bluuebunny/crossref_metadata_2025_split huggingface dataset:
37-OR: Distinct Functional Beta-Cell Subpopulations in Intact Islets of Langerhans
Authors: KRAVETS VIRA , PISCOPIO ROBERT A. , SCHLEICHER WOLFGANG , BENNINGER RICHARD K. 
Published: June 2019

Glucose-stimulated insulin secretion is driven by the coordinated Ca2+ response in pancreatic islets following glucose elevation. In mouse islets, spatial and temporal Ca2+ dynamics are disproportionally controlled by subpopulations of β-cells, as identified by optogenetics. It is unknown which factors underlie this functional heterogeneity of β-cells in intact islets. Here, we tested if distinct β-cell subpopulations may be identified based on Ca2+ response to glucose elevation, and if their Ca2+ uptake efficiency, metabolic activity and electrical coupling are significantly different. We used MIP-CreER GCaMP6s mouse model which expresses Ca2+-sensitive GFP specifically in β-cells. We performed simultaneous Ca2+ dynamics and metabolic activity (NADH) response to [2-11] mM glucose elevation, along with gap junction permeability measurements in individual islets. We observed three functional subpopulations of β-cells distinct from an islet average: cells with 1) the fastest response to glucose elevation (1st responders); 2) the fastest 2nd phase oscillatory Ca2+ response (wave-initiators); and 3) the non-coordinated Ca2+ oscillations (un-coordinated). While 1st responders and wave-initiators were in different sub-regions of the islet, both subpopulations accumulated more Ca2+ during initial Ca2+ elevation (p=0.0403, p=0.0101) compared to the islet-average. Wave-initiators were more metabolically active (p=0.0223). The un-coordinated cells accumulated less Ca2+ (p&lt;0.001) and were less metabolically active (p=0.0296). Gap junction permeability was not significantly different between subpopulations.
In conclusion, the 1st phase Ca2+ uptake and 2nd phase Ca2+ oscillations emerge in spatially- and metabolically-distinct subregions of the islet. This is likely due to increased metabolic activity of the β-cells in these regions which leads to greater membrane depolarization and thus, disproportionately enhances the islet Ca2+response. (NIH R01 DK102950 R01 DK106412)

Disclosure
V. Kravets: None. R.A. Piscopio: None. W. Schleicher: None. R.K. Benninger: None.

Funding
National Institutes of Health
385-P: Blocking the Nicotinic Receptors of the Parasympathetic Nervous System Prevents Severe Hypoglycemia-Induced Fatal Cardiac Arrhythmias in Rats
Authors: RENO CANDACE M. , BAYLES JUSTIN , HUANG YIQING , OXSPRING MILAN B. , FISHER SIMON 
Published: June 2019

In response to hypoglycemia, excessive stimulation of the parasympathetic nervous system (PNS) may induce bradycardia and fatal heart block. Since signaling via nicotinic receptors mediates the PNS response, it was hypothesized that these receptors may mediate hypoglycemia-induced cardiac arrhythmias. To test this hypothesis, mecamylamine (a nicotinic receptor antagonist; 7.5 mg/kg, n = 17) or saline (control; n = 20) was infused intravenously in Sprague Dawley rats during insulin-induced (0.2mU/kg/min) severe hypoglycemic (10-15 mg/dl) clamps for 3 hours with electrocardiogram recordings. Compared to controls, mecamylamine-treated rats required a 3-fold higher glucose infusion rate during severe hypoglycemia, consistent with lower peak epinephrine levels (5698±557 vs. 2418±396 pg/ml; p &lt; 0.001). In control rats, hypoglycemia led to 2nd degree heart block (1.8±1.7/min), 3rd degree heart block (32%), and mortality (25%). However, mecamylamine treatment completely prevented 2nd and 3rd degree heart block resulting in 100% survival (*p &lt; 0.05).
In summary, blocking nicotinic receptors prevents cardiac arrhythmias and mortality during severe hypoglycemia. Clinically, targeting the parasympathetic nervous system could be a logical approach to prevent sudden death in people with insulin-treated diabetes at risk for hypoglycemia.

Disclosure
C.M. Reno: None. J. Bayles: None. Y. Huang: None. M.B. Oxspring: None. S. Fisher: None.

Funding
National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; JDRF
390-P: Changes in Glycaemic Variability after RYGB: A One-Year Prospective Study with Comparison to Patients with Post-bariatric Hypoglycaemia
Authors: THARAKAN GEORGE , ILESANMI IBIYEMI I. , BEHARY PREESHILA , ALEXIADOU KLEOPATRA , DOYLE CHEDIE S. , CHAHAL HARVINDER , PURKAYASTHA SANJAY , MIRAS ALEXANDER , OLIVER NICK , AHMED AHMED , BLOOM STEPHEN , TAN TRICIA M. 
Published: June 2019

Some patients suffer disabling hypoglycaemia after RYGB, typically post prandially: Post Bariatric Hypoglycaemia (PBH). We hypothesised that these patients have increased glycaemic variability (GV), as assessed by continuous glucose monitoring (CGM).
Method: Prospective study of 6 patients undergoing RYGB with mixed meal tests (MMT) and CGM at baseline (BL), at 1 month and at 12 months. This cohort was compared to 15 patients with hypoglycaemia.
Results: RYGB leads to improvement in postprandial glucose tolerance at 120 minutes, preceded by an early peak of glucose and insulin at 30 minutes (Figure 1). Compared to pre-surgery, hypoglycaemic patients have significantly elevated peak glucose and insulin levels at 30 minutes followed by hypoglycaemia at 120 minutes. GV increases post RYGB: mean amplitude of glycaemic excursions (MAGE) median (95% CI) at BL 3.1 (2.3-6.8); 1 m 2.8 (2.2-4.2); 12 m 4.5 (3.4-5.5). PBH patients exhibit similar GV: MAGE 4.4 (3.7-6.5). The %time in range (TIR) glucose &lt;3.9 increases post-surgery (BL 0 (0-3.8); 1 m 1.8 (0.5-4.1); 12 m 8.0 (0-25.8) but patients with PBH exhibit similar %TIR&lt;3.9: 6.8 (3.5-11.9).
Conclusion: PBH patients exhibit exaggerated early glucose and insulin secretion to MMT. ‘Real-world’ CGM demonstrates that GV and time in hypoglycaemia is not significantly different between RYGB without PBH and patients with PBH. All patients post RYGB are at risk of hypos.

Disclosure
G. Tharakan: None. I.I. Ilesanmi: None. P. Behary: None. K. Alexiadou: None. C.S. Doyle: None. H. Chahal: None. S. Purkayastha: None. A. Miras: None. N. Oliver: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Dexcom, Inc., Roche Diabetes Care. Speaker's Bureau; Self; Dexcom, Inc., Sanofi. A. Ahmed: None. S. Bloom: None. T.M. Tan: Other Relationship; Self; Novo Nordisk A/S.

Funding
Medical Research Council UK
392-P: Impact of Late Glucose Checks on Hypoglycemia Incidence
Authors: DUNLAP LAURA J. , WEBER ALANA D. , SCAPINELLO JESSIE , SCHRADER ANDERSON , BURGESS WILLIAM P. 
Published: June 2019

Objective: Hypoglycemia (hypo) is frequently associated with blood glucose (BG) readings that are late. However, there are few reports describing the quantitative effect of untimely BG readings. This work focused on the quantitative evaluation of BG timing and hypo events related to insulin infusion therapy.
Methods: This study is a retrospective, quantitative analysis of incidence of hypo, defined as &lt; 70 mg/dL, relative to the lateness of the BG determination. The dataset includes 3.55 million de-identified BG readings and recorded times from 5 unaffiliated systems using the same eGMS for intravenous insulin infusion therapy between 2007-2017. The timing of all BGs scheduled for every 1 and 2 hour were calculated from the dataset without any restrictions or exclusions. Incidence of hypo events occurring from BG readings 5 minutes (min) late or less was used as a baseline to measure the relative risk of later, low BGs in 10 min increments. The relative risk of late BGs was further stratified by hospital, year, and goal range.
Results: For all hospitals, goal ranges, and for each hospital database stratified by year, the relative risk of hypo appeared to have the same relationship as a function of minutes late. The results reveal that between 15-25 min late the risk of a hypo event was almost 2-fold and between 55-65 min late was 4-fold higher when compared to the baseline.
Discussion: The timing of the next BG has a profound effect on the incidence of hypo. The relationship of increased risk of hypo with lateness of BG readings remains irrespective of the goal range, year, hospital, or overall incidence of hypo in that hospital. All data within this study is from an eGMS with accurate time data. Future research efforts can compare different insulin dosing applications for the purpose of analyzing late BG checks and hypo.
Conclusion: Late BG readings contribute significantly to hypo. These observations should be an important mainstay of bedside care education. The findings also strongly endorse the use of alerts to maintain proper timing of BG readings

Disclosure
L.J. Dunlap: Employee; Self; Monarch Medical Technologies. A.D. Weber: Employee; Self; Monarch Medical Technologies. J. Scapinello: None. A. Schrader: Employee; Self; Monarch Medical Technologies. W.P. Burgess: Consultant; Self; Monarch Medical Technologies.
397-P: Relationship between HbA1c and Declines in Racial Differences of Serious Hypoglycemia in the Veteran Health Administration (VHA) 2004-2015
Authors: TSENG CHIN-LIN , SOROKA ORYSYA , MYERS CATHERINE E. , ARON DAVID C. , POGACH LEONARD M. 
Published: June 2019

Annual rates of emergency department visits or hospitalizations for hypoglycemia (HYPO) were evaluated using a serial cross-sectional study design (2004-2015) of VHA/Medicare enrolled patients. Subjects were ≥65 years receiving secretagogues only (Secr), or insulin with or without Secr (Ins), and who had HbA1c value(s). Separately for Secr/Ins groups and by race/ethnicity, we assessed age/sex adjusted HYPO rates (per 1000 patients) and A1c values (from prior to an event or end of year for those without an event). In 2015, subjects were 99% men, 10% [B]lack, 6% [H]ispanic, and 75% [W]hite; 75% had major comorbidity categories; 24% had cardiovascular conditions only, and 9% advanced diabetes only. Ins use increased by 88%, similar among B/H/W. HYPO rates markedly declined for Ins and Secr in all races but remained higher for B. The percent of patients with A1c &lt;7% decreased: 44.2%/32.9%[B], 51.0%/32.6%[W], and 41.3%/28.4%[H]; the percentage for A1c 7.0-7.9% increased: 28.6%/31.6%[B], 30.6%/35.8%[W], and 30.8%/32.4%[H]; the percentage for &gt;9% also increased: 11.9%/15.8%% [B], 6.4/12.2%[W], and 12.0/17.6%[H]. Mean A1c values also increased in B/H/W, and were similar (difference ≤0.2%) between patients with and without HYPO. Guideline recommendations (post 2008) for individualized A1c goals may have mediated reductions in racial disparities for HYPO rates.

Disclosure
C. Tseng: None. O. Soroka: None. C.E. Myers: None. D.C. Aron: None. L.M. Pogach: None.

Funding
U.S. Department of Veterans Affairs (IIR14-082)
405-P: Transcription Factor Tcf21 Regulates Fibrosis in Ischemic or Hyperglycemic State
Authors: BABA YUSUKE , MAEZAWA YOSHIRO , KONDOU NAOMICHI , KOBAYASHI YOSHIO , YOKOTE KOUTARO 
Published: June 2019

Cardiac fibrosis after ischemic heart diseases or in diabetic cardiomyopathy is critical for maintaining cardiac functions. Tcf21 is a bHLH transcription factor expressed in epicardium and cardiac fibroblasts. Tcf21 knockout mice die immediately after birth because of cardiac malformation. On the other hand, little is known about its function in the adult heart. Therefore, we aimed to elucidate the role of Tcf21 after cardiac injury. Tcf21 was deleted after birth using inducible Cre-LoxP system to circumvent the lethality (iTcf21 KO). Isoproterenol (ISO) was injected (200 mg/kg) at eight weeks of age. Mice were sacrificed seven days and four weeks after ISO injection, and histological analysis was performed. Besides, cardiac fibroblasts were isolated from Tcf21 knockout embryos and subjected to RNA-seq analysis. Fibroblasts proliferation capacity was also assessed by BrdU uptake. Finally, Tcf21 expression in hyperglycemic state induced by streptozocin (STZ) was evaluated. At day 7, 1.98 ± 0.40% of the total cardiac area showed fibrosis in control, however, the fibrosis area was smaller in iTcf21 KO mice (0.67 ± 0.14%, P &lt; 0.001). Cardiac ultrasound revealed fractional shortening was maintained in iTcf21 KO mice compared to control. Immunostaining demonstrated Ki67-positive cells decreased in iTcf21 KO (57.1% compared to controls, P = 0.032). Isolated cardiac fibroblasts from Tcf21 KO showed lower BrdU uptake (76.0 ± 3.3% for controls and 47.8 ± 7.4% for Tcf21 KO, P = 0.002) and decreased phosphorylation of Erk. RNA-seq analysis revealed potential downstream targets for Tcf21 including Il33 and Col1a1. Gene Ontology analysis demonstrated involvements of Tcf21 in the extracellular matrix and angiogenesis. STZ-induced hyperglycemic state did not evoke significant fibrosis but upregulate Tcf21 expression compared with control. These findings suggest lack of Tcf21 suppresses fibrosis after cardiac injury. Tcf21 and its targets would be a potential novel therapeutic target for cardiac diseases.

Disclosure
Y. Baba: None. Y. Maezawa: None. N. Kondou: None. Y. Kobayashi: Speaker's Bureau; Self; Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited. K. Yokote: None.
418-P: The Branched-Chain Amino Acids Valine and Leucine Predict All-Cause Mortality in Cardiovascular Disease Patients Independently from the Presence of Type 2 Diabetes Mellitus
Authors: MUENDLEIN AXEL , LEIHERER ANDREAS , SAELY CHRISTOPH H. , VONBANK ALEXANDER , LARCHER BARBARA , MADER ARTHUR , FRAUNBERGER PETER , DREXEL HEINZ 
Published: June 2019

Circulating branched-chain amino acids (BCAAs) are linked with mortality in population-based studies. Whether they also predict mortality in patients with established cardiovascular disease (CVD) is unclear. We therefore determined serum BCAAs by NMR spectroscopy in 327 patients with established CVD. Prospectively, deaths were recorded over a mean follow-up period of 8.1±3.5 years. At baseline, serum valine, leucine and isoleucine were significantly associated with T2DM (all p-values &lt;0.001). Prospectively, death occurred in 49.5% of patients with T2DM and in 37.2% nondiabetic patients (p=0.036). Table 1 shows the associations of BCAAs with mortality univariately and after multivariate adjustment including presence of T2DM in the total study cohort as well as separately for patients with T2DM and for nondiabetic patients. Low valine as well as low leucine predicted mortality independently from the presence of T2DM in the total cohort and, in subgroup analysis, specifically in patients with T2DM. We conclude that low valine and leucine serum levels predict mortality in patients with established CVD independently from the presence of T2DM.

Disclosure
A. Muendlein: None. A. Leiherer: None. C.H. Saely: None. A. Vonbank: None. B. Larcher: None. A. Mader: None. P. Fraunberger: None. H. Drexel: None.
423-P: Racial and Ethnic Disparities in Mortality and Cardiovascular Disease in Patients with Type 2 Diabetes in a U.S. Integrated Health-Care System
Authors: AN JAEJIN , NICHOLS GREGORY A. , QIAN LEI , WEI RONG , HARRISON TERESA , MUNIS MERCEDES A. , LI ZHUOXIN , WEISS TRACEY , IGLAY KRISTY , RAJPATHAK SWAPNIL , REYNOLDS KRISTI 
Published: June 2019

Previous research has documented higher mortality rates and risk of diabetes complications in ethnic minorities in the U.S. While genetic predisposition and lifestyle are potential important factors associated with this disparity, the role of access to care has not been well studied. We examined all-cause mortality and incidence of cardiovascular disease (CVD) by race/ethnicity in a type 2 diabetes (T2DM) population within in a large U.S. integrated healthcare system. We identified adult patients with incident T2DM between 1/1/2003-12/31/2014 using electronic health record (EHR) data and followed them through 6/30/2018. Patient demographics, CVD risk factors, medical history, and medication use were ascertained from the EHR. Age- and sex-adjusted all-cause mortality and incidence rates of myocardial infarction (MI) and heart failure (HF) were estimated by race/ethnicity. Hazard ratios were estimated using multivariable Cox proportional hazards models. We identified 135,199 patients with incident T2DM (mean±SD age: 58±13 years, 48% female, and median follow-up 6 years). 36% were white, 35% Hispanic, 12% Asian, and 12% black. All-cause mortality and incidence of MI and HF were highest among whites followed by blacks (Table). These findings suggest that improving access to quality care may help reduce racial/ethnic health disparities among patients with T2DM.

Disclosure
J. An: Research Support; Self; Merck & Co., Inc. G.A. Nichols: Research Support; Self; Amarin Corporation, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Scientific Affairs, LLC., Merck Sharp & Dohme Corp. L. Qian: None. R. Wei: None. T. Harrison: None. M.A. Munis: None. Z. Li: None. T. Weiss: Employee; Self; Merck & Co., Inc. K. Iglay: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. S. Rajpathak: None. K. Reynolds: Research Support; Self; Amarin Corporation, Amgen Inc., Merck Sharp & Dohme Corp., Novartis AG.
428-P: Heart Failure (HF) and Its Risk Factors in Long-Duration Type 1 Diabetes (T1D)
Authors: GUO JINGCHUAN , COSTACOU TINA , ORCHARD TREVOR J. 
Published: June 2019

To assess HF incidence in childhood onset, T1D, and its risk factors, we used 25 year follow-up data from the Epidemiology of Diabetes Complications Study (n=644, baseline age and T1D duration 27 and 19 years respectively). HF was determined by clinic exams, hospitalization, and/or self-reports. In a separate analysis, serum NT-proBNP (electrochemiluminescence immunoassay) was measured in the earliest available sample (n=572; HF diagnostic cutoff of 450 pg/mL). Hazard ratios (HR) per 1 s.d. increase in risk factor levels were estimated with Cox models.
Forty-one (6.3%) HF cases (3 baseline prevalent and 38 incident) were identified during follow-up. The 5.9% (38/642) cumulative incidence of HF yielded an incidence density of 2.97/1000 person-years. In the overall population (and not including NT-proBNP), allowing for a wide range of potential baseline confounders (sex, T1D duration, smoke, BMI, hypertension, HbA1c, lipids, WBC, eGFR and albumin excretion), T1D duration (HR=1.7, p=0.003), ever smoking (HR=2.4, p=0.02) and non-HDLc (HR=1.4, p=0.04) were strongly associated with incident HF after backward elimination.
In the sub analysis of 572 participants with NT-proBNP, 21 had values &gt;450 pg/mL, 85.6% (18) of whom had end stage renal disease (ESRD) including 3 with concurrent HF. In those without ESRD at the time of NT-proBNP testing (n=551), NT-proBNP significantly predicted incident HF (32 clinically defined events, HR=1.7, p=0.03). Although in a backward elimination model (removal criterion: p≥ 0.2), allowing for other risk factors, NT-proBNP (HR=1.5, p=0.09) became marginal, it was retained in this final model along with T1D duration (HR=1.8, p=0.003), ever smoking (HR=2.6, p=0.01) and non-HDLc (HR=1.4, p=0.05).
HF incidence in this long-duration T1D cohort is increased compared to the general population with similar age (e.g., incidence=0.97/1000 pyrs). Diabetes duration, smoking and non-HDLc are strong risk factors of HF; while in those without ESRD, NT-proBNP is a moderate predictor.

Disclosure
J. Guo: None. T. Costacou: None. T.J. Orchard: Consultant; Self; Boehringer Ingelheim International GmbH.

Funding
National Institutes of Health
433-P: Serum Ceramides and Type 2 Diabetes Are Mutually Independent Predictors of Cardiovascular Events in Patients with Peripheral Artery Disease
Authors: LEIHERER ANDREAS , MUENDLEIN AXEL , SAELY CHRISTOPH H. , LAAKSONEN REJO , LAAPERI MITJA , VONBANK ALEXANDER , LARCHER BARBARA , MADER ARTHUR , FRAUNBERGER PETER , BAUMGARTNER IRIS , DREXEL HEINZ , DOPHEIDE JÖRN F. 
Published: June 2019

Ceramides are enriched in atherosclerotic plaques, and a set of circulating ceramides including Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), and Cer(d18:1/24:0) has recently emerged as predictors of cardiovascular outcomes in coronary artery disease patients. However, their power to predict cardiovascular events in patients with peripheral artery disease (PAD) is unknown and is addressed in the present study. We measured the serum concentrations of the above mentioned ceramides in a cohort of 380 patients with sonographically proven PAD, of whom 107 had type 2 diabetes (T2DM). Prospectively, we recorded 221 cardiovascular events over a mean follow-up time of 6.3±2.3 years. Cardiovascular event risk was higher in T2DM patients than in those who did not have diabetes (69 vs. 52%, p=0.001). The ceramides Cer(18:1/16:0) and Cer(18:1/24:1) and the respective ratios Cer(18:1/16:0)/Cer(18:1/24:0) and Cer(18:1/24:1)/Cer(18:1/24:0) were significant predictors of cardiovascular events both univariately and after multivariate adjustment including the presence of T2DM (Figure). Conversely, T2DM predicted cardiovascular events independently from the investigated ceramides (adjusted HR 1.76 [1.31-2.35], p&lt;0.001). We conclude that the investigated ceramides and T2DM are mutually independent predictors of cardiovascular events in PAD patients.

Disclosure
A. Leiherer: None. A. Muendlein: None. C.H. Saely: None. R. Laaksonen: None. M. Laaperi: None. A. Vonbank: None. B. Larcher: None. A. Mader: None. P. Fraunberger: None. I. Baumgartner: None. H. Drexel: None. J.F. Dopheide: None.
434-P: Diabetes in Patients with Pancreatic Cancer: Relationship of Tumor Grade with Glycemic Control
Authors: BOEDDEKER JAN STEFFEN , BURKART VOLKER , STRASSBURGER KLAUS , GORETZKI PETER E. , KNOEFEL WOLFRAM TRUDO , MOEBIUS CHRISTIAN , HINSCH NORA , ESPOSITO IRENE , RODEN MICHAEL , MUESSIG KARSTEN 
Published: June 2019

Diseases of the exocrine pancreas can result in impaired function of the endocrine pancreas with disturbed glucose homeostasis and ultimately overt diabetes mellitus. In diabetes which develops secondary to pancreatic carcinoma (type 3c diabetes or diabetes of the exocrine pancreas, DEP), the relationship between disturbed glycemic control and carcinoma is not fully understood. We hypothesized that the severity of pancreatic carcinoma positively associates with the degree of impairment of glycemic control. In 92 patients with potentially resectable pancreas neoplasm without diabetes (NOD, n=53, age 67±2 years, BMI 24.8±0.5 kg/m2), DEP (n=20, 71±3 years, 25.3±1.0 kg/m2) or preexisting type 2 diabetes (T2D, n=19, 71±3 years, 27.1±0.8 kg/m2), preoperative fasting glucose, insulin and HbA1c were measured. Pancreatic carcinoma was assessed by TNM classification and tumor grading. Patients with DEP or T2D had higher fasting glycemia (135±9 vs. 142±11 mg/dl), HbA1c (55±3 vs. 58±3 mmol/mol) and insulin resistance, as assessed by homeostatic model assessment for insulin resistance (HOMA-IR) (4.1±1.0 vs. 3.7±0.5), than NOD patients (88±2 mg/dl, 38±1 mmol/mol, 2.0 ± 0.3; all p&lt;0.01). Tumor grading revealed that patients with tumor grade G3 had higher levels of fasting glucose (124±36 mg/dl) and HbA1c (53±2 mmol/mol) compared to patients with non-malignant neoplastic lesions (103±38 mg/dl, 42±2 mmol/mol; all p&lt;0.01). Distribution patterns of tumor grades differed between DEP and T2D (p&lt;0.05) and NOD (p&lt;0.001), respectively. Particularly, the prevalence of G3 tumors was higher in DEP (79%) than in T2D (33%) or NOD patients (16%). Tumor stages did not relate to glycemic control.
In conclusion, patients with pancreas carcinoma exhibit a higher diabetes prevalence, which relates to higher tumor grades but not stages.

Disclosure
J. Boeddeker: None. V. Burkart: None. K. Strassburger: None. P.E. Goretzki: None. W. Knoefel: None. C. Moebius: None. N. Hinsch: None. I. Esposito: 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. K. Muessig: None.

Funding
German Ministry of Culture and Science of the State of North Rhine-Westphalia; German Federal Ministry of Health; German Federal Ministry of Education and Research; German Center for Diabetes Research