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Lifestyle intervention (LI) can prevent type 2 diabetes, but response to LI varies depending on risk subphenotypes. We tested whether individuals with prediabetes with low risk (LR) benefit from conventional LI and individuals with high risk (HR) benefit from an intensification of LI in a multicenter randomized controlled intervention over 12 months with 2 years’ follow-up. A total of 1,105 individuals with prediabetes based on American Diabetes Association glucose criteria were stratified into an HR or LR phenotype based on previously described thresholds of insulin secretion, insulin sensitivity, and liver fat content. LR individuals were randomly assigned to conventional LI according to the Diabetes Prevention Program (DPP) protocol or control (1:1) and HR individuals to conventional or intensified LI with doubling of required exercise (1:1). A total of 908 (82%) participants completed the study. In HR individuals, the difference between conventional and intensified LI in postchallenge glucose change was −0.29 mmol/L [95% CI −0.54; −0.04], P = 0.025. Liver fat (−1.34 percentage points [95% CI −2.17; −0.50], P = 0.002) and cardiovascular risk (−1.82 percentage points [95% CI −3.13; −0.50], P = 0.007) underwent larger reductions with intensified than with conventional LI. During a follow-up of 3 years, intensified compared with conventional LI had a higher probability of normalizing glucose tolerance (P = 0.008). In conclusion, it is possible in HR individuals with prediabetes to improve glycemic and cardiometabolic outcomes by intensification of LI. Individualized, risk phenotype–based LI may be beneficial for the prevention of diabetes.

Background and Aims: People with different glucose response patterns during the 2-h oral glucose tolerance test (OGTT) have substantially different clinical characteristics and risk for long-term outcomes in the general population. We aimed to identify comparable glucose response patterns in pregnancy and their association with maternal and fetal outcomes. Materials and Methods: We used latent class trajectory modelling to identify glucose response patterns using 5-point 75g OGTT in 470 pregnant women at 27.3±2.2 weeks of gestation. We assessed these classes and investigated pregnancy outcomes in an independent cohort of 7073 pregnant women with 3-point OGTTs. Results: We identified five different glucose response patterns (classes) . Rate of gestational diabetes (GDM) was lowest in class 1 (< 7%) and highest in class 5 (100%) for both cohorts. Class 3 was characterized by transient hyperinsulinemia at 30 minutes but the prevalence of GDM was only 25-36%. Compared to class 1, women in class 3 had an increased gestational weight gain (GWG, β=0.85 SE: 0.31kg, p=0.0065, adjusted for age, gestational age, pre-gestational BMI, GDM treatment and AUCGlucose) . New-borns in class 3 had the highest risk of macrosomia (OR 1.47 95% CI: [1.12, 1.93] vs. class 1) after adjustment for maternal age, parity and smoking, but this was attenuated by additional adjustment for pre-pregnancy BMI and GWG. Conclusion: We found an easily identifiable group of pregnant women who have an increased risk of macrosomia without formally meeting GDM diagnosis. These women would most likely benefit from a therapy (e.g. nutritional counselling) aiming at preventing excessive glucose excursions and GWG. Note: LF and AH contributed equally to this work. Disclosure L.Fritsche: None. R.Wagner: Advisory Panel; Akcea Therapeutics, Daiichi Sankyo, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. A.Hulman: None. K.Prystupa: None. M.Heni: Advisory Panel; Boehringer Ingelheim International GmbH, Research Support; Boehringer Ingelheim International GmbH, Sanofi, Speaker's Bureau; Amryt Pharma Plc, Boehringer Ingelheim International GmbH, Novo Nordisk. A.L.Birkenfeld: None. A.Peter: None. A.Fritsche: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. A.Kun: None. A.Tabak: Consultant; 77 Elektronika Kft., Boehringer Ingelheim International GmbH, Speaker's Bureau; 77 Elektronika Kft., AstraZeneca, Sanofi_aventis Zrt. Funding The PREG study is supported in part by a grant from the Federal Ministry of Education and Research (BMBF) (01GI0925) to the German Center for Diabetes Research (DZD)

Background: Recent data proposed a role of the citrate transporter INDY (I’m Not Dead Yet) in the development of obesity, insulin resistance and NAFLD suggesting its potential as a therapeutic target for metabolic-related disorders. The aim of our study is to determine if mammalian INDY (mINDY) inhibitors can be introduced as a new therapeutic option for NAFLD/NASH. Methods: Six-week-old C57Bl/6N mice were fed a western diet (WD) for 18 weeks to induce NASH. After 12 weeks of feeding, mice received mINDY inhibitor (PF-06649298, mINDYi; 100 mg/kg) or vehicle bid until end of week 18. During the treatment period, body weight and composition were monitored. ipGTT and FACS analysis of liver inflammatory cells were performed. Results: mINDYi-treated mice exhibited lower body weight, fat mass and higher lean mass compared to vehicle-treated mice. Results from ipGTT revealed improved glucose tolerance and insulin sensitivity. The latter was further confirmed through increased insulin-stimulated Akt phosphorylation in liver, gonadal WAT and BAT. Treatment with mINDYi attenuated WD-induced hepatic injury, steatosis and inflammation as shown histologically and biochemically by reduction in plasma ALT and AST, decrease in hepatic triglyceride accumulation and reduced hepatic lymphoid and myeloid immune cell populations. Interestingly, these effects were associated with a significant rise in plasma and hepatic Fgf21 together with increased hepatic phosphorylation of LKB1 and AMPK and decreased mTOR. Results from primary mouse hepatocytes revealed that mINDYi-induction of Fgf21 is partially dependent on AMPK activation. Conclusion: Our study shows for the first time that mINDYi attenuates diet-induced steatohepatitis; offering a promising novel treatment strategy for NAFLD. Further investigations are currently ongoing to elucidate the molecular mechanisms underlying mINDY inhibition and whether it is dependent on Fgf21-AMPK signaling. Disclosure N.El-agroudy: None. G.Zahn: Employee; Eternygen GmbH. C.Herrmann: None. G.Mingrone: Advisory Panel; Fractyl Health, Inc., Novo Nordisk, Consultant; ReCor Medical, Inc. T.C.Alves: None. A.L.Birkenfeld: None.

Objective: Fat accumulation in liver, pancreas, skeletal muscle, and visceral bed relates to type 2 diabetes (T2D) . However, distribution of fat in these compartments is heterogenous and it is unclear if specific distribution patterns indicate high T2D risk. We therefore investigated fat distribution patterns and their link to future T2D. Methods: From 2168 individuals without diabetes undergoing computed tomography in Japan, this case-cohort study included 658 randomly selected individuals and 146 incident cases of T2D with a 6-year follow-up. Data-driven analysis (k-means) was applied to develop clusters based on fat content in liver, pancreas, muscle, and visceral bed. Hazard ratios (HRs) for association of clusters and incident T2D were estimated using weighted Cox regression. In 3 individuals without diabetes with magnetic resonance imaging and metabolic phenotyping in Germany, cluster validation with additional assessment of glycemic traits from OGTTs was conducted. Results: We identified four clusters of fat distribution: cluster 1 (Hepatic steatosis cluster) , cluster 2 (Pancreatic steatosis cluster) , cluster 3 (Myosteatosis dominant cluster) , cluster 4 (Steatopenic cluster) . Compared with Steatopenic cluster, the adjusted-HRs (95%CIs) for incident T2D were 4.02 (2.27-7.12) in Hepatic steatosis cluster, 3.38 (1.65-6.91) in Pancreatic steatosis cluster, and 1.95 (1.07-3.54) in Myosteatosis dominant cluster. The clusters were replicated in the German cohort with similar distribution of AUC-glucose to the diabetes hazard in the Japanese cohort. Insulin sensitivity and insulin secretion were different across clusters with the lowest insulin sensitivity and highest insulin secretion in Hepatic steatosis cluster. Conclusions: Extending evidence about fat accumulation in single compartments, we identified specific patterns of fat distribution with different T2D risk presumably due to differences in insulin sensitivity and insulin secretion. Disclosure H.Yamazaki: None. N.Stefan: Advisory Panel; Gilead Sciences, Inc., GlaxoSmithKline plc., Sanofi, Consultant; AstraZeneca, Intercept Pharmaceuticals, Inc., Novo Nordisk, Pfizer Inc., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck Sharp & Dohme Corp. A.Fritsche: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. A.L.Birkenfeld: None. R.Wagner: Advisory Panel; Akcea Therapeutics, Daiichi Sankyo, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. M.Heni: Advisory Panel; Boehringer Ingelheim International GmbH, Research Support; Boehringer Ingelheim International GmbH, Sanofi, Speaker's Bureau; Amryt Pharma Plc, Boehringer Ingelheim International GmbH, Novo Nordisk. S.Tauchi: None. J.Machann: None. T.Haueise: None. Y.Yamamoto: None. M.Dohke: None. N.Hanawa: None. Y.Kodama: Other Relationship; Eisai Co., Ltd. A.Katanuma: None. Funding the German Center for Diabetes Research (DZD, 01GI0925) , the state of Baden-Württemberg (32-5400/58/2, Forum Gesundheitsstandort Baden-Württemberg) , and JSPS KAKENHI Grant Number 19K16978

Introduction: Finerenone reduced the risk of cardiovascular (CV) and kidney outcomes, without affecting HbA1c, in CKD and T2D patients in the FIDELITY prespecified pooled analysis of the FIDELIO-DKD and FIGARO-DKD studies. Here, we evaluate the effect of finerenone by baseline HbA1c, HbA1c variability, and diabetes duration. Methods: Patients with T2D and CKD (UACR ≥30-≤5000 mg/g and eGFR ≥25 mL/min/1.73 m2) were randomized to finerenone or placebo. Effects of finerenone vs. placebo on CV (CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and kidney (kidney failure, sustained ≥57% eGFR decline from baseline, or renal death) composite outcomes were analyzed by baseline HbA1c quartiles, HbA1c variability (first year of treatment) , and diabetes duration quartiles. Results: In 13,026 patients included in the analysis, mean baseline HbA1c was 7.7% and diabetes duration was 15.4 years. Higher baseline HbA1c quartiles had longer diabetes duration and more diabetes-related complications. Risk reductions in the CV and kidney composite outcomes with finerenone vs. placebo were consistent across HbA1c (p-interaction 0.52 and 0.09, respectively) and diabetes duration (p-interaction 0.12 and 0.75) quartiles. HbA1c variability in the first year of treatment was associated with higher cardiorenal risks; each 1 unit increase in mean absolute residual of HbA1c was associated with a 20% increased risk of a CV event (HR 1.20; 95% CI 1.07-1.35; p=0.0016) and a 36% increased risk of a kidney event (HR 1.36; 95% CI 1.21-1.52; p Conclusion: Greater variability in HbA1c was associated with increased risks of cardiorenal outcomes. Risk reductions in the CV and kidney outcomes with finerenone in patients with CKD and T2D were not modified by baseline HbA1c, HbA1c variability, or duration of diabetes. Disclosure J. B. Mcgill: Advisory Panel; Gilead Sciences, Inc., Lilly Diabetes, MannKind Corporation, Novo Nordisk A/S, Provention Bio, Inc., Salix Pharmaceuticals, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; Dexcom, Inc., Novo Nordisk. M. Brinker: Employee; Bayer AG. A. Joseph: Employee; Bayer AG. A. Z. Lage: None. R. Lawatscheck: None. C. Scott: Employee; Bayer AG. P. Rossing: Consultant; Astellas Pharma Inc., AstraZeneca, Bayer AG, Gilead Sciences, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Speaker’s Bureau; Eli Lilly and Company. R. Agarwal: Advisory Panel; Akebia Therapeutics, Inc., Bayer AG, Board Member; Chinook Therapeutics Inc., DiaMedica Therapeutics, Inc., Vertex Pharmaceuticals Incorporated, Consultant; Boehringer Ingelheim International GmbH, Reata Pharmaceuticals, Inc., Vifor Pharma Management Ltd. S. Anker: Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Novartis AG, Novo Nordisk, Vifor Pharma Management Ltd., Research Support; Abbott. G. Bakris: Consultant; Alnylam Pharmaceuticals, Inc., AstraZeneca, DiaMedica Therapeutics, Inc., Horizon Therapeutics plc, Ionis Pharmaceuticals, Merck & Co., Inc., Other Relationship; Novo Nordisk. G. Filippatos: Other Relationship; Amgen Inc., Amgen Inc., Bayer AG, Boehringer Ingelheim International GmbH, Medtronic, Novartis AG, Servier Laboratories, Vifor Pharma Management Ltd. B. Pitt: Advisory Panel; Merck & Co., Inc., Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Vifor Pharma Management Ltd. L. M. Ruilope: Consultant; Bayer AG. A. L. Birkenfeld: None. L. Caramori: Advisory Panel; Bayer AG, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Research Support; Bayer AG, Novartis AG.

Objective: The intrauterine environment is known to affect the offspring's long-term risk for obesity and diabetes. Previous data show that maternal metabolism and gestational weight gain (GWG) are associated with autonomic nervous system (ANS) function in fetuses in utero, which can be assessed with heart rate variability (HRV) . We have now examined whether this association is also present in 2-year-old children and addressed the impact of gestational diabetes (GDM) . Research Design and Methods: We examined children of participants of the ongoing PREG study (NCT04270578) who had a 5-point 75g oral glucose tolerance test during pregnancy. To assess HRV, a 10-minute ECG was recorded in the offspring. We analyzed time domain (beats per minute (BPM) , Root Mean Square of successive differences (RMSSD)) , Standard Deviation of RR-Intervals (SDNN) and frequency domain parameters (low frequency (LF) , high frequency (HF) and LF/HF) of HRV. Results: We examined 67 children (33 girls, 34 boys, age 25.3±1.6 months) . During pregnancy, 30 of their mothers had GDM, which was treated according to national guidelines. There were no differences between groups in birth weight, weight at age 2, and body fat. We observed statistically significant associations of GWG with heart rate, RMSSD, SDNN, HF power, and HF/LF, indicating a lower parasympathetic tone in children of mothers with low GWG. This association was attenuated in GDM-exposed children. ANS function correlated with body weight and body fat only in children from normoglycemic pregnancies (NGT) . Conclusion: We found an impact of maternal GWG on offspring ANS function, which was missing in the presence of treated GDM. The balance of the ANS was related to offspring body composition only in children from NGT pregnancies. Our results point towards a critical impact of maternal weight gain during pregnancy on the developing ANS with longstanding consequences for body composition. Disclosure L.Fritsche: None. H.Preissl: None. M.Heni: Advisory Panel; Boehringer Ingelheim International GmbH, Research Support; Boehringer Ingelheim International GmbH, Sanofi, Speaker's Bureau; Amryt Pharma Plc, Boehringer Ingelheim International GmbH, Novo Nordisk. J.Hartkopf: None. J.Hummel: None. D.Löffler: None. H.Häring: None. A.Peter: None. A.L.Birkenfeld: None. R.Wagner: Advisory Panel; Akcea Therapeutics, Daiichi Sankyo, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. A.Fritsche: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. Funding The PREG study is supported in part by a grant from the Federal Ministry of Education and Research (BMBF) (01GI0925) to the German Center for Diabetes Research (DZD) and by grant from the Deutsche Diabetes Stiftung (380/02/16) to LF

Introduction: Pancreatic fat accumulation is a potential pathogenic factor in type 2 diabetes. Evidence from hypocaloric diet indicates that reduction of pancreatic fat could contribute to an improvement in ß-cell function. There is no established pharmacological approach to reduce pancreatic steatosis. We now tested the ability of empagliflozin to reduce pancreatic fat content in overweight and obese persons with prediabetes. Methods: In this double-blind, placebo-controlled randomized trial (NCT03227484) , 40 participants were 1:1 randomized to receive 25 mg empagliflozin qd or placebo for 8 weeks. Pancreatic fat was quantified by magnetic resonance imaging (6-point Dixon technique) . Insulin sensitivity and insulin secretion was estimated from 75g oral glucose tolerance test. The study was adequately powered to detect effects on pancreatic fat previously reported from the DiRECT trial. Results: There was no significant change in pancreatic fat content in either treatment group (empagliflozin group -0.88 % ± 2.71 %, placebo group 0.22 % ± 3.02 % [mean±SD], both p≥0.2) and the course of pancreatic fat content was comparable between treatments (p=0.2) . Insulin secretion, as assessed by Disposition Index and AUC-C-peptide0-30/AUC-glucose0-30 (adjusted for insulin sensitivity) did not differ between treatments (p=0.3 and p=0.7, respectively) . Discussion: This randomized, controlled trial did not detect effects of empagliflozin on pancreatic fat content and insulin secretion in persons with prediabetes. This implicates that the beneficial effects of empagliflozin on liver fat and systemic glucose metabolism do not rely on alterations in pancreatic fat. Consequently, further options for pancreatic fat reduction need to be evaluated. Disclosure J.Hummel: None. M.Heni: Advisory Panel; Boehringer Ingelheim International GmbH, Research Support; Boehringer Ingelheim International GmbH, Sanofi, Speaker's Bureau; Amryt Pharma Plc, Boehringer Ingelheim International GmbH, Novo Nordisk. J.Machann: None. C.Dannecker: None. S.Kullmann: Other Relationship; Novo Nordisk. A.L.Birkenfeld: None. H.Häring: None. A.Peter: None. A.Fritsche: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. R.Wagner: Advisory Panel; Akcea Therapeutics, Daiichi Sankyo, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. Funding This study was supported by Boehringer Ingelheim through an Independent Research Grant. Boehringer Ingelheim had role in the study design, in the collection, analysis or interpretation of data, or in writing of this abstract.

Background: INDY (I’m Not Dead Yet) is a plasma membrane citrate transporter and is highly expressed in liver and brain. In mammals, whole body deletion of the coding gene (mIndy, Slc13a5) increased energy expenditure and protected mice from diet-induced obesity and insulin resistance. Generation of neuronal mIndy-KO (NINKO) mice revealed improved insulin sensitivity (IS) in these mice, mediated through better hepatic IS. Gene expression studies in wildtype C57Bl/6 mice revealed high expression of mIndy in the hypothalamus (HTM), which is the main brain area regulating hepatic glucose metabolism. One mechanisms is the regulation through AMPK. Reduced hypothalamic AMPK phosphorylation is known to reduce hepatic glucose output, probably mediated via vagal nerve signaling. Hypothesis: Hepatic glucose production is regulated via mIndy expression in the HTM. Methods: Hyperinsulinemic-euglycemic clamp studies were performed to assess IS after hepatic vagotomy of NINKO mice. NestinCre+ controls were sham-denervated. Ex vivo brain slices of C57Bl/6 mice and the neuronal hypothalamic cell line CLU183 were acutely stimulated with 1 mM sodium citrate to investigate the effect of citrate on the brain and neurons. Results: Acute stimulation of brain slices and CLU183 cells with citrate decreased cellular respiration (-19.7%, p≤0.01), ATP production (-37.7%, p≤0.01) and increased AMPK phosphorylation (+24.7%, p≤0.001). In line with that, AMPK phosphorylation in the HTM of NINKO mice was significantly reduced (-68.1%, p≤0.05). With hepatic branch vagotomy, no differences in hepatic IS could be observed anymore (suppression of basal hepatic glucose output (%); NestinCre+: 100.0±27.2, NINKO: 99.4±8.8). Conclusion: These data suggest that neuronal mIndy is a critical regulator of glucose homeostasis in mammals, probably regulated via AMPK phosphorylation in the HTM and vagal nerve signaling. Further studies will address the exact mechanisms involved in the effect. Disclosure A. Kurzbach: None. M. Schell: None. D.M. Willmes: None. N. El-Agroudy: None. A. Kleinridders: None. A.L. Birkenfeld: None.

Obesity is one of the main drivers of the globally rising prevalence of type 2 diabetes (T2D). Yet, obesity is not uniformly associated with metabolic consequences. The location of fat accumulation is critical for metabolic health. Specific patterns of body fat distribution, such as an increased ratio of visceral to subcutaneous fat, are closely related to insulin resistance which is crucial in the pathogenesis of T2D. There might be further, hitherto unknown features of body fat distribution which could additionally contribute to the disease. We used a machine learning approach with dense convolutional neural networks (DCNN) to detect diabetes related variables from 2371 T1-weighted whole-body magnetic resonance image (MRI) data sets. Each single measurement was labelled by sex, age, BMI, insulin sensitivity, HbA1c and prediabetes or incident diabetes. The result was compared to conventional models using segmented body fat compartment volumes. Anatomical labels were assigned to locations in the DCNN gradient heatmaps that are critical for discrimination. The AUC-ROC was 0.87 for the discrimination of diabetes and 0.68 for prediabetes. Classification performance was superior to conventional models. Mean absolute regression errors were comparable to those of the conventional models. Heatmaps clearly showed that lower visceral abdominal regions were most critical in diabetes classification, while other significant areas comprised upper legs, arms and the neck region.Our results show that diabetes is detectable from whole-body MRI without any blood glucose measurement. Our technique of heatmap visualization unravels plausible anatomical regions and highlights the leading role of fat accumulation in the lower abdomen in the pathogenesis of T2D. Disclosure R. Wagner: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Eli Lilly and Company. B. Dietz: None. J. Machann: None. P. Schwab: Employee; Self; Roche Pharma. J.K. Dienes: Advisory Panel; Spouse/Partner; Novo Nordisk A/S. Speaker’s Bureau; Spouse/Partner; Novo Nordisk A/S. Other Relationship; Spouse/Partner; Eli Lilly and Company. S. Reichert: Other Relationship; Self; Lilly Diabetes. A.L. Birkenfeld: None. H. Haering: None. F. Schick: None. N. Stefan: None. M. Heni: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S. H. Preissl: None. B. Schölkopf: None. S. Bauer: None. A. Fritsche: None. Funding German Federal Ministry of Education and Research (01GI0925)

Background and Aims: Incretins are crucial for an adequate insulin secretion in response to ingestions of nutrients. In patients with diabetes, prediabetes or a specific genetic background, this incretin effect is blunted. Data on incretin secretion and action during pregnancy are scarce. Here we investigated the incretin response during an oral glucose tolerance test (OGTT) in pregnant women with and without gestational diabetes. Methods: Pregnant women from the ongoing PREG study underwent 5-point OGTT with 75 g glucose. We measured plasma glucose, insulin and C-peptide at all time points and total GLP-1 at minute 0, 30 and 120. Indices of insulin secretion and GLP-1 increase were calculated from the difference at min 0 and 30. We used linear regression to analyze the relation of GLP-1 and glucose with insulin secretion. Results: We examined 163 women during gestational week 26.8 (±2.0 SD), GDM was present in 30 (18.4%) women. Insulin secretion was significantly lower in women with GDM (p=0.04, adjusted for BMI, age, week of gestation, insulin sensitivity). GLP-1 levels increased after glucose intake with a peak at 30 min. GLP-1 levels at minute 30 and AUCGLP-1 was significantly higher in women with GDM (by ∼20%, both p=0.03, adjusted for age, BMI and week of gestation). The GLP-1 increase was associated with insulin secretion only in GDM, but not in women with normal glucose tolerance. This association remained significant even after adjustment for increase of glucose and basal insulin levels (GDM group: p Conclusion: Women with GDM had lower insulin secretion despite increased GLP-1 levels during OGTT. The more pronounced GLP-1 increase in women with GDM could be part of a compensatory mechanism counteracting GLP-1 resistance. In addition to incretin resistance, this phenomenon suggests a dysfunction of glucose stimulated insulin secretion. Disclosure L. Fritsche: None. M. Heni: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S. S.S. Eckstein: None. M.J. Winzenried: None. J. Hummel: None. A.L. Birkenfeld: None. H. Preissl: None. H. Haering: None. A. Peter: None. A. Fritsche: None. R. Wagner: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Eli Lilly and Company. Funding German Federal Ministry of Education and Research (01GI0925)

Introduction: Type 2 diabetes is not only associated with insulin resistance but also with decreased insulin clearance. Insulin is mostly eliminated from portal blood during the first pass through the liver. The magnitude of this effect is closely related to systemic insulin sensitivity. As insulin resistance is often accompanied by fatty liver, we here investigated whether there is a causal link between liver fat and hepatic insulin clearance (IC). Methods: We computed IC using data from oral glucose tolerance tests in 3391 non diabetic individuals and the oral C-peptide and Insulin Minimal Models. Liver fat was quantified by 1H-MR-spectroscopy in 1211 participants. We performed Mendelian randomization analyses to test for causal determination of IC by liver fat and potentially related traits using established single nucleotide polymorphisms (liver fat: 115 SNPs, alanine-aminotransferase: 155 SNPs, insulin sensitivity: 37 SNPs, C-reactive protein: 193 SNPs). Results: IC associated inversely with liver fat content (β=-0.1±0.03, p Conclusion: This study supports the hypothesis that systemic effects such as inflammatory activity and/or genetic factors determining insulin resistance might modulate insulin extraction in the liver. Disclosure A. Lamprinou: None. J. Machann: None. F. Schick: None. S.S. Eckstein: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. R. Visentin: None. N. Stefan: None. A.L. Birkenfeld: None. A. Peter: None. H. Haering: None. A. Fritsche: None. M. Heni: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S. R. Wagner: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Eli Lilly and Company. Funding German Center of Diabetes Research (01GI0925)

Background and Aims: Postprandial thermogenesis is thought to be important for the control of metabolism. This process could be reflected by minute changes in body temperature after glucose load. In this study, we measured body temperature before and its change during a glucose challenge and investigated the relationships with anthropometric and glycemic traits. Methods: We prospectively studied 383 volunteers (251 females, 132 males) with a mean age of 46.6 (SD ± 16) years and a BMI of 27.9 kg/m2 (SD ± 5.9). All participants underwent a 75 g oral glucose tolerance test (OGTT) and repeated bilateral measurements of intra-auricular temperature at time points 0, 30 and 120 minutes during the OGTT using a tympanic thermometer (Covidien Genius 2). Results: Baseline temperature was 0.17°C lower in males compared to females (p = 0.001) and inversely associated with age (p < 0.0001). During the OGTT, there was a significant increase in body temperature (0.18 ± 0.34°C). This response was present in females and males. BMI was negatively associated with the increase of temperature during the OGTT (p = 0.0147). Participants with higher BMI displayed higher fasting temperatures, but less increase of temperature during the OGTT. Body temperature was not associated with glycemia, insulin sensitivity or insulin secretion, neither in females nor males. Conclusions: There is a robust increase in body temperature during a glucose load that can be captured by intra-auricular temperature measurements. We did not detect any associations of the body temperature with glucose metabolism, arguing against a major contribution of the variability of body temperature in the pathogenesis of diabetes. However, the rise in temperature in response to oral glucose is reduced in obesity and might therefore be involved in body weight regulation. Disclosure: A. Vosseler: None. L. Fritsche: None. J. Hummel: None. C. Dannecker: None. N. Stefan: None. A.L. Birkenfeld: None. H. Haering: None. A. Fritsche: None. R. Wagner: Advisory Panel;Self;Novo Nordisk A/S. Speaker's Bureau;Self;Novo Nordisk A/S. Other Relationship;Self;Eli Lilly and Company. M. Heni: Research Support;Self;Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau;Self;Novo Nordisk A/S. Funding: German Federal Ministry of Education and Research (01GI0925) [ABSTRACT FROM AUTHOR] Copyright of Diabetes is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Type 2 diabetes (T2D) associates with nonalcoholic fatty liver disease (NAFLD), which itself contributes to both insulin resistance and excessive cardiovascular risk of diabetes. Nevertheless, there is currently no established therapy for NAFLD in T2D. This trial examined whether treatment with the sodium glucose transporter 2 inhibitor empagliflozin (EMPA) reduces liver fat content (HCL, primary outcome) in metabolically well-controlled patients with short known disease duration. T2D patients (n=84; 63±8 years; body mass index (BMI) 32.2±4.5 kg/m2, HbA1c 6.6±0.5%, disease duration 38±27 months) were randomly assigned to 24-week treatment with either EMPA 25 mg per day or placebo (PLAC). HCL was measured by 1H-magnetic resonance (MR) spectroscopy (STEAM) and fat-selective MR imaging (IDEAL). Statistical analysis was done by ANCOVA adjusted for the respective baseline value, age, sex and BMI. After treatment, HCL was reduced compared to baseline (relative change (RC) EMPA -33%[95% confidence interval -43;-23], p In conclusion, empagliflozin effectively reduces HCL in well-controlled T2D patients and increases serum adiponectin with beneficial effects on hepatocellular integrity. Thus, empagliflozin may improve NAFLD via distinct different mechanisms. Disclosure S. Kahl: None. S. Gancheva: None. K. Strassburger: None. C. Herder: None. J. Machann: None. H. Katsuyama: None. S. Kabisch: Research Support; Self; California Walnut Commission, Institute for Grain Processing, Nuthetal, J. Rettenmaier Söhne, Südzucker / Beneo. Other Relationship; Self; Berlin-Chemie AG, Sanofi. E. Henkel: None. S. Kopf: None. K. Kantartzis: None. Y. Kupriyanova: None. O. Kuss: None. J. Hwang: None. C. Kasperk: None. N. Stefan: Research Support; Self; AstraZeneca. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., Sanofi. A.F. Pfeiffer: Advisory Panel; Self; Abbott, Berlin-Chemie AG, Novo Nordisk A/S. Speaker's Bureau; Self; Lilly Diabetes, Novartis AG, Sanofi-Aventis Deutschland GmbH. A.L. Birkenfeld: None. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc. Funding Boehringer Ingelheim Pharma GmbH

Exploratory analyses of PIONEER 3 (NCT02607865) assessed the efficacy (HbA1c change from baseline [BL], achievement of HbA1c HbA1c was reduced across all BL HbA1c and OAD groups in all treatment arms; reductions were greater with higher BL HbA1c. HbA1c reductions were significantly greater with oral sema 7 and 14 mg vs. sita in all groups, except for 7 mg in the HbA1c ≤8.0% group (Figure 1). Achievement of HbA1c In conclusion, oral sema 7 and 14 mg significantly improved glycemic control vs. sita across most HbA1c groups, and irrespective of background OAD use. Disclosure J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Melior Pharmaceuticals, Inc., Bukwang Pharm. Co., Ltd., Merck & Co., Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc. Other Relationship; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. D.C. Allison: Advisory Panel; Self; Novo Nordisk Inc. Research Support; Self; Bayer US, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Kowa Pharmaceutical Europe Co. Ltd., Sanofi. A.L. Birkenfeld: None. T.M. Blicher: Employee; Self; Novo Nordisk A/S. S. Deenadayalan: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. A. Kousholt: Employee; Self; Novo Nordisk A/S. M.J. Davies: Advisory Panel; Self; Eli Lilly and Company, Janssen Global Services, LLC., Novo Nordisk A/S, Sanofi-Aventis, Servier. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk Foundation. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Sanofi-Aventis, Takeda Pharmaceutical Company Limited. Funding Novo Nordisk A/S

Metabolic surgery improves insulin resistance and type 2 diabetes possibly because of weight loss. We performed a novel sleeve gastrectomy in rats that resects ∼80% of the glandular portion, leaving the forestomach almost intact (glandular gastrectomy [GG]) and compared subsequent metabolic remodeling with a sham operation. GG did not affect body weight, at least after 10 weeks; improved hepatic and peripheral insulin sensitivity likely through increased Akt, glycogen synthase kinase 3, and AMPK phosphorylation; and reduced ectopic fat deposition and hepatic glycogen overaccumulation. Body adipose tissue was redistributed, with reduction of intraabdominal fat. We found a reduction of circulating ghrelin levels, increased GLP-1 plasma concentration, and remodeling of gut microbiome diversity characterized by a lower relative abundance of Ruminococcus and a higher relative abundance of Lactobacillus and Collinsella. These data suggest that at least in rat, the glandular stomach plays a central role in the improvement of insulin resistance, even if obesity persists. GG provides a new model of the metabolically healthy obese phenotype.

INDY (I’m Not Dead Yet) is a transporter of TCA cycle intermediates, mediating cellular citrate uptake and is highly expressed in liver and brain. Reduced expression of Indy in lower organisms extended lifespan, reduced whole body fat content and increased mitochondrial biogenesis. In mammals, whole body deletion of the mammalian Indy homolog (mIndy, Slc13a5) increased energy expenditure and protected mice from diet and aging induced obesity and insulin resistance. Here, we address the role of neuronal mIndy in energy homeostasis. We generated a neuronal mIndy knockout (NINKO) mouse model by crossing mIndy-floxed to NestinCre mice. Deletion of mIndy in neurons led to an increase in energy expenditure compared to NestinCre mice after 8 weeks of high fat diet (HFD) feeding (average 24h EE: NestinCre: 11.5±0.5 kcal/h/kg lean mass (lm); NINKO: 13.6±0.6 kcal/h/kg lm; p Disclosure A. Kurzbach: None. D.M. Willmes: None. T. Schumann: None. C. Henke: None. N. El-Agroudy: None. A. Kleinridders: None. A.L. Birkenfeld: None.

OBJECTIVE To investigate the role of desnutrin in adipose tissue triacylglycerol (TAG) and fatty acid metabolism. RESEARCH DESIGN AND METHODS We generated transgenic mice overexpressing desnutrin (also called adipose triglyceride lipase [ATGL]) in adipocytes (aP2-desnutrin) and also performed adenoviral-mediated overexpression of desnutrin in 3T3-L1CARΔ1 adipocytes. RESULTS aP2-desnutrin mice were leaner with decreased adipose tissue TAG content and smaller adipocyte size. Overexpression of desnutrin increased lipolysis but did not result in increased serum nonesterified fatty acid levels or ectopic TAG storage. We found increased cycling between diacylglycerol (DAG) and TAG and increased fatty acid oxidation in adipocytes from these mice, as well as improved insulin sensitivity. CONCLUSIONS We show that by increasing lipolysis, desnutrin overexpression causes reduced adipocyte TAG content and attenuation of diet-induced obesity. Desnutrin-mediated lipolysis promotes fatty acid oxidation and re-esterification within adipocytes.

OBJECTIVE—Atrial natriuretic peptide (ANP) regulates arterial blood pressure. In addition, ANP has recently been shown to promote human adipose tissue lipolysis through cGMP-mediated hormone-sensitive lipase activation. We hypothesized that ANP increases postprandial free fatty acid (FFA) availability and energy expenditure while decreasing arterial blood pressure. RESEARCH DESIGN AND METHODS—We infused human ANP (25 ng · kg−1 · min−1) in 12 men (age 32 ± 0.8 years, BMI 23.3 ± 0.4 kg/m2) before, during, and 2 h after ingestion of a standardized high-fat test meal in a randomized, double-blind, cross-over fashion. Cardiovascular changes were monitored by continuous electrocardiogram and beat-by-beat blood pressure recordings. Metabolism was monitored through venous blood sampling, intramuscular and subcutaneous abdominal adipose tissue microdialysis, and indirect calorimetry. RESULTS—ANP infusion decreased mean arterial blood pressure by 4 mmHg during the postprandial phase (P < 0.01 vs. placebo). At the same time, ANP induced lipolysis systemically (P < 0.05 vs. placebo) and locally in subcutaneous abdominal adipose tissue (P < 0.0001 vs. placebo), leading to a 50% increase in venous glycerol (P < 0.01) and FFA (P < 0.05) concentrations compared with placebo. The increase in FFA availability with ANP was paralleled by a 15% increase in lipid oxidation rates (P < 0.05 vs. placebo), driving a substantial increase in postprandial energy expenditure (P < 0.05 vs. placebo). CONCLUSIONS—Our data identify the ANP system as a novel pathway regulating postprandial lipid oxidation, energy expenditure, and concomitantly arterial blood pressure. The findings could have therapeutic implications.

Mitochondrial GTP (mtGTP)-insensitive mutations in glutamate dehydrogenase (GDHH454Y) result in fasting and amino acid–induced hypoglycemia in hyperinsulinemia hyperammonemia (HI/HA). Surprisingly, hypoglycemia may occur in this disorder despite appropriately suppressed insulin. To better understand the islet-specific contribution, transgenic mice expressing the human activating mutation in β-cells (H454Y mice) were characterized in vivo. As in the humans with HI/HA, H454Y mice had fasting hypoglycemia, but plasma insulin concentrations were similar to the controls. Paradoxically, both glucose- and glutamine-stimulated insulin secretion were severely impaired in H454Y mice. Instead, lack of a glucagon response during hypoglycemic clamps identified impaired counterregulation. Moreover, both insulin and glucagon secretion were impaired in perifused islets. Acute pharmacologic inhibition of GDH restored both insulin and glucagon secretion and normalized glucose tolerance in vivo. These studies support the presence of an mtGTP-dependent signal generated via β-cell GDH that inhibits α-cells. As such, in children with activating GDH mutations of HI/HA, this insulin-independent glucagon suppression may contribute importantly to symptomatic hypoglycemia. The identification of a human mutation causing congenital hypoglucagonemic hypoglycemia highlights a central role of the mtGTP–GDH–glucagon axis in glucose homeostasis.

We measured the mRNA and protein expression of the key gluconeogenic enzymes in human liver biopsy specimens and found that only hepatic pyruvate carboxylase protein levels related strongly with glycemia. We assessed the role of pyruvate carboxylase in regulating glucose and lipid metabolism in rats through a loss-of-function approach using a specific antisense oligonucleotide (ASO) to decrease expression predominantly in liver and adipose tissue. Pyruvate carboxylase ASO reduced plasma glucose concentrations and the rate of endogenous glucose production in vivo. Interestingly, pyruvate carboxylase ASO also reduced adiposity, plasma lipid concentrations, and hepatic steatosis in high fat–fed rats and improved hepatic insulin sensitivity. Pyruvate carboxylase ASO had similar effects in Zucker Diabetic Fatty rats. Pyruvate carboxylase ASO did not alter de novo fatty acid synthesis, lipolysis, or hepatocyte fatty acid oxidation. In contrast, the lipid phenotype was attributed to a decrease in hepatic and adipose glycerol synthesis, which is important for fatty acid esterification when dietary fat is in excess. Tissue-specific inhibition of pyruvate carboxylase is a potential therapeutic approach for nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes.