Efficacy, Safety, and Mechanistic Insights of Cotadutide, a Dual Receptor Glucagon-Like Peptide-1 and Glucagon Agonist

2019 ◽  
Vol 105 (3) ◽  
pp. 803-820 ◽  
Author(s):  
Victoria E R Parker ◽  
Darren Robertson ◽  
Tao Wang ◽  
David C Hornigold ◽  
Marcella Petrone ◽  
...  
Keyword(s):  
Gastric Emptying ◽  
Area Under The Curve ◽  
Tolerance Test ◽  
Double Blind ◽  
Glucose Lowering ◽  
End Of Treatment ◽  
Gastric Emptying Time ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Underlying Mechanisms

Abstract Context Cotadutide is a dual receptor agonist with balanced glucagon-like peptide-1 and glucagon activity. Objective To evaluate different doses of cotadutide and investigate underlying mechanisms for its glucose-lowering effects. Design/setting Randomized, double-blind, phase 2a study conducted in 2 cohorts at 5 clinical trial sites. Patients Participants were 65 adult overweight/obese patients with type 2 diabetes mellitus; 63 completed the study; 2 were withdrawn due to AEs. Intervention Once-daily subcutaneous cotadutide or placebo for 49 days. Doses (50–300 µg) were uptitrated weekly (cohort 1) or biweekly (cohort 2). Main outcome measures Co-primary end points (cohort 1) were percentage changes from baseline to end of treatment in glucose (area under the curve from 0 to 4 hours [AUC0–4h]) post–mixed-meal tolerance test (MMTT) and weight. Exploratory measures included postprandial insulin and gastric emptying time (GET; cohort 2). Results Patients received cotadutide (cohort 1, n = 26; cohort 2, n = 20) or placebo (cohort 1, n = 13; cohort 2, n = 6). Significant reductions were observed with cotadutide vs placebo in glucose AUC0–4h post MMTT (least squares mean [90% CI], −21.52% [−25.68, −17.37] vs 6.32% [0.45, 12.20]; P < 0.001) and body weight (−3.41% [−4.37, −2.44] vs −0.08% [−1.45, 1.28]; P = 0.002). A significant increase in insulin AUC0–4h post MMTT was observed with cotadutide (19.3 mU.h/L [5.9, 32.6]; P = 0.008) and GET was prolonged on day 43 with cotadutide vs placebo (t½: 117.2 minutes vs −42.9 minutes; P = 0.0392). Conclusion These results suggest that the glucose-lowering effects of cotadutide are mediated by enhanced insulin secretion and delayed gastric emptying. Trial Registration ClinicalTrials.gov, NCT03244800.

scholarly journals Policaptil Gel Retard Intake Reduces Postprandial Triglycerides, Ghrelin and Appetite in Obese Children: A Clinical Trial

Nutrients ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 214
Author(s):  
Elena Fornari ◽  
Anita Morandi ◽  
Claudia Piona ◽  
Mara Tommasi ◽  
Massimiliano Corradi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Area Under The Curve ◽  
Obese Children ◽  
Double Blind ◽  
Postprandial Period ◽  
Postprandial Triglycerides ◽  
Double Blind Clinical Trial ◽  
Affect Body Weight ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The aim of this study is to test the hypothesis that the intake of Policaptil Gel Retard® (PGR) is able to affect appetite, metabolic and hormonal postprandial profile in obese children. 46 obese children were randomly assigned to treatment with PGR or placebo, in a double blind clinical trial. Two PGR tablets or placebo were given in fasting condition, before the ingestion of a mixed meal (15 kcal/kg lean body mass). Blood samples were taken at baseline and for 4 h, for measuring blood lipids, glucose, insulin, ghrelin, and glucagon like peptide-1 (GLP-1). Appetite was quantified using a visual analog scale. Children assuming PGR had a significantly lower increase of postprandial triglycerides (area under the curve (AUC): 3021 (2879) vs. 5038 (3738) mg × 240 min/Dl) and appetite (−234 (274) vs. 36 (329)) than children assuming placebo. The AUC of ghrelin was significantly lower after PGR ingestion, than after placebo (−8179 (8073) vs. −2800 (7579) pg × 240 min/mL). Blood glucose, insulin, non-esterified fatty acids (NEFA) and GLP-1 profiles were not significantly different in the two groups. In conclusion, a single intake of two tablets of PGR was associated with a significant reduction of appetite, ghrelin, and triglycerides in the postprandial period in obese children. Further investigation will assess if a chronic intake of PGR may affect body weight and glucose metabolism.

Inhibition of gastric emptying by acarbose is correlated with GLP-1 response and accompanied by CCK release

2001 ◽  
Vol 281 (3) ◽  
pp. G752-G763 ◽  
Author(s):  
Feruze Y. Enç ◽  
Neşe I˙meryüz ◽  
Levent Akin ◽  
Turgut Turoğlu ◽  
Fuat Dede ◽  
...  
Keyword(s):  
Gastric Emptying ◽  
Peptide Yy ◽  
Area Under The Curve ◽  
Gut Hormones ◽  
Random Order ◽  
Mixed Meal ◽  
Carbohydrate Absorption ◽  
Plasma Response ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

We investigated the effect of acarbose, an α-glucosidase and pancreatic α-amylase inhibitor, on gastric emptying of solid meals of varying nutrient composition and plasma responses of gut hormones. Gastric emptying was determined with scintigraphy in healthy subjects, and all studies were performed with and without 100 mg of acarbose, in random order, at least 1 wk apart. Acarbose did not alter the emptying of a carbohydrate-free meal, but it delayed emptying of a mixed meal and a carbohydrate-free meal given 2 h after sucrose ingestion. In meal groups with carbohydrates, acarbose attenuated responses of plasma insulin and glucose-dependent insulinotropic polypeptide (GIP) while augmenting responses of CCK, glucagon-like peptide-1 (GLP-1), and peptide YY (PYY). With mixed meal + acarbose, area under the curve (AUC) of gastric emptying was positively correlated with integrated plasma response of GLP-1 ( r = 0.68 , P < 0.02). With the carbohydrate-free meal after sucrose and acarbose ingestion, AUC of gastric emptying was negatively correlated with integrated plasma response of GIP, implying that prior alteration of carbohydrate absorption modifies gastric emptying of a meal. The results demonstrate that acarbose delays gastric emptying of solid meals and augments release of CCK, GLP-1, and PYY mainly by retarding/inhibiting carbohydrate absorption. Augmented GLP-1 release by acarbose appears to play a major role in the inhibition of gastric emptying of a mixed meal, whereas CCK and PYY may have contributory roles.

PRIOR INGESTION OF A KETONE MONOESTER SUPPLEMENT REDUCES POSTPRANDIAL GLYCEMIC RESPONSES IN YOUNG HEALTHY WEIGHT INDIVIDUALS

2020 ◽  
Author(s):  
Grant Greaves ◽  
Richard Xiang ◽  
Hossein Rafiei ◽  
Adeeb Malas ◽  
Jonathan P. Little
Keyword(s):  
Fatty Acid ◽  
Gastric Emptying ◽  
Area Under The Curve ◽  
Postprandial Glucose ◽  
Tolerance Test ◽  
Healthy Weight ◽  
Mixed Meal ◽  
Double Blind ◽  
Acute Ingestion ◽  
Beta Hydroxybutyrate

The main objective of this study was to determine whether acute ingestion of a ketone monoester (KME) supplement impacted mixed meal tolerance test (MMTT) glucose area under the curve (AUC). Nineteen healthy young volunteers (10 males/9 females, 24.7 ± 4.9 years, BMI = 22.7 ± 2.4) participated in a double-blind, placebo-controlled crossover study. Following overnight fasting (≥10 h), participants consumed 0.45mL/kg of a KME supplement or taste-matched placebo followed by a MMTT 15 minutes later. Blood samples were collected every 15-30 minutes over 2.5 hours. KME supplementation acutely raised beta-hydroxybutyrate (β-OHB) AUC (590%, P < 0.0001, d = 2.4) and resulted in decreases in blood glucose AUC (-9.4%, P = 0.03, d = 0.56) and non-esterified fatty acid (NEFA) AUC (-27.3%, P = 0.023, d = 0.68) compared to placebo. No differences were found for plasma insulin AUC (P = 0.70) or gastric emptying estimated by co-ingested acetaminophen AUC (P = 0.96) between ketone and placebo. Overall, results indicate that KME supplementation attenuates postprandial glycemic and NEFA responses when taken 15 min prior to a mixed meal in young healthy individuals. Future studies are warranted to investigate whether KME supplementation may benefit individuals with impaired glycemic control. Novelty Bullets • Acute ketone monoester supplementation 15 min prior to a mixed meal decreased postprandial glucose and non-esterified fatty acid (NEFA) levels without significantly impacting postprandial insulin or estimates of gastric emptying. • Glucose and NEFA lowering effects of ketone monoester supplementation are apparently not mediated by changes in insulin release or gastric emptying.

scholarly journals Effects of oligofructose on appetite profile, glucagon-like peptide 1 and peptide YY3-36 concentrations and energy intake

2011 ◽  
Vol 106 (11) ◽  
pp. 1757-1762 ◽  
Author(s):  
Sanne P. M. Verhoef ◽  
Diederick Meyer ◽  
Klaas R. Westerterp
Keyword(s):  
Energy Intake ◽  
Human Subjects ◽  
Hormone Secretion ◽  
Area Under The Curve ◽  
Double Blind ◽  
Time Treatment ◽  
Satiety Hormone ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Reduce Energy Intake

In rats, oligofructose has been shown to stimulate satiety hormone secretion, reduce energy intake and promote weight loss. The present study aimed to examine the effect of oligofructose supplementation on appetite profiles, satiety hormone concentrations and energy intake in human subjects. A total of thirty-one healthy subjects (ten men and twenty-one women) aged 28 (sem 3) years with a BMI of 24·8 (sem 0·3) kg/m2 were included in a randomised double-blind, cross-over study. The subjects received 10 g oligofructose, 16 g oligofructose or 16 g placebo (maltodextrin) daily for 13 d, with a 2-week washout period between treatments. Appetite profile, active glucagon-like peptide 1 (GLP-1) and peptide YY3-36 (PYY) concentrations and energy intake were assessed on days 0 and 13 of the treatment period. Time × treatment interaction revealed a trend of reduction in energy intake over days 0–13 by oligofructose (P = 0·068). Energy intake was significantly reduced (11 %) over time on day 13 compared with day 0 with 16 g/d oligofructose (2801 (sem 301) v. 3217 (sem 320) kJ, P < 0·05). Moreover, energy intake was significantly lower with 16 g/d oligofructose compared with 10 g/d oligofructose on day 13 (2801 (sem 301) v. 3177 (sem 276) kJ, P < 0·05). Area under the curve (AUC) for GLP-1 on day 13 was significantly higher with 16 g/d oligofructose compared with 10 g/d oligofructose (45 (sem 4) v. 41 (sem 3) pmol/l × h, P < 0·05). In the morning until lunch, AUC0–230 min for PYY on day 13 was significantly higher with 16 g/d oligofructose compared with 10 g/d oligofructose and placebo (409 (sem 35) v. 222 (sem 19) and 211 (sem 20) pg/ml × h, P < 0·01). In conclusion, 16 g/d and not 10 g/d oligofructose may be an effective dose to reduce energy intake, possibly supported by higher GLP-1 and PYY concentrations.

scholarly journals Ghrelin Stimulates Gastric Emptying and Hunger in Normal-Weight Humans

2006 ◽  
Vol 91 (9) ◽  
pp. 3296-3302 ◽  
Author(s):  
F. Levin ◽  
T. Edholm ◽  
P. T. Schmidt ◽  
P. Grybäck ◽  
H. Jacobsson ◽  
...  
Keyword(s):  
Gastric Emptying ◽  
Peptide Yy ◽  
Hormone Secretion ◽  
Normal Weight ◽  
Lag Phase ◽  
Double Blind ◽  
Gastric Emptying Rate ◽  
Ghrelin Receptor ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Context: Ghrelin is produced primarily by enteroendocrine cells in the gastric mucosa and increases gastric emptying in patients with gastroparesis. Main Objective: The objective of the study was to evaluate the effect of ghrelin on gastric emptying, appetite, and postprandial hormone secretion in normal volunteers. Design: This was a randomized, double-blind, crossover study. Subjects: Subjects included normal human volunteers and patients with GH deficiency. Intervention: Intervention included saline or ghrelin (10 pmol/kg·min) infusion for 180 min after intake of a radioactively labeled omelette (310 kcal) or GH substitution in GH-deficient patients. Main Outcome Measures: Measures consisted of gastric empty-ing parameters and postprandial plasma levels of ghrelin, cholecystokinin, glucagon-like peptide-1, peptide YY, and motilin. Results: The emptying rate was significantly faster for ghrelin (1.26 ± 0.1% per minute), compared with saline (0.83% per minute) (P &lt; 0.001). The lag phase (16.2 ± 2.2 and 26.5 ± 3.8 min) and half-emptying time (49.4 ± 3.9 and 75.6 ± 4.9 min) of solid gastric emptying were shorter during ghrelin infusion, compared with infusion of saline (P &lt; 0.001). The postprandial peak in plasma concentration for cholecystokinin and glucagon-like peptide-1 occurred earlier and was higher during ghrelin infusion. There was no significant effect of ghrelin on plasma motilin or peptide YY. There was no difference in gastric emptying before and after GH substitution. Conclusion: Our results demonstrate that ghrelin increases the gastric emptying rate in normal humans. The effect does not seem to be mediated via GH or motilin but may be mediated by the vagal nerve or directly on ghrelin receptors in the stomach. Ghrelin receptor agonists may have a role as prokinetic agents.

scholarly journals Acute Effects of Lixisenatide on Energy Intake in Healthy Subjects and Patients with Type 2 Diabetes: Relationship to Gastric Emptying and Intragastric Distribution

Nutrients ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1962 ◽  
Author(s):  
Ryan Jalleh ◽  
Hung Pham ◽  
Chinmay S. Marathe ◽  
Tongzhi Wu ◽  
Madeline D. Buttfield ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Gastric Emptying ◽  
Energy Intake ◽  
Double Blind ◽  
Distal Stomach ◽  
Induce Weight Loss ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Intragastric Distribution

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.

Long-term metabolic benefits of exenatide in mice are mediated solely via the known glucagon-like peptide 1 receptor

2014 ◽  
Vol 306 (7) ◽  
pp. R490-R498 ◽  
Author(s):  
Krystyna Tatarkiewicz ◽  
Emmanuel J. Sablan ◽  
Clara J. Polizzi ◽  
Christiane Villescaz ◽  
David G. Parkes
Keyword(s):  
Body Weight ◽  
Gastric Emptying ◽  
Food Intake ◽  
High Fat Diet ◽  
Tolerance Test ◽  
Metabolic Effects ◽  
Oral Glucose ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide 1 receptors (GLP-1R) are expressed in multiple tissues and activation results in metabolic benefits including enhanced insulin secretion, slowed gastric emptying, suppressed food intake, and improved hepatic steatosis. Limited and inconclusive knowledge exists regarding whether the effects of chronic exposure to a GLP-1R agonist are solely mediated via this receptor. Therefore, we examined 3-mo dosing of exenatide in mice lacking a functional GLP-1R (Glp1r−/−). Exenatide (30 nmol·kg−1·day−1) was infused subcutaneously for 12 wk in Glp1r−/− and wild-type (Glp1r+/+) control mice fed a high-fat diet. Glycated hemoglobin A1c (HbA1c), plasma glucose, insulin, amylase, lipase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), body weight, food intake, terminal hepatic lipid content (HLC), and plasma exenatide levels were measured. At the end of the study, oral glucose tolerance test (OGTT) and rate of gastric emptying were assessed. Exenatide produced no significant changes in Glp1r−/− mice at study end. In contrast, exenatide decreased body weight, food intake, and glucose in Glp1r+/+ mice. When compared with vehicle, exenatide reduced insulin, OGTT glucose AUC0–2h, ALT, and HLC in Glp1r+/+ mice. Exenatide had no effect on plasma amylase or lipase levels. Exenatide concentrations were approximately eightfold higher in Glp1r−/− versus Glp1r+/+ mice after 12 wk of infusion, whereas renal function was similar. These data support the concept that exenatide requires a functional GLP-1R to exert chronic metabolic effects in mice, and that novel “GLP-1” receptors may not substantially contribute to these changes. Differential exenatide plasma levels in Glp1r+/+ versus Glp1r−/− mice suggest that GLP-1R may play an important role in plasma clearance of exenatide and potentially other GLP-1-related peptides.

scholarly journals The Impact of a Large Bolus Dose of l-leucine and l-isoleucine on Enteroendocrine and Pancreatic Hormones, and Glycemia in Healthy, Inactive Adults

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2650 ◽  
Author(s):  
Daniel E. Newmire ◽  
Eric Rivas ◽  
Sarah E. Deemer ◽  
Darryn S. Willoughby ◽  
Victor Ben-Ezra
Keyword(s):  
Bolus Dose ◽  
Glucose Tolerance Test ◽  
Area Under The Curve ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Pancreatic Hormones ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Insulinotropic Peptide ◽  
The Impact

Background: The ingestion of whey protein and amino acids with carbohydrate (CHO) enhances the release of glucagon-like peptide-1 (GLP-1) and glucose-dependent-insulinotropic peptide (GIP) that promote insulin secretion. It is unknown if L-isoleucine (Ile) and L-leucine (Leu) have this same effect. The purpose of this study was to examine how Ile and Leu influence both GLP-1 and GIP, subsequent pancreatic hormones, and glycemia in healthy, inactive adults. Methods: Twelve adults (6F/6M; age 27.4 ± 2 years; BMI 26.3 ± 2 kg/m2; lean body mass 53.2 ± 5 kg; body fat 34.1 ± 3%) completed four conditions in a randomized, cross-over fashion. Treatments standardized (0.3 g/kg·LBM−1) (1) Leu, (2) Ile, (3) Equal (1:1 g) of Leu + Ile, and (4) placebo (Pla, 3.5 g inert stevia) ingested 30 min prior to an oral glucose tolerance test (OGTT). Samples of plasma glucose, insulin, glucagon, GIPTotal, and GLP-1Active were assessed. Results: A treatment (p = 0.01) effect comparing Ile vs. Leu (p = 0.02) in GIPTotal. Area under the curve showed an increase in GIPTotal from Ile compared to Leu and Pla (p = 0.03). No effect was found on GLP-1. The ingestion of Ile prior to CHO augmented GIP concentration greater than Leu or Pla. No correlation was found between GIP, insulin, and glucose between conditions. Conclusions: Ile impacts GIP concentration, which did not relate to either insulin or glucose concentrations. Neither Ile, nor Leu seem to have an effect on hyperglycemia ingested prior to a CHO drink.

scholarly journals Prandial subcutaneous injections of glucagon-like peptide-1 cause weight loss in obese human subjects

2004 ◽  
Vol 91 (3) ◽  
pp. 439-446 ◽  
Author(s):  
Erik Näslund ◽  
N. King ◽  
S. Mansten ◽  
N. Adner ◽  
J. J. Holst ◽  
...  
Keyword(s):  
Weight Loss ◽  
Gastric Emptying ◽  
Food Intake ◽  
Double Blind ◽  
Gastric Emptying Rate ◽  
Subcutaneous Injections ◽  
Subcutaneous Infusion ◽  
Continuous Subcutaneous Infusion ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Recombinant glucagon-like peptide-1 (7–36)amide (rGLP-1) was recently shown to cause significant weight loss in type 2 diabetics when administered for 6 weeks as a continuous subcutaneous infusion. The mechanisms responsible for the weight loss are not clarified. In the present study, rGLP-1 was given for 5d by prandial subcutaneous injections (PSI) (76nmol 30min before meals, four times daily; a total of 302·4nmol/24h) or by continuous subcutaneous infusion (CSI) (12·7nmol/h; a total of 304·8nmol/24h). This was performed in nineteen healthy obese subjects (mean age 44·2 (sem 2·5) years; BMI 39·0 (sem 1·2)kg/m2) in a prospective randomised, double-blind, placebo-controlled, cross-over study. Compared with the placebo, rGLP-1 administered as PSI and by CSI generated a 15% reduction in mean food intake per meal (P=0·02) after 5d treatment. A weight loss of 0·55 (sem 0·2) kg (P<0·05) was registered after 5d with PSI of rGLP-1. Gastric emptying rate was reduced during both PSI (P<0·001) and CSI (P<0·05) treatment, but more rapidly and to a greater extent with PSI of rGLP-1. To conclude, a 5d treatment of rGLP-1 at high doses by PSI, but not CSI, promptly slowed gastric emptying as a probable mechanism of action of increased satiety, decreased hunger and, hence, reduced food intake with an ensuing weight loss.

Sign in / Sign up

Export Citation Format

Share Document