ORCID Profile
0000-0003-1656-9210
Current Organisation
University of Adelaide
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-12-2015
Publisher: Wiley
Date: 17-12-2012
DOI: 10.1111/DOM.12043
Abstract: Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), secreted by enteroendocrine L-cells located most densely in the colon and rectum, are of fundamental importance in blood glucose and appetite regulation. In animal models, colonic administration of bile acids can stimulate GLP-1 and PYY by TGR5 receptor activation. We evaluated the effects of taurocholic acid (TCA), administered as an enema, on plasma GLP-1 and PYY, as well as gastrointestinal sensations in 10 healthy male subjects, and observed that rectal administration of TCA promptly stimulated secretion of both GLP-1 and PYY, and increased fullness, in a dose-dependent manner. These observations confirm that topical application of bile acids to the distal gut may have potential for the management of type 2 diabetes and obesity.
Publisher: Elsevier
Date: 2010
Publisher: MDPI AG
Date: 26-08-2022
DOI: 10.3390/NU14173506
Abstract: Background: Gastrointestinal symptoms have been reported to occur frequently in diabetes, but their prevalence in Chinese community-dwelling in iduals 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.
Publisher: Wiley
Date: 11-11-2014
DOI: 10.1111/DME.12622
Abstract: To evaluate the effects of the dipeptidyl peptidase-4 inhibitor sitagliptin on blood pressure and heart rate, measured during a previously reported study, in which the effects of sitagliptin during intraduodenal glucose infusion at the rate of 2 kcal/min on glucose homeostasis were examined in patients with Type 2 diabetes. A total of 10 people with Type 2 diabetes were studied on two different days, 30 min after oral ingestion of sitagliptin (100 mg) or placebo. Intraduodenal glucose was infused at 2 kcal/min (60 g over 120 min), and blood pressure, heart rate, plasma glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (total and intact), glucose, insulin and glucagon responses were evaluated. In response to intraduodenal glucose infusion, heart rate (treatment effect: P = 0.001) and serum insulin concentration (treatment × time interaction: P = 0.041) were higher after sitagliptin treatment than placebo, without a significant difference in blood pressure, plasma glucagon or glucose. During intraduodenal glucose infusion, there was a substantial increase in plasma total glucose-dependent insulinotropic polypeptide on both days (time effect: P < 0.001), but not in total glucagon-like peptide-1. After sitagliptin, plasma intact glucagon-like peptide-1 concentration increased slightly (treatment × time interaction: P = 0.044) and glucose-dependent insulinotropic polypeptide concentration increased substantially (treatment × time interaction: P = 0.003).The heart rate response to intraduodenal glucose was related directly to plasma intact glucose-dependent insulinotropic polypeptide concentrations (r = 0.75, P = 0.008). Sitagliptin increased the heart rate response to intraduodenal glucose infusion at 2 kcal/min in people with Type 2 diabetes, which was associated with augmentation of plasma intact glucose-dependent insulinotropic polypeptide concentrations. These observations warrant further clarification of a potential role for glucose-dependent insulinotropic polypeptide in the control of the 'gut-heart' axis.
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.COPH.2013.09.002
Abstract: The motility of the gastrointestinal (GI) tract is modulated by complex neural and hormonal networks the latter include gut peptides released from enteroendocrine cells during both the interdigestive and postprandial periods. Conversely, it is increasingly recognised that GI motility is an important determinant of gut hormone secretion, in that the transit of luminal contents influences the degree of nutrient stimulation of enteroendocrine cells in different gut regions, as well as the overall length of gut exposed to nutrient. Of particular interest is the relationship between gallbladder emptying and enteroendocrine secretion. The inter-relationships between GI motility and enteroendocrine secretion are central to blood glucose homeostasis, where an understanding is fundamental to the development of novel strategies for the management of diabetes mellitus.
Publisher: Springer Science and Business Media LLC
Date: 13-01-2013
DOI: 10.1007/S11695-015-1925-Y
Abstract: Duodenal-jejunal bypass (DJB) induces rapid and durable improvement in glucose and lipid metabolism. Besides bypassing the proximal gut, DJB also erts bile acids (BAs) into the distal gut, increasing luminal and systemic BAs that are essential to metabolic homeostasis. The aim of this study is to evaluate whether bile ersion (BD) alone can recapitulate the effects of DJB on glucose and lipid metabolism. BD, DJB and SHAM procedures were performed in a diabetic rat model induced by high-fat diet (HFD)/streptozotocin (STZ). Body weight, energy intake, blood glucose, serum hormones, insulin sensitivity, lipid profiles, and luminal and systemic BAs were measured postsurgery. BD reduced body weight, independently of energy intake, whereas DJB had no effects. Luminal and serum BAs were increased after both DJB and BD, and were higher after BD than DJB. During glucose tolerance test, both fasting and postprandial blood glucose concentrations were reduced with DJB and BD, and were lower after DJB than BD. Insulin sensitivity was improved after DJB, but remained unchanged after BD. Fasting and postprandial GLP-1 were equally increased after DJB and BD. Serum triglyceride and free fatty acids were decreased more after BD than DJB, while hepatic triglyceride storage was reduced more after DJB. These observations indicate that BD, which increases luminal and systemic BAs and postprandial GLP-1, represents an important component of DJB in restoring glucose and lipid homeostasis in diabetic state. However, other mechanisms associated with DJB also appear to make complementary contributions to metabolic regulation.
Publisher: Wiley
Date: 17-03-2023
DOI: 10.1111/DOM.15042
Abstract: To evaluate the effect of gastric distension, induced using a gastric ‘barostat’, on the secretion of glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) in the presence and absence of small intestinal nutrients in healthy in iduals. Eight healthy participants (two females, six males, mean age 69.3 ± 1.2 years, body mass index 23.5 ± 0.8 kg/m 2 ) were each studied on four occasions when they received an intraduodenal infusion of either (i) 0.9% saline or (ii) glucose delivered at a rate of 3 kcal/min both with, and without, an intragastric balloon with the pressure set to 8 mmHg above the intragastric minimum distending pressure. Following intraduodenal saline or glucose infusion, there was no difference in plasma GLP‐1 with or without gastric distension ( P = 1.00 for both saline and glucose infusions). There was also no difference in plasma GIP with or without gastric distension ( P = 1.00 for saline infusion and P = .99 for glucose infusion). Gastric distension, either alone or during small intestinal glucose exposure, does not stimulate incretin hormone secretion significantly in healthy humans.
Publisher: Informa UK Limited
Date: 17-01-2018
Publisher: MDPI AG
Date: 28-03-2021
DOI: 10.3390/NU13041104
Abstract: 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.
Publisher: American Diabetes Association
Date: 18-10-2021
DOI: 10.2337/DC20-2987
Publisher: The Endocrine Society
Date: 20-07-2018
Abstract: The mechanisms regulating the postprandial suppression of ghrelin secretion remain unclear, but recent observations in rats indicate that an increase in duodenal osmolarity is associated with a reduction in ghrelin levels. Several hormones have been implicated in the regulation of ghrelin. We hypothesized that intraduodenal infusion of a hyperosmolar solution would lower plasma ghrelin concentrations. Eighteen healthy young men were studied after an overnight fast on two occasions in a randomized double-blinded fashion. A nasoduodenal catheter was positioned and isoosmolar (300 mOsm/L) or hyperosmolar (1500 mOsm/L) saline was infused intraduodenally (4 mL/min, t = 0 to 45 minutes). Venous blood was s led at t = −45, −30, −15, 0, 15, 30, 45, 60, 75, 90, 120, and 180 minutes. Plasma concentrations of ghrelin, glucagonlike peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), glucagon, pancreatic polypeptide (PP), neurotensin (NT), peptide YY (PYY), motilin, and glucose. Ghrelin concentrations were suppressed with hyperosmolar when compared with isoosmolar saline, and remained lower until t = 180 minutes. CCK, NT, GLP-1, PYY, and glucagon all increased during hyperosmolar, but not isoosmolar, saline infusion (P & 0.01 for all), whereas GIP, PP, and motilin levels were not affected by either infusion. Plasma ghrelin concentrations are lowered, whereas CCK, GLP-1, PYY, NT, and glucagon concentrations are augmented, by hyperosmolar duodenal content in healthy in iduals. These observations have implications for the evaluation of studies comparing the effects of different types and loads of nutrients and chemicals on gut hormone secretion.
Publisher: Frontiers Media SA
Date: 22-02-2019
Publisher: Wiley
Date: 30-09-2019
DOI: 10.1111/DOM.13864
Abstract: To determine the effects of the dipeptidyl peptidase-4 inhibitor, sitagliptin, on gastric emptying (GE) of a high-carbohydrate meal and associated glycaemic and blood pressure (BP) responses in type 2 diabetes mellitus (T2DM). Fourteen patients with T2DM (nine men, five women age 67.8 ± 1.5 years body mass index 31.2 ± 0.9 kg/m Sitagliptin reduced postprandial plasma glucose (P < .005) without affecting GE (P = .88). The magnitude of the glucose-lowering effect (change in incremental area under the curve In T2DM, while sitagliptin has no effect on either GE or postprandial BP, its ability to lower postprandial glucose are dependent on the basal rate of GE.
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.NUT.2015.11.004
Abstract: Hydroxycitric acid (HCA), derived from the fruit Garcinia cambogia, reduces the rate of glucose absorption and lowers postprandial glycemia in rodents, but its effect in humans is unknown. The aim of this study was to investigate the effects of small intestinal perfusion with HCA on glucose absorption, as well as the incretin and glycemic responses to a subsequent intraduodenal glucose infusion, in both healthy in iduals and patients with type 2 diabetes. Twelve healthy participants and 8 patients with type 2 diabetes received an intraduodenal infusion of HCA (2800 mg in water) or control (water) over 60 min, followed by an intraduodenal infusion of 60 g glucose over 120 min, in a double-blind, randomized crossover design. In healthy in iduals, 5 g 3-O-methylglucose (3-OMG) was co-infused with glucose as a marker of glucose absorption. Blood was s led frequently. In healthy in iduals, blood glucose was lower with HCA than control, both before and during the intraduodenal glucose infusion (P < 0.05 for each). Plasma glucose-dependent insulinotropic polypeptide (GIP P = 0.01) and glucagon (P = 0.06) were higher with HCA, but there were no differences in plasma glucagon-like peptide (GLP)-1, insulin, or serum 3-OMG concentrations. In patients with type 2 diabetes, blood glucose, and plasma GIP, GLP-1, and insulin did not differ between HCA and control either before or after intraduodenal glucose, but during glucose infusion, plasma glucagon was higher with HCA (P = 0.04). In healthy in iduals, small intestinal exposure to HCA resulted in a modest reduction in glycemia and stimulation of plasma GIP and glucagon, but no effect on plasma GLP-1 or insulin, or on glucose absorption. HCA had no effect on glycemia in patients with type 2 diabetes.
Publisher: American Diabetes Association
Date: 17-07-2014
DOI: 10.2337/DB13-1627
Abstract: The impact of variations in gastric emptying, which influence the magnitude of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) secretion, on glucose lowering by dipeptidyl peptidase-4 (DPP-4) inhibitors is unclear. We evaluated responses to intraduodenal glucose infusion (60 g over 120 min [i.e., 2 kcal/min], a rate that predominantly stimulates GIP but not GLP-1) after sitagliptin versus control in 12 healthy lean, 12 obese, and 12 type 2 diabetic subjects taking metformin 850 mg b.i.d. versus placebo. As expected, sitagliptin augmented plasma-intact GIP substantially and intact GLP-1 modestly. Sitagliptin attenuated glycemic excursions in healthy lean and obese but not type 2 diabetic subjects, without affecting glucagon or energy intake. In contrast, metformin reduced fasting and glucose-stimulated glycemia, suppressed energy intake, and augmented total and intact GLP-1, total GIP, and glucagon in type 2 diabetic subjects, with no additional glucose lowering when combined with sitagliptin. These observations indicate that in type 2 diabetes, 1) the capacity of endogenous GIP to lower blood glucose is impaired 2) the effect of DPP-4 inhibition on glycemia is likely to depend on adequate endogenous GLP-1 release, requiring gastric emptying & kcal/min and 3) the action of metformin to lower blood glucose is not predominantly by way of the incretin axis.
Publisher: American Diabetes Association
Date: 13-11-2013
DOI: 10.2337/DC13-0958
Publisher: Informa UK Limited
Date: 06-02-2014
DOI: 10.1586/17474124.2014.887439
Abstract: Recent developments in the field of diabetes and obesity management have established the central role of the gut in glucose homeostasis not only is the gut the primary absorptive site, but it also triggers neurohumoral feedback responses that regulate the pre- and post-absorptive phases of glucose metabolism. Structural and/or functional disorders of the intestine have the capacity to enhance (e.g.: diabetes) or inhibit (e.g.: short-gut syndrome, critical illness) glucose absorption, with potentially detrimental outcomes. In this review, we first describe the normal physiology of glucose absorption and outline the methods by which it can be quantified. Then we focus on the structural and functional changes in the small intestine associated with obesity, critical illness, short gut syndrome and other malabsorptive states, and particularly Type 2 diabetes, which can impact upon carbohydrate absorption and overall glucose homeostasis.
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.CLNU.2018.12.014
Abstract: Whey protein and guar gum have both been reported to reduce postprandial glycemia in health and type 2 diabetes, associated with stimulation of glucagon-like peptide-1 (GLP-1) and/or slowing of gastric emptying. Our aim was to evaluate, in type 2 diabetes, the acute effects of low dose "preloads" of whey and guar, given alone or in combination before a meal, on postprandial glycemia, insulin, GLP-1, and gastric emptying. 21 patients with type 2 diabetes, managed by diet or metformin alone, were each studied on 4 days. They received a preload "shake" 15min before a mashed potato meal (368.5 kcal) labeled with Postprandial blood glucose concentrations were lower with W and WG compared to C (each P < 0.0001, treatment × time interaction), and lower after G than C only at 30min. Insulin, GLP-1, and glucagon concentrations were higher after W than WG, G, or C (P < 0.05, treatment × time interaction), without differences between the latter three. Gastric emptying was slower with W (T50: 179.6 ± 6.1 min, P < 0.05) and WG (T50: 197.6 ± 9.7 min, P 0.99). Both whey and whey/guar preloads reduced postprandial glycemia, associated with slowing of gastric emptying. Low dose guar was less effective as a preload for glucose-lowering and did not slow gastric emptying. Australian and New Zealand Clinical Trials Registry, Trial ID ACTRN12615001272583, www.anzctr.org.au.
Publisher: Springer International Publishing
Date: 2015
DOI: 10.1007/164_2015_9
Abstract: Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the known incretin hormones in humans, released predominantly from the enteroendocrine K and L cells within the gut. Their secretion is regulated by a complex of integrated mechanisms involving direct contact for the activation of different chemo-sensors on the brush boarder of K and L cells and several indirect neuro-immuno-hormonal loops. The biological actions of GIP and GLP-1 are fundamental determinants of islet function and blood glucose homeostasis in health and type 2 diabetes. Moreover, there is increasing recognition that GIP and GLP-1 also exert pleiotropic extra-glycaemic actions, which may represent therapeutic targets for human diseases. In this review, we summarise current knowledge of the biology of incretin hormones in health and metabolic disorders and highlight the therapeutic potential of incretin hormones in metabolic regulation.
Publisher: Wiley
Date: 07-10-2019
DOI: 10.1111/DOM.13869
Abstract: Type 2 diabetes mellitus (T2DM) is an increasingly prevalent chronic condition, characterized by abnormally elevated blood glucose concentrations and, as a consequence, increased risk of micro- and macrovascular complications. Metformin is usually the first-line glucose-lowering medication in T2DM however, despite being used for more than 60 years, the mechanism underlying the glucose-lowering action of metformin remains incompletely understood. Although metformin reduces hepatic glucose production, there is persuasive evidence that the gastrointestinal tract is crucial in mediating this effect, particularly via secretion of the incretin hormone glucagon-like peptide 1 (GLP-1). It is now well recognized that bile acids, in addition to their established function in fat digestion and absorption, are important regulators of glucose metabolism. Exposure of the small and large intestine to bile acids induces GLP-1 secretion, modulates the composition of the gut microbiota, and reduces postprandial blood glucose excursions in humans with and without T2DM. Metformin reduces intestinal bile acid resorption substantially, such that intraluminal bile acids may, at least in part, account for its glucose-lowering effect. The present review focuses on the conceptual shift in our understanding as to how metformin lowers blood glucose in T2DM, with a particular emphasis on the role of intestinal bile acids.
Publisher: Wiley
Date: 16-07-2021
DOI: 10.1111/DOM.14473
Publisher: The Endocrine Society
Date: 04-06-2020
Abstract: Exposure of the small intestine to nutrients frequently leads to marked reductions in blood pressure (BP) in type 2 diabetes (T2DM). It remains unclear whether the region of the gut exposed to nutrients influences postprandial cardiovascular responses. To evaluate the cardiovascular responses to proximal and distal small intestinal glucose infusion in health and T2DM. Double-blind, randomized, crossover design. Single center in Australia. 10 healthy subjects and 10 T2DM patients. Volunteers were studied on 2 occasions, when a transnasal catheter was positioned with infusion ports opening 13 cm and 190 cm beyond the pylorus. A 30-g bolus of glucose was infused into either site and 0.9% saline into the alternate site over 60 minutes. BP, heart rate (HR), and superior mesenteric artery (SMA) blood flow were measured over 180 minutes. Systolic BP was unchanged in response to both infusions in health, but decreased in T2DM, with a greater reduction after proximal versus distal infusion (all P ≤ .01). The increment in HR did not differ between treatments in health, but was greater after distal versus proximal infusion in T2DM (P = .02). The increases in SMA blood flow were initially greater, but less sustained, with proximal versus distal infusion in health (P & .001), a pattern less evident in T2DM. In T2DM, postprandial hypotension may be mitigated by ersion of nutrients from the proximal to the distal small intestine.
Publisher: American Diabetes Association
Date: 14-02-2019
DOI: 10.2337/DC18-2156
Abstract: Cells releasing glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are distributed predominately in the proximal and distal gut, respectively. Hence, the region of gut exposed to nutrients may influence GIP and GLP-1 secretion and impact on the incretin effect and gastrointestinal-mediated glucose disposal (GIGD). We evaluated glycemic and incretin responses to glucose administered into the proximal or distal small intestine and quantified the corresponding incretin effect and GIGD in health and type 2 diabetes mellitus (T2DM). Ten healthy subjects and 10 patients with T2DM were each studied on four occasions. On two days, a transnasal catheter was positioned with infusion ports opening 13 cm and 190 cm beyond the pylorus, and 30 g glucose with 3 g 3-O-methylglucose (a marker of glucose absorption) was infused into either site and 0.9% saline into the alternate site over 60 min. Matching intravenous isoglycemic cl studies were performed on the other two days. Blood glucose, serum 3-O-methylglucose, and plasma hormones were evaluated over 180 min. In both groups, blood glucose and serum 3-O-methylglucose concentrations were higher after proximal than distal glucose infusion (all P & 0.001). Plasma GLP-1 increased minimally after proximal, but substantially after distal, glucose infusion, whereas GIP increased promptly after both infusions, with concentrations initially greater, but less sustained, with proximal versus distal infusion (all P & 0.001). Both the incretin effect and GIGD were less with proximal than distal glucose infusion (both P ≤ 0.009). The distal, as opposed to proximal, small intestine is superior in modulating postprandial glucose metabolism in both health and T2DM.
Publisher: Wiley
Date: 08-03-2022
DOI: 10.1111/DOM.14673
Publisher: Wiley
Date: 21-11-2016
DOI: 10.1111/DOM.12812
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.
Publisher: The Endocrine Society
Date: 29-03-2023
Abstract: Premenopausal women are at a lower risk of type 2 diabetes (T2D) compared to men, but the underlying mechanism(s) remain elusive. The secretion of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), from the small intestine is a major determinant of glucose homeostasis and may be influenced by sex. This study compared blood glucose and plasma insulin and incretin responses to intraduodenal glucose infusions in healthy young males and females. In Study 1, 9 women and 20 men received an intraduodenal glucose infusion at 2 kcal/min for 60 minutes. In Study 2, 10 women and 26 men received an intraduodenal glucose at 3 kcal/min for 60 minutes. Venous blood was s led every 15 minutes for measurements of blood glucose and plasma insulin, GLP-1 and GIP. In response to intraduodenal glucose at 2 kcal/min, the incremental area under the curve between t = 0-60 minutes (iAUC0-60min) for blood glucose and plasma GIP did not differ between the 2 groups. However, iAUC0-60min for plasma GLP-1 (P = 0.016) and insulin (P = 0.011) were ∼2-fold higher in women than men. In response to intraduodenal glucose at 3 kcal/min, iAUC0-60min for blood glucose, plasma GIP, and insulin did not differ between women and men, but GLP-1 iAUC0-60min was 2.5-fold higher in women (P = 0.012). Healthy young women exhibit comparable GIP but a markedly greater GLP-1 response to intraduodenal glucose than men. This disparity warrants further investigations to delineate the underlying mechanisms and may be of relevance to the reduced risk of diabetes in premenopausal women when compared to men.
Publisher: American Association for Cancer Research (AACR)
Date: 05-2020
DOI: 10.1158/1055-9965.EPI-19-1446
Abstract: The impact of light-intensity physical activity (LPA) in preventing cancer mortality has been questioned. To address this concern, the present meta-analysis aimed to quantify the association between objectively-measured LPA and risk of cancer mortality. We conducted a systematic literature search in PubMed and Scopus to January 2020. Prospective cohort studies reporting the association between objectively-measured LPA using activity monitors (e.g., accelerometers) and risk of cancer mortality in the general population were included. The summary hazard ratios (HR) per 30 min/day of LPA and 95% confidence intervals (CI) were obtained using a random-effects model. Dose–response analysis was used to plot their relationship. Five prospective cohort studies were included, in which the definition of LPA based on accelerometer readings was mainly set within 100 to 2,100 counts/min. The summary HR for cancer mortality per 30 min/day of LPA was 0.86 (95% CI, 0.79–0.95 I2 & 1%), and the association between LPA and risk reduction in cancer mortality was linearly shaped (Pnonlinearity = 0.72). LPA exhibited a comparable magnitude of risk reduction in cancer mortality of moderate-to-vigorous physical activity regardless of equal time-length (0.87 per 30 min/day vs. 0.94 per 30 min/day, Pinteraction = 0.46) or equal amount (0.74 vs. 0.94 per 150 metabolic equivalents-min/day, Pinteraction = 0.11). Furthermore, replacing sedentary time by LPA of 30 min/day decreased the risk of cancer mortality by 9%. Objectively-measured LPA conferred benefits in decreasing the risk of cancer mortality. LPA should be considered in physical activity guidelines to decrease the risk of cancer mortality.
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.DIABRES.2014.08.004
Abstract: Metformin was reported to increase plasma intact glucagon-like peptide-1 (GLP-1) concentrations in type 2 diabetes. This is, at least partly, attributable to stimulation of GLP-1 secretion. A reduction in soluble dipeptidyl peptidase-4 activity may also make a modest contribution.
Publisher: The Endocrine Society
Date: 06-09-2016
DOI: 10.1210/JC.2016-2813
Abstract: The rate of gastric emptying is an important determinant of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) secretion and may influence the magnitude of glucose lowering by dipeptidyl peptidase-4 (DPP-4) inhibitors. To evaluate the effects of the DPP-4 inhibitor, vildagliptin (VILD), during intraduodenal (ID) glucose infusion at 2 different rates within the physiological range of gastric emptying, in type 2 diabetes. A total of 16 diet-controlled type 2 diabetic patients were studied on 4 separate days in double-blind, randomized, fashion. On each day, either 5-mg VILD or placebo (PLBO) was given 60 minutes before a 120-minute ID glucose infusion at 2 or 4 kcal/min (ID2 or ID4). Plasma glucose and hormones were measured frequently. Plasma glucose, insulin, C-peptide, glucagon, total GIP, and total and intact GLP-1 concentrations were higher during ID4 than ID2 (P & .01 for each). Compared with PLBO, VILD was associated with higher intact GLP-1, insulin, and C-peptide and lower glucose and total GIP and GLP-1 (P & .01 for each), without affecting glucagon. There were significant interactions between the rate of ID glucose and VILD treatment on plasma glucose, intact and total GLP-1, and GIP (P & .05 for each) but not insulin, C-peptide, or glucagon. The reduction in glucose and the increment in intact GLP-1 after VILD vs PLBO were 3.3- and 3.8-fold greater, respectively, during ID4 compared with ID2. These observations warrant further study to clarify whether type 2 diabetic patients with relatively more rapid gastric emptying have greater glucose lowering during treatment with DPP-4 inhibitors.
Publisher: Future Medicine Ltd
Date: 11-2016
Abstract: The GI tract is central to the regulation of postprandial glycemia, with the rate of gastric emptying and the secretion of the incretin hormones, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, being key determinants. Gastric emptying exhibits a large interin idual variation the latter not only accounts for differences in postprandial glycemia but also determines postprandial incretin profiles. Accordingly, the rate of gastric emptying may affect the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors. In contrast, glucagon-like peptide-1 receptor agonists lower postprandial glycemia predominantly by their action to slow gastric emptying. This review discusses the inter-relationship between gastric emptying and the incretin axis in the context of changes in blood glucose, with an emphasis on the relevant clinical implications.
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.PEPTIDES.2016.10.010
Abstract: The importance of the region, as opposed to the length, of small intestine exposed to glucose in determining the secretion of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) remains unclear. We sought to compare the glycemic, insulinemic and incretin responses to glucose administered to the proximal (12-60cm beyond the pylorus), or more distal (>70cm beyond the pylorus) small intestine, or both. 10 healthy subjects (9M,1F aged 70.3±1.4years) underwent infusion of glucose via a catheter into the proximal (glucose proximally GP), or distal (glucose distally GD) small intestine, or both (GPD), on three separate days in a randomised fashion. Blood glucose, serum insulin and plasma GLP-1, GIP and CCK responses were assessed. The iAUC for blood glucose was greater in response to GPD than GP (P<0.05), with no difference between GD and GP. GP was associated with minimal GLP-1 response (P=0.05), but substantial increases in GIP, CCK and insulin (P<0.001 for all). GPD and GD both stimulated GLP-1, GIP, CCK and insulin (P<0.001 for all). Compared to GP, GPD induced greater GLP-1, GIP and CCK responses (P<0.05 for all). Compared with GPD, GD was associated with greater GLP-1 (P<0.05), but reduced GIP and CCK (P<0.05 for both), responses. We conclude that exposure of glucose to the distal small intestine appears necessary for substantial GLP-1 secretion, while exposure of both the proximal and distal small intestine result in substantial secretion of GIP.
Publisher: The Endocrine Society
Date: 16-05-2018
Publisher: Wiley
Date: 05-12-2019
DOI: 10.1111/DOM.13906
Abstract: To evaluate the effects of the dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin on glycaemic and energy expenditure responses during intraduodenal fat infusion, as well as the contribution of endogenous glucagon-like peptide-1 (GLP-1) signalling, in people with type 2 diabetes (T2DM). A total of 15 people with T2DM managed by diet and/or metformin (glycated haemoglobin 49.3 ± 2.1 mmol/mol) were studied on three occasions (two with vildagliptin and one with placebo) in a double-blind, randomized, crossover fashion. On each day, vildagliptin 50 mg or placebo was given orally, followed by intravenous exendin (9-39) 600 pmol/kg/min, on one of the two vildagliptin treatment days, or 0.9% saline over 180 minutes. At between 0 and 120 minutes, a fat emulsion was infused intraduodenally at 2 kcal/min. Energy expenditure, plasma glucose and glucose-regulatory hormones were evaluated. Intraduodenal fat increased plasma GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon, and energy expenditure, and decreased plasma glucose (all P < 0.05). On the two intravenous saline days, plasma glucose and glucagon were lower, plasma intact GLP-1 was higher (all P < 0.05), and energy expenditure tended to be lower after vildagliptin (P = 0.08) than placebo. On the two vildagliptin days, plasma glucose, glucagon and GLP-1 (both total and intact), and energy expenditure were higher during intravenous exendin (9-39) than saline (all P < 0.05). In well-controlled T2DM during intraduodenal fat infusion, vildagliptin lowered plasma glucose and glucagon, and tended to decrease energy expenditure, effects that were mediated by endogenous GLP-1.
Publisher: MDPI AG
Date: 17-08-2021
DOI: 10.3390/NU13082826
Abstract: 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.
Publisher: American Diabetes Association
Date: 11-07-2013
DOI: 10.2337/DC12-1663
Abstract: Glutamine reduces postprandial glycemia when given before oral glucose. We evaluated whether this is mediated by stimulation of insulin and/or slowing of gastric emptying. Ten healthy subjects were studied during intraduodenal (ID) infusion of glutamine (7.5 or 15 g) or saline over 30 min, followed by glucose (75 g over 100 min), while recording antropyloroduodenal pressures. Ten patients with type 2 diabetes mellitus (T2DM) were also studied with 15 g glutamine or saline. ID glutamine stimulated glucagon-like peptide 1 (GLP-1 healthy: P & 0.05 T2DM: P & 0.05), glucose-dependent insulinotropic polypeptide (GIP P = 0.098 P & 0.05), glucagon (P & 0.01 P & 0.001), insulin (P = 0.05 P & 0.01), and phasic pyloric pressures (P & 0.05 P & 0.05), but did not lower blood glucose (P = 0.077 P = 0.5). Glutamine does not lower glycemia after ID glucose, despite stimulating GLP-1, GIP, and insulin, probably due to increased glucagon. Its capacity for pyloric stimulation suggests that delayed gastric emptying is a major mechanism for lowering glycemia when glutamine is given before oral glucose.
Publisher: Springer Science and Business Media LLC
Date: 08-11-2013
DOI: 10.1007/S10735-013-9547-Y
Abstract: In type 2 diabetes mellitus, pancreatic stellate cells (PSCs) are present within and surrounding pancreatic islets and may cause progressive fibrosis and deterioration of pancreatic beta cell function. However, it is unknown whether pancreatic beta cells influence the biological behavior of PSCs. In the present study, we examined the impact of pancreatic beta cells on the proliferation, migration and extracellular matrix (ECM) production of PSCs. PSCs were treated with conditioned media from INS-1 cells (supernatant, SN). Although the proliferation of PSCs incubated with INS-1-SN was increased compared to control, INS-1-SN treatment induced matrix metalloproteinase-2 activity and reduced the production of ECM and TGF-β1. In addition, PSCs treated with INS-1-SN reduced the secretion of cytokines that are known to mediate pancreatic beta cell death, such as FADD, Fas, IFN-γ, IL-1, TNF-α, and TRAIL. Our findings suggest that pancreatic beta cells may ameliorate islet fibrosis and the progression of islet dysfunction.
Publisher: The Endocrine Society
Date: 13-11-2021
Abstract: Both gastric emptying and the secretion of glucagon-like peptide-1 (GLP-1) are major determinants of postprandial glycemia in health and type 2 diabetes (T2D). GLP-1 secretion after a meal is dependent on the entry of nutrients into the small intestine, which, in turn, slows gastric emptying. To define the relationship between gastric emptying and the GLP-1 response to both oral and small intestinal nutrients in subjects with and without T2D. We evaluated: (i) the relationship between gastric emptying (breath test) and postprandial GLP-1 levels after a mashed potato meal in 73 in iduals with T2D (ii) inter-in idual variations in GLP-1 response to (a) intraduodenal glucose (4 kcal/min) during euglycemia and hyperglycemia in 11 healthy and 12 T2D, subjects, (b) intraduodenal fat (2 kcal/min) in 15 T2D subjects, and (c) intraduodenal protein (3 kcal/min) in 10 healthy subjects and (iii) the relationship between gastric emptying (breath test) of 75 g oral glucose and the GLP-1 response to intraduodenal glucose (4 kcal/min) in 21 subjects (9 healthy, 12 T2D). The GLP-1 response to the mashed potato meal was unrelated to the gastric half-emptying time (T50). The GLP-1 responses to intraduodenal glucose, fat, and protein varied substantially between in iduals, but intra-in idual variation to glucose was modest. The T50 of oral glucose was related directly to the GLP-1 response to intraduodenal glucose (r = 0.65, P = 0.002). In a given in idual, gastric emptying is not a determinant of the postprandial GLP-1 response. However, the intrinsic gastric emptying rate is determined in part by the responsiveness of GLP-1 to intestinal nutrients.
Publisher: Wiley
Date: 14-02-2019
DOI: 10.1111/DOM.13633
Abstract: To evaluate the effects of the prandial glucagon-like peptide-1 receptor agonist lixisenatide on gastric emptying and blood pressure (BP) and superior mesenteric artery (SMA) blood flow, and the glycaemic responses to a 75-g oral glucose load in healthy people and those with type 2 diabetes (T2DM). Fifteen healthy participants (nine men, six women mean ± SEM age 67.2 ± 2.3 years) and 15 participants with T2DM (nine men, six women mean ± SEM age 61.9 ± 2.3 years) underwent measurement of gastric emptying, BP, SMA flow and plasma glucose 180 minutes after a radiolabelled 75-g glucose drink on two separate days. All participants received lixisenatide (10 μg subcutaneously) or placebo in a randomized, double-blind, crossover fashion 30 minutes before the glucose drink. Lixisenatide slowed gastric emptying (retention at 120 minutes, P < 0.01), attenuated the rise in SMA flow (P < 0.01) and markedly attenuated the decrease in systolic BP (area under the curve [AUC] 0-120 minutes, P < 0.001) compared to placebo in healthy participants and those with T2DM. Plasma glucose (incremental AUC 0-120 minutes) was greater in participants with T2DM (P < 0.005) than in healthy participants, and lower after lixisenatide in both groups (P < 0.001). In healthy participants and those with T2DM, the marked slowing of gastric emptying of glucose induced by lixisenatide was associated with attenuation of the increments in glycaemia and SMA flow and decrease in systolic BP. Accordingly, lixisenatide may be useful in the management of postprandial hypotension.
Publisher: Informa UK Limited
Date: 26-12-2016
DOI: 10.1080/17474124.2017.1273769
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.
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.PEPTIDES.2017.08.001
Abstract: The interaction of nutrients with the small intestine stimulates the secretion of numerous enteroendocrine hormones that regulate postprandial metabolism. However, differences in gastrointestinal hormonal responses between the macronutrients are incompletely understood. In the present study, we compared blood glucose and plasma hormone concentrations in response to standardised intraduodenal (ID) fat and glucose infusions in healthy humans. In a parallel study design, 16 healthy males who received an intraduodenal fat infusion were compared with 12 healthy males who received intraduodenal glucose, both at a rate of 2kcal/min over 120min. Venous blood was s led at frequent intervals for measurements of blood glucose, and plasma total and active glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon. Plasma concentrations of the incretin hormones (both total and active GLP-1 and GIP) and glucagon were higher, and plasma insulin and blood glucose concentrations lower, during intraduodenal fat, when compared with intraduodenal glucose, infusion (treatment by time interaction: P<0.001 for each). Compared with glucose, intraduodenal fat elicits substantially greater GLP-1, GIP and glucagon secretion, with minimal effects on blood glucose or plasma insulin in healthy humans. These observations are consistent with the concept that fat is a more potent stimulus of the 'gut-incretin' axis than carbohydrate.
Publisher: The Endocrine Society
Date: 04-2013
DOI: 10.1210/JC.2012-3961
Abstract: In vitro and animal studies suggest that bile acids have the capacity to reduce blood glucose by stimulating glucagon-like peptide-1 (GLP-1) and, thereby, insulin. This study evaluated the effects of intrajejunal taurocholic acid (TCA) on blood glucose, GLP-1, and insulin responses to jejunal glucose infusion in healthy men. Ten healthy men were each studied on 2 days in a double-blind, randomized order. After the subjects fasted overnight, a jejunal catheter was positioned and a balloon inflated 30 cm beyond the pylorus with aspiration of endogenous bile. Two grams TCA in saline, or saline control, was infused beyond the balloon over 30 minutes, followed by 2 g TCA or control, together with 60 g glucose, over the next 120 minutes. Blood was s led frequently for the measurements of blood glucose, total GLP-1, insulin, C-peptide, and glucagon. Intrajejunal infusion of TCA alone (t = -30 to 0 minutes) had no effect on blood glucose, GLP-1, insulin, C-peptide, or glucagon concentrations. During intrajejunal glucose infusion (t = 0 to 120 minutes), blood glucose concentrations were lower (P < .001), and plasma GLP-1 (P < .001) and the C-peptide/glucose ratio (P = .008) were both greater, whereas plasma insulin, C-peptide, and glucagon levels were not significantly different after TCA than after control. In healthy humans, small intestinal infusion of TCA potently reduces the glycemic response to small intestinal glucose, associated with an increase in GLP-1 and C-peptide/glucose ratio. These observations indicate the potential for bile acid-based therapy in type 2 diabetes.
Publisher: Wiley
Date: 28-01-2020
DOI: 10.1111/DOM.13956
Abstract: To evaluate the effects of 8 weeks' administration of exenatide (EXE) once weekly on gastric emptying of solids and liquids (using the "gold standard" technique, scintigraphy), glucose absorption and postprandial glycaemia in healthy people. A total of 32 healthy participants were randomized to receive either EXE once weekly (2 mg/wk subcutaneously six men, 10 women, mean age 59.9 ± 0.9 years, mean body mass index [BMI] 29.6 ± 0.6 kg/m The study treatments were well tolerated. Scores for nausea were consistently low, with no difference between the EXE once weekly and PBO groups. EXE once weekly slowed gastric emptying of solids (area under the curve [AUC] In healthy participants, 8 weeks' administration of the "long-acting" glucagon-like peptide-1 receptor agonist EXE, slowed gastric emptying of solids and liquids substantially, with consequent reductions in glucose absorption and postprandial glycaemia.
Publisher: American Physiological Society
Date: 15-12-2014
Abstract: Endothelial function, measured by flow-mediated dilatation (FMD), predicts cardiovascular events and is impaired postprandially. The objective of this study was to evaluate the effects of changes in composition or duration of ingestion of a meal, which slows gastric emptying and/or small intestinal nutrient exposure, on postprandial endothelial function. Twelve healthy subjects (6 male, 6 female 33 ± 6 yr) were each studied on three occasions, in a randomized crossover design. After an overnight fast, subjects consumed a [ 13 C]octanoic acid-labeled mashed potato meal (“ meal 1”), or meal 1 mixed with 9 g guar (“ meal 2”) within 10 min, or meal 1 ided into 12 equal portions over 60 min (“ meal 3”). Brachial artery FMD was measured every 30 min for 120 min. Blood glucose, serum insulin, and gastric emptying (breath test) were evaluated for 240 min. Data are means ± SE. Compared with meal 1, meal 2 was associated with slower gastric emptying (half-emptying time 285 ± 27 vs. 208 ± 15 min, P 0.05), lower postprandial blood glucose and insulin ( P 0.001 for both), and a delayed, but more sustained, suppression of FMD ( P 0.001). After meal 3, both glycemic increment and reduction in FMD were less than after meal 2 ( P 0.05 for both). The decrement in FMD was directly related to the increment in blood glucose ( r = 0.46, P = 0.02). We conclude that, in health, postprandial FMD is influenced by perturbation of gastric emptying and the duration of meal consumption, which also impact on glycemia.
Publisher: Springer Science and Business Media LLC
Date: 03-2018
DOI: 10.1038/S41366-018-0047-8
Abstract: Evidence from animal studies highlights an important role for serotonin (5-HT), derived from gut enterochromaffin (EC) cells, in regulating hepatic glucose production, lipolysis and thermogenesis, and promoting obesity and dysglycemia. Evidence in humans is limited, although elevated plasma 5-HT concentrations are linked to obesity. We assessed (i) plasma 5-HT concentrations before and during intraduodenal glucose infusion (4 kcal/min for 30 min) in non-diabetic obese (BMI 44 ± 4 kg/m Plasma 5-HT was twofold higher in obese than control responders prior to (P = 0.025), and during (iAUC, P = 0.009), intraduodenal glucose infusion, and related positively to BMI (R Human obesity is characterized by an increased capacity to produce and release 5-HT from the proximal small intestine, which is strongly linked to higher body mass, and glycemic control. Gut-derived 5-HT is likely to be an important driver of pathogenesis in human obesity and dysglycemia.
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.JPBA.2016.09.023
Abstract: This study aimed to obtain information on bile acid profiles in diabetic (db/db) mice and their wild type (wt) littermates for the understanding of pathogenesis and discovery of potential biomarkers of type 2 diabetes. Analytical methods based on protein precipitation or solid-phase extraction together with liquid chromatography-tandem mass spectrometry were developed for the determination of 25 bile acids in plasma, urine and feces s les collected from db/db and wt mice. GLP-1 concentration and hepatic genes related to bile acid synthesis were also investigated. The results showed that the concentrations of in idual bile acids varied notably both interin idually and temporally. However, plasma, urine and feces s les displayed discriminating bile acid profiles between the db/db and wt groups, with the plasma profile showing the best differentiation capacity. In plasma and urine, the concentration variation of taurine-conjugated bile acids was more correlated with that of other taurine-conjugated bile acids, and vice versa for the unconjugated bile acids. Transcription of hepatic gene Cyp7b1 was downregulated, and Hsd3b7 upregulated in db/db mice. In conclusion, the bile acid profile, particularly that in plasma, can distinguish the two animal groups and is a promising biomarker for type 2 diabetes.
Publisher: Wiley
Date: 30-03-2020
DOI: 10.1111/BCP.14274
Publisher: Wiley
Date: 22-03-2022
DOI: 10.1111/DOM.14683
Abstract: To determine the serum bile acid (BA) response to 75‐g oral glucose in in iduals without diabetes, and whether this is attenuated in patients with ‘early’ type 2 diabetes (T2D) and related to the glycaemic response at 2 hours in either group. Forty newly diagnosed, treatment‐naïve Han Chinese T2D subjects and 40 age‐, gender‐, and body mass index‐matched controls without T2D ingested a 75‐g glucose drink after an overnight fast. Plasma glucose and serum concentrations of total and in idual BAs, fibroblast growth factor‐19 (FGF‐19), total glucagon‐like peptide‐1 (GLP‐1), and insulin, were measured before and 2 hours after oral glucose. Fasting total BA levels were higher in T2D than control subjects ( P .05). At 2 hours, the BA profile exhibited a shift from baseline in both groups, with increases in conjugated BAs and/or decreases in unconjugated BAs. There were increases in total BA and FGF‐19 levels in control (both P .05), but not T2D, subjects. Plasma glucose concentrations at 2 hours related inversely to serum total BA levels in control subjects ( r = −0.42, P = .006). Total GLP‐1 and the insulin/glucose ratio were increased at 2 hours in both groups, and the magnitude of the increase was greater in control subjects. The serum BA response to a 75‐g oral glucose load is attenuated in patients with ‘early’ T2D, as is the secretion of FGF‐19 and GLP‐1, while in in iduals without T2D it correlates with 2‐hour plasma glucose levels. These observations support a role for BAs in the regulation of postprandial glucose metabolism.
Publisher: Wiley
Date: 03-09-2020
DOI: 10.1111/DOM.14166
Publisher: American Diabetes Association
Date: 17-09-2013
DOI: 10.2337/DB13-0581
Abstract: We previously established that the intestinal sweet taste receptors (STRs), T1R2 and T1R3, were expressed in distinct epithelial cells in the human proximal intestine and that their transcript levels varied with glycemic status in patients with type 2 diabetes. Here we determined whether STR expression was 1) acutely regulated by changes in luminal and systemic glucose levels, 2) disordered in type 2 diabetes, and 3) linked to glucose absorption. Fourteen healthy subjects and 13 patients with type 2 diabetes were studied twice, at euglycemia (5.2 ± 0.2 mmol/L) or hyperglycemia (12.3 ± 0.2 mmol/L). Endoscopic biopsy specimens were collected from the duodenum at baseline and after a 30-min intraduodenal glucose infusion of 30 g/150 mL water plus 3 g 3-O-methylglucose (3-OMG). STR transcripts were quantified by RT-PCR, and plasma was assayed for 3-OMG concentration. Intestinal STR transcript levels at baseline were unaffected by acute variations in glycemia in healthy subjects and in type 2 diabetic patients. T1R2 transcript levels increased after luminal glucose infusion in both groups during euglycemia (+5.8 × 104 and +5.8 × 104 copies, respectively) but decreased in healthy subjects during hyperglycemia (−1.4 × 104 copies). T1R2 levels increased significantly in type 2 diabetic patients under the same conditions (+6.9 × 105 copies). Plasma 3-OMG concentrations were significantly higher in type 2 diabetic patients than in healthy control subjects during acute hyperglycemia. Intestinal T1R2 expression is reciprocally regulated by luminal glucose in health according to glycemic status but is disordered in type 2 diabetes during acute hyperglycemia. This defect may enhance glucose absorption in type 2 diabetic patients and exacerbate postprandial hyperglycemia.
Publisher: Wiley
Date: 08-12-2016
DOI: 10.1111/DOM.12822
Publisher: Wiley
Date: 22-10-2020
DOI: 10.1111/DOM.14202
Abstract: Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) are the recommended first injectable therapy in type 2 diabetes. However, long‐term persistence is suboptimal and partly attributable to gastrointestinal tolerability, particularly during initiation/escalation. Gradual titration of fixed‐ratio combination GLP‐1 RA/insulin therapies may improve GLP‐1 RA gastrointestinal tolerability. We compared gastrointestinal adverse event (AE) rates for iGlarLixi versus GLP‐1 RAs during the first 12 weeks of therapy, including a sensitivity analysis with IDegLira. The PICO framework was used to identify studies from MEDLINE, EMBASE and CENTRAL searches using a proprietary, web‐based, standardized tool with single data extraction. Gastrointestinal AEs were modelled using a Bayesian network meta‐analysis (NMA), using fixed and random effects for each recommended dose (treatment‐specific NMA) and class (drug‐class NMA). Treatment‐specific NMA included 17 trials (n = 9030 3665 event‐weeks). Nausea rates were significantly lower with iGlarLixi versus exenatide 10 μg twice daily (rate ratio: 0.32 95% credible interval: 0.15, 0.66), once‐daily lixisenatide 20 μg (0.35 0.24, 0.50) and liraglutide 1.8 mg once daily (0.48 0.23, 0.98). Rates were numerically, but not statistically, lower versus once‐weekly semaglutide 1 mg (0.60 0.30, 1.23) and dulaglutide 1.5 mg (0.60 0.29, 1.26), and numerically, but not statistically, higher versus once‐weekly exenatide (1.91 0.91, 4.03). Sensitivity analysis results were similar. In a naïve, pooled analysis, vomiting was lower with iGlarLixi versus other GLP‐1 RAs. During the first 12 weeks of treatment, iGlarLixi was generally associated with less nausea and vomiting than single‐agent GLP‐1 RAs. Enhanced gastrointestinal tolerability with fixed‐ratio combinations may favour treatment persistence.
Publisher: MDPI AG
Date: 22-11-2020
DOI: 10.3390/PH13110410
Abstract: 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.
Publisher: Wiley
Date: 30-01-2019
DOI: 10.1111/DOM.13632
Abstract: Metformin has been shown to modulate the cardiovascular response to intraduodenal glucose in patients with type 2 diabetes (T2DM), and may have the capacity to regulate postprandial blood pressure (BP), which is often inadequately compensated in T2DM, resulting in postprandial hypotension. In the present study, we evaluated the acute effects of metformin on the BP and heart rate (HR) responses to oral glucose in patients with T2DM. Ten diet-controlled T2DM patients were evaluated on two occasions in a double-blind, randomized, crossover design. Participants received either metformin 1 g or saline (control) intraduodenally 60 minutes before ingesting a 50 g glucose drink labelled with 150 mg
Publisher: SAGE Publications
Date: 20-10-2016
Abstract: To evaluate the effects of the glucagon-like peptide-1 receptor agonist, exenatide, on blood pressure and heart rate during an intraduodenal glucose infusion in type 2 diabetes. Nine subjects with type 2 diabetes were randomised to receive intravenous exenatide or saline control in a crossover design. Glucose (3 kcal min −1 ) was infused via an intraduodenal manometry catheter for 60 min. Blood pressure, heart rate, and the frequency and litude of duodenal pressure waves were measured at regular intervals. Gastrointestinal symptoms were monitored using 100 mm visual analogue scales. During intraduodenal glucose infusion (0–60 min), diastolic ( p (0–60) = 0.03) and mean arterial ( p (0–60) = 0.03) blood pressures and heart rate ( p (0–60) = 0.06 p (0–120) = 0.03)) were higher with exenatide compared to placebo. The increase in the area under the curve for diastolic blood pressure and mean arterial blood pressure was related directly to the suppression of the duodenal motility index with exenatide compared to control ( p = 0.007 and 0.04, respectively). In type 2 diabetes, intravenous exenatide increases mean arterial blood pressure and heart rate during an intraduodenal glucose infusion, supporting the need for further research with exenatide for its potential use in postprandial hypotension.
Publisher: MDPI AG
Date: 05-11-2019
DOI: 10.3390/NU11112666
Abstract: 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.
Publisher: Elsevier BV
Date: 11-2023
Publisher: MDPI AG
Date: 07-2020
DOI: 10.3390/NU12071962
Abstract: 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.
Publisher: The Endocrine Society
Date: 04-2019
Abstract: Gastric emptying is a major determinant of postprandial glycemia and is often delayed in long-standing, complicated type 2 diabetes mellitus (T2DM). However, there is little information about gastric emptying in well-controlled T2DM. To evaluate the rate of gastric emptying in community-based patients with relatively well-controlled T2DM compared with young and older control subjects without diabetes. A total of 111 patients with T2DM managed by diet (n = 52) or metformin monotherapy (n = 59) (HbA1c 6.6 ± 0.1%/49.0 ± 0.9 mmol/mol), 18 age- and body mass index (BMI)-matched older subjects without diabetes, and 15 young healthy subjects consumed a standardized mashed potato meal (368.5 kcal) containing 100 μL 13C-octanoic acid. Gastric emptying (by breath test) and blood glucose were evaluated over 240 minutes. Gastric emptying was slower in the older than in the young subjects without diabetes (2.3 ± 0.1 vs 3.0 ± 0.1 kcal/min, P = 0.0008). However, relative to the age- and BMI-matched subjects without diabetes, gastric emptying (2.8 ± 0.1 kcal/min) was faster in patients with T2DM (P = 0.0005). Furthermore, gastric emptying was faster in the metformin-treated (3.0 ± 0.1 kcal/min) than in the diet-controlled (2.7 ± 0.1 kcal/min) patients with T2DM (P = 0.011), although there were no differences in age, BMI, HbA1c, or the duration of known diabetes. The increments in blood glucose (at t = 30 and 60 minutes and the incremental area under the curve during t = 0 to 120 minutes) after the meal were related directly to the rate of gastric emptying in the subjects with T2DM regardless of treatment with or without metformin (P < 0.05 each). Gastric emptying is slowed with aging but otherwise is relatively more rapid in patients with well-controlled T2DM. This provides a strong rationale for slowing gastric emptying to improve postprandial glycemic control in these patients.
Publisher: Wiley
Date: 02-2018
DOI: 10.14814/PHY2.13610
Publisher: Elsevier BV
Date: 08-2021
Publisher: Elsevier
Date: 2017
Publisher: Wiley
Date: 21-11-2018
DOI: 10.1111/DOM.13567
Abstract: The gastrointestinal tract, particularly the lower gut, may be key to the anti-diabetic action of metformin. We evaluated whether administration of metformin into the distal, vs the proximal, small intestine would be more effective in lowering plasma glucose by stimulating glucagon-like pepetide-1 (GLP-1) and/or slowing gastric emptying (GE) in type 2 diabetes (T2DM). Ten diet-controlled T2DM patients were studied on three occasions. A transnasal catheter was positioned with proximal and distal infusion ports located 13 and 190 cm beyond the pylorus, respectively. Participants received infusions of (a) proximal + distal saline (control), (b) proximal metformin (1000 mg) + distal saline or (c) proximal saline + distal metformin (1000 mg) over 5 minutes, followed 60 minutes later by a glucose drink containing 50 g glucose and 150 mg Compared with control, both proximal and distal metformin reduced plasma glucose and augmented GLP-1 responses to oral glucose comparably (P < 0.05 each), without affecting plasma insulin or glucagon. GE was slower after proximal metformin than after control (P < 0.05) and tended to be slower after distal metformin, without any difference between proximal and distal metformin. In diet-controlled T2DM patients, glucose-lowering via a single dose of metformin administered to the upper and lower gut was comparable and was associated with stimulation of GLP-1 and slowing of GE. These observations suggest that the site of gastrointestinal administration is not critical to the glucose-lowering capacity of metformin.
Publisher: Elsevier BV
Date: 2016
Abstract: Resveratrol has been reported to lower glycemia in rodent models of type 2 diabetes associated with the stimulation of glucagon-like peptide 1 (GLP-1), which is known to slow gastric emptying, stimulate insulin secretion, and suppress glucagon secretion and energy intake. We evaluated the effects of 5 wk of resveratrol treatment on GLP-1 secretion, gastric emptying, and glycemic control in type 2 diabetes. Fourteen patients with diet-controlled type-2 diabetes [mean ± SEM glycated hemoglobin (HbA1c): 6.4 ± 0.2% (46.4 ± 2.2 mmol/mol)] received resveratrol (500 mg twice daily) or a placebo over two 5-wk intervention periods with a 5-wk washout period in between in a double-blind, randomized, crossover design. Before and after each intervention period (4 visits), body weight and HbA1c were measured, and patients were evaluated after an overnight fast with a standardized mashed-potato meal labeled with 100 μg (13)C-octanoic acid to measure blood glucose and plasma GLP-1 concentrations and gastric emptying (breath test) over 240 min. Daily energy intake was estimated from 3-d food diaries during the week before each visit. Fasting and postprandial blood glucose and plasma total GLP-1 as well as gastric emptying were similar at each assessment, and the change in each variable from weeks 0 to 5 did not differ between resveratrol and placebo groups. Similarly, changes in HbA1c, daily energy intake, and body weight after 5 wk did not differ between the 2 treatments. In patients with diet-controlled type 2 diabetes, 5 wk of twice-daily 500 mg-resveratrol supplementation had no effect on GLP-1 secretion, glycemic control, gastric emptying, body weight, or energy intake. Our observations do not support the use of resveratrol for improving glycemic control. This trial was registered at www.anzctr.org.au as ACTRN12613000717752.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2015
DOI: 10.1038/NUTD.2015.5
Abstract: To determine the independent and commingling effect of android and gynoid percent fat (measured using Dual Energy X-Ray Absorptiometry) on cardiometabolic dysregulation in normal weight American adults. The 2005–2006 data ( n =1802) from the United States National Health and Nutritional Examination Surveys (NHANES) were used in this study. Associations of android percent fat, gynoid percent fat and their joint occurrence with risks of cardiometabolic risk factors were estimated using prevalence odds ratios from logistic regression analyses. Android-gynoid percent fat ratio was more highly correlated with cardiometabolic dysregulation than android percent fat, gynoid percent fat or body mass index. Commingling of android and gynoid adiposities was associated with much greater odds of cardiometabolic risk factors than either android or gynoid adiposities. Commingling of android and gynoid adiposities was associated with 1.75 (95% confidence interval (CI)=1.42–2.93), 1.48 (95% CI=1.32–1.91), 1.61 (95% CI=1.50–1.89), 3.56 (95% CI=2.91–4.11) and 1.86 (95% CI=1.49–1.96) increased odds of elevated glucose, elevated blood pressure, elevated low-density lipoprotein-cholesterol, elevated triglyceride and low high-density lipoprotein-cholesterol, respectively. Normal weight subjects who present with both android and gynoid adiposities should be advised of the associated health risks. Both android and gynoid fat accumulations should be considered in developing public health strategies for reducing cardiometabolic disease risk in normal weight subjects.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2015
DOI: 10.1038/NUTD.2015.6
Abstract: The region of enteral nutrient exposure may be an important determinant of postprandial incretin hormone secretion and blood glucose homoeostasis. We compared responses of plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon, and blood glucose to a standardised glucose infusion into the proximal jejunum and duodenum in healthy humans. Ten healthy males were evaluated during a standardised glucose infusion (2 kcal min −1 over 120 min) into the proximal jejunum (50 cm post pylorus) and were compared with another 10 healthy males matched for ethnicity, age and body mass index who received an identical glucose infusion into the duodenum (12 cm post pylorus). Blood was s led frequently for measurements of blood glucose and plasma hormones. Plasma GLP-1, GIP and insulin responses, as well as the insulin:glucose ratio and the insulinogenic index 1 (IGI 1 ) were greater ( P .05 for each) after intrajejunal (i.j.) than intraduodenal glucose infusion, without a significant difference in blood glucose or plasma glucagon. Pooled analyses revealed direct relationships between IGI 1 and the responses of GLP-1 and GIP ( r =0.48 and 0.56, respectively, P .05 each), and between glucagon and GLP-1 ( r =0.70, P .001). In conclusion, i.j. glucose elicits greater incretin hormone and insulin secretion than intraduodenal glucose in healthy humans, suggesting regional specificity of the gut–incretin axis.
Publisher: Wiley
Date: 04-01-2019
DOI: 10.1111/DOM.13604
Abstract: To evaluate the effects of 12 weeks of treatment with a whey/guar preload on gastric emptying, postprandial glycaemia and glycated haemoglobin (HbA1c) levels in people with type 2 diabetes (T2DM). A total of 79 people with T2DM, managed on diet or metformin (HbA1c 49 ± 0.7 mmol/mol [6.6 ± 0.1%]), were randomized, in single-blind fashion, to receive 150 mL flavoured preloads, containing either 17 g whey protein plus 5 g guar (n = 37) or flavoured placebo (n = 42), 15 minutes before two meals, each day for 12 weeks. Blood glucose and gastric emptying (breath test) were measured before and after a mashed potato meal at baseline (without preload), and after the preload at the beginning (week 1) and end (week 12) of treatment. HbA1c levels, energy intake, weight and body composition were also evaluated. Gastric emptying was slower (P < 0.01) and postprandial blood glucose levels lower (P < 0.05) with the whey/guar preload compared to placebo preload, and the magnitude of reduction in glycaemia was related to the rate of gastric emptying at both week 1 (r = -0.54, P < 0.001) and week 12 (r = -0.54, P < 0.0001). At the end of treatment, there was a 1 mmol/mol [0.1%] reduction in HbA1c in the whey/guar group compared to the placebo group (49 ± 1.0 mmol/mol [6.6 ± 0.05%] vs. 50 ± 0.8 mmol/mol [6.7 ± 0.05%] P < 0.05). There were no differences in energy intake, body weight, or lean or fat mass between the groups. In patients with well-controlled T2DM, 12 weeks' treatment with a low-dose whey/guar preload, taken twice daily before meals, had sustained effects of slowing gastric emptying and reducing postprandial blood glucose, which were associated with a modest reduction in HbA1c, without causing weight gain.
Publisher: American Diabetes Association
Date: 12-06-2013
DOI: 10.2337/DC12-2294
Abstract: Macronutrient “preloads” can reduce postprandial glycemia by slowing gastric emptying and stimulating glucagon-like peptide-1 (GLP-1) secretion. An ideal preload would entail minimal additional energy intake and might be optimized by concurrent inhibition of dipeptidyl peptidase-4 (DPP-4). We evaluated the effects of a low-energy d-xylose preload, with or without sitagliptin, on gastric emptying, plasma intact GLP-1 concentrations, and postprandial glycemia in type 2 diabetes. Twelve type 2 diabetic patients were studied on four occasions each. After 100 mg sitagliptin (S) or placebo (P) and an overnight fast, patients consumed a preload drink containing either 50 g d-xylose (X) or 80 mg sucralose (control [C]), followed after 40 min by a mashed potato meal labeled with 13C-octanoate. Blood was s led at intervals. Gastric emptying was determined. Both peak blood glucose and the litude of glycemic excursion were lower after PX and SC than PC (P & 0.01 for each) and were lowest after SX (P & 0.05 for each), while overall blood glucose was lower after SX than PC (P & 0.05). The postprandial insulin-to-glucose ratio was attenuated (P & 0.05) and gastric emptying was slower (P & 0.01) after d-xylose, without any effect of sitagliptin. Plasma GLP-1 concentrations were higher after d-xylose than control only before the meal (P & 0.05) but were sustained postprandially when combined with sitagliptin (P & 0.05). In type 2 diabetes, acute administration of a d-xylose preload reduces postprandial glycemia and enhances the effect of a DPP-4 inhibitor.
Publisher: American Diabetes Association
Date: 19-01-2016
DOI: 10.2337/DC15-2298
Abstract: Nutrient “preloads” given before meals can attenuate postprandial glycemic excursions, at least partly by slowing gastric emptying and stimulating secretion of the incretins (i.e., glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]). This study was designed to evaluate whether a protein preload could improve the efficacy of the dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin to increase incretin concentrations, slow gastric emptying, and lower postprandial glycemia in type 2 diabetes. Twenty-two patients with type 2 diabetes treated with metformin were studied on four occasions, receiving either 50 mg vildagliptin (VILD) or placebo (PLBO) on both the evening before and the morning of each study day. The latter dose was followed after 60 min by a preload drink containing either 25 g whey protein (WHEY) or control flavoring (CTRL), and after another 30 min by a 13C-octanoate–labeled mashed potato meal. Plasma glucose and hormones, and gastric emptying, were evaluated. Compared with PLBO/CTRL, PLBO/WHEY reduced postprandial peak glycemia, increased plasma insulin, glucagon, and incretin hormones (total and intact), and slowed gastric emptying, whereas VILD/CTRL reduced both the peak and area under the curve for glucose, increased plasma intact incretins, and slowed gastric emptying but suppressed plasma glucagon and total incretins (P & 0.05 each). Compared with both PLBO/WHEY and VILD/CTRL, VILD/WHEY was associated with higher plasma intact GLP-1 and GIP, slower gastric emptying, and lower postprandial glycemia (P & 0.05 each). In metformin-treated type 2 diabetes, a protein preload has the capacity to enhance the efficacy of vildagliptin to slow gastric emptying, increase plasma intact incretins, and reduce postprandial glycemia.
Publisher: American Diabetes Association
Date: 29-05-2020
DOI: 10.2337/DC20-0190
Abstract: Tachyphylaxis for slowing of gastric emptying is seen with continuous exposure to glucagon-like peptide 1 (GLP-1). We therefore aimed to establish whether prolonged use of a “short-acting” GLP-1 receptor agonist, lixisenatide, achieves sustained slowing of gastric emptying and reduction in postprandial glycemia. A total of 30 patients with metformin-treated type 2 diabetes underwent assessment of gastric emptying (scintigraphy) and glucose metabolism (dual tracer technique) after a 75-g glucose drink, before and after 8 weeks’ treatment with lixisenatide (20 μg subcutaneously daily) or placebo, in a double-blind randomized parallel design. Gastric retention of the glucose drink was markedly increased after lixisenatide versus placebo (ratio of adjusted geometric means for area under the curve [AUC] over 240 min of 2.19 [95% CI 1.82, 2.64], P & 0.001), associated with substantial reductions in the rate of systemic appearance of oral glucose (P & 0.001) and incremental AUC for blood glucose (P & 0.001). Lixisenatide suppressed both glucagon (P = 0.003) and insulin (P = 0.032), but not endogenous glucose production, over 120 min after oral glucose intake. Postprandial glucose lowering over 240 min was strongly related to the magnitude of slowing of gastric emptying by lixisenatide (r = −0.74, P = 0.002) and to the baseline rate of emptying (r = 0.52, P = 0.048) but unrelated to β-cell function (assessed by β-cell glucose sensitivity). Eight weeks’ treatment with lixisenatide is associated with sustained slowing of gastric emptying and marked reductions in postprandial glycemia and appearance of ingested glucose. Short-acting GLP-1 receptor agonists therefore potentially represent an effective long-term therapy for specifically targeting postprandial glucose excursions.
Publisher: Elsevier BV
Date: 04-2023
Publisher: American Diabetes Association
Date: 12-02-2018
DOI: 10.2337/DC17-1916
Publisher: Wiley
Date: 25-05-2022
DOI: 10.1111/DOM.14730
Abstract: Cholecystectomy has been reported to be associated with increased risk of diabetes in cross‐sectional studies. In the current study, we performed both cross‐sectional and prospective analyses to examine the association between cholecystectomy and dysglycaemia in Chinese community‐dwelling adults. A total of 1612 participants (n = 1564 without cholecystectomy and n = 48 with cholecystectomy) were evaluated for glycaemic status (according to the World Health Organization (WHO) 1999 criteria) and then followed up over ~3.2 years. Percent changes (Δ) in fasting blood glucose and HbA1c from baseline at the follow‐up visit were calculated to define glycaemic control as stable (−10% ≤ Δ 10%), improved (Δ −10%), or worsened (Δ ≥ 10%). The baseline cross‐sectional analyses indicated that cholecystectomy was associated with an increased risk of both prediabetes and diabetes, while the prospective analysis indicated that cholecystectomy was also associated with a greater risk of deterioration in glycaemic control (ΔFPG ≥10% and ΔHbA1c ≥10%) ( P 0.05 for each, both before and after adjusting for potential confounding covariates). These observations suggest that in iduals in the Chinese community‐dwelling population who have undergone cholecystectomy are at increased risk of dysglycaemia. Further studies are warranted to both delineate the underlying mechanisms and to clarify whether more intense surveillance for future development of diabetes is needed in this group.
Publisher: American Diabetes Association
Date: 12-07-2016
DOI: 10.2337/DBI16-0023
Publisher: American Diabetes Association
Date: 15-10-2015
DOI: 10.2337/DB15-0893
Abstract: The short-acting glucagon-like peptide 1 receptor agonist exenatide reduces postprandial glycemia, partly by slowing gastric emptying, although its impact on small intestinal function is unknown. In this study, 10 healthy subjects and 10 patients with type 2 diabetes received intravenous exenatide (7.5 μg) or saline (−30 to 240 min) in a double-blind randomized crossover design. Glucose (45 g), together with 5 g 3-O-methylglucose (3-OMG) and 20 MBq 99mTc-sulfur colloid (total volume 200 mL), was given intraduodenally (t = 0–60 min 3 kcal/min). Duodenal motility and flow were measured using a combined manometry-impedance catheter and small intestinal transit using scintigraphy. In both groups, duodenal pressure waves and antegrade flow events were fewer, and transit was slower with exenatide, as were the areas under the curves for serum 3-OMG and blood glucose concentrations. Insulin concentrations were initially lower with exenatide than with saline and subsequently higher. Nausea was greater in both groups with exenatide, but suppression of small intestinal motility and flow was observed even in subjects with little or no nausea. The inhibition of small intestinal motor function represents a novel mechanism by which exenatide can attenuate postprandial glycemia.
Publisher: MDPI AG
Date: 21-08-2020
DOI: 10.3390/PHARMACEUTICS12090790
Abstract: It is now widely appreciated that gastrointestinal function is central to the regulation of metabolic homeostasis. Following meal ingestion, the delivery of nutrients from the stomach into the small intestine (i.e., gastric emptying) is tightly controlled to optimise their subsequent digestion and absorption. The complex interaction of intraluminal nutrients (and other bioactive compounds, such as bile acids) with the small and large intestine induces the release of an array of gastrointestinal hormones from specialised enteroendocrine cells (EECs) distributed in various regions of the gut, which in turn to regulate gastric emptying, appetite and postprandial glucose metabolism. Stimulation of gastrointestinal hormone secretion, therefore, represents a promising strategy for the management of metabolic disorders, particularly obesity and type 2 diabetes mellitus (T2DM). That EECs are distributed distinctively between the proximal and distal gut suggests that the region of the gut exposed to intraluminal stimuli is of major relevance to the secretion profile of gastrointestinal hormones and associated metabolic responses. This review discusses the process of intestinal digestion and absorption and their impacts on the release of gastrointestinal hormones and the regulation of postprandial metabolism, with an emphasis on the differences between the proximal and distal gut, and implications for the management of obesity and T2DM.
Publisher: American Diabetes Association
Date: 13-01-2021
DOI: 10.2337/DCI20-0067
Publisher: American Diabetes Association
Date: 03-03-2017
DOI: 10.2337/DC16-2391
Abstract: 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. 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. Systolic (P = 0.002) and diastolic (P & 0.001) BP were lower and HR greater (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 & 0.001), without any difference in systolic or diastolic BP. 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.
No related grants have been discovered for Tongzhi Wu.