The small intestine is traditionally viewed as an organ that mediates nutrient digestion and absorption. This view has recently been revised owing to the ability of the duodenum to sense nutrient influx and trigger negative feedback loops to inhibit glucose production and food intake to maintain metabolic homeostasis. Further, duodenal nutrient-sensing defects are acquired in diabetes and obesity, leading to increased glucose production. In contrast, jejunal nutrient sensing inhibits glucose production and mediates the early antidiabetic effect of bariatric surgery, and gut microbiota composition may alter intestinal nutrient-sensing mechanisms to regain better control of glucose homeostasis in diabetes and obesity in the long term. This perspective highlights nutrient-sensing mechanisms in the gut that regulate glucose homeostasis and the potential of targeting gut nutrient-sensing mechanisms as a therapeutic strategy to lower blood glucose concentrations in diabetes.

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.

Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe the discovery of the orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nanomolar potency. Incorporation of a carboxylic acid moiety provided considerable GLP-1R potency gains with improved off-target pharmacology and reduced metabolic clearance, ultimately resulting in the identification of danuglipron. Danuglipron increased insulin levels in primates but not rodents, which was explained by receptor mutagensis studies and a cryogenic electron microscope structure that revealed a binding pocket requiring a primate-specific tryptophan 33 residue. Oral administration of danuglipron to healthy humans produced dose-proportional increases in systemic exposure (NCT03309241). This opens an opportunity for oral small-molecule therapies that target the well-validated GLP-1R for metabolic health.

The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing offtarget pharmacology led to the discovery of 16h. Compound 16h has a superior balance of ghrelin receptor pharmacology and off-target selectivity. On the basis of its promising pharmacological and safety profile, 16h was advanced to human clinical trials.

The future for new weight-loss approaches to treat obesity looks promising. Current therapies have shown modest effects on weight loss in the general obese population but will have greater impact in smaller homogeneous sub-populations of obese subjects using personalized medicine. Drug combinations that target multiple, complementary pathways have the potential to promote double-digit weight loss in a broader, heterogeneous patient population. Furthermore, the development of advanced subcutaneous delivery technologies has opened up opportunities to develop breakthrough peptide and biologic agents for the treatment of obesity.

Background and purpose: Oxytocin is believed to be involved in ejaculation by increasing sperm number and contracting ejaculatory tissues. However, oxytocin may mediate these effects via oxytocin or vasopressin (AVP) receptors. The aim of this study was to determine the effect of oxytocin and AVP on peripheral tissues involved in ejaculation and to identify the receptor subtype(s) involved. Experimental approach: Standard tissue bath techniques were used to measure isometric tension from tissues involved in ejaculation and erection. Key results: Oxytocin and AVP failed to elicit a tonic contractile response in rat and rabbit testes, vas deferens, epididymis, seminal vesicles and prostate. In contrast, oxytocin and AVP elicited large tonic contractions in erectile (corpus spongiosum and corpus cavernosum) and ejaculatory (prostatic urethra, bladder neck and ejaculatory duct) tissues in a concentrationdependent manner. Conclusions and implications:The contractile effect of oxytocin on rat and rabbit ejaculatory and erectile tissues is mediated via V 1A receptors. Endothelin-1-induced contractions are not due to endogenous oxytocin or AVP release. V 1A receptor antagonists may have a therapeutic role in both erectile dysfunction and premature ejaculation.

AIMTo evaluate safety, tolerability and pharmacokinetics of oral PF-05190457, an oral ghrelin receptor inverse agonist, in healthy adults. METHODSSingle (SAD) and multiple ascending dose (MAD) studies were randomised, placebo-controlled, double-blind studies. Thirty-five healthy men (age 38.2 ± 10.4 years; body mass index 24.8 ± 3.1 kg m -2 [mean ± standard deviation]) received ≥1 dose (2, 10, 40 [divided], 50, 100, 150, and 300 [single or divided] mg) of PF-05190457 and/or placebo in the SAD. In the MAD study, 35 healthy men (age 39.7 ± 10.1 years; body mass index 25.9 ± 3.3 kg m -2 ) received ≥1 dose (2, 10, 40 and 100 mg twice daily) of PF-05190457 and/or placebo daily for 2 weeks. RESULTSPF-05190457 absorption was rapid with a T max of 0.5-3 hours and a half-life between 8.2-9.8 hours. PF-05190457 dosedependently blocked ghrelin (1 pmol kg -1 min -1 )-induced growth hormone (GH) release with (mean [90% confidence interval]) 77% [63-85%] inhibition at 100 mg. PF-05190457 (150 mg) delayed gastric emptying lag time by 30% [7-58%] and half emptying time by 20% [7-35%] with a corresponding decrease in postprandial glucose by 9 mg dL -1 . The most frequent adverse event reported by 30 subjects at doses ≥50 mg was somnolence. PF-05190457 plasma concentrations also increased heart rate up to 13.4 [4.8-58.2] beats min -1 and, similar to the effect on glucose and ghrelin-induced GH, was lost within 2 weeks. CONCLUSIONSPF-05190457 is a well-tolerated first-in-class ghrelin receptor inverse agonist with acceptable pharmacokinetics for oral daily dosing. Blocking ghrelin receptors inhibits ghrelin-induced GH, and increases heart rate, effects that underwent tachyphylaxis with chronic dosing. PF-051940457 has the potential to treat centrally-acting disorders such as insomnia. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• PF-05190457 is a selective inverse agonist of the ghrelin receptor with a nonclinical profile supporting human dosing.• Endogenous ghrelin and exogenous infusions in healthy subjects release growth hormone, stimulate hunger and increases gastric motility WHAT THIS STUDY ADDS• PF-05190457 is the first reported ghrelin receptor inverse agonist profiled in humans. It is safe and well-tolerated in healthy subjects with pharmacokinetics supporting daily oral dosing.• PF-05190457 blocks ghrelin receptors in healthy subjects, dose-dependently increases heart rate, delays gastric emptying, induces somnolence and maximal inhibition for 2 weeks yields tachyphylaxis. Tables of Links IntroductionGhrelin is an endogenous 28-amino acid acylated peptide synthesised within the stomach fundus associated with modulating growth hormone secretion, gastric motility, gastric acid secretion and hunger. Acylated ghrelin is the only peripheral hunger-stimulating hormone that elevates preprandially in plasma, suggesting a role in meal initiation in humans [3]. Circulating endogenous baseline and pulsatile patterns of total ghrelin are inhibited in obese subjects following gastric bypass surgery [4,5]; however, not all studies ha...

Development of the pacemaker system in the small intestine depends upon signalling via tyrosine kinase (Kit) receptors. The downstream pathways initiated by Kit in interstitial cells of Cajal (ICC) have not been investigated. Wortmannin and 2‐(4‐morpholinyl)‐8‐phenyl‐4H‐1‐benzopyran‐4‐one (LY 294002), inhibitors of phosphatidylinositol 3′‐kinase (PI3‐kinase), were used to test the involvement of this pathway in the development and maintenance of ICC and electrical rhythmicity in the murine small intestine. ICC and electrical slow waves were present in the murine jejunum at birth. ICC and electrical rhythmicity continued to develop in neonates such that adult activity was recorded after 1 week. Development of ICC and rhythmicity were maintained in organ culture. Wortmannin or LY 294002 inhibited the development of slow waves and blocked rhythmicity within 2‐4 days. Loss of slow waves was preceded by disappearance of Kit‐positive cells from the myenteric (IC‐MY) and deep muscular plexus (IC‐DMP) regions. Wortmannin or LY 294002 had no acute effect on slow waves. Muscles from older animals (day 10‐day 30) developed resistance to wortmannin treatment, but when the exposure to wortmannin was increased to 35 days, damage to ICC networks and electrical dysrhythmias were observed. PI3‐kinase appears to be a critical downstream signalling element linking Kit receptors to ICC development and maintenance of phenotype. ICC are more sensitive to Kit or PI3‐kinase blockade at birth, but the importance of the PI3‐kinase signalling in the maintenance of ICC persists into adulthood. Interference with PI3‐kinase signalling in immature or adult animals could result in disruption of ICC and gastrointestinal dysrhythmias.