l‐phenylalanine (PHE) and l‐glutamine (GLN) on appetite, gastrointestinal hormone responses (including ghrelin, cholecystokinin (CCK), peptide YY (PYY) and glucagon‐like peptide‐1 [GLP‐1]), glycemia (glucagon, insulin and glucose) and test meal size in healthy males, we retrospectively analyzed data from four published independent, randomized, double‐blind, placebo‐controlled studies of 90‐min intraduodenal infusions of the individual AAs. The designs of the studies were identical, except the dose of TRP (0.15 kcal/min) was lower than that of the other AAs (0.45 kcal/min) because higher doses of this AA were not well tolerated. TRP and LEU decreased intake more than PHE (reductions relative to control, ~219 ± 68, ~170 ± 48 and ~12 ± 57 kcal, respectively), and TRP decreased intake more than GLN (~31 ± 82 kcal). These effects of TRP and LEU versus GLN, but not versus PHE, were paralleled by greater decreases in plasma ghrelin, and increases in CCK, concentrations. TRP increased PYY more than GLN or LEU, but not PHE. LEU increased PYY less than PHE. No significant differences were detected for GLP‐1. PHE increased glucagon more than TRP or LEU, and increased insulin more than TRP. Under our experimental conditions, intraduodenal TRP and LEU were more satiating than PHE and GLN. The greater satiating efficacy of LEU versus PHE was significantly dissociated from the effects of these AAs on PYY, while the greater satiating potency of TRP versus PHE was significantly dissociated from the effects of these AAs on insulin and glucagon. In contrast, ghrelin and CCK, and potentially other mechanisms, including central sensing of individual AAs, appear to be stronger candidate mechanisms for the relative satiating effects obtained.

Tactical Diversity in Militant Violence

Abstract: Militant groups, like all organizations, face crucial decisions about the strategies that they employ In this article, we assess why some militant organizations successfully diversify into multiple tactics, while others limit themselves to just one or a few This is an important puzzle because militant organizations with more diversified tactics are more likely to stretch counterterrorist defenses Drawing on literatures from business, economics, and organizational studies, we theorize that pressure and competition incentivize groups to diversify their tactical portfolios The results, which include tests drawn from multiple datasets, show robust support for the notion that tactical diversification is a response to organizational stress stemming from state repression and organizational rivalry The policy implication is that while countries cannot anticipate the character of future tactical innovations, they may be able to anticipate which groups will most readily adopt them

Effects of Vildagliptin and Metformin on Blood Pressure and Heart Rate Responses to Small Intestinal Glucose in Type 2 Diabetes

Abstract: OBJECTIVE To evaluate effects of vildagliptin and metformin on blood pressure (BP) and heart rate (HR) responses to intraduodenal (ID) glucose in diet-controlled type 2 diabetes. RESEARCH DESIGN AND METHODS Study A compared vildagliptin (50 mg) and placebo, given 60 min before a 120-min ID glucose infusion at 2 or 4 kcal/min (ID2 or ID4) in 16 patients. Study B compared metformin (850 mg) and placebo, given 30 min before ID2 over 120 min in 9 patients. RESULTS Systolic ( P = 0.002) and diastolic ( P P = 0.005) after vildagliptin compared with placebo, without interaction between vildagliptin and the glucose infusion rate. In contrast, HR was greater after metformin than placebo ( P CONCLUSIONS Vildagliptin reduces BP and increases HR, whereas metformin increases HR without affecting BP during ID glucose infusion in type 2 diabetes. These distinct cardiovascular profiles during enteral nutrient exposure may have implications for postprandial hypotension.

Lixisenatide as add-on treatment among patients with different β-cell function levels as assessed by HOMA-β index

Abstract: Background The effect of lixisenatide—a prandial once-daily glucagon-like peptide-1 receptor agonist—on glycaemic control in patients with inadequately controlled type 2 diabetes mellitus (T2DM), stratified by baseline β-cell function, was assessed. Methods The 24-week GetGoal-M, -P and -S trials evaluated the efficacy and safety of lixisenatide in combination with oral antidiabetic agents. This post hoc analysis used data from patients receiving lixisenatide in these trials, divided into matched cohorts by propensity scoring, and stratified according to baseline homeostasis model assessment of β-cell function (HOMA-β) index levels, high HOMA-β: > median HOMA-β (28.49%); low HOMA-β: ≤ median. Results The matched “low” and “high” HOMA-β index cohorts (N = 546 patients) had comparable baseline parameters. Mean change from baseline in glycated haemoglobin (HbA1c) was −0.85% and −0.94% for low and high HOMA-β cohorts, respectively (P = .2607). Reductions from baseline in fasting plasma glucose (FPG; −0.77 vs −1.04 mmol/L; P = .1496) and postprandial plasma glucose (PPG; −5.82 vs −5.61 mmol/L; P = .7511) were similar in the low versus high HOMA-β index cohorts. Reduction in body weight was significantly greater in the low versus high HOMA-β index cohort (–2.06 vs –1.13 kg, respectively; P = .0006). Conclusions In patients with T2DM, lixisenatide was associated with reduction in HbA1c and improvements in both FPG and PPG, regardless of β-cell function, indicating that lixisenatide is effective in reducing hyperglycaemia, even in patients with more advanced stages of T2DM and poor residual β-cell function.

Acute effects of the glucagon-like peptide-1 receptor agonist, exenatide, on blood pressure and heart rate responses to intraduodenal glucose infusion in type 2 diabetes:

Abstract: Sony S Thazhath, Chinmay S Marathe, Tongzhi Wu, Jessica Chang, Joan Khoo, Paul Kuo, Helen L Checklin, Michelle J Bound, Rachael S Rigda, Michael Horowitz, Karen L Jones, and Christopher K Rayner

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

Abstract: 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.

Tactical Diversity in Militant Violence

Abstract: Militant groups, like all organizations, carefully consider the tactics and strategies that they employ. We assess why some militant organizations diversify into multiple tactics while others limit themselves to just one or a few. This is an important puzzle because militant organizations that employ multiple approaches to violence are more likely to stretch state defenses, achieve tactical success, and threaten state security. We theorize that militant organizations respond to external pressure by diversifying their tactics to ensure their survival and continued relevance, and that the primary sources of such pressure are government repression and interorganizational competition. We find consistent support for these propositions in tests of both the Global Terrorism Database (GTD) and Minorities at Risk Organizational Behavior (MAROB) data sets. We bolster these findings with an additional specification that employs ethnic fractionalization in the first stage of a multi-process recursive model. These findings are relevant not only for academic research but for policy as well. While it is difficult for countries to anticipate the character of future tactical choices, they may be able to anticipate which groups will most readily diversify and thereby complicate counterterrorism efforts.

Antecedent Hypoglycemia Does Not Attenuate the Acceleration of Gastric Emptying by Hypoglycemia.

Abstract: Context: Acute hypoglycemia accelerates gastric emptying and increases cardiac contractility. However, antecedent hypoglycemia attenuates counterregulatory hormonal responses to subsequent hypoglycemia. Objective: To determine the effect of antecedent hypoglycemia on gastric and cardiac responses to subsequent hypoglycemia in health. Design: A prospective, single-blind, randomized, crossover study (performed at the Royal Adelaide Hospital, Adelaide, South Australia, Australia). Patients: Ten healthy young men 18 to 35 years of age were studied for 36 hours on two occasions. Interventions: Participants were randomly assigned to either antecedent hypoglycemia [three 45-minute periods of strict hypoglycemia (2.8 mmol/L] or control [three 45-minute periods of strict euglycemia (6 mmol/L)] during the initial 12-hour period. Participants were monitored overnight, and the following morning blood glucose was clamped at 2.8 mmol/L for 60 minutes and then at 6 mmol/L for 120 minutes. At least 6 weeks later participants returned for the alternative intervention. Gastric emptying and cardiac fractional shortening were measured with scintigraphy and two-dimensional echocardiography, respectively, on the morning of all 4 study days. Results: A single, acute episode of hypoglycemia accelerated gastric emptying (P = 0.01) and augmented fractional shortening (P < 0.01). Gastric emptying was unaffected by antecedent hypoglycemia (P = 0.74) whereas fractional shortening showed a trend to attenuation (P = 0.06). The adrenaline response was diminished (P < 0.05) by antecedent hypoglycemia. Conclusions: In health, the acceleration of gastric emptying during hypoglycemia is unaffected by antecedent hypoglycemia, whereas the increase in cardiac contractility may be attenuated.

Nutrient stimulation of mesenteric blood flow - implications for older critically ill patients

Abstract: Nutrient ingestion induces a substantial increase in mesenteric blood flow. In older persons (aged ≥ 65 years), particularly those with chronic medical conditions, the cardiovascular compensatory response may be inadequate to maintain systemic blood pressure during mesenteric blood pooling, leading to postprandial hypotension. In older ambulatory persons, postprandial hypotension is an important pathophysiological condition associated with an increased propensity for syncope, falls, coronary vascular events, stroke and death. In older critically ill patients, the administration of enteral nutrition acutely increases mesenteric blood flow, but whether this pathophysiological response is protective, or precipitates mesenteric ischaemia, is unknown. There are an increasing number of older patients surviving admission to intensive care units, who are likely to be at increased risk of postprandial hypotension, both during, and after, their stay in hospital. In this review, we describe the prevalence, impact and mechanisms of postprandial hypotension in older people and provide an overview of the impact of postprandial hypotension on feeding prescriptions in older critically ill patients. Finally, we provide evidence that postprandial hypotension is likely to be an unrecognised problem in older survivors of critical illness and discuss potential options for management.

Intragastric Lysine Lowers the Circulating Glucose and Insulin Responses to a Mixed-Nutrient Drink without Slowing Gastric Emptying in Healthy Adults

Abstract: Background: Lysine is reported to lower the glycemic response to oral glucose in humans and, albeit at high loads, to slow gastric emptying of glucose and decrease food intake in rats.Objective: We investigated the effects of intragastrically administered lysine on early (15 min) and later (60 min) blood glucose and insulin responses to and gastric emptying of a mixed-nutrient drink, and effects on subsequent energy intake.Methods: Twelve healthy volunteers (7 men and 5 women; mean ± SEM age: 24 ± 2 y) received intragastric infusions (200 mL) containing 5 or 10 g l-lysine or a control solution within 2 min on 3 different occasions in randomized order. Fifteen minutes later, participants consumed a mixed-nutrient drink (300 mL, 400 kcal, and 56 g carbohydrates) within 1 min. For the next hour (t = 0-60 min), we collected blood samples every 15 min (to measure blood glucose, plasma insulin, and plasma glucagon) and breath samples every 5 min (to measure gastric emptying via a 13C-acetate breath test). We then quantified subjects' energy intake from a buffet-style meal (t = 60-90 min).Results: There were no differences between the 2 lysine treatments; hence, data were pooled for further analysis. Lysine did not affect blood glucose at 15 min or the blood glucose area under the curve from 0 to 60 min (AUC0-60min) but it decreased blood glucose at 60 min compared with the control solution (-9.1% ± 3.1%, P < 0.01). Similarly, the early insulin response and insulin AUC0-60min were not affected by lysine, but plasma insulin at 60 min was 20.9% ± 5.6% lower than after the control (P < 0.05). Plasma glucagon at both 15 min (20.7% ± 4.7%, P < 0.001) and 60 min (14.1% ± 5.4%, P < 0.05) and the glucagon AUC0-60min (P < 0.01) were greater after lysine than after the control. Lysine did not slow gastric emptying, and there was no effect on energy intake.Conclusion: In healthy adults, lysine slightly reduced the glycemic response to an oral mixed-macronutrient drink, an effect that was apparently independent of insulin or slowing of gastric emptying. This trial was registered at www.anzctr.orgau as 12614000837628.

Gut feelings about diabetes and GLP-1 receptor agonists: lessons to be learnt from studies in functional gastrointestinal disorders

Abstract: “The only mistake I ever made was not listening to my gut.” Lee Iacocca, former US motor industry executive Until recently, the diabetes community paid inappropriately little attention to the gastrointestinal (GI) tract, particularly its role in glycaemic control and its capacity to generate symptoms that affect quality of life adversely. We know from the literature on functional GI disorders that, even in the general population, GI symptoms are remarkably common but often are not reported unless individuals are specifically asked, and that the use of validated instruments is essential to assess them accurately. It is logical that the GI tract, particularly the emptying of ingested nutrients from the stomach and their transit, digestion and absorption from the intestines, should be central to the postprandial blood glucose response. Yet, only with the widespread use of therapies based on the gut-derived incretin peptide, glucagon-like peptide-1 (GLP-1), have these concepts been appreciated widely. GLP-1 receptor agonists (GLP-1 RAs) lower glycaemia by stimulating insulin and suppressing glucagon secretion in a glucosedependent manner that minimises the risk of hypoglycaemia. However, their ability to slow gastric emptying (and probably also small intestinal transit) enables them to target postprandial hyperglycaemia specifically, providing the rationale for their increasing use in combination with basal insulin which is effective in the management of fasting/preprandial hyperglycaemia. GI symptoms are the most commonly reported adverse events, and account for a substantial proportion of withdrawals in clinical trials of GLP-1 Ras. Major limitations to the available information in this area are that collection of GI symptom data has almost always relied on self-reports by patients in an ad hoc manner, rather than validated assessment tools, and has in most cases involved comparison of one GLP-1 RA with another, so that the rate of underlying gut symptoms in the patient population has not been taken into account. Furthermore, most studies in this area have been open-label, and typically have not reported what patients were told to expect in the information provided at enrolment. Thus, symptom reporting may potentially have been influenced by an expectation of adverse GI effects (“nocebo” effect), or of one drug being less prone to GI effects than another (“precebo” effect). When people in the general population are questioned specifically, the prevalence of GI symptoms is high, with up to 20% of communitydwelling adults suffering from weekly acid reflux, and approximately 10% to 15% reporting symptoms consistent with functional dyspepsia and irritable bowel syndrome (IBS). Indeed, the issue of selection of “healthy” controls is often inadequately considered; in one study that examined recruitment of non-patients as a control group for those with IBS, about one third were reclassified subsequently as “non-healthy” on the basis of a validated GI symptom questionnaire. Chronic GI symptoms have an important negative impact on quality of life and contribute substantially to healthcare costs. Symptom “turnover” occurs frequently, but the prevalence remains relatively constant because the onset of symptoms is balanced by their disappearance. In type 1 and type 2 diabetes there is an increased prevalence of upper and lower GI symptoms when compared with ageand sexmatched controls, although their pathogenesis remains poorly defined. Studies of patients drawn from specialized tertiary referral centres may be subject to bias, but an excess of symptoms is also apparent in large community-based surveys. For example, upper GI symptoms such as nausea or bloating were reported in approximately 15% of people with diabetes compared to 12% of controls, diarrhea was reported in 16% vs 10%, respectively, and constipation was reported in 11% vs 9%, respectively; overall, more than 40% of people with diabetes had at least one GI symptom during the preceding 3 months. Symptoms are reported by women more often than men, with or without diabetes, and those with psychological co-morbidity, such as anxiety or depression, are at greater risk. Symptoms are often not volunteered, especially those deemed embarrassing, such as faecal incontinence. GI symptoms are probably more prevalent with worsening glycaemic control, but appear unrelated to the duration of diabetes. Of particular relevance to type 2 diabetes is that, in the general population, obesity is an independent risk factor for “oesophageal” symptoms, abdominal pain and diarrhea. GI symptoms in diabetes may reflect disordered gut motility secondary to autonomic dysfunction; in particular, gastric emptying is Correspondence Christopher K. Rayner MBBS, PhD, Discipline of Medicine and Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, Australia. Email: chris.rayner@adelaide.edu.au. Received: 31 October 2016 Accepted: 4 November 2016

Long-term mortality of critically ill patients with diabetes who survive admission to the intensive care unit.

Abstract: OBJECTIVE: Long-term outcomes of critically ill patients with diabetes are unknown. Our objectives were to evaluate the effect of diabetes on both long-term survival rates and the average number of years of life lost for patients admitted to an intensive care unit who survived to hospital discharge. DESIGN AND PARTICIPANTS: A data linkage study evaluating all adult patients in South Australia between 2004 and 2011 who survived hospitalisation that required admission to a public hospital ICU. MAIN OUTCOME MEASURES: All patients were evaluated using hospital coding for diabetes, which was crossreferenced with registration with the Australian National Diabetes Services Scheme for a diagnosis of diabetes. This dataset was then linked to the Australian National Death Index. Longitudinal survival was assessed using Cox proportional hazards regression. Life-years lost were calculated using age- and sex-specific life-tables from the Australian Bureau of Statistics. RESULTS: 5450 patients with diabetes and 17 023 patients without diabetes were included. Crude mortality rates were 105.5 per 1000 person-years (95% CI, 101.6-109.6 per 1000 person-years) for patients with diabetes, and 67.6 per 1000 person-years (95% CI, 65.9-69.3 per 1000 personyears) for patients without diabetes. Patients with diabetes were older and had higher illness severity scores on admission to the ICU, were more likely to die after hospital discharge (unadjusted hazard ratio [HR], 1.52 [95% CI, 1.45-1.59]; adjusted HR, 1.16 [95% CI, 1.10-1.21]; P < 0.0001) and suffered a greater number of average lifeyears lost. CONCLUSIONS: Our study indicates that crude mortality for ICU survivors with pre-existing diabetes is considerable after hospital discharge, and the risk of mortality is greater than for survivors without diabetes.

Impact of artificial sweeteners on glycaemic control in healthy humans

Abstract: R.L. Young, N.J. Isaacs, G. Schober, T. Wu, N. Cvijanovic, N. Pezos, M. Bound, D.J. Keating, C.K. Rayner, M. Horowitz; Medicine, The University of Adelaide, Adelaide, Australia, Nutrition & Metabolism, South Australian Health & Medical Research Institute, Adelaide, Australia, Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide, Australia, Human Physiology, Flinders University, Adelaide, Australia.

Effects of small intestinal glucose on glycaemia, insulinaemia and incretin hormone release are load-dependent in obese subjects.

Abstract: Studies concerning the glycaemic response to oral glucose, or meals in obesity have usually failed to account for gastric emptying. It has been suggested that the incretin effect may be diminished in obesity as a result of a reduction in glucagon-like peptide-1 (GLP-1) secretion. We sought to determine the effect of two different rates of intraduodenal glucose infusions on glycaemic, insulinaemic and incretin hormone responses in lean and obese subjects and compare the effects of oral and intraduodenal glucose in obese subjects. Eleven obese subjects (age 37.5±4.1 years, body mass index (BMI) 35.7±1.4 kg m−2) and 12 controls (age 34.7±4.0 years, BMI 23.9±0.7 kg m−2) received intraduodenal infusions of glucose at 1 or 3 kcal min−1, or saline for 60 min (t=0–60 min), followed by intraduodenal saline (t=60–120 min). In obese subjects, an oral glucose tolerance test was performed. Blood glucose, serum insulin, plasma total GLP-1 and total gastric inhibitory polypeptide (GIP) were measured. In both the groups (P<0.001), the incremental areas under the curve (iAUC)0–60 min for glucose was greater with the 3 kcal min−1 than the 1 kcal min−1 infusion; the iAUC0–120 min for glucose during 3 kcal min−1 was greater (P<0.05), in the obese. Insulin responses to 1 kcal min−1 and, particularly, 3 kcal min−1 were greater (P<0.001) in the obese. Stimulation of GLP-1 and GIP were greater (P<0.001) in response to 3 kcal min−1, compared with 1 kcal min−1 and saline, without any difference between the groups. In the obese, glycaemic, insulinaemic and GIP, but not GLP-1, responses to oral and intraduodenal glucose were related (P<0.05). The rate of duodenal glucose delivery is a major determinant of glycaemia, insulinaemia and incretin hormone release in obese subjects. Obesity is not apparently associated with impaired GLP-1 secretion.

Comparative effects of glucose and water drinks on blood pressure and cardiac function in older subjects with and without postprandial hypotension.

Abstract: Postprandial hypotension (PPH) occurs frequently and is thought to reflect an inadequate increase in cardiac output to compensate for the rise in splanchnic blood flow after a meal. Gastric distension by water attenuates the postprandial fall in blood pressure (BP). Cardiac hemodynamics (stroke volume (SV), cardiac output (CO), and global longitudinal strain (GLS)) have hitherto not been measured in PPH. We sought to determine the comparative effects of water and glucose drinks on cardiac hemodynamics in healthy older subjects and individuals with PPH. Eight healthy older subjects (age 71.0 ± 1.7 years) and eight subjects with PPH (age 75.5 ± 1.0 years) consumed a 300 mL drink of either water or 75 g glucose (including 150 mg 13C-acetate) in randomized order. BP and heart rate (HR) were measured using an automatic device, SV, CO, and GLS by transthoracic echocardiography and gastric emptying by measurement of 13CO2. In both groups, glucose decreased systolic BP (P < 0.001) and increased HR, SV, and CO (P < 0.05 for all). The fall in systolic BP was greater (P < 0.05), and increase in HR less (P < 0.05), in the PPH group, with no difference in SV or CO. Water increased systolic BP (P < 0.05) in subjects with PPH and, in both groups, decreased HR (P < 0.05) without affecting SV, CO, or GLS. In subjects with PPH, the hypotensive response to glucose and the pressor response to water were related (R = −0.75, P < 0.05). These observations indicate that, in PPH, the hypotensive response to oral glucose is associated with inadequate compensatory increases in CO and HR, whereas the pressor response to water ingestion is maintained and, possibly, exaggerated.

Persistent hemifacial spasm after microvascular decompression: a risk assessment model.

Abstract: Objective: Microvascular decompression (MVD) for hemifacial spasm (HFS) provides resolution of disabling symptoms such as eyelid twitching and muscle contractions of the entire hemiface. The primar...

Gastrointestinal motility in people with type 1 diabetes and peripheral neuropathy.

Abstract: To the Editor: We read with interest the recent paper by Farmer et al [1]. These authors studied 48 individuals with type 1 diabetes (mean age 50 years and mean duration of diabetes, 32 years) with diabetic sensorimotor polyneuropathy (DSPN); they reported that, as assessed by a wireless motility capsule (WMC) test, gastric emptying, and small intestinal and colonic transit were delayed in this group when compared with age-matched healthy control participants. The paper raises several issues, specifically: