Postprandial GLP-1 Research Articles

Effects of Delayed-Release Olive Oil and Hydrolyzed Pine Nut Oil on Glucose Tolerance, Incretin Secretion and Appetite in Humans.

Background: To investigate the potential synergistic effects of olive oil releasing 2-oleoylglycerol and hydrolyzed pine nut oil containing 20% pinolenic acid on GLP-1 secretion, glucose tolerance, insulin secretion and appetite in healthy individuals, when delivered to the small intestine as potential agonists of GPR119, FFA1 and FFA4. Methods: Nine overweight/obese individuals completed three 6-h oral glucose tolerance tests (OGTTs) in a crossover design. At −30 min, participants consumed either: no oil, 6 g of hydrolyzed pine nut oil (PNO-FFA), or a combination of 3 g hydrolyzed pine nut oil and 3 g olive oil (PNO-OO) in delayed-release capsules. Repeated measures of glucose, insulin, C-peptide, GLP-1, GIP, ghrelin, subjective appetite and gastrointestinal tolerability were done. Results: PNO-FFA augmented GLP-1 secretion from 0–360 min compared to no oil and PNO-OO (p < 0.01). GIP secretion was increased from 240–360 min after both PNO-FFA and PNO-OO versus no oil (p < 0.01). Both oil treatments suppressed subjective appetite by reducing hunger and prospective food consumption and increasing satiety (p < 0.05). Conclusions: In support of previous findings, 6 g of delayed-release hydrolyzed pine nut oil enhanced postprandial GLP-1 secretion and reduced appetite. However, no synergistic effect of combining hydrolyzed pine nut oil and olive oil on GLP-1 secretion was observed. These results need further evaluation in long-term studies including effects on bodyweight and insulin sensitivity.

Canagliflozin Increases Intestinal Adenoma Burden in Female ApcMin/+ Mice.

The diabetes drug canagliflozin extends life span in male mice. Since malignant neoplasms are the major cause of death in most mouse strains, this observation suggests that canagliflozin might exert anti-neoplastic effects in male mice. Here, we treated a mouse neoplasia model, the adenoma-prone ApcMin/+ strain, with canagliflozin, to test the effects of this drug on intestinal tumor burden. Surprisingly, canagliflozin increased the total area of intestine involved by adenomas, an effect most marked in the distal intestine and in female mice. Immunohistochemical analysis suggested that canagliflozin may not influence adenoma growth via direct SGLT1/2 inhibition in neoplastic cells. Our results are most consistent with a model where canagliflozin aggravates adenoma development by altering the anatomic distribution of intestinal glucose absorption, as evidenced by increases in postprandial GLP-1 levels driven by delayed glucose absorption. We hypothesize that canagliflozin exacerbates adenomatosis in the ApcMin/+ model via complex, cell-non-autonomous mechanisms, and that sex differences in GLP-1 responses may in part underlie sexually dimorphic effects of this drug on life span.

Динаміка секреції глюкагоноподібного пептиду-1 після лапароскопічної рукавної резекції шлунка у хворих на цукровий діабет 2-го типу, асоційованого з ожирінням

Laparoscopic sleeve gastrectomy (LSG) proved to be a valuable procedure for treating obesity complicated by type 2 diabetes mellitus (T2DM). The mechanism of T2DM resolution after LSG is not yet clearly defined. The objective of the study was to investigate the effect of LSG on the secretion of GLP-1 in patients with T2DM associated with obesity. Plasma GLP-1 levels were evaluated by starvation and 15, 30, 60 and 90 min after the standard carbohydrate preload for breakfast, which included 125 ml of balanced high energy Nutricia Nutridrink Protein. Evaluations were made on the eve of the procedure, for 4 days and 3 months after the operation. In 7 patients with T2DM were diagnosed for the first time, in 3 patients with diabetic history 2 years, in 1 patient – 3.5 years and in 1 patient – 10 years. Mean glycated hemoglobin before surgery was 7.7 ± 1.6%, 3 months after LSG – 5.9 ± 0.4%. The concentration of GLP-1 in 30 minutes before surgery was 6.7 ± 0.9 ng/ml. On the 4th day after LSG, the mean level of GLP-1 was 9.6 ± 0.2 ng/ml, which statistically differed from its level in the pre-operative period, and after 3 months the mean level of GLP-1 statistically increased to 13.7 ± 0.3 ng/ml. Thus LSG leads to an early and significant increase in post-prandial secretion GLP-1 in T2DM patients associated with obesity. The rapid postoperative improvement in signs of carbohydrate metabolism indicates the importance of the incretin effect LSG in the implementation of early compensation mechanisms for T2DM and explains the metabolic activity of this operation.

1214-P: Urocortin3 Is Overexpressed in GLP-1 Positive Enteroendocrine Cells in Human Obesity

UCN3 acts via CRHR2, increases pAKT, pCREB and promotes somatostatin (SST) secretion from D cells. It is unknown whether UCN3 is expressed in gastrointestinal mucosa and its role in obesity. We studied 34 participants, 17 normal weight (age 38±13, 59% female), and 17 with obesity (age 39±9, 65% female). Colonic biopsies were obtained. Single Cell-transcriptomics were completed using the Chromium 10X Genomics platform and Illumina HiSeq4000. Blood was collected at fasting and postprandial at 15, 45, and 90 minutes. RTqPCR and Immunofluorescence (IF) were used to detect UCN3. Blood GLP1 levels were determined by ELISA. HT29 cells were incubated with Sauvagine (2µM), a CRHR2 agonist, for 0, 10, 30, and 60 mins. Cells and supernatant were harvested to perform RTqPCR for SST and CRHR2, western blot for pAKT and pCREB, and ELISA for SST. scRNA-Seq library revealed expression of UCN3 in GLP1 positive cells, confirmed by IF. Ileum and colonic UCN3 mRNA expression was significantly higher in obesity vs. lean (p Therefore, UCN3 is overexpressed in GLP1 positive cells in human obesity. UCN3 increases the secretion of SST, which may explain the association with lower postprandial GLP1. Disclosure M. Ricardo silgado: None. A. Acosta: n/a. C. Yun: None. A. Mcrae: None. G. Calderon: None. G. Daniel: None. C. Alejandro: None. L. Cifuentes: None. A. Hashem: None. M. D. Hurtado: n/a.

Effects of Manipulating Circulating Bile Acid Concentrations on Postprandial GLP-1 Secretion and Glucose Metabolism After Roux-en-Y Gastric Bypass.

BackgroundAltered bile acid (BA) turnover has been suggested to be involved in the improved glucose regulation after Roux-en-Y gastric bypass (RYGB), possibly via stimulation of GLP-1 secretion. We investigated the role of exogenous as well as endogenous BAs for GLP-1 secretion after RYGB by administering chenodeoxycholic acid (CDCA) and the BA sequestrant colesevelam (COL) both in the presence and the absence of a meal stimulus.MethodsTwo single-blinded randomized cross-over studies were performed. In study 1, eight RYGB operated participants ingested 200 ml water with 1) CDCA 1.25 g or 2) CDCA 1.25 g + colesevelam 3.75 g on separate days. In study 2, twelve RYGB participants ingested on separate days a mixed meal with addition of 1) CDCA 1.25 g, 2) COL 3.75 g or 3) COL 3.75 g × 2, or 4) no additions.ResultsIn study 1, oral intake of CDCA increased circulating BAs, GLP-1, C-peptide, glucagon, and neurotensin. Addition of colesevelam reduced all responses. In study 2, addition of CDCA enhanced meal-induced increases in plasma GLP-1, glucagon and FGF-19 and lowered plasma glucose and C-peptide concentrations, while adding colesevelam lowered circulating BAs but did not affect meal-induced changes in plasma glucose or measured gastrointestinal hormones.ConclusionIn RYGB-operated persons, exogenous CDCA enhanced meal-stimulated GLP-1 and glucagon secretion but not insulin secretion, while the BA sequestrant colesevelam decreased CDCA-stimulated GLP-1 secretion but did not affect meal-stimulated GLP-1, C-peptide or glucagon secretion, or glucose tolerance. These findings suggest a limited role for endogenous bile acids in the acute regulation of postprandial gut hormone secretion or glucose metabolism after RYGB.

Severe sleep restriction suppresses appetite independent of effects on appetite regulating hormones in healthy young men without obesity

ObjectiveSeveral nights of moderate (4–5 hr/night) sleep restriction increases appetite and energy intake, and may alter circulating concentrations of appetite regulating hormones. Whether more severe sleep restriction has similar effects is unclear. This study aimed to determine the effects of severe, short-term sleep restriction on appetite, ad libitum energy intake during a single meal, appetite regulating hormones, and food preferences. MethodsRandomized, crossover study in which 18 healthy men (mean ± SD: BMI 24.4 ± 2.3 kg/m2, 20 ± 2 yr) were assigned to three consecutive nights of sleep restriction (SR; 2 hr sleep opportunity/night) or adequate sleep (AS; 7–9 hr sleep opportunity/night) with controlled feeding and activity designed to maintain energy balance throughout the 3-day period. On day 4, participants consumed a standardized breakfast. Appetite, assessed by visual analogue scales, and circulating ghrelin, peptide-YY (PYY), glucagon-like peptide (GLP-1), insulin, and glucose concentrations were measured before and every 20–60 min for 4hr after the meal. Ad libitum energy and macronutrient intakes were then measured at a provided buffet lunch. Food preferences were measured by Leeds Food Preference Questionnaire (LFPQ) administered before and after the lunch. ResultsArea under the curve (AUC) of postprandial hunger (-23%), desire to eat (-23%), and prospective consumption (-18%) ratings were all lower, and postprandial fullness AUC (25%) was higher after SR relative to after AS (p ≤ 0.02). Ad libitum energy intake at the lunch meal was 332 kcal [95% CI: -479, -185] (p<0.001) lower after SR relative to after AS, but relative macronutrient intakes and LFPQ scores did not differ. Postprandial glucose, insulin, PYY, GLP-1, and ghrelin AUCs did not differ between phases. However, mean concentrations of PYY (-11%) and GLP-1 (-4%) over the 4-hr testing period were lower, and glucose concentrations were 6% higher, after SR relative to after AS (p ≤ 0.01). ConclusionIn contrast with reported effects of moderate sleep restriction, severe sleep restriction reduced appetite and energy intake, had no impact food preferences, and had little impact on appetite regulating hormones. Findings suggest that severe sleep restriction may suppress appetite and food intake, at least at a single meal, by a mechanism independent of changes in food preference or appetite regulating hormones.

食後ホルモンインスリン・GLP-1の求心性迷走神経を介した摂食・糖代謝調節

食後ホルモンインスリン・GLP-1の求心性迷走神経を介した摂食・糖代謝調節

Factors associated with weight regain post-bariatric surgery: a systematic review.

To systematically review the literature to assess the incidence and risk factors of weight regain (WR) after bariatric surgery. Bariatric surgery is the most effective intervention for sustained weight loss of morbidly obese patients, but WR remains a concern. A PRISMA compliant systematic literature review was performed using the PubMed database, Embase and the Cochrane Library in July of 2019. Studies that reported ≥ 10% WR after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) were included. The Newcastle-Ottawa scale (NOS) was used for assessing study quality. Out of 2915 retrieved abstracts, 272 full papers were reviewed, and 32 studies included (25 of high and 7 of fair quality) reporting weight outcomes on 7391 RYGB and 5872 SG patients. 17.6% (95% CI 16.9-18.3) had a WR ≥ 10%. Risk factors related with WR fell into 5 categories, namely anatomical, genetic, dietary, psychiatric, and temporal. Specifically, gastrojejunal stoma diameter, gastric volume following sleeve, anxiety, time after surgery, sweet consumption, emotional eating, portion size, food urges, binge eating, loss of control/disinhibition when eating, and genetics have been positively associated with WR while postprandial GLP-1, eagerness to change physical activity habits, self-esteem, social support, fruit and zinc consumption, HDL, quality of life have been negatively associated. At least 1 in 6 patients after bariatric surgery had ≥ 10% WR. This review identified several factors related to WR that can be used to counsel patients preoperatively and direct postoperative strategies that minimize WR risk.

Carbonic anhydrase 8 (CAR8) negatively regulates GLP-1 secretion from enteroendocrine cells in response to long-chain fatty acids.

Glucagon-like peptide-1 (GLP-1) is an incretin secreted from enteroendocrine preproglucagon (PPG)-expressing cells (traditionally known as L cells) in response to luminal nutrients that potentiates insulin secretion. Augmentation of endogenous GLP-1 secretion might well represent a novel therapeutic target for diabetes treatment in addition to the incretin-associated drugs currently in use. In this study, we found that PPG cells substantially express carbonic anhydrase 8 (CAR8), which has been reported to inhibit inositol 1,4,5-trisphosphate (IP3) binding to the IP3 receptor and subsequent Ca2+ efflux from the endoplasmic reticulum in neuronal cells. In vitro experiments using STC-1 cells demonstrated that Car8 knockdown increases long-chain fatty acid (LCFA)-stimulated GLP-1 secretion. This effect was reduced in the presence of phospholipase C (PLC) inhibitor; in addition, Car8 knockdown increased the intracellular Ca2+ elevation caused by α-linolenic acid, indicating that CAR8 exerts its effect on GLP-1 secretion via the PLC/IP3/Ca2+ pathway. Car8wdl null mutant mice showed significant increase in GLP-1 response to oral corn oil administration compared with that in wild-type littermates, with no significant change in intestinal GLP-1 content. These results demonstrate that CAR8 negatively regulates GLP-1 secretion from PPG cells in response to LCFAs, suggesting the possibility of augmentation of postprandial GLP-1 secretion by CAR8 inhibition.NEW & NOTEWORTHY This study focused on the physiological significance of carbonic anhydrase 8 (CAR8) in GLP-1 secretion from enteroendocrine preproglucagon (PPG)-expressing cells. We found an inhibitory role of CAR8 in LCFA-induced GLP-1 secretion in vitro and in vivo, suggesting a novel therapeutic approach to diabetes and obesity through augmentation of postprandial GLP-1 secretion by CAR8 inhibition.

Association Between Ketosis and Changes in Appetite Markers with Weight Loss Following a Very Low-Energy Diet.

The purpose of this study was to examine whether the degree of ketosis, measured as plasma β-hydroxybutyrate (βHB) in fasting, was associated with changes in appetite feelings and plasma concentration of appetite-related hormones after weight loss. A total of 87 individuals with obesity (BMI: 36.5 ± 4.0 kg/m2 ; age: 42.4 ± 9.7 years; 39 males) underwent 8 weeks of a very low-energy diet. Body weight/composition, plasma concentration of βHB, and appetite-related hormones (active ghrelin, active glucagon-like peptide 1 [GLP-1], total peptide YY, cholecystokinin [CCK], and insulin) and subjective appetite feelings were measured at baseline and week 9. Participants lost 17.7 ± 4.1 kg and were ketotic (βHB: 1.24 ± 0.82 mmol/L in fasting) at week 9. A negative association was found between βHB in fasting at week 9 and changes in basal (r = -0.315, P = 0.003) and postprandial ghrelin concentration (r = -0.286, P = 0.008), and a positive association was found with the change in postprandial GLP-1 (r = 0.244, P = 0.025) and CCK (r = 0.228, P = 0.035). No association was seen between βHB in fasting and changes in peptide YY or subjective feelings of appetite. βHB plasma concentration in fasting is associated with lower concentrations of the hunger hormone ghrelin and increased concentrations of the satiety hormones GLP-1 and CCK. Future studies should explore the molecular mechanisms by which βHB modulates the secretion of gut hormones.

Diet-induced obesity enhances postprandial glucagon-like peptide-1 secretion in Wistar rats, but not in diabetic Goto-Kakizaki rats.

Glucagon-like peptide-1 (GLP-1) is postprandially secreted from enteroendocrine L-cells and enhances insulin secretion. Currently, it is still controversial whether postprandial GLP-1 responses are altered in obesity and diabetes. To address the issue and to find out possible factors related, we compared postprandial GLP-1 responses in normal rats and in diabetic rats chronically fed an obesogenic diet. Male Wistar rats and diabetic Goto-Kakizaki (GK) rats were fed either a control diet or a high-fat/high-sucrose (HFS, 30 % fat and 40 % sucrose) diet for 26 weeks. Meal tolerance tests were performed for monitoring postprandial responses after a liquid diet administration (62·76 kJ/kg body weight) every 4 or 8 weeks. Postprandial glucose, GLP-1 and insulin responses in Wistar rats fed the HFS diet (WH) were higher than Wistar rats fed the control diet (WC). Although GK rats fed the HFS diet (GH) had higher glycaemic responses than GK rats fed the control diet (GC), these groups had similar postprandial GLP-1 and insulin responses throughout the study. Jejunal and ileal GLP-1 contents were increased by the HFS diet only in Wistar rats. Furthermore, mRNA expression levels of fatty acid receptors (Ffar1) in the jejunum were mildly (P = 0·053) increased by the HFS diet in Wistar rats, but not in GK rats. These results demonstrate that postprandial GLP-1 responses are enhanced under an obesogenic status in normal rats, but not in diabetic rats. Failure of adaptive enhancement of GLP-1 response in GK rats could be partly responsible for the development of glucose intolerance.

A plant-based meal affects thalamus perfusion differently than an energy- and macronutrient-matched conventional meal in men with type 2 diabetes, overweight/obese, and healthy men: A three-group randomized crossover study

Reward circuitry in the brain plays a key role in weight regulation. We tested the effects of a plant-based meal on these brain regions. A randomized crossover design was used to test the effects of two energy- and macronutrient-matched meals: a vegan (V-meal) and a conventional meat (M-meal) on brain activity, gastrointestinal hormones, and satiety in participants with type 2 diabetes (T2D; n=20), overweight/obese participants (O; n=20), and healthy controls (H; n=20). Brain perfusion was measured, using arterial spin labeling functional brain imaging; satiety was assessed using a visual analogue scale; and plasma concentrations of gut hormones were determined at 0 and 180min. Repeated-measures ANOVA was used for statistical analysis. Bonferroni correction for multiple comparisons was applied. The Hedge's g statistic was used to measure the effect size for means of paired difference between the times (180-0min) and meal types (M-V meal) for each group. Thalamus perfusion was the highest in patients with T2D and the lowest in overweight/obese individuals (p=0.001). Thalamus perfusion decreased significantly after ingestion of the M-meal in men with T2D (p=0.04) and overweight/obese men (p=0.004), and it decreased significantly after ingestion of the V-meal in healthy controls (p<0.001; Group x Meal x Time: F=3.4; p=0.035). The effect size was-0.41 (95% CI,-1.14 to 0.31; p=0.26) for men with diabetes;-0.72 (95% CI,-1.48 to 0.01; p=0.05) for overweight/obese men; and 0.82 (95% CI, 0.09 to 1.59; p=0.03) for healthy men. Postprandial secretion of active GLP-1 increased after the V-meal compared with the M-meal by 42% (95% CI 25-62%; p=0.003) in men with T2D and by 41% (95% CI 24-61%; p=0.002) in healthy controls. Changes in thalamus perfusion after ingestion of both test meals correlated with changes in satiety (r=+0.68; p<0.01), fasting plasma insulin (r=+0.40; p<0.01), C-peptide (r=+0.48; p<0.01) and amylin (r=+0.55; p<0.01), and insulin secretion at 5mmol/l (r=+0.77; p<0.05). The higher postprandial GLP-1 secretion after the V-meal in men with T2D, with concomitant greater satiety and changes in thalamus perfusion, suggest a potential use of plant-based meals in addressing the key pathophysiologic mechanisms of food intake regulation. Trial registration ClinicalTrials.gov number, NCT02474147.

2165-PUB: Jabuticaba Juice Improve Glucagon-Like Peptide-1 in Healthy Participants: Results from a Pilot, Single-Blinded, Randomized Controlled Trial

Introduction: The effects of jabuticaba on health, particularly on glucose metabolism and GLP-1 deserve further clinical investigation. Objective: The objective was to evaluate whether consumption of a jabuticaba juice preload containing 503 mg gallic acid equivalent and 2g of fibers would exert any effect on postprandial glycaemia, insulin, C-peptide, GLP-1, and appetite sensations. Methods: Sixteen healthy subjects (11 women; 5 men; 28.4 ± 3.8 years; BMI 21.7 ± 2.3 kg m−2) completed a randomized, crossover intervention study. Jabuticaba or control beverage was consumed before a white wheat bread (WWB) challenge meal. Blood samples were taken frequently over the following 2 h. Blood glucose, serum insulin, C-peptide, and antioxidant capacity, plasma GLP-1, and appetite sensations were evaluated. Results: Postprandial GLP-1 response as AUC, was higher after consumption of jabuticaba juice compared with control (95.6±41.4 vs. 82.7±24.6 ng/mL; p = 0.03). The GLP-1 significantly increased after jabuticaba juice, peaking at 60 min (1.21±0.5 vs. 0.71±0.2 ng/mL; p = 0,019). The AUC of antioxidant capacity was higher for jabuticaba juice vs. control (37.9±19.4 mmol TE/mL vs. 32.4±8.4; p = 0.005). Postprandial glucose, insulin, C-peptide levels, and appetite sensations were not significantly different between groups. Conclusion: Inclusion of jabuticaba juice before a WWB challenge meal might be beneficial for antioxidant status and GLP-1 concentrations, but we did not find supporting evidence in glycaemia, C-peptide, insulin, insulin sensitivity and appetite sensations in healthy subjects. Disclosure M.V. Geraldi: None. C.B.B. Cazarin: None. A.J. Vasques: None. B.G. Neto: None. M.R. Marostica Junior: None. Funding Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES) (001); CNPq (403328/2016-0; 301108/2016-1); FAPESP (2015/50333-1)

Costus pictus D. Don leaf extract stimulates GLP-1 secretion from GLUTag L-cells and has cytoprotective effects in BRIN-BD11 β-cells

Costus pictus D. Don, commonly known as insulin plant, is a traditional Indian antidiabetic herbal medicine with glucose-lowering and insulin secretory effects having been reported in animal models and humans with Type 2 diabetes. However, its effects on GLP-1 secretion from intestinal endocrine L-cells and potential metabolic and protective effects in insulin secreting pancreatic β-cells are not yet fully understood. This study is aimed to elucidate the effects of Costus pictus D. Don leaf extract (CPE) on L-cell function and GLP-1 secretion using the established murine GLUTag L-cell model and to investigate its potential cytoprotective effects against detrimental effects of palmitate and cytokines in pancreatic β-cells using BRIN-BD11cells. Costus pictus D. Don dried leaf powder was extracted by soxhlet method. Cell viability was determined by MTT assay. Changes in gene and protein expression were quantified by qPCR and western blotting, respectively. GLP-1 and insulin secretion were measured by ELISA. CPE significantly enhanced the percentage of viable BRIN-BD11 and GLUTag cells and protected BRIN-BD11cells against palmitate- and proinflammatory cytokine-induced toxicity. CPE enhanced acute GLP-1 secretion 6.4-16.3-fold from GLUTag cells at both low (1.1mM) and high (16.7mM) glucose (P<0.01) concentrations. Antioxidant (Nrf2, Cat & Gpx1) and pro-proliferative (Erk1 and Jnk1) gene expression were upregulated by 24h culture with CPE, while proinflammatory transcription factor NF-κB was downregulated. Diminished postprandial GLP-1 secretion and loss of insulin secreting β-cells are known contributors of T2DM. Our data suggests that CPE acutely stimulates GLP-1 secretion from L-cells. Long term exposure of the BRIN-BD11cells to CPE enhances cell number and may protect against palmitate and proinflammatory cytokines by activating multiple pathways. Thus, the current study suggests that the possible antidiabetic properties of CPE may be linked to enhanced GLP-1 secretion and β-cell protection which could be beneficial in the management of T2DM.

Physical activity is associated with accelerated gastric emptying and increased ghrelin in obesity.

Rapid gastric emptying, increased food intake, and alterations in gastrointestinal hormones are associated with obesity. The effect of regular physical activity (PA) on food intake, gastric emptying (GE), gastric accommodation, and gastrointestinal (GI) hormones in adults with obesity remains unclear. Our aim was to compare, at time of presentation, weight trends, eating behavior, GE, and GI hormone levels among individuals with obesity who engage in regular PA compared to those who do not. In 270 participants with obesity, we performed validated measurements of GI phenotypes: GE of solids and liquids, gastric volume (GV) during fasting and after consumption of 200mL Ensure®, satiety by kcal intake (T-kcal) during a buffet meal, satiation (volume to fullness [VTF] and maximal tolerated volume [MTV]) of a liquid nutrient, and plasma levels of fasting and postprandial GLP-1, PYY, CCK, and ghrelin. Physical Activity Stages of Change Questionnaire was used to assess whether participants were regularly PA or not. PA was associated with lower BMI (Δ 2.01kg/m2 , P=.001) and body weight (Δ 4.42kg, P=.0278). GE of solids (T-50% Δ 7.54min, P=.021) and liquids (T-50% Δ 2.99min, P=.029%) was significantly more rapid in physically active participants. PA was also associated with relatively higher postprandial ghrelin AUC (Δ 10.4pg/mL, P=.015). There was no significant difference in postprandial satiation, satiety, GV, or other GI hormones (CCK, PYY, or GLP-1) between groups. Physical activity is associated with lower BMI, but faster GE and higher postprandial ghrelin levels, two factors that are also associated with obesity.

Ileo-colonic delivery of conjugated bile acids improves glucose homeostasis via colonic GLP-1-producing enteroendocrine cells in human obesity and diabetes

BackgroundThe bile acid (BA) pathway plays a role in regulation of food intake and glucose metabolism, based mainly on findings in animal models. Our aim was to determine whether the BA pathway is altered and correctable in human obesity and diabetes. MethodsWe conducted 3 investigations: 1) BA receptor pathways were studied in NCI-H716 enteroendocrine cell (EEC) line, whole human colonic mucosal tissue and in human colonic EEC isolated by Fluorescence-activated Cell Sorting (ex vivo) from endoscopically-obtained biopsies colon mucosa; 2) We characterized the BA pathway in 307 participants by measuring during fasting and postprandial levels of FGF19, 7αC4 and serum BA; 3) In a placebo-controlled, double-blind, randomised, 28-day trial, we studied the effect of ileo-colonic delivery of conjugated BAs (IC-CBAS) on glucose metabolism, incretins, and lipids, in participants with obesity and diabetes. FindingsHuman colonic GLP-1-producing EECs express TGR5, and upon treatment with bile acids in vitro, human EEC differentially expressed GLP-1 at the protein and mRNA level. In Ussing Chamber, GLP-1 release was stimulated by Taurocholic acid in either the apical or basolateral compartment. FGF19 was decreased in obesity and diabetes compared to controls. When compared to placebo, IC-CBAS significantly decreased postprandial glucose, fructosamine, fasting insulin, fasting LDL, and postprandial FGF19 and increased postprandial GLP-1 and C-peptide. Increase in faecal BA was associated with weight loss and with decreased fructosamine. InterpretationsIn humans, BA signalling machinery is expressed in colonic EECs, deficient in obesity and diabetes, and when stimulated with IC-CBAS, improved glucose homeostasis. ClinicalTrials.gov number, NCT02871882, NCT02033876. FundingResearch support and drug was provided by Satiogen Pharmaceuticals (San Diego, CA). AA, MC, and NFL report grants (AA- C-Sig P30DK84567, K23 DK114460; MC- NIH R01 DK67071; NFL- R01 DK057993) from the NIH. JR was supported by an Early Career Grant from Society for Endocrinology.

Effect of tasteless calorie-free gum chewing before meal on postprandial plasma glucose, insulin, glucagon, and gastrointestinal hormones in Japanese men without diagnosed glucose metabolism disorder: a pilot randomized crossover trial.

This pilot study aimed to examine the effect of pre-meal tasteless calorie-free gum chewing on post-meal blood levels of glucose, insulin, glucagon, and gastrointestinal hormones. This was an open-label, randomized, 2-sequence, 3-period, 2-treatment crossover trial with a 1:1 allocation. Sixteen Japanese adult male volunteers aged between 30 and 49years without diagnosed glucose metabolism disorderwere enrolled. Ingestion of 200-g cooked rice after 15-min tasteless calorie-free gum chewing (GUM+ treatment) was compared to that without preceding gum chewing (GUM- treatment). Cooked rice was divided into twelve equally sized portions and consumed by chewing each portion 30 times before swallowing. Treatment sessions were separated by an at least 1-week interval and attended after an overnight fast. Circulating levels of glucose, insulin, glucagon, active glucagon-like peptide (GLP)-1 and ghrelin were measured at baseline (before treatment) and 0, 15, 30, 60, and 120min after completion of the meal ingestion, and the postprandial change from baseline was assessed. As a result, the change in glucose levels at 0min was significantly lower in the GUM+ treatment than in the GUM- treatment (P = 0.004). Furthermore, the GUM+ treatment demonstrated higher incremental insulin levels at 15min (P = 0.041) and higher incremental active GLP-1 levels at 30 and 60min (P = 0.018 and 0.021, respectively); whereas, postprandial glucagon and ghrelin levels were not significantly different. In conclusion, the current pilot study demonstrated that tasteless calorie-free gum chewing before rice eating had a significant but limited impact on the increase of postprandial active GLP-1 levels in male individuals without diagnosed glucose metabolism disorder.

Secretin effects on gastric functions, hormones and symptoms in functional dyspepsia and health: randomized crossover trial.

Abnormal gastric accommodation (GA) and gastric emptying contribute to pathophysiology in functional dyspepsia (FD). Secretin is a key regulator of GA in animal studies. Our aim was to study the effects of secretin on gastric motility, satiation, postprandial symptoms, and key hormones. We performed two double-blind, randomized, saline-controlled crossover trials in 10 healthy volunteers and 10 patients with FD by Rome IV criteria. We used measured GA (by validated SPECT method) after a 111In radiolabeled Ensure 300-mL meal and quantified gastric emptying for 30 min by scintigraphy. Satiation was measured by volume to fullness (VTF) and maximum tolerated volume (MTV) on an Ensure nutrient drink test and postprandial symptoms 30 min post-MTV. Fasting and postprandial GLP-1, GIP, and HPP were measured. The ages and sex distribution of healthy controls and patients with FD were similar. Compared with placebo, secretin delayed gastric emptying at 30 min in both health [-11% (-16, -4), P = 0.004]; and FD [-8% (-9, 0), P = 0.03]. Satiation (VTF and MTV), GA, and plasma levels of GLP-1, GIP, and HPP did not differ between treatment arms in health or FD. On ANCOVA analysis (adjusting for age and sex), secretin did not consistently increase postprandial symptoms in health or FD. Secretin delayed gastric emptying in both health and FD without significantly altering GA, VTF, or MTV or selected hormones. Thus, secretin receptor activation may provide a novel therapeutic mechanism for patients with FD and rapid gastric emptying.NEW & NOTEWORTHY The naturally occurring hormone secretin retards gastric emptying of solids without deleteriously affecting gastric accommodation, satiation, other upper gastrointestinal hormones, or postprandial symptoms. Given these findings, a subset of patients with rapid gastric emptying (e.g., the estimated 20% of patients with functional dyspepsia) could be candidates for treatments that stimulate a secretin receptor such as sacubitril, which inhibits neprilysin, an enzyme that degrades secretin.

Towards precision medicine: defining and characterizing adipose tissue dysfunction to identify early immunometabolic risk in symptom-free adults from the GEMM family study

ABSTRACT Interactions between macrophages and adipocytes are early molecular factors influencing adipose tissue (AT) dysfunction, resulting in high leptin, low adiponectin circulating levels and low-grade metaflammation, leading to insulin resistance (IR) with increased cardiovascular risk. We report the characterization of AT dysfunction through measurements of the adiponectin/leptin ratio (ALR), the adipo-insulin resistance index (Adipo-IRi), fasting/postprandial (F/P) immunometabolic phenotyping and direct F/P differential gene expression in AT biopsies obtained from symptom-free adults from the GEMM family study. AT dysfunction was evaluated through associations of the ALR with F/P insulin-glucose axis, lipid-lipoprotein metabolism, and inflammatory markers. A relevant pattern of negative associations between decreased ALR and markers of systemic low-grade metaflammation, HOMA, and postprandial cardiovascular risk hyperinsulinemic, triglyceride and GLP-1 curves was found. We also analysed their plasma non-coding microRNAs and shotgun lipidomics profiles finding trends that may reflect a pattern of adipose tissue dysfunction in the fed and fasted state. Direct gene differential expression data showed initial patterns of AT molecular signatures of key immunometabolic genes involved in AT expansion, angiogenic remodelling and immune cell migration. These data reinforce the central, early role of AT dysfunction at the molecular and systemic level in the pathogenesis of IR and immunometabolic disorders.

Ileo-Colonic Delivery of Conjugated Bile Acids Improves Glucose Homeostasis &lt;i&gt;via&lt;/i&gt; Colonic GLP-1-Producing Enteroendocrine Cells in Human Obesity and Diabetes

Background: The bile acid (BA) pathway plays a role in regulation of food intake and glucose metabolism, based mainly on findings in animal models. Our aim was to determine whether the BA pathway is altered and correctable in human obesity and diabetes. Methods: We conducted 3 investigations: 1) BA receptor pathways were studied in NCI-H716 enteroendocrine cell (EEC) line, whole human colonic mucosal tissue and in human colonic EEC isolated by Fluorescence-activated Cell Sorting (ex vivo) from endoscopically-obtained biopsies colon mucosa; 2) We characterized the BA pathway in 307 participants by measuring during fasting and postprandial levels of FGF19, 7αC4 and serum BA; 3) In a placebo-controlled, double-blind, randomized, 28-day trial, we studied the effect of ileo-colonic delivery of conjugated BAs (IC-CBAS) on glucose metabolism, incretins, and lipids, in participants with obesity and diabetes. Results: Human colonic GLP-1-producing EECs express TGR5, and upon treatment with bile acids in vitro, human EEC differentially expressed GLP-1 at the protein and mRNA level. In Ussing Chamber, GLP-1 release was stimulated by Taurocholic acid in either the apical or basolateral compartment. FGF19 was decreased in obesity and diabetes compared to controls. When compared to placebo, IC-CBAS significantly decreased postprandial glucose, fructosamine, fasting insulin, fasting LDL, and postprandial FGF19 and increased postprandial GLP-1 and C-peptide. Increase in fecal BA was associated with weight loss and with decreased fructosamine. Conclusions: In humans, BA signaling machinery is expressed in colonic EECs, deficient in obesity and diabetes, and when stimulated with IC-CBAS, improved glucose homeostasis. Trial Registration: ClinicalTrials.gov number, NCT02871882, NCT02033875. Funding Statement: Research support and drug was provided by Satiogen Pharmaceuticals (San Diego, CA). The study was conducted in the clinical research unit (supported by Mayo Clinic Center for Clinical and Translational Science [CCaTS] grant UL1- TR000135). AA, MC, and NFL report grants (AA- C-Sig P30DK84567, K23 DK114460; MC- NIH R01 DK67071; NFL- R01 DK057993) from the NIH. JR was supported by an Early Career Grant from Society for Endocrinology. Declaration of Interests: AA is a stockholder in Gila Therapeutics, Phenomix Sciences and Lipiquester; he serves as a consultant for Rhythm Pharmaceuticals, General Mills, Gila Therapeutics. MC is a stockholder in Phenomix Sciences and serves as a consultant to Takeda, Allergan, Rhythm, Salix, Arena, Enterin. BG is a stockholder in Satiogen Pharmaceuticals. All other authors report no relevant financial or personal conflicts of interest. Ethics Approval Statement: Surgical specimens of fresh human colon were obtained from Tissue Bank at Addenbrooke's Hospital (Cambridge, UK) and used for experiments approved by the Research Ethics Committee. The study was approved by the Mayo Clinic Institutional Review Board, and all participants gave written informed consent.