SCO-267, a GPR40 Full Agonist, Stimulates Islet and Gut Hormone Secretion and Improves Glycemic Control in Humans

SCO-267 is a full agonist of the free fatty acid receptor 1 (GPR40), which regulates the secretion of islet and gut hormones. In this phase 1 study, we aimed to evaluate the clinical profile of single and multiple once-daily oral administration of SCO-267 in healthy adults and patients with diabetes. Plasma SCO-267 concentration was seen to increase in a dose-dependent manner after administration, and its plasma exposure was maintained for 24 h. Repeated dose did not alter the pharmacokinetic profile of SCO-267 in healthy adults. SCO-267 was generally safe and well tolerated at all evaluated single and multiple doses. Single and repeated doses of SCO-267 stimulated the secretion of insulin, glucagon, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, and peptide YY in healthy adults. Furthermore, a single dose of SCO-267 stimulated the secretion of these hormones, decreased fasting hyperglycemia, and improved glycemic control during an oral glucose tolerance test in patients with diabetes, without inducing hypoglycemia. This study is the first to demonstrate the clinical effects of a GPR40 full agonist. SCO-267 is safe and well tolerated and exhibits once-daily oral dosing potential. Its robust therapeutic effects on hormonal secretion and glycemic control make SCO-267 an attractive drug candidate for the treatment of diabetes.

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SCO-267, a GPR40 Full Agonist, Stimulates Islet and Gut Hormone Secretion and Improves Glycemic Control in Humans

10.2337/figshare.15036009 ◽

2021 ◽

Author(s):

Harunobu Nishizaki ◽

Osamu Matsuoka ◽

Tomoya Kagawa ◽

Akihiro Kobayashi ◽

Masanori Watanabe ◽

...

Keyword(s):

Glycemic Control ◽

Healthy Adults ◽

Oral Glucose ◽

Therapeutic Effects ◽

Clinical Effects ◽

Dependent Manner ◽

Once Daily ◽

Full Agonist ◽

Gut Hormone ◽

Patients With Diabetes

SCO-267 is a full agonist of the free fatty acid receptor 1 (GPR40), which regulates the secretion of islet and gut hormones. In this phase 1 study, we aimed to evaluate the clinical profile of single and multiple once-daily oral administration of SCO-267 in healthy adults and patients with diabetes. Plasma SCO-267 concentration was seen to increase in a dose-dependent manner after administration, and its plasma exposure was maintained for 24 h. Repeated dose did not alter the pharmacokinetic profile of SCO-267 in healthy adults. SCO-267 was generally safe and well tolerated at all evaluated single and multiple doses. Single and repeated doses of SCO-267 stimulated the secretion of insulin, glucagon, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, and peptide YY in healthy adults. Furthermore, a single dose of SCO-267 stimulated the secretion of these hormones, decreased fasting hyperglycemia, and improved glycemic control during an oral glucose tolerance test in patients with diabetes, without inducing hypoglycemia. This study is the first to demonstrate the clinical effects of a GPR40 full agonist. SCO-267 is safe and well tolerated and exhibits once-daily oral dosing potential. Its robust therapeutic effects on hormonal secretion and glycemic control make SCO-267 an attractive drug candidate for the treatment of diabetes.

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Effect of the Natural Sweetener Xylitol on Gut Hormone Secretion and Gastric Emptying in Humans: A Pilot Dose-Ranging Study

Nutrients ◽

10.3390/nu13010174 ◽

2021 ◽

Vol 13 (1) ◽

pp. 174

Author(s):

Anne Christin Meyer-Gerspach ◽

Jürgen Drewe ◽

Wout Verbeure ◽

Carel W. le Roux ◽

Ludmilla Dellatorre-Teixeira ◽

...

Keyword(s):

Uric Acid ◽

Gastric Emptying ◽

Blood Lipids ◽

Tap Water ◽

Hormone Secretion ◽

Gastrointestinal Symptoms ◽

Gut Hormones ◽

Double Blind ◽

Gut Hormone ◽

Dose Dependent

Sugar consumption is associated with a whole range of negative health effects and should be reduced and the natural sweetener xylitol might be helpful in achieving this goal. The present study was conducted as a randomized, placebo-controlled, double-blind, cross-over trial. Twelve healthy, lean volunteers received intragastric solutions with 7, 17 or 35 g xylitol or tap water on four separate days. We examined effects on: gut hormones, glucose, insulin, glucagon, uric acid, lipid profile, as well as gastric emptying rates, appetite-related sensations and gastrointestinal symptoms. We found: (i) a dose-dependent stimulation of cholecystokinin (CCK), active glucagon-like peptide-1 (aGLP-1), peptide tyrosine tyrosine (PYY)-release, and decelerated gastric emptying rates, (ii) a dose-dependent increase in blood glucose and insulin, (iii) no effect on motilin, glucagon, or glucose-dependent insulinotropic peptide (GIP)-release, (iv) no effect on blood lipids, but a rise in uric acid, and (v) increased bowel sounds as only side effects. In conclusion, low doses of xylitol stimulate the secretion of gut hormones and induce a deceleration in gastric emptying rates. There is no effect on blood lipids and only little effect on plasma glucose and insulin. This combination of properties (low-glycemic sweetener which stimulates satiation hormone release) makes xylitol an attractive candidate for sugar replacement.

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Transformation of postingestive glucose responses after deletion of sweet taste receptor subunits or gastric bypass surgery

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00163.2012 ◽

2012 ◽

Vol 303 (4) ◽

pp. E464-E474 ◽

Cited By ~ 49

Author(s):

Maartje C. P. Geraedts ◽

Tatsuyuki Takahashi ◽

Stephan Vigues ◽

Michele L. Markwardt ◽

Andongfac Nkobena ◽

...

Keyword(s):

Gastric Bypass ◽

Glycemic Control ◽

Large Intestine ◽

Molecular Mechanisms ◽

Hormone Secretion ◽

Taste Receptor ◽

Sweet Taste ◽

Oral Glucose ◽

Isolated Pancreatic Islets ◽

Sweet Taste Receptor

The glucose-dependent secretion of the insulinotropic hormone glucagon-like peptide-1 (GLP-1) is a critical step in the regulation of glucose homeostasis. Two molecular mechanisms have separately been suggested as the primary mediator of intestinal glucose-stimulated GLP-1 secretion (GSGS): one is a metabotropic mechanism requiring the sweet taste receptor type 2 (T1R2) + type 3 (T1R3) while the second is a metabolic mechanism requiring ATP-sensitive K+(KATP) channels. By quantifying sugar-stimulated hormone secretion in receptor knockout mice and in rats receiving Roux-en-Y gastric bypass (RYGB), we found that both of these mechanisms contribute to GSGS; however, the mechanisms exhibit different selectivity, regulation, and localization. T1R3−/−mice showed impaired glucose and insulin homeostasis during an oral glucose challenge as well as slowed insulin granule exocytosis from isolated pancreatic islets. Glucose, fructose, and sucralose evoked GLP-1 secretion from T1R3+/+, but not T1R3−/−, ileum explants; this secretion was not mimicked by the KATPchannel blocker glibenclamide. T1R2−/−mice showed normal glycemic control and partial small intestine GSGS, suggesting that T1R3 can mediate GSGS without T1R2. Robust GSGS that was KATPchannel-dependent and glucose-specific emerged in the large intestine of T1R3−/−mice and RYGB rats in association with elevated fecal carbohydrate throughout the distal gut. Our results demonstrate that the small and large intestines utilize distinct mechanisms for GSGS and suggest novel large intestine targets that could mimic the improved glycemic control seen after RYGB.

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P-O01 A patient education video to support the management of post-gastrectomy / oesophagectomy syndromes

British Journal of Surgery ◽

10.1093/bjs/znab430.111 ◽

2021 ◽

Vol 108 (Supplement_9) ◽

Author(s):

Geoffrey Roberts ◽

Andrew Stone ◽

Nicola Sunderland ◽

Sam Grimes ◽

Frank Reimann ◽

...

Keyword(s):

Gastric Cancer ◽

Patient Education ◽

Hormone Secretion ◽

Eating Behaviour ◽

Physiological Basis ◽

Upper Gi ◽

Gut Hormone ◽

Patient Representatives ◽

Upper Gi Cancer ◽

Nutritional Strategies

Abstract Background Oesophagectomy and gastrectomy result in profound and life-long changes in eating behaviour and appetite, and significant post-prandial symptoms. Despite decades of research, and recent advantages in the understanding of gut physiology, medical approaches to post-resectional patient care remain limited. The mainstay of treatment is patient education. Using clinical and lab-based studies, we investigated the effects of altered gut hormone secretion in patients after surgery for oesophageal and gastric cancer. We then produced a partially animated patient information video to better equip our patients to manage their altered alimentation. Methods The scientific background to the video was previously presented at AUGIS, and published. Studies included examination of eating behaviour, post-prandial symptoms, glucose homeostasis, gut hormone profiles and intestinal transcriptomic / peptidomic changes in a cohort of patients after oesophagectomy and gastrectomy. The movie storyboard and script were written by a team of surgeons, dietitians, patient representatives, clinical scientists and communications specialists. The goal was to communicate the physiological basis of altered eating in post-operative patients and appropriate nutritional strategies. Results The video is now freely available on Vimeo at: https://vimeo.com/356892336 It is in routine use for pre- and post-operative patient education. Conclusions Multimedia patient education is a useful tool to help manage the late effects of upper GI cancer treatment.

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Proximal and distal gut hormone secretion in slow transit constipation

Gastroenterology ◽

10.1016/s0016-5085(00)83277-1 ◽

2000 ◽

Vol 118 (4) ◽

pp. A297

Author(s):

C. Penning ◽

J.B. Delemarre ◽

I. Biemond ◽

C.B. Lamers ◽

A.A. Masclee

Keyword(s):

Hormone Secretion ◽

Slow Transit Constipation ◽

Gut Hormone ◽

Slow Transit ◽

Transit Constipation

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A Pilot Study of Gut-Brain Signaling After Octreotide Therapy for Unintentional Weight Loss After Esophagectomy

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa697 ◽

2020 ◽

Vol 106 (1) ◽

pp. e204-e216

Author(s):

Conor F Murphy ◽

Nicholas Stratford ◽

Neil G Docherty ◽

Brendan Moran ◽

Jessie A Elliott ◽

...

Keyword(s):

Weight Loss ◽

Pilot Study ◽

Food Intake ◽

Eating Behavior ◽

Hormone Secretion ◽

Symptom Burden ◽

Octreotide Lar ◽

Gut Hormone ◽

Ad Libitum ◽

Brain Reward

Abstract Background Recurrence-free patients after esophageal cancer surgery face long-term nutritional consequences, occurring in the context of an exaggerated postprandial gut hormone response. Acute gut hormone suppression influences brain reward signaling and eating behavior. This study aimed to suppress gut hormone secretion and characterize reward responses and eating behavior among postesophagectomy patients with unintentional weight loss. Methods This pilot study prospectively studied postoperative patients with 10% or greater body weight loss (BWL) beyond 1 year who were candidates for clinical treatment with long-acting octreotide (LAR). Before and after 4 weeks of treatment, gut hormone secretion, food cue reactivity (functional magnetic resonance imaging), eating motivation (progressive ratio task), ad libitum food intake, body composition, and symptom burden were assessed. Results Eight patients (7 male, age: mean ± SD 62.8 ± 9.4 years, postoperative BWL: 15.5 ± 5.8%) participated. Octreotide LAR did not significantly suppress total postprandial plasma glucagon-like peptide-1 response at 4 weeks (P = .08). Postprandial symptom burden improved after treatment (Sigstad score median [range]: 12 [2-28] vs 8 [3-18], P = .04) but weight remained stable (pre: 68.6 ± 12.8 kg vs post: 69.2 ± 13.4 kg, P = .13). There was no significant change in brain reward system responses, during evaluation of high-energy or low-energy food pictures, nor their appeal rating. Moreover, treatment did not alter motivation to eat (P = .41) nor ad libitum food intake(P = .46). Conclusion The protocol used made it feasible to characterize the gut-brain axis and eating behavior in this cohort. Inadequate suppression of gut hormone responses 4 weeks after octreotide LAR administration may explain the lack of gut-brain pathway alterations. A higher dose or shorter interdose interval may be required to optimize the intervention.

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Effect of L-Tryptophan and L-Leucine on Gut Hormone Secretion, Appetite Feelings and Gastric Emptying Rates in Lean and Non-Diabetic Obese Participants: A Randomized, Double-Blind, Parallel-Group Trial

PLoS ONE ◽

10.1371/journal.pone.0166758 ◽

2016 ◽

Vol 11 (11) ◽

pp. e0166758 ◽

Cited By ~ 18

Author(s):

Anne Christin Meyer-Gerspach ◽

Simon Häfliger ◽

Julian Meili ◽

Alison Doody ◽

Jens F Rehfeld ◽

...

Keyword(s):

Gastric Emptying ◽

Hormone Secretion ◽

Double Blind ◽

Parallel Group ◽

Gut Hormone ◽

Parallel Group Trial ◽

Group Trial

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Peripheral Pathways in the Food-Intake Control towards the Adipose-Intestinal Missing Link

International Journal of Endocrinology ◽

10.1155/2013/598203 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Hugo Mendieta Zerón ◽

Ma. Victoria Domínguez García ◽

María del Socorro Camarillo Romero ◽

Miriam V. Flores-Merino

Keyword(s):

Diabetes Mellitus ◽

Genetic Basis ◽

Physiological State ◽

Hormone Secretion ◽

Gut Hormones ◽

Diabetic Patients ◽

Early Presentation ◽

Gut Hormone ◽

Unknown Factor

In the physiological state a multitude of gut hormones are released into the circulation at the same time depending on the quality and quantity of the diet. These hormones interact with receptors at various points in the “gut-brain axis” to affect short-term and intermediate-term feelings of hunger and satiety. The combined effects of macronutrients on the predominant gut hormone secretion are still poorly understood. Besides, adipokines form an important part of an “adipoinsular axis” dysregulation which may contribute toβ-cell failure and hence to type 2 diabetes mellitus (T2DM). Even more, gestational diabetes mellitus (GDM) and T2DM seem to share a genetic basis. In susceptible individuals, chronic exaggerated stimulation of the proximal gut with fat and carbohydrates may induce overproduction of an unknown factor that causes impairment of incretin production and/or action, leading to insufficient or untimely production of insulin, so that glucose intolerance develops. The bypass of the duodenum and jejunum might avoid a putative hormone overproduction in the proximal foregut in diabetic patients that might counteract the action of insulin, while the early presentation of undigested or incompletely digested food to the ileum may anticipate the production of hormones such as GLP1, further improving insulin action.

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