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Abstract Background The immune microenvironment impacts tumor growth, invasion, metastasis, and patient survival and may provide opportunities for therapeutic intervention in pancreatic ductal adenocarcinoma (PDAC). Although never studied as a potential modulator of the immune response in most cancers, Keratin 17 (K17), a biomarker of the most aggressive (basal) molecular subtype of PDAC, is intimately involved in the histogenesis of the immune response in psoriasis, basal cell carcinoma, and cervical squamous cell carcinoma. Thus, we hypothesized that K17 expression could also impact the immune cell response in PDAC, and that uncovering this relationship could provide insight to guide the development of immunotherapeutic opportunities to extend patient survival. Methods Multiplex immunohistochemistry (mIHC) and automated image analysis based on novel computational imaging technology were used to decipher the abundance and spatial distribution of T cells, macrophages, and tumor cells, relative to K17 expression in 235 PDACs. Results K17 expression had profound effects on the exclusion of intratumoral CD8+ T cells and was also associated with decreased numbers of peritumoral CD8+ T cells, CD16+ macrophages, and CD163+ macrophages (p

Abstract Background Gastric emptying (GE), with wide inter-individual but lesser intra-individual variations, is a major determinant of postprandial glycaemia in health and type 2 diabetes (T2D). However, it is uncertain whether GE of a carbohydrate-containing liquid meal is predictive of the glycaemic response to physiological meals, and whether antecedent hyperglycaemia influences GE in T2D. We evaluated the relationships of (i) the glycaemic response to both a glucose drink and mixed meals with GE of a 75 g glucose drink, and (ii) GE of a glucose drink with antecedent glycaemic control, in T2D. Methods Fifty-five treatment-naive Chinese adults with newly diagnosed T2D consumed standardised meals at breakfast, lunch and dinner with continuous interstitial glucose monitoring. On the subsequent day, a 75 g glucose drink containing 150 mg 13C-acetate was ingested to assess GE (breath test) and plasma glucose response. Serum fructosamine and HbA1c were also measured. Results Plasma glucose incremental area under the curve (iAUC) within 2 hours after oral glucose was related inversely to the gastric half-emptying time (T50) (r = −0.34, P = 0.012). The iAUCs for interstitial glucose within 2 hours after breakfast (r = −0.34, P = 0.012) and dinner (r = −0.28, P = 0.040) were also related inversely to the T50 of oral glucose. The latter, however, was unrelated to antecedent fasting plasma glucose, 24-hour mean interstitial glucose, serum fructosamine, or HbA1c. Conclusions In newly diagnosed, treatment-naive, Chinese with T2D, GE of a 75 g glucose drink predicts the glycaemic response to both a glucose drink and mixed meals, but is not influenced by spontaneous short-, medium- or longer-term elevation in glycaemia.

It is well established that high-protein diets (i.e. ~25–30% of energy intake from protein) provide benefits for achieving weight loss, and subsequent weight maintenance, in individuals with obesity, and improve glycemic control in type 2 diabetes (T2D). These effects may be attributable to the superior satiating property of protein, at least in part, through stimulation of both gastrointestinal (GI) mechanisms by protein, involving GI hormone release and slowing of gastric emptying, as well as post-absorptive mechanisms facilitated by circulating amino acids. In contrast, there is evidence that the beneficial effects of greater protein intake on body weight and glycemia may only be sustained for 6–12 months. While both suboptimal dietary compliance and metabolic adaptation, as well as substantial limitations in the design of longer-term studies are all likely to contribute to this contradiction, the source of dietary protein (i.e. animal vs. plant) has received inappropriately little attention. This issue has been highlighted by outcomes of recent epidemiological studies indicating that long-term consumption of animal-based protein may have adverse effects in relation to the development of obesity and T2D, while plant-based protein showed either protective or neutral effects. This review examines information relating to the effects of dietary protein on appetite, energy intake and postprandial glycemia, and the relevant GI functions, as reported in acute, intermediate- and long-term studies in humans. We also evaluate knowledge relating to the relevance of the dietary protein source, specifically animal or plant, to the prevention, and management, of obesity and T2D.

Introduction To use the ‘gold standard’ technique of scintigraphy to quantify gastric emptying (GE) as soon as practicable during an admission with diabetic ketoacidosis (DKA) and following its resolution at least 7 days later.Research design and methods Five patients with type 1 diabetes, age 29±12 years; Body Mass Index 23±3 kg/m2; hemoglobin A1c 11.3%±1.9%, were studied during an admission with DKA and following its resolution. Solid and liquid GE were measured using scintigraphy. Solid emptying was assessed via the percentage intragastric retention at 100 min and that of liquid by the 50% emptying time.Results There was no difference in either solid or liquid GE at the initial study compared with the follow-up. Median (IQR) solid retention was 47±20 versus 38%±33%, respectively; p=0.31, and time to empty 50% of liquid was 37±25 min versus 35±15 min, p=0.31, at the initial and follow-up GE study, respectively.Conclusions GE of solids and liquids is not affected by moderate DKA, inferring that earlier reintroduction of oral intake may be appropriate.

Abstract Background Caloric supplements are increasingly used by older people, aiming to increase their daily protein intake. These high caloric drinks, rich in glucose and whey-protein in particular, may result in potential harmful decreases in blood pressure (BP). The effect of ingesting whey-protein with glucose and fat on BP is unknown. It has also been assumed that the maximum fall in systolic blood pressure occurs within 2 h of a meal. Methods This study aimed to determine in older men, the effects of whey-protein, alone and mixed with other macronutrients, on systolic (SBP) and diastolic (DBP) blood pressure and heart rate (HR) in older men for 3 h. Thirteen older men (age 75 ± 2yrs; body mass index (BMI) 25.6 ± 0.6 kg/m2) ingested a drink on separate study days: (i) 70 g whey-protein (P280); (ii) 14 g whey-protein, 28 g carbohydrate, 12.4 g fat (M280); (iii) 70 g whey-protein, 28 g carbohydrate, 12.4 g fat (M504); or (iv) a non-caloric control drink (C). Results SBP decreased after all three nutrient drinks compared to the C, with the greatest reduction after the M504 drink (P = 0.008). Maximal decreases in SBP (C: -14 ± 2 mmHg, P280: -22 ± 2 mmHg, M280: -22 ± 4 mmHg, M504: -24 ± 3 mmHg) occurred about 2 h after drink ingestion and this fall was sustained thereafter (120-180 min: P280 and M504 vs. C P

Background: The pattern of the plasma glucose response curve during an oral glucose tolerance test (OGTT) is of prognostic significance with “biphasic” when compared with “monophasic” patterns being associated with greater insulin sensitivity/secretion and a reduced risk of progression to diabetes. The relationships of the glucose response curves with gastric emptying and incretin hormone secretion are not known. Methods: Thirty-six adults (age > 65 years) without known diabetes consumed a 300 mL drink containing 75 g glucose and 150 mg C13-acetate at baseline and follow-up after 5.8 ± 0.1 years. Plasma glucose, glucagon-like peptide-1 (GLP-1), glucose independent insulinotropic polypeptide (GIP) and insulin were measured, and participants classified according to the pattern of their glucose response. Gastric emptying was measured on breath samples (stable isotope breath test). Results: At baseline, 22 participants had a “monophasic” and 14 a “biphasic” glucose response. The 1 h plasma glucose response curve was greater and the GLP-1 AUC0–120 min and insulin secretion lower in the monophasic group. There were no differences in gastric emptying, GIP or insulin sensitivity. At the follow-up, the 1 h glucose response curve was greater again, while GLP-1 AUC0–120 min was lower in the monophasic group. Conclusions: A biphasic curve is associated with a higher 60 min glucose response curve and increases in GLP-1, but no difference in either GIP or gastric emptying.

Intraduodenal quinine, in the dose of 600 mg, stimulates glucagon-like peptide-1 (GLP-1), cholecystokinin and insulin; slows gastric emptying (GE); and lowers post-meal glucose in men. Oral sensitivity to bitter substances may be greater in women than men. We, accordingly, evaluated the dose-related effects of quinine on GE, and the glycaemic responses to, a mixed-nutrient drink in females, and compared the effects of the higher dose with those in males. A total of 13 female and 13 male healthy volunteers received quinine-hydrochloride (600 mg (‘QHCl-600’) or 300 mg (‘QHCl-300’, females only) or control (‘C’), intraduodenally (10 mL bolus) 30 min before a drink (500 kcal, 74 g carbohydrates). Plasma glucose, insulin, C-peptide, GLP-1, glucose-dependent insulinotropic polypeptide (GIP) and cholecystokinin were measured at baseline, for 30 min after quinine alone, and then for 2 h post-drink. GE was measured by 13C-acetate breath-test. QHCl-600 alone stimulated insulin, C-peptide and GLP-1 secretion compared to C. Post-drink, QHCl-600 reduced plasma glucose, stimulated C-peptide and GLP-1, and increased the C-peptide/glucose ratio and oral disposition index, while cholecystokinin and GIP were less, in females and males. QHCl-600 also slowed GE compared to C in males and compared to QHCl-300 in females (p < 0.05). QHCl-300 reduced post-meal glucose concentrations and increased the C-peptide/glucose ratio, compared to C (p < 0.05). Magnitudes of glucose lowering and increase in C-peptide/glucose ratio by QHCl-600 were greater in females than males (p < 0.05). We conclude that quinine modulates glucoregulatory functions, associated with glucose lowering in healthy males and females. However, glucose lowering appears to be greater in females than males, without apparent differential effects on GI functions.

Abstract 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

Dietary protein causes dose-dependent hyperglycemia in individuals with type 1 diabetes (T1D). This study investigated the effect of consuming 50 g of protein on overnight blood glucose levels (BGLs) following late-afternoon moderate-intensity exercise. Six participants (3M:3F) with T1D, HbA1c 7.5 ± 0.8% (58.0 ± 8.7 mmol/mol) and aged 20.2 ± 3.1 years exercised for 45 min at 1600 h and consumed a protein drink or water alone at 2000 h, on two separate days. A basal insulin euglycemic clamp was employed to measure the mean glucose infusion rates (m-GIR) required to maintain euglycemia on both nights. The m-GIR on the protein and water nights during the hypoglycemia risk period and overnight were 0.27 ± 043 vs. 1.60 ± 0.66 mg/kg/min (p = 0.028, r = 0.63) and 0.51 ± 0.16 vs. 1.34 ± 0.71 mg/kg/min (p = 0.028, r = 0.63), respectively. Despite ceasing intravenous glucose infusion on the protein night, the BGLs peaked at 9.6 ± 1.6 mmol/L, with a hypoglycemia risk period mean of 7.8 ± 1.5 mmol/L compared to 5.9 ± 0.4 mmol/L (p = 0.028) on the water night. The mean plasma glucagon levels were 51.5 ± 14.1 and 27.2 ± 10.1 ng/L (p = 0.028) on the protein and water night, respectively. This suggests that an intake of protein is effective at reducing the post-exercise hypoglycemia risk, potentially via a glucagon-mediated stimulation of glucose production. However, 50 g of protein may be excessive for maintaining euglycemia.

Background: Gastrointestinal symptoms have been reported to occur frequently in diabetes, but their prevalence in Chinese community-dwelling individuals with diabetes is unknown. The present study aimed to address this issue and explore the risk factors for gastrointestinal symptoms. Methods: A total of 1304 community-dwelling participants (214 with diabetes, 360 with prediabetes and 730 with normoglycemia) were surveyed for gastrointestinal symptoms using the Diabetes Bowel Symptom Questionnaire. Logistic regression analyses were applied to identify risk factors for gastrointestinal symptoms. Results: Of the overall study population, 18.6% reported at least one gastrointestinal symptom, without a significant difference between subjects with normoglycemia (17.7%), prediabetes (19.7%) and diabetes (20.1%). In all three groups, lower gastrointestinal symptoms, particularly diarrhea and constipation, were the most frequent. There was an interaction between age (≥65 years) and diabetes on the prevalence of at least one gastrointestinal symptom (p = 0.01) and of constipation (p = 0.004), with these being most frequent in subjects with diabetes aged ≥ 65 years. After multivariable adjustment, female gender and older age were associated with increased odds of at least one gastrointestinal symptom, specifically lower gastrointestinal symptoms. Older age was also associated with an increase in upper gastrointestinal symptoms. Conclusions: Gastrointestinal symptoms are common in Chinese community-dwelling adults with and without diabetes. Females, and the elderly with diabetes, are at an increased risk of symptoms.

Abstract Background Postprandial hypotension (PPH) occurs frequently in the elderly and patients with type 2 diabetes, and lacks a satisfactory treatment. Gastric distension and the α-glucosidase inhibitor, acarbose, may attenuate the postprandial fall in blood pressure (BP) by complementary mechanisms. We aimed to determine whether gastric distension and acarbose have additive effects to attenuate the fall in BP induced by oral sucrose. Methods Ten healthy older adults (74.0 ± 1.4 yr) had measurements of BP and superior mesenteric artery (SMA) blood flow for 120 min after receiving either (i) the ‘study drink’ of 100 g sucrose in 300 mL of water (control treatment), (ii) a 300 mL water ‘preload’ 15 min before the ‘study drink’ (distension treatment), (iii) 100 mg acarbose dissolved in the ‘study drink’ (acarbose treatment) or (iv) a 300 ml water ‘preload’ 15 min before 100 mg acarbose dissolved in the ‘study drink’ (acarbose and distension treatment). Results The area under the curve (AUC)0–120min for mean arterial pressure (MAP) was greater (P = 0.005) and the maximum fall in MAP was less (P = 0.006) during treatments with acarbose. Gastric distension did not affect the MAP-AUC0–120min response to acarbose (P = 0.44) and there was no effect of gastric distension alone (P = 0.68). Both acarbose treatments attenuated the rise in SMA blood flow (P = 0.003), whereas gastric distension had no effect. Conclusions In healthy older adults, acarbose (100 mg), but not gastric distension, attenuates the fall in BP and rise in SMA blood flow after oral sucrose. The observations support the use of acarbose, but not gastric distension, to attenuate a postprandial fall in BP. Trial registration The study was retrospectively registered at (ACTRN12618000152224) on February 02nd 2018.

The ingestion of dietary protein with, or before, carbohydrate may be a useful strategy to reduce postprandial hyperglycemia, but its effect in older people, who have an increased predisposition for type 2 diabetes, has not been clarified. Blood glucose, plasma insulin and glucagon concentrations were measured for 180 min following a drink containing either glucose (120 kcal), whey-protein (120 kcal), whey-protein plus glucose (240 kcal) or control (~2 kcal) in healthy younger (n = 10, 29 ± 2 years; 26.1 ± 0.4 kg/m2) and older men (n = 10, 78 ± 2 years; 27.3 ± 1.4 kg/m2). Mixed model analysis was used. In both age groups the co-ingestion of protein with glucose (i) markedly reduced the increase in blood glucose concentrations following glucose ingestion alone (p < 0.001) and (ii) had a synergistic effect on the increase in insulin concentrations (p = 0.002). Peak insulin concentrations after protein were unaffected by ageing, whereas insulin levels after glucose were lower in older than younger men (p < 0.05) and peak insulin concentrations were higher after glucose than protein in younger (p < 0.001) but not older men. Glucagon concentrations were unaffected by age. We conclude that the ability of whey-protein to reduce carbohydrate-induced postprandial hyperglycemia is retained in older men and that protein supplementation may be a useful strategy in the prevention and management of type 2 diabetes in older people.

Postprandial hypotension (PPH) occurs frequently in older people >65 years old. Protein-rich supplements, particularly whey protein (WP), are increasingly used by older people for various health benefits. We have reported that 70 g WP drinks cause significant, and in some cases marked, falls in blood pressure (BP) in older men. The effects of lower, more widely used, doses (~30 g) on systolic (SBP) and diastolic (DBP) blood pressure and heart rate (HR) are not known. In a randomized order, eight older men (age: 72 ± 1 years; body mass index (BMI): 25 ± 1 kg/m2) after overnight fast ingested a drink containing (i) a non-caloric control (~2 kcal), (ii) 30 g of whey protein (120 kcal; ‘WP30’), or (iii) 70 g of whey protein (280 kcal; ‘WP70’). The BP and HR were measured in this pilot study with an automated device before and at 3-min intervals for 180 min following drink ingestion. Drink condition effects were determined by repeated-measures ANOVA. The SBP decreased after both WP drinks compared to the control (p = 0.016), particularly between 120 and 180 min, with no difference in the effects of WP30 and WP70. The SBP decreased by ≥20 mmHg in more than 50% of people after both WP drinks (WP30: 63%; WP70: 75%) compared to 38% after the control. The maximum fall in the SBP occurred during the third hour, with the nadir occurring latest after WP70. The DBP decreased non-significantly by several mmHg more after the WP drinks than after the control. The maximum HR increases occurred during the third hour, with the greatest increase after WP70. The SBP decreased after both WP drinks compared to the control, with the effects most evident between 120 and 180 min. Accordingly, ingestion of even relatively modest protein loads in older men has the potential to cause PPH.

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.

Introduction The insulinotropic capacity of exogenous glucagon like peptide-1 (GLP-1) is reduced in type 2 diabetes and the insulin-resistant obese. We have tested the hypothesis that this response is the consequence of a reduced pancreatic GLP-1 receptor (GLP-1r) density in insulin-resistant obese animals.Research design and methods GLP-1r density was measured in lean and insulin-resistant adult miniature pigs after the administration of a 68Ga-labeled GLP-1r agonist. The effect of hyperinsulinemia on GLP-1r was assessed using sequential positron emission tomography (PET), both in the fasted state and during a clamp. The impact of tissue perfusion, which could account for changes in GLP-1r agonist uptake, was also investigated using 68Ga-DOTA imaging.Results GLP-1r binding potential in the obese pancreas was reduced by 75% compared with lean animals. Similar reductions were evident for fat tissue, but not for the duodenum. In the lean group, induced hyperinsulinemia reduced pancreatic GLP-1r density to a level comparable with that of the obese group. The reduction in blood to tissue transfer of the GLP-1r ligand paralleled that of tissue perfusion estimated using 68Ga-DOTA.Conclusions These observations establish that a reduction in abdominal tissue perfusion and a lower GLP-1r density account for the diminished insulinotropic effect of GLP-1 agonists in type 2 diabetes.

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.

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 [...]

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.

(1) Background: Whey protein lowers postprandial blood glucose in health and type 2 diabetes, by stimulating insulin and incretin hormone secretion and slowing gastric emptying. The branched-chain amino acids, leucine, isoleucine and valine, abundant in whey, may mediate the glucoregulatory effects of whey. We investigated the comparative effects of intragastric administration of leucine, isoleucine and valine on the plasma glucose, C-peptide and glucagon responses to and gastric emptying of a mixed-nutrient drink in healthy men. (2) Methods: 15 healthy men (27 ± 3 y) received, on four separate occasions, in double-blind, randomised fashion, either 10 g of leucine, 10 g of isoleucine, 10 g of valine or control, intragastrically, 30 min before a mixed-nutrient drink. Plasma glucose, C-peptide and glucagon concentrations were measured before, and for 2 h following, the drink. Gastric emptying of the drink was quantified using 13C-acetate breath-testing. (3) Results: Amino acids alone did not affect plasma glucose or C-peptide, while isoleucine and valine, but not leucine, stimulated glucagon (p < 0.05), compared with control. After the drink, isoleucine and leucine reduced peak plasma glucose compared with both control and valine (all p < 0.05). Neither amino acid affected early (t = 0–30 min) postprandial C-peptide or glucagon. While there was no effect on overall gastric emptying, plasma glucose at t = 30 min correlated with early gastric emptying (p < 0.05). (4) Conclusion: In healthy individuals, leucine and isoleucine lower postprandial blood glucose, at least in part by slowing gastric emptying, while valine does not appear to have an effect, possibly due to glucagon stimulation.

We present a case of a 20-year-old man with tetralogy of Fallot status post-repair with a transannular patch and left pulmonary artery reconstruction at age 1 and subsequent pulmonary valve replacement with bioprosthetic valve 3 years ago. A transthoracic echocardiogram revealed severe bioprosthetic valve insufficiency. Cardiac magnetic resonance with 4-dimensional flow revealed a paravalvular leak. (Level of Difficulty: Intermediate.)

Sensing nutrients within the gastrointestinal tract engages the enteroendocrine cell system to signal within the mucosa, to intrinsic and extrinsic nerve pathways, and the circulation. This signaling provides powerful feedback from the intestine to slow the rate of gastric emptying, limit postprandial glycemic excursions, and induce satiation. This review focuses on the intestinal sensing of sweet stimuli (including low-calorie sweeteners), which engage similar G-protein-coupled receptors (GPCRs) to the sweet taste receptors (STRs) of the tongue. It explores the enteroendocrine cell signals deployed upon STR activation that act within and outside the gastrointestinal tract, with a focus on the role of this distinctive pathway in regulating glucose transport function via absorptive enterocytes, and the associated impact on postprandial glycemic responses in animals and humans. The emerging role of diet, including low-calorie sweeteners, in modulating the composition of the gut microbiome and how this may impact glycemic responses of the host, is also discussed, as is recent evidence of a causal role of diet-induced dysbiosis in influencing the gut-brain axis to alter gastric emptying and insulin release. Full knowledge of intestinal STR signaling in humans, and its capacity to engage host and/or microbiome mechanisms that modify glycemic control, holds the potential for improved prevention and management of type 2 diabetes.

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.

Bile acids are cholesterol-derived metabolites with a well-established role in the digestion and absorption of dietary fat. More recently, the discovery of bile acids as natural ligands for the nuclear farnesoid X receptor (FXR) and membrane Takeda G-protein-coupled receptor 5 (TGR5), and the recognition of the effects of FXR and TGR5 signaling have led to a paradigm shift in knowledge regarding bile acid physiology and metabolic health. Bile acids are now recognized as signaling molecules that orchestrate blood glucose, lipid and energy metabolism. Changes in FXR and/or TGR5 signaling modulates the secretion of gastrointestinal hormones including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), hepatic gluconeogenesis, glycogen synthesis, energy expenditure, and the composition of the gut microbiome. These effects may contribute to the metabolic benefits of bile acid sequestrants, metformin, and bariatric surgery. This review focuses on the role of bile acids in energy intake and body weight, particularly their effects on gastrointestinal hormone secretion, the changes in obesity and T2D, and their potential relevance to the management of metabolic disorders.

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.

Ageing is associated with changes in feeding behavior. We have reported that there is suppression of energy intake three hours after whey protein drink ingestion in young, but not older, men. This study aimed to determine these effects over a time period of 9 h. Fifteen younger (27 ± 1 years, 25.8 ± 0.7 kg/m2) and 15 older (75 ± 2 years, 26.6 ± 0.8 kg/m2) healthy men were studied on three occasions on which they received, in a randomized order, a 30 g/120 kcal, 70 g/280 kcal whey-protein, or control (~2 kcal) drink. Ad-libitum energy intake (sum of breakfast, lunch, and dinner) was suppressed in a protein load responsive fashion (P = 0.001). Suppression was minimal at breakfast, substantial at lunch (~−16%, P = 0.001), no longer present by dinner, and was less in older than younger men (−3 ± 4% vs. −8 ± 4%, P = 0.027). Cumulative protein intake was increased in the younger and older men (+20% and +42%, P < 0.001). Visual analogue scale ratings of fullness were higher and desire to eat and prospective food consumption were lower after protein vs. control, and these effects were smaller in older vs. younger men (interaction effect P < 0.05). These findings support the use of whey-protein drink supplements in older people who aim to increase their protein intake without decreasing their overall energy intake.

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

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 ± 1 years). In each part, participants received on three separate occasions, in randomised, double-blind fashion, 5 g (Phe-5 g) or 10g (‘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 = −0.4, p = 0.027), and tended to be associated with stimulation of PYY (r = −0.31, p = 0.082). Both Phe-10 g and Phe-5 g stimulated insulin and glucagon (all p < 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.

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

The gastrointestinal tract stores ingested nutrients in the stomach which are then delivered to the small intestine at a controlled rate to optimize their digestion and absorption. The interaction of nutrients with the small and large intestine generates feedback that slows gastric emptying, induces satiation, and reduces postprandial glycemic excursions. The mechanisms underlying these nutrient-gut interactions are complex; it has only recently been appreciated that the gut has the capacity to detect intraluminal contents in much the same way as the tongue, via activation of specific G-protein-coupled receptors, and that ensuing signaling mechanisms modulate the release of an array of gut hormones that influence gastrointestinal motility, appetite and glycemia. Interestingly, evidence from preclinical models supports a functional link between intestinal bitter taste receptor (BTRs) and gastrointestinal hormone secretion, and the outcomes of recent studies indicate that stimulation of intestinal BTRs may be used to modulate gastrointestinal function, to diminish energy intake and limit postprandial blood glucose excursions in humans. This review summarizes current evidence about the expression and function of intestinal BTRs in relation to enteroendocrine hormone release and discusses the clinical implications of this pathway for the management of obesity and type 2 diabetes.

A whey protein/guar gum preload reduces postprandial glycaemia in type 2 diabetes through slowing gastric emptying. However, gastric emptying has previously been assessed using a stable isotope breath test technique, which cannot discriminate between slowing of gastric emptying and small intestinal absorption. This preload also may be useful in the management of postprandial hypotension. We evaluated the effects of a whey protein/guar preload on gastric emptying, glucose absorption, glycaemic/insulinaemic and blood pressure (BP) responses to an oral glucose load. Eighteen healthy older participants underwent measurements of gastric emptying (scintigraphy), plasma glucose and insulin, glucose absorption, superior mesenteric artery (SMA) flow, BP and heart rate (HR) after ingesting a 50 g glucose drink, with or without the preload. The preload reduced plasma glucose (p = 0.02) and serum 3-O-methylglucose (3-OMG) (p = 0.003), and increased plasma insulin (p = 0.03). There was no difference in gastric emptying or BP between the two days. The reduction in plasma glucose on the preload day was related to the reduction in glucose absorption (r = 0.71, p = 0.002). In conclusion, the glucose-lowering effect of the preload may relate to delayed small intestinal glucose absorption and insulin stimulation, rather than slowing of gastric emptying.

The fatty acid, lauric acid (‘C12’), and the amino acid, tryptophan (‘Trp’), when given intraduodenally at loads that individually do not affect energy intake, have recently been shown to stimulate plasma cholecystokinin, suppress ghrelin and reduce energy intake much more markedly when combined. Both fatty acids and amino acids stimulate insulin secretion by distinct mechanisms; fatty acids enhance glucose-stimulated insulin secretion, while amino acids may have a direct effect on pancreatic β cells. Therefore, it is possible that, by combining these nutrients, their effects to lower blood glucose may be enhanced. We have investigated the potential for the combination of C12 and Trp to have additive effects to reduce blood glucose. To address this question, plasma concentrations of glucose, insulin and glucagon were measured in 16 healthy, lean males during duodenal infusions of saline (control), C12 (0.3 kcal/min), Trp (0.1 kcal/min), or C12+Trp (0.4 kcal/min), for 90 min. Both C12 and C12+Trp moderately reduced plasma glucose compared with control (p < 0.05). C12+Trp, but not C12 or Trp, stimulated insulin and increased the insulin-to-glucose ratio (p < 0.05). There was no effect on plasma glucagon. In conclusion, combined intraduodenal administration of C12 and Trp reduced fasting glucose in healthy men, and this decrease was driven primarily by C12. The effects of these nutrients on postprandial blood glucose and elevated fasting blood glucose in type 2 diabetes warrant evaluation.

The Stolen Island: Searching for 'Ata, by Scott Hamilton. Wellington: Bridget Williams Books, 2016. 112pp. ISBN 978-0-947518-11-0. LOCATED even further south than temperate Noumea, Tonga’s tiny island of ‘Ata might have become the jewel of the kingdom’s burgeoning tourist industry. Imagine a Tongan resort that would not only be mild in winter, but pleasant in summer.

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

Whey protein is rich in the branched-chain amino acids, L-leucine, L-isoleucine and L-valine. Thus, branched-chain amino acids may, at least in part, mediate the effects of whey to reduce energy intake and/or blood glucose. Notably, 10 g of either L-leucine or L-isoleucine, administered intragastrically before a mixed-nutrient drink, lowered postprandial blood glucose, and intraduodenal infusion of L-leucine (at a rate of 0.45 kcal/min, total: 9.9 g) lowered fasting blood glucose and reduced energy intake from a subsequent meal. Whether L-valine affects energy intake, and the gastrointestinal functions involved in the regulation of energy intake, as well as blood glucose, in humans, is currently unknown. We investigated the effects of intraduodenally administered L-valine on antropyloroduodenal pressures, plasma cholecystokinin, blood glucose and energy intake. Twelve healthy lean men (age: 29 ± 2 years, BMI: 22.5 ± 0.7 kg/m2) were studied on 3 separate occasions in randomised, double-blind order. Antropyloroduodenal pressures, plasma cholecystokinin, blood glucose, appetite perceptions and gastrointestinal symptoms were measured during 90-min intraduodenal infusions of L-valine at 0.15 kcal/min (total: 3.3 g) or 0.45 kcal/min (total: 9.9 g), or 0.9% saline (control). Energy intake from a buffet-meal immediately after the infusions was quantified. L-valine did not affect antral, pyloric (mean number; control: 14 ± 5; L-Val-0.15: 21 ± 9; L-Val-0.45: 11 ± 4), or duodenal pressures, plasma cholecystokinin (mean concentration, pmol/L; control: 3.1 ± 0.3; L-Val-0.15: 3.2 ± 0.3; L-Val-0.45: 3.0 ± 0.3), blood glucose, appetite perceptions, symptoms or energy intake (kcal; control: 1040 ± 73; L-Val-0.15: 1040 ± 81; L-Val-0.45: 1056 ± 100), at either load (p > 0.05 for all). In conclusion, intraduodenal infusion of L-valine, at loads that are moderately (3.3 g) or substantially (9.9 g) above World Health Organization valine requirement recommendations, does not appear to have energy intake- or blood glucose-lowering effects.

Factors underlying disturbed appetite perception in anorexia nervosa (AN) are poorly characterized. We examined in patients with AN whether fasting and postprandial appetite perceptions, gastrointestinal (GI) hormones, GI symptoms and state anxiety (i) differed from healthy controls (HCs) and (ii) were modified by two weeks of refeeding. 22 female adolescent inpatients with restricting AN, studied on hospital admission once medically stable (Wk0), and after one (Wk1) and two (Wk2) weeks of high-calorie refeeding, were compared with 17 age-matched HCs. After a 4 h fast, appetite perceptions, GI symptoms, state anxiety, and plasma acyl-ghrelin, cholecystokinin (CCK), peptide tyrosine tyrosine (PYY) and pancreatic polypeptide (PP) concentrations were assessed at baseline and in response to a mixed-nutrient test-meal (479 kcal). Compared with HCs, in patients with AN at Wk0, baseline ghrelin, PYY, fullness, bloating and anxiety were higher, and hunger less, and in response to the meal, ghrelin, bloating and anxiety were greater, and hunger less (all p < 0.05). After two weeks of refeeding, there was no change in baseline or postprandial ghrelin or bloating, or postprandial anxiety, but baseline PYY, fullness and anxiety decreased, and baseline and postprandial hunger increased (p < 0.05). We conclude that in AN, refeeding for 2 weeks was associated with improvements in PYY, appetite and baseline anxiety, while increased ghrelin, bloating and postprandial anxiety persisted.

OBJECTIVE:Stress induced hyperglycemia occurs in critically ill patients who have normal glucose tolerance following resolution of their acute illness. The objective was to evaluate the association between stress induced hyperglycemia and incident diabetes in survivors of critical illness. DESIGN:Retrospective cohort study. SETTING:All adult patients surviving admission to a public hospital intensive care unit (ICU) in South Australia between 2004 and 2011. PATIENTS:Stress induced hyperglycemia was defined as a blood glucose ≥ 11.1 mmol/L (200 mg/dL) within 24 hours of ICU admission. Prevalent diabetes was identified through ICD-10 coding or prior registration with the Australian National Diabetes Service Scheme (NDSS). Incident diabetes was identified as NDSS registration beyond 30 days after hospital discharge until July 2015. The predicted risk of developing diabetes was described as sub-hazard ratios using competing risk regression. Survival was assessed using Cox proportional hazards regression. MAIN RESULTS:Stress induced hyperglycemia was identified in 2,883 (17%) of 17,074 patients without diabetes. The incidence of type 2 diabetes following critical illness was 4.8% (821 of 17,074). The risk of diabetes in patients with stress induced hyperglycemia was approximately double that of those without (HR 1.91 (95% CI 1.62, 2.26), p

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

Glutamine is a potent stimulus for the release of glucagon-like peptide-1, which increases postprandial insulin and slows gastric emptying (GE). We determined the effects of glutamine on GE of, and glycaemic responses to, low- and high-nutrient drinks in eight healthy males (mean age 21.6 ± 0.7 years and BMI 22.9 ± 0.7 kg/m2). Participants were studied on four occasions on which they consumed either a low-nutrient (beef soup; 18 kcal) or high-nutrient (75 g dextrose; 255 kcal) drink, each with or without 30 g of glutamine (120 kcal), in a randomised, crossover design. GE (2D ultrasound), blood glucose and plasma insulin concentrations were measured concurrently. Glutamine slowed GE (half emptying time (T50)) of both low- (45 ± 3 min vs. 26 ± 2 min, p < 0.001), and high-nutrient, (100 ± 5 min vs. 77 ± 5 min, p = 0.03) drinks, however, there was no effect on GE of the high nutrient drinks when expressed as kcal/min (3.39 ± 0.21 kcal/min vs. 3.81 ± 0.20 kcal/min, p = 0.25). There was no change in blood glucose after the low-nutrient drinks with or without glutamine, despite a slight increase in plasma insulin with glutamine (p = 0.007). The rise in blood glucose following the high-nutrient drink (p = 0.0001) was attenuated during the first 60 min by glutamine (p = 0.007). We conclude that in healthy subjects, glutamine slows GE of both low- and high-nutrient drinks comparably and attenuates the rise in blood glucose after the high-nutrient glucose drink.

Tryptophan stimulates plasma cholecystokinin and pyloric pressures, both of which slow gastric emptying. Gastric emptying regulates postprandial blood glucose. Tryptophan has been reported to decrease energy intake. We investigated the effects of intragastric tryptophan on the glycaemic response to, and gastric emptying of, a mixed-nutrient drink, and subsequent energy intake. Lean and obese participants (n = 16 each) received intragastric infusions of 1.5 g (“Trp-1.5g”) or 3.0 g (“Trp-3.0g”) tryptophan, or control, and 15 min later consumed a mixed-nutrient drink (56 g carbohydrates). Gastric emptying (13C-acetate breath-test), blood glucose, plasma C-peptide, glucagon, cholecystokinin and tryptophan concentrations were measured (t = 0–60 min). Energy intake was assessed between t = 60–90 min. In lean individuals, Trp-3.0g, but not Trp-1.5g, slowed gastric emptying, reduced C-peptideAUC and increased glucagonAUC (all P < 0.05), but did not significantly decrease the blood glucose response to the drink, stimulate cholecystokinin or reduce mean energy intake, compared with control. In obese individuals, Trp-3.0g, but not Trp-1.5g, tended to slow gastric emptying (P = 0.091), did not affect C-peptideAUC, increased glucagonAUC (P < 0.001) and lowered blood glucose at t = 30 min (P < 0.05), and did not affect cholecystokinin or mean energy intake. In obese individuals, intragastrically administered tryptophan may reduce postprandial blood glucose by slowing gastric emptying; the lack of effect on mean energy intake requires further investigation.

Protein-rich supplements are used widely for the prevention and management of malnutrition in older people. We have reported that healthy older, compared to younger, adults have less suppression of energy intake by whey-protein—effects on appetite-related hormones are unknown. The objective was to determine the effects of intraduodenally administered whey-protein on glucose, gut hormone, and amino acid concentrations, and their relation to subsequent ad libitum energy intake at a buffet meal, in healthy older and younger men. Hydrolyzed whey-protein (30 kcal, 90 kcal, and 180 kcal) and a saline control (~0 kcal) were infused intraduodenally for 60 min in 10 younger (19–29 years, 73 ± 2 kg, 22 ± 1 kg/m2) and 10 older (68–81 years, 79 ± 2 kg, 26 ± 1 kg/m2) healthy men in a randomized, double-blind fashion. Plasma insulin, glucagon, gastric inhibitory peptide (GIP), glucagon-like peptide-1 (GLP-1), peptide tyrosine-tyrosine (PYY), and amino acid concentrations, but not blood glucose, increased, while ghrelin decreased during the whey-protein infusions. Plasma GIP concentrations were greater in older than younger men. Energy intake correlated positively with plasma ghrelin and negatively with insulin, glucagon, GIP, GLP-1, PYY, and amino acids concentrations (p < 0.05). In conclusion, intraduodenal whey-protein infusions resulted in increased GIP and comparable ghrelin, insulin, glucagon, GIP, GLP-1, PYY, and amino acid responses in healthy older and younger men, which correlated to subsequent energy intake.

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

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.

The application of novel techniques to quantify gastric motor function and gastric emptying has yielded important insights into the prevalence, pathogenesis and clinical sequelae of gastroparesis. Both acute and chronic gastroparesis occur frequently; gastric emptying of solids is delayed in 30% to 50% of patients with diabetes mellitus, functional dyspepsia and gastroesophageal reflux disease. While many patients with gastroparesis experience upper gastrointestinal symptoms that adversely affect quality of life, the concept that symptoms are inevitably the direct outcome of delay in gastric emptying is now recognized to be overly simplistic. In contrast, the potential impact of gastroparesis on oral drug absorption and blood glucose control in patients with diabetes mellitus has probably been underestimated. While the use of prokinetic drugs (cisapride, domperidone, metoclopramide and erythromycin) forms the mainstay of therapy in symptomatic patients with gastroparesis, a number of novel pharmacological therapies are being evaluated, and preliminary studies using gastric pacing show promise.

It is not well recognized that in the elderly weight loss is more common than weight gain. The aim of this analysis was to determine the effect of ageing on appetite (hunger/fullness) and energy intake, after overnight fasting and in a postprandial state, by meta-analyses of trials that included at least two age groups (>18 years). We hypothesized that appetite and energy intake would be less in healthy older compared with younger adults. Following a PubMed-database systematic search up to 30 June 2015, 59 studies were included in the random-effects-model meta-analyses. Energy intake was 16%–20% lower in older (n = 3574/~70 years/~71 kg/~25 kg/m2) than younger (n = 4111/~26 years/~69 kg/~23 kg/m2) adults (standardized mean difference: −0.77 (95% confidence interval −0.90 to −0.64)). Hunger was 25% (after overnight fasting; weighted mean difference (WMD): −17 (−22 to −13) mm) to 39% (in a postprandial state; WMD: −14 (−19 to −9) mm) lower, and fullness 37% (after overnight fasting; WMD: 6 mm (95% CI: 1 to 11 mm)) greater in older than younger adults. In conclusion, appetite and energy intake are less in healthy older than younger adults, suggesting that ageing per se affects food intake.

This study determined the effects of increasing loads of intraduodenal (ID) dairy protein on plasma amino acid (AA) concentrations, and their relationships with serum insulin, plasma glucagon-like peptide-1 (GLP-1) and energy intake. Sixteen healthy men had concentrations of AAs, GLP-1 and insulin measured in response to 60-min ID infusions of hydrolysed whey protein administered, in double-blinded and randomised order, at 2.1 (P2.1), 6.3 (P6.3) or 12.5 (P12.5) kJ/min (encompassing the range of nutrient emptying from the stomach), or saline control (C). Energy intake was quantified immediately afterwards. Compared with C, the concentrations of 19/20 AAs, the exception being cysteine, were increased, and this was dependent on the protein load. The relationship between AA concentrations in the infusions and the area under the curve from 0 to 60 min (AUC0–60 min) of each AA profile was strong for essential AAs (R2 range, 0.61–0.67), but more variable for non-essential (0.02–0.54) and conditional (0.006–0.64) AAs. The AUC0–60 min for each AA was correlated directly with the AUC0–60 min of insulin (R2 range 0.3–0.6), GLP-1 (0.2–0.6) and energy intake (0.09–0.3) (p < 0.05, for all), with the strongest correlations being for branched-chain AAs, lysine, methionine and tyrosine. These findings indicate that ID whey protein infused at loads encompassing the normal range of gastric emptying increases plasma concentrations of 19/20 AAs in a load-dependent manner, and provide novel information on the close relationships between the essential AAs, leucine, valine, isoleucine, lysine, methionine, and the conditionally-essential AA, tyrosine, with energy intake, insulin and GLP-1.

The planarian Schmidtea mediterranea is a powerful model organism for studying stem cell biology due to its extraordinary regenerative ability mediated by neoblasts, a population of adult somatic stem cells. Elucidation of the S. mediterranea transcriptome and the dynamics of transcript expression will increase our understanding of the gene regulatory programs that regulate stem cell function and differentiation. Here, we have used RNA-Seq to characterize the S. mediterranea transcriptome in sexual and asexual animals and in purified neoblast and differentiated cell populations. Our analysis identified many uncharacterized genes, transcripts, and alternatively spliced isoforms that are differentially expressed in a strain or cell type-specific manner. Transcriptome profiling of purified neoblasts and differentiated cells identified neoblast-enriched transcripts, many of which likely play important roles in regeneration and stem cell function. Strikingly, many of the neoblast-enriched genes are orthologs of genes whose expression is enriched in human embryonic stem cells, suggesting that a core set of genes that regulate stem cell function are conserved across metazoan species.

Influenza viruses elude immune responses and antiviral chemotherapeutics through genetic drift and reassortment. As a result, the development of new strategies that attack a highly conserved viral function to prevent and/or treat influenza infection is being pursued. Such novel broadly acting antiviral therapies would be less susceptible to virus escape and provide a long lasting solution to the evolving virus challenge. Here we report the in vitro and in vivo activity of a human monoclonal antibody (A06) against two isolates of the 2009 H1N1 pandemic influenza virus. This antibody, which was obtained from a combinatorial library derived from a survivor of highly pathogenic H5N1 infection, neutralizes H5N1, seasonal H1N1 and 2009 "Swine" H1N1 pandemic influenza in vitro with similar potency and is capable of preventing and treating 2009 H1N1 influenza infection in murine models of disease. These results demonstrate broad activity of the A06 antibody and its utility as an anti-influenza treatment option, even against newly evolved influenza strains to which there is limited immunity in the general population.