Sanofi-Aventis Deutschland GmbH Research Articles

1794-PUB: Potential for Improving CGM Systems? Anticipated Benefits from Increasing the Glucose Prediction of Current CGM Algorithms

Current CGM algorithms allow a glucose prediction up to 30 minutes. To elaborate on the potential to improve current CGM systems, we investigated if a possible increase in this prediction window to up to 2 hours would be perceived as a significant benefit. People with type 1 and type 2 diabetes currently using a CGM system were invited to participate. Participants were presented with a scenario depicting the potential of a hypothetical CGM algorithm to predict the course of glucose for up to 2 hours. They were instructed to imagine how such a long-term prediction would affect their diabetes management. They were asked to complete the T1-Diabetes Distress Scale (T1-DDS) and the Hypoglycemia Fear Survey (HFS-II) and rate each item regarding the perceived potential change from using such a long-term prediction (scale: -2 strong deterioration, -1 deterioration, 0 no change, 1 improvement, 2 strong improvement). 206 people participated (29.1% type 2 diabetes). Participants expected moderate improvements in hypoglycemia and management distress (Box plots shown in Figure 1 for T1-DDS). Similar improvements in HFS-II scores (0.57±0,49) were seen with no differences between diabetes types. Increasing the glucose prediction to up to 2 hours would be seen as a potential improvement regarding reductions in hypoglycemia distress and fear of hypoglycemia by both people with type 1 and type 2 diabetes. Disclosure D.Ehrmann: Advisory Panel; Roche Diabetes Care, mySugr, Dexcom, Inc., Speaker's Bureau; Berlin-Chemie AG, Dexcom, Inc. T.Glatzer: Employee; Roche Diabetes Care, Berlin-Chemie AG. L.Priesterroth: Speaker's Bureau; Ypsomed AG. B.Olesen: Advisory Panel; AstraZeneca, Evivamed, Berlin-Chemie AG, Speaker's Bureau; Medtronic, Medtrixx. B.Kulzer: Advisory Panel; Berlin-Chemie AG, Abbott Diabetes, Bayer Inc., Dexcom, Inc., Novo Nordisk, Insulet Corporation, embecta, Research Support; Sanofi, Roche Diabetes Care. N.Hermanns: Advisory Panel; Insulet Corporation, Research Support; Sanofi-Aventis Deutschland GmbH, Roche Diagnostics, Becton, Dickinson and Company, Speaker's Bureau; Dexcom, Inc., Berlin-Chemie AG. Funding Roche Diabetes Care

1841-PUB: Diabetes as a Risk Factor of Death in Hospitalized COVID-19 Patients—An Analysis of a National Hospitalization Database from Poland, 2020

Introduction: Diabetes has been linked with poor clinical prognosis of hospitalized COVID-19 patients. In this nationwide database retrospective study we evaluated diabetes as a risk factor of in-hospital death. Methods: We analysed data from discharge reports from 2020 of hospitalized COVID-19 patients sent to the Polish National Health Fund. To assess the risk of in-hospital death attributed to diabetes, several multivariate logistic regression models were used. In each model in-hospital death was estimated with explanatory variables, including diabetes. Models were built either on the whole cohorts or cohorts matched with propensity score matching (PSM). They examined either main effects or included interaction of diabetes with other variables. Results: We included 174,621 patients with COVID-19 infection hospitalized in Poland in 2020. There were 40,168 diabetic patients (DPs), proportion higher than in the general population (23.0% vs. 9.5%, p<0.001). Overall, 17,438 in-hospital deaths were recorded, the mortality was higher in DPs vs. nondiabetics (16.3% vs. 8.1%, p<0.001). Multivariate logistic regressions showed that diabetes was an independent risk factor of death, regardless of sex and age. In the main effect analysis, odds of in-hospital death were higher by 28.3% for DPs than for nondiabetic patients. Similarly, PSM analysis including 101,578 patients, of whom 19,050 had diabetes, showed that the risk of death was higher in DPs regardless of sex and age. Odds of in-hospital death were higher by 34.9% for DPs. The impact of diabetes on COVD-19 in-hospital death differed among age groups and was the highest for patients aged 60-69. Conclusions: This nationwide study confirmed that diabetes was an independent risk of in-hospital death in the course of COVID-19. However, the relative risk attributed to diabetes might be lower than reported earlier from most of other populations and differ significantly across the age groups. Disclosure M. Kania: None. B. Kon: None. K.M. Kaminski: Other Relationship; Roche Pharmaceuticals. J. Hohendorff: Speaker's Bureau; Abbott, Novo Nordisk, Ascensia Diabetes Care, Dexcom, Inc., Bayer Inc. T. Klupa: Speaker's Bureau; Medtronic. Advisory Panel; Abbott Diabetes. Speaker's Bureau; Abbott Diabetes. Advisory Panel; Ascensia Diabetes Care. Speaker's Bureau; Eli Lilly and Company, Novo Nordisk. Advisory Panel; Sanofi, BIOTON S.A. Speaker's Bureau; Boehringer Ingelheim Inc., Servier Laboratories. P.W. Witek: Other Relationship; Abbott Diabetes, Ascensia Diabetes Care, Medtronic, Novo Nordisk, Sanofi-Aventis Deutschland GmbH, Boehringer-Ingelheim, Roche Diabetes Care, BIOTON S.A., KRKA. M. Malecki: Advisory Panel; Abbott Diabetes. Speaker's Bureau; AstraZeneca, AlfaSigma. Advisory Panel; Novo Nordisk, Lilly, Sanofi. Speaker's Bureau; Merck & Co., Inc. Research Support; Medtronic. Advisory Panel; Dexcom, Inc. Speaker's Bureau; BIOTON S.A., Servier Laboratories, KRKA. Advisory Panel; Bayer Inc. Funding National Centre for Research and Development CRACoV-HHS project (SZPITALE-JEDNOIMIENNE/18/2020)

794-P: Effectiveness and Safety of iGlarLixi in People with Type 2 Diabetes (Pw2D), Not at Target on Basal Insulin (BI) and Oral Antidiabetic Therapy (BOT)—Results from the Observational, Prospective Study CHANCE

iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and lixisenatide, is a once-daily treatment advancement option for Pw2D not at target on BOT. CHANCE investigated effectiveness and safety of switching the BI to iGlarLixi in daily clinical practice. Primary objective was to assess absolute change in HbA1c 24 weeks (W24) after switching to iGlarLixi. Secondary objectives included changes in fasting plasma glucose (FPG), bodyweight (BW), use of oral antidiabetic drugs (OADs), dose of previous BI, and hypoglycemia incidence. Overall, data from 70 Pw2D were analyzed. Mean BI dose was 38.9 units per day and individual target HbA1c was 6.9%. iGlarLixi was started with 30 dose steps per day (DS/d); at W24, mean dose was 41.6 DS/d. HbA1c decreased by -0.7% (P < 0.001), while FPG trended down by ~20 mg/dL. This was accompanied by a -3.0 kg decrease in BW (P = 0.442). Numbers of OADs used decreased markedly 24 weeks after switching to iGlarLixi (P < 0.05). Hypoglycemia incidence was low before and did not change significantly after switching to iGlarLixi. In conclusion, advancing BOT by switching the BI to iGlarLixi, improved glycemic control of Pw2D in daily clinical practice without BW gain and with low hypoglycemia incidence; however, titration was not sufficient to reach glycemic targets after 24 weeks. Disclosure T.Wiesner: Advisory Panel; Roche Diabetes Care, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Sanofi-Aventis Deutschland GmbH, Lilly Diabetes, Boehringer Ingelheim Inc., Abbott Diabetes, Novo Nordisk, Dexcom, Inc., Novartis. M.Pfohl: Advisory Panel; Boehringer Ingelheim and Eli Lilly Alliance, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Sanofi-Aventis Deutschland GmbH. K.Pegelow: Employee; Sanofi-Aventis Deutschland GmbH, Stock/Shareholder; Sanofi-Aventis Deutschland GmbH. J.Müller: Employee; Sanofi-Aventis Deutschland GmbH, Stock/Shareholder; Bayer Inc., Inmunebio Inc. J.Seufert: Advisory Panel; Abbott Diabetes, Boehringer Ingelheim Pharma GmbH&Co.KG, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Abbott Diabetes, Bayer Inc., Boehringer Ingelheim Pharma GmbH&Co.KG, Merck Sharp & Dohme Corp., Sanofi-Aventis Deutschland GmbH, Novartis, Novo Nordisk. Funding Sanofi-Aventis Deutschland GmbH

732-P: Biomarkers of Inflammation and Long-Term Microvasculature Integrity in Weight Loss–Induced Prediabetes Remission

The Diabetes Prevention Program Outcomes Study demonstrated that even temporary resolution of prediabetes (remission) to normal glucose regulation (NGR) prevents development of T2D and vascular complications. However, cellular mechanisms are unknown. We have previously shown in the Prediabetes Lifestyle Intervention Study, a German Center for Diabetes Research multicenter study (n = 1105), that lifestyle intervention (LI)-mediated weight loss-induced remission of prediabetes to NGR vs. non-remission is largely driven by improved insulin sensitivity. We hypothesized that these two groups differ by markers of chronic low-grade inflammation. Therefore, we analyzed 31 cytokines implicated in energy metabolism and T2D complications before and after LI in subjects losing ≥5% body weight (n = 113) to compare responders achieving NGR (R, n = 40) to non-responders not achieving NGR (NR, n = 73). Cytokines linked to insulin resistance and T2D such as TNF-α (p = 0.73), IFNγ (p = 0.45) and IL-6 (p = 0.34) did not differ between groups. However, responders showed a significantly stronger reduction of lymphotoxin α (LTα, -0.15 ± 0.29-fold in NR vs. -0.23 ± 0.32 in R, p = 0.02). VCAM (-0.04 ± 0.14 NR vs. -0.08 ±10.9 R, p = 0.02) and ICAM (-0.11 ±0.15 NR vs. -0.16 ± 0.14 R, p = 0.02), which are induced by LTα and have been implied in mediating cardiovascular complications, were also more strongly reduced in responders. To assess if this is linked with long-term microvasculature integrity, we applied optoacoustic mesoscopy up to 5 years after LI (n = 22). Total vessel and junction density and number of junction to endpoint branches (NJEB) were higher in responders at follow-up (NJEB: 154.9 ± 25.3 vs. 186.9 ± 16.1, p < 0.01). These data describe a distinct pattern of reduced low-grade inflammation characterizing remission of prediabetes to NGR. Although limited by low n, this pattern may help explain the positive effects of prediabetes remission on vascular complications. Disclosure A.Sandforth: None. J.Szendroedi: None. S.M.Meyhöfer: Speaker's Bureau; Novo Nordisk, AstraZeneca, Lilly, Amgen Inc., Boehringer-Ingelheim, Novartis. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. L.Fritsche: None. N.Stefan: Advisory Panel; Pfizer Inc., Research Support; Sanofi, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Lilly Diabetes, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. A.Fritsche: Advisory Panel; Novo Nordisk, Lilly, Sanofi, Boehringer-Ingelheim, Speaker's Bureau; AstraZeneca, SYNLAB Holding Deutschland GmbH. R.Jumpertz von schwartzenberg: Other Relationship; Sanofi, Amgen Inc., Lilly, Novo Nordisk. A.L.Birkenfeld: None. S.Katzenstein: None. J.Seissler: None. S.R.Bornstein: None. N.Perakakis: Advisory Panel; Bayer Inc., Other Relationship; Novo Nordisk, Novo Nordisk. S.Kabisch: Other Relationship; Berlin-Chemie AG, Sanofi, Lilly, Boehringer Ingelheim Inc., JuZo Akademie, Research Support; J. Rettenmaier / Söhne, Wilhelm-Doerenkamp Foundation, German Center of Diabetes Research. A.F.Pfeiffer: Advisory Panel; Abbott Diabetes, Speaker's Bureau; Novo Nordisk, Sanofi-Aventis Deutschland GmbH. H.Häring: None. M.Blüher: Advisory Panel; Boehringer Ingelheim Inc., Lilly, Novo Nordisk, Consultant; Novo Nordisk Foundation, Speaker's Bureau; Amgen Inc., AstraZeneca, Bayer Inc., Daiichi Sankyo, Novartis, Sanofi-Aventis Deutschland GmbH.

789-P: Real-Life Effectiveness of iGlarLixi (Insulin Glargine 100 U/ml and Lixisenatide) in People with Type 2 Diabetes (T2D) according to Prior Insulin Use

Little is known in real life clinical practice about the effectiveness and safety of iGlarLixi in insulin naïve compared to insulin treated people with T2D. In the European REALI pooled database, we analyzed patient-level data of 1317 people with T2D initiating a 24-week iGlarLixi treatment: 718 were insulin naïve (55%) and 598 insulin treated (45%), with a median treatment duration of 2.5 years. Demographics were similar among groups with an overall mean±SD age of 61±9 years and BMI 32.2±5.5 kg/m². Median T2D duration was 8 years in the naïve group and 10 years in the treated group. At Baseline, mean HbA1c was 9.39% in the naïve and 8.76% in the treated (p<0.001). The least square (LS) mean HbA1c change from Baseline to Week 24 (using MMRM) was -1.57% in the naïve and -1.29% in the treated (Fig 1); the LS mean [95% CI] fasting plasma glucose change was -52.5 [-54.9; -50.1] and -50.4 [-53.4; -47.5] mg/dL, respectively. Mean±SD body weight decreased by 1.8±4.6 kg at Week 24, with no difference between groups. Mean iGlarLixi daily dose at Baseline was 14.3U in the naïve and 24.4U in the treated, and reached 30.7U and 36.4U, respectively, at Week 24. Symptomatic hypoglycemia reports and gastrointestinal side effects were low in both groups. This analysis demonstrated effectiveness and safety of iGlarLixi in both insulin naïve and insulin treated people with T2D in clinical practice. Disclosure J.Seufert: Advisory Panel; Abbott Diabetes, Boehringer Ingelheim Pharma GmbH&Co.KG, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Abbott Diabetes, Bayer Inc., Boehringer Ingelheim Pharma GmbH&Co.KG, Merck Sharp & Dohme Corp., Sanofi-Aventis Deutschland GmbH, Novartis, Novo Nordisk. N.Freemantle: Advisory Panel; AstraZeneca, Research Support; Galderma, ALK-Abelló A/S, Ipsen Biopharmaceuticals, Inc., Vertex Pharmaceuticals Incorporated, Thea, Speaker's Bureau; Abbott Singapore, ALK Shanghai. C.Guja: Advisory Panel; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Speaker's Bureau; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Servier Laboratories, Viatris Inc. M.Haluzik: Advisory Panel; Novo Nordisk, Lilly Diabetes, Boehringer-Ingelheim, Research Support; Sanofi, Speaker's Bureau; Abbott, AstraZeneca. G.Bigot: None. M.Tournay: None. M.Bonnemaire: Employee; Sanofi, Stock/Shareholder; Sanofi. J.T.Kis: None. Funding Sanofi

1325-P: Continuous Representation of Type 2 Diabetes Heterogeneity on a Tree-Like Graph Structure Stratifies Risk of Complications

Heterogeneity in type 2 diabetes (T2D) can be represented by a tree-like structure using reverse graph-embedded dimensionality reduction. We aimed to validate this approach and study if intensified phenotyping stratifies complications. Participants (n=927) of the German Diabetes Study (GDS) with recent-onset T2D were mapped onto a two-dimensional tree based on HbA1c, BMI, total and HDL cholesterol, triglycerides, alanine aminotransferase, creatinine, systolic and diastolic blood pressure, residualized for age and sex. A subset (n=447) had follow-up examinations after 5 years. Phenotypic variability rendered on a tree structure showed gradients for insulin sensitivity (hyperinsulinemic-euglycemic clamp, both dimensions: p<0.001) and insulin secretion (intravenous glucose tolerance test, both dimensions: p<0.001) (Fig 1). Individuals in the tree branch with the lowest insulin sensitivity had the highest liver fat content (1H-MR spectroscopy, pdim1<0.001, pdim2=0.04), elevated cardiovascular hazard (nevents=147, HRmax 4.0, pdim1=0.2, pdim2<0.001) and diabetic retinopathy (nevents=36, fundus photography, HRmax 2.5, pdim1=0.04, pdim2=0.2). This method provides an alternative approach to discrete clusters in identifying persons at high risk of certain diabetes-related diseases, potentially providing a framework for precision diabetology. Disclosure M.Schön: None. G.J.Bönhof: None. A.L.Birkenfeld: None. J.Seissler: None. A.F.Pfeiffer: Advisory Panel; Abbott Diabetes, Speaker's Bureau; Novo Nordisk, Sanofi-Aventis Deutschland GmbH. M.Blüher: Advisory Panel; Boehringer Ingelheim Inc., Lilly, Novo Nordisk, Consultant; Novo Nordisk Foundation, Speaker's Bureau; Amgen Inc., AstraZeneca, Bayer Inc., Daiichi Sankyo, Novartis, Sanofi-Aventis Deutschland GmbH. S.R.Bornstein: None. J.Szendroedi: None. S.Meyhoefer: None. V.Burkart: None. V.Schrauwen-hinderling: None. K.Prystupa: Other Relationship; Berlin-Chemie AG. O.Kuss: Consultant; Berlin-Chemie AG. E.Pearson: Speaker's Bureau; Novo Nordisk, Lilly, Illumina. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. The german diabetes study (gds) group: n/a. T.Mori: None. O.P.Zaharia: None. K.Bódis: None. Y.Kupriyanova: None. A.Nair: None. A.Strom: None. R.Guthoff: Other Relationship; Alimera, Bayer Inc., Novartis, Allergan. Funding German Diabetes Center; German Federal Ministry of Health (Berlin, Germany); Ministry of Culture and Science of the state North Rhine-Westphalia (Düsseldorf, Germany); German Federal Ministry of Education and Research; German Center for Diabetes Research

728-P: Biomarkers of Low-Grade Inflammation in Novel Subtypes of Patients at Risk for Diabetes

In the Tübingen Family Study recently 6 subtypes of prediabetic metabolism were identified. Cluster 3, 5 and 6 have a moderate to high risk for T2D or its associated complications. Cluster 3 is characterized by low insulin secretion, cluster 5 by insulin resistance and high liver fat content. Individuals in cluster 6 have an elevated risk of nephropathy despite a delayed diabetes development. Low-grade inflammation has been implicated in the development of T2D and cardiorenal complications. We hypothesized that the subtypes differ in levels of inflammatory biomarkers. Thus, we measured 31 inflammatory biomarkers associated with metabolic disease. We used Bio-Plex® multiplex immunoassays in 145 individuals who were recruited in Tübingen from the Prediabetes Lifestyle Intervention Study (PLIS) - a multicenter study conducted in individuals with ADA-defined prediabetes. Cluster comparison was done using ANOVA models, raw unadjusted values are reported. We identified eight biomarkers which differed among diabetes-risk subtypes, namely MIP1a, MIP1b, IL18, Osteopontin (OPN), IFNy, TNFb, and soluble TNFa-Receptor (sTNF-R)- 1 and -2. High risk cluster 3, 5 and 6 had significantly elevated levels of several inflammatory biomarkers compared to low risk cluster 2 with the lowest levels of these biomarkers. Within the high-risk groups, cluster 5 had increased biomarker levels compared to cluster 3 (e.g., IL-18: cluster 5: 86.2 pg/ml ± 3.9 vs cluster 3: 66.8 pg/ml ± 4.8, p=0.018; OPN: 16.8 ng/ml ± 1.0 vs. 12.8 ng/ml ± 0.8, p = 0.022; MIP1a 2.2 pg/ml ± 0.1 vs. 1.6 pg/ml ± 0.1, p < 0.001). Cluster 6 showed lower levels of IFNy than cluster 3 (2.2pg/ml ± 0.3 vs 3.5pg/ml ± 0.2, P=0.019). Our data show that the novel T2D risk subtypes differ in inflammatory biomarkers. This suggests that a low-grade inflammation may be involved in the progression from prediabetes to T2D and complications. A more precise mechanistic understanding is needed in order to establish precise preventive strategies for different risk phenotypes. Disclosure S.Katzenstein: None. J.Szendroedi: None. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. L.Fritsche: None. N.Stefan: Advisory Panel; Pfizer Inc., Research Support; Sanofi, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Lilly Diabetes, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. A.Fritsche: Advisory Panel; Novo Nordisk, Lilly, Sanofi, Boehringer-Ingelheim, Speaker's Bureau; AstraZeneca, SYNLAB Holding Deutschland GmbH. A.L.Birkenfeld: None. R.Jumpertz von schwartzenberg: Other Relationship; Sanofi, Amgen Inc., Lilly, Novo Nordisk. A.Sandforth: None. V.Minelli faiao: None. J.Seissler: None. S.R.Bornstein: None. N.Perakakis: Advisory Panel; Bayer Inc., Other Relationship; Novo Nordisk, Novo Nordisk. A.Schürmann: None. S.Kabisch: Other Relationship; Berlin-Chemie AG, Sanofi, Lilly, Boehringer Ingelheim Inc., JuZo Akademie, Research Support; J. Rettenmaier / Söhne, Wilhelm-Doerenkamp Foundation, German Center of Diabetes Research. M.Blüher: Advisory Panel; Boehringer Ingelheim Inc., Lilly, Novo Nordisk, Consultant; Novo Nordisk Foundation, Speaker's Bureau; Amgen Inc., AstraZeneca, Bayer Inc., Daiichi Sankyo, Novartis, Sanofi-Aventis Deutschland GmbH.

1564-P: Impaired Insulin Secretion Increases Glucagon Action on the Liver

The transition from prediabetes to diabetes is characterized by defects in insulin secretion and glucagon suppression in response to glucose. However, simultaneous estimation of both hormones actions on endogenous glucose production (EGP) remains a challenge. To address this, we studied 36 nondiabetic subjects on 2 occasions when endogenous hormone secretion was inhibited by somatostatin. Glucagon was infused at 0.65 ng/kg/min, at 0 min to prevent a fall in its concentration (non-suppressed - NS) or at 120 min to create a transient fall (suppressed - S). [3-3H]-glucose was infused to mimic an oral glucose challenge together with a prandial insulin infusion - one group received the full dose (100%), another 80% and another 60%. We tested models describing EGP as a function of glucose, insulin and glucagon concentrations. The optimal model assumes that EGP is suppressed by the actions of glucose, its rate of change and insulin in a remote compartment, while plasma glucagon stimulated EGP (through parameter SGn), with an effect that is evanescent. With 60% replacement (corresponding to severely impaired insulin secretion), SGn was significantly higher than with 80% (moderately impaired) and 100% replacement (p=0.02, Fig.1). This demonstrates that glucagon action on EGP is modulated by insulin concentrations, emphasizing the need to quantify secretion and action of both hormones when measuring postprandial islet function. Disclosure A. Tonello: None. M.C. Laurenti: None. C. Cobelli: None. A. Vella: Other Relationship; Novo Nordisk. Advisory Panel; Rezolute, Inc. Consultant; Crinetics Pharmaceuticals, Inc., Hanmi Pharm. Co., Ltd., Zealand Pharma A/S. C. Dalla Man: Research Support; Sanofi-Aventis Deutschland GmbH, Becton, Dickinson and Company. Funding Italian Minister for Education; National Institutes of Health (DK116723)

1702-P: Altered Gene Expression Signatures following COVID-19 Infections and/or mRNA Vaccination in Human Adipose Tissue

Obesity is associated with an increase in morbidity and mortality from Coronavirus disease- 2019 (COVID-19). Adipose tissue (AT) demonstrates high expression of angiotensin-converting enzyme 2 (ACE2), a host cell entry factor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 has been shown to infect AT, where it continues to proliferate, thereby contributing to local inflammation. Since visceral AT inflammation may play a role in the pathogenesis of type 2 diabetes, we investigated the molecular and histological AT signatures after a Covid-19 infection and/or mRNA vaccination. We investigated 54 paired subcutaneous (SC) and visceral adipose tissue (VAT) biopsies from the Leipzig Obesity BioBank in subgroups based on positive versus negative SARS-CoV-2 infection as well as mRNA vaccination status in comparison to BMI and age matched controls obtained before appearance of Covid-19 (N=27). We compared gene expression signatures by RNA-Sequencing analyses, morphology changes in AT as well as circulating inflammation markers across the groups. In relation to a Covid-19 infection, we find a distinct gene expression signature and morphology in AT suggesting that SARS-CoV-2 affects AT and may mediate the disease course. In this context, inflammation of AT, but also an altered secretion profile from AT could link obesity to its metabolic complications, but also to long Covid-19 disease courses. Disclosure S.Krupka: None. M.Blüher: Advisory Panel; Boehringer Ingelheim Inc., Lilly, Novo Nordisk, Consultant; Novo Nordisk Foundation, Speaker's Bureau; Amgen Inc., AstraZeneca, Bayer Inc., Daiichi Sankyo, Novartis, Sanofi-Aventis Deutschland GmbH. N.Klöting: None.

985-P: Is Insulin Titration Supported by a Titration App Safe? Safety Results of an RCT

A multicenter RCT in people with type 2 diabetes has shown that the use of a basal insulin titration app (myDose Coach) reduced A1c levels by 0.35 percentage points compared to titration without an app. Is the use of such a titration app associated with safety issues? We used negative binomial regressions to analyze the occurrence of adverse and serious adverse events (AE, SAE) and exposure to dangerously low (<54 mg/dl) or high (>250 mg/dl) glucose levels in 251 participants (age 60.0 years IQR 56.0 - 66.5; HbA1c 8.2 IQR 7.7 - 9.1%) randomized equally to the control and intervention groups. A total of 30 AEs (16 vs. 14 events) occurred in the control and intervention groups, of which 14 were SAEs (7 vs. 7 events). No event was judged to be associated with study participation or the interventions. The rates of dangerous low and high glucose in the control and intervention group were 0.12% vs. 0.10% for %< 54 mg/dl and 4.9% vs. 3.6% for %< 250 mg/dl, respectively (see Figure 1 for IRR and p values for superiority). A post-hoc non-inferiority test for the occurrence of %< 54 mg/dl and >250 mg/dl with non-inferiority margins of < 1% and < 5%, respectively, showed significant non-inferiority regarding the intervention group (both p < 0.01) with a post-hoc power by 75% respectively 55%. The results did not indicate an increased risk for insulin titration by the evaluated app compared to the control condition in terms of AE or extreme glucose excursions. Disclosure B.Kulzer: Advisory Panel; Berlin-Chemie AG, Abbott Diabetes, Bayer Inc., Dexcom, Inc., Novo Nordisk, Insulet Corporation, embecta, Research Support; Sanofi, Roche Diabetes Care. D.Ehrmann: Advisory Panel; Roche Diabetes Care, mySugr, Dexcom, Inc., Speaker's Bureau; Berlin-Chemie AG, Dexcom, Inc. T.Roos: None. K.Finke-groene: None. N.Hermanns: Advisory Panel; Insulet Corporation, Research Support; Sanofi-Aventis Deutschland GmbH, Roche Diagnostics, Becton, Dickinson and Company, Speaker's Bureau; Dexcom, Inc., Berlin-Chemie AG. Funding Sanofi

1452-P: Type 1 Diabetes Subphenotypes—A Cluster Analysis

Adult-onset type 1 diabetes (T1D) is a chronic disease with progressive beta-cell destruction. However, individuals with adult-onset T1D are metabolically dissimilar. We aimed to identify metabolically distinct groups in a comprehensively phenotyped cohort of individuals with recent-onset T1D. Participants with T1D (n=550) were split by presence of glutamic-acid decarboxylase antibody (GADA) into a GADA- (n=95) and GADA+ groups (n=455). GADA+ was clustered using partitioning around medoids based on fasting C-peptide, glucose, triglycerides and HDL resulting in 2 distinguished GADA+ clusters. All 3 clusters were compared at baseline (first year of diabetes diagnosis) and after five years of follow-up using ANOVA, chi-squared test and logistic regression adjusted for age and sex. The larger GADA+ cluster (n=285) with younger age, lower BMI and lower C-peptide was termed “classic T1D”. The other GADA+ cluster (n=170) combined features of type 1 and type 2 diabetes and was named “mixed T1D”. Patients of the “mixed T1D” cluster did not gain weight over 5 years (p=0.29), which was not the case for “classic T1D” cluster (p<0.001, increased BMI with an effect size 0.07) and GADA-cluster (p=0.01, effect size 0.04) participants. The “classic T1D” cluster had the highest insulin sensitivity at baseline (p<0.001) that sharply decreased during five years of follow-up. At five years, there was no difference in insulin sensitivity across the 3 clusters (p=0.78). There were no differences in HbA1c levels across clusters neither at baseline (p=0.48) nor after 5 years (p=0.64). Classic T1D participants reported a higher incidence of hypoglycemia (OR 4.92, 95% CI 1.9-13.5, p=0.001). The incidence of both distal peripheral sensory (OR 2.89, 95%CI1.05-8.29, p= 0.041) and cardiac autonomic neuropathy (OR 9.61, 95%CI 2.35-49.8, p= 0.003), was higher in “mixed T1D”. Based on rapidly available laboratory variables, individuals with recent-onset adult type 1 diabetes can be stratified into clusters with different clinical course and complication risk Disclosure K.Prystupa: Other Relationship; Berlin-Chemie AG. S.M.Meyhöfer: Speaker's Bureau; Novo Nordisk, AstraZeneca, Lilly, Amgen Inc., Boehringer-Ingelheim, Novartis. O.P.Zaharia: None. N.Saatmann: None. M.Huttasch: None. K.Strassburger: None. V.Burkart: None. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. A.Fritsche: Advisory Panel; Novo Nordisk, Lilly, Sanofi, Boehringer-Ingelheim, Speaker's Bureau; AstraZeneca, SYNLAB Holding Deutschland GmbH. G.J.Bönhof: None. A.Strom: None. M.Heni: Advisory Panel; Boehringer-Ingelheim, Sanofi, Research Support; Boehringer Ingelheim Inc., Speaker's Bureau; Lilly, Bayer Inc., Sanofi, Boehringer-Ingelheim, Novo Nordisk, Amryt Pharma Plc. J.Seissler: None. J.Szendroedi: None. A.F.Pfeiffer: Advisory Panel; Abbott Diabetes, Speaker's Bureau; Novo Nordisk, Sanofi-Aventis Deutschland GmbH. M.W.Stumvoll: None.

665-P: Longitudinal Impact of Daily Experienced Diabetes Distress and Affective Symptoms on the Incidence and Remission of Depressive Symptoms—Results of the DIA-LINK 1 and 2 Studies

We analyzed whether daily experience of diabetes distress and affective symptoms, assessed with ecological momentary assessment (EMA) can predict incidence or remission of elevated depressive symptoms in people with type 1 and type 2 diabetes. In the DIA-LINK studies, 203 people with type 1 and 193 people with type 2 diabetes participated. In the 17-day EMA phase, participants completed daily prompts assessing different affective symptoms and diabetes distress. 358 participants completed the CES-Depression questionnaire at baseline and 3 months later. Incidence and remission of elevated depressive symptoms were defined by a cut-off score of 22. Area under receiver operating characteristics curves were used to analyse the predictive performance of EMA variables on incidence and remission of depressive symptoms. Incidence of elevated depressive symptoms was 18.3% while 32.3% showed a remission. Predictive performances of 15 different EMA variables are shown in Table 1. Daily experience of diabetes distress and affective symptoms can predict incidence and remission of elevated depressive symptoms. These variables could be used for designing just-in-time adaptive interventions for preventing elevated depressive symptoms in people with diabetes experiencing daily emotional burden of living with diabetes. Disclosure D.Ehrmann: Advisory Panel; Roche Diabetes Care, mySugr, Dexcom, Inc., Speaker's Bureau; Berlin-Chemie AG, Dexcom, Inc. A.J.Schmitt: None. B.Olesen: Advisory Panel; AstraZeneca, Evivamed, Berlin-Chemie AG, Speaker's Bureau; Medtronic, Medtrixx. B.Kulzer: Advisory Panel; Berlin-Chemie AG, Abbott Diabetes, Bayer Inc., Dexcom, Inc., Novo Nordisk, Insulet Corporation, embecta, Research Support; Sanofi, Roche Diabetes Care. N.Hermanns: Advisory Panel; Insulet Corporation, Research Support; Sanofi-Aventis Deutschland GmbH, Roche Diagnostics, Becton, Dickinson and Company, Speaker's Bureau; Dexcom, Inc., Berlin-Chemie AG. Funding German Center for Diabetes Research (FKZ82DZD1102A)

254-OR: Effects of Roux-en-Y Gastric Bypass on Postprandial Glucose Turnover Assessed through the Single-Tracer Oral Minimal Model

Rearrangements of gastrointestinal anatomy after Roux-en-Y gastric bypass (RYGB) surgery alter postprandial glucose metabolism. However, the impact on different components of glucose homeostasis remain incompletely understood. Here, we aim to evaluate the effects of RYGB on postprandial glucose turnover, production (P) and disposal (D) glucose effectiveness (GEP, GED) and production and disposal sensitivity to insulin (SIP, SID). Ten RYGB (2M, age=39.2±3.1 y, BMI=28±1 kg/m2- mean±SE) subjects and 10 healthy controls (5M, age=36.4±3.2 y, BMI=26±1 kg/m2) ingested 60g of glucose (G) labelled with [6,6-2H2]-glucose. Plasma samples were frequently drawn to measure G, insulin (I) and tracer concentrations in the following 180 min. The Single-Tracer Oral Minimal Model was used to estimate meal glucose rate of appearance (Ra), endogenous glucose production (EGP), glucose disposal (Rd), GEP, GED, SIP and SID. Incremental area under the G curve (iAUC(G)) was not different in the two groups, while iAUC(I) was significantly higher in RYGB (8346±803 vs. 5451±602 μU/mL*min, p=0.011); iAUC(Ra) normalized to the G dose was significantly higher in the first 60 min after the meal (0.72±0.04 vs. 0.28±0.03, p<0.001) while, throughout the experiment, EGP suppression (EGPs) normalized to basal (EGPb) was significantly lower (0.31±0.06 vs. 0.55±0.05, p=0.006) and iAUC(Rd) normalized to basal (Rdb) was higher (3.46±0.10 vs. 2.82±0.08, p<0.001) in RYGB than controls. Model predicted SIP was significantly lower in RYGB than controls (2.0±0.5 vs. 5.1±1.2 10-4 dL/kg/min per μU/mL, p=0.033) while no differences were observed in GEP, GED and SID. We concluded that the abnormally high I concentration in RYGB was responsible for the higher iAUC(Rd) in the operated individuals, while the reduced SIP likely works as a protective mechanism against postprandial hypoglycaemia by reducing EGPs despite the high circulating I. Disclosure A.Brunasso: None. C.Dalla man: Research Support; Sanofi-Aventis Deutschland GmbH, Becton, Dickinson and Company. D.Herzig: None. L.Bally: Research Support; Dexcom, Inc., Ypsomed AG. M.Schiavon: None. Funding Italian Minister for Education (Law 232/2016); Swiss National Science Foundation (PCEGP3_186978)

1547-P: The Differential Effect of Glucagon-Like Peptide-1 Receptor Blockade on Glucose Metabolism in People With and Without Type 2 Diabetes

Glucagon-Like Peptide-1 (GLP-1) is present within the islet but the effects of GLP-1 Receptor (GLP1R) blockade on islet function in humans remains unknown. To address this, we studied 12 nondiabetic individuals (54 ± 2 years, 33 ± 1 kg/m2) and 11 people with type 2 diabetes (DM2 - 58 ± 2 years, 34 ± 2 kg/m2) on 2 occasions in random order. On each occasion, after an overnight fast, [3-3H] glucose was used to measure glucose turnover during fasting and a hyperglycemic clamp (~9 mmol/l) using the tracer dilution technique. On one occasion exendin-9,39 (300pmol/kg/min) was infused to block GLP1R, while on the other saline was infused. Exendin-9,39 increased fasting glucose concentrations in those without (4.6 ± 0.4 vs. 5.5 ± 0.1 mmol/l, saline vs. exendin-9,39 respectively, p = 0.04) and in those with DM2 (7.3 ± 0.5 vs. 8.3 ± 0.6 mmol/l, p = 0.03). Fasting islet hormone concentrations were unchanged, but inappropriate for the higher fasting glucose observed during exendin-9,39 infusion. The same pattern was seen in people with DM2 except that fasting glucagon concentrations increased (8.3 ± 0.5 vs. 10.2 ± 0.6 pmol/l, p < 0.01) and remained elevated throughout hyperglycemia (4.7 ± 0.4 vs. 7.7 ± 0.6 pmol/l, p < 0.02). Insulin secretion rate calculated by deconvolution of C-peptide concentrations was also decreased in DM2 (0.54 ± 0.08 vs. 0.51 ± 0.08 nmol/min, p = 0.02). Consequently, suppression of endogenous glucose production by hyperglycemia was impaired in people with DM2 (2.9 ± 0.4 vs. 5.7 ± 0.3 μmol/kg/min, p < 0.01). Intriguingly, 1st phase response to hyperglycemia was decreased in those without DM2 (3.5 ± 0.6 vs. 2.5 ± 0.5 nmol per 10 min, p = 0.04). These data show that in humans, GLP1R blockade impairs fasting α- and β-cell function resulting in fasting hyperglycemia. Subtle effects are also present in response to hyperglycemia. This implies that intra-islet GLP1R activation sustains islet responses to glucose and it does so to a greater degree in people with DM2. Disclosure A.A. Welch: None. R.A. Farahani: None. M. Zeini: None. A.M. Egan: None. M.C. Laurenti: None. C. Cobelli: None. C. Dalla Man: Research Support; Sanofi-Aventis Deutschland GmbH, Becton, Dickinson and Company. A. Vella: Other Relationship; Novo Nordisk. Advisory Panel; Rezolute, Inc. Consultant; Crinetics Pharmaceuticals, Inc., Hanmi Pharm. Co., Ltd., Zealand Pharma A/S. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126206)

932-P: Impact of a Titration App for Basal Insulin on Glycaemic Outcomes in People with Type 2 Diabetes on an Oral-Basal Insulin Regimen—Results of an RCT

A multicenter RCT analyzed the efficacy of a basal insulin titration app (myDose Coach; MDC) in people with type 2 diabetes and newly initiated or existing basal insulin treatment. We randomized 251 participants in a 1:1 ratio to either the intervention arm (insulin titration with MDC) or the control arm (insulin titration without App). The primary outcome was A1c reduction after 3-month. Baseline data (median age 60.0 years IQR 56.0 - 66.5; HbA1c 8.2 IQR 7.7 - 9.1%) showed no significant differences. After a median follow-up of 91.0 days, the intervention group showed a reduction in HbA1c of 0.93, IQR 0.40 - 1.57 percentage points compared to the control group (0.6; IQR 0.10 -1.40); adjusted difference between groups 0.35; 95% CI 0.35 0.01 - 0.69; p=0.0064. Improvements in follow-up A1c were evident across the range of A1c values (Figure 1). The respective differences between groups in glucose level (19.3; 95% CI 9.10 - 29.97 mg/dl; p=0.0012), fasting glucose (10.5; 95% CI 1.5 - 19. 0 mg/dl) and % < 180 mg/dl (12.2; 95% CI 3.8 - 20.5; p=0.0065) all favored the intervention group, while % < 70 mg/dl (−0.2; 95% CI −1.0 - 0.6; p=0.8778) did not differ substantially. Titration of basal insulin with the MDC app significantly improved glycemic management, without increasing exposure to low glucose values substantially. Thus, titration with the MDC app has a medical benefit beyond usual care. Disclosure N.Hermanns: Advisory Panel; Insulet Corporation, Research Support; Sanofi-Aventis Deutschland GmbH, Roche Diagnostics, Becton, Dickinson and Company, Speaker's Bureau; Dexcom, Inc., Berlin-Chemie AG. D.Ehrmann: Advisory Panel; Roche Diabetes Care, mySugr, Dexcom, Inc., Speaker's Bureau; Berlin-Chemie AG, Dexcom, Inc. T.Roos: None. K.Finke-groene: None. B.Kulzer: Advisory Panel; Berlin-Chemie AG, Abbott Diabetes, Bayer Inc., Dexcom, Inc., Novo Nordisk, Insulet Corporation, embecta, Research Support; Sanofi, Roche Diabetes Care. Funding Sanofi

666-P: How Satisfied Are People with Type 2 Diabetes with a Basal Insulin Titration App? Findings from the Intervention Group of a Randomized Controlled Trial

A randomized controlled trial (RCT) was conducted to evaluate the efficacy of the myDoseCoach app, an insulin titration app for basal insulin for people with type 2 diabetes. We asked app users in this study to evaluate the quality of the app via a modified version of the Mobile App Rating Scale (MARS). A total of 120 participants (median age: 60.0 yrs; A1C 8.1%; BMI 31.8 kg/m², diabetes duration 10.0 yrs., 39.0% female) of the intervention arm completed the MARS. Reliability of the 11 item version was high with Cronbach’s α = 0.915. Mean MARS rating was 4.4 (range 1-5), indicating a rather high quality rating. Less than 10% indicated a low quality of the app (rating <3); 10% were indifferent and more that 70% rated the quality of the app as “4” or higher. Figure 1 shows the ratings of the 11 single items. Bivariate correlations showed that neither older age (r=-0.064; p=0.322) nor gender (r=0.102; p=0.180) were significantly associated with the quality rating. The results indicate that the vast majority of the app users evaluated the quality of the App positively with regard to its engagement, functionality, aesthetics, and information quality. Disclosure D.Ehrmann: Advisory Panel; Roche Diabetes Care, mySugr, Dexcom, Inc., Speaker's Bureau; Berlin-Chemie AG, Dexcom, Inc. N.Hermanns: Advisory Panel; Insulet Corporation, Research Support; Sanofi-Aventis Deutschland GmbH, Roche Diagnostics, Becton, Dickinson and Company, Speaker's Bureau; Dexcom, Inc., Berlin-Chemie AG. T.Roos: None. K.Finke-groene: None. B.Kulzer: Advisory Panel; Berlin-Chemie AG, Abbott Diabetes, Bayer Inc., Dexcom, Inc., Novo Nordisk, Insulet Corporation, embecta, Research Support; Sanofi, Roche Diabetes Care. Funding Sanofi

698-P: Interoperability as an Important Factor for Achieving the Full Potential of a Digital Diabetes Logbook

A randomized controlled trial (RCT) has demonstrated the efficacy of a digital diabetes logbook (mySugr) in reducing diabetes distress compared to a control group without such an app. In a sub-group analysis, we analyzed whether those who have paired their glucose meter (glucose values were directly imported into the app) benefit differently than those who manually entered their glucose values. A total of 282 people were randomized to the intervention group using the app for 3 months (2:1 randomization; age: 51.2±14.6 years; 13.1% type 1, 66.7% type 2, 20.2% gestational diabetes). The per protocol population within the intervention group consisted of 232 participants who completed the 3-month follow-up and have used the app on ≥10% of the study days. Analysis of covariance was conducted with diabetes distress at the 3-month follow-up at dependent variable and connected glucose meter (yes/no) as independent variable, controlled for diabetes distress at baseline. Diabetes distress was measured with the Problem Areas in Diabetes (PAID) questionnaire. Within the per protocol population, 134 participants of the intervention group (57.8%) have used a connected glucose meter. Participants with a connected meter had significantly less diabetes distress at follow-up compared to participants who manually entered their glucose values (16.9±1.05 vs. 20.5±1.2, p = 0.027). There was no significant difference in demographic characteristics between the two groups. Participants with a connected meter had significantly more meal logs (3.3±2.2 vs. 2.0±1.2, p = 0.01) on days they have used the app. Overall, the digital diabetes logbook was able to reduce diabetes distress over a 3-month period. This reduction in diabetes distress was more pronounced in participants who used an interoperable glucose meter that automatically transferred glucose data into the app. Interestingly, there seems to be an increased interaction with the app regarding logging of meals in participants with a connected meter. Disclosure B.Kulzer: Advisory Panel; Berlin-Chemie AG, Abbott Diabetes, Bayer Inc., Dexcom, Inc., Novo Nordisk, Insulet Corporation, embecta, Research Support; Sanofi, Roche Diabetes Care. D.Ehrmann: Advisory Panel; Roche Diabetes Care, mySugr, Dexcom, Inc., Speaker's Bureau; Berlin-Chemie AG, Dexcom, Inc. N.Hermanns: Advisory Panel; Insulet Corporation, Research Support; Sanofi-Aventis Deutschland GmbH, Roche Diagnostics, Becton, Dickinson and Company, Speaker's Bureau; Dexcom, Inc., Berlin-Chemie AG. I.Vesper: None. V.L.Schaefer: Employee; Roche Diabetes Care. S.Silbermann: Employee; Roche Diabetes Care. J.Kober: Employee; mySugr. K.Finke-groene: None. T.Roos: None. E.Bingol: Employee; Roche Diabetes Care. Funding Roche Diabetes Care GmbH (DC000097)

96-OR: Liver Fibrosis Scores in Novel Subclusters of Patients at Risk for Type 2 Diabetes

Metabolic diseases such as type 2 diabetes (T2D) are linked to the development of fatty liver, steatohepatitis and liver fibrosis. We have previously described novel clusters of patients at risk for T2D. Three clusters (3, 5 and 6) either had a high risk to progress to T2D or to develop cardiorenal complications. While high-risk clusters differ in liver fat content, it remains unknown if they also harbor a different risk for hepatic fibrosis. Thus, we determined clinically applicable scores of liver fibrosis in 1115 subjects at risk for T2D from the TUEF/TULIP study, which were categorized into high-risk clusters (n=602). Liver fat content was determined by 1H-magnetic resonance spectroscopy. The AST-to-platelet-ratio index (APRI), fibrosis-4 score (FIB-4) and NAFLD fibrosis score (NFS) were used to determine fibrosis risk. ANCOVA model analysis adjusted for liver fat content was performed. Of the high-risk clusters (3: n= 83, 5: n= 203, 6: n= 316), cluster 6 had the highest BMI 44.1±9.7 kg/m² (vs. cluster 3: 29.7±3.1 kg/m², p<0.001 and cluster 5: 42.8.0±8.7, p=0.32) and cluster 5 had the highest liver fat content (13.4±8.8% vs. cluster 3: 8.0±6.5, p<0.001 and cluster 6: 9.0±6.7, p<0.001). All fibrosis scores correlated with liver fat content (e.g. FIB-4: r= 0.45, p< 0.0001). Although FIB-4, APRI and NFS were generally low, they were highest in cluster 5, but despite highest liver fat content, they did not differ from cluster 3 and 6 (e.g. FIB-4: cluster 5: 0.19±0.45 vs. cluster 3: 0.14±0.01, p=0.59 and cluster 6: 0.12±0.15, p=0.39). Interestingly, cluster 3 with the lowest liver fat content exhibited higher FIB-4 compared to cluster 6 (p=0.02). According to clinically applicable scores, the most insulin resistant cluster 5 has the highest FIB-4 score. The insulin deficient cluster 3 has a relatively high FIB-4 score despite relatively low liver fat content and BMI. Further studies are needed to investigate the clinical relevance of these findings. Disclosure V.Minelli faiao: None. A.Peter: None. A.L.Birkenfeld: None. N.Stefan: Advisory Panel; Pfizer Inc., Research Support; Sanofi, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Lilly Diabetes, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. R.Jumpertz von schwartzenberg: Other Relationship; Sanofi, Amgen Inc., Lilly, Novo Nordisk. A.Sandforth: None. S.Katzenstein: None. A.Fritsche: Advisory Panel; Novo Nordisk, Lilly, Sanofi, Boehringer-Ingelheim, Speaker's Bureau; AstraZeneca, SYNLAB Holding Deutschland GmbH. L.Fritsche: None. J.Machann: None. F.Schick: None. H.Häring: None. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi.

1646-P: The Effect of Glucagon-Like Peptide-1 Receptor Blockade and Acute Insulin Resistance on Islet Function and Glucose Metabolism in People without Diabetes

Intra-islet Glucagon-Like Peptide-1 (GLP-1) is increased by islet inflammation and diabetes. GLP-1 Receptor (GLP1R) blockade with exendin-9,39 impairs fasting islet function in people with and without type 2 diabetes (DM2). In addition, it decreases insulin secretion and glucagon suppression in response to hyperglycemia in people with DM2. We sought to examine if free fatty acid (FFA) elevation to induce acute insulin resistance in people without DM2 replicated the effects of GLP1R blockade seen in DM2. We studied 6 nondiabetic individuals (54 ± 4 years, 33 ± 1 kg/m2) on 4 occasions in random order. Glucose metabolism was measured after an overnight fast and during a hyperglycemic clamp (~9 mmol/l) using [3-3H] glucose. On two occasions Intralipid® and heparin were infused to raise FFA. Exendin-9,39 (300pmol/kg/min) was infused to block GLP1R in the presence or absence of FFA elevation, while on the other days saline was infused. In the absence of FFA elevation, exendin-9,39 infusion increased fasting glucose concentrations (5.0 ± 0.1 vs. 5.4 ± 0.1 mmol/l, saline vs. exendin-9,39 respectively, p = 0.01). This pattern was also observed when FFA were elevated (5.3 ± 0.1 vs. 5.7 ± 0.2 mmol/l, p = 0.02). Fasting insulin, C-peptide (without FFA: 0.9 ± 0.1 vs. 0.8 ± 0.1 nmol/l, p = 0.17; with FFA: 1.1 ± 0.1 vs. 1.0 ± 0.1 nmol/l, p = 0.08) and glucagon concentrations were unchanged, but inappropriate for the higher fasting glucose observed during exendin-9,39 infusion. Exendin-9,39 infusion did not alter islet hormone secretion during the clamp in the presence or absence of FFA elevation. The magnitude of changes induced by exendin-9,39 did not differ in the presence or absence of FFA elevation (p > 0.10). These experiments confirm the effects of GLP1R blockade on fasting α- and β-cell function in people without DM2. However, FFA elevation does not replicate the abnormalities of islet function observed in people with DM2 when exendin-9,39 is infused. Disclosure M. Zeini: None. R.A. Farahani: None. A.A. Welch: None. M.C. Laurenti: None. C. Cobelli: None. C. Dalla Man: Research Support; Sanofi-Aventis Deutschland GmbH, Becton, Dickinson and Company. A.M. Egan: None. A. Vella: Other Relationship; Novo Nordisk. Advisory Panel; Rezolute, Inc. Consultant; Crinetics Pharmaceuticals, Inc., Hanmi Pharm. Co., Ltd., Zealand Pharma A/S. Funding National Institutes of Health (DK126206)

1645-P: Diabetes-Associated Variation in TCF7L2 Is Associated with a Longitudinal Decline in Glucose Tolerance Accompanied by Impaired Suppression of Postprandial Glucagon Secretion

Diabetes-associated alleles in TCF7L2 increase the rate of conversion from prediabetes to type 2 diabetes (T2DM). Multiple studies have shown an association of the T allele at rs7903146 with impaired β-cell function and more recently with defective suppression of α-cell secretion by glucose. However, the temporal relationship of these abnormalities is uncertain. To study the longitudinal changes in islet function, we recruited 140 individuals half of whom were homozygous for the diabetes-associated allele (TT) at rs7903146. The remainder were homozygous for the protective allele (CC). Subjects were studied on 2 occasions, 3 years apart using an oral 75g glucose challenge. This was labelled with 13C-glucose, in concert with intravenously infused tracers to enable measurement of endogenous glucose production, meal appearance and glucose disposal. Indices for insulin secretion and action were estimated using the oral minimal model. Fasting, peak and integrated (443 ± 27 vs. 428 ± 50 mmol/l per 6hr, p = 0.54) post-prandial glucose concentrations did not differ over time in people with the CC genotype. In contrast, post-prandial integrated glucose concentrations increased (441 ± 29 vs. 544 ± 37 mmol/l per 6hr, p < 0.01) in people with the TT genotype. This was accompanied by an increase in integrated postprandial glucagon concentrations (526 ± 39 vs. 618 ± 61 pmol/l per 2hr, p = 0.04) that was not observed in the CC genotype (537 ± 50 vs. 525 ± 65 pmol/l per 2hr, p = 0.07). There were no baseline differences in β-cell function between genotype groups. Disposition Index in both TT (950 ± 130 vs. 868 ± 92 10-4 dl/kg/min per μU/ml, baseline vs. follow-up study respectively, p=0.42) and CC (896 ± 177 vs. 1062 ± 289 10-4 dl/kg/min per μU/ml, p=0.65) groups did not change. This data would suggest that α-cell dysfunction associated with the TT genotype (rs7903146) precedes β-cell dysfunction in people prior to the development of T2DM. Disclosure M.Zeini: None. K.Muthusamy: None. A.M.Egan: None. M.C.Laurenti: None. C.Cobelli: None. C.Dalla man: Research Support; Sanofi-Aventis Deutschland GmbH, Becton, Dickinson and Company. A.Vella: Advisory Panel; Rezolute, Inc., Consultant; Crinetics Pharmaceuticals, Inc., Hanmi Pharm. Co., Ltd., Zealand Pharma A/S, Other Relationship; Novo Nordisk. Funding National Institutes of Health (DK116723)