Gastrointestinal effects of GLP-1 receptor agonists: mechanisms, management, and future directions.

The availability of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) such as liraglutide and semaglutide, and a GLP-1 and glucose dependent insulinotropic polypeptide coagonist (tirzepatide) represents a paradigm shift in the management of both type 2 diabetes and obesity. There is now considerable attention, including in the public media, on the effect of both long-acting and short-acting GLP-1RAs to delay gastric emptying. Although slowed gastric emptying is integral to reducing post-prandial blood glucose responses in type 2 diabetes, marked slowing of gastric emptying might also increase the propensity for longer intragastric retention of food, with a consequent increased risk of aspiration at the time of surgery or upper gastrointestinal endoscopy. This Personal View summarises current knowledge of the effects of GLP-1 and GLP-1RAs on gastrointestinal physiology, particularly gastric emptying, and discusses the implications for the development of sound pre-operative or pre-procedural guidelines. The development of pre-procedural guidelines is currently compromised by the poor evidence base, particularly in relation to the effect of long-acting GLP-1RAs on gastric emptying. We suggest pre-procedural management pathways for individuals on GLP-1RA-based therapy and discuss priorities for future research.

Randomised comparison of intravenous and subcutaneous routes of glucagon-like peptide-1 administration for lowering plasma glucose in hyperglycaemic subjects with type 2 diabetes.

AIM: To perform a direct, double-blind, randomised, crossover comparison of subcutaneous and intravenous glucagon-like peptide-1 (GLP-1) in hyperglycaemic subjects with type 2 diabetes naïve to GLP-1-based therapy. MATERIALS AND METHODS: Ten fasted, hyperglycaemic subjects (1 female, age 63 ± 10 years [mean ± SD], glycated haemoglobin 73.5 ± 22.0 mmol/mol [8.9% ± 2.0%], both mean ± SD) received subcutaneous GLP-1 and intravenous saline, or intravenous GLP-1 and subcutaneous saline. Infusion rates were doubled every 120 min (1.2, 2.4, 4.8 and 9.6 pmol·kg-1·min-1 for subcutaneous, and 0.3, 0.6, 1.2 and 2.4 pmol·kg-1·min-1 for intravenous). Plasma glucose, total and intact GLP-1, insulin, C-peptide, glucagon and gastrointestinal symptoms were evaluated over 8 h. The results are presented as mean ± SEM. RESULTS: Plasma glucose decreased more with intravenous (by ~8.0 mmol/L [144 mg/dL]) than subcutaneous GLP-1 (by ~5.6 mmol/L [100 mg/dL]; p < 0.001). Plasma GLP-1 increased dose-dependently, but more with intravenous than subcutaneous for both total (∆max 154.2 ± 3.9 pmol/L vs. 85.1 ± 3.8 pmol/L; p < 0.001), and intact GLP-1 (∆max 44.2 ± 2.2 pmol/L vs. 12.8 ± 2.2 pmol/L; p < 0.001). Total and intact GLP-1 clearance was higher for subcutaneous than intravenous GLP-1 (p < 0.001 and p = 0.002, respectively). The increase in insulin secretion was greater, and glucagon was suppressed more with intravenous GLP-1 (p < 0.05 each). Gastrointestinal symptoms did not differ (p > 0.05 each). CONCLUSIONS: Subcutaneous GLP-1 administration is much less efficient than intravenous GLP-1 in lowering fasting plasma glucose, with less stimulation of insulin and suppression of glucagon, and much less bioavailability, even at fourfold higher infusion rates.

Sex differences in the plasma glucagon responses to a high carbohydrate meal and a glucose drink in type 2 diabetes.

Elevated fasting glucagon concentrations and/or attenuated postprandial glucagon suppression are characteristics of type 2 diabetes (T2D) and contribute to hyperglycaemia. This study shows that hyperglucagonaemia is more prominent in males than females after a nutrient load in T2D, adding insights into sex differences in relation to the pathophysiology of T2D.

Effect of lixisenatide on liquid gastric emptying in type 2 diabetes - Implications for the use of GLP-1 receptor agonists before procedures.

Gastric emptying of a glucose drink was measured in people with type 2 diabetes given lixisenatide (20 µg/day or placebo) for 8 weeks. Intragastric retention at 240 min (2 (0-11)% vs 48 (3-97)%; P < 0.0001) was much greater with lixisenatide than placebo. Accordingly, lixisenatide may delay liquid gastric emptying markedly.

Gastric emptying in newly diagnosed, treatment-naïve Han Chinese with type 2 diabetes and the impact of 4-week insulin pump therapy.

AIM: To evaluate gastric emptying (GE) and the glycaemic response to a 75-g oral glucose load in newly diagnosed, treatment-naïve Han Chinese with type 2 diabetes (T2D) before insulin pump therapy, after 4 weeks of insulin pump therapy, and 12-15 months after insulin pump therapy. MATERIALS AND METHODS: Twenty participants with T2D (baseline glycated haemoglobin [± SD] 10.7% [± 1.2%] 93 [± 10] mmol/mol) ingested a 75-g glucose drink containing 150 mg 13C-acetate, to determine the gastric half-emptying time, and underwent assessment of plasma glucose and serum insulin, C-peptide and glucagon-like peptide-1 (GLP-1) over 180 min before and after 4 weeks of insulin pump therapy (discontinued for 48 h before re-assessment). Data were compared to those in 19 healthy participants matched for sex and age. After 12-15 months, GE was re-measured in 14 of the T2D participants. RESULTS: At baseline, participants with T2D exhibited substantially augmented fasting and post-glucose glycaemia, diminished insulin secretion, and more rapid GE (p < 0.05 each), but comparable GLP-1, compared to healthy participants. Following insulin pump therapy, insulin secretion increased, GLP-1 secretion was attenuated, fasting and post-glucose glycaemia were lower, and GE was slowed (p < 0.05 each). The slowing of GE in T2D participants was sustained over 12-15 months of follow-up. CONCLUSIONS: In newly diagnosed Han Chinese with T2D, GE is often accelerated despite poor glycaemic control and is slowed by short-term insulin pump therapy. The effect on GE is maintained for at least 12 months.

Gastric emptying is slower in women than men with type 2 diabetes and impacts on postprandial glycaemia.

AIM: To evaluate sex differences in gastric emptying and the glycaemic response to a glucose drink and a high carbohydrate meal in type 2 diabetes (T2D). METHODS: In cohort 1, 70 newly diagnosed, treatment-naïve Chinese patients with T2D (44 men) recruited from a diabetes outpatient clinic ingested a 75-g glucose drink containing 150 mg 13C-acetate. In cohort 2, 101 Australian patients with T2D (67 male) recruited from the community, managed by diet and/or metformin monotherapy, ingested a semi-solid mashed potato meal, labelled with 100 µl 13C-octanoic acid. Breath samples were collected over 3 and 4 h, respectively, for assessment of gastric emptying, and venous blood was sampled for evaluation of glycaemia (with and without adjustment for each participant's estimated total blood volume). RESULTS: Gastric emptying was slower in female than male subjects in both cohorts (both p < .01). Multiple linear regression analyses revealed that gastric emptying was independently associated with sex (both p < .05). Without adjustment for blood volume, the glycaemic responses to oral glucose and the mixed meal were greater in female subjects (both p < .001). However, after adjustment for blood volume, the glycaemic responses were greater in men (both p < .05). CONCLUSIONS: Gastric emptying is slower in women than men with T2D, associated with a reduced blood volume-adjusted glycaemic response to oral glucose and a mixed meal in women. These observations highlight the sex difference in postprandial glucose handling, which is relevant to the personalized management of postprandial glycaemia in T2D.

Impact of the timing of metformin administration on glycaemic and glucagon-like peptide-1 responses to intraduodenal glucose infusion in type 2 diabetes: a double-blind, randomised, placebo-controlled, crossover study.

AIMS/HYPOTHESIS: Metformin lowers postprandial glycaemic excursions in individuals with type 2 diabetes by modulating gastrointestinal function, including the stimulation of glucagon-like peptide-1 (GLP-1). The impact of varying the timing of metformin administration on postprandial glucose metabolism is poorly defined. We evaluated the effects of metformin, administered at different intervals before an intraduodenal glucose infusion, on the subsequent glycaemic, insulinaemic and GLP-1 responses in metformin-treated type 2 diabetes. METHODS: Sixteen participants with type 2 diabetes that was relatively well-controlled by metformin monotherapy were studied on four separate days in a crossover design. On each day, participants were randomised to receive a bolus infusion of metformin (1000 mg in 50 ml 0.9% saline) via a nasoduodenal catheter at t = -60, -30 or 0 min (and saline at the other timepoints) or saline at all timepoints (control), followed by an intraduodenal glucose infusion of 12.56 kJ/min (3 kcal/min) at t = 0-60 min. The treatments were blinded to both participants and investigators involved in the study procedures. Plasma glucose, insulin and total GLP-1 levels were measured every 30 min between t = -60 min and t = 120 min. RESULTS: There was a treatment-by-time interaction for metformin in reducing plasma glucose levels and increasing plasma GLP-1 and insulin levels (p<0.05 for each). The reduction in plasma glucose levels was greater when metformin was administered at t = -60 or -30 min vs t = 0 min (p<0.05 for each), and the increases in plasma GLP-1 levels were evident only when metformin was administered at t = -60 or -30 min (p<0.05 for each). Although metformin did not influence insulin sensitivity, it enhanced glucose-induced insulin secretion (p<0.05), and the increases in plasma insulin levels were comparable on the 3 days when metformin was given. CONCLUSIONS/INTERPRETATION: In well-controlled metformin-treated type 2 diabetes, glucose-lowering by metformin is greater when it is given before, rather than with, enteral glucose, and this is associated with a greater GLP-1 response. These observations suggest that administration of metformin before meals may optimise its effect in improving postprandial glycaemic control. TRIAL REGISTRATION: www.anzctr.org.au ACTRN12621000878875 FUNDING: The study was not funded by a specific research grant.

Gastric emptying during and following resolution of moderate diabetic ketoacidosis in type 1 diabetes: a case series.

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

Gastric emptying of a glucose drink is predictive of the glycaemic response to oral glucose and mixed meals, but unrelated to antecedent glycaemic control, in type 2 diabetes.

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

The herbal preparation, STW5-II, reduces proximal gastric tone and stimulates antral pressures in healthy humans.

BACKGROUND: The herbal preparation, STW5-II, improves upper gastrointestinal symptoms, including abdominal fullness, early satiation, and epigastric pain, in patients with functional dyspepsia, and in preclinical models decreases fundic tone and increases antral contractility. The effects of STW5-II on esophago-gastric junction pressure, proximal gastric tone and antropyloroduodenal pressures, disturbances of which may contribute to symptoms associated with disorders of gut-brain interaction, including functional dyspepsia, in humans, have, hitherto, not been evaluated. METHODS: STW5-II or placebo (matched for color, aroma, and alcohol content) were each administered orally, at the recommended dose (20 drops), to healthy male and female volunteers (age: 27 ± 1 years) in a double-blind, randomized fashion, on two separate occasions, separated by 3-7 days, to evaluate effects on (i) esophago-gastric junction pressures following a standardized meal using solid-state high-resolution manometry (part 1, n = 16), (ii) proximal gastric volume using a barostat (part 2, n = 16), and (iii) antropyloroduodenal pressures assessed by high-resolution manometry (part 3, n = 18), for 120 min (part 1) or 180 min (parts 2, 3). KEY RESULTS: STW5-II increased maximum intrabag volume (ml; STW5-II: 340 ± 38, placebo: 251 ± 30; p = 0.007) and intrabag volume between t = 120 and 180 min (p = 0.011), and the motility index of antral pressure waves between t = 60 and 120 min (p = 0.032), but had no effect on esophago-gastric junction, pyloric, or duodenal pressures. CONCLUSIONS & INFERENCES: STW5-II has marked region-specific effects on gastric motility in humans, which may contribute to its therapeutic efficacy in functional dyspepsia.

Comparison of energy intake in critical illness survivors, general medical patients, and healthy volunteers: A descriptive cohort study.

BACKGROUND: Intensive care unit (ICU) survivors have reduced oral intake; it is unknown whether intake and associated barriers are unique to this group. OBJECTIVE: To quantify energy intake and potential barriers in ICU survivors compared with general medical (GM) patients and healthy volunteers. DESIGN: A descriptive cohort study in ICU survivors, GM patients, and healthy volunteers. Following an overnight fast, participants consumed a 200 ml test-meal (213 kcal) and 180 min later an ad libitum meal to measure energy intake (primary outcome). Secondary outcomes; taste recognition, nutrition-impacting symptoms, malnutrition, and quality of life (QoL). Data are mean ± SD, median (interquartile range [IQR]) or number [percentage]). RESULTS: Twelve ICU survivors (57 ± 17 years, BMI: 30 ± 6), eight GM patients (69 ± 19 years, BMI: 30 ± 6), and 25 healthy volunteers (58 ± 27 years, BMI: 25 ± 4) were included. Recruitment ceased early because of slow recruitment and SARS-CoV-2. Energy intake was lower in both patient groups than in health (ICU: 289 [288, 809], GM: 426 [336, 592], health: 815 [654, 1165] kcal). Loss of appetite was most common (ICU: 78%, GM: 67%). For ICU survivors, GM patients and healthy volunteers, respectively, severe malnutrition prevalence; 40%, 14%, and 0%; taste identification; 8.5 [7.0, 11.0], 8.5 [7.0, 9.5], and 8.0 [6.0, 11.0]; and QoL; 60 [40-65], 50 [31-55], and 90 [81-95] out of 100. CONCLUSIONS: Energy intake at a buffet meal is lower in hospital patients than in healthy volunteers but similar between ICU survivors and GM patients. Appetite loss potentially contributes to reduced energy intake.

Characterizing infection prevention programs and urinary tract infection prevention practices in nursing homes: A mixed-methods study.

OBJECTIVE: US policies require robust nursing home (NH) infection prevention and control (IPC) programs to ensure safe care. We assessed IPC resources and practices related to catheter and non-catheter-associated urinary tract infection (CAUTI and UTI) prevention among NHs. METHODS: We conducted a mixed-methods study from April 2018 through November 2019. Quantitative surveys assessed NH IPC program resources, practices, and communication during resident transfer. Semistructured qualitative interviews focused on IPC programs, CAUTI and UTI prevention practices, and resident transfer processes. Using a matrix as an analytic tool, findings from the quantitative survey data were combined with the qualitative data in the form of a joint display. RESULTS: Representatives from 51 NHs completed surveys; interviews were conducted with 13 participants from 7 NHs. Infection preventionists (IPs) had limited experience and/or additional roles, and in 36.7% of NHs, IPs had no specific IPC training. IP turnover was often mentioned during interviews. Most facilities were aware of their CAUTI and UTI rates and reported using prevention practices, such as hydration (85.7%) or nurse-initiated catheter discontinuation (65.3%). Qualitative interviewees confirmed use of these practices and expressed additional concerns about overuse of urine testing and antibiotics. Although transfer sheets were used by 84% to communicate about infections, the information received was described as suboptimal. CONCLUSIONS: NHs identified IP challenges related to turnover, limited education, and serving multiple roles. However, most NHs reported awareness of their CAUTI and UTI rates as well as their use of prevention practices. Importantly, we identified opportunities to enhance communication between NHs and hospitals to improve resident care and safety.

A Biphasic Glucose Response during an Oral Glucose Tolerance Test Is Associated with Greater Plasma Insulin and GLP-1 Responses and a Reduction in 1-Hour Glucose but Does Not Relate to the Rate of Gastric Emptying in Healthy, Older Adults.

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

Serum alanine transaminase is predictive of fasting and postprandial insulin and glucagon concentrations in type 2 diabetes.

The liver plays a key role in glucose homeostasis. Serum liver enzyme levels, including alanine transaminase (ALT), aspartate transaminase (AST) and gamma-glutamyl transferase (GGT), are reportedly predictive of the risk of type 2 diabetes (T2D). However, the link between the liver enzyme profile and metabolic derangements in T2D, particularly the secretion of both insulin and glucagon, is not clear. This study evaluated its relationships with glycemia, insulin and glucagon both during fasting and after an oral glucose load or a mixed meal in T2D. 15 healthy and 43 T2D subjects ingested a 75 g glucose drink. 86 T2D subjects consumed a mixed meal. Venous blood was sampled for measurements of blood glucose and plasma insulin, C-peptide and glucagon. Blood glucose, plasma insulin, C-peptide and glucagon concentrations, both fasting and after oral glucose, correlated directly with ALT, while fewer and weaker correlations were observed with GGT or AST. Subgroup analysis in T2D subjects ascertained that plasma insulin, C-peptide and glucagon concentrations after oral glucose were higher with increasing ALT. Similar findings were observed in the T2D subjects who received a mixed meal. In conclusion, serum liver enzyme profile, particularly ALT, reflects dysregulated fasting and nutrient-stimulated plasma insulin and glucagon concentrations in T2D.

Eliciting and prioritising determinants of improved care in multimorbidity: A modified online Delphi study.

Background: Multimorbidity is a major challenge to health and social care systems around the world. There is limited research exploring the wider contextual determinants that are important to improving care for this cohort. In this study, we aimed to elicit and prioritise determinants of improved care in people with multiple conditions. Methods: A three-round online Delphi study was conducted in England with health and social care professionals, data scientists, researchers, people living with multimorbidity and their carers. Results: Our findings suggest a care system which is still predominantly single condition focused. 'Person-centred and holistic care' and 'coordinated and joined up care', were highly rated determinants in relation to improved care for multimorbidity. We further identified a range of non-medical determinants that are important to providing holistic care for this cohort. Conclusions: Further progress towards a holistic and patient-centred model is needed to ensure that care more effectively addresses the complex range of medical and non-medical needs of people living with multimorbidity. This requires a move from a single condition focused biomedical model to a person-based biopsychosocial approach, which has yet to be achieved.

An integrated approach for early in vitro seizure prediction utilizing hiPSC neurons and human ion channel assays.

Seizure liability remains a significant cause of attrition throughout drug development. Advances in stem cell biology coupled with an increased understanding of the role of ion channels in seizure offer an opportunity for a new paradigm in screening. We assessed the activity of 15 pro-seizurogenic compounds (7 CNS active therapies, 4 GABA receptor antagonists, and 4 other reported seizurogenic compounds) using automated electrophysiology against a panel of 14 ion channels (Nav1.1, Nav1.2, Nav1.6, Kv7.2/7.3, Kv7.3/7.5, Kv1.1, Kv4.2, KCa4.1, Kv2.1, Kv3.1, KCa1.1, GABA α1ß2γ2, nicotinic α4ß2, NMDA 1/2A). These were selected based on linkage to seizure in genetic/pharmacological studies. Fourteen compounds demonstrated at least one "hit" against the seizure panel and 11 compounds inhibited 2 or more ion channels. Next, we assessed the impact of the 15 compounds on electrical signaling using human-induced pluripotent stem cell neurons in microelectrode array (MEA). The CNS active therapies (amoxapine, bupropion, chlorpromazine, clozapine, diphenhydramine, paroxetine, quetiapine) all caused characteristic changes to electrical activity in key parameters indicative of seizure such as network burst frequency and duration. The GABA antagonist picrotoxin increased all parameters, but the antibiotics amoxicillin and enoxacin only showed minimal changes. Acetaminophen, included as a negative control, caused no changes in any of the parameters assessed. Overall, pro-seizurogenic compounds showed a distinct fingerprint in the ion channel/MEA panel. These studies highlight the potential utility of an integrated in vitro approach for early seizure prediction to provide mechanistic information and to support optimal drug design in early development, saving time and resources.