bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence against Pathway-Selective Hepatic Insulin Resistance in Mice
Authors: VATNER DANIEL F. , PETERSEN MAX C. , LI XIRUO , ROGERS JILLIAN C. , CLINE GARY , SAMUEL VARMAN , SHULMAN GERALD I. 
Published: June 2018

Insulin suppresses hepatic glucose production and increases hepatic de novo lipogenesis (DNL). Paradoxically, hepatic DNL remains elevated in insulin-resistant subjects, leading to the hypothesis that hepatic insulin resistance is pathway-selective. Prior studies of DNL in hepatic insulin resistance are complicated by confounders, such as use of markedly unphysiologic animal models or comparison of animals on different diets and thus different availability of DNL precursors. We measured DNL in InsrT1150A knockin (KI) mice, a strain protected from diacylglycerol-mediated hepatic insulin resistance, and in littermate controls. Diets were matched: 60% high fat diet (HFD) with 1% dextrose in drinking water. After two days of fat-feeding, before the development of significant insulin resistance, KI and WT mice displayed similar rates of DNL (KI 24.3% ± 3.6; WT 22.2% ± 3.5). After 9 days of HFD, when WT but not KI mice have developed hepatic insulin resistance, rates of DNL were reduced in WT mice but preserved in KI mice (KI 16.4% ± 2.4; WT 7.4% ± 1.3; P &lt; 0.01). After 4 weeks of HFD, with the development of skeletal muscle resistance, rates of DNL increased in WT mice to reach those observed in KI mice (KI 19.3% ± 2.6; WT 15.9% ± 2.3). Consistent with the insulin-resistant phenotype, Srebp-1c cleavage was reduced in the setting of hepatic insulin resistance in WT mice; this effect was attenuated in KI mice. The Srebp-regulated lipogenic proteins Fasn and Scd1 were both reduced in 9d HFD fed livers regardless of genotype; at 4 weeks, protein abundance remained suppressed in WT mice but was restored in KI mice. Pklr, a protein associated with DNL but not regulated by Srebp, was unaffected by HFD-induced hepatic insulin resistance.
Conclusion: Regulation of DNL is subject to lipid-induced hepatic insulin resistance, challenging the selective hepatic insulin resistance hypothesis. Increased DNL seen in insulin resistant subjects may be due to hyperinsulinemia and diversion of substrate from the insulin resistant periphery.

Disclosure
D.F. Vatner: None. M.C. Petersen: None. X. Li: None. J.C. Rogers: None. G. Cline: None. V. Samuel: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc.. Research Support; Self; Gilead Sciences, Inc..
Incidence and Evolution of Prediabetes among Older Adults—A Population-Based Cohort Study
Authors: SHANG YING , FRATIGLIONI LAURA , MARSEGILIA ANNA , WANG RUI , WELMER ANNA-KARIN , WANG HUIXIN , XU WEILI 
Published: June 2018

Objective: The incidence and evolution of prediabetes in older adults is still unclear. We aimed to estimate the incidence of prediabetes, the rates of prediabetes reverting to normoglycemia or progressing to type 2 diabetes, and to identify possible prognostic factors among older adults with prediabetes.
Methods: In the Swedish National Study on Aging and Care-Kungsholmen Project, 3049 diabetes-free participants aged ≥60 years were examined at baseline (2001-2004), and were followed-up to 12 years (2013-2016). At each wave, type 2 diabetes was ascertained based on self-report, antidiabetic drug use, medical records, or glycated haemoglobin (HbA1c) ≥6.5% (48 mmol/mol). In diabetes-free participants, prediabetes was assessed as HbA1c ≥5.7% (39 mmol/mol), and normoglycemia was defined as HbA1c &lt;5.7%. Data were analysed with Poisson regression and multinomial logistic regression.
Results: During 12 years follow-up, among 1972 (64.7%) participants with normoglycemia, 505 (25.6%) developed prediabetes (incidence=4.3/100 person-years, 95% CI 3.9-4.8). Of the 1077 (35.3%) participants with prediabetes at baseline, 204 (18.9%) reverted to normoglycemia (reversion rate=3.1/100 person-years, 95% CI: 2.6-3.6) and 119 (11.0%) progressed to type 2 diabetes (progression rate=1.7/100 person-years, 95% CI: 1.3-2.1). The reversal to normoglycemia was significantly associated with lower systolic blood pressure and weight loss, while, obesity and weight gain were risk factors for progression to type 2 diabetes.
Conclusions: The incidence of prediabetes is high (about 26%) among older adults. Around 19% of people with prediabetes may revert to normoglycemia and 11% progress to type 2 diabetes. Weight change and systolic blood pressure may play a role in such evolution.

Disclosure
Y. Shang: None. L. Fratiglioni: None. A. Marsegilia: None. R. Wang: None. A. Welmer: None. H. Wang: None. W. Xu: None.
Differential Impacts of Insulin Analogs Lispro and Glulisine on Glucose and Lipid Homeostasis during Hyperinsulinemic Euglycemic Clamp in Streptozotocin-Induced Diabetic Rats
Authors: BRIAND FRANÇOIS , BROUSSEAU EMMANUEL , BURCELIN RÉMY , SULPICE THIERRY 
Published: June 2018

In addition to their benefits on glycemia, the specific actions of insulin analogs on glucose and lipid metabolism should be depicted. Here we analyzed the effects of Lispro (LIS) and Glulisine (GLU) insulin-analogs in diabetic rats. Diabetes was induced in Wistar male rats following an i.v. injection of streptozotocin (STZ) at 60mg/kg. Conscious rats underwent a 2-hour hyperinsulinemic (LIS or GLU at 0.8U/kg/h) euglycemic clamp with a constant infusion of 3H-glucose (4µCi/kg/min), with n=8 rats per each group. Glycemia was monitored continuously to adjust glucose infusion rate (GIR) to maintain euglycemia during the LIS or GLU perfusion. Blood, muscle and liver samples were collected for biochemical and radioactivity analysis. Compared to GLU, mean GIR was 51% higher in LIS treated rats (LIS: 18 +/- 1mg/kg/min, GLU: 12 +/- 1 mg/kg/min, p&lt;0.01). Importantly, the higher GIR observed with LIS was associated with a strong inhibition of hepatic glucose production, which remained elevated in rats treated with GLU (LIS: 0.4 +/- 0.9mg/kg/min, GLU: 6.4 +/-1.6 mg/kg/min, p&lt;0.01). Whole body glycolysis, glycogen, as well as liver and muscle glycogen synthesis rates remain similar between groups. Compared with LIS, rats treated with GLU showed a better reduction in plasma free fatty acids and glycerol levels during the clamp experiment, with a 50% and 139% lower plasma free fatty acids and glycerol area under the curve (p&lt;0.and p&lt;0.01 vs. LIS, respectively). 3H-glucose incorporation in muscle and liver lipid stores was not different, indicating that lipolysis rather than lipogenesis was differentially impacted.
In conclusion, hyperinsulinemic euglycemic clamps in STZ rats enabled to detect a strong inhibition of hepatic glucose production by LIS, while GLU better suppresses lipolysis. Our experimental setting should help to differentiate other insulin analogs and dissect their mechanisms of action.

Disclosure
F. Briand: Employee; Self; Physiogenex S.A.S.. Stock/Shareholder; Self; Physiogenex S.A.S. E. Brousseau: Employee; Self; Physiogenex S.A.S. R. Burcelin: Stock/Shareholder; Self; Physiogenex S.A.S. T. Sulpice: Employee; Self; Physiogenex S.A.S.. Stock/Shareholder; Self; Physiogenex S.A.S..
Improving Sleep by Trazodone Improves Glucose Control
Authors: SAKKAL SAAD 
Published: June 2018

Background: 77% of people with diabetes have some form of insomnia. Sleep disturbance results in impaired glucose control in healthy individuals or worsens glucose control in people with diabetes. Short-term sleep studies (1-6 weeks) improved glucose control and insulin resistance in obese “healthy” individuals. We have shown before the superior benefit Trazodone has in treating neuropathy over gabapentin. We show, in this abstract, the impact of improving sleep may have on glucose control.
Methods: we treated 200 type 2 patients with diabetic neuropathy with either trazodone (100), or Gabapentin(100), compared the change in neuropathy, sleep and glucose control. We quantified their neuropathy with our previously published neuropathy grading system (Sakkal’s Scale: level of vibration sensory loss by the 128 tuning fork) we quantified their sleep with shortening latency of sleep onset, and sleep duration extension. We measured their glucose control with AM insulin-to-glucose ratio, HgA1c, and in-target glucose when CGMS was available (20 patients). We excluded patients with OSA. All patients followed our standard diabetes treatment protocol for type 2.
Results: At 12 months, Trazodone improved the scale of diabetic neuropathy in 80% of patients, sleep hygiene in 70%; Sleep increased by 40 minutes, and sleep onset latency decreased by 10 minutes. Insulin/glucose ratio was 21/142=0.147, HgA1c 7.2%, HgA1c&lt;7 in 68%, and in-target glucose in 72% on CGMS(12 patients). Gabapentin improved the scale of diabetic neuropathy in 66%, sleep hygiene in 44%; with sleep increasing by 14 minutes, and sleep onset latency decreased by 4 minutes. Insulin -to-Glucose ratio was 33/166=0.19, HgA1c 7.8%,HgA1c,7 in 56%, and in-target-glucose in 58% on CGMS (8 patients.) analysis. A maximum number of diabetes medications used were 3 in both groups. Percentage needing basal insulin at the end was 12% in the Trazodone group, 21% in the Gabapentin group.
Conclusion: Improved sleep and neuropathy with Trazodone improved glucose control.

Disclosure
S. Sakkal: None.
Population Screening for T1D and Celiac Disease—Autoimmunity Screening for Kids (ASK)
Authors: GENO RASMUSSEN CRISTY R. , REWERS MARIAN , BAXTER JUDITH , WAUGH KATHLEEN , STECK ANDREA , FROHNERT BRIGITTE I. , YU LIPING , LIU EDWIN 
Published: June 2018

Early detection can prevent morbidity associated with type 1 diabetes (T1D) and celiac disease (CD). ASK is a 4-year program with the goal to screen Denver metro-area children for pre-symptomatic T1D and CD, increase public awareness of these diseases, and provide evidence for universal screening. We are reporting first-ever prevalence data for pre-symptomatic T1D and CD in the U.S. general population children aged 2-17 y.
In 2017, ASK approached ∼15,000 children for consent, screened 5090 with results available for 4915. Study participant age, sex, and race/ethnicity closely reflected Denver’s general population; 4% had a T1D first-degree relative (FDR). Standard radiobinding assays (RBA) and more specific electrochemiluminescence (ECL) assays for autoantibodies to insulin, GAD, IA-2, ZnT8 and transglutaminase (TGA) were used for screening and confirmation. Children with confirmed persistent islet autoantibodies received follow-up with education to prevent DKA, psychological support, and referrals to prevention trials or clinical services.
Multiple islet autoantibodies, predicting a 44% 5-y risk of T1D, were found in 32 (0.7%) children; of the 30 children retested to date, all remained persistently positive, six developed dysglycemia and one progressed to T1D. A single islet autoantibody, confirmed as high-affinity by ECL (29% 5-y risk of T1D), was found in 27 (0.5%); 18/19 children retested remained positive, 5 developed dysglycemia and one T1D. Over 86% (50/59) of the screening-detected children at risk for T1D did not have an FDR with T1D. The prevalence of TGA by both RBA and ECL was 2.2% and persistent in 74/76 (97%) children retested so far.
This novel population-based screening program for the two most common autoimmune diseases of childhood reports high prevalence of pre-symptomatic T1D and CD in Denver children. Prospective follow-up of screening-detected cases for clinical outcomes and cost-effectiveness analysis will inform potential future universal screening.

Disclosure
C.R. Geno Rasmussen: None. M. Rewers: None. J. Baxter: None. K. Waugh: None. A. Steck: None. B.I. Frohnert: None. L. Yu: None. E. Liu: None.
MEDI0382, a GLP-1/Glucagon Receptor Dual Agonist, Dramatically Reduces Hepatic Collagen in a Mouse Model of NASH
Authors: BEATON MICHELLE , GUIONAUD SILVIA , CONWAY JAMES P. , GRIMSBY JOE , RHODES CHRISTOPHER J. , JERMUTUS LUTZ , TREVASKIS JAMES 
Published: June 2018

Nonalcoholic steatohepatitis (NASH), characterized by hepatic steatosis, inflammation and fibrosis is an unmet medical need. MEDI0382, a balanced GLP-1/glucagon dual receptor agonist, is under development for the treatment of T2DM. Here we examined the effects of MEDI0382 on NASH compared to liraglutide, a GLP-1 analog. Leptin-deficient ob/ob mice were maintained on high trans-fat, fructose and cholesterol diet for 8 weeks to induce NASH then randomized to four treatment groups: vehicle, MEDI0382 (30 nmol/kg), liraglutide (30 nmol/kg) or vehicle-treated and switched to low-fat diet (LFD). Treatment with MEDI0382 and liraglutide reduced body weight and improved glucose tolerance. Hepatic lipid was reduced by 40% with MEDI0382 treatment (p&lt;0.0001), which was more effective than liraglutide or switch to LFD. Hepatic collagen, quantified by type 1 collagen immunohistochemistry, was increased more than 2-fold with NASH and was reduced by 40% in MEDI0382-treated mice (p=0.005). Consistently, type 1 collagen gene expression increased 2-fold with NASH and was reduced by 85% in MEDI0382-treated livers (p&lt;0.0001). No reductions in collagen were observed with liraglutide or switch to LFD. The NASH score, integrating pathology scores for steatosis, lobular inflammation, fibrosis, hepatocyte ballooning, biliary hyperplasia, and CD68 expression was significantly reduced by MEDI0382 (p&lt;0.0001), greater than liraglutide or switch to LFD. Consistent with histopathology improvements, MEDI0382 treatment also reduced inflammatory gene expression (Tnf, Tgfb1, Il1b, and Ccl2) to a greater extent than liraglutide or LFD switch.
In conclusion, MEDI0382 exerted similar metabolic control relative to liraglutide, but exhibited superior effects on primary NASH endpoints.

Disclosure
M. Beaton: Employee; Self; MedImmune. Employee; Spouse/Partner; MedImmune. S. Guionaud: None. J.P. Conway: None. J. Grimsby: Employee; Self; AstraZeneca. C.J. Rhodes: Stock/Shareholder; Self; AstraZeneca. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. J. Trevaskis: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca.
Sex Differences in the Response of C57BL/6 Mice to Ketogenic Diets
Authors: COCHRAN JESSE , TAUFALELE PAUL V. , LIN KEVIN D. , ZHANG YUAN , DALE ABEL E. 
Published: June 2018

Since the initial use of ketogenic diets (KD) as adjunctive treatment for epilepsy, these diets are being increasingly used to promote weight loss and to reduce the risk of metabolic sequelae of obesity. Typical KD are very low in carbohydrate and high in fat, promoting hepatic production of ketone bodies. Few studies have evaluated gender differences in response to KD, and many animal studies tend to be performed in male mice. To explore sex differences in response to KD, female and male wild type mice on the C57BL/6J background were fed either a control diet (CD- 7% fat, 47% carb., 19% protein) or KD (75% fat, 3% carb., 8% protein), following weaning. Females on the CD manifested higher levels of circulating β-hydroxybutyrate (β-HB) than males (2.86-fold, p&lt;0.05). Circulating β-HB concentrations increased with KD in males and females (1.30-fold and 5.05-fold, p&lt;10-4 and p&lt;0.01 respectively) with higher concentrations in females. After 8 weeks, females on KD displayed an increase in body weight (1.07-fold KD vs. CD, p&lt;0.05) while body weight declined in males (0.88-fold, p&lt;0.05). Nuclear magnetic resonance analysis revealed elevated lean mass in females (1.07-fold, p&lt;0.05), but a significant reduction in fat mass in males (0.49-fold, p&lt;0.05) relative to sex-matched mice on CD. The female mice on KD developed impaired glucose tolerance with a 1.35-fold increase in glucose tolerance test area under the curve (GTT AUC) relative to females on CD (p&lt;0.001). In contrast, fasting glucose levels were lower in males on KD (131.8 ± 12.5 mg/ dl vs. 169.2 ± 6.3 mg/dl, p&lt;0.05). Despite no significant change in GTT AUC, the male mice on KD displayed elevated blood glucose concentrations 30 minutes after injection relative to males on CD (344.9 ± 18.7 mg/dl vs. 272.0 ± 10.3 mg/dl, p&lt;0.05). However, after 120 minutes, blood glucose levels returned to initial fasting levels.
In conclusion, significant sex differences exist in terms of body composition and metabolism in response to ketogenic diets via mechanisms that remain to be elucidated.

Disclosure
J. Cochran: None. P.V. Taufalele: None. K.D. Lin: None. Y. Zhang: None. E. Abel: None.
Iron Overload Plays an Important Role in ER Stress-Induced Insulin Resistance in Human Skeletal Muscle Cells
Authors: LEE KWANWOO , CUI RIHUA , KIM DAE JUNG , CHOI SUNGE , LEE WHA JOUNG , KANG YUP , KIM TAE HO , MOON HYUN UK , JEON JA YOUNG , HAN SEUNG JIN , KIM HAE JIN 
Published: June 2018

Aim: In this study, we investigated the relationship and molecular mechanisms between iron-overload and ER-stress-induced insulin resistance in human skeletal muscle cells.
Methods: Intracellular iron was measured using calcein AM. Iron metabolism-related genes were analyzed by immunoblotting and PCR. The study was conducted using iron supplementation, which was achieved by palmitate, FeSO4 and FeCl3 administration, and iron reduction, which occurred by DFO, DS and Bapta AM administration, and knockdown of tfR1 or IRP2 genes, to investigate the effects of iron metabolism on insulin sensitivity in HSMMs. Intracellular calcium was detected using Fluo-3/AM staining. TfR1 internalization regulated by calcium was detected by GFP-labelled transferrin.
Results: Endoplasmic reticulum stress by tunicamycin, thapsigargin, or palmitate evoked insulin resistance and simultaneously increased intracellular iron. Iron chelator, DFO, dramatically prevented ER-stress inducer-induced insulin resistance and iron donor impaired insulin sensitivity in vitro and in vivo through activation of JNK. Among several iron metabolism-related genes, tfR1 plays a predominant role for maintaining iron homeostasis in HSMMs. Treatment of ER-stress inducer positively regulated translocation of tfR1 by intracellular calcium, but protein levels of tfR1 did not change. Iron reduction, by adding iron chelator, calcium chelator, or knockdown of tfR1 or IRP2, dramatically prevented ER-stress-induced insulin resistance through the reduction of iron-overload.
Conclusions/Interpretation: The current study shows ER-stress inducer evoked insulin resistance through iron overload. Reduction of intracellular iron, by iron chelator, significantly prevents insulin resistance. Therefore, attempts to block iron overload might be a strategy for preventing insulin resistance and diabetes.

Disclosure
K. Lee: None. R. Cui: None. D. Kim: None. S. Choi: None. W. Lee: None. Y. Kang: None. T. Kim: None. H. Moon: None. J. Jeon: None. S. Han: None. H. Kim: None.
The Mediterranean Diet and Two-Year Changes in Cognitive Function in Puerto Rican Adults With vs. Without Type 2 Diabetes
Authors: MATTEI JOSIEMER , BIGORNIA SHERMAN J. , SOTOS-PRIETO MERCEDES , SCOTT TAMMY , GAO XIANG , TUCKER KATHERINE L. 
Published: June 2018

People with type 2 diabetes (T2D), especially uncontrolled T2D, have high risk of cognitive decline. The role of a Mediterranean diet on cognitive function has not been assessed for adults with vs. without T2D within the same population. We aimed to determine associations of a Mediterranean diet score (MeDS) with 2 year changes in cognitive function by T2D status and by glycemic control status. We used data from the Boston Puerto Rican Health Study (mean (SD) age= 57.2 (7.6) y; n=711 without T2D; n=465 with T2D defined as fasting plasma glucose ≥ 126 mg/dL or medication use). Glycemic control at baseline was categorized as uncontrolled (hemoglobin A1c ≥7%; 74% of T2D sample)) vs. controlled (26%). Two-y changes in glycemic control were defined as stable/improved (32%) vs. poor/declined (68%). Baseline MeDS ranged from 0-9 by scoring participants within the sex-specific healthy median intake of 9 foods and nutrients. The primary outcome was 2 year change in global cognitive function z-score, which included 7 cognitive tests. Adjusting for baseline sociodemographic and lifestyle factors, comorbidities, and baseline measure, MeDS was positively associated with 2 year change in global cognitive function in adults with T2D (β ± SE=0.027 ± 0.011; p=0.016) but not without T2D (-0.002 ± 0.008; p=0.80). Similar results were noted for single cognitive tests (i.e., mini-mental state examination, word recognition, digit span, clock drawing). Better global cognitive function over 2 years with higher MeDS was noted with glycemic control at baseline (0.062 ± 0.020; p=0.004) or stable/improved over 2 years (0.053 ± 0.019; p=0.007), but not for uncontrolled or poor/declined glycemic control. Adhering to a Mediterranean diet is associated with positive 2 year changes in cognitive function among adults with T2D. Glycemic control further sustains these benefits, suggesting that both a healthy Mediterranean diet and effective clinical management may help preserve optimal cognitive function in adults with T2D.

Disclosure
J. Mattei: None. S.J. Bigornia: None. M. Sotos-Prieto: None. T. Scott: None. X. Gao: None. K.L. Tucker: None.
Effects of Hyperglycemia on Skeletal Muscle Glucose Metabolism in Healthy Subjects
Authors: SHANNON CHRIS , MEROVCI AURORA , TRIPATHY DEVJIT , ABDUL-GHANI MUHAMMAD , NORTON LUKE , DEFRONZO RALPH A. 
Published: June 2018

Background: Physiological hyperglycemia can induce skeletal muscle insulin resistance and alterations in metabolic glucose partitioning. We investigated the mechanisms driving this muscle glucotoxicity in response to a three day elevation of plasma glucose concentrations.
Methods: Twenty-five lean, glucose tolerant subjects (mean ± SD age 46 ± 4 years; BMI 25 ± 1 kg/m2) underwent a euglycemic insulin clamp (80 mU/m2·min) at baseline and following three days of saline (n=5) or glucose (n=20) infusion to raise plasma glucose by 45 mg/dL. Oxidative (GOX), non-oxidative (NOGD) and total (TGD) glucose disposal were calculated from indirect calorimetry and glucose infusion rate. Skeletal muscle biopsies were obtained prior to and after each clamp for the determination of metabolite concentrations, protein phosphorylation and pyruvate dehydrogenase (PDH) activation status (PDHa). Data are presented as mean ± SE and were analyzed using two-way ANOVA.
Results: Three days of glucose infusion increased basal (1.2 ± 0.1 vs. 4.3 ± 0.3) and insulin-stimulated (2.3 ± 0.2 vs. 4.8 ± 0.3 mg/kg/min) GOX by 3.5 and 2.2-fold, respectively (P&lt;0.001), whereas NOGD was 51% lower (9.2 ± 2.6 vs. 4.5 ± 2.1 mg/kg/min; P&lt;0.001), resulting in a 16% reduction in TGD (10.3 ± 2.4 vs. 8.7 ± 2.1 mg/kg/min; P&lt;0.01). Muscle glycogen content was doubled (343 ± 18 vs. 759 ± 47 mmol/kg dry weight; P&lt;0.001) and glycogen synthase phosphorylation (Ser641) was increased by 46% (P=0.03), whilst GSK3β phosphorylation (Ser9) tended to be reduced (P=0.07). Glucose infusion also reduced insulin-stimulated PDHa by 20% (P=0.02) and Akt phosphorylation (Ser473) by 27% (P=0.03). No changes were observed in the saline group.
Conclusion: Hyperglycemia caused a robust increase in basal GOX, such that further insulin-stimulated activation of GOX (distal insulin signaling and PDH) was impaired. Deficits in NOGD, and subsequently, TGD likely occur as a consequence of perturbed glycogen synthase activation in the face of augmented muscle glycogen concentrations.

Disclosure
C. Shannon: None. A. Merovci: None. D. Tripathy: None. M. Abdul-Ghani: None. L. Norton: None. R.A. DeFronzo: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc..