bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Hormone-Sensitive Lipase Overexpression on Lipotoxic Cardiomyopathy in Mice Lacking Adipose Triglyceride Lipase
Authors: YAMADA MIKA , SUZUKI JINYA , HIROSE MASAMICHI , NAKAYA TAKAHIRO , ICHIKAWA MAI , SATO SATSUKI , IMAGAWA MICHIKO , ZENIMARU YASUO , KRAEMER FREDRIC B. , KONOSHITA TADASHI , ISHIZUKA TAMOTSU 
Published: June 2018

Lipotoxic cardiomyopathy, which is associated with obesity and diabetes, is characterized by intracellular triacylglycerol (TAG) droplet accumulation (steatosis). The first step of TAG hydrolysis is catalyzed by adipose triglyceride lipase (ATGL), and its deficiency results in extreme cardiac steatosis in mice and humans. Although hormone-sensitive lipase (HSL) functions as a diacylglycerol (DAG) lipase in the heart, we hypothesized that activated HSL might catalyze cardiac TAG hydrolysis. To test this hypothesis we generated transgenic mice with cardiac-specific HSL-overexpression (cHSL) and crossed them with ATGL-knockout (KO) mice. By crossing ATGL-KO and cHSL lines, we generated homozygous ATGL-KO (AKO) mice, AKO mice with cardiac HSL-overexpression (AKO/cHSL), and wild type (Wt) mice. Cardiac lipid content was measured and its function was assessed by ultrasonography. Histological investigation was performed by transmission electron microscopy. Cardiac TAG content of AKO mice was 160-fold greater than that of Wt mice, whereas that of AKO/cHSL mice was as low as that of Wt hearts. Cardiac systolic function (fractional shortening; FS) was markedly reduced in AKO mice compared to that of Wt mice (28% vs. 49%), while AKO/cHSL mice showed comparable FS to that of Wt mice (48% vs. 49%). Electron microscopy showed accumulation of huge lipid droplets, damaged mitochondria with destroyed cristae and vacuole degeneration, and disrupted intercalated discs (where gap junctions and desmosomes are localized) in the cardiomyocytes of AKO mice. In contrast, the cardiomyocytes of AKO/cHSL mice showed no such morphological characteristics. These results indicate that cardiac overexpression of HSL normalizes lipotoxic cardiomyopathy in AKO mice and suggest that activation of cardiac HSL could be a potent strategy to regulate the lipotoxic cardiomyopathies that occur in metabolic disorders.

Disclosure
M. Yamada: None. J. Suzuki: None. M. Hirose: None. T. Nakaya: None. M. Ichikawa: None. S. Sato: None. M. Imagawa: None. Y. Zenimaru: None. F.B. Kraemer: None. T. Konoshita: None. T. Ishizuka: None.
Large Relative Skeletal Muscle Mass May Protect against Diabetes Irrespective of Glycometabolic Parameters
Authors: KIM GYURI , CHOI MIN SUN , JIN SANG-MAN , LEE MOON-KYU , KIM JAE HYEON 
Published: June 2018

Background: Skeletal muscle mass was negatively associated with the prevalence of diabetes in previous cross-sectional studies. The aim of the study was to investigate the impact of baseline relative skeletal muscle mass on the development of diabetes in a large population-based 7-year longitudinal study.
Methods: A total of 18,269 individuals who underwent medical health check-up examination in a university-affiliated tertiary hospital without diabetes were included. Skeletal muscle mass was estimated by bioelectrical impedance analysis and presented as appendicular skeletal muscle mass (ASM) / body mass index (BMI). We analyzed hazard ratio for developing diabetes associated with ASM/BMI using Cox regression models and evaluated the effects of preexisting impaired fasting glucose (IFG).
Results: Compared to subjects in the lowest baseline sex-specific ASM/BMI tertile, those in the highest ASM/BMI tertile were significantly associated with a decreased adjusted HR (AHR=0.69, 95% CI=0.59-0.81, P &lt;0.001) for incident diabetes after adjusting for age, family history of diabetes, smoking status, regular exercise, metabolic syndrome, and CRP. The reduction in the risk of developing diabetes was also significant in the highest tertile of sex-specific ASM/BMI tertile in the presence (AHR=0.81, 95% CI=0.68-0.97, P&lt;0.001) and in the absence of IFG (AHR=0.51, 95% CI=0.39-0.67, P&lt;0.001) compared to the lowest tertile.
Conclusion: The large relative skeletal muscle mass has a potential preventive effect on developing diabetes, independently of glycometabolic parameters. In particular, in subjects with IFG who are at high risk for diabetes, larger relative skeletal muscle mass may provide a substantial benefit to prevent diabetes.

Disclosure
G. Kim: None. M. Choi: None. S. Jin: None. M. Lee: None. J. Kim: None.
Falsely Decreased HbA1c in Diabetic Patient due to Dapsone
Authors: ALJENAEE KHALED , ALI SULAIMAN HAJI , PAZDERSKA AGNIESZKA 
Published: June 2018

HbA1c and fructosamine are glycated proteins used to monitor glucose control over time in patients with diabetes. Many factors can affect HbA1c values leading to spuriously low or elevated results. We report a case of a 67 year old woman with type 1 diabetes with good glycaemic control based on HbA1c values ranging from 44-52 mmol/mol over 7 year follow-up. She was commenced on dapsone for treatment of granuloma anulare; four months into this treatment her HbA1c was 25 mmol/mol. The record of self-monitoring blood glucose showed that most of her glucose values were within the recommended target. She had normal hypoglycaemia awareness and reported only 3 episodes of symptomatic hypoglycaemia in the preceding four months. Given the history of dapsone therapy and the discordant result of self-monitoring blood glucose and HbA1c concentrations, we suspected methemoglobinemia as a cause.
Dapsone treatment has been recognised to cause falsely low HbA1c results by two mechanisms: haemolysis by reducing the erythrocyte life span and the formation of methemoglobin which interferes with HPLC used to measure HbA1c.
In conclusion, dapsone is commonly used in diabetic patients who have other autoimmune diseases. HbA1c monitoring in patients treated with dapsone is unreliable and other markers such as capillary blood glucose records, and other glycated proteins such as fructosamine should be used as an alternative for monitoring of glucose control is such patients.
Table 1 Laboratory resultPrior to dapsone4 months after dapsoneHb level (g/dl)13.211.7MCV (fl/cell)92105Absolute reticulocyte counts (109/L)53303Total bilirubin level (micromol/L)1312Methehaemoglobin fraction(%)4.7HbA1c (mmol/mol)X25

Disclosure
K. Aljenaee: None. S. Haji Ali: None. A. Pazderska: None.
The Flexible Lifestyles Empowering Change (FLEX) Intervention Trial for Adolescents with Type 1 Diabetes—Primary and Secondary Outcomes
Authors: MAYER-DAVIS ELIZABETH J. , BISHOP FRANZISKA K. , DRISCOLL KIMBERLY A. , HUNTER CHRISTINE M. , MAAHS DAVID M. , SEID MICHAEL , STANDIFORD DEBRA , THOMAS JOAN ,   FLEX STUDY GROUP
Published: June 2018

Youth with T1D often have poor glycemic control and compromised health and well-being. Our aim was to test the efficacy of the FLEX adaptive behavioral intervention on the primary (HbA1c) and secondary (psychosocial and metabolic) outcomes at 18 months.
Youth (n=258) aged 13-16 years, diagnosed &gt;1 year with T1D with HbA1c from 8.0-13.0%, were randomized at two sites to FLEX or usual care control. Mean (sd) duration of diabetes was 6.4 (3.8) years, 50% were girls, 78% non-Hispanic white, mean HbA1c was 9.6% (1.2) and 71% used insulin pump therapy. FLEX used motivational interviewing and problem-solving skills training to enhance self-management. Intervention fidelity was assessed via random selection of audiotaped sessions for counseling strategy and session content. Intent-to-treat analyses used mixed effects models, with fixed effects of site, timepoint, intervention group, intervention by timepoint and baseline level of primary or secondary outcomes, with a random intercept (alpha=0.05).
Retention was 97%, with intervention fidelity 4.6 out of 5 for counseling strategy and 97.4% complete for session content. HbA1c was not statistically significantly different between intervention and control at 18 months. Among secondary outcomes at 18 months, the intervention was associated with improved scores for symptoms of depression (p=0.04), quality of life (p=0.01), motivation (p=0.009), problem-solving (p=0.04), and diabetes self-management profile (p=0.01), as well as better total cholesterol (p=0.04), and better diastolic blood pressure (p=0.01).
The FLEX intervention did not change the primary outcome, but did positively effect psychosocial outcomes over the 18 months of the trial. Further analyses will reveal information regarding drivers of positive response to the intervention and will point to directions for improvement in the approach, perhaps incorporating more specific direction towards achievement of glycemic targets.

Disclosure
E.J. Mayer-Davis: None. F.K. Bishop: None. K.A. Driscoll: None. C.M. Hunter: None. D.M. Maahs: Advisory Panel; Self; Insulet Corporation. Consultant; Self; Abbott. Research Support; Self; Medtronic, Bigfoot Biomedical, Dexcom, Inc., Insulet Corporation, Roche Diabetes Care Health and Digital Solutions. M. Seid: None. D. Standiford: None. J. Thomas: None.
Effects of Dulaglutide and Insulin Glargine on Estimated Glomerular Filtration Rate in a Real-World Setting
Authors: BOYE KRISTINA , MODY REEMA , WU JIANMIN , LAGE MAUREEN J. , BOTROS FADY T. , WOODWARD BRAD 
Published: June 2018

Dulaglutide (Trulicity) treatment of patients with type 2 diabetes (T2D) and moderate to severe chronic kidney disease was associated with lesser estimated glomerular filtration rate (eGFR) decline compared to insulin glargine (glargine) in a clinical trial. This study examined the relationship between dulaglutide or glargine use and eGFR for adults with T2D using real-world data from a U.S. electronic health records from 10/25/2013 to 6/18/2017.
There were 13,869 glargine and 1,222 dulaglutide patients included in the descriptive analyses. Patients with initial eGFR &lt; 60 or &lt; 30 mL/min/1.73m2 were more likely to be treated with glargine than dulaglutide (31.3% v 17.1%, p&lt;0.01; 5.3% v 1.0%, p&lt;0.01, respectively). Multivariable analyses on a matched cohort (N=2,366) found dulaglutide use, compared to glargine use, was associated with a significantly smaller decline in eGFR and a smaller proportion of patients with ≥30% decline in eGFR in the 1-year post-period (Figure 1). With the caveat of limited numbers of patients with severe renal impairment, dulaglutide treatment, compared to glargine, was associated with a smaller decline in renal function in a real-world setting.

Disclosure
K. Boye: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. R. Mody: Employee; Self; Eli Lilly and Company. J. Wu: None. M.J. Lage: Consultant; Self; Eli Lilly and Company. Consultant; Spouse/Partner; Eli Lilly and Company. F.T. Botros: Employee; Self; Eli Lilly and Company. B. Woodward: Employee; Self; Eli Lilly and Company.
Trends of Nontraumatic Lower Extremity Amputation in End-Stage Renal Disease and Diabetes, U.S. 2000-2014
Authors: HARDING JESSICA L. , PAVKOV MEDA E. , BURROWS NILKA , GREGG EDWARD W. , HORA ISRAEL A. 
Published: June 2018

Non-traumatic lower extremity amputation (NLEA) is a complication of end-stage renal disease (ESRD) and diabetes mellitus (DM). Global data suggest hospitalization rates for NLEA among people with DM are declining. Contemporary data from the U.S. and among those with ESRD is lacking. We estimated NLEA hospitalizations during 2000-2014 in adults aged ≥18 years with ESRD and DM (ESRD-DM) and in the broader DM population. We determined NLEA hospitalisations rates (ICD-9 CM procedure codes: 8411-8419, excluding diagnosis codes 895-897) for ESRD-DM using the U.S. Renal Data System and for DM using the U.S. National Health Interview Survey and the National Inpatient Sample. We assessed trends over time using Joinpoint regression. In the ESRD-DM population, age-standardised NLEA rates per 1,000 persons decreased from 61.5 (95% CI: 59.8-63.2) in 2000 to 39.7 (38.4-41.0) in 2014 (Figure). In the DM population, NLEA rates decreased from 10.8 (9.2-12.4) in 2000 to 6.1 (5.1-7.0) in 2009, and then increased to 8.7 (7.7-9.6) by 2014. NLEA rates remained 4.6 times (95% CI: 4.5-4.7) higher in ESRD-DM compared with DM only. Rates of NLEA hospitalisations declined during 2000-2014 in ESRD-DM, while they declined then increased in the population with DM. Increased attention to preventive care among ESRD-DM and DM populations is needed.

Disclosure
J.L. Harding: None. M.E. Pavkov: None. N. Burrows: None. E.W. Gregg: None. I.A. Hora: None.
Effect of Metformin on Mitochondrial Pathways in Human Skeletal Muscle Cells
Authors: SACKS JESSICA , MULYA ANNY , FEALY CIARAN E. , FITZGERALD KELLY M. , HUANG EMILY , KIRWAN JOHN P. 
Published: June 2018

Metformin (Met) is the most commonly prescribed antidiabetic agent worldwide. Although it has been marketed in the U.S. for over two decades, the exact molecular mechanisms of Met remain controversial. In addition to suppression of hepatic gluconeogenesis, increasing evidence suggests Met induces extrahepatic tissue-specific effects, such as in skeletal muscle (SKM), where the mitochondrion is believed to be the primary cellular target. We investigated the effects of Met on mitochondrial pathways in human SKM cells isolated by percutaneous needle biopsy from lean control, obese nondiabetic, and type 2 diabetic (T2D) volunteers. Mitochondrial function was assessed by Seahorse XF24 analyzer in SKM cells treated with or without Met for 24 hours. Glycolytic rate increased in Met-treated SKM cells from lean (P&lt;0.01), obese (P&lt;0.0001), and T2D subjects (P&lt;0.01) compared to untreated cells. In contrast, basal respiration and ATP production were dramatically reduced in SKM cells treated with Met (P&lt;0.0001 for all phenotypes). Evaluation of the insulin signaling pathway revealed increased Akt phosphorylation at Ser473 (P&lt;0.05) and Thr308 (P&lt;0.01) in cells pre-treated with Met compared to insulin stimulation alone, indicating an additive effect of Met on insulin action. As expected, muscle cells incubated with Met showed enhanced AMPK phosphorylation at Thr172 (P&lt;0.001). Recent studies have identified a direct link between AMPK activation and mitochondrial dynamics pathways. We therefore assessed changes in markers of mitochondrial fission and fusion and found that Met treatment significantly induced phosphorylation of mitochondrial fission factor (MFF; P&lt;0.01) in human SKM cells. Our data suggest Met may mediate improvements in glycemic control by activating AMPK to directly regulate the mitochondrial fission machinery and alter cellular bioenergetics. Functional morphometric and biochemical studies are ongoing to validate mechanisms by which Met exerts its antihyperglycemic effects in SKM.

Disclosure
J. Sacks: None. A. Mulya: None. C.E. Fealy: None. K.M. Fitzgerald: None. E. Huang: None. J.P. Kirwan: None.
Microvascular Disease Burden and All-Cause Mortality in Type 1 Diabetes-A 10-Year Follow-Up Study
Authors: GAROFOLO MONIA , GIANNARELLI ROSA , ARAGONA MICHELE , LUCCHESI DANIELA , GIUSTI LAURA , SANCHO-BORNEZ VERONICA , DANIELE GIUSEPPE , MICCOLI ROBERTO , PENNO GIUSEPPE , PRATO STEFANO DEL 
Published: June 2018

Type 1 diabetes (T1D) is associated with a sustantially increased risk of cardiovascular (CV) events and premature death. The effect of the microvascular disease (MD) burden, i.e., the cumulative burden of retinopathy, nephropathy and peripheral neuropathy on all-cause mortality was evaluated in 774 T1D (age 40.2±11.7; DD 19.4±12.2 years; HbA1c 7.8±1.2%) in a mean follow-up of 10.6±2.5 years. Distribution of MD was: no-MD: n. 425 (54.9%); MD1: 250 (32.3%); MD2: 75 (9.7%); MD3: 24 (3.1%). Distribution was unchanged after esclusion of 41 T1D (5.3%) with previous CV events (CV+; 57.0%, 32.2%, 8.5% and 2.3%, respectively). Compared to no-MD, MD1-3 groups showed an adverse CV risk profile with steeply increase in age, DD, BMI, WHR, BP, HbA1c, uric acid and EURODIAB PCS risk score for major vascular outcomes (p&lt;0.0001); total and LDL cholesterol, and triglycerides (p&lt;0.05). eGFR (CKD-EPI) decreased, albuminuria progressively increased (p&lt;0.0001). Rate of CV events and that of EURODIAB score ≥20 increased with MD: 1.6%, 5.6%, 17.3%, and 29.2%; 4.0%, 14.4%, 41.3% and 79.2%, respectively (p&lt;0.0001). Consistently, rate of subjects on BP-lowering agents, RAS-blockers, statins e anti-platelet drugs increased (p&lt;0.0001). A total of 52 deaths occurred during the 8,184 person-years of follow-up (6.7%; 6.36 x1000 person-years). Death rate increased with MD: no-MD 1.9%; MD1 6.8% (HR: 3.75, 95% CI 1.62-8.69); MD2 14.7% (7.10, 2.85-17.67); MD3 66.7% (45.64, 19.50-106.79; K-M, p&lt;0.0001). Death rate was unchanged after esclusion of 41 CV+: 1.9%, 6.4%, 12.9% and 64.7% (p&lt;0.0001). After adjustment for age and sex, HRs were: MD1 2.61 (95% CI 1.11-6.14); MD2 3.42 (1.29-9.06); MD3 16.21 (6.20-42.35; p&lt;0.0001). In fully adjusted model, HRs were: MD1 2.51 (95% CI 1.01-6.23); MD2 2.97 (1.07-8.25); MD3 9.68 (3.19-29.36; p=0.001), with independent effects for age (HR 1.06), uric acid (HR 1.37) and smoking history (HR 2.45). Thus, the cumulative burden of MD independently affects the risk of all-cause death in T1D.

Disclosure
M. Garofolo: None. R. Giannarelli: None. M. Aragona: None. D. Lucchesi: None. L. Giusti: None. V. Sancho-Bornez: None. G. Daniele: None. R. Miccoli: None. G. Penno: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Intarcia Therapeutics, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Servier, Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Takeda Pharmaceuticals U.S.A., Inc.. Advisory Panel; Self; Janssen Biotech, Inc., Abbott.
FreeStyle Libre™ Use for Self-Management of Diabetes in Teenagers and Young Adults
Authors: CAMPBELL FIONA , BOLINDER JAN 
Published: June 2018

The challenges of caring for diabetes in teenagers and young adults are well known. We analyzed two research studies (IMPACT and SELFY) that evaluated FreeStyle LibreTM Flash Glucose Monitoring System as a replacement for self-monitoring of blood glucose (SMBG), looking specifically at outcomes in patients aged 13-24 years. IMPACT enrolled 241 patients with well controlled type 1 diabetes (T1DM), HbA1c 6.74±0.56% (50.1±6.1 mmol/mol), age 43.7±13.9 years (mean±SD) into a 6 month European RCT (23 sites). The control group (n=121) used SMBG and the intervention group used FreeStyle Libre for self-management. Of the 241 patients, 19 were aged 18-24 years. SELFY enrolled 76 young people aged 10.3±4.0 years (mean±SD), baseline HbA1c 7.9±1.0% (62.9±11.1 mmol/mol) into a 10 week single arm European study (10 sites). The study consisted of 2 weeks baseline masked (blinded) wear, followed by 8 weeks open use. Of the 76 patients, 25 were aged 13-17 years. IMPACT study results at 6 months showed no significant interaction of age with treatment group for the primary endpoint of time in hypoglycemia &lt;70 mg/dL. For the younger adults, time in range (TIR) (70-180 mg/dL) significantly increased by 2.9±0.89 hours/day (mean±SE); p=0.0055. Time in hyperglycemia (&gt;180 mg/dL) also significantly improved with a reduction of 2.40±0.834 hours/day (mean±SE); p=0.0113. Intervention group patients scanned the sensor on average 11.3 times daily. Teenagers in the SELFY study significantly improved the primary endpoint of TIR (70-180 mg/dL) by 1.2±2.5 hours/day (mean±SD), p=0.0254. HbA1c also significantly improved, -0.7±0.6%, p&lt;0.0001. Time in hyperglycemia (&gt;180 mg/dL) significantly reduced by -1.7±2.9 hours/day, p=0.0093, no statistically significant changes were observed in hypoglycemia (time&lt;55 mg/dL, baseline 0.7±1.0 hours/day). Scan frequency of FreeStyle Libre was on average 9.7 times daily. The IMPACT and SELFY studies both demonstrated improvements in glycemic control in the teenager and young adult age groups.

Disclosure
F. Campbell: Research Support; Self; Abbott. Consultant; Self; Eli Lilly and Company, Novo Nordisk A/S, Johnson & Johnson Diabetes Institute, LLC., Sanofi, Medtronic, Roche Diabetes Care Health and Digital Solutions. J. Bolinder: Advisory Panel; Self; Abbott. Speaker's Bureau; Self; Abbott. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S, Eli Lilly and Company.
Sex Differences in Insulin Sensitivity Are Related to Muscle Tissue Acylcarnitines and Serum Lysophosphatidylcholines but Not Subcellular Lipid Distribution in Humans
Authors: BROUSSARD JOSIANE L. , PERREAULT LEIGH , NEWSOM SEAN A. , KAHN DARCY E. , KEREGE ANNA , HARRISON KATHLEEN A. , BERGMAN BRYAN 
Published: June 2018

Sex differences in insulin sensitivity are present throughout the lifespan, though mechanisms that account for these differences are unclear. Accumulation of diacylglycerol (DAG) and sphingolipids in skeletal muscle are thought to promote insulin resistance, and localization plays an important role. Other lipids and lipid intermediates found in muscle and plasma such as acylcarnitines also relate to insulin sensitivity. However, it is not known whether there are sex differences in accumulation of these lipids that may affect insulin sensitivity. We evaluated insulin sensitivity and sub-cellular localization of skeletal muscle DAG and sphingolipids, as well as muscle acylcarnitines and serum lipidomics, in 25 obese, nondiabetic men and women (13F). Insulin sensitivity was assessed with a hyperinsulinemic-euglycemic clamp. Muscle biopsies were taken during basal and insulin stimulated conditions and fractionated into sub-cellular compartments. Lipids were measured using LC/MS/MS. Insulin sensitivity was significantly lower in men (p=0.05), however we found no sex-differences in localization of DAG or sphingolipids in skeletal muscle. Men had higher total acylcarnitines in muscle tissue (p&lt;0.05) and higher serum lysophosphatidylcholines (LPCs; p&lt;0.01), and both were correlated with insulin sensitivity (r=-0.42 and -0.43, respectively; p&lt;0.05). After correcting for multiple comparisons, the linoleoylcarnitine species (18:2AC) was significantly elevated in men during insulin stimulation (p=0.001), and was negatively associated with insulin sensitivity (r=-0.43; p&lt;0.05). Combined, these data suggest differences in content of acylcarnitines between sexes consistent with differences in fatty acid processing and oxidation that may impact insulin sensitivity. Further, greater serum LPC species may play an important role in the decreased insulin sensitivity associated with male sex.

Disclosure
J.L. Broussard: None. L. Perreault: Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Advisory Panel; Self; Merck & Co., Inc.. Speaker's Bureau; Self; Merck & Co., Inc., AstraZeneca, Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Sanofi. S.A. Newsom: None. D.E. Kahn: None. A. Kerege: None. K.A. Harrison: None. B. Bergman: Research Support; Self; Eli Lilly and Company. Advisory Panel; Spouse/Partner; Novo Nordisk Inc., Merck & Co., Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company.