Diabetes Academy Research Articles

126-OR: Fat Catch-Up Growth in Early Infancy and Cardiometabolic Outcomes at 5 Years of Age

Introduction: The role of infant fat growth in childhood obesity and adult type 2 diabetes is not clear. We have previously used latent class analysis (LCA) to identify four distinct fat mass (FM) growth patterns in early infancy. Here we examine their associations with adiposity and cardiometabolic outcomes at 5 years (y) of age. Methods: Air Displacement Plethysmography (ADP) was used to repeatedly measure FM from 0-6 months of age in a cohort of 314 healthy urban-living Ethiopian infants and LCA was used to identify FM growth patterns (catch-up, accelerated, average and delayed) (Figure 1). At 5y of age, cardiometabolic outcomes were obtained from ADP and blood samples. Multiple linear regression was used to examine associations between infant FM growth patterns and cardiometabolic outcomes at 5y, adjusted for gender, birthweight, breastfeeding, maternal age and education and SES. Results: Overall mean (SD) BMI at 5y was 14.98 (1.19) kg/m2. Compared to children with an “average fat” growth pattern, children with a "catch-up fat" pattern had significantly higher BMI (0.79 kg/m2 [95% CI, 0.04; 1.54]) and FMI (0.69 kg/m2 [95% CI, 0.06; 1.37]), but not FFMI (0.05 kg/m2 [-0.51; 0.62]) at 5y of age (Figure 1). There were no differences in any other cardiometabolic outcomes. Conclusions: Fat catch-up growth in early infancy was associated with a higher BMI in childhood, which was almost entirely fueled by increased adipose tissue. Disclosure G.S. Andersen: Stock/Shareholder; Self; Novo Nordisk Inc. R. Wibaek: None. B. Admassu: None. D. Vistisen: Stock/Shareholder; Self; Novo Nordisk A/S. M.E. Jørgensen: Research Support; Self; Amgen Inc., AstraZeneca, Danish Diabetes Association, Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S. K.F. Michaelsen: None. J.C. Wells: None. H. Friis: Research Support; Self; Arla Food for Health. Funding Danish Council for Strategic Research; Danida (104.Dan.8-1207); Danish Diabetes Academy; Innovation Fund, Denmark

1971-P: SGLT1-Mediated Glucose Absorption Is Important for Incretin Hormone Secretion after Gastric Bypass Surgery

Postprandial GLP-1 secretion is greatly enhanced after Roux-en-Y gastric bypass (RYGB) and seems important for the reduced food intake and improved insulin secretion postoperatively. Understanding the mechanisms of gut hormone release after RYGB could aid the discovery of new drugs for the treatment of diabetes and obesity. Glucose is particularly potent for stimulating the release of GLP-1 as well as GIP compared with protein and fat in RYGB operated patients. It is unclear how glucose triggers gut hormone secretion in humans, but animal studies suggest a crucial role of sodium-glucose transporter 1 (SGLT1). Our aim was to investigate secretion of GLP-1 and GIP in response to an oral glucose load (50 g) on two separate days with or without acute pretreatment of 600 mg of the dual SGLT1/SGLT2 inhibitor canagliflozin (CANA) in 10 RYGB operated patients with no history of diabetes (age 47 ± 5 years, BMI 36 ± 7 kg/m2, HbA1c 35 ± 4 mmol/mol, time from surgery 6 ± 1 years, mean ± SD). CANA lowered peak glucose (11.8 vs. 8.4 mmol/l, p<0.01) and tended to decrease glucose concentrations during the 4-hour test period (AUC placebo: 1453, CANA: 1343 min mmol/l, p=0.08). CANA inhibited the early rise in GLP-1 secretion with a 28% reduction in peak concentration (p=0.03, 95% CI [-46%, -2.9%]), but a prolonged secretion was seen at later timepoints and overall GLP-1 secretion was comparable (AUC above basal 6067 vs. 7273 min pmol/l, p=0.23). GIP secretion was diminished by CANA (peak by 57%, p>0.01, and AUC above basal by 28%, p=0.01, respectively). In addition, CANA reduced the postprandial rise in lactate concentrations and pulse rate and caused marked glucosuria (0.2 vs. 11 g). SGLT1/2 inhibition by canagliflozin during glucose ingestion reduced glycemic excursions and diminished early release of GLP-1 and GIP in RYGB operated patients. The results support that glucose absorption via SGLT1 is important for incretin hormone secretion after gastric bypass. Disclosure C. Martinussen: None. S. Veedfald: None. K.N. Bojsen-Moller: None. C. Dirksen: None. M.S. Svane: None. V. Kristiansen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. S. Madsbad: None. Funding European Union Horizon 2020 Research and Innovation Program (695069-Bypass Without Surgery); Danish Diabetes Academy; Novo Nordisk Foundation (NNF15OC0017188); Research Foundation for Health Research of the Capital Region of Denmark; Hvidovre Hospital

Metformin increases endogenous glucose production in non-diabetic individuals and individuals with recent-onset type 2 diabetes.

Metformin is the endorsed first-line glucose-lowering drug for treating patients with type 2 diabetes but despite more than 50years of use, no consensus has been reached on its mechanisms of action. In this study, we investigated the glucose-lowering effects of metformin in individuals with type 2 diabetes and non-diabetic individuals. We performed a randomised, placebo-controlled trial in 24 individuals with recent-onset type 2 diabetes (diabetes duration 50 [48] months) who had good glycaemic control (HbA1c 48mmol/mmol [6.5%]). The studies were conducted at Aarhus University Hospital between 2013 and 2016. Participants were randomised to receive either metformin (2000mg/day, n = 12, MET group) or placebo (n = 12, PLA group) for 90days, using block randomisation set up by an unblinded pharmacist. Two participants withdrew from the study prior to completion and were replaced with two new participants receiving the same treatment. In addition, we recruited a group of non-diabetic individuals with similar age and BMI (n = 12, CONT group), who were all treated with 2000mg metformin daily. Before and after treatment all individuals underwent studies of whole-body glucose metabolism by non-steady-state [3-3H]glucose kinetics, hyperinsulinaemic-euglycaemic clamping, indirect calorimetry, metabolomics, dual x-ray absorptiometry and muscle biopsies. The primary study endpoint was the effect of metformin treatment on lipid kinetics as well as glucose rate of disappearance (Rd) and endogenous glucose production (EGP). One participant from the CONT group withdrew due to intolerable gastrointestinal side-effects and was excluded from analysis. As expected, metformin treatment lowered fasting plasma glucose (FPG) in the MET group (~1.5mmol/l, p < 0.01), whereas no effect was observed in the PLA and CONT groups. Body weight and composition did not change in any of the groups. In both of the metformin-treated groups (MET and CONT), basal glucose Rd, EGP and glucagon levels increased by ~30% (p < 0.05) whereas this was not the case in the PLA group. Ninety days of metformin treatment resulted in similar increases in EGP and glucose Rd in individuals with recent-onset type 2 diabetes and in non-diabetic control individuals. These results challenge the existing paradigm that metformin primarily acts in the liver by inhibiting EGP, at least in individuals with type 2 diabetes of short duration and who have discretely affected glycaemic status. Whether metformin increases basal glucose Rd by facilitating glucose uptake in other tissues such as the intestines remains to be further clarified. ClinicalTrials.gov NCT01729156 FUNDING: This study was supported by grants from The Danish Council for Independent Research | Medical Sciences, Aase Danielsen Fund, the Novo Nordisk Foundation, the Danish Diabetes Association and the Danish Diabetes Academy supported by the Novo Nordisk Foundation.

Parkin the progression of sarcopenia.

Parkin the progression of sarcopenia.

Preserved glucose response to low-dose glucagon after exercise in insulin-pump-treated individuals with type 1 diabetes: a randomised crossover study.

This study aimed to compare the increase in plasma glucose after a subcutaneous injection of 200μg glucagon given after 45min of cycling with resting (study 1) and to investigate the effects of glucagon when injected before compared with after 45min of cycling (study 2). We hypothesised that: (1) the glucose response to glucagon would be similar after cycling and resting; and (2) giving glucagon before the activity would prevent the exercise-induced fall in blood glucose during exercise and for 2h afterwards. Fourteen insulin-pump-treated individuals with type 1 diabetes completed three visits in a randomised, placebo-controlled, participant-blinded crossover study. They were allocated by sealed envelopes. Baseline values were (mean and range): HbA1c 54mmol/mol (43-65mmol/mol) or 7.1% (6.1-8.1%); age 45years (23-66years); BMI 26kg/m2 (21-30kg/m2); and diabetes duration 26years (8-51years). At each visit, participants consumed a standardised breakfast 2h prior to 45min of cycling or resting. A subcutaneous injection of 200μg glucagon was given before or after cycling or after resting. The glucose response to glucagon was compared after cycling vs resting (study 1) and before vs after cycling (study 2). The glucose response to glucagon was higher after cycling compared with after resting (mean ± SD incremental peak: 2.6 ± 1.7 vs 1.8 ± 2.0mmol/l, p = 0.02). As expected, plasma glucose decreased during cycling (-3.1 ± 2.8mmol/l) but less so when glucagon was given before cycling (-0.9 ± 2.8mmol/l, p = 0.002). The number of individuals reaching glucose values ≤3.9mmol/l was the same on the 3days. Moderate cycling for 45min did not impair the glucose response to glucagon compared with the glucose response after resting. The glucose fall during cycling was diminished by a pre-exercise injection of 200μg glucagon; however, no significant difference was seen in the number of events of hypoglycaemia. Clinicaltrials.gov NCT02882737 FUNDING: The study was funded by the Danish Diabetes Academy founded by Novo Nordisk foundation and by an unrestricted grant from Zealand Pharma.

Fifth ASPED/ISPAD Diabetes Academy Proceedings, 11th-13th April 2019, Muscat, Oman

The 5th ASPED-ISPAD Diabetes Academy is an initiative by the Arab Society of Pediatric Endocrinology (ASPED) in collaboration with International Society of Pediatric and Adolescence Diabetes (ISPAD) and is exclusively sponsored by Lilly, Gulf, and UAE. The 5th ASPED/ISPAD Diabetes academy was held on 11-13 April, 2019 in Muscat, Oman. The course was accredited with 12 CME hours, by the Omani Pediatric Society. It targets young healthcare professionals in the field of pediatric endocrinology and diabetes with a primary focus on actively supporting training and education in the region. An expert faculty panel from both ISPAD and ASPED from 11 different countries selected candidates following a competitive enrollment process, announced on each organizations respective websites. This year 67 candidates were accepted (out of 117 applicants) from 15 countries. The curriculum is delivered in three main formats; plenary, workshop and debate sessions. The plenary sessions covered novel therapeutic approaches, diabetes emergencies, use of technology in diabetes management, comprehensive diabetes care, dietary challenges, monogenic and rare types of diabetes, psychology and patient empowerment, obesity and type hyperlipidemia in children. In workshops, the focus was on research methodology, clinical cases, nutrition, psychology and technology within smaller groups, which provided a forum for candidates to present either a diabetes research project or unique presentation of a clinical case. Winners selected by the steering committee members presented in the final plenary session. This intensive 3 days course has consistently aimed and successfully provided a concrete educational platform for seamless exchange of clinical and scientific information. This has contributed to improvement of care and outcome for children and youth with diabetes in the ASPED region.

The Simultaneous Changes of Endogenous Glucose Production, Postprandial Glucagon, and Fasting Glutamine during Weight Loss in Type 2 Diabetes

In type 2 diabetes, high blood glucose levels are associated with increased glucagon levels and insufficient suppression of endogenous glucose production (EGP). Notably, glutamine, a gluconeogenic amino acid, is decreased compared to healthy individuals. We randomized 32 overweight patients with type 2 diabetes to either a Paleolithic diet (PD) or a Paleolithic diet combined with supervised exercise (PD-EX). Study duration was 12 weeks. Subjects conducted a solid mixed meal test: glucagon, insulin and glucose were measured at 0, 30, 60, 120 and 180 min with calculation of the total area under the curve for the response. On another study day, fasting glutamine was measured with GC-MS and suppression of EGP was examined with the hyperinsulinemic euglycemic clamp technique with [6,6-2H2]glucose as a tracer and with an insulin infusion of 40 mIU/m2/min. Median weight loss was 7 kg in both study groups. Fasting glucose and fasting insulin decrease significantly only in the PD-EX group. Postprandial glucose decreased by 13% in the PD group (P&amp;lt;0.05) and by 26% in the PD-EX group (P&amp;lt;0.01), without difference between groups. Fasting glucagon tended to decrease in both study groups. Postprandial glucagon decreased by 22% in the PD-group (P&amp;lt;0.01) and by 21% in the PD-EX group (P=0.13). Fasting glutamine increased non-significantly in both groups. Suppression of EGP increased by 26% in the PD group (P&amp;lt;0.05) and by 10% in the PD-EX group (P=0.75). During the intervention, the increased suppression of EGP was associated with a) reduction of postprandial glucagon levels (rS=-0.65, P&amp;lt;0.01), b) decreasing fasting glucagon (rS=-0.51, P&amp;lt;0.05) and c) the increasing fasting glutamine levels (rS=0.51, P&amp;lt;0.05). We conclude that glucagon, an activator of EGP, decreases in concert with improved suppression of EGP during weight loss in type 2 diabetes patients. An increase in plasma glutamine may be due to decreased gluconeogenesis. Disclosure J. Otten: None. A. Stomby: None. M. Waling: None. E. Chorell: None. M. Ryberg: None. M.B. Svensson: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Olsson: None.

Lean Subjects with Fatty Liver Show Decreased GLP-1 and GIP Response during OGTT

Subjects with nonalcoholic fatty liver disease (NAFLD) are at high risk of type 2 diabetes even if they are not obese and recent studies have indicated that liver fat (LF)&amp;gt;2.5% was already associated with alteration in glucose and insulin metabolism. Our aim was to investigate if having LF as low as 2.5% was associated to impairment in insulin sensitivity, secretion (ISR) and/or incretin hormones glucagon-like peptide (GLP) 1 and glucose-dependent insulinotropic peptide (GIP) released during an oral glucose tolerance test (OGTT). We studied 49 nondiabetic non-obese subjects (age 52±4; BMI 24.2±0.4 kg/m2). All subjects underwent a 2 h OGTT with plasma insulin, C-peptide, GLP-1, and GIP concentrations were measured every 15-30 min and ISR was quantitated by C-peptide deconvolution. Insulin sensitivity was quantified by HOMA and Matsuda index. Liver fat (LF) accumulation was quantified by magnetic resonance spectroscopy (MRS). In this group of non-obese subjects the great majority were non-NAFLD (31 had LF&amp;lt;2.5%), while 18 had NAFLD (9 had LF 2.5-5% and 9 had LF&amp;gt;5%). Age, BMI, HOMA (1.4±0.2 vs. 1.1±0.2), Matsuda index (7.3±0.7 vs. 10.6±1.3), fasting glucose (5.2±0.1 vs. 5.2±0.1 mmol/l), insulin (6.1±0.7 vs. 4.7±0.7 mU/l), ALT (20±1 vs. 19±1 U/l) and TG (96±22 vs. 88±6 mg/dl) were similar in NAFLD and non-NAFLD. Subjects with LF&amp;gt;2.5% had lower GLP-1 [GLP-1_AUC0-120 was 2.8±0.3 vs. 3.7±0.3, p=0.03], insulin secretion [ISR_AUC60-120 was 61±5 vs. 78±5 nmol, p=0.03] and insulin clearance [MCRI0-120 69±6 vs. 91±7 ml/kg/min, p=0.01] but not GIP [GIP_AUC0-120 was 4.6±0.3 vs. 5.3±0.3, p=ns] response compared to NAFLD; glucose and insulin concentrations during OGTT were similar [Glu0-120 6.7±0.3 vs. 7.3±0.3 mmol/l; Ins0-120 39.9±3.7 vs. 37.5±3.3 mU/l]. Conclusions: Liver fat accumulation (LF&amp;gt;2.5%) is associated with reduced GLP-1, ISR and MCRI; this can help to explain the increased risk of T2D of subjects with NAFLD. Disclosure A. Gastaldelli: Advisory Panel; Self; Gilead Sciences, Inc.. Other Relationship; Self; European Foundation for the Study of Diabetes. Consultant; Self; INVENTIVA SA. J. Garduno-Garcia: Speaker's Bureau; Self; Sanofi-Aventis, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., AstraZeneca. R.A. DeFronzo: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. N. Musi: None.

GLP-1 Secretion Is Increased upon Blockade of the Somatostatin Receptor Subtype 2 and 5 Resulting in GLP-1 Receptor-Mediated Lowering of Blood Glucose in Mice

Somatostatin (SS) is a hormone inhibiting the secretion of the incretin hormone, glucagon-like peptide-1 (GLP-1) by binding to 5 SS receptors (SSTr). However, which SSTrs involved is still unclear. We hypothesized that antagonizing the SSTrs on enteroendocrine L-cells may increase secretion of GLP-1 and via GLP-1 receptor mediated mechanism lead to lowering of blood glucose. To investigate the level of the SSTrs we did expression analysis on L-cells isolated from throughout the murine intestine (n=3). We perfused the proximal small intestine from mice (n=6-7) to investigate the impact of SSTr2 and 5 on GLP-1 secretion using intra-arterial administration of specific antagonists. Lastly we performed oral glucose tolerance tests (OGTT) on mice (n=5-8) after giving 1mg/ml SSTr2 or 5 antagonist with and without the GLP-1 receptor antagonist exendin(9-39) to investigate the role of these receptors on the glucose profile and to elucidate if their effect was mediated via GLP-1. The expression levels of the SSTrs showed that SSTr2 and especially 5 had the highest expression on L-cells throughout the intestine. The SSTr2 antagonist resulted in a increase in GLP-1 secretion from the perfused intestine (100nM, 4.96pM±0.56; 1µM, 14.55pM±1.4; 10µM, 16.46pM±1.18pM; all p&amp;lt;0.0001). The same doses of SSTr5 antagonist gave a more potent GLP-1 secretion in this setup (100nM, 5.82pM±0.7 p=0.0004; 1µM, 19.79pM±1.2 p&amp;lt;0.0001; 10µM, 48pM±2.6 p&amp;lt;0.0001). Both SSTr2 and SSTr5 antagonists significantly reduced the blood glucose during an OGTT compared to the control (p=0.00and p=0.0072 respectively). This reduction in blood glucose was significantly increased when adding exendin(9-39) together with either the SSTr2 or 5 antagonist (p&amp;lt;0.0001 for SSTr2, p=0.0036 for SSTr5). Our results demonstrate that inhibiting the SSTr2 and SSTr5 increases GLP-1 secretion which in turn may cause the lowering in blood glucose during an OGTT. Disclosure S.L. Jepsen: None. N.J. Wewer Albrechtsen: Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp.. Other Relationship; Self; Mercodia, Alpco. J. Pedersen: None. M.S. Engelstoft: None. C.F. Deacon: Other Relationship; Self; Merck &amp; Co., Inc., Eli Lilly and Company. Employee; Spouse/Partner; Merck Sharp &amp; Dohme Corp.. Stock/Shareholder; Spouse/Partner; Merck &amp; Co., Inc. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics.

Circulating Exosomal miRNA Signature in Gestational Diabetes Mellitus Influences Glucose Metabolism in Placental Cells

There is increasing evidence that miRNA, which are enriched in small nanovesicles called exosomes, are important regulators of gene expression. In this study, we tested the hypothesis that circulating exosomes from womem with gestational diabetes mellitus (GDM) carry a specific set of miRNAs which regulate genes associated with placental glucose metabolism. Exosomes were isolated from plasma obtained from normal glucose tolerant women (NGT; n=12) and women with GDM (n=12) pregnancies at delivery by differential and buoyant density centrifugation. Exosomal RNA was extracted and an Illumina TrueSeq Small RNA kit was used to construct a small RNA library. Gene target identification and gene ontology analysis for miRNAs was performed using the Ingenuity pathway analysis (IPA). The effect of exosomes on glucose metabolism in placental cells was assessed using a human glucose metabolism array. In plasma, a total of 44 miRNAs were upregulated in exosomes from women with GDM compared to NGT pregnant women (p&amp;lt;0.005). IPA showed that exosomal miRNAs isolated from women with GDM regulates the expression of placental genes associated with the glycolytic pathway including 6-phosphofructokinase and phosphopyruvate hydratase. Interestingly, exosomes from women with GDM increases the expression of placental genes associated with glycolysis and decrease the expression of genes associated with pentose phosphate pathway. After integration of the miRNA and mRNA data, we identified 74 differentially expressed exosomal miRNAs associated with the modulation of 10 potential target mRNAs in placental cells, which are associated with glucose metabolism. This data suggests that circulating exosomes under diabetic conditions might modulate the placental metabolic state to enhance glycogen metabolism in GDM. Disclosure S. Nair: None. V. Ormazabal: None. N. Jayabalan: None. D. Guanzon: None. A. Lai: None. H. McIntyre: Speaker's Bureau; Self; Novo Nordisk Inc.. Research Support; Self; Danish Diabetes Academy. M. Lappas: None. C. Salomon: None.

After Roux-en-Y Gastric Bypass, Enterohepatic Bile Circulation Is Altered and Bile Acid Retention Increased while Bile Acid Homeostasis Remains Normal after Sleeve Gastrectomy

Introduction: Elevated bile acid (BA) concentrations have been suggested to partly drive metabolic improvements after bariatric surgery but the mechanisms remain poorly understood. We assessed flow of bile and foods using scintigraphy after Roux-en-Y Gastric Bypass (RYGB) and Sleeve Gastrectomy (SG). Materials and Methods: 15 RYGB, 10 SG and 15 gender, age and BMI matched controls (C) underwent a combined cholescintigraphy and fatty test-meal with frequent blood sampling, for concomitant visualization of radiolabeled bile and food markers in the GI tract. BA retention was estimated 7 days after ingestion of a radiolabeled taurine-conjugated BA analogue (75Se-HCAT). Results: Prior to meal intake, gallbladder filling was lower (mean ± SEM: RYGB 23% ± 4, SG 39 ± 4, C 36 ± 5, RYGB vs. C p = 0.04) and more bile marker had passed passively into the small intestine in RYGB but not SG (RYGB 48% ± 6, SG 21 ± 5, C 20 ± 6, RYGB vs. C p &amp;lt; 0.01). Postprandial gallbladder emptying was complete in all groups. Gastric retention of foods was negligible in RYGB and lower in SG at 10 min after meal intake (RYGB 12% ± 2, SG 59 ± 7, C 90 ± 4, RYGB vs. C p &amp;lt; 0.01, SG vs. C p &amp;lt; 0.01) resulting in instant mixing of food with bile in RYGB and accelerated mixing in SG (RYGB 78% ± 3, SG 35 ± 8, C 8 ± 4, RYGB vs. C p &amp;lt; 0.01, SG vs. C p &amp;lt; 0.01). BA-retention over 7 days was only increased in RYGB (RYGB 54% ± 6, SG 34 ± 4, C 33 ± 5, RYGB vs. C: p = 0.02). Peak S-cholecystokinin (CCK) was comparably increased in RYGB and SG (RYGB 13 pmol/l ± 3, SG 15 ± 3, C 6 ± 1, RYGB vs. C p = 0.03, SG vs. C p = 0.01). Conclusion: After RYGB, enteric BA appearance is altered (more hepatic less gallbladder derived) and food is instantly mixed with bile due to negligible retention of foods in the gastric pouch. BA retention is increased. In contrast, BA appearance and retention remains normal after SG, although gastric emptying is accelerated. The metabolic impact of the changes in BA circulation after RYGB needs further evaluation. Disclosure A. Eiken: None. S. Fuglsang: None. M.L. Eiken: None. M.S. Svane: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. K.N. Bojsen-Moller: None. S. Madsbad: Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Eli Lilly and Company, Eli Lilly and Company. Advisory Panel; Self; Merck Sharp &amp; Dohme Corp., Sanofi-Aventis, Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. J.L. Madsen: None. C. Dirksen: None.

Individual and Combined Glucose-Lowering Effects of Glucagon Receptor Antagonism and Dipeptidyl Peptidase-4 Inhibition

Type 2 diabetes is characterized by absolute or relative hypoinsulinemia and hyperglucagonemia. Dipeptidyl peptidase 4 inhibitors (DPP-4i) augment insulin secretion and decrease glucagon secretion, but if glucagon is removed from the metabolic equation, the effect of DPP-4i is unknown. In a randomized, placebo-controlled, double-dummy, double-blinded, cross-over study, patients with type 2 diabetes (n=12, age [mean (SD)]: 60.9 (7.8) years, BMI 34.6 (7.1) kg/m2; HbA1c 50.3 (10.5) mmol/mol) underwent four 4-hour liquid mixed meal tests preceded by single-dose administration of 1) placebo, 2) DPP-4i (5 mg linagliptin) 2 hours before the meal, 3) glucagon receptor antagonist (GRA) (300 mg LY2409021) 12 hours before the meal, and 4) GRA + DPP-4i. Compared to placebo, fasting plasma glucose (FPG) was lowered by GRA but not DPP-4i. Adding DPP-4i to GRA did not lower FPG further. Compared to placebo, DPP-4i increased insulin responses to the meal (C-peptide AUC) (P&amp;lt;0.01), but did not result in a difference in plasma glucose excursions (Figure). GRA alone lowered glucose AUC, and the combination of GRA and DPP-4i lowered glucose AUC further. In conclusion, the combination of DPP-4i and GRA has additive effects on postprandial glucose excursions. This seems to be driven by the efficient reduction in FPG by GRA combined with additional reduction in postprandial glucose excursions by DPP-4i. Disclosure S. Haedersdal: None. A.B. Lund: Other Relationship; Self; Novo Nordisk A/S. E. Nielsen-Hannerup: None. H. Maagensen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.

The Role of Glucagon-Like Peptide-1 for the Postprandial Effects of Metformin in Type 2 Diabetes

Metformin is the most widely used plasma glucose-lowering drug for the treatment of type 2 diabetes. It has been shown that metformin increases plasma concentrations of glucagon-like peptide-1 (GLP-1), but it remains unknown whether metformin-induced GLP-1 secretion plays any role for the beneficial effects of metformin on postprandial glucose metabolism. We investigated the effect of metformin-induced GLP-1 secretion during meal ingestion in patients with type 2 diabetes using the GLP-1 receptor antagonist exendin[9-39]. In a double-blinded, double dummy, placebo-controlled, randomized, cross-over study, 15 participants with type 2 diabetes (medians: age 71 years, BMI 30.07 kg/m2, HbA1c 50 mmol/mol) were subjected to 14 days’ metformin and placebo treatment, respectively, in randomized order with at least a 2-week washout period between treatments. At the end of each treatment period, two randomized 4-hour mixed meal tests with either concomitant exendin[9-39] (450 pmol/kg/min) or saline infusion, were carried out. Metformin treatment significantly lowered fasting plasma glucose and postprandial plasma glucose excursions compared to placebo. We observed equal metformin-induced reductions in postprandial plasma glucose excursions during saline and exendin[9-39] infusions. Based on postprandial plasma glucose excursions, using the GLP-1 receptor antagonist exendin[9-39], we cannot confirm that GLP-1 secretion is involved in the beneficial postprandial glucose-lowering effects of metformin in patients with type 2 diabetes. Disclosure L.S. Hansen: None. L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. A. Brønden: None. N.B. Dalsgaard: None. E. Bahne: None. P.H. Sørensen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Consultant; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Research Support; Self; Eli Lilly and Company, Novo Nordisk A/S. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.

Acarbose and Pasireotide Reduce Hypoglycemia in Roux-en-Y Gastric Bypass Operated Subjects

Introduction: Hypoglycemia is a severe complication after Roux-en-Y gastric bypass (RYGB), with no effective treatment options. We investigated the glucose stabilizing effects of five therapeutic agents in RYGB operated subjects with hypoglycemia. Methods: In a randomized crossovers study, 11 RYGB operated subjects with documented hypoglycemia (blood glucose &amp;lt;70.2 mg/dL) underwent six separate meal tolerance tests (Fresubin Energy Drink) preceded by either: no treatment (NT), acarbose 50 mg (A), sitagliptin 100 mg for 1 week (S), verapamil 120 mg for 1 week (V), liraglutide 1.2 mg for 3 weeks (L) or pasireotide 300 µg (P). Blood samples were drawn at fixed time intervals from -20 to 180 minutes. Hormonal responses were calculated as the incremental area under the curve (iAUC), and the glucose response was further specified as the area above (+iAUC) and below (-iAUC) baseline values. Data were analyzed by use of linear mixed models. Results: Treatment with A and P significantly reduced -iAUCglucose (NT: 106±14 mmolxL-1xmin (mean±SEM) A: 63±14 mmolxL-1xmin, p=0.02; P: 0±0 mmolxL-1xmin, p&amp;lt;0.0001). Additionally A reduced +iAUCglucose, whereas P increased this area (NT: 182±18 mmolxL-1xmin; A: 78±18 mmolxL-1xmin, p=0.0008; P: 1,144±62 mmolxL-1xmin, p&amp;lt;0.0001). Time spent in hypoglycemia decreased with both A and P (NT: 48±12 min; A: 5±3 min, p=0.02; P: 0±0 min, p&amp;lt;0.0001), whereas time in hyperglycemia (&amp;gt;140.4 mg/dL) decreased with A but increased with P (NT: 29±4 min; A: 5±5 min, p=0.0017; P: 159±6 min, p&amp;lt;0.0001). Treatment with A and P both reduced iAUCinsulin (NT: 534±8 nmolxL-1xmin; A: 22±3 nmolxL-1xmin, p=0.0009; P: 14±2 nmolxL-1xmin, p&amp;lt;0.0001). Treatment with S, V and L did not have a significant impact on any of the measurements. Conclusion: Acarbose reduced both hypoglycemia and hyperglycemia, whereas pasireotide resolved hypoglycemia, but at the cost of increased hyperglycemia. Both acarbose and pasireotide can be considered in the treatment of hypoglycemia after RYGB. Disclosure C. øhrstrôm: None. U. Kielgast: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. D. Worm: None. D.L. Hansen: None.

The Impact of Restricted Gestational Weight Gain on Fetal Growth during Dietary Treatment in Women with Gestational Diabetes Mellitus

Aim: To investigate the impact of maternal gestational weight gain during dietary treatment (GWG-diet) on fetal growth in pregnancies complicated by gestational diabetes (GDM). Material and Methods: A retrospective cohort study of 382 consecutive women diagnosed with GDM &amp;lt;34 weeks and live singleton births in our center in 2011-2017. The women were stratified according to restricted (53%), appropriate (17%) and excessive (31%) weekly GWG-diet (Institute of Medicine guidelines) to estimate compliance to a calorie-restricted diabetes diet (1700 kcal daily). Insulin therapy was initiated according to local clinical guidelines. Results: Glucose tolerance, HbA1c, GWG before dietary treatment (GWG-before) and fetal abdominal circumference standard deviation (SD) score were comparable across the three GWG-diet groups at referral at 276±51 weeks. The women were followed for 100 ±51 weeks, 54% received insulin therapy and the average GWG-diet in the three groups was 0 kg, 3 kg and 5 kg, respectively. Women with excessive weekly GWG-diet, also had increasing HbA1c (p=0.014) during dietary treatment and infants with a birth weight SD-score of 0.59 ±1.6, while women with restricted weekly GWG-diet also had decreasing HbA1c (p=0.001) during dietary treatment, and infants with a birth weight SD-score of 0.15 ±1.1, without intrauterine growth restriction. Excessive GWG-diet and late pregnancy HbA1c were predictors of infant birth weight SD-score (p&amp;lt;0.001) after correction for parity, uptake area, pre-pregnancy BMI and insulin therapy. Conclusion: Restricted GWG-diet was associated with more appropriate fetal growth in women with GDM. GWG-diet and late pregnancy HbA1c were modifiable clinical predictors of infant birth weight SD-score. Disclosure L. Kurtzhals: None. S. Nørgaard: None. H. Ronneby: None. A.L. Secher: None. A. Tabor: None. H. McIntyre: Speaker's Bureau; Self; Novo Nordisk Inc.. Research Support; Self; Danish Diabetes Academy. P. Damm: Advisory Panel; Self; Novo Nordisk A/S. Other Relationship; Self; Novo Nordisk A/S. E.R. Mathiesen: Speaker's Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Novo Nordisk A/S, Novo Nordisk Foundation, Novo Nordisk A/S.

Effects of Simple Carbohydrates on GLP-1 Responses in Gastric Bypass Patients and Matched Controls

Exaggerated postprandial secretion of GLP-1 seems to contribute importantly to the metabolic effects of Roux-en-Y gastric bypass (RYGB). The surgery accelerates nutrient entry to the distal intestine, which is believed to augment GLP-1 secretion. In un-operated individuals, slowly digested carbohydrates are also absorbed in the distal intestine and may accordingly produce greater GLP-1 responses than rapidly absorbed ones. Our aim was to investigate GLP-1 secretion in response to isomolar (0.1385 mol) oral loads of glucose (glu) and fructose (fru), either given as separate monosaccharides (25 g glu and 25 g fru) or as disaccharides in the form of 47.5 g sucrose (suc) +/- alpha glucosidase inhibition (by acarbose (aca)) or 47.5 g isomaltulose (iso), which is slower digested than suc, on 4 separate days in 10 RYGB patients and 10 controls (CON) matched on BMI, age and sex. Glu/fru and suc induced similar glucose excursions and responses of C-peptide and GLP-1, the latter being 3-fold greater in RYGB compared to CON. Digestion of iso was slow in comparison with suc in both groups. Mean GLP-1 response (positive iAUC) to iso was ∼50% and ∼160% greater than to suc in RYGB (p=0.11) and CON (p=0.01), respectively. Aca effectively slowed suc digestion in both groups, resulting in lower peak concentrations of glucose (RYGB: 9.3 vs. 6.7 mmol/l, CON: 7.7 vs. 6.6 mmol/l) and C-peptide (RYGB: 2762 vs. 1341 pmol/l, CON: 2367 vs. 1520 pmol/l) compared with suc alone (p&amp;lt;0.01). Aca diminished mean suc stimulated GLP-1 secretion by ∼50% in RYGB (p&amp;lt;0.01), but this effect was absent in CON. The slowly absorbed disaccharide isomaltulose elicits a greater GLP-1 response than sucrose. The same effect is not evident when digestion of sucrose is inhibited by acarbose, which in RYGB diminishes sucrose induced GLP-1 secretion. Understanding the digestive processes involved in carbohydrate induced GLP-1 release after gastric bypass is an important step towards mimicking the effects of the surgery by pharmacological means. Disclosure C. Martinussen: None. K.N. Bojsen-Moller: None. C. Dirksen: None. M.S. Svane: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. S. Madsbad: Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Eli Lilly and Company, Eli Lilly and Company. Advisory Panel; Self; Merck Sharp &amp; Dohme Corp., Sanofi-Aventis, Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S.

Glucagon-Like Peptide-1 Is a Significant Determinant of the Second-Meal Effect in Patients with Type 2 Diabetes

Background and Aim: The mechanisms behind the second-meal effect, i.e., the capability of a small premeal to reduce plasma glucose excursions during a main meal in type 2 diabetes, remain unknown. We investigated the involvement of the gut-derived hormone glucagon-like peptide-1 (GLP1) in the second-meal effect in patients with type 2 diabetes. Methods: In a randomized, double-blinded, placebo-controlled, double-dummy, cross-over study, the second-meal effect was investigated in 15 male patients with metformin-treated type 2 diabetes over two days by administering a premeal (30 g of whey protein in 100 ml water) or a non-caloric flavor-controlled drink 30 minutes before a standardized liquid main meal. During both conditions, the second-meal effect was evaluated twice: with concomitant iv infusion of the GLP1 receptor antagonist exendin[9-39] and saline (placebo), respectively. Results: A second-meal effect was observed in 9 out of 15 participants, defined as responders, in whom the premeal significantly reduced postprandial glucose excursions during the main meal by 11% (assessed by area under the plasma glucose curve). The second-meal effect was completely abolished by iv infusion of exendin[9-39], during which the premeal resulted in a 5% exacerbation of postprandial glucose excursions. Significant GLP1-mediated second-meal effects on postprandial insulin (56%) and C-peptide responses (86%) were also observed. Conclusions: By antagonizing the GLP1 receptor, premeal-induced beta cell secretion is significantly reduced and the glucose-lowering effect of a premeal on a subsequent main meal, the second-meal effect, is annulled in patients with type 2 diabetes. This suggests that premeal-induced GLP1 secretion constitutes a significant determinant of the second-meal effect in type 2 diabetes patients. Disclosure S. Bergmann: None. N.C. Bergmann: Employee; Self; Zealand Pharma A/S. L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Consultant; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Research Support; Self; Eli Lilly and Company, Novo Nordisk A/S. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.

Extracellular Volume Expansion Uncovers a Natriuretic Action of Glucagon-Like Peptide-1

We have previously demonstrated that the gut hormone glucagon-like peptide-1 (GLP-1) does not affect renal hemodynamics or function at baseline conditions in healthy individuals and in patients with type 2 diabetes mellitus. However, it is possible that GLP-1 promotes renal NaCl excretion under conditions with addition of salt and water to the extracellular fluid (mimicking a mixed meal/daily NaCl load). The present study was designed to investigate whether GLP-1 induces natriuresis in healthy, volume overloaded individuals. Under fixed sodium intake, 8 healthy men were examined twice in random order during a 3-hour infusion of either GLP-1(1.5 pmol kg-1 min-1) or vehicle together with an intravenous infusion of 0.9% NaCl (750 ml/hour) given throughout both experiments. Timed urine collections were conducted throughout the experiments at voluntary voiding, and subjects remained supine during the experiments. Renal plasma flow (RPF), glomerular filtration rate (GFR), and uptake/release of hormones and ions were measured using Fick’s Principle after catheterization of a renal vein and an artery. During GLP-1 infusion, urinary sodium excretion increased compared to vehicle infusion (193 ± 40 mmol/180 min vs. 89 00B110 mmol/180 min, p&amp;lt;0.05), whereas GLP-1 had no significant effect on urine flow rate (1666 ± 284 ml/180 min vs. 1189 ± 132 ml/180 min, p=0.184). Plasma renin levels decreased similarly on both days, whereas angiotensin II levels decreased significantly only during GLP-1 infusion. During GLP-1 infusion, GLP-1 was extracted by the kidneys by about 50%. RPF and GFR remained unchanged on both days. Plasma proANP, ANP, and BNP levels remained unchanged on both days. This study shows that physiologically relevant changes in GLP-1 induce significant natriuresis independent of measurable changes in RPF and GFR in volume overloaded subjects. The natriuresis is likely brought about via a tubular mechanism secondary to suppression angiotensin II. Disclosure A. Asmar: None. P.K. Cramon: Employee; Spouse/Partner; Novo Nordisk A/S. L. Simonsen: None. M. Asmar: None. C.M. Sorensen: None. S. Madsbad: Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Eli Lilly and Company, Eli Lilly and Company. Advisory Panel; Self; Merck Sharp &amp; Dohme Corp., Sanofi-Aventis, Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. C. Moro: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. B.L. Jensen: None. J. Bülow: None.

Individual and Combined Glucose-Lowering Effects of Glucagon Receptor Antagonism and Sodium-Glucose Cotransporter 2 Inhibition

Studies suggest that sodium-glucose cotransporter 2 inhibitors (SGLT2i) induce hyperglucagonemia, which might counteract its glucose-lowering ability in type 2 diabetes. In a randomized, placebo-controlled, double-dummy, double-blinded, cross-over study, 12 middle-aged patients with type 2 diabetes (BMI [mean (SD)]: 30.3 (5.8) kg/m2; HbA1c: 50.3 (10.5) mmol/mol) underwent four 4-hour liquid mixed meal tests preceded by single-dose administration: 1) Placebo, 2) SGLT2i (25 mg empagliflozin), 3) glucagon receptor antagonist (GRA) (300 mg LY2409021), and 4) GRA + SGLT2i. The SGLT2i and GRA individually lowered fasting plasma glucose (FPG) compared to placebo and the combination further decreased FPG. SGLT2i reduced postprandial glucose excursions as assessed by baseline-subtracted area under curve (bsAUC) whereas GRA increased bsAUC compared to placebo (Figure). The paradoxical GRA-induced increment in bsAUC was annulled by a potent SGLT2i-induced reduction of bsAUC during the combination of SGLT2i and GRA (Figure). In conclusion, SGLT2i and GRA combined reduce FPG beyond their individual capacity in patients with type 2 diabetes, and in the context of GRA, SGLT2i’s beneficial effect on postprandial glucose excursions seems to be potentiated. Disclosure S. Haedersdal: None. A.B. Lund: Other Relationship; Self; Novo Nordisk A/S. H. Maagensen: None. E. Nielsen-Hannerup: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. T. Vilsbøll: None.

Postprandial Effects of Individual and Combined GIP and GLP-1 Receptor Antagonization in Healthy Subjects

The gut-derived incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are known for insulinotropic and glucose-lowering effects. However, their individual roles in postprandial glucose homeostasis are unknown. We infused the GIP receptor antagonist GIP(3-30)NH2 and the GLP-1 receptor antagonist exendin(9-39) during a meal to determine the roles of endogenous GIP and GLP-1 on postprandial glucose metabolism. On four separate days, 12 healthy men (age 19-65 years, BMI 20-25 kg/m2) received a liquid mixed meal test with randomized and double-blinded infusions of GIP(3-30)NH2 (800 pmol/kg/min) + Ex(9-39) (450 pmol/kg/min) (A), GIP(3-30)NH2 (B), Ex(9-39) (C), and saline (D). On Day A, B and C, glucose excursions were significantly increased by 85%, 55% and 15%, respectively, compared to D. Day A and B excursions were significantly higher than C (Figure). Glucagon levels at 60 min differed between Day A and B (11.5±1.2 vs. 7.5±0.6 pmol/l, P=0.01), and Day B and C (11.5±1.2 vs. 12.9±1.5 pmol/l, P=0.008). GLP-1 was higher on Day A (P=0.01) and C (P=0.02) than D. No significant effects on insulin, C-peptide, gastric emptying, or GIP were observed. We conclude that endogenous GIP affects postprandial plasma glucose excursions more pronouncedly than GLP-1, and that both hormones additively contribute to control postprandial glycemia in healthy subjects. Disclosure L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. M.M. Helsted: None. A.H. Sparre-Ulrich: Employee; Self; Antag Therapeutics ApS. A.R. Lanng: None. S. Stensen: None. M. Jakobsen: None. B. Hartmann: None. M.B. Christensen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Consultant; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Research Support; Self; Eli Lilly and Company, Novo Nordisk A/S. M.M. Rosenkilde: Other Relationship; Self; Antag Therapeutics. Advisory Panel; Spouse/Partner; Novo Nordisk A/S. Board Member; Spouse/Partner; Zealand Pharma A/S. Speaker's Bureau; Spouse/Partner; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Spouse/Partner; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Spouse/Partner; Antag Therapeutics. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.