GLP-1 Levels Research Articles

S112 Implications of Butyrate Kinase and Intestinal Microbiota on Diabetes Risk in a Community Enriched With Native Hawaiians

Introduction: The incidence of type 2 diabetes mellitus (T2DM) within the Native Hawaiian population among the highest of any major ethnic group within the state of Hawaii. Modern research is beginning to mechanistically understand ancient Hawaiian concepts and practices demonstrating the importance of environment to human health. Environmental factors, such as socioeconomic status, toxicants, diet/nutrition, etc, contribute to individual risk of T2DM, where impacts on the gut microbiome may play key roles in inflammatory and metabolic dysregulation characteristic of diabetes. In this study, we focused on understanding the relationship between the gut microbiome and T2DM risk in the Native Hawaiian population. Methods: The study enrolled a cohort of Hawaii residents (16 years or older) in a community enriched with Native Hawaiians. Microbial DNA was isolated from self-collected stool samples of all participants and used for 16S amplicon-based sequencing for metagenomic analyses and for quantifying microbial-specific butyrate kinase (BUK) gene expression levels using qPCR approaches. From each participant, anthropometric measures and blood levels of HbA1c, a diagnostic indicator of T2DM, were taken. Blood was collected by venous puncture from which plasma was isolated to measure inflammatory and metabolic biomarkers. Herein, we identified and describe significant differences between diabetic and non-diabetic microbiome composition and diversity. Results: Consistent with other studies, we observed increased levels of CRP (p< 0.01) and decreased levels of leptin (p=0.04) in the plasma of diabetic compared to non-diabetic participants. Additionally, we observed that BUK levels were negatively correlated with that of HbA1c (R=-0.18, p=0.04), and positively correlated with that of metabolic hormones PYY (R=0.30; p=0.007) and GLP-1 (R=0.19; p=0.04), which were largely attributed to diabetes status. Higher plasma levels of PYY and GLP-1 have previously been associated with reduced T2DM risk. Conclusion: Altogether, our data suggest a role for butyrate-producing gut bacteria in the maintenance of the homeostatic inflammatory and metabolic states that are dysregulated in the progression of T2DM and implicates novel targets for reducing T2DM risk among health disparate populations.

The Levels of Ghrelin, Glucagon, Visfatin and Glp-1 Are Decreased in the Peritoneal Fluid of Women with Endometriosis along with the Increased Expression of the CD10 Protease by the Macrophages.

The aim of this study was to evaluate the levels of ten energy metabolism factors: C-peptide, ghrelin, GIP, GLP-1, glucagon, insulin, leptin, PAI-1 (total), resistin, and visfatin, and to determine the expression of GLP1R receptors, CD10, CD26 proteases, and pro-inflammatory marker CD86 by macrophages in the peritoneal fluid (PF) in patients with endometriosis. The study included 54 women with endometriosis and a control group of 30 women with uterine myoma without signs of endometriosis. The levels of factors in PF were assessed by a multiplex method. Expression of GLP1R receptors, CD10, CD26 proteases, and CD86 by macrophages was evaluated using flow cytometry. It was found that in women with endometriosis, the concentrations of ghrelin, GLP-1, glucagon, and visfatin in PF were reduced (p = 0.007, p = 0.009, p = 0.002, p = 0.008, respectively). At the same time, there was a noted increase in the CD10 protease expression by peritoneal macrophages (p = 0.044). Correlation analysis showed a positive correlation of ghrelin and GLP-1 levels with CD86 macrophage expression (p = 0.044, p = 0.022, respectively) in the study group; a positive correlation was also found between the levels of GLP-1, glucagon, and visfatin with CD26 macrophage expression (p = 0.041, p = 0.048, p = 0.015, respectively) in PF. No correlations were found in the control group. These results indicate that a decrease in the levels of ghrelin, GLP-1, glucagon, and visfatin in PF may contribute to endometriosis development through their impact on the expression of pro-inflammatory markers of PF macrophages.

407.2: Successful Pregnancy in a Small Bowel Syndrome Patient Without Any Nutritional Support. Case Report: GLP-2 Levels in Pregnancy and Breastfeeding

Introduction: Pregnant patients with Short Bowel Syndrome (SBS) and chronic intestinal failure (CIF) can successfully reach to term their pregnancies while on Parenteral Nutrition (PN) but with high rates of complications. The availability of entero-hormones, especially semisynthetic glucagon like peptide 2 (sGLP2) has increased the chances to achieve intestinal sufficiency. Case report: We report the case of a 33-year-old female patient with SBS/CIF (anatomy type 2), weaned off PN using sGLP-2. After 3.7 years of treatment, she became pregnant. The first decision was to interrupt the use of sGLP-2 as pregnancy is a contraindication for its use. She was able to successfully carry out the pregnancy to term without any additional PN support. She had adequate weight gain (59,0 to 66,15 kgs); the newborn weight was 2,450 kgs, and she was able to breastfeed her without complications. Our initial hypothesis was that endogenous fetal GLP-2 (eGLP2) levels could have been a sufficient source to maintain an adequate maternal intestinal absorption, if able to cross the placental barrier. Thus, during the pregnancy, we decided to determine eGLP-2 levels in paired neonatal (cord blood) and maternal plasma samples from pregnant with (n=1) or without SBS (controls, n=2) during the partum and the immediate breastfeeding period (1 and 6 months postpartum); we also aimed to measure and compare eGLP-2 plasma levels between pregnant (n=1) and a non-pregnant SBS patients (Anatomy type 2 (n=7); Anatomy type 3 (n= 5)). Materials and Methods: Blood samples were collected in ice chilled 10 ml tubes containing ethylenediaminetetraacetic acid (EDTA) and a specific dipeptidyl peptidase IV inhibitor. Plasma was immediately separated and stored at −80°C until analyzed. Results: Our results indicated that eGLP-2 levels were significantly lower in neonatal than maternal plasma from our pregnant SBS patient compared to controls (Table 1). During postpartum, eGLP-2 levels increased up to the six-month in both groups (Figure 1). Interestingly, our pregnant SBS patient showed significantly higher GLP-2 levels respect than controls (Figure 1) and non-pregnant SBS patients (Figure 2). Conclusions: We observed that the endogenous neonatal GLP-2 does not represent an extra source of this entero-hormone to improve the adequate intestinal absorption during pregnancy in SBS patients. However, this study suggests that long periods of sGLP-2 treatment in SBS patients could reach an effective intestinal rehabilitation sufficient not only to improve intestinal absorption (to carry out the full pregnancy and to sustain breast feeding), but also to probably increase the eGLP-2 production. This study should be reproduced in experimental models and larger series to validate those results.TAKEDA.

The Effect of Short-term Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) Diet on Hunger Hormones, Anthropometric Parameters, and Brain Structures in Middle-aged Overweight and Obese Women: A Randomized Controlled Trial.

Background: The rising prevalence of obesity, as well as its detrimental effects on the brain, has drawn attention to specific dietary patterns. This study aimed to examine the effect of the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) pattern on anthropometric parameters, hunger hormones, and brain structures in overweight and obese women.Methods: This randomized trial was conducted in Shiraz between October 2018 and March 2019. We analyzed 37 healthy women with a mean age of 48±5.38 years and a Body Mass Index (BMI) of 32±0.69 Kg/m2. Participants were randomly allocated to a hypocaloric modified MIND diet or a hypocaloric control diet. Differences in anthropometric, laboratory analysis, and brain structure were determined at baseline and three-month follow-up. Data were analyzed using SPSS 22.0. Independent and paired sample t test were used to determine between and within differences. We also used mixed-model ANOVA to compare the mean differences between two-factor groups.Results: A more significant weight reduction (P<0.0001), BMI (P<0.0001), percentage of body fat (P=0.03), waist circumference (P=0.01), and Leptin concentration (P=0.03) were found in the MIND diet group. The results also showed a significant increase in Ghrelin (P=0.002) and GLP-1 (P=0.01) levels in the MIND diet group. The findings revealed no differences in the whole and regional brain structures between the two groups.Conclusion: For the first time, this study showed that the MIND diet intervention could improve the devastating effect of obesity on metabolic profiles and anthropometric parameters. However, we could not find its effect on brain structures.Trial registration number: IRCT20190427043387N1.A preprint of this study was published at https://www.medrxiv.org/content/10.1101/2020.06.28.20142018v1.

Design and exploration of gut-restricted bifunctional molecule with TGR5 agonistic and DPP4 inhibitory effects for treating ulcerative colitis

Ulcerative colitis (UC) is a gastrointestinal disease with complex etiology, and the shortage of the treatment further intensifies the need to discover new therapies based on novel mechanisms and strategies. TGR5 and DPP4 are beneficial to treat UC through multiple mechanisms, notably increasing GLP-2 levels by promoting secretion and inhibiting degradation respectively. However, some unwanted systemic effects caused by systemic exposure hinder development, especially the gallbladder-filling effects. Herein, we firstly reported a series of high-potency gut-restricted TGR5-DPP4 bifunctional molecules by gut-restriction and multitarget strategies to utilize the positive impacts of TGR5 and DPP4 on UC and avoid unwanted systemic effects. In particularly, racemic compound 15, a high-potency TGR5-DPP4 bifunctional molecule, showed favorable intestinal distribution, preferable efficacy in mice colitis model and good gallbladder safety. Therefore, the feasibility of gut-restricted TGR5-DPP4 bifunctional molecule was confirmed for the treatment UC, providing a new insight into the development of anti-UC drugs.

SP2.1.4 Predictors of Type-2 Diabetes Remission Following Bariatric Surgery After a Two-Year Follow Up

Abstract Purpose Bariatric surgery is evolving as a successful tool for managing morbid obesity and T2DM. This study aimed to identify predictors of diabetes remission after two types of bariatric procedures. Methods This prospective study enrolled 172 patients with morbid obesity associated with T2DM scheduled for bariatric surgery. Two laparoscopic bariatric procedures were done; single anastomosis gastric bypass (SAGB, n=83) and sleeve gastrectomy (LSG, n=68). Lipid accumulation product index (LAP) and quantitative insulin sensitivity check index (QUICKI) were used to evaluate lipid profile and insulin sensitivity. Two years after surgery condition of DM was evaluated as complete remission (CR), partial remission (PR), or improvement. The primary outcome measure was predictors of diabetes remission. Results Two years after surgery, 151 patients were available for evaluation, where 75 patients (49.7%) achieved CR, while PR was found in 36 (23.8%). CR was significantly associated with younger age, shorter duration of DM (p &amp;lt; 0.001, for both), higher C-peptide and GLP-1 levels (p &amp;lt; 0.001 and p = 0.002, respectively), and bypass surgery (p = 0.027). On multivariate analysis, shorter duration of DM, lower BMI, and higher C-peptide levels were the independent factors predicting CR. Conclusion Complete remission of T2DM can be achieved in nearly half of the patients two years after SG or SAGB. The duration of diabetes and preoperative BMI and C-peptide levels are the independent factors predicting complete remissions.

Amelioration of intracerebroventricular streptozotocin-induced cognitive dysfunction by Ocimum sanctum L. through the modulation of inflammation and GLP-1 levels.

DPP-4 inhibitors have been shown to reverse amyloid deposition in Alzheimer's disease (AD) patients with cognitive impairment. Ocimum sanctum L. leaves reported the presence of important phytoconstituents which are reported to have DPP-4 inhibitory activity. To investigate the effects of petroleum ether extract of Ocimum sanctum L. (PEOS) in Intracerebroventricular streptozotocin (ICV-STZ) induced AD rats. ICV-STZ (3mg/kg) was injected bilaterally into male Wistar rats, while sham animals received the artificial CSF. The ICV-STZ-induced rats were administered with three doses of PEOS (100, 200, and 400mg/kg, p.o.) for thirty days. All experimental rats were subjected to behaviour parameters (radial arm maze task and novel object recognition test), neurochemical parameters such as GLP-1, Aβ42, and TNF-α levels, and histopathological examination (Congo red staining) of the left brain hemisphere. PEOS significantly reversed the spatial learning and memory deficit exhibited by ICV-STZ-induced rats. Furthermore, PEOS also shows promising results in retreating Aβ deposition, TNF α, and increasing GLP-1 levels. The histopathological study also showed a significant dose-dependent reduction in amyloid plaque formation and dense granule in PEOS -treated rats as compared to the ICV-STZ induced rats (Negative control). The results show that extract of Ocimum sanctum L. attenuated ICV-STZ-induced learning and memory deficits in rats and has the potential to be employed in the therapy of AD.

Consumption of probiotic yogurt and vitamin D-fortified yogurt increases fasting level of GLP-1 in obese adults undergoing low-calorie diet: A double-blind randomized controlled trial.

Energy restriction and manipulation of macronutrient composition of the diet are the main approaches that are used by people who aim to lose weight. When such strategies are employed, appetite and endocrine regulators of satiety, such as gut peptides, all are deeply affected. The gut microbiota–brain axis controls energy homeostasis in humans by affecting central satiety and gut peptides. The purpose of this study was to evaluate if the synergistic effect of probiotics and vitamin D in yogurt matrix can modulate this effect. In the double‐blind, randomized, placebo‐controlled trial, 140 obese adults were randomly allocated into four groups: 1) regular yogurt plus low‐calorie diet; 2) PY plus low‐calorie diet; 3) vitamin D‐fortified yogurt plus low‐calorie diet, and 4) probiotic and vitamin D co‐fortified yogurt plus low‐calorie diet. All groups were encouraged to increase their physical activity. Glucagon‐like peptide‐1 (GLP‐1), peptide Tyrosin‐Tysrosin (PYY), ghrelin, anthropometric variables, insulin, fasting blood sugar (FBS), insulin resistance/sensitivity, 1,25(OH)2 D3, dietary intake, and physical activity were measured before and after 10 weeks. The difference between groups for GLP‐1 after 10 weeks was significant after adjusting for baseline GLP‐1 and protein intake as confounders. PY showed the largest effect size (ES) on GLP‐1 (p = 14.2) and FBS (p = 14) compared with others. Pairwise comparison of yogurts effect sizes on GLP‐1 showed a significant difference in group 1 vs. group 2 (p = .001), group 1 vs. group 3 (p = .003), and group 1 vs. group 4 (p = .048). Vitamin D‐fortified yogurt had the largest effect size on the serum level of vitamin D and it showed a significant difference with RY (p = .018) and PY (p = .002). Consumption of vitamin D‐fortified yogurt and PY could be regarded as a promising approach during calorie restriction.

Circulating levels of five proglucagon-derived peptides in response to intravenous or oral glucose or lipids and to a mixed-meal in subjects with normal weight, overweight, and obesity

Proglucagon-derived peptides (PGDPs) secreted by the gut and pancreas play a major role in metabolism. We measured concentrations of five PGDPs in response to per os (PO) or intravenous (IV) glucose or lipid intake and a mixed meal test (MMT) consumed by subjects with normal weight, overweight or obesity. GLP-1, oxyntomodulin and glicentin (gut-secreted PGDPs) and glucagon and MPGF (pancreas-secreted PGDPs) were assessed in: (a) 32 subjects receiving PO or IV glucose, lipids or water over 6h, (b) 33 subjects with normal weight, overweight or obesity who consumed a MMT. (a) GLP-1, oxyntomodulin, glicentin and glucagon levels increase more profoundly and persistently after lipids PO (2.5g/kg) than glucose PO (2.5g/kg) or IV lipids (Intralipid/Liposyn II 20% at 0.35ml/kg/hand Intralipid/Liposyn II 20% at 0.83ml/kg/h for 6h) or IV glucose (10% glucose at 3.6ml/kg/hfor 6h). Oxyntomodulin and glicentin increased more than GLP-1 in response to lipids PO. MPGF levels decrease in response to glucose PO or IV indicating a shift towards preferential production of gut-secreted peptides. (b) Fasting and postprandial areas under the curve (AUCs) after MMT of GLP-1, MPGF and glucagon levels correlated positively with BMI. The fasting levels of glucagon and MPGF were elevated in obesity and remained elevated after the MMT. Circulating levels of PGDPs are differentially regulated by body weight, the type of macronutrients administered and the respective route of administration. Mechanistic studies are needed to define the exact mechanisms underlying this regulation. Study 1 has the NCT01520454 and the NCT04888325 number in ClinicalTrials.gov. Study 2 has the number NCT01495754 in ClinicalTrials.gov.

Biochemical Investigation of Therapeutic Potentials of Plant-Based Bioactive Compounds as Stimulators of Glucagon like peptide-1 Secretion.

This study was aimed to investigate the therapeutic potentials of plant-based bioactive compounds; lutein and resveratrol alone and/or in combination with DPP-4 enzyme inhibitor; sitagliptin on the secretion and bioavailability of Glucagon like peptide-1(GLP). For this, experimental rats were divided into seven groups. Group 1 was marked as control, while other six groups received streptozotocin (60 mg/kg I.P.). Later, group 2 was kept disease-control. While group 3 received 10 mg/kg/day sitagliptin (DDP-4i). Group 4 received 40 mg/kg/day lutein (LUT) and group 5 received 30 mg/kg/day resveratrol (RES). While group 6 and 7 were received combination of DPP-4i+LUT and DPP-4i+RES, respectively. Combined administration of DPP-4i+LUT or DPP-4i+RES showed expected therapeutic effects by lowering the fasting blood glucose and maintaining the serum insulin concentrations with improved glucose sensitivity and reduced insulin resistance. Further, co-administration of LUT and RES with DPP-4i revealed beneficial effects on measures of insulin resistance, circulating lipids, glycemic index, oxidative stress, and inflammatory status along with restoration of histological morphology of pancreatic cells and enterocytes that seemed to improve the level of GLP-1. Hence, substantial verdicts of this study showing therapeutic potentials of LUT and RES would surely help to recognize the potential effects in combination with DPP-4i as stimulators of GLP-1 secretion.

GLP-1 mediates the neuroprotective action of crocin against cigarette smoking-induced cognitive disorders via suppressing HMGB1-RAGE/TLR4-NF-κB pathway

Cigarette smoking (CS) has been associated with an increased risk of cognitive disorders. Although HMGB1 has been connected to various neurological ailments, its role in the pathogenesis of CS-induced cognitive impairments is undefined. With the ability of GLP-1 to lower HMGB1 expression and improve learning and memory performance, we sought to assess the potential neuroprotective efficacy of Crocin (Cro) as a GLP-1 stimulator against CS-induced cognitive impairments, with a focus on the HMGB1-RAGE/TLR4-NF-κB pathway. Fifty adult rats were specified into: Control; Cro (30 mg/kg); CS; Cro then CS and CS concurrently with Cro. Cognitive functions were assessed by MWM, EMP, and passive avoidance tests. Hippocampal levels of GLP-1, HMGB1, pro-inflammatory cytokines, and apoptotic markers were detected using ELISA, western blotting, and immunohistochemistry. Hippocampal oxidant/antioxidant status was evaluated via colorimetric determination of MDA and TAC. The results revealed that Cro either before or along with CS produced a significant improvement in learning and memory. Cro markedly hindered HMGB1-RAGE/TLR4-NF-κB pathway through enhancing GLP-1 level and expression, which in turn suppressed TNF-α and IL-1β levels and alleviated CS-induced neuroinflammation. Cro significantly counteracted CS-triggered oxidative stress as evidenced by reducing MDA level and raising TAC. Histopathologically, Cro lessened neuronal apoptosis by lowering Bax/Bcl-2 ratio at hippocampal CA2 region. These findings confirmed a GLP-1-dependent neuroprotective action of Cro against CS-induced cognitive disorders via suppressing HMGB1-RAGE/TLR4-NF-κB axis.

Anti-diabetic effect of banana peel dietary fibers on type 2 diabetic mellitus mice induced by streptozotocin and high-sugar and high-fat diet.

We used a high-fat diet (HFD) and streptozotocin (STZ) to induce type 2 diabetic mellitus (T2DM) mice and evaluated the effect of banana peel dietary fibers (BP-DFs) as potential hypoglycemic agents. After 5 weeks of intervention with banana peel dietary fibers (BP-DFs), food intake was reduced, body weight was increased, blood lipids and glucose were reduced, fasting insulin and GLP-1 levels were increased, and liver and pancreatic tissue damage was reduced. Banana peel soluble dietary fiber (BP-SDF) has the most significant effect. The results of fecal microbiota analysis showed that BP-DFs could ameliorates gut microbiome dysbiosis, and all three types of dietary fibers have obvious effects. The results of fecal short-chain fatty acids (SCFAs) showed that the content of fecal SCFAs was increased after BP-DFs dietary intervention, and BP-SDF had the most obvious effect. RT-PCR experiment results show that BP-DFs can up-regulate the mRNA expression levels of PI3K, AKT, IRS-1, and FOXO1 in the liver of diabetic mice, which indicates that BD-DFs may play a role in improving insulin resistance and insulin signal transduction via the IRS/PI3K/AKT pathway, improving insulin resistance and insulin signal transduction. Our research may be extended to BP-DFs, especially BP-SDF, as the basis for potential dietary intervention to prevent or treat type 2 diabetic mellitus. This work supports future research studies of the anti-diabetic properties of BP-SDF in humans. PRACTICAL APPLICATIONS: Diabetes can lead to a variety of complications that have a huge impact on health. Dietary fiber may help in lowering blood sugar. Our experimental results showed that banana peel dietary fibers have the effect of reducing food intake, blood sugar, improving liver and pancreas function, increasing the abundance of intestinal flora, and improving the IRS/PI3K/AKT pathway in T2DM mice. Therefore, this study could provide a theoretical basis for the development of functional foods with banana peel dietary fiber.

Association of GLP1R Polymorphisms With the Incretin Response.

Polymorphisms in the gene encoding the glucagon-like peptide-1 receptor (GLP1R) are associated with type 2 diabetes but their effects on incretin levels remain unclear. We evaluated the physiologic and hormonal effects of GLP1R genotypes before and after interventions that influence glucose physiology. Pharmacogenetic study conducted at 3 academic centers in Boston, Massachusetts. A total of 868 antidiabetic drug-naïve participants with type 2 diabetes or at risk for developing diabetes. We analyzed 5 variants within GLP1R (rs761387, rs10305423, rs10305441, rs742762, and rs10305492) and recorded biochemical data during a 5-mg glipizide challenge and a 75-g oral glucose tolerance test (OGTT) following 4 doses of metformin 500 mg over 2 days. We used an additive mixed-effects model to evaluate the association of these variants with glucose, insulin, and incretin levels over multiple timepoints during the OGTT. During the OGTT, the G-risk allele at rs761387 was associated with higher total GLP-1 (2.61 pmol/L; 95% CI, 1.0.72-4.50), active GLP-1 (2.61 pmol/L; 95% CI, 0.04-5.18), and a trend toward higher glucose (3.63; 95% CI, -0.16 to 7.42 mg/dL) per allele but was not associated with insulin. During the glipizide challenge, the G allele was associated with higher insulin levels per allele (2.01 IU/mL; 95% CI, 0.26-3.76). The other variants were not associated with any of the outcomes tested. GLP1R variation is associated with differences in GLP-1 levels following an OGTT load despite no differences in insulin levels, highlighting altered incretin signaling as a potential mechanism by which GLP1R variation affects T2D risk.

Association between CLOCK 3111 T/C polymorphism with ghrelin, GLP-1, food timing, sleep and chronotype in overweight and obese Iranian adults

BackgroundCircadian Locomotor Output Cycles Kaput (CLOCK), an essential element of the positive regulatory arm in the human biological clock, is involved in metabolic regulation. The aim was to investigate the behavioral (sleep duration, food timing, dietary intake, appetite and chronobiologic characteristics) and hormonal (plasma ghrelin and Glucagon-like peptide-1 concentrations) factors that could explain the previously reported association between the CLOCK 3111 T/C SNP and obesity.MethodsThis cross-sectional study included 403 subjects, overweight and/or obesity, aged 20- 50 years from Iran. The CLOCK rs1801260 data were measured by the PCR–RFLP method. Dietary intake, food timing, sleep duration, appetite and Chrono-type were assessed using validated questionnaires. Ghrelin and GLP-1 were measured by ELIZA in plasma samples. Participants were also divided into three groups based on BMI. Logistic regression models and general linear regression models were used to assess the association between CLOCK genotype and study parameters. Univariate linear regression models were used to assess the interaction between CLOCK and VAS, Food timing, chronotype and sleep on food intakes.ResultsAfter controlling for confounding factors, there was a significant difference between genotypes for physical activity (P = 0.001), waist circumference (P˂0.05), BMI (˂0.01), weight (P = 0.001), GLP-1 (P = 0.02), ghrelin (P = 0.04), appetite (P˂0.001), chronotype (P˂0.001), sleep (P˂0.001), food timing (P˂0.001), energy (P˂0.05), carbohydrate (P˂0.05) and fat intake (P˂0.001). Our findings also show that people with the minor allele C who ate lunch after 3 PM and breakfast after 9 AM are more prone to obesity (P˂0.05). furthermore, there was significant interactions between C allele carrier group and high appetite on fat intake (Pinteraction = 0.041), eat lunch after 3 PM on energy intake (Pinteraction = 0.039) and morning type on fat intake (Pinteraction = 0.021).ConclusionSleep reduction, changes in ghrelin and GLP-1 levels, changes in eating behaviors and evening preference that characterized CLOCK 3111C can all contribute to obesity. Furthermore, the data demonstrate a clear relationship between the timing of food intake and obesity. Our results support the hypothesis that the influence of the CLOCK gene may extend to a wide range of variables related to human behaviors.

277-OR: Increased Liver Fat Is Associated with Severe Metabolic Perturbations in Men Born with a Low Birth Weight

Background: Ectopic fat deposition resulting from impaired subcutaneous adipose tissue expandability may take center stage in the pathophysiological events linking low birth weight (LBW) with increased risk of developing Type 2 diabetes (T2D) . However, the extent to which adult LBW subjects exhibit increased hepatic fat accumulation is controversial. Methods and Results: Using 1H MR spectroscopy, we found a significantly increased hepatic fat content (P=0.014) in 26 early middle-aged and non-obese LBW males compared with 21 BMI- and age-matched normal birth weight (NBW) controls. Interestingly, 5 LBW (20%) versus no NBW subjects, had previously unrecognized overt nonalcoholic fatty liver disease (NAFLD) with a median hepatic fat content of 9.45%. The LBW w/NAFLD displayed widespread metabolic changes compared with both NBW and LBW w/o NAFLD subjects including hepatic insulin resistance (P=0.02) , increased fasting plasma triglycerides (TGs) (P=0.03) , cholesterol (P=0.05) , leptin, C-peptide and GLP-1 levels, as well as decreased adiponectin levels (P-range: 0.02-0.007) . Among 65 distinct metabolites and 279 lipids identified by untargeted serum metabolomic and lipidomic analyses, the levels of 7 metabolites including ornithine and citrulline, were different (P&amp;lt;0.05) between LBW w/NAFLD and NBW subjects, pointing towards increased urea cycling in the LBW w/NAFLD subjects. Moreover, the LBW w/NAFLD subjects displayed disproportionately increased levels of phosphatidylcholines and TGs (P&amp;lt;0.05) , with both lipid species qualitatively changed in the LBW w/NAFLD subjects consisting of an increased amount of long chain fatty acids as well as fewer double bonds. These structural lipid characteristics are known to be associated with T2D. Conclusion: The data support a role for ectopic fat deposition in the pathophysiological events and trajectories linking LBW with increased risk of developing T2D and associated cardiometabolic traits including dyslipidemia. Disclosure L.Elingaard-larsen: None. T.Hansen: None. C.Brøns: Stock/Shareholder; Novo Nordisk. A.A.Vaag: Stock/Shareholder; AstraZeneca. L.Justesen: None. S.O.Villumsen: None. A.B.Thuesen: None. J.Størling: None. L.M.Sparks: None. M.Kim: None. C.Legido-quigley: None. E.R.Danielsen: None. Funding Novo Nordisk Foundation (NNF15OC0016692) , Aase and Ejnar Danielsens Fond, Augustinus Foundation, Simon Spies Fonden, TrygFonden.

58-LB: Antidiabetic Effects of Pediococcus acidilactici pA1c on HFD-Induced Mice

Prediabetes (PreD) , which is associated with impaired glucose tolerance and fasting blood glucose, is a potential risk factor for type 2 diabetes mellitus (T2D) . Growing evidence suggests the role of the gastrointestinal microbiota in both PreD and T2D, which opens the possibility for a novel nutritional approach, based on probiotics, for improving glucose regulation and delaying disease progression of PreD to T2D. In this light, the present study aimed to assess the antidiabetic properties of Pediococcus acidilactici pA1c (pA1c) in a murine model of high-fat diet (HFD) -induced T2D. For that purpose, C57BL/6 mice were given HFD enriched with either probiotic (1×10E10 CFU/day) or placebo for 12 weeks. We determined body weight, fasting blood glucose, glucose tolerance, HOMA-IR and HOMA-β index, C-peptide, GLP-1, leptin, and lipid profile. We also measured hepatic gene expression (G6P, PEPCK, GCK, IL-1β, and IL-6) and ex-amined pancreatic and intestinal histology (% of GLP-1+ cells, % of goblet cells and villus length) . We found that pA1c supplementation significantly attenuated body weight gain, mitigated glucose dysregulation by reducing fasting blood glucose levels, glucose tolerance test, leptin levels, and insulin resistance, increased C-peptide and GLP-1 levels, enhanced pancreatic function, and improved intestinal histology. These findings indicate that pA1c improved HFD-induced T2D derived insulin resistance and intestinal histology, as well as protected from body weight increase. Together, our study proposes that pA1c may be a promising new dietary management strategy to improve metabolic disorders in PreD and T2D. Disclosure M. Cabello: None. M. Oneca: Employee; GENBIOMA APLICACIONES SL. M. J. Pajares: None. J. Ayo: Board Member; Genbioma Aplicaciones S. L., Employee; Genbioma Aplicaciones S. L. I. J. Encío: Other Relationship; Genbioma Aplicaciones SL. M. Araña: None. M. Barajas: None. Funding Government of Navarre (Ref 0011-1365-2020-000290) and the European Regional Development Fund (ERDF) . Maria Oneca is supported by Torres-Quevedo grants from the Spanish Ministry of Science and innovation (Ayudas para contratos Torres Quevedo PTQ2019-010384/AEI/10.13039/501100011033)

1363-P: Remission of Type 2 Diabetes and Improvement in Incretins, Cardiovascular Risk Factors, and Weight Loss with a High-Protein Diet

The incretins GLP-1 and GIP have important roles in insulin sensitivity and have been shown to be effective in pharmacological treatment of type 2 diabetes (T2D) . Therefore, we studied these incretin level changes with remission of T2D and weight loss using a high protein (HP) diet in 12 obese women and men with T2D. Our studies have shown that subjects with T2D on a 6 month HP diet (30%protein,30%fat, 40%CHO) had 100% remission of T2D compared to only 33% on a HC diet (15%protein,30%fat, 55%CHO) . Effects of HP and HC diets on ghrelin levels were determined since HP subjects had increased satiety compared to HC diet. GLP-1, GIP, and Ghrelin levels were determined with a Meal Tolerance Test (MTT) at baseline and after 6 mo on HP and HC diets where all food was provided. Since cardiovascular risk factors (CVRF) decreased more in the HP than the HC diet, we determined if the B-Type Natriuretic Peptide (BNP) released from the heart was affected by either diet. As shown in Table, HP diet had a greater increase in GLP-1 and GIP than the HC diet. BNP decrease demonstrates improvement in heart tissue with the HP diet having a greater effect than the HC diet. Weight loss was similar (9.8% in HP vs. 11.3% in HC, p=0.692) . this study demonstrates that the HP diet increases GLP-1 and GIP which may be responsible in part for the improved insulin sensitivity and decreased BNP with greater improvement in CVRF with remission of T2D Disclosure F.B.Stentz: None. A.Ammons: None. J.V.Christman: None. Funding AD Baskin Research Grant

Maintenance of plasma glucose variability after an acute session of aerobic exercise despite changes in insulin and glucagon-like peptide-1 levels in type 2 diabetes.

The present study aimed to evaluate glucose variability and hormonal responses during and after an aerobic exercise session performed after breakfast in type 2 diabetes patients treated with metformin. In this quasi-experimental study individuals underwent clinical and laboratory evaluations and maximal exercise test. After two weeks an aerobic exercise session (30 minutes at 60%-70% of the peak heart rate) was performed. At rest, during and after the exercise session, glucose variability (mean amplitude glucose excursions, glucose coefficient of variation, and glucose standard deviation) and levels of plasma glucose, insulin, glucagon, and glucagon-like-peptide-1 were evaluated. Thirteen patients were enrolled in the study. Plasma glucose increased at 15 minutes during the exercise session (244.6 ± 61.9 mg/dL), and decreased at 60 min after exercise (195.6 ± 50.0 mg/dL). Glucose variability did not show any difference before and after exercise. Insulin levels at 15 min [27.1 μU/mL (14.2-42.1)] and 30 min [26.3 μU/mL (14.6-37.4)] during the exercise were higher than those at fasting [11.2 μU/mL (6.7-14.9)] but decreased 60 minutes after exercise (90 minutes) [16.6 μU/mL (8.7-31.7)]. Glucagon levels did not show any difference. GLP-1 levels increased at 30 min [7.9 pmol/L (7.1-9.2)] during exercise and decreased 60 min after exercise (90 minutes) [7.7 pmol/L (6.8-8.5)]. Subjects with type 2 diabetes presented expected changes in insulin, glucagon and GLP-1 levels after breakfast and a single aerobic exercise session, not accompanied by glycemic variability changes.

The Sensory Mechanisms of Nutrient-Induced GLP-1 Secretion.

The enteroendocrine system of the gut regulates energy homeostasis through the release of hormones. Of the gut-derived hormones, GLP-1 is particularly interesting, as analogs of the hormone have proven to be highly effective for the treatment of type 2 diabetes mellitus and obesity. Observations on increased levels of GLP-1 following gastric bypass surgery have enhanced the interest in endogenous hormone secretion and highlighted the potential of endogenous secretion in therapy. The macronutrients and their digestive products stimulate the secretion of GLP-1 through various mechanisms that we have only begun to understand. From findings obtained from different experimental models, we now have strong indications for a role for both Sodium-Glucose Transporter 1 (SGLT1) and the K+ATP channel in carbohydrate-induced GLP-1 secretion. For fat, the free fatty acid receptor FFA1 and the G-protein-coupled receptor GPR119 have been linked to GLP-1 secretion. For proteins, Peptide Transporter 1 (Pept1) and the Calcium-Sensing Receptor (CaSR) are thought to mediate the secretion. However, attempts at clinical application of these mechanisms have been unsuccessful, and more work is needed before we fully understand the mechanisms of nutrient-induced GLP-1 secretion.

The alpha-7 nicotinic acetylcholine receptor agonist GTS-21 engages the glucagon-like peptide-1 incretin hormone axis to lower levels of blood glucose in db/db mice.

To establish if alpha-7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 exerts a blood glucose-lowering action in db/db mice, and to test if this action requires coordinate α7nAChR and GLP-1 receptor (GLP-1R) stimulation by GTS-21 and endogenous GLP-1, respectively. Blood glucose levels were measured during an oral glucose tolerance test (OGTT) using db/db mice administered intraperitoneal GTS-21. Plasma GLP-1, peptide tyrosine tyrosine 1-36(PYY1-36), glucose-dependent insulinotropic peptide (GIP), glucagon, and insulin levels were measured by ELISA. A GLP-1R-mediated action of GTS-21 that is secondary to α7nAChR stimulation was evaluated using α7nAChR and GLP-1R knockout (KO) mice, or by co-administration of GTS-21 with the dipeptidyl peptidase-4 inhibitor, sitagliptin, or the GLP-1R antagonist, exendin (9-39). Insulin sensitivity was assessed in an insulin tolerance test. Single or multiple dose GTS-21 (0.5-8.0mg/kg) acted in a dose-dependent manner to lower levels of blood glucose in the OGTT using 10-14 week-old male and female db/db mice. This action of GTS-21 was reproduced by the α7nAChR agonist, PNU-282987, was enhanced by sitagliptin, was counteracted by exendin (9-39), and was absent in α7nAChR and GLP-1R KO mice. Plasma GLP-1, PYY1-36, GIP, glucagon, and insulin levels increased in response to GTS-21, but insulin sensitivity, body weight, and food intake were unchanged. α7nAChR agonists improve oral glucose tolerance in db/db mice. This action is contingent to coordinate α7nAChR and GLP-1R stimulation. Thus α7nAChR agonists administered in combination with sitagliptin might serve as a new treatment for type 2 diabetes.