Glucagon-like Peptide-1 Responses Research Articles

Food temperature altered macronutrients induced changes in satiety hormones; glucagon - like peptide -1 and cholecystokinin and their correlation with subjective satiety

Abstract: BACKGROUND: The benefits of dietary macronutrients for weight management depend on the integrity of gut hormones. The role of food temperature in the release of satiety hormones and satiety needs elucidation. We aimed to determine the impact of different food temperatures with varying macronutrient compositions on satiety-related gut hormones glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) and find the correlation of satiety hormones with appetite scores and remainder-day food (energy) intake. MATERIALS AND METHODS: Thirteen healthy participants (eight males and five females) aged 25–35 years with body mass index 18.5–24.9 kg/m2 with no medical illnesses or eating disorders consumed three compositions of meals (high carbohydrate, high fat, and high protein meals) each at three temperatures (cold, warm, and hot) in a randomized, double-blind, controlled crossover design. Plasma concentrations of peptide hormones were determined at 0, 30, and 240 minutes by enzyme-linked immunosorbent assay, and 24-hours food recall was used for remainder-day food intake (remainder energy). RESULTS: A comparison of the three meals at the three temperatures (total of nine groups), showed that the GLP-1 and CCK plasma concentrations were significantly different (P < 0.001). GLP-1 and CCK responses increased more after hot meals than cold meals. Overall, high-fat meals had more effective gut hormone secretions. The area under the curve was increased for GLP-1 in high-fat meals and for CCK in hot meals. The peptide hormones (GLP-1 and CCK) were positively correlated with satiety scores and inversely with remainder food intake. CONCLUSION: The temperature of food was found to be an effective stimulus for the regulation of CCK and GLP-1 secretion. Hot food temperature increased satiety hormones (CCK and GLP-1), independent of food macronutrient composition.

Patients with autoimmune liver disease have glucose disturbances that mechanistically differ from steatotic liver disease.

Autoimmune liver diseases are associated with an increased risk of diabetes, yet the underlying mechanisms remain unknown. In this cross-sectional study, we investigated the glucose-regulatory disturbances in patients with autoimmune hepatitis (AIH, n=19), primary biliary cholangitis (PBC, n=15), and primary sclerosing cholangitis (PSC, n=6). Healthy individuals (n=24) and patients with metabolic dysfunction-associated steatotic liver disease (MASLD, n=18) were included as controls. Blood samples were collected during a 120 min oral glucose tolerance test. We measured the concentrations of glucose, C-peptide, insulin, glucagon, the two incretin hormones glucose insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We calculated the homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin resistance (Matsuda index), insulin clearance, and insulinogenic index. All patient groups had increased fasting plasma glucose and impaired glucose responses compared with healthy controls. Beta-cell secretion was increased in AIH, PBC, and MASLD but not in PSC. AIH and MASLD patients had hyperglucagonemia and hepatic, as well as peripheral, insulin resistance and decreased insulin clearance, resulting in hyperinsulinemia. Patients with autoimmune liver disease had an increased GIP response, and those with AIH or PBC had an increased GLP-1 response. Our data demonstrate that the mechanism underlying glucose disturbances in patients with autoimmune liver disease differs from that underlying MASLD, including compensatory incretin responses in patients with autoimmune liver disease. Our results suggest that glucose disturbances are present at an early stage of the disease.

Investigation of glucagon-like peptide-1 response to six oral carbohydrates in ponies

Glucagon-like peptide-1 (GLP-1), the principal incretin in horses, may play a role in the pathophysiology of insulin dysregulation (ID). This study aimed to describe its concentration in response to three preserved forages and four dynamic tests for ID in ponies. Twelve adult ponies of mixed ID status were given a meal of hay, soaked hay or haylage, an in-feed oral glucose test (OGT), oral sugar test (OST), an oral test using a proprietary breakfast cereal (WEET) or a combined glucose-insulin tolerance test (CGIT) weekly in a randomised cross-over study. Glucose, insulin and GLP-1 concentrations were measured before and following each intervention. Ponies were designated ID or non-ID and insulin resistant (IR) or non-IR according to OGT and CGIT results, respectively.All interventions apart from the CGIT provoked a GLP-1 response within 30 min. The OGT and WEET interventions, (containing the greatest dose of non-structural carbohydrate, 1.06 and 1 g/kg BW, respectively), resulted in a greater area under the curve (AUC) for GLP-1 compared to all other interventions (P < 0.001). No difference in GLP-1 response was detected according to ID or IR status, despite there being strong positive correlations (rs [95 % CI]) between GLP-1 and insulin concentrations measured at individual time points (0.67 [0.62 – 0.71]; P < 0.001) and as AUC (0.66 [0.49–0.79], P < 0.001). These data do not support of the use of GLP-1 as an adjunctive diagnostic test for ID or IR, as defined by conventional intravenous or oral dynamic tests.

Impact of the timing of metformin administration on glycaemic and glucagon-like peptide-1 responses to intraduodenal glucose infusion in type 2 diabetes: a double-blind, randomised, placebo-controlled, crossover study.

Metformin lowers postprandial glycaemic excursions in individuals with type 2 diabetes by modulating gastrointestinal function, including the stimulation of glucagon-like peptide-1 (GLP-1). The impact of varying the timing of metformin administration on postprandial glucose metabolism is poorly defined. We evaluated the effects of metformin, administered at different intervals before an intraduodenal glucose infusion, on the subsequent glycaemic, insulinaemic and GLP-1 responses in metformin-treated type 2 diabetes. Sixteen participants with type 2 diabetes that was relatively well-controlled by metformin monotherapy were studied on four separate days in a crossover design. On each day, participants were randomised to receive a bolus infusion of metformin (1000 mg in 50 ml 0.9% saline) via a nasoduodenal catheter at t = -60, -30 or 0 min (and saline at the other timepoints) or saline at all timepoints (control), followed by an intraduodenal glucose infusion of 12.56 kJ/min (3 kcal/min) at t = 0-60 min. The treatments were blinded to both participants and investigators involved in the study procedures. Plasma glucose, insulin and total GLP-1 levels were measured every 30 min between t = -60 min and t = 120 min. There was a treatment-by-time interaction for metformin in reducing plasma glucose levels and increasing plasma GLP-1 and insulin levels (p<0.05 for each). The reduction in plasma glucose levels was greater when metformin was administered at t = -60 or -30 min vs t = 0 min (p<0.05 for each), and the increases in plasma GLP-1 levels were evident only when metformin was administered at t = -60 or -30 min (p<0.05 for each). Although metformin did not influence insulin sensitivity, it enhanced glucose-induced insulin secretion (p<0.05), and the increases in plasma insulin levels were comparable on the 3 days when metformin was given. In well-controlled metformin-treated type 2 diabetes, glucose-lowering by metformin is greater when it is given before, rather than with, enteral glucose, and this is associated with a greater GLP-1 response. These observations suggest that administration of metformin before meals may optimise its effect in improving postprandial glycaemic control. www.anzctr.org.au ACTRN12621000878875 FUNDING: The study was not funded by a specific research grant.

The acute effect of a β-glucan-enriched oat bread on gastric emptying, GLP-1 response, and postprandialglycaemia and insulinemia: a randomised crossover trial in healthy adults.

The cereal fibre β-glucan reduces postprandial glycaemia, however, the underlying mechanisms are not fully understood. Thus, the aim of this study was to investigate the acute effect of a β-glucan-enriched oat bread on gastric emptying half-time (T1/2), gastric emptying lag phase (Tlag), and gastric emptying rate (GER), and the secretion of glucagon-like peptide-1 (GLP-1) as potential means to influence postprandial glycaemia. A randomised crossover trial was conducted in 22 healthy adults (age 24.6 ± 3.1years, BMI 23.1 ± 2.7kg/m2) receiving 25g available carbohydrates from a β-glucan-enriched oat bread or a control whole-wheat bread at two non-consecutive days. T1/2, Tlag, and GER were determined based on ultrasound measures of the cross-sectional gastric antrum area in the fasting state and 15, 30, 45, 60, 90, and 120min postprandially. Capillary glucose, serum insulin, and plasma GLP-1 concentrations were measured at the same time points. A biphasic pattern of gastric emptying with a distinct Tlag before the commencement of emptying was observed in most subjects for both bread types. While no differences in GER were evident (p = 0.562), consumption of the oat bread significantly increased T1/2 by 18min and Tlag by 14min compared with the whole-wheat bread (p = 0.005 and p = 0.010, respectively). In addition, the oat bread significantly reduced iAUC2h for glucose and insulin responses compared with the whole-wheat bread (p = 0.001 and p < 0.001, respectively). There were no significant differences in GLP-1 response between the two breads (p = 0.892). The increased T1/2 and Tlag could offer a potential mechanism for the observed attenuation of postprandial glycaemia and insulinemia after consumption of the β-glucan-enriched oat bread compared with the whole-wheat bread. The study is registered at clinicaltrails.gov (NCT04571866).

Maternal GLP-1 receptor activation inhibits fetal growth.

Glucagon-like peptide 1 (GLP-1) regulates food intake, insulin production, and metabolism. Our recent study demonstrated that pancreatic α-cells-secreted (intraislet) GLP-1 effectively promotes maternal insulin secretion and metabolic adaptation during pregnancy. However, the role of circulating GLP-1 in maternal energy metabolism remains largely unknown. Our study aims to investigate systemic GLP-1 response to pregnancy and its regulatory effect on fetal growth. Using C57BL/6 mice, we observed a gradual decline in maternal blood GLP-1 concentrations. Subsequent administration of the GLP-1 receptor agonist semaglutide (Sem) to dams in late pregnancy revealed a modest decrease in maternal food intake during initial treatment. At the same time, no significant alterations were observed in maternal body weight or fat mass. Notably, Sem-treated dams exhibited a significant decrease in fetal body weight, which persisted even following the restoration of maternal blood glucose levels. Despite no observable change in placental weight, a marked reduction in the placenta labyrinth area from Sem-treated dams was evident. Our investigation further demonstrated a substantial decrease in the expression levels of various pivotal nutrient transporters within the placenta, including glucose transporter one and sodium-neutral amino acid transporter one, after Sem treatment. In addition, Sem injection led to a notable reduction in the capillary area, number, and surface densities within the labyrinth. These findings underscore the crucial role of modulating circulating GLP-1 levels in maternal adaptation, emphasizing the inhibitory effects of excessive GLP-1 receptor activation on both placental development and fetal growth.NEW & NOTEWORTHY Our study reveals a progressive decline in maternal blood glucagon-like peptide 1 (GLP-1) concentration. GLP-1 receptor agonist injection in late pregnancy significantly reduced fetal body weight, even after restoration of maternal blood glucose concentration. GLP-1 receptor activation significantly reduced the placental labyrinth area, expression of some nutrient transporters, and capillary development. Our study indicates that reducing maternal blood GLP-1 levels is a physiological adaptation process that benefits placental development and fetal growth.

Association of GLP-1 secretion with parameters of glycemic control in women after gestational diabetes mellitus

IntroductionWomen with a history of gestational diabetes mellitus (GDM) are at high risk of developing type 2 diabetes, while the exact mechanisms underlying its pathophysiology are still unclear. We investigated...

The roles of NADPH oxidase and PKC pathways in the modulation of GLP-1 induced-vasorelaxation in diabetic rat aorta

A hormone of the incretin system known as glucagon-like peptide-1 (GLP-1) is important for a number of glucoregulatory functions. This study aimed to investigate the effect of inhibitors on the vasorelaxant response of GLP-1 in T1D rats. A single subcutaneous injection of 50 mg/kg of streptozotocin (STZ) was used to develop diabetes mellitus. Eighty aortic rings from twenty male albino rats were prepared. An Automatic Organ Bath was used. In our study, apocynin increased vascular response to GLP- 1 in the non-diabetic group with (Emax:72.40±0.350) and (pD2: -9.923±0.444). In induced diabetes, the NADPH oxidase inhibitor decreased GLP-1 vasodilatation property with (Emax; 68.91±2.002) and (pD2: -9.480±0.138). The results show that bisindolylmaleimide IX (RO31-8220) has an increased effect on GLP-1 vasodilation in non-diabetic groups with (Emax:88.45±38.18) and (pD2: -10.81±0.281). While in induced diabetic rat’s vascular relaxation of GLP-1 decreased with (Emax: 77.73±2.801) and (pD2: - 10.28±0.203). The data analysis demonstrated that rotenone with (Emax: 63.69±35.10) (pD2: - 9.612±0.246), and in diabetic rats with (Emax:69.98±22.94) and (pD2: -9.612±0.246). In our study oxypurinol with (Emax: 82.16±16.10) and (pD2: - 9.434±0.443), and in diabetic rats with (Emax: 58.03±8.350) and (pD2: -9.612±0.246). We concluded that inhibitors could increase the vasorelaxant response of GLP-1 in non-diabetic rats, while this vasorelaxant response of GLP-1 diminished in diabetic-induced rats.

GLP-1 response during pregnancy: variations between trimesters and associations with appetite sensations and usual energy intake.

Further research is required to understand hormonal regulation of food intake during pregnancy and its association with energy intake. The objectives are to (i) compare postprandial responses of plasma glucagon-like peptide-1 (GLP-1) between trimesters, (ii) compare postprandial appetite sensations between trimesters, and (iii) examine trimester-specific associations between GLP-1 levels, appetite sensations, and usual energy intake. At each trimester, participants (n=26) consumed a standard test meal following a 12 h fast. Plasma GLP-1 levels were measured by enzyme-linked immunosorbent assay method at fasting and at 30, 60, 120, and 180 min postprandial. A visual analogue scale assessing appetite sensations was completed at fasting and at 15, 30, 45, 60, 90, 120, 150, and 180 min postprandial. Mean energy intake was assessed using three web-based 24 h dietary recalls at each trimester. Lower postprandial GLP-1 responses were observed in the 2nd (p=0.004) and 3rd trimesters (p<0.001) compared to the 1st trimester. Greater postprandial sensations of desire to eat, hunger, and prospective food consumption were noted in the 3rd trimester compared to the 1st trimester (p<0.04, for all). Fasting GLP-1 was negatively associated with fasting appetite sensations (except fullness) at the 2nd trimester (p<0.02, for all). Postprandially, significant associations were observed for incremental areas under the curve from 0 to 30 min between GLP-1 and fullness at the 2nd (p=0.01) and 3rd trimesters (p=0.03). No associations between fasting or postprandial GLP-1 and usual energy intake were observed. Overall, GLP-1 and appetite sensation responses significantly differ between trimesters, but few associations were observed between GLP-1, appetite sensations, and usual energy intake.

Altered Glucagon and GLP-1 Responses to Oral Glucose in Children and Adolescents With Obesity and Insulin Resistance.

Pediatric obesity is characterized by insulin resistance, yet it remains unclear whether insulin resistance contributes to abnormalities in glucagon and incretin secretion. To examine whether fasting and stimulated glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) concentrations differ between children and adolescents with obesity and insulin resistance (OIR), obesity and normal insulin sensitivity (OIS), and controls with normal weight (NW). 80 (34 boys) children and adolescents, aged 7-17 years with OIR (n = 22), OIS (n = 22), and NW (n = 36) underwent an oral glucose tolerance test with measurements of serum insulin, plasma glucose, glucagon, total GLP-1, and total GIP. Homeostatic model assessment of insulin resistance (HOMA-IR), single point insulin sensitivity estimator (SPISE), Matsuda index, insulinogenic index (IGI), and oral disposition index (ODI) were calculated. Fasting concentrations of glucagon and GLP-1 were higher in the OIR group, with no significant differences for GIP. The OIR group had higher glucagon total area under the curve (tAUC0-120) and lower GLP-1 incremental AUC (iAUC0-120), with no significant differences in GIP iAUC0-120. Higher fasting glucagon was associated with higher HOMA-IR, lower Matsuda index, lower SPISE, higher IGI, and higher plasma alanine transaminase, whereas higher fasting GLP-1 was associated with higher HOMA-IR, lower Matsuda index, and lower ODI. Higher glucagon tAUC0-120 was associated lower SPISE and lower Matsuda index, whereas lower GLP-1 iAUC0-120 was associated with a higher HOMA-IR, lower Matsuda index, and lower ODI. Children and adolescents with OIR have elevated fasting concentrations of glucagon and GLP-1, higher glucagon and lower GLP-1 responses during an OGTT compared to those with OIS and NW. In contrast, individuals with OIS have similar hormone responses to those with NW.

Gut microbiota regulates postprandial GLP-1 response via ileal bile acid-TGR5 signaling

ABSTRACT The gut microbiota interacts with intestinal epithelial cells through microbial metabolites to regulate the release of gut hormones. We investigated whether the gut microbiota affects the postprandial glucagon-like peptide-1 (GLP-1) response using antibiotic-treated mice and germ-free mice. Gut microbiome depletion completely abolished postprandial GLP-1 response in the circulation and ileum in a lipid tolerance test. Microbiome depletion did not influence the GLP-1 secretory function of primary ileal cells in response to stimulators in vitro, but dramatically changed the postprandial dynamics of endogenous bile acids, particularly ω-muricholic acid (ωMCA) and hyocholic acid (HCA). The bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) but not farnesoid X receptor (FXR), participated in the regulation of postprandial GLP-1 response in the circulation and ileum, and ωMCA or HCA stimulated GLP-1 secretion via TGR5. Finally, fecal microbiota transplantation or ωMCA and HCA supplementation restored postprandial GLP-1 response. In conclusion, gut microbiota is indispensable for maintaining the postprandial GLP-1 response specifically in the ileum, and bile acid (ωMCA and HCA)-TGR5 signaling is involved in this process. This study helps to understand the essential interplay between the gut microbiota and host in regulating postprandial GLP-1 response and opens the foundation for new therapeutic targets.

Characterization of Postprandial Bile Acid Profiles and Glucose Metabolism in Cerebrotendinous Xanthomatosis.

Cerebrotendinous xanthomatosis (CTX) is a rare inherited disease characterized by sterol 27-hydroxylase (CYP27A1) deficiency and, thus, a lack of bile acid synthesis with a marked accumulation of 7α-hydroxylated bile acid precursors. In addition to their renowned lipid-emulgating role, bile acids have been shown to stimulate secretion of the glucose-lowering and satiety-promoting gut hormone glucagon-like peptide 1 (GLP-1). In this paper, we examined postprandial bile acid, glucose, insulin, GLP-1 and fibroblast growth factor 19 (FGF19) plasma profiles in patients with CTX and matched healthy controls. Seven patients and seven age, gender and body mass index matched controls were included and subjected to a 4 h mixed meal test with regular blood sampling. CTX patients withdrew from chenodeoxycholic acid (CDCA) and statin therapy three weeks prior to the test. Postprandial levels of total bile acids were significantly lower in CTX patients and consisted of residual CDCA with low amounts of ursodeoxycholic acid (UDCA). The postprandial plasma glucose peak concentration occurred later in CTX patients compared to controls, and patients' insulin levels remained elevated for a longer time. Postprandial GLP-1 levels were slightly higher in CTX subjects whereas postprandial FGF19 levels were lower in CTX subjects. This novel characterization of CTX patients reveals very low circulating bile acid levels and FGF19 levels, aberrant postprandial glucose and insulin profiles, and elevated postprandial GLP-1 responses.

The effects of postprandial exercise and meal glycemic index on plasma glucose and glucoregulatory hormone responses after Roux-en-Y gastric bypass.

Postprandial hypoglycemia is a complication of Roux-en-Y gastric bypass (RYGB), but the effects of postprandial exercise and meal glycemic index (GI) on postprandial glucose and glucoregulatory hormone responses are unknown. Ten RYGB-operated and 10 age and weight-matched unoperated women completed four test days in random order ingesting mixed meals with high GI (HGI, GI = 93) or low GI (LGI, GI = 54), but matched on energy and macronutrient content. Ten minutes after meal completion, participants rested or cycled for 30 min at 70% of maximum oxygen uptake (V̇o2max). Blood was collected for 4 h. Postprandial exercise did not lower plasma nadir glucose in RYGB after HGI (HGI/rest 3.7 ± 0.5 vs. HGI/Ex 4.1 ± 0.4 mmol/L, P = 0.070). Replacing HGI with LGI meals raised glucose nadir in RYGB (LGI/rest 4.1 ± 0.5 mmol/L, P = 0.034) and reduced glucose excursions (Δpeak-nadir) but less so in RYGB (-14% [95% CI: -27; -1]) compared with controls (-33% [-51; -14]). Insulin responses mirrored glucose concentrations. Glucagon-like peptide 1 (GLP-1) responses were greater in RYGB versus controls, and higher with HGI versus LGI. Glucose-dependent insulinotropic polypeptide (GIP) responses were greater after HGI versus LGI in both groups. Postexercise glucagon responses were lower in RYGB than controls, and noradrenaline responses tended to be lower in RYGB, whereas adrenaline responses were similar between groups. In conclusion, moderate intensity cycling shortly after meal intake did not increase the risk of postprandial hypoglycemia after RYGB. The low GI meal increased nadir glucose and reduced glucose excursions compared with the high GI meal. RYGB participants had lower postexercise glucagon responses compared with controls.NEW & NOTEWORTHY We investigate the effect of moderate exercise after a high or a low glycemic index meal on nadir glucose and glucoregulatory hormones in gastric bypass-operated individuals and in matched unoperated controls. Cycling shortly after meal intake did not increase the risk of hypoglycemia in operated individuals. The low glycemic index meal increased glucose nadir and reduced excursions compared with the high glycemic index meal. Operated individuals had lower postexercise glucagon responses compared with controls.

A Biphasic Glucose Response during an Oral Glucose Tolerance Test Is Associated with Greater Plasma Insulin and GLP-1 Responses and a Reduction in 1-Hour Glucose but Does Not Relate to the Rate of Gastric Emptying in Healthy, Older Adults.

The pattern of the plasma glucose response curve during an oral glucose tolerance test (OGTT) is of prognostic significance with "biphasic" when compared with "monophasic" patterns being associated with greater insulin sensitivity/secretion and a reduced risk of progression to diabetes. The relationships of the glucose response curves with gastric emptying and incretin hormone secretion are not known. Thirty-six adults (age > 65 years) without known diabetes consumed a 300 mL drink containing 75 g glucose and 150 mg C13-acetate at baseline and follow-up after 5.8 ± 0.1 years. Plasma glucose, glucagon-like peptide-1 (GLP-1), glucose independent insulinotropic polypeptide (GIP) and insulin were measured, and participants classified according to the pattern of their glucose response. Gastric emptying was measured on breath samples (stable isotope breath test). At baseline, 22 participants had a "monophasic" and 14 a "biphasic" glucose response. The 1 h plasma glucose response curve was greater and the GLP-1 AUC0-120 min and insulin secretion lower in the monophasic group. There were no differences in gastric emptying, GIP or insulin sensitivity. At the follow-up, the 1 h glucose response curve was greater again, while GLP-1 AUC0-120 min was lower in the monophasic group. A biphasic curve is associated with a higher 60 min glucose response curve and increases in GLP-1, but no difference in either GIP or gastric emptying.

Dietary Vitamin A Affects the Function of Incretin-Producing Enteroendocrine Cells in Male Mice Fed a High-Fat Diet

BackgroundRetinol-binding protein 2 (RBP2) is an intracellular carrier for vitamin A in the absorptive enterocytes. Mice lacking RBP2 (Rbp2−/−) display an unexpected phenotype of obesity, glucose intolerance, and elevated glucose-dependent insulinotropic polypeptide (GIP) levels. GIP and glucagon-like peptide 1 (GLP-1) are incretin hormones secreted by enteroendocrine cells (EECs). We recently demonstrated the presence of RBP2 and other retinoid-related proteins in EECs. ObjectivesGiven RBP2’s role in intracellular retinoid trafficking, we aimed to evaluate whether dietary vitamin A affects incretin-secreting cell function and gene expression. MethodsMale Rbp2−/− mice and sex- and age-matched controls (n = 6–9) were fed a high-fat diet (HFD) for 18 wk containing normal (VAN, 4000 IU/kg of diet) or low (VAL, 25% of normal) vitamin A concentrations. Body weight was recorded biweekly. Plasma GIP and GLP-1 levels were obtained fasting and 30 min after an oral fat gavage at week 16. Glucose tolerance tests were also performed. Mice were killed at week 18, and blood and tissue samples were obtained. ResultsRbp2−/− mice displayed greater weight gain on the VAN compared with the VAL diet from week 7 of the intervention (P ≤ 0.01). Stimulated GIP levels were elevated in Rbp2−/− mice compared with their controls fed the VAN diet (P = 0.02), whereas their GIP response was lower when fed the VAL diet (P = 0.03). Although no differences in GLP-1 levels were observed in the VAN diet group, a lower GLP-1 response was seen in Rbp2−/− mice fed the VAL diet (P = 0.02). Changes in incretin gene expression and that of other genes associated with EEC lineage and function were consistent with these observations. Circulating and hepatic retinoid levels revealed no systemic vitamin A deficiency across dietary groups. ConclusionsOur data support a role for RBP2 and dietary vitamin A in incretin secretion and gene expression in mice fed a HFD.

Safety and Efficacy of Liraglutide, 3.0 mg, Once Daily vs Placebo in Patients With Poor Weight Loss Following Metabolic Surgery

Metabolic surgery leads to weight loss and improved health, but these outcomes are highly variable. Poor weight loss is associated with lower circulating levels of glucagon-like peptide-1 (GLP-1). To assess the efficacy and safety of the GLP-1 receptor agonist, liraglutide, 3.0 mg, on percentage body weight reduction in patients with poor weight loss and suboptimal GLP-1 response after metabolic surgery. The Evaluation of Liraglutide 3.0 mg in Patients With Poor Weight Loss and a Suboptimal Glucagon-Like Peptide-1 Response (BARI-OPTIMISE) randomized placebo-controlled trial recruited adult patients at least 1 year after metabolic surgery who had experienced 20% or less body weight loss from the day of surgery and a suboptimal nutrient-stimulated GLP-1 response from 2 hospitals in London, United Kingdom, between October 2018 and November 2019. Key exclusion criteria were type 1 diabetes; severe concomitant psychiatric, gastrointestinal, cardiac, kidney or metabolic disease; and use of insulin, GLP-1 receptor analogues, and medication that can affect weight. The study period was 24 weeks followed by a 4-week follow-up period. Last participant follow-up was completed in June 2020. All participants and clinical study personnel were blinded to treatment allocation. Of 154 assessed for eligibility, 70 met trial criteria and were included in the study, and 57 completed follow-up. Liraglutide, 3.0 mg, once daily or placebo as an adjunct to lifestyle intervention with a 500-kcal daily energy deficit for 24 weeks, on a 1:1 allocation by computer-generated randomization sequence, stratified by surgery type (Roux-en-Y gastric bypass [RYGB] or sleeve gastrectomy [SG]) and type 2 diabetes status. The primary outcome was change in percentage body weight from baseline to the end of the 24-week study period based on an intention-to-treat analysis. Participant safety was assessed through monitoring of biochemical parameters, including kidney and liver function, physical examination, and assessment for adverse events. A total of 70 participants (mean [SD] age, 47.6 [10.7] years; 52 [74%] female) with a poor weight loss response following RYGB or SG were randomized to receive 3.0-mg liraglutide (n = 35) or placebo (n = 35). All participants received at least 1 dose of the trial drug. Eight participants discontinued treatment (4 per group), and 2 in the 3.0-mg liraglutide group and 1 in the placebo group were lost to follow-up. Due to COVID-19 restrictions, 3 participants in the 3.0-mg liraglutide group and 7 in the placebo group were unable to attend their final in-person assessment. Estimated change in mean (SD) percentage body weight from baseline to week 24 was -8.82 (4.94) with liraglutide, 3.0 mg (n = 31), vs -0.54 (3.32) with placebo (n = 26). The mean difference in percentage body weight change for liraglutide, 3.0 mg, vs placebo was -8.03 (95% CI, -10.39 to -5.66; P < .001). Adverse events, predominantly gastrointestinal, were more frequent with liraglutide, 3.0 mg (28 events [80%]), than placebo (20 events [57%]). There were no serious adverse events and no treatment-related deaths. These findings support the use of adjuvant liraglutide, 3.0 mg, for weight management in patients with poor weight loss and suboptimal GLP-1 response after metabolic surgery. ClinicalTrials.gov Identifier: NCT03341429.

1299-P: Predictors of Glucagon-Like Peptide-1 Responses following OGTT in Treatment-Naïve Type 2 Diabetes Mellitus among Three Ethnic Groups in Malaysia

Introduction: Predictors of glucagon-like peptide-1 (GLP-1) responses following OGTT in treatment-naïve type 2 diabetes mellitus (T2DM) have not been fully elucidated. In this respect, we aim to investigate the various predictors of GLP-1 responses following OGTT in treatment-naïve T2DM. Aim: To assess the clinical and biochemical predictors of GLP-1 responses following OGTT in treatment-naïve T2DM among three ethnic groups in Malaysia. Methods : Thirty-one treatment-naive T2DM subjects underwent a 75-g OGTT. Total GLP-1 concentrations were measured at 0, 30 and 120 min. By using area under the curve (AUC) for GLP-1 (AUCGLP-1) as an index of GLP-1 secretory response, predictors of GLP-1 responses following OGTT were assessed using multiple linear regression analysis. Results: Majority of the treatment-naïve T2DM patients were newly-diagnosed (n=28, 96.6%). The GLP-1 levels at 0, 30- and 120-min were 25.59 ± 10.87 pmol/L, 46.86 ± 18.36 pmol/L and 27.02 ± 13.37 pmol/L respectively. There was a positive correlation between increasing age and AUCGLP-1 (Β = 8.55, p&amp;lt;0.001). Male had higher GLP-1 response to OGTT than female (Β = -303.04, p&amp;lt;0.001). The Indian ethnicity exhibited higher GLP-1 secretion than the Malays (Β = 244.17, p&amp;lt;0.001). Fasting insulin was positively correlated with AUCGLP-1 (Β = 8.73, p=0.001). AUCGLP-1 was positively correlated with increased systolic blood pressure (Β = 3.65, p=0.03), total cholesterol (Β = 174.32, p=0.004) and LDL-cholesterol (Β = 202.35, p=0.002). Conclusions: Older age, male and Indian ethnicity were independent predictors of GLP-1 responses following OGTT in treatment-naïve T2DM. The positive correlation between risk factors associated with insulin resistance and GLP-1 suggested that these risk factors are responsible for driving GLP-1 secretion. Disclosure S.Chong: None. N.Sukor: None. S.A.Robert: None. K.Ng: None. N.A.Kamaruddin: Advisory Panel; Zuellig Pharma Holdings Pte. Ltd., Other Relationship; American Association of Clinical Endocrinologists, Speaker's Bureau; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk. Funding National University of Malaysia (GUP-2017-066); Malaysian Endocrine &amp; Metabolic Society (L12-MEMS6)

609-P: Postprandial GLP-1 Response to Two Diabetes-Specific Formulas Compared with Instant Oatmeal in Adults With Type 2 Diabetes

Diabetes specific formulas (DSFs) are designed with an optimized macronutrient profile as a meal or snack replacement to meet the nutritional needs of people with diabetes while helping to manage blood glucose response. Macronutrients found in DSFs have been shown to promote glucagon-like peptide-1 (GLP-1) secretion, a key hormone involved in regulating incretin response to manage blood glucose levels during the postprandial period. We tested the postprandial GLP-1 response in two randomized, controlled crossover studies in adults with T2D with two DSFs (DSF-1; Study 1, DSF-2; Study 2) varying in macronutrient composition compared to isocaloric instant oatmeal (IOM). In each study, participants were randomly allocated to receive IOM or the study DSF on two test days separated by 4 - 14 days. Total GLP-1 concentration was measured at baseline, 15, 30, 45, 60, 90, 120, 180, and 240 minutes after consumption. Outcome parameters included adjusted peak GLP-1 concentration, and positive area under the curve (pAUC) over 0 - 240 minutes for each participant. Respectively, Study 1 and Study 2 included 26 (n = 15 males, n = 11 females; mean age = 63.6 ± 1.4 years; mean BMI = 30.0 ± 0.9) and 22 (n = 14 males, n = 8 females; mean age = 64.6 ± 2.0 years; BMI = 32.8 ± 0.9) completed participants. Median (1st and 3rd quartile) adjusted peak GLP-1 concentration was significantly higher for DSF-1 (9.2 (6.4, 16.5) pmol/L vs. 3.7 (2.5, 9.0) pmol/L; p = 0.012) and DSF-2 (10.8 (7.5, 20.0) pmol/L vs. 6.3 (4.3, 9.4) pmol/L; p &amp;lt; 0.001) compared to IOM. DSFs significantly increased pAUC for GLP-1 response (DSF-1: 901 (410, 1091) vs. IOM: 177 (47, 421); p &amp;lt;0.001 and DSF-2: 1122 (682, 1820) vs. IOM: 403 (183, 778); p &amp;lt; 0.001) by 410% and 178%, respectively. As part of a diabetes management plan, DSFs can serve as a convenient tool to meet nutritional needs while improving GLP-1 response to help manage blood glucose. Disclosure S.Thomas: Employee; Abbott Nutrition. B.Besecker: Employee; Abbott Nutrition, Stock/Shareholder; Abbott Nutrition. Y.Choe: Employee; Abbott Nutrition.

1300-P: Glucagon-Like Peptide-1 Levels Mirror Insulin Resistant States in Treatment-Naïve Type 2 Diabetes Mellitus

Introduction: In some Asian populations incretin system has been shown to be preserved in type 2 diabetes mellitus (T2DM). The association between fasting and post-OGTT glucagon-like peptide-1 (GLP-1) levels and insulin resistance in treatment-naïve T2DM population has not been clearly defined. Aim: To assess the insulin resistant states (IRS) by means of insulin resistance index (HOMA-IR) and relate this to the fasting and post-OGTT GLP-1 responses in treatment-naïve T2DM. Methods : Thirty-one treatment-naive T2DM subject underwent a 75-g OGTT. Fasting plasma glucose and insulin levels were obtained for HOMA-IR analyses along with plasma total GLP-1 concentrations measured at 0, 30 and 120 min. Results: Majority of the treatment-naïve T2DM patients were newly-diagnosed (n=28, 96.6%). The GLP-1 levels at 0, 30- and 120-min were 25.59 ± 10.87 pmol/L, 46.86 ± 18.36 pmol/L and 27.02 ± 13.37 pmol/L respectively. Fasting GLP-1, incremental GLP-1 at 30 min (∆GLP-130min) and ∆GLP-1120min were positively correlated with HOMA-IR (r=0.654, p&amp;lt;0.001; r=0.421, p=0.018; r=0.574, p=0.001 respectively). Conclusions: The novel finding of this study is that fasting and post-OGTT GLP-1 levels increased proportionately to IRS. This suggests an adaptive compensatory GLP-1 responses to overcome the worsening insulin resistance in treatment-naïve newly-diagnosed T2DM patients. Disclosure S.Chong: None. N.Sukor: None. S.A.Robert: None. K.Ng: None. N.A.Kamaruddin: Advisory Panel; Zuellig Pharma Holdings Pte. Ltd., Other Relationship; American Association of Clinical Endocrinologists, Speaker's Bureau; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk. Funding National University of Malaysia (GUP-2017-066); Malaysian Endocrine &amp; Metabolic Society (L12-MEMS6)

1479-P: Targeted Exome Sequencing for Long-Term Efficacy and Weight Loss of Dulaglutide in Type 2 Diabetes

Introduction: There are individual differences in glucose lowering effect and weight reduction of dulaglutide, long-acting glucagon-like peptide-1 (GLP-1) receptor agonist. It is expected that genetic variations in the mechanism of action of drugs are involved in treatment response to drugs. This study aims to investigate genetic variants associated with long-term efficacy and weight reduction of dulaglutide using targeted next-generation sequencing. Methods: We recruited 77 patients those who were treated with dulaglutide at least one year after switching from DPP-4 inhibitors (±basal insulin) due to uncontrolled type 2 diabetes (HbA1c ≥8.0%) at Korean VHS medical center between September 2018 and October 2019, and followed up until March 2021. The responder was defined by ≥1.0% HbA1c reduction at 24 weeks and achievement of HbA1c ≤7.5% at 52 weeks. We designed targeted exome panel based on the mechanism of drug action, and candidate genetic variants included known GLP-1 response related genes (n=10), gastric emptying related genes (n=18), pancreatic insulin secretion related genes (n=25). At the same time, we also performed whole exome sequencing. Results: During follow-up period of median 2.5±1.3 years, HbA1c was 9.7±1.3% at baseline and reduced to 8.2±1.5% at 6 months, and maintained thereafter up to 4 years. Glycemic response was associated with GNB3, SPARC, and COL4A1 genes. Weight loss (n=13) was more frequently observed in patients with minor G alleles of COL4A1 gene (OR 2.516, 95% CI 1.013, 6.249, p=0.047). Glycemic effectiveness of dulaglutide therapy is associated with genetic variants (OR 2.106, 95% CI 1.358, 3.265, p=0.001) as well as baseline HbA1c (OR 1.682, 95% CI 1.067, 2.650, p=0.025). Conclusion: The glucose lowering effect of dulaglutide, which exempts some patients from insulin therapy, has been associated with GNB3, SPARC, and COL4A1 variants. Polymorphisms in COL4A1 gene was associated with weight loss, although further studies are needed for validation. Disclosure Y.Kim: None. J.Seo: None. Funding VHS Medical Center (VHSMC20026)