Cagrilintide is not associated with clinically relevant QTc prolongation: A thorough QT study in healthy participants.

Aims: The combination of cagrilintide and semaglutide (CagriSema) is being developed for the treatment of obesity and type 2 diabetes. The objective of this thorough QT study was to confirm that cagrilintide does not result in a clinically relevant prolongation in cardiac repolarization compared with placebo.

Materials And Methods: This was a double-blind study (NCT05804162) in which healthy participants were randomized to cagrilintide, administered as a once-weekly subcutaneous injection dose escalated to 4.

Effect of oral semaglutide on energy intake, appetite, control of eating and gastric emptying in adults living with obesity: A randomized controlled trial.

Aim: To investigate the effects of once-daily oral semaglutide 50 mg on energy intake, appetite, control of eating and gastric emptying.

Methods: A clinical pharmacology, double-blind study was conducted in 61 adults with obesity randomized to once-daily oral semaglutide (dose-escalated to 50 mg) or placebo for 20 weeks. Energy intake was measured during an ad libitum lunch, and participant-reported appetite ratings and Control of Eating Questionnaire responses were assessed.

Biased GLP-2 agonist with strong G protein-coupling but impaired arrestin recruitment and receptor desensitization enhances intestinal growth in mice.

Background And Purpose: Glucagon-like peptide-2 (GLP-2) is secreted postprandially by enteroendocrine L-cells and stimulates growth of the gut and bone. One GLP-2 analogue is approved for short bowel syndrome (SBS). To improve therapeutic efficacy, we developed biased GLP-2 receptor (GLP-2R) agonists through N-terminal modifications.

Glucose-dependent insulinotropic polypeptide receptor antagonist treatment causes a reduction in weight gain in ovariectomised high fat diet-fed mice.

Background And Purpose: The incretin hormone, gastric inhibitory peptide/glucose-dependent insulinotropic polypeptide (GIP), secreted by the enteroendocrine K-cells in the proximal intestine, may regulate lipid metabolism and adiposity, but its exact role in these processes is unclear.

Experimental Approach: We characterized in vitro and in vivo antagonistic properties of a novel GIP analogue, mGIPAnt-1. We further assessed the in vivo pharmacokinetic profile of this antagonist, as well as its ability to affect high-fat diet (HFD)-induced body weight gain in ovariectomised mice during an 8-week treatment period.

N-terminal alterations turn the gut hormone GLP-2 into an antagonist with gradual loss of GLP-2 receptor selectivity towards more GLP-1 receptor interaction.

Background And Purpose: To fully elucidate the regulatory role of the GLP-2 system in the gut and the bones, potent and selective GLP-2 receptor (GLP-2R) antagonists are needed. Searching for antagonist activity, we performed systematic N-terminal truncations of human GLP-2(1-33).

Experimental Approach: COS-7 cells were transfected with the human GLP-2R and assessed for cAMP accumulation or competition binding using I-GLP-2(1-33)[M10Y].

GIP and GLP-2 together improve bone turnover in humans supporting GIPR-GLP-2R co-agonists as future osteoporosis treatment.

The intestinal hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are key regulators of postprandial bone turnover in humans. We hypothesized that GIP and GLP-2 co-administration would provide stronger effect on bone turnover than administration of the hormones separately, and tested this using subcutaneous injections of GIP and GLP-2 alone or in combination in humans. Guided by these findings, we designed series of GIPR-GLP-2R co-agonists as template for new osteoporosis treatment.

Novel agonist and antagonist radioligands for the GLP-2 receptor. Useful tools for studies of basic GLP-2 receptor pharmacology.

Background: Glucagon-like peptide-2 (GLP-2) is a pro-glucagon-derived hormone secreted from intestinal enteroendocrine L cells with actions on gut and bones. GLP-2(1-33) is cleaved by DPP-4, forming GLP-2(3-33), having low intrinsic activity and competitive antagonism properties at GLP-2 receptors. We created radioligands based on these two molecules.

Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist.

Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist. Therefore, we hypothesized that the integrated potency and signaling properties of tirzepatide provide a unique pharmacological profile tailored for improving broad metabolic control.

Molecular interactions of full-length and truncated GIP peptides with the GIP receptor - A comprehensive review.

Enzymatic cleavage of endogenous peptides is a commonly used principle to initiate, modulate and terminate action for instance among cytokines and peptide hormones. The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and the related hormone glucagon-like peptide-2 (GLP-2) are all rapidly N-terminally truncated with severe loss of intrinsic activity. The most abundant circulating form of full length GIP(1-42) is GIP(3-42) (a dipeptidyl peptidase-4 (DPP-4) product).

Paracrine crosstalk between intestinal L- and D-cells controls secretion of glucagon-like peptide-1 in mice.

DPP-4 inhibitors, used for treatment of type 2 diabetes, act by increasing the concentrations of intact glucagon-like peptide-1 (GLP-1), but at the same time, they inhibit secretion of GLP-1, perhaps by a negative feedback mechanism. We hypothesized that GLP-1 secretion is feedback regulated by somatostatin (SS) from neighboring D-cells, and blocking this feedback circuit results in increased GLP-1 secretion. We used a wide range of experimental techniques, including gene expression analysis, immunohistochemical approaches, and the perfused mouse intestine to characterize the paracrine circuit controlling GLP-1 and SS.

Enhanced agonist residence time, internalization rate and signalling of the GIP receptor variant [E354Q] facilitate receptor desensitization and long-term impairment of the GIP system.

In patients with type 2 diabetes mellitus (T2DM), the insulinotropic action of the GIP system is desensitized, whereas this is not the case for the GLP-1 system. This has raised an interesting discussion of whether GIP agonists or antagonists are most suitable for future treatment of T2DM together with GLP-1-based therapies. Homozygous carriers of the GIP receptor (GIPR) variant, [E354Q], display lower bone mineral density, increased bone fracture risk and slightly increased blood glucose.

GLP-2 and GIP exert separate effects on bone turnover: A randomized, placebo-controlled, crossover study in healthy young men.

Background: Glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP) both inhibit bone resorption in humans but the underlying mechanisms are poorly understood. In vitro, GLP-2 activates the GIP-receptor (GIPR).

Objective: Based on in vitro studies, we hypothesized that the antiresorptive effect of GLP-2 was mediated through the GIPR.

Separate and Combined Glucometabolic Effects of Endogenous Glucose-Dependent Insulinotropic Polypeptide and Glucagon-like Peptide 1 in Healthy Individuals.

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are secreted postprandially and contribute importantly to postprandial glucose tolerance. In this study, we assessed the individual and combined contributions of endogenous GIP and GLP-1 to the postprandial changes in glucose and glucoregulatory hormones using the novel GIP receptor antagonist GIP(3-30)NH and the well-established GLP-1 receptor antagonist exendin(9-39)NH During 4-h oral glucose tolerance tests (75 g) combined with an ad libitum meal test, 18 healthy men received on four separate days in randomized, double-blinded order intravenous infusions of A) GIP(3-30)NH (800 pmol/kg/min) plus exendin(9-39)NH (0-20 min: 1,000 pmol/kg/min; 20-240 min: 450 pmol/kg/min), B) GIP(3-30)NH, C) exendin(9-39)NH, and D) saline, respectively. Glucose excursions were significantly higher during A than during B, C, and D, while glucose excursions during B were higher than during C and D.

Neuromedin U Does Not Act as a Decretin in Rats.

Studies on isolated pancreatic islets suggest that neuromedin U (NMU), a brain and gastrointestinal peptide, acts as a decretin hormone, inhibiting glucose-stimulated insulin secretion. We investigated whether this effect could be reproduced in vivo and in isolated perfused rat pancreas. Unlike the incretin hormone, glucagon-like peptide 1 (GLP-1), intravenous NMU administration had no effects on blood glucose and plasma insulin and glucagon in vivo.

Insulin Secretion Depends on Intra-islet Glucagon Signaling.

The intra-islet theory states that glucagon secretion is suppressed when insulin secretion is stimulated, but glucagon's role in intra-islet paracrine regulation is controversial. This study investigated intra-islet functions of glucagon in mice. We examined glucagon-induced insulin secretion using isolated perfused pancreata from wild-type, GLP-1 receptor (GLP-1R) knockout, diphtheria toxin-induced proglucagon knockdown, β cell-specific glucagon receptor (Gcgr) knockout, and global Gcgr knockout (Gcgr) mice.

The impact of short-chain fatty acids on GLP-1 and PYY secretion from the isolated perfused rat colon.

The colonic epithelium harbors a large number of endocrine cells, but little is known about the endocrine functions of the colon. However, the high density of glucagon like peptide-1 (GLP-1)- and peptide-YY (PYY)-secreting L cells is of great interest because of the potential antidiabetic and antiobesity effects of GLP-1 and PYY. Short-chain fatty acids (SCFAs) produced by local bacterial fermentation are suggested to activate the colonic free fatty acid receptors FFAR2 (GPR43) and FFAR3 (GPR41), stimulating the colonic L cells.

Glucose-lowering effects and mechanisms of the bile acid-sequestering resin sevelamer.

Aims: Sevelamer, a non-absorbable amine-based resin used for treatment of hyperphosphataemia, has been demonstrated to have a marked bile acid-binding potential alongside beneficial effects on lipid and glucose metabolism. The aim of this study was to investigate the glucose-lowering effect and mechanism(s) of sevelamer in patients with type 2 diabetes.

Materials And Methods: In this double-blinded randomized controlled trial, we randomized 30 patients with type 2 diabetes to sevelamer (n = 20) or placebo (n = 10).

Oxyntomodulin: Actions and role in diabetes.

Oxyntomodulin is a product of the glucagon precursor, proglucagon, produced and released from the endocrine L-cells of the gut after enzymatic processing by the precursor prohormone convertase 1/3. It corresponds to the proglucagon sequence 33-69 and thus contains the entire glucagon sequence plus a C-terminal octapeptide, comprising in total 37 amino acids. As might have been expected, it has glucagon-like bioactivity, but also and more surprisingly also activates the receptor for GLP-1.

Glucose-dependent insulinotropic polypeptide (GIP) receptor antagonists as anti-diabetic agents.

Glucose-dependent insulinotropic polypeptide (GIP) is an intestinal hormone with a broad range of physiological actions. In the postprandial state, the hormone stimulates insulin secretion and during eu- and hypoglycemia, it stimulates glucagon secretion. In addition, GIP increases triacylglycerol (TAG) uptake in adipose tissue and decreases bone resorption.

Human GIP(3-30)NH inhibits G protein-dependent as well as G protein-independent signaling and is selective for the GIP receptor with high-affinity binding to primate but not rodent GIP receptors.

GIP(3-30)NH is a high affinity antagonist of the GIP receptor (GIPR) in humans inhibiting insulin secretion via G protein-dependent pathways. However, its ability to inhibit G protein-independent signaling is unknown. Here we determine its action on arrestin-recruitment and receptor internalization in recombinant cells.

Circulating Glucagon 1-61 Regulates Blood Glucose by Increasing Insulin Secretion and Hepatic Glucose Production.

Glucagon is secreted from pancreatic α cells, and hypersecretion (hyperglucagonemia) contributes to diabetic hyperglycemia. Molecular heterogeneity in hyperglucagonemia is poorly investigated. By screening human plasma using high-resolution-proteomics, we identified several glucagon variants, among which proglucagon 1-61 (PG 1-61) appears to be the most abundant form.

GIP(3-30)NH is an efficacious GIP receptor antagonist in humans: a randomised, double-blinded, placebo-controlled, crossover study.

Aims/hypothesis: Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted postprandially from enteroendocrine K cells, but despite therapeutically interesting effects, GIP physiology in humans remains incompletely understood. Progress in this field could be facilitated by a suitable GIP receptor antagonist. For the first time in humans, we investigated the antagonistic properties of the naturally occurring GIP(3-30)NH in in vivo and in in vitro receptor studies.

GIP(3-30)NH is a potent competitive antagonist of the GIP receptor and effectively inhibits GIP-mediated insulin, glucagon, and somatostatin release.

Alternative processing of the precursor protein pro-GIP results in endogenously produced GIP(1-30)NH, that by DPP-4 cleavage in vivo results in the metabolite GIP(3-30)NH. We showed previously that GIP(3-30)NH is a high affinity antagonist of the human GIPR in vitro. Here we determine whether it is suitable for studies of GIP physiology in rats since effects of GIP agonists and antagonists are strictly species-dependent.

Placental Sonolucencies in the First Trimester: Incidence and Clinical Significance.

Objectives: The aims of this study were to determine the incidence of placental sonolucencies on first-trimester screening sonograms in a general obstetric population and assess whether these findings are associated with adverse obstetric outcomes.

Methods: A retrospective cohort analysis of 201 pregnant patients screened at a high-risk prenatal diagnostic center was conducted with first-trimester cine clips reviewed by 2 radiologists. Placental sonolucencies were defined as intraplacental anechoic or heterogeneous areas 0.