AIMS:To determine whether gastric emptying of an oral glucose load is related to the glucagon-like peptide-1 (GLP-1) response to intestinal glucose exposure in healthy individuals. MATERIALS AND METHODS:42 healthy participants (20F/22 M, age: 35.1 ± 2.1 years; BMI 24.5 ± 0.6 kg/m2) were evaluated on 2 days. On Day 1, participants ingested a 75 g glucose drink containing 150 mg 13C-acetate, with the gastric half-emptying time (T50) (breath test) and blood glucose concentrations determined over 180 min. On Day 2, participants received an intraduodenal glucose infusion at 4kcal/min for 30 min. Plasma insulin, C-peptide and total GLP-1 concentrations were measured at frequent intervals. RESULTS:There was a direct relationship between the T50 of oral glucose and the incremental area under the curve (iAUC) for GLP-1 (t = 0-120 min) in response to intraduodenal glucose (r = 0.33, P = 0.03). When participants were stratified into tertiles according to T50, GLP-1 iAUC0-120min in response to intraduodenal glucose infusion was greater in participants with slower vs. faster gastric emptying (P = 0.02). CONCLUSIONS:In healthy individuals, gastric emptying of a glucose drink is related to the magnitude of the GLP-1 response to intestinal glucose exposure. This finding supports the concept of intestinal 'sensitivity' to nutrients as a determinant of gastric emptying.

Secreted by enteroendocrine L-cells along the intestinal epithelium, glucagon-like peptide-1 (GLP-1) is a key regulator of glucose and energy homeostasis in health, obesity and type 2 diabetes. Understanding the stimuli and mechanisms governing GLP-1 secretion is fundamental to the development of novel therapies for metabolic disorders. Mechanistic studies have, hitherto, relied largely on well-based static incubation of immortalised cell lines or primary intestinal tissues, approaches that have limited physiological relevance and lack the capacity to monitor dynamic hormone release under biomimetic conditions. This study aimed to develop a microfluidic 'gut-on-a-chip' (GOC) platform to enable assessment of dynamic GLP-1 secretion from primary mouse intestinal tissue in a biomimetic environment. We initially characterised regional GLP-1 secretion capacity along the mouse small intestine to inform device design. A polymethyl methacrylate microchip was then micromachined to accommodate a segment of intestinal tissue and support parallel luminal and serosal perfusion via peristaltic microfluidic pumps. In proof-of-concept experiments, physiological GLP-1 secretagogues (taurocholic acid and glucose) were subsequently delivered to the luminal or serosal surface of duodenal and colonic tissue under continuous or intermittent perfusion. The GOC platform demonstrated superiority over static incubation for studying GLP-1 secretion in primary intestinal tissue, capturing dynamic serosal concentration changes over 2 h while better preserving tissue viability and morphology. This novel system provides a powerful tool to elucidate the mechanisms underlying gut hormone release and to screen candidate GLP-1 secretagogues for potential therapeutic development.

Aims Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are key regulators of glucose homeostasis in health and type 2 diabetes (T2D). Whether their secretion is influenced by antecedent glycaemic control in T2D remains unclear. This study compared GLP-1 and GIP responses to intraduodenal glucose infusion between individuals with well- and poorly-controlled T2D. Methods 24 diet-controlled participants with T2D (n = 12 with HbA1c < 7.0% and n = 12 with HbA1c > 8.5%) received an intraduodenal infusion of 30 g glucose with 3 g 3-O-methylglucose (3-OMG; a marker of intestinal glucose absorption) over 30 min. Blood glucose was maintained comparably (6.4 ± 0.4 vs. 6.1 ± 0.3 mmol/L) by intravenous insulin. Plasma GIP, GLP-1 and C-peptide and serum 3-OMG were measured at frequent intervals. Results Basal hormone concentrations were comparable between groups. In response to intraduodenal glucose infusion, the GIP response was greater in the poorly-controlled group (P = 0.02 for time*group interaction), with a trend for higher iAUC0-60min compared with well-controlled group (1329.9 ± 163.7 vs. 1009.5 ± 108.3 pmol/L*min, P = 0.12 unadjusted; P = 0.09 adjusted for age, sex and BMI). GLP-1 responses were lower in the poorly-controlled group (P = 0.007 for time*group interaction), with lower iAUC0-60min (453.3 ± 110.6 vs. 1037.5 ± 177.1 pmol/L*min, P = 0.01), but this difference became non-significant after adjustment for age, sex and BMI. C-peptide and 3-OMG responses were comparable. Conclusions Poor glycaemic control in T2D is associated with a greater GIP, and lower GLP-1, response to small intestinal glucose, independent of intestinal glucose absorption. However, differences in GLP-1 may be influenced by age, sex and BMI, so should be interpreted cautiously and validated in larger cohorts.

BACKGROUND:Idiopathic gastroparesis (IGP) treatment guidelines have to date focused on delayed gastric emptying as the cause of the associated symptoms of postprandial nausea, vomiting, early satiety, fullness, and pain. However the diagnostic hallmark-delayed gastric emptying-correlates poorly with symptoms, and the efficacy of treatments targeting gastric emptying is low. Clinically, there is substantial overlap with functional gastroduodenal disorders and eating disorders. As a result, current international guidelines provide limited guidance with low consensus. Recent advances support reconceptualizing IGP as a sensorimotor disorder, on a spectrum with functional dyspepsia, arising within the biopsychosocial model of disease. OBJECTIVE:To provide clear guidance to clinicians on the assessment and management of IGP, as a sensorimotor disorder, using a multidisciplinary framework. METHODS:Following formal review of the literature, a national multidisciplinary working group devised 20 consensus statements with a grade of evidence and strength of recommendation using a modified Delphi approach, and a suggested treatment algorithm. External review was obtained via patient representation, expert review, and public comment. CONCLUSION:A novel treatment algorithm and 20 consensus statements are provided to guide clinicians in the multidisciplinary assessment and management of IGP as a sensorimotor disorder, alongside its overlapping comorbidities. We call for review of the current definition of IGP and a shift in research efforts to identify novel therapeutic targets.

Gastric emptying, which exhibits a substantial interindividual, but much lesser intraindividual, variation in health and is frequently disordered (particularly delayed) in diabetes, is now appreciated to be a major determinant of postprandial glycemia. The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted in the proximal and distal small intestine, respectively, in response to nutrients. GLP-1, together with peptide tyrosine-tyrosine (PYY), stimulates potent negative feedback on gastric emptying. Modulation of gastric emptying, through dietary, pharmacologic, and surgical therapies, has been utilized in current clinical practice for the treatment of hyperglycemia, particularly relating to type 2 diabetes. We review the complex, interdependent relationships between gastric emptying, small intestinal transit, glucose absorption, neurohormonal regulatory responses, and postprandial glycemia. We discuss how this has informed fundamental advances in the understanding and rational management of obesity, stress hyperglycemia, type 1 and 2 diabetes, and gestational diabetes, and we provide recommendations for research priorities that have the potential to impact practice. We also discuss the frequent complication of abnormally delayed gastric emptying (gastroparesis) in both type 1 and type 2 diabetes, the implications for management of diabetes, and the impact of treatment on gastric emptying. With the increasing recognition of the importance of gastric emptying in the management of conditions associated with disordered glucose metabolism, and the advent and increasing use of GLP-1 receptor agonists, an improved definition of the interactions between gastrointestinal motility (gastric emptying and small intestinal transit) and enteropancreatic hormonal responses is essential.

Metabolic dysfunction-associated steatotic liver disease (MASLD) may be an important comorbidity in nonobese Chinese adults with type 1 diabetes (T1D). We assessed the likelihood of hepatic steatosis using the hepatic steatosis index (HSI) in 47 nonobese Chinese adults with T1D (mean age 46.9 ± 14.1 years; BMI 22.6 ± 2.5 kg/m2) and examined its association with insulin requirements. Overall, 27.7% of participants had an HSI >36, indicating a high likelihood of MASLD. Compared with those with HSI <30 (low likelihood of MASLD), individuals with HSI >36 required higher bolus and total daily insulin doses, while achieving comparable glycemic profiles. These findings demonstrate that an HSI >36 is relatively common in nonobese Chinese adults with T1D and is associated with higher insulin requirements. MASLD may therefore represent an under-recognized but clinically relevant comorbidity in nonobese Chinese adults with T1D, warranting greater attention in screening and management strategies.

Background Insulin-like peptide 5 (INSL5) is an enteroendocrine hormone expressed in distal colonic ‘L cells’. Bile acid receptor agonists are known to stimulate INSL5 secretion in primary cell culture, and administration of an INSL5 analogue in animals promotes colonic motility. Objective This study used a new immunoassay to measure INSL5 in human blood samples, enabling assessment of whether rectal bile acids stimulate INSL5 release in humans and whether INSL5 levels are altered in patients with chronic diarrhoea. Design Serum/plasma samples from previously performed studies were used, including healthy volunteers (n=7) who received a rectal enema of taurocholic acid (TCA); fasting and post prandial samples from healthy volunteers (n=10); patients with bile acid diarrhoea (BAD) (n=19) or irritable bowel syndrome with diarrhoea (IBS-D) (n=8); and patients with IBS-D (n=64) treated with ondansetron or placebo. Results Rectal TCA but not a control enema promptly elevated plasma INSL5, with the increase in INSL5 correlating negatively with time to, and positively with desire to, defecate post enema. Healthy volunteers had low INSL5 levels (<100 pg/mL), with no change following a mixed meal. Patients with BAD had elevated INSL5 levels, with average stool consistency being positively correlated with serum INSL5 (p<0.001). In people with IBS-D, INSL5 was elevated (>100 pg/mL) in 42%, and this subgroup showed greater improvements in stool consistency with ondansetron therapy (p<0.05). Conclusion The study highlights that rectal bile acids stimulate INSL5 secretion in humans, and that INSL5 levels are associated with a colonic pro-motility response and pathophysiology of chronic diarrhoea.

Foods and beverages sweetened with non-nutritive sweeteners (NNSs) are increasingly common in modern diets and widely promoted as healthy alternatives to their sugar-sweetened counterparts, with attendant benefits for individuals with preclinical or clinical metabolic disease. Despite this position, the evidence base supporting the purported health benefits of NNSs is limited and equivocal, particularly in individuals with type 2 diabetes. This review discusses the metabolic effects of NNSs from the standpoint of epidemiological studies and focuses on evidence from the hitherto limited number of prospective clinical trials, as well as potential modes of interaction. Non-nutritive sweeteners are capable of binding to sweet taste receptors (STRs, a heterodimer of T1R2-T1R3) in a wide variety of tissues, including the tongue, pancreas, and small intestine. In cellular, tissue and preclinical models, the binding of NNSs to intestinal STRs triggers the release of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which, in turn, evoke pancreatic insulin release. Sweet taste receptor activation also triggers release of the intestinotrophic peptide, glucagon-like peptide 2 (GLP-2), which augments the expression and function of the primary apical glucose transporter in the intestine, sodium-glucose co-transporter-1 (SGLT-1). In addition, the NNSs saccharin and sucralose disrupt the composition of the gut microbiome in both pre-clinical and clinical settings in health, and do so in a manner that is individualized and causally related to glucose intolerance. Correspondingly, NNSs have the potential to impact metabolic outcomes directly via host-mediated pathways, as well as secondary to changes in the hosted microbiota. To date, most clinical trials have focused on the acute or subacute effects of NNSs on gut hormone release, glycemic control, and weight management. There is now broad recognition that longer-term, prospective randomized clinical trials are required to add mechanistic insight into how NNSs impact glycemic control in health and in type 2 diabetes.

AIMS:Glucose-dependent insulinotropic polypeptide (GIP) may exert both insulinotropic and glucagonotropic effects. While its insulinotropic action is reportedly attenuated or abolished with worsening of glycaemic control in type 2 diabetes (T2D), the relationship between GIP and glucagon secretion across different levels of glycaemic control remains unclear. This study evaluated the relationship between postprandial GIP and glucagon responses to a mixed meal in T2D and to intraduodenal fat and glucose infusion in healthy and/or T2D individuals. MATERIALS AND METHODS:Data were analysed from three clinical studies: mixed-meal testing in T2D (n = 79), intraduodenal fat infusion (2 kcal/min over 120 min) in T2D (n = 15) and intraduodenal glucose infusion (2 kcal/min over 60 min) in health and T2D (n = 10 each). Relationships between postprandial GIP and glucagon or insulin following the mixed meal were also determined after stratification by HbA1c (< 6.5%, 6.5%-7.0%, > 7.0%). RESULTS:Following mixed-meal ingestion, early postprandial (0-30 min) glucagon secretion correlated positively with GIP, with the strength of this association increasing with higher HbA1c levels. In contrast, the insulinogenic index correlated with GIP only in subgroups with HbA1c < 6.5% and between 6.5%-7.0%. During intraduodenal fat infusion, glucagon and GIP responses correlated strongly in T2D. Following intraduodenal glucose infusion, early glucagon and GIP increments (0-15 min) were closely related in T2D, but not in healthy individuals. CONCLUSIONS:These observations indicate a glycaemia-dependent shift in endogenous GIP action in T2D, characterised by attenuation of insulinotropic effects and relative amplification of glucagonotropic effects with deteriorating glycaemic control. TRIAL REGISTRATION:ACTRN12614001131640, ACTRN12614001117606 and ACTRN12615001240538.

Understanding the relative contributions of basal and postprandial hyperglycaemia (BH and PPH) to hyperglycaemia is pivotal to optimising the therapeutic strategies for type 2 diabetes (T2D). We used continuous glucose monitoring (CGM) to quantify longitudinal changes in the relative contributions of BH and PPH to overall hyperglycaemia in 22 treatment-naïve Han Chinese adults with T2D before and after 3 months of intensive glucose-lowering therapy. At baseline (HbA1c 10.0 ± 0.3%), BH predominated, contributing ~73-77% of overall hyperglycaemia. Following treatment (HbA1c 7.1 ± 0.2%), the contribution of BH decreased markedly (~35-38%), while PPH became the dominant contributor of hyperglycaemia (~62-66%). The improvement in glycaemic control was also accompanied by enhanced insulin secretion and sensitivity, without changes in gastric emptying. These findings provide longitudinal, CGM-based evidence of a dynamic shift in glycaemic determinants with therapy. Therapeutic strategies should be adapted accordingly, with initial focus on BH followed by increasing emphasis on PPH as glycaemic control improves.

Hepatic glucose flux plays a crucial role in the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), promoting de novo lipogenesis, inflammation and fibrosis. This study aimed to evaluate the kinetics of oral glucose absorption and one of its key modulators, gastric emptying, in individuals with early-stage MASLD vs matched control individuals. We quantified glucose metabolic fluxes during a 75 g OGTT using stable isotopes in individuals with MASLD without fibrosis and in healthy control individuals. In a separate cohort, we measured the gastric emptying rate using the 13C-acetate breath test during an OGTT and estimated hepatic steatosis risk. Compared with the control group, in the MASLD group the rate of appearance of oral ingested glucose (RaO) normalised to body weight was 34

Glucagon-like peptide-1 (GLP-1) receptor agonists improve dyslipidemia and reduce cardiovascular risk in type 2 diabetes (T2D), but the role of endogenous GLP-1 in lipid metabolism remains unclear. We evaluated the effect of dipeptidyl peptidase 4 (DPP-4) inhibition on the plasma triglycerides (TGs) response to intraduodenal lipid and a mixed meal, and the impact of GLP-1 receptor blockade with exendin(9-39) in T2D. Fifteen participants with T2D, managed by diet and/or metformin were studied on three occasions in a double-blind, randomized, crossover design. Vildagliptin (50 mg) or placebo was administered orally (t=-60min), followed by intravenous (i.v.) exendin(9-39) from t=-60-150min on one of the two vildagliptin days or 0.9% saline on two other days. A lipid emulsion was infused intraduodenally (2 kcal/min, t=0-120min), followed by a mixed meal (t=120-150min). Plasma TG levels, quantified by liquid chromatography-tandem mass spectrometry, increased after lipid and meal, with most individual TGs corresponding to those in the lipid emulsion. Vildagliptin reduced TG(54:4) and TG(54:5) concentrations (each P<0.01), without affecting total TGs. Blocking endogenous GLP-1 during vildagliptin treatment increased plasma total TGs (P<0.001), associated with ten individual TG species elevated significantly (P<0.05 each). These outcomes suggest that endogenous GLP-1 contributes to the physiological modulation of postprandial TG appearance in T2D.

The pharmacological actions of glucose-dependent insulinotropic polypeptide (GIP) in type 2 diabetes (T2D) remain incompletely defined. We evaluated the acute effects of intravenous GIP infusion at a pharmacological dose on glucose homeostasis and cardiovascular responses during hyperglycemia in individuals with T2D. Ten participants, whose T2D was managed by diet and/or metformin monotherapy (n = 4 men and 6 women; mean ± SEM age 68.2 ± 3.4 years, BMI 31.7 ± 1.2 kg/m2, HbA1c 6.9% ± 0.6%), were studied on two occasions in a double-blind, randomized, crossover design. During each study visit, hyperglycemia (∼15 mmol/L) was maintained for 210 min by variable intravenous (IV) glucose infusion, and GIP(1-42) (4 pmol/kg/min) or 0.9% saline was infused IV. Plasma insulin, C-peptide, glucagon, glucose infusion requirements, mean glucose/insulin ratio (M/I ratio; a surrogate for insulin sensitivity), heart rate, and blood pressure were assessed. GIP increased baseline-subtracted insulin and C-peptide responses between 0 and 210 min (mean ± SEM 8,717 ± 1,827 vs. 3,074 ± 698 mU/L*min, P = 0.003; and 383.1 ± 58.9 vs. 185.0 ± 35.0 nmol/L*min, P = 0.0005, respectively) and increased glucose infusion requirements to maintain hyperglycemia (mean ± SEM 6.1 ± 0.6 vs. 4.9 ± 0.4 mg/kg/min; P = 0.02), but attenuated glucagon suppression (P = 0.03) and reduced the M/I ratio (P < 0.0001). GIP also increased heart rate and reduced systolic and diastolic blood pressures (P < 0.01 each). These findings demonstrate that pharmacological GIP retains substantial biological activity in relatively well-controlled T2D, influencing both glucose metabolism and cardiovascular regulation. ARTICLE HIGHLIGHTS:The clinical success of dual glucagon-like peptide 1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists has renewed interest in the pharmacological actions of GIP in type 2 diabetes (T2D), although its metabolic and cardiovascular effects remain incompletely understood. The study evaluated the effects of a pharmacological GIP infusion on glucose homeostasis and cardiovascular responses during hyperglycemia in individuals with T2D. GIP stimulated insulin secretion and increased whole-body glucose disposal during hyperglycemia while modestly attenuating glucagon suppression and impairing insulin sensitivity. GIP also augmented heart rate and reduced blood pressure. Our findings demonstrate that GIP remains biologically active in T2D and pharmacological doses modulate glucose metabolism and cardiovascular function.

AIMS:Current hypertension guidelines fail to discriminate between fasting and postprandial blood pressure (BP) measurements. Meal ingestion often triggers a marked increase in splanchnic blood flow, potentially inducing a sustained fall in systolic BP of ≥20 mmHg, termed postprandial hypotension (PPH). This study aimed to evaluate BP responses to a 75 g glucose drink and its implications for detecting hypertension and PPH in community-dwelling adults. METHODS AND RESULTS:A stratified multi-stage random sampling method was used to obtain a nationally representative sample of n = 4429 adult residents between April 2020 and January 2021 in China. BP and heart rate (HR) were measured before, and 1 and 2 h after, a 75 g glucose drink. When fasting, 38.4% of the study population had high BP (BP ≥140/90 mmHg). Following the glucose drink, SBP and DBP decreased (SBP by 6.2 [95% CI: 5.8, 6.6] mmHg and 8.1 [7.7, 8.5] mmHg, DBP by 4.7 [4.4, 4.9] mmHg and 6.1 [5.8, 6.4] mmHg), and HR increased (by 4.3 [4.0, 4.5] bpm and 2.6 [2.4, 2.9] bpm) at 1 and 2 h (P < 0.001 for all), with only 30.9% and 27.0% of the study population having high BP at 1 and 2 h, respectively. After adjustment for age and sex distribution, 19.9% of the general population was estimated to have PPH. Postprandial hypotension was associated with an increased risk of combined cardiovascular disease and stroke. CONCLUSION:Ingestion of a 75 g glucose drink often lowers BP, frequently leading to PPH and influencing the detection of hypertension. Accordingly, guidelines for measurements of BP and interpretation of outcomes should consider the potential impact of meal ingestion on BP.

BACKGROUND AND AIMS:Combined standard chemotherapy and phosphorus-32 (32P) microparticle intratumoral implantation has revealed encouraging results in locally advanced pancreatic cancer (LAPC). We compared chemotherapy and 32P implantation with standard therapy (chemotherapy ± chemoradiotherapy) using a propensity score-weighted analysis (PSWA). METHODS:We conducted a retrospective cohort study comparing clinical outcomes of combined chemotherapy and EUS-guided 32P implantation against standard therapy for patients with LAPC from 2 tertiary hospitals. Landmark analysis was used to address immortal time bias. PSWA was applied to reduce bias due to confounding. The primary outcome was overall survival within 30 months after first-line treatment initiation, with treatment effect expressed as restricted mean survival time (RMST). RESULTS:One hundred four patients were considered. The landmark date was designated as 3 months after initiation of first-line chemotherapy. After excluding patients who died before the landmark or had 32P implantation after it, 86 patients were included (35 combination vs 51 standard). The RMST within 30 months after chemotherapy commencement was an estimated 189 days longer for patients with combination therapy (527.2 [95% CI, 437.8-634.8] vs 338.0 [95% CI 284.2-402], P = .002). The local progression-free RMST within 30 months was estimated to be 168.6 days longer (95% CI, 79.9-257.2), and the probability of downstaging was 23.9% higher (95% CI, 6.3-41.3; P = .008) in patients treated with combination therapy. CONCLUSIONS:In this comparative study between combined chemotherapy and 32P microparticles implantation with standard chemotherapy for patients with LAPC, the combination showed better survival, disease control, and downstaging. The outcomes highlight the need for a randomized controlled trial.