bluuebunny/crossref_metadata_2025 huggingface dataset:
1436-P: Metformin Increases Skeletal Muscle Mitochondrial Function and Acute Phase Insulin Sensitivity in Obstructive Sleep Apnea
Authors: ZUNICA ELIZABETH R.M. , HEINTZ ELIZABETH C. , HEBERT REBEKAH C. , TANKSLEY MAKAYLA C. , MADER EDWARD C. , KIRWAN JOHN P. , AXELROD CHRISTOPHER L. , SINGH PRACHI
Published: May 2022

Introduction: Obstructive sleep apnea (OSA) is a prevalent sleep disorder with high type 2 diabetes (T2D) risk. OSA therapy includes positive airway pressure (PAP) treatment, which resolves breathing events but modestly improves metabolic health. Metformin is recommended for T2D prevention but is not advocated in patients with OSA. Our pilot study evaluated the effects of metformin on glucose metabolism and mitochondrial function in OSA patients.

Methods: Sixteen adults (50.5±1.6 years, BMI: 36.4±0.8 kg/m2) with OSA (apnea hypopnea index: 53.2±21.1 events/hour) were randomized to receive placebo (n=8) or metformin (n=8) treatment along with PAP for 3 months in a double-blind parallel-group design. Whole body and adipose tissue-specific insulin sensitivity (IS) was determined by oral glucose tolerance test (OGTT) . Skeletal muscle mitochondrial function was determined by high-resolution respirometry using biopsies obtained at baseline and after 3 months of treatment.

Results: Change in whole body IS (Matsuda index) was not different in metformin or placebo treated groups (p=0.46) . However, improved acute phase responses during OGTT - glucose uptake (p=0.02) , insulin release (p=0.03) , and suppressed lipolysis (p=0.03) were observed with metformin treatment relative to control. Increased skeletal muscle mitochondrial function was evident with metformin relative to control. Specifically, metformin increased complex I phosphorylation and complex IV electron transfer capacity.

Conclusion: Metformin treatment improves acute phase IS and insulin suppression of lipolysis in OSA patients. Strikingly, metformin improved skeletal muscle mitochondrial function independent of changes in second phase glucose disposal and BMI, indicating improved tissue metabolic function. These data suggest that in patients with OSA, improvement in tissue level metabolic function may precede changes in whole-body IS and metformin may improve metabolism.

Disclosure

E.R.M.Zunica: None. E.C.Heintz: None. R.C.Hebert: None. M.C.Tanksley: None. E.C.Mader: None. J.P.Kirwan: None. C.L.Axelrod: None. P.Singh: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (DK123456789) ;National Institute of General Medical Sciences (GM123456789)
1441-P: Fidelity of BMI and Waist Circumference as Adiposity Measures in White and Black Adults
Authors: LIU ZHAO , PATEL AVNISHA A. , DAGOGO-JACK SAMUEL
Published: May 2022

Background: Body mass index (BMI) and waist circumference (WC) are routine clinical estimates of obesity. We tested the fidelity of BMI and WC against direct body fat measures in Black (B) vs. White (W) Americans.

Subjects and Methods: We analyzed the relationship between BMI vs. total fat, WC vs. trunk fat, and weight vs. lean fat free mass (FFM) in healthy B and W adults. Assessments included clinical exam, biochemistries and a 75-g OGTT. All subjects had normal fasting and 2-hr OGTT glucose levels. Total fat mass, trunk fat mass and FFM were measured using DXA.

Results: The participants (n=376; 217 B, 159 W) had an age range of 18-65 years and BMI range of 16.8-66.3 kg/m2 (mean 30.1) . The W vs. B values were: age 46.5 ± 10.5 vs. 42.5 ± 10.3 y, P=0.0003; BMI 28.8 ± 6.78 vs. 31.2 ± 7.40, P=0.0015; total fat mass 29.4 ± 13.21 vs. 31.8 ± 13.76 kg, P=0.11; trunk fat mass 14.77 ± 6.96 vs. 15.34 ± 7.50 kg, P=0.48; FFM 50.12 ± 11.9 vs. 53.± 11.74 kg, P= 0.03. There were tight correlations between adiposity measures: total fat and BMI (r=0.90 in W, 0.92 in B) ; trunk fat and WC (r=0.85 in W, 0.82 in B) ; FFM and weight (r=0.83 in W, 0.87 in B) , with heterogeneity by sex and race. White men and women (vs B) tended to have more body fat per unit BMI or WC and less FFM per unit weight. We assessed 3 integrated ratios (total Fat/BMI, trunk Fat/Waist, FFM/Weight) by sex and race. Total fat/BMI was higher (P<0.0001) in W vs. B (men: 0.946 ± 0.159 vs. 0.833 ± 0.210; women: 1.36 ± 0.189 vs. 1.25 ± 0.164) . Trunk fat/waist was higher in W vs. B men (0.294 + 0.043 in W vs. 0.257 + 0.072, P=0.0046) but similar in women. In contrast, FFM/weight ratio showed no race disparities (men: 0.696 ± 0.055 vs. 0.678 ± 0.200; women: 0.586 ± 0.1vs 0.579 ± 0.076) . The proportion with >3 metabolic syndrome markers was 24.5% in W and 15.7% in B.

Conclusion: Among otherwise healthy subjects with a wide BMI range, African Americans had lower body fat than Whites. This finding that argues for ethnic-specific BMI cut-offs for obesity classification.

Disclosure

Z.Liu: None. A.A.Patel: None. S.Dagogo-jack: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Sanofi.

Funding

American Diabetes Association (7-07-MN-13) ; NIH, R01 DK067269
151-LB: Postprandial Glucose Metabolism Differs between Early Adolescents and Adults with Type 1 Diabetes
Authors: RUCHI FNU , ROMERES DAVIDE , GURURAJ SUPRAJA , DEBOER MARK D. , BASU RITA , BASU ANANDA
Published: May 2022

Postprandial glucose turnover in adolescents with type 1 diabetes (T1D) has not been investigated. To do so, we studied adolescents (n=15, age 11.5±0.5 yrs, BMI 19±2.3 kg/m2, HbA1c 7.5±1%, diabetes duration 4.6±3 yrs) and adults (n=15, age 36.3±9.4 yrs, BMI 27.1±2.1 kg/m2, HbA1c 6.9±1.1%, diabetes duration 18.1±9.6 yrs) with T1D after a mixed meal. Healthy adults (n=14, age 26.9 ± 7 yrs, BMI 24.9±2.5 kg/m2, HbA1c 5.0±0.3%) served as controls. T1D subjects administered their customary insulin bolus dose at meal onset. Rates of endogenous glucose production (EGP) , meal glucose appearance (MRa) and glucose disappearance (Rd) were calculated by the triple tracer method with stable isotopes ([1-13C] glucose, [2-13C] glucose and [6, 6-2H2] glucose) . Integrated glucose excursions did not differ between adolescents and adults with T1D during early (0-120 min) and total (0-300 min) postprandial periods. While basal EGP at start of the meal was higher (p<0.01) , integrated rates of EGP, MRa, Rd and glucose clearance were all lower (p<0.03) in adolescents than in adults with T1D during the early postprandial period and were numerically lower (p=0.08) during the total postprandial period (Figure1) . Taken together, the data demonstrates significant differences in postprandial glucose metabolism between adolescents and adults with T1D. Additional studies are ongoing to determine the causes of these differences.

Disclosure

F. Ruchi: None. D. Romeres: None. S. Gururaj: None. M. D. Deboer: Research Support; Dexcom, Inc., Tandem Diabetes Care, Inc. R. Basu: Consultant; Sparrow Pharmaceuticals Inc, Research Support; Abbott Diabetes, AstraZeneca. A. Basu: Speaker's Bureau; Zealand Pharma A/S.

Funding

DK 124886, DK 085516, DK 029953
153-OR: Ventromedial Hypothalamic Nucleus Controls Glucose Metabolism through Adipose Tissue Lipolysis
Authors: AFFINATI ALISON , FLAK JONATHAN , KODUR NANDAN , HASHSHAM ABDULLAH , TOMLINSON ABIGAIL J. , KRAMER NADEJDA BOZADJIEVA , LI CHIEN , MYERS MARTIN G.
Published: May 2022

The central nervous system (CNS) coordinates metabolic target organ function to optimize blood glucose levels, while dysregulation of this system leads to impaired glycemia. Attempts to improve glucose control through CNS targeting are hindered by a incomplete understanding of the specific neuronal populations involved and how these cells coordinate peripheral metabolic target organ function. We found that cholecystokinin b receptor-expressing neurons of the ventromedial nucleus of the hypothalamus (VMN; VMNCCKBR neurons) mediate glucose mobilization during counter-regulatory responses to hypoglycemia and regulate glucose levels in normal and diabetic mice. Silencing VMNCCKBR neurons with tetanus toxin (CCKBRTT) attenuates hyperglycemia in ob/ob mice and decreases baseline blood glucose by suppressing hepatic gluconeogenesis despite decreased insulin and elevated glucagon. CCKBRTT mice have elevated hepatic gluconeogenic enzyme expression and normal glycemic responses to exogenous gluconeogenic substrates, suggesting that silencing VMNCCKBR neurons decreases blood glucose through impaired gluconeogenic substrate mobilization. To determine which gluconeogenic substrates contribute to VMNCCKBR-neuron mediated glucose production, we expressed channel rhodopsin in VMNCCKBR neurons to optogenetically activate VMNCCKBR neurons in freely moving mice. In addition to elevating plasma glucose, optogenetic activation resulted in a β3-adrenergic receptor-dependent increase in plasma ketones and glycerol, suggesting that VMNCCKBR neurons increase lipolysis though SNS innervation of white adipose tissue (WAT) . Consistent with this observation, CCKBRTT mice exhibited decreased fasting plasma glycerol and in vivo lipolysis, while β3-agonist treatment elevated these appropriately. Hence, VMNCCKBR neuron-mediated SNS outflow to WAT promotes lipolysis to provide gluconeogenic substrates and support baseline blood glucose in mice.

Disclosure

A.Affinati: Other Relationship; Novo Nordisk A/S. J.Flak: Research Support; Eli Lilly and Company. N.Kodur: None. A.Hashsham: None. A.J.Tomlinson: None. N.Bozadjieva kramer: None. C.Li: Employee; Novo Nordisk. M.G.Myers: Advisory Panel; Regeneron Pharmaceuticals Inc., Research Support; AstraZeneca, Novo Nordisk.

Funding

National Institutes of Health (F32DK122660)
163-LB: Impact of Preexisting Type 2 Diabetes (T2D) and Concurrent Cardiovascular Disease (CVD) on Patients with COVID-19 (C-19)
Authors: NGUYEN CHI , CROWE CHRISTOPHER , KUTI EFFIE , NARSIPUR NIHAL , DONATO BONNIE M.K. , PEPE REBECCA S. , DJARAHER RACHEL L. , SEMAN LEO J. , GRAETER NANCY , POWER THOMAS P. , MEHRA RINKU , WILLEY VINCENT
Published: May 2022

Objective: The association of T2D and severe C-19 outcomes has been reported, but data are scarce on whether pre-existing CVD impacts C-19 outcomes in T2D patients. This study compared the clinical outcomes among C-19 patients with pre-existing T2D, T2D+CVD, or neither.

Methods: Retrospective study of claims and lab data to identify C-19 patients from 3/1/20 - 5/31/21 and stratify them by the presence of T2D and CVD. Outcomes included hospital/ICU admission and mortality. Propensity score matching and multivariable analyses were performed.

Results: After matching, 6,967 patients were identified for each group with a mean follow-up of 5.4 months; minimal residual baseline differences remained. Adjusted analyses (Table) show that C-19 patients with T2D+CVD or T2D only were more likely to be admitted to the hospital/ICU than those with neither (all p <0.01) , with the T2D+CVD group having greater odds. C-19 patients with T2D+CVD had a higher mortality risk compared to those with neither (p=0.02) . Among all T2D+CVD patients, acute respiratory distress syndrome (31%) , acute kidney disease (24%) , and ventilator use (8%) were observed.

Conclusion: Our study highlights the incrementally poorer outcomes associated with pre-existing T2D+CVD in C-19 patients and may suggest consideration of a more aggressive management approach in these patients with a less favorable prognosis.

Disclosure

C. Nguyen: Employee; HealthCore Inc. T. P. Power: None. R. Mehra: None. V. Willey: Employee; HealthCore Inc. C. Crowe: None. E. Kuti: Employee; Boehringer Ingelheim International GmbH. N. Narsipur: Employee; Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC. B. M. K. Donato: Employee; Boehringer Ingelheim International GmbH. R. S. Pepe: None. R. L. Djaraher: None. L. J. Seman: n/a. N. Graeter: Employee; Boehringer Ingelheim International GmbH.

Funding

Boehringer Ingelheim Pharmaceuticals Inc.
165-LB: The Impact of COVID-19 Vaccination on Development of Hyperglycemic Crisis
Authors: MODZELEWSKI KATHERINE L. , ALEXANIAN SARA
Published: May 2022

Hyperglycemic crisis (HC) has been reported in patients with COVID-19 infection, but there is little data about HC following COVID-19 vaccination, with 10 patients described to date. We performed a retrospective observational study examining the correlation between COVID-19 vaccination and HC in adult patients admitted from 1/1/21-7/1/21 at our institution. There were 91 admissions for HC during the study period. Forty-one were admissions for diabetic ketoacidosis (DKA) in patients with type 1 diabetes (T1D) , 2 of which also had hyperglycemic hyperosmolar state (HHS) . In patients with type 2 diabetes (T2D) , there were 49 admissions for DKA, 6 of which also had HHS, and 1 admission for HHS alone. In patients with T1D, 17 admissions occurred following COVID-19 vaccination, ranging from <24 hours to more than 3 months after, including 1 new diagnosis of T1D. All cases had a trigger of insulin omission or other medical illness, including 7 with admission for COVID-19 infection. In patients with T2D, 20 DKA or overlap admissions and 1 HHS admission occurred following COVID-19 vaccination, ranging from 1 to 40 days after. Six of these patients had no clear trigger of medical illness or insulin omission, 3 of which were new diagnoses of T2D. Two were following the first vaccination and 4 following the second vaccination. Hemoglobin A1c at admission was >11% in all 6 of these patients. Among patients with T1D, there were no cases of HC that appeared to be attributable to COVID-19 vaccination. In patients with T2D, while there were six cases following vaccination with no other clear trigger, the degree of hemoglobin A1C elevation at the time of admission was suggestive of longer duration of poor glycemic control. Three of these cases did have acute symptom onset following vaccination within one week of presentation, so it is possible that HC was provoked by vaccination in these patients. While it is not clear that COVID vaccination leads to HC in T1D, it may be an acute trigger for HC in patients with T2D who have poor underlying glycemic control. Large scale population studies are needed to better assess rates of HC following COVID-19 vaccination.

Disclosure

K. L. Modzelewski: None. S. Alexanian: None.
167-LB: Persisting Disparity in Prevalence of Diabetes in Appalachian Region of Kentucky between 2016–2020
Authors: RAJ RISHI , SADEK BATOUL , SEETHA MALAVIKA , HASHEM MOHAMED , KANNAN LAKSHMI , BOULAY JUDES
Published: May 2022

Background: People in the Appalachian region of KY face serious and unique health challenges influenced by socioeconomic status, rural location, and culture. Diabetes prevalence in the Appalachian region of KY is known to be consistently higher when compared to national and state-wide rates.

Objectives: Determine the prevalence trend of diabetes in the Appalachian Region of KY in the last five years and compare it with the prevalence rate in Non-Appalachian KY. Identify potential factors that influence higher diabetes prevalence in the Appalachian region of KY.

Methods: We obtained data from the 2016-2020 Behavioral Risk Factor Surveillance System (BRFSS) , a cross-sectional telephone survey of U.S. residents, to collect data on health-related risk behaviors, chronic health conditions, and use of preventive services. Prevalence of diabetes in the United States, KY, Appalachian KY, and Non-Appalachian KY was obtained and plotted on a graph. Data on baseline variables such as gender, age, education level, annual household income, body mass index (BMI) , smoking status, and health insurance was also obtained.

Results: In comparison to the United States (10.5-10.9%) , the prevalence rate of diabetes was higher in KY (12.8-13.7 %) throughout 2016-2020. Diabetes prevalence was even higher in Appalachian KY (15.8-17.2%) compared to Non-Appalachian KY (11.2 -12.5%) . This gap in diabetes prevalence rate has persisted over the last 5 years. A cross tabulation analysis of socioeconomic variables identified higher diabetes prevalence among adults aged 50-64 years, education level less than high school, and annual income less than $25000 in Appalachian vs. Non-Appalachian KY.

Conclusion: This study highlights the persisting high prevalence of diabetes in Appalachian KY, compared to Non- Appalachian KY. Overall, adults with diabetes in the Appalachian Region of KY have lower education and lower annual household income. Efforts that focus on addressing the most significant differences between the Appalachian and Non-Appalachian regions of KY can help decrease the prevalence of diabetes in this region.

Disclosure

R. Raj: None. B. Sadek: None. M. Seetha: None. M. Hashem: None. L. Kannan: None. J. Boulay: None.
169-OR: Census Tract SES Coding to Assess Impact of the Pandemic on Care of Youth with T1D
Authors: ADAM ATIF , CHEN CHARLOTTE , OJUKWU SANDO , KAUSHAL TARA , TINSLEY LIANE J. , VOLKENING LISA K. , LAFFEL LORI M.
Published: May 2022

The pandemic required altering care delivery to a hybrid model of telehealth and in-person visits. We evaluated if SES disparities during the pandemic impacted clinical visit adherence and CGM device use in youth with T1D. Retrospective EHR captured data on youth with T1D, ≤18 years old, with ≥1 clinical visit both pre-pandemic (9/15/18-3/15/20) and during the pandemic (4/1/20-12/22/21) . Patient addresses were geocoded to link with census tract SES measures from the 20American Community Survey. Low education status defined as ≥30% of residents having HS or lower education and low income as median household income ≤$40,000. Poisson and logistic regression models assessed appointment adherence and CGM device use, respectively, during the pandemic vs. pre-pandemic. Models were adjusted for age, gender, baseline A1c, and T1D duration. In both periods, 689 youth (age 13.8±3.3 years; male 49%; T1D duration 7.4 ±3.6 years) had clinical encounters. There were more visits in the pandemic vs. pre-pandemic (8 [IQR 5-11] vs. 6 [IQR 5-9], p<.001) . In adjusted models, youth living in tracts with low education or low income had 1.16x (95% CI 1.06-1.27, p-.002) and 1.20x (95% CI 1.09-1.32, p<.001) ,respectively, greater rates of increased visits during the later time period vs. those not living in lower education or income tracts. W/R to CGM use, 57% (n=392) used CGM pre-pandemic and 21% (n=83) stopped using CGM during the pandemic. In adjusted models, youth in tracts with low vs. high education had 2.81-fold increased odds (95% CI 1.56-5.07, p<.001) of stopping CGM during the pandemic. Similarly, youth from low vs. high income tracts had 2.49-fold increased odds (95% CI 1.39-4.46, p<.001) of stopping CGM. These data indicate variability in appointment adherence and CGM use during the pandemic based on census SES status. Vulnerable youth by SES factors appear to benefit from hybrid care model W/R to maintaining visits, although such youth appear more likely to stop CGM. Further research is needed further reduce health disparities.

Disclosure

A.Adam: None. C.Chen: None. S.Ojukwu: None. T.Kaushal: None. L.J.Tinsley: None. L.K.Volkening: None. L.M.Laffel: Advisory Panel; Medtronic, Roche Diabetes Care, Consultant; Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompé, Insulet Corporation, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk, Provention Bio, Inc.
173-LB: Cognitive Performance and Diabetic Retinopathy
Authors: FARIA ANA CRISTINA R.A.
Published: May 2022

Background: Diabetic retinopathy (DR) is a chronic diabetes complication. People with type 2 diabetes mellitus (T2DM) have two times the risk for dementia, suggesting it is a new chronic diabetes complication.

Objective: Evaluate the association of DR with cognitive performance in a T2DM population.

Methods: Cross-sectional study with 400 T2DM adults from whom socio-demographic, clinical, laboratory data, screening test for depression symptoms [Patient Health Questionaire-9 (PHQ-9) ], Mini Mental State Examination (MMSE) , Semantic Verbal Fluency test, Trail Making test A and B, Word Memory test were collected and performed. All cognitive test scores were converted into Global Cognition z-Score [GCS (z) ]. The association between GCS (z) < 0 with DR was performed using backward multivariate binary logistic regression model adjusted forage ≥ 65 years, school years ≤ 6 years, DM duration ≥ 10 years, depression symptoms score > 9 at PHQ-9, arterial hypertension, physical activity, diabetic retinopathy, macular edema and cardiovascular disease.

Results: After exclusions, the 251 eligible patients were 56.6% female, mean age 61.1 (±9.8) years, DM duration of 12.6 (±8.9) years and 7.6 (±4.2) years of school education. DR prevalence was 46.5%. Multivariate Binaric Logistic Regression Model showed an association between DR and GCS (z) < 0, with odds ratio (CI95%) of 2.50 (1.18-5.34) , adjusted for age, low education level, arterial hypertension and depression symptoms [OD and CI95%respectively: 5.46 (2.42-12.34) ; 12.19 (5.62-26.46) ; 2.55 (0.88-7.39) ; 3.53 (1.55-8.07) ].

Conclusion: In this T2DMpopulation, having DR increased the chance for worse cognitive performance even when adjusted for age, low education level, presence of arterial hypertension, and depression symptoms.

Disclosure

A. R. A. Faria: None.
178-OR: Prescription Patterns of Cardiovascular and Kidney Protective Therapies among Patients with Type 2 Diabetes
Authors: MONTEALEGRE JULIO A. LAMPREA , MADDEN ERIN , TUMMALAPALLI SRI LEKHA , CHU CHI , DU YUXIAN , SINGH RAKESH , KONG SHELDON , TUOT DELPHINE S. , PERALTA CARMEN , SHLIPAK MICHAEL G. , ESTRELLA MICHELLE
Published: May 2022

Background: Recent guidelines recommend use of SGLT2i and/or GLP1-RA in persons with type 2 diabetes (T2D) and CVD or CKD, regardless of glycemic control. The degree of adoption of these recommendations thus far is unclear

Methods: Among T2D patients receiving care within the VA Health Care System, we evaluated the prevalence and correlates of SGLT2i and GLP1-RA prescription during 20 and 2020. Logistic regression was used to examine associations of atherosclerotic CVD (ASCVD) , heart failure, and CKD (defined by lab values and/or administrative codes) as well as predicted risks of ASCVD and end-stage kidney disease (ESKD) , with prescription of SGLT2i and GLP1-RA

Results: Of 1,319,500 adults with T2D, 10% and 7% were prescribed SGLT2is and GLP1-RAs, respectively. Prescription prevalence of SGLT2i and GLP1-RA were 13% and 9% in patients with established ASCVD; 14% and 11% in those with heart failure; and 11% and 10% in those with CKD. In adjusted models, patients with severe albuminuria were less likely to be prescribed an SGLT2i or a GLP1-RA versus non-albuminuric patients with CKD: aOR (95% CI) = 0.89 (0.87, 0.91) and 0.95 (0.93, 0.98) , respectively. In patients with 10-year ASCVD risk >20% versus those with risk <5%, ASCVD risk was inversely associated with prescription: SGLT2i OR=0.70 (0.60, 0.80) and GLP1-RA OR=0.60 (0.50, 0.70) . Patients with 5-year ESKD risk >5% were less likely to be prescribed an SGLT2i: OR=0.61 (0.57, 0.66) , versus those with ESKD risk <1%

Conclusions: Among a national VA cohort of patients with T2D, prescription of SGLT2i and GLP1-RA was pervasively low across conditions for which they are currently indicated to lower the risk of CVD and CKD progression. Furthermore, we observed a “risk-treatment paradox”, where patients with higher risk of adverse outcomes were less likely to receive these therapies. Intensive implementation efforts are needed to prioritize prescription of these medications to patients who would derive the largest benefit.

Disclosure

J.A. Lamprea Montealegre: Research Support; Bayer AG. E. Madden: None. S. Tummalapalli: Consultant; Bayer AG. Research Support; Scanwell Health. C. Chu: Research Support; Bayer AG. Y. Du: Employee; Bayer AG. Stock/Shareholder; Bayer AG. R. Singh: None. S. Kong: Employee; Bayer AG. D.S. Tuot: None. C. Peralta: Employee; Cricket Health, Inc. Research Support; American Heart Association, National Institutes of Health. M.G. Shlipak: Advisory Panel; TAI Diagnostics. Consultant; Cricket Health, Intercept Pharmaceuticals, Inc. Research Support; Bayer AG. Other Relationship; AstraZeneca, Boehringer Ingelheim International GmbH. M. Estrella: Research Support; Bayer AG. Other Relationship; AstraZeneca, Boehringer Ingelheim International GmbH.
18-LB: Hypertriglyceridemic-Waist Phenotype in Relation to Carotid Artery Atherosclerosis in Patients with Type 2 Diabetes
Authors: ZHANG LEI , YANG YUXIU , WANG JUN , DONG YANHU
Published: May 2022

Aims: The aim of this study was to study the relationship between the hypertriglyceridemic-waist (HTGW) phenotype and the risk of carotid artery atherosclerosis (CAA) in Chinese patients with type 2 diabetes.

Methods: A total of 2651 consecutive in-patients with type 2 diabetes (mean age 56±11 years, 58% women) were included. CAA was determined by Color Doppler Ultrasonography and defined by the formation of detectable carotid artery plaques. Logistic regression analysis was applied to relate HTGW phenotype to CAA.

Results: The prevalence of CAA was 46.3% and 26.2% respectively in patients with and without HTGW. Compared with participants who had no HTGW, those with the HTGW phenotype had higher levels of systolic blood pressure (139.2 mmHg vs. 132.7 mmHg, p < 0.05) , fasting plasma glucose (9.1 mmol/L vs. 8.5 mmol/L, p < 0.05) , HbA1c [73 mmol/mol (8.83%) vs. 63 mmol/mol (7.95%) , p < 0.05], apolipoprotein B (0.95 g/L vs. 0.89 g/L, p < 0.05) , C-reactive protein (8.23 mg/L vs. 4.92 mg/L, p < 0.05) , TNF-α (26.46 pg/ml vs. 16.80 pg/ml, p < 0.05) and mean intima-media thickness (0.85 mm vs. 0.79 mm, p < 0.05) , but lower levels of apolipoprotein A1 (1.21 g/L vs. 1.33 g/L, p < 0.05) . The hypertriglyceridemic-waist phenotype was associated with CAA (OR 1.55, 95% CI 1.07-2.24) , after adjusting for age, sex, duration of diabetes, body mass index, smoking, HbA1c, apolipoprotein B and C-reactive protein.

Conclusion: Among patients with type 2 diabetes, simultaneous measurement of waist circumference and triglycerides could be used as an inexpensive and simple approach to identify individuals with CAA.

Disclosure

L. Zhang: n/a. Y. Yang: None. J. Wang: None. Y. Dong: None.
180-OR: Empagliflozin Does Not Affect Pancreatic Fat Content and Insulin Secretion in Humans with Prediabetes
Authors: HUMMEL JULIA , MACHANN JÜRGEN , DANNECKER CORINNA , KULLMANN STEPHANIE , BIRKENFELD ANDREAS L. , HÄRING HANS-ULRICH , PETER ANDREAS , FRITSCHE ANDREAS , WAGNER ROBERT , HENI MARTIN
Published: May 2022

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.
19-LB: The Impact of Diabetes on 30-Day Readmission, In-Hospital Mortality, and Medical Cost in ST-Segment Elevation Myocardial Infarction after Primary Percutaneous Coronary Intervention—A Nationwide Readmissions Database Analysis
Authors: KANG YU MI , JANG SUN-JOO
Published: May 2022

Background: ST-elevation myocardial infarction (STEMI) poses significant morbidity, mortality and economic burden in people with diabetes. We sought to determine the impact of diabetes on the short-term outcome and hospital costs post-percutaneous coronary intervention (PCI) for STEMI.

Methods: STEMI hospitalizations were selected in the Nationwide Readmissions Database from 2010 to 2014. From the patients who underwent PCI, we examined the 30-day readmission, in-hospital mortality, and total cost according to the presence of diabetes, prior stroke, and prior MI. All statistical analyses were performed using R statistical software version 4.1.2.

Results: Among 539,171 index STEMI hospitalizations for primary PCI, 10.1% were readmitted within 30 days and 4.6% died in hospital. The readmission rates were 10.2%, 12.9%, 14.4%, 17.5%, and 18.4% in the reference (i.e., no diabetes, prior MI or stroke) , diabetes-only, diabetes and MI, diabetes and stroke, diabetes, MI, and stroke groups, respectively (P<0.001) . The corresponding adjusted hazard ratios for 30-day readmission were 1.14 (95% CI 1.10-1.18) , 1.23 (1.12-1.35) , 1.24 (1.10-1.39) , and 1.29 (0.99-1.68) . In-hospital mortality rates during index hospitalization were 4.3%, 5.3%, 5.5%, 7.2%, and 7.4% in the reference, diabetes-only, diabetes and MI, diabetes and stroke, diabetes, MI, and stroke groups, respectively (P<0.001) . The corresponding adjusted odds ratios for mortality were 1.24 (95% CI 1.15-1.33) , 1.55 (1.28-1.87) , 1.51 (1.22-1.87) , and 2.03 (1.27-3.25) . The median overall cost increased by 4.5% and 11.8% in the diabetes-only group and diabetes, MI, and stroke group, respectively, compared with the reference group (P<0.001) .

Conclusion: Within 30 days of PCI for STEMI, diabetes increases readmission rate, in-hospital mortality, and financial burden with and without prior CVD. These findings underscore the importance of aggressive optimization in STEMI patients with diabetes.

Disclosure

Y. Kang: None. S. Jang: None.
19-OR: KidneyIntelX Association with Clinical Outcomes in Diabetic Kidney Disease
Authors: NADKARNI GIRISH N. , TAKALE DIPTI , NEAL BRUCE , MAHAFFEY KENNETH W. , YAVIN YSHAI , HANSEN MICHAEL K. , FLEMING FERGUS , HEERSPINK HIDDO L. , COCA STEVEN
Published: May 2022

Individuals with diabetic kidney disease (DKD) are at risk for progression, heart failure, and death. We assessed the association of KidneyIntelX, a bioprognostictest validated for DKD progression, with a composite time-to-event endpoint of 57% eGFR decline, kidney failure, heart failure hospitalization (HFH) , or death in a posthoc analysis of a subgroup of CANVAS participants with DKD. sTNFR-1, sTNFR-2, and KIM-1 were measured via proprietary assays, and KidneyIntelX scores were calculated using the existing algorithm. Hazard ratios for high vs. low-risk strata for the composite outcome were adjusted for age, sex, race, treatment arm, baseline CVD, HbA1c, SBP, DBP, LDL, BMI) . During 5.6 years follow-up, 282 (22%) of the 1278 CANVAS participants with DKD experienced the outcome (57% decline in eGFR/ESKD 3%, HFH 6%, death 16%) . The adjusted HR for the composite outcome in KidneyIntelX high-risk group was 2.7 (95% CI 1.9 to 3.8) vs. the low-risk group. Canagliflozin reduced the risk for the composite event vs. placebo, with larger absolute risk reductions for the high-risk stratum (11%) , compared to intermediate (6%) or low-risk strata (4%) (p<0.01) .

In conclusion, KidneyIntelX successfully risk-stratified adults with DKD for clinical outcomes. Absolute risk reductions with canagliflozin were greatest in the high-risk stratum, thereby potentially allowing its use to identify patients most likely to benefit from treatment.

Disclosure

G.N.Nadkarni: Advisory Panel; Renalytix, Consultant; AstraZeneca, Reata Pharmaceuticals, Inc., Renalytix, Siemens, Other Relationship; Renalytix, Stock/Shareholder; Renalytix. D.Takale: None. B.Neal: Other Relationship; Janssen Research & Development, LLC. K.W.Mahaffey: Consultant; Novo Nordisk. Y.Yavin: Employee; Janssen Research & Development, LLC. M.K.Hansen: Employee; Janssen Research & Development, LLC. F.Fleming: Employee; Renalytix. H.L.Heerspink: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., Goldfinch Bio, Inc., Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Mundipharma, Traveere Pharmaceuticals, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. S.Coca: Advisory Panel; 3ive Labs, Nuwellis, Reprieve Cardiovascular, Consultant; Axon Therapies, Bayer AG, Boehringer Ingelheim International GmbH, Vifor Pharma Management Ltd., Stock/Shareholder; pulseData, Renalytix.

Funding

Renalytix
194-LB: Tacrolimus-Induced Hyperglycemic Emergencies in Posttransplant Patients—A Case Series
Authors: GUPTA SHAVETA , LOVRE DRAGANA , GALAGAN ROBERT
Published: May 2022

Introduction: Tacrolimus is effective immunosuppressant in posttransplant patients. It inhibits calcineurin and prevents T cell activation. Post-transplantation diabetes mellitus (PTDM) is a well-established adverse effect of tacrolimus. We report the rare occurrences of DKA and hyperosmolar hyperglycemia syndrome respectively in 2 patients on tacrolimus after renal transplants.

Description Case 1: A 25 year old obese (BMI 37.7 kg/m2) black female with no history of DM received a live donor kidney transplant. She was on mycophenolate 720 mg po bid, tacrolimus 7 mg po bid, and prednisone 5 mg daily. Eleven weeks after transplant she presented with polyuria and polydipsia and was admitted for DKA. Labs revealed glucose 1000 mg/dL (74-106) , HCO3 7.0 meq/L (21-32) , beta-hydroxybutyric acid 8.4 mg/dL (0.2 - 2.8) , tacrolimus trough levels 19.6 ng/mL (4.1 - 10.7) . Her A1c was 10.6% compared to 5.3% pre-transplant. Case 2: A 50 year old obese (BMI 35.6 kg/m2) black female with no prior history of DM received a cadaveric kidney transplant due to ESRD. Patient was on mycophenolate 360 mg bid, and tacrolimus 8 mg bid. She was admitted to hospital for HHS 9 weeks later. Labs revealed a glucose 940 mg/dL, serum osmolality 341 msom/kg (275-295) , HCO3 22 mmol/L, tacrolimus trough levels 12.1 ng/mL. Her A1c was 8.7% compared to 5.3% pre-transplant.

Discussion: Our 2 patients with no history of DM developed hyperglycemic emergencies within 3 months of receiving kidney transplants and initiating tacrolimus. Both responded well to IV fluids and insulin and were transitioned to SQ insulin by discharge. Risk factors for post-transplant de novo DKA and HHS common to both patients were African American ethnicity, high BMI, and tacrolimus treatment with elevated trough levels. Tacrolimus inhibits insulin secretion and is linked to increased rates of PTDM, which is often reversible with tacrolimus dosage reduction. Both of our patients were prescribed tacrolimus at reduced dosage and were scheduled for outpatient Endocrine clinic evaluation to determine whether they should continue insulin treatment.

Disclosure

S. Gupta: None. D. Lovre: Other Relationship; AstraZeneca, Bayer AG, Novo Nordisk. R. Galagan: None.
197-LB: Adipocyte ZAG Improves Obesity-Triggered Insulin Resistance by Reshaping Macrophages Populations in Adipose Tissue
Authors: XIAO XINHUA , LIAO ZHEZHEN , WANG YA-DI , QI XIAO-YAN
Published: May 2022

Adipose tissues macrophages (ATMs) serve as critical effectors in the mediating occurrence of metabolic inflammation to impact whole-body insulin sensitivity in obesity. Discovering the key adipokines mediating crosstalk of adipocyte-macrophage and understanding the molecular mechanism of ATMs polarization and function have become hot topic issues in the immunometabolism fields. Zinc-α2-glycoprotein (ZAG) as an anti-inflammatory adipokines plays important roles in obesity-related metabolic diseases. We attempt to explore the precise role of adipose ZAG in metabolic inflammation and obesity-associated insulin resistance. Here we showed that Omental ZAG was positively associated with insulin sensitivity and M2 macrophages markers. ZAG-specific ablation in adipocyte aggravated insulin resistance and adipose tissues inflammation as evidenced by enhanced M1 macrophages proportion and inhibited AKT signaling pathway in mice fed with a high-fat diet. ZAG overexpression attenuated insulin resistance and accumulation of pro-inflammatory macrophages. Exogenous ZAG inhibits PA-induced M1 macrophage polarization via β3-AR/PKA/STAT3 signaling in RAW264.7 macrophages. These findings suggest that adipocyte ZAG maintains insulin sensitivity via the cross talk with adipose-resident macrophages.

Keywords: ZAG; inflammation; insulin resistance; obesity; adipose tissue macrophages

Disclosure

X. Xiao: None. Z. Liao: None. Y. Wang: None. X. Qi: None.

Funding

National Natural Science Foundation of China (82070873, 82000813) , Natural Science Foundation of Hunan province (2020JJ8097, 2021JJ40496) and Major special projects of Hunan provincial health and family planning commission (A2017011)
198-LB: The Loss of the Lysine Acetyltransferase KAT8 in Adipocytes Confers Lipodystrophy and Metabolic Dysfunction in Male and Female Mice
Authors: RICHARD ALLISON J. , MENDOZA TAMRA M. , STEPHENS JACQUELINE M.
Published: May 2022

KAT8, also known as MOF or MYST1, is a lysine acetyltransferase with both histone and non-histone substrates. While KAT8 is the major H4K16 acetyltransferase in Drosophila and mammals and is essential for embryonic development, its role in specific cell types is not well understood. Moreover, studies within the past decade have demonstrated lineage-, differentiation state-, or stress-dependent roles of KAT8. Our recent efforts have shown that KAT8 is necessary for in vitro adipogenesis prior to or during the proliferative phase. Notably, several, independent genetic studies reveal that single nucleotide polymorphisms (SNPs) within or near the KAT8 gene are associated with body mass index and/or waist circumference. To investigate the role of KAT8 in differentiated adipocytes and to understand the contribution of KAT8-deficient adipocytes to whole-body glucose and lipid metabolism, we generated both congenital and doxycycline-inducible adipocyte-specific knockout mice, in which Kat8 gene deletion occurs only in adiponectin-expressing cells. Adult mice lacking adipocyte KAT8 exhibited significant fat mass loss with no change in lean mass. While the size of inguinal and brown adipose tissue was significantly reduced in both sexes fed either chow or high-fat, high-sucrose (HFHS) diet, male mice also had decreased gonadal, retroperitoneal, and mesenteric depots. Histological assessments revealed substantial remodeling within adipose tissue depots, and these mice demonstrated reduced insulin sensitivity and increased lipid accumulation in the liver when fed HFHS diet. Although further investigation is necessary to identify KAT8 targets that confer lipodystrophy, these studies are the first to show the impact of the loss of adipocyte KAT8 in vivo.

Disclosure

A. J. Richard: n/a. T. M. Mendoza: None. J. M. Stephens: None.

Funding

National Institutes of Health COBRE P&F grant (P30 GM118430)
199-OR: Exercise Decreases Mouse and Human Islet Senescence through Glucagon-Mediated AMPK Activation
Authors: CARAPETO PRISCILA , KAHNG JIHO , WAGNER ANA BARBARA T. ALVES , MIDDELBEEK ROELAND , HIRSHMAN MICHAEL F. , GOODYEAR LAURIE J. , AGUAYO-MAZZUCATO CRISTINA
Published: May 2022

Aging is a major risk factor for type 2 diabetes (T2D) and cellular senescence plays a critical role in β-cell dysfunction leading to T2D. Exercise is a central component in the treatment of T2D and has been shown to attenuate many of the biochemical changes that occur with aging including senescence, but nothing is known about the effects of exercise on β-cells and their aging process. To test the hypothesis that exercise decreases β-cell senescence we used two mouse models of insulin resistance: high-fat diet (HFD, 60% kcal from fat, 6 wks) and insulin receptor antagonist S961 (40nM/wk for 2 wks) . Exercise (treadmill, 1 h/day, 5 times/wk for 2 wks at 17 cm/s and 5% incline) prevented entrance of β-cells into senescence and reversed established senescence in both males and females across the lifespan (started at 1.5-9m or 14m old mice) as seen by a decrease in one or several of the following markers: βGal, p21Cip1 and p16Ink4a. This decrease in senescence was accompanied by improved glucose stimulated insulin secretion characterized by recovery of glucose responsiveness in islets from HFD and S961 exercised animals. Islets cultured with serum from trained animals showed decreased p21Cip1 mRNA, indicating a circulatory factor (s) was responsible for these effects. Exercise increased serum glucagon expression, identified as such factor. Incubation of human and mouse islets with glucagon (1nM) decreased p21Cip1 mRNA, and using AMPK agonist (1uM C99) and antagonist (5uM Compound C) , we found that AMPK mediates the glucagon-stimulated decrease in p21Cip1. Human cadaveric donor islets treated with serum obtained before and after 10-weeks of exercise-training in people with T2D demonstrated that training decreased senescence markers through AMPK activation.

In conclusion, exercise has anti-aging effects on mouse and human pancreatic islets by decreasing senescence and improving function. This is a novel mechanism of the effects of exercise on β-cell aging with implications for the treatment of T2D.

Disclosure

P.Carapeto: None. J.Kahng: None. A.T.Alves wagner: None. R.Middelbeek: Research Support; Novo Nordisk. M.F.Hirshman: Stock/Shareholder; Abbott, AbbVie Inc., Amgen Inc., Colgate-Palmolive, Eli Lilly and Company, Medtronic. L.J.Goodyear: None. C.Aguayo-mazzucato: Consultant; eGenesis.

Funding

American Diabetes Association (1-17-PMF-009) ; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001; Short-Term Research Experience for Underrepresented Persons (1R25DK113652) ; NIDDK grant (K23-DK114550) ; NIH grant (R01DK099511) and the Joslin Diabetes Center DRC (P30 DK36836) .
201-LB: Overexpression of GOT1 in Brown Adipose Tissue Enhances Thermogenesis and Glucose Metabolism by Activating the Malate-Aspartate Shuttle
Authors: PARK CHUL-HONG , CHENG HELIA , LEE SANG R. , EILERTSEN KENNETH , SUK CHANG JI
Published: May 2022

Brown adipose tissue (BAT) is characterized by thermogenic and glucose-consuming properties. BAT takes up large amounts of circulating glucose during cold exposure or pharmacological stimulation of β3-adrenergic receptors (β3AR) , but glucose oxidation in mitochondria only modestly contributes as a fuel source for thermogenesis. How glucose metabolism supports thermogenesis is incompletely understood. Here, we identify a novel role of the malate-aspartate shuttle (MAS) in enhancing thermogenesis, glucose uptake and glycolysis in brown adipose tissue. We found that glutamic-oxaloacetic transaminase 1 (GOT1) , a key enzyme of the MAS, exists at very low levels in BAT but is markedly induced by cold or β3AR agonists, while other MAS enzymes (GOT2 and MDH1/2) remain unchanged. Enforced expression of Got1 in BAT increased energy expenditure in mice and further enhanced thermogenesis upon cold exposure or β3-adrenergic stimulation. Moreover, mice overexpressing Got1 in BAT exhibited enhanced glucose tolerance. Mechanistically, Got1 overexpression stimulated mitochondrial uncoupled respiration. MAS-driven thermogenesis in turn led to AMPK activation, which likely explains enhanced glucose uptake and glycolysis. Collectively, our data demonstrate a novel GOT1-MAS-AMPK axis that regulates thermogenesis and glucose metabolism in cold-activated BAT.

Disclosure

C. Park: None. H. Cheng: None. S. R. Lee: None. K. Eilertsen: None. J. Chang: None.

Funding

NIH (DK104748, 1P30GM118430, P30DK072476)
201-OR: Evaluation of the Effects of Harmine on ß-Cell Function and Proliferation in Standardized Human Islets Using 3D High-Content Confocal Imaging and Automated Analysis
Authors: TITLE ALEXANDRA C. , KARSAI MARIA , MIR-COLL JOAN , GRINING OZLEM YAVAS , RUFER CHANTAL , SONNTAG SEBASTIAN , FORSCHLER FELIX , JAWUREK SAYRO , KLEIN THOMAS , YESILDAG BURCAK
Published: May 2022

Restoration of β-cell mass by inducing proliferation of residual β-cells represents an attractive therapeutic approach for diabetes treatment. Native and dispersed primary human islets undergo rapid loss of viability and function ex vivo, complicating their use in proliferation studies. Here, we establish a novel method for evaluating compound effects on β-cell proliferation and count using reaggregated primary human islet microtissues (MTs) , of homogeneous size and architecture and that maintain stable viability and function for 4 weeks in culture. We utilized this platform to evaluate the effects of short- and long-term harmine treatment on β-cell proliferation and function in a dose-dependent manner. Following harmine treatment and EdU incorporation, islet MTs were stained in 3D for DAPI (nuclear marker) , NKX6.1 (β-cell marker) , and EdU (proliferation marker) , imaged on a high-content confocal microscope, and subjected to automated 3D analysis of numbers of total cells, β-cells, and proliferating β- and non-β-cells per islet MT. In parallel, assessment of insulin secretion, intracellular insulin and ATP contents, and Caspase 3/7 activity was performed for a comprehensive overview of islet MT function and viability. We observed that 4 days of harmine treatment increased β- and non-β-cell proliferation, NKX6.1 expression, and basal and stimulated insulin secretion in a dose-dependent manner, whereas fold-stimulation of secretion peaked at intermediate doses. Interestingly, 15-day harmine treatment led to a general reduction in proliferative effects as well as altered dose-dependent trends. The methodology presented here thus constitutes a unique tool for in vitro high-throughput evaluation of short- and long-term changes in human β-cell proliferation, count and fraction in parallel with a variety of functional parameters, in a representative and standardized 3D human islet microtissue model.

Disclosure

A.C.Title: None. B.Yesildag: None. M.Karsai: None. J.Mir-coll: None. O.Yavas grining: None. C.Rufer: None. S.Sonntag: None. F.Forschler: None. S.Jawurek: None. T.Klein: Employee; Boehringer Ingelheim International GmbH.