bluuebunny/crossref_metadata_2025 huggingface dataset:
289-OR: JAK Inhibitors Block Interferon and Common Gamma Chain Cytokine Signaling to Reverse Diabetes in NOD Mice
Authors: JHALA GAURANG , GE TINGTING , KRISHNAMURTHY BALASUBRAMANIAN , KAY THOMAS , THOMAS HELEN E.
Published: June 2020

Cytokines that signal through the JAK-STAT pathway, such as interferon-γ (IFN-γ) and common γ chain cytokines, play an important role in facilitating the destruction of insulin-secreting β cells by CD8+ T cells in type 1 diabetes. We previously showed that inhibiting JAK1/JAK2 reversed autoimmune insulitis in non-obese diabetic (NOD) mice and also blocked IFN-γ mediated MHC class I upregulation on β cells. Blocking interferons on their own did not prevent diabetes in knockout NOD mice, so we tested whether JAK inhibitor action on signaling downstream of common γ chain family cytokines, including IL-2, IL-21, IL-7 and IL-15, may also affect progression of diabetes in NOD mice. Common γ chain cytokines activate JAK1 and JAK3 to regulate T cell proliferation. We compared JAK1-selective inhibitors with our previous data with JAK1/JAK2 inhibition. JAK1-selective inhibitors reduced IL-21, IL-2 and IL-7 signaling in T cells (p<0.05) and IFN-γ signaling in β cells, but did not affect GM-CSF signaling in granulocytes. When given in vivo to NOD mice, JAK1-selective inhibitors reduced CD8+ T cell proliferation (Ki-67) in islets, reduced immune cell infiltration into islets and prevented MHC class I upregulation on β cells as measured by flow cytometry. Newly diagnosed diabetes was reversed in 94% NOD mice treated twice daily with JAK1-selective inhibitors.

Our results indicate that JAK inhibitors block common γ chain cytokines in lymphocytes and interferons in lymphocytes and β cells and are thus more effective against diabetes pathogenesis than IFNγ receptor deficiency alone. Our studies pave the way for use of this class of drug in clinical trials for type 1 diabetes.

Disclosure

G. Jhala: None. T. Ge: None. B. Krishnamurthy: None. T. Kay: None. H.E. Thomas: None.

Funding

National Health and Medical Research Council of Australia (GNT1145507); JDRF (1-SRA-2018-599-S-B)
298-OR: Disruption of Multiple Cell-Autonomous Protein Phosphorylation Networks Underlies Muscle Insulin Resistance in Type 2 Diabetes
Authors: BATISTA THIAGO M. , ALBRECHTSEN NICOLAI J. WEWER , ZIERATH JULEEN R. , MANN MATTHIAS , KAHN C. RONALD
Published: June 2020

Skeletal muscle insulin resistance is the earliest defect in type 2 diabetes (T2D), however, whether this represents a cell-autonomous defect or is secondary to changes in hormones and other circulating factors in vivo is unclear. To identify primary drivers of skeletal muscle insulin resistance in T2D without interference of these systemic factors, we have developed a “disease-in-a-dish” model by differentiating induced pluripotent stem cells (iPSCs) from T2D patients and controls into skeletal myoblasts (iMyos) and studied their function in vitro (n=8 subjects per group). We find that T2D iMyos retain multiple features of in vivo insulin resistance including altered insulin signaling downstream of the IRS/AKT pathway, impaired insulin-stimulated glucose uptake, and reduced mitochondrial oxidation. More importantly, using global phosphoproteomics we identify nearly 1,000 phosphorylation sites that were significantly increased or decreased (FDR < 0.05) by T2D status. While many of the observed signaling defects in T2D iMyos occurred inside the classical insulin signaling pathway and included dysregulation of Akt, mTOR and forkhead box transcription factors, over 85% of these changes occurred in basal protein phosphorylation. These included phosphorylation of proteins in many pathways not typically involved in insulin resistance, such as mRNA splicing and processing, gene transcription, chromatin remodeling and cytoskeleton dynamics. Motif analysis revealed enrichment of a multiplicity of kinases including ROCK, mTOR/S6K and PKCs with potential targets involved in insulin action, cytoskeleton and cell cycle, without changes in total protein content. This broad dysregulated phosphorylation network reveals a new dimension in the complexity of the cell-autonomous mechanisms underlying insulin resistance in T2D, as well as new targets for therapy or prevention of the disease.

Disclosure

T.M. Batista: None. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S, Novo Nordisk Foundation. Speaker’s Bureau; Self; Merck Sharp & Dohme Corp. J.R. Zierath: None. M. Mann: None. C. Kahn: Advisory Panel; Self; ERX Pharmaceuticals, Kaleido Biosciences. Consultant; Self; AntriaBio, Flagship Pioneering, Sana-Cobalt.

Funding

National Institutes of Health (R01DK031036, R01DK033201); Swedish Research Council (2015-00165); Novo Nordisk Foundation (NNF18CC0034900)
302-OR: ADA Presidents’ Select Abstract: The Balance of Vascular Tone in the Afferent (RA) and Efferent (RE) Arterioles Associates with Diabetic Kidney Lesions and Predicts Progression to End Stage Kidney Disease (ESKD) in Type 2 Diabetes (T2D)
Authors: SAULNIER PIERRE-JEAN , LOOKER HELEN C. , MAUER MICHAEL , NELSON ROBERT G. , BJORNSTAD PETTER
Published: June 2020

The balance of RA and RE, a major determinant of intraglomerular pressure (P<glo), may be important in the initiation and progression of diabetic kidney disease (DKD). Although RA and RE are not directly measurable in humans these parameters can be estimated by the Gomez equation using measures of whole-kidney GFR and renal plasma flow (RPF), mean arterial pressure (MAP), hematocrit, and plasma oncotic pressure. We examined the association of the RA/RE ratio with ESKD incidence in 212 Pima Indians with T2D who underwent measures of GFR (iothalamate) and RPF (p-aminohippurate). RA/RE ratio’s association with kidney structural lesions was also examined in a subset of 111 participants. Of the 212 subjects (29% men; mean age 52 years, diabetes duration 22 years, MAP 92 mmHg, HbA1c 10.1%, GFR 111 ml/min; median ACR 99 mg/g), 57 progressed to ESKD during median follow-up of 18.4 years. Cox regression, adjusting for sex, baseline age, diabetes duration, HbA1c, renin-angiotensin system blocker use and GFR, indicated that each 1 SD increment in the RA/RE ratio conferred higher risk of ESKD (4.19; 95%CI 2.18-8.04). In addition, the correlation between the RA/RE ratio and mesangial fractional volume, a key predictor of DKD progression (R2=15%, P<0.0001), was stronger than the correlation between GFR and mesangial fractional volume (R2=7%, P=0.004). Elevated RA/RE ratio, reflective of low P<glo, strongly associates with incident ESKD, independent of GFR, and with the glomerular structural lesion that best predicts this ESKD progression. These data, directly challenging the hypothesis that intraglomerular hypertension drives DKD, are derived from whole-kidney GFR and RPF, and therefore do not necessarily reflect single-nephron function. Nevertheless, identifying the mechanisms underlying this hemodynamic imbalance and its potential ischemic influences may provide new therapeutic targets.

Disclosure

P. Saulnier: None. H.C. Looker: None. M. Mauer: None. R.G. Nelson: None. P. Bjornstad: Advisory Panel; Self; XORTX Therapeutics Inc. Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Novo Nordisk Foundation. Research Support; Self; Horizon Pharma.

Funding

American Diabetes Association (1-08-CR-42 to R.G.N.); National Institute of Diabetes and Digestive and Kidney Diseases
312-OR: Gender-Specific Effects on Hepatic Fat Metabolism in Type 2 Diabetes before and after Remission
Authors: AL-MRABEH AHMAD , MELHEM SHADEN , ZHYZHNEUSKAYA SVIATLANA V. , PETERS CARL , BARNES ALISON C. , HOLLINGSWORTH KIEREN G. , SATTAR NAVEED , LEAN MICHAEL E. , TAYLOR ROY
Published: June 2020

Men are more susceptible to type 2 diabetes and NAFLD than women, possibly secondary to differences in hepatic lipoprotein metabolism. The Tyneside cohort of Diabetes Remission Clinical Trial (34M/30F, 52.3±8.0 years, BMI 35.1±4.5kg/m2) were studied at baseline and to 24 months after weight loss. 3-point Dixon MRI was used for intra-organ fat. Hepatic VLDL-TG production was measured using a competitive blocking method. In the nondiabetic group, both liver and pancreas fat differed markedly in men and women (5.4± 1.1 vs. 3.4±0.1%, p=0.005, and 7.6±0.5 vs. 4.7±0.4%, p=0.0006, respectively). In diabetes, both liver and pancreas fat were similar in men and women at baseline (15.4±1.9 vs. 16.9±1.9%, p=0.57; and 8.5±0.4 vs. 8.4±0.5%, p=0.66, respectively). They decreased similarly after weight loss in both men and women (liver fat: 2.6±0.6% and 3.6±0.7%; pancreas fat: 7.6 ±0.4% and 7.5±0.5%, p<0.0001 vs. baseline for both). VLDL-TG production was also similar at baseline (554±39 vs. 559±33mg/kg/day, p=0.96) and after weight loss (418±28 vs. 448±37mg/kg/day, p=0.29). Women had a lower VLDL-TG pool size (p=0.002), lower plasma VLDL-TG (p<0.0001), lower fasting glucagon (p<0.05), higher adiponectin (p<0.001), and lower visceral adipose tissue (p<0.0001) volumes than men regardless of diabetes status. However, diabetic women had higher: subcutaneous fat (p<0.0001), leptin (p<0.0001), fasting NEFA (p=0.004), GDF-15 (p=0.044), and FGF-21 (p=0.008). After 24 months of intervention, men and women remained significantly different in VLDL-TG pool, NEFA, SAT, VAT, leptin, and adiponectin (p<0.05 for all). Women are likely to process lipoproteins more rapidly and safely store VLDL-TG. This minimizes delivery of toxic lipid metabolites from VLDL-TG to pancreatic islets. These data demonstrate important gender differences in hepatic fat handling, and underscore the importance of considering this when designing metabolic studies.

Disclosure

A. Al-Mrabeh: None. S. Melhem: None. S.V. Zhyzhneuskaya: None. C. Peters: Speaker’s Bureau; Self; Sanofi-Aventis. A.C. Barnes: None. K.G. Hollingsworth: None. N. Sattar: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Sanofi. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. M.E. Lean: None. R. Taylor: Speaker’s Bureau; Self; Novo Nordisk Foundation.

Funding

Diabetes UK
313-OR: Diurnal Pattern of Meal Tolerance in Type 2 Diabetes
Authors: YADAV YOGESH R. , ROMERES DAVIDE , RUCHI FNU , SAWLEH SAFIA , CARTER RICKEY , BASU ANANDA , BASU RITA
Published: June 2020

The existence of a diurnal pattern of post prandial glucose tolerance is relevant for management of patients with type 2 diabetes (T2D). We studied 10 healthy (4M) and 9 T2D (6M) subjects matched for age (56±3 vs. 58±3 yrs) and BMI (29±2 vs. 32±2 kg/m2). OGTT was done in healthy subjects to rule out diabetes. Identical mixed meals (8 kcal/kg/meal; 75 gm carb) were ingested during breakfast (B), lunch (L), and dinner (D) at 0700, 1300, and 1900 h in randomized latin square order with one labeled test meal/day on 3 consecutive days. Physical activity was kept same. Postprandial glucose turnover was measured utilizing the triple tracer technique modified with all stable isotopes ([1-13C] Glucose, [2-13C] Glucose and [6, 6-2H2] Glucose). Results shown in Fig 1. Fasting and post-meal glucose were higher while fasting and post-meal insulin and C-peptide concentrations lower in T2D for all three meals compared to healthy. Although meal glucose appearance did not differ between meals in either group, fasting endogenous glucose production (EGP) was higher, percent suppression of EGP lower in T2D and glucose disappearance (corrected for urine glucose loss) lower in T2D than healthy for all meals consumed. This data correlates with lower insulin sensitivity, B-cell responsivity to glucose and disposition index in T2D than healthy throughout the day. Our results suggest an emerging diurnal pattern to glucose tolerance and fluxes in humans, and that the pattern is different in T2D.

Disclosure

Y.R. Yadav: None. D. Romeres: None. F. Ruchi: None. S. Sawleh: None. R. Carter: None. A. Basu: Consultant; Spouse/Partner; GENFIT. Research Support; Spouse/Partner; AstraZeneca. R. Basu: Consultant; Self; GENFIT. Research Support; Self; AstraZeneca.

Funding

National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.), (DK059637, DK020593)
321-OR: Deletion of 14-3-3ζ in Pancreatic ß-Cells Increase Mitochondrial Activity and Insulin Secretion
Authors: MUGABO YVES , GALIPEAU MARIA , TAN JU JING , FADZEYEVA EVGENIA , GRYGORCZYK RYSZARD , LIM GARETH E.
Published: June 2020

Pancreatic β-cells continuously sense blood glucose levels and secrete insulin to maintain normoglycemia. In β-cells, ATP generated by glycolysis promotes the closure of ATP-sensitive K+ channels, thereby increasing intracellular calcium and ultimately insulin secretion. 14-3-3 proteins, and in particular 14-3-3ζ, have been found to regulate ATP synthase and mitochondrial respiration, suggesting that members of this family of scaffold proteins in β-cells may influence glucose-stimulated insulin secretion (GSIS) and glucose homeostasis. To date, we have identified critical contributions of 14-3-3 proteins to GSIS. In mouse and human islets, pan-inhibition of 14-3-3 proteins with cell-permeable inhibitors potentiated ex-vivo GSIS. This was associated with increased mitochondrial function, as oxygen consumption and ATP synthesis rates were significantly enhanced. Moreover, increased ATP production was confirmed with luciferase-based assays. Of the seven isoforms, we previously reported critical metabolic roles of 14-3-3ζ in glucose homeostasis, and to understand its role in β-cells, β-cell-specific knockout mice (Ins1CreThor:14-3-3ζfl/fl, β-KO) were generated. When compared to control mice, no differences in body weights or glucose and insulin tolerance were observed, but β-KO mice displayed significantly enhanced insulin secretion following i.p. glucose (2 g/kg), and ex vivo islet perifusion studies revealed enhanced 2nd-phase secretion of GSIS from β-KO islets. Similar to pan-14-3-3 inhibition, increased mitochondrial activity and ATP synthesis were detected in islets of β-KO mice.

In summary, these results demonstrate critical functions of 14-3-3ζ and its related proteins in mitochondrial activity in β-cells and the regulation of GSIS. These data also suggest that 14-3-3ζ inhibition may represent a promising target to enhance pancreatic β-cell function in the context of diabetes.

Disclosure

Y. Mugabo: None. M. Galipeau: None. J. Tan: None. E. Fadzeyeva: None. R. Grygorczyk: None. G.E. Lim: None.

Funding

Canadian Institutes of Health Research; Canada Research Chairs Program (PJT-153144)
322-OR: Impairment of Alpha-Cell Bioenergetics Contributes to Increased Basal Yet Decreased Glucose Stimulated Oxygen Consumption Rates of Isolated Human Pancreatic Islets in T1DM and T2DM
Authors: DOLIBA NICOLAI M. , ROZO ANDREA V. , QIN WEI , ROMAN JEFFREY , LIU CHENGYANG , NAJI ALI , KAESTNER KLAUS H. , STOFFERS DORIS A. , MATSCHINSKY FRANZ
Published: June 2020

Fuel stimulated hormone release (HR) and the oxygen consumption rates (OCR) of isolated normal pancreatic islets are positively correlated illustrating that cellular energy state is a critical determinant of stimulus-secretion coupling. We investigated the relationship between hormone release and OCR in islets from donors with T1DM and T2DM, using unique oxygen measurement technology and optimized perifusion protocols. HR and OCR were quantified in 20 human donor islet preparations obtained from the Human Islet Resource Center at the University of Pennsylvania within 3-4 days after isolation (5 each of nondiabetic, T1DM, T2DM and anti-islet AutoAntiBody positive (AAB+). A physiological amino acid mixture (4mM) was used to stimulate glucagon release, then 3 and 16.7mM glucose were added to stimulate insulin release and inhibit glucagon release. Respiration was then uncoupled with FCCP and finally blocked by NaN3. Basal OCR was increased in islets from AAB+, T1DM and T2DM donors compared to controls. Low glucose failed to increase OCR in T1DM and T2DM islets while high glucose-stimulated OCR was both decreased and delayed. Glucose stimulated insulin release much less effectively and failed to suppress glucagon release in both T1DM and T2DM islets. AAB+ islets showed normal insulin release but lacked glucose suppression of glucagon release. The observation of increased basal-OCR of islets in all diabetes related conditions and reduced glucose-stimulated-OCR in T1DM and T2DM islets unrelated to hormone release rates is striking and indicates a profound alteration of bioenergetics regulation in these conditions hitherto unrecognized. Common to this pathophysiology are an increase in relative alpha-cell mass (T1DM and T2DM) or a functional defect of these cells (AAB+) providing a plausible explanation for this phenomenology and implying impaired alpha-cell energy metabolism.

Disclosure

N.M. Doliba: None. A.V. Rozo: None. W. Qin: None. J. Roman: None. C. Liu: None. A. Naji: None. K.H. Kaestner: None. D.A. Stoffers: None. F. Matschinsky: None.

Funding

National Institutes of Health (UC4DK112217)
326-OR: Faricimab for Diabetic Macular Edema: A Novel Anti–Angiopoietin-2/Anti–Vascular Endothelial Growth Factor Bispecific Antibody in Clinical Trials
Authors: SHETH VEERAL , SAHNI JAYASHREE , STOILOV IVAYLO , WILLIS JEFFREY R. , WEIKERT ROBERT
Published: June 2020

In the United States, diabetic retinopathy (DR) and diabetic macular edema (DME) are a leading cause of blindness among working-age adults. The introduction of vascular endothelial growth factor-A (VEGF) inhibitors has improved the management of DME and allowed regression of DR severity. However, DR/DME is a multifactorial disease, and targeting additional pathways holds promise for better outcomes. Angiopoietin-2 (Ang-2) is upregulated in the eyes of patients with diabetes and promotes vascular destabilization and inflammation. Faricimab, a novel bispecific antibody targeting both Ang-2 and VEGF, was evaluated in the BOULEVARD (NCT02699450) phase 2 trial for DME. Patients (N = 168 treatment-naïve [TN]; N = 61 previously anti-VEGF treated) were randomized 1:1:1 to intravitreal ranibizumab 0.3 mg, faricimab 1.5 mg (TN only), or faricimab 6.0 mg, every 4 weeks for 20 weeks followed by 16 weeks of observation. BOULEVARD met its primary outcome: faricimab 6.0 mg achieved greater mean gains (letters) from baseline in best-corrected visual acuity than ranibizumab at week 24 in TN patients (faricimab 6.0 mg, +13.9; faricimab 1.5 mg, +11.7; ranibizumab, +10.3; faricimab 6.0 mg vs. ranibizumab, +3.6; P = 0.03; 80% CI, 1.5, 5.6). The Early Treatment Diabetic Retinopathy Study DR Severity Scale (DRSS) was used to score vascular abnormalities and disease severity on color fundus images. A change of ≥ 2 steps is considered clinically significant. The proportion of TN patients with ≥ 2-step improvement from baseline at week 24 on the DRSS was 38.6%, 27.7%, and 12.2%, respectively. There were no new or unexpected safety outcomes with faricimab.

In conclusion, faricimab achieved better vision outcomes versus anti-VEGF monotherapy in TN patients, suggesting Ang-2 is a viable target for DR/DME. Phase 3 trials YOSEMITE (NCT03622580) and RHINE (NCT03622593) for faricimab in DME are ongoing.

Disclosure

V. Sheth: Consultant; Self; Genentech, Inc. J. Sahni: Employee; Self; Roche Pharma. Stock/Shareholder; Self; Roche Pharma. I. Stoilov: Employee; Self; Genentech, Inc. J.R. Willis: Employee; Self; Genentech, Inc. R. Weikert: Employee; Self; Roche Pharma.

Funding

F. Hoffmann-La Roche, Ltd.; Genentech, Inc.
329-OR: REDD1 Suppresses the Retinal Antioxidant Response to Diabetes by Destabilizing Nrf2
Authors: MILLER WILLIAM P. , TORO ALLYSON , GIORDANO JOSEPH , DENNIS MICHAEL D.
Published: June 2020

Oxidative stress is a major contributor to the pathophysiology of diabetes. To combat oxidative stress, the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2) promotes the expression of an array of antioxidant gene products. However, in both the retina of diabetic patients and in preclinical diabetes models, there is a failure to properly upregulate Nrf2 activity. We previously demonstrated that retinal REDD1 protein expression is enhanced by diabetes-induced hyperglycemia and necessary for both the rise in retinal reactive oxygen species and the development of visual dysfunction in diabetic mice. In the present study, we investigated the hypothesis that signaling events downstream of REDD1 act to limit the retinal Nrf2 antioxidant response to the diabetic metabolic environment. We found that REDD1 ablation not only enhanced retinal Nrf2 activity, but also prevented the suppressive effect of streptozotocin-induced diabetes as compared to wild type mice. Nuclear Nrf2 protein expression and activity were enhanced in REDD1 knockout human MIO-M1 retinal Müller cells in culture, independent of a change in Nrf2 mRNA abundance. REDD1 deletion prevented oxidative stress in response to hyperglycemic conditions, and this protective effect was absent upon Nrf2 knockdown. REDD1 suppressed Nrf2 stability independent of Keap1 by promoting GSK3-mediated nuclear exclusion and proteasomal degradation via the ubiquitin ligase adapter β transducin repeat containing protein (β-TrCP). In the retina of diabetic REDD1-deficient mice, enhanced GSK3 phosphorylation was associated with a decrease in oxidative stress as compared to diabetic wild type mice. Pharmacological inhibition was used to suppress GSK3 activity in both cells in culture and in the retina of diabetic mice. Remarkably, GSK3 inhibition prevented the suppressive effect on Nrf2. Overall these findings support therapeutic approaches targeting REDD1 to prevent diabetes-induced visual dysfunction.

Disclosure

W.P. Miller: None. A. Toro: None. J. Giordano: None. M.D. Dennis: None.

Funding

American Diabetes Association/Pathway to Stop Diabetes (1-14-INI-04 to M.D.D.); National Eye Institute (1F31EY031199-01)
33-OR: A Novel Data Mining Approach to Detect Adverse Events of New Diabetes Drugs in Routine Care
Authors: FRALICK MIKE , KULLDORFF MARTIN , WANG SHIRLEY , SCHNEEWEISS SEBASTIAN , REDELMEIER DONALD , PATORNO ELISABETTA
Published: June 2020

Clinical trials are underpowered to detect serious but rare adverse events (AEs). We applied a novel data mining approach to detect potential AEs for canagliflozin (CANA), the first marketed SGLT2 inhibitor, prior to public awareness of its potential safety concerns. In a U.S. commercial claims dataset (3/2013-9/2015), two pair-wise cohorts of patients with T2DM initiating CANA or a comparator, i.e., a DPP-4i or a GLP-1RA, were identified and propensity score matched. We used variable ratio matching with up to 4 comparators for each CANA initiator (44,733 CANA vs. 99,458 DPP-4i; and 55,974 CANA vs. 74,727 GLP-1RA). Using a tree-based scan statistic data mining method, we assessed thousands of incident outcomes in CANA vs. comparator initiators, scanning for statistical AE alerts after adjusting for multiple testing. Incident outcomes were defined by hierarchical groupings of clinically related ICD-9 codes. For inpatient and emergency room diagnoses, diabetic ketoacidosis was the only severe AE associated with CANA (p<0.05 in both cohorts) (Table). When outpatient diagnoses were also considered, alerts for female and male genital infections emerged in both cohorts (p<0.05). The identification of known but no other AEs provides reassurance for the safety of CANA in adults and suggests that the tree-based scan statistic is a useful post-market safety monitoring tool for new diabetes drugs.

Disclosure

M. Fralick: None. M. Kulldorff: None. S. Wang: Research Support; Self; Boehringer Ingelheim International GmbH, Johnson & Johnson, Novartis Pharmaceuticals Corporation. S. Schneeweiss: None. D. Redelmeier: None. E. Patorno: Other Relationship; Self; Boehringer Ingelheim International GmbH.

Funding

National Institute on Aging (K08AG055670)
34-LB: Reliability of the UENS for Primary Care Neuropathy Screening
Authors: FOSTER-PALMER STORMY C. , SINGLETON J. ROBINSON , REVERE CATHY , MARCUS ROBIN L. , SHAKERI MEHRNOOSH , CASTILLO ALMA , SHAFI SONIA
Published: June 2020

Background: Metabolic syndrome polyneuropathy (MSP), sensory peripheral neuropathy associated with diabetes or prediabetic metabolic syndrome affects more than 10% of Americans over 40 years old. Screening exam measures commonly used in primary care (PC), such as 10 gram monofilament testing measure loss of protective sensation and predict development of foot ulcers and infection, but are not sensitive enough to detect early sensory loss. The Utah Early Neuropathy Scale (UENS) is a 2-minute exam scale focused on sensory loss to pin sensation in the foot that has been validated for early neuropathy screening.

Objectives: To examine reliability of the UENS when performed by medical assistants in a PC setting.

Methods: PC medical assistants were trained to perform the UENS, then screened consenting primary care patients selected by best practice alert (BPA) for age >40 and BMI > 30 with 3 neuropathy-focused questions and the UENS. A blinded neurologist (JRS), performed UENS and a brief exam at the same visit to examine reliability.

Results: 135 patients meeting BPA criteria were screened with UENS. Of these, 18% had a UENS score >4, suggesting neuropathy. Intraclass correlation coefficient for 20 comparison UENS exams was 86%. Sub-scores for pin sensation, strength and joint position sense were highly coherent, while vibration sense proved less reliable. Pin (37.9%), vibration (34.8%) and deep tendon reflex (23.4%) sub scores contributed the most to total UENS score overall, with pin sub score most likely to contribute to UENS scores 4-8 (44%).

Discussion: UENS can be performed reliably by medical assistants in a primary care setting, and is a sensitive screening modality for MSP. Pin and vibration contribute the bulk of UENS score points in patients with mild neuropathy, suggesting that a simplified UENS could be used in PC screening.

Disclosure

S.C. Foster-Palmer: None. J. Singleton: None. C. Revere: None. R.L. Marcus: None. M. Shakeri: None. A. Castillo: None. S. Shafi: None.

Funding

University of Utah Health
340-OR: Outcomes of a Digital Diabetes Self-Management Support Program Stratified by A1C
Authors: PATTERSON JONATHAN , ALLISON MATT , BRASSIL KELLY J. , BURTON STEPHEN B. , NORBU THUPTEN T. , RASULNIA MAZI , PATEL DHIREN
Published: June 2020

Background: Diabetes Self-Management Support (DSMS) programs are designed to assist people with diabetes as they implement and sustain the behaviors needed to manage their disease. In-person DSMS programs have many attendance barriers that can be mitigated through digital delivery. This study looks at results from the only ADA recognized online digital DSMS program (as of Jan 2020). The program collects diverse Patient Reported Outcomes (PROs) to track patient progress and program impact. This analysis presents digital DSMS program outcomes, focusing on individuals with an A1c >9%, for whom health risk is markedly increased.

Methods: A retrospective analysis of individuals enrolled in a 12-week digital DSMS program evaluated changes from baseline to program completion. Changes in anxiety, depression, financial toxicity, overall physical and mental health, medication adherence, stress, diabetes distress, body mass index, and A1c were evaluated for cohorts delineated by baseline A1c values. Descriptive statistics define frequency and data collected from validated PROs were analyzed to evaluate the outcomes of the digital DSMS program.

Results: To date, 1,349 people with diabetes have participated in the digital DSMS program. Of these, 843 completed and provided both baseline and 3-month outcome measures. Across all A1c categories, there were significant improvements in physical health, medication adherence, stress, and BMI (p < 0.05). Elevated A1c categories (A1c ≥ 7%) all showed decreased A1c values at month 3 compared to enrollment (p < 0.01), people with higher baseline A1c values saw the greatest decrease, A1c ≥ 10% decreased 4.17% (pre:11.32 - post: 7.15%), A1c 9-9.9% decreased 1.34% (pre: 9.29 - post: 7.95%). Conclusions: Outcomes suggest that a digital DSMS program can improve glycemic control, as previously reported, but also PROs, and that a digital delivery of a DSMS program is an effective intervention, particularly for individuals with elevated A1c for whom health risks are elevated.

Disclosure

J. Patterson: None. M. Allison: Employee; Self; Pack Health. K.J. Brassil: None. S.B. Burton: None. T.T. Norbu: None. M. Rasulnia: None. D. Patel: None.
349-OR: Pancreas Volume Is Smaller in Individuals with Stage 1 Type 1 Diabetes (T1D) and Correlates with Disease Progression
Authors: VIROSTKO JOHN , WILLIAMS JONATHAN M. , HILMES MELISSA A. , WRIGHT JORDAN J. , HAMMEL BRENNA D. , DU LIPING , KANG HAKMOOK , RUSSELL WILLIAM E. , POWERS ALVIN C. , MOORE DANIEL J.
Published: June 2020

Pancreas size is smaller at the onset of T1D and in individuals at risk for T1D, as measured by MRI. To determine whether pancreas volume predicts T1D progression, we measured pancreas size and dynamics in Type 1 Diabetes TrialNet Pathway to Prevention study participants with Stage 1 T1D, as defined by the presence of two or more autoantibodies and normal glucose tolerance. Individuals with Stage 1 T1D (n = 25, median age = 13.9 y.o.) exhibited a smaller pancreas volume than controls without T1D (n = 34, median age = 15.2 y.o, p < 0.001), but larger than individuals with Stage 3 T1D (n = 67, median age = 13.4 y.o, p < 0.05). This intermediate pancreas size in individuals with Stage 1 T1D persisted when pancreas volume was normalized by either body weight (pancreas volume index) or BMI. There was no correlation between the number or specificity of autoantibodies expressed and the pancreas volume index. Using longitudinal pancreas MRI in 25 autoantibody-positive individuals (total of 80 MRIs), we found that pancreas volume was stable over time, with no increase or decrease up to three years after the initial MRI (95% CI of slope: -0.094 to 0.5788 ml/month). Two of the 25 autoantibody-positive participants who developed Stage 3 T1D during follow up had the smallest pancreas volume index at study entry (0.43 +/- 0.04 ml/kg, p < 0.005 compared with those who did not progress to Stage 3). An additional 11 of the 25 participants developed impaired glucose tolerance during follow up. Initial pancreas volume index in the 13 total participants who developed Stage 2 or Stage 3 T1D (0.75 +/- 0.06 ml/kg) was significantly smaller (p < 0.05) than the 12 participants who retained normal glucose tolerance over the course of the study (0.95 +/- 0.05 ml/kg). These data suggest that small pancreas size may be predictive of progression of T1D.

Disclosure

J. Virostko: None. J.M. Williams: None. M.A. Hilmes: None. J.J. Wright: None. B.D. Hammel: None. L. Du: None. H. Kang: None. W.E. Russell: None. A.C. Powers: None. D.J. Moore: None.

Funding

JDRF (3-SRA-2019-759-M-B, 3-SRA-2015-102-M-B)
353-OR: Oral Small Molecule GLP-1R Agonist PF-06882961 Robustly Reduces Plasma Glucose and Body Weight after 28 Days in Adults with T2DM
Authors: SAXENA ADITI , GORMAN DONAL , CHIDSEY KRISTIN , BUCKERIDGE CLARE , KIM ALBERT M. , BERGMAN ARTHUR
Published: June 2020

Background: PF-06882961 is an oral small molecule glucagon-like peptide-1 receptor (GLP-1R) agonist with efficacy in nonclinical models comparable to injectable peptidic GLP-1R agonists. This randomized, double-blind, placebo-controlled, multiple ascending dose, Phase 1 study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics (PD) of PF–06882961 administered for 28 days in patients with type 2 diabetes mellitus (T2DM).

Methods: A total of 98 patients with T2DM taking metformin were randomized, in 8 cohorts (5 planned, 3 optional), to PF–06882961 (up to 120 mg twice daily [BID]) or placebo in a 3:1 ratio for 28 days, and 92 completed the inpatient study. Fasting plasma glucose (FPG), 24-hour mean daily glucose (MDG) and body weight were assessed at baseline and at Day 28.

Results: Multiple, oral doses of PF-06882961 were safe and well tolerated in adult participants with T2DM, and resulted in robust reductions in FPG, MDG and body weight at Day 28. The majority of adverse events (AEs) were mild, with AEs of nausea, dyspepsia, diarrhea, headache, constipation, and vomiting most commonly reported. There were no deaths and no serious AEs related to dosing of PF–06882961. No clinically significant adverse trends in labs, electrocardiogram or vital sign abnormalities were apparent.

Disclosure

A. Saxena: Employee; Self; Pfizer Inc. Stock/Shareholder; Self; Pfizer Inc. D. Gorman: Employee; Self; Pfizer Inc. K. Chidsey: None. C. Buckeridge: Employee; Self; Pfizer Inc. A.M. Kim: Employee; Self; Pfizer Inc. A. Bergman: Employee; Self; Pfizer Inc.
356-OR: Effect of Dulaglutide on Kidney Function–Related Outcomes in Type 2 Diabetes: Post Hoc Analysis from the REWIND Trial
Authors: SHAW JONATHAN E. , BOTROS FADY T. , MALIK RALEIGH , ATISSO CHARLES , COLHOUN HELEN M. , GERSTEIN HERTZEL C.
Published: June 2020

In participants with type 2 diabetes (T2D) in the REWIND trial, dulaglutide (DU) use for median follow-up of 5.4 years was associated with reduced composite renal outcomes, defined as the first occurrence of new macroalbuminuria, sustained decline in estimated glomerular filtration rate (eGFR) of ≥30%, or chronic renal replacement therapy. The objective of this post-hoc analysis was to evaluate the effect of dulaglutide on renal outcomes related to kidney function that are typically used in renal outcomes studies, defined as the composite endpoint of sustained eGFR decline ≥40%, end-stage renal disease (ESRD), or all-cause death. Participants with T2D at cardiovascular (CV) risk were randomized (1:1) to DU 1.5 mg once-weekly or placebo. This post-hoc analysis used Cox proportional hazards modeling for time to first event to determine the risk of renal outcomes. Sensitivity analyses were conducted by replacing the all-cause death component with CV or renal death, or renal death. At baseline, treatment groups had similar eGFR (mean±SD: DU=77.2±22.7; placebo=76.6±22.8). The incidence rate of the composite endpoint was significantly lower for the DU group compared with placebo (Table). Treatment with DU 1.5 mg was associated with a 17% risk reduction in kidney function-related outcomes, suggesting potential delay in progression of diabetic kidney disease in patients with T2D at CV risk.

Disclosure

J.E. Shaw: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mylan, Sanofi. Research Support; Self; AstraZeneca. Speaker’s Bureau; Self; Eli Lilly and Company, Mylan. F.T. Botros: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. R. Malik: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. C. Atisso: Employee; Self; Eli Lilly and Company. H.M. Colhoun: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Novo Nordisk Inc., Pfizer Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Speaker’s Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. Other Relationship; Self; Eli Lilly and Company, Sanofi. H.C. Gerstein: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Kowa Pharmaceuticals America, Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Sanofi.

Funding

Eli Lilly and Company
357-OR: Efficacy and Safety of Dulaglutide 3mg and 4.5mg vs. Dulaglutide 1.5mg: 52-Week Results from AWARD-11
Authors: FRIAS JUAN P. , BONORA ENZO , NEVAREZ RUIZ LUIS A. , LI GRACE , YU ZHUOXIN , MILICEVIC ZVONKO , MALIK RALEIGH , BETHEL ANGELYN , COX DAVID
Published: June 2020

Dulaglutide (DU) is approved at 2 doses (0.75 and 1.5 mg) for treatment of T2D. In this phase 3 study, once weekly DU 3 mg and 4.5 mg were compared to DU 1.5 mg for efficacy and safety through 52 weeks (wks) (primary endpoint at 36 wks) in patients with inadequately controlled T2D on metformin therapy. Patients were randomized (1:1:1) to once weekly DU 1.5 mg (n=612), DU 3 mg (n=616), and DU 4.5 mg (n=614). All patients were initiated on once weekly DU 0.75 mg for 4 wks, followed by step-wise dose escalation every 4 wks to the randomized dose of 1.5 mg, 3 mg, or 4.5 mg. Efficacy measures were analyzed based on data on-treatment without initiation of rescue medication. Mean age was 57.1 yrs, mean baseline (BL) A1C was 8.6%, and mean BL body weight (BW) was 95.7 kg. DU 1.5 mg, 3 mg and 4.5 mg showed significance (p<0.001) compared to BL for A1C, BW and fasting serum glucose (Table). DU 3 mg and 4.5 mg were both superior to DU 1.5 mg at the 36 wk primary endpoint, and remained significantly greater at 52 wks, for improvements in measures of glycemic control and body weight (Table). As expected for the GLP-1 receptor agonist class, commonly reported adverse events were nausea, diarrhea, and vomiting (Table). There were no new safety findings with the higher DU doses.

In conclusion, escalation from DU 1.5 mg to DU 3 mg or 4.5 mg provided clinically relevant, dose-related improvements in glycemic control and body weight with an acceptable safety profile.

Disclosure

J.P. Frias: Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., LifeScan, Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; Allergan plc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi. Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. E. Bonora: Advisory Panel; Self; Lilly Diabetes, Novartis AG, Sanofi. Speaker’s Bureau; Self; Abbott, Lilly Diabetes, Novo Nordisk A/S, Sanofi. L.A. Nevarez Ruiz: None. G. Li: Employee; Self; Eli Lilly and Company. Z. Yu: None. Z. Milicevic: Employee; Self; Eli Lilly and Company. R. Malik: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. A. Bethel: Employee; Self; Eli Lilly and Company. D. Cox: Employee; Self; Eli Lilly and Company.
366-OR: Characterization of Gene Expression Networks That Are Oppositely Regulated by Human and Mouse Metabolic Disease Using a Humanized Mouse Model
Authors: CAO HAIMING
Published: June 2020

Mouse is the most widely used preclinical animal model yet the translational rate from mouse studies to therapies of human disease is dismal. To identify differentially expressed gene networks that underlie the distinct pathophysiological responses in human and mouse, we compared the patterns of gene regulation by nonalcoholic fatty liver disease (NAFLD) in human and mouse. As expected, we identified approximately 1,600 genes whose expressions are similarly regulated by NAFLD in human and mouse. Intriguingly, however, we also identified a similar number of genes that exhibit completely opposite regulation. Pathway analysis revealed that similarly regulated genes performed similar function in human and mouse whereas oppositely regulated genes perform very different function, despite the same set of genes were analyzed in either mouse or human. To determine if these oppositely regulated genes truly reflect differences in human and mouse liver biology, we analyzed gene expression in chimera mice in which human and mouse hepatocytes co-exist in the humanized liver and are exposed to identical in vivo metabolic milieu. Strikingly, we were able to recapitulate a sizable fraction of oppositely regulated genes in a fast/refeeding cycle. We further analyzed the promoter activities and RNA stability of regulated genes and found that promoter occupancy by RNA pol II and a HuR-dependent post-transcriptional mechanism both contribute to the divergent regulations. Our findings suggest that there are a core set of genes, despite their conserved molecular function, might be differentially regulated and contribute to distinct physiological outcomes in human and mouse. Thus our work provide a timely resource to understand the molecular basis for divergent metabolic responses in human and mouse liver and also highlight the areas of human liver biology where mouse is not a suitable model, and a human or humanized system is needed for translational studies.

Disclosure

H. Cao: None.

Funding

National Institutes of Health
367-OR: High-Fat and Fructose Feeding Severely Impairs Hepatic Glucose Effectiveness
Authors: EDGERTON DALE S. , KRAFT GUILLAUME , FARMER BEN , SCOTT MELANIE , SMITH MARTA S. , CHERRINGTON ALAN D.
Published: June 2020

Diets high in fat and fructose (HFFD) disrupt glucose metabolism. The aim of this study was to determine if HFFD impairs hepatic glucose effectiveness (i.e., the ability of glucose per se to stimulate net hepatic glucose uptake [NHGU] and/or to suppress glucose production [Ra]). In overnight fasted dogs fed either a chow diet or HFFD for 1 month, somatostatin, 3-3H-glucose, and basal hepatic portal vein infusions of insulin and glucagon were given. After a basal sampling period, these infusions continued for 4h while glucose was infused to create a 3-fold rise in plasma glucose. Since hepatic glucose uptake is also stimulated by a negative arterial to portal vein glucose gradient, such as occurs with glucose ingestion, glucose was either all infused into a peripheral vein (Chow-PeG, n=6; HFFD-PeG, n=6), or a portion was also given into the portal vein (4 mg/kg/min; Chow-PoG, n=5; HFFD-PoG, n=5). There were no differences in plasma insulin, glucagon, arterial glucose, or hepatic glucose load between groups. In response to hyperglycemia, the liver switched from making (basal period) to storing (last h) glucose in the chow fed groups (1.1±0.1 to -2.0±0.5* mg/kg/min in Chow-PeG, and 1.3±0.1 to -3.0±0.9* in Chow-PoG; a negative rate indicates uptake). Conversely, HFFD markedly reduced liver glucose effectiveness. In fact, with HFFD the liver did not take up glucose in response to hyperglycemia whether the portal signal was absent (1.4±0.1 to 1.0±0.3 in HFFD-PeG) or present (1.6±0.3 to 0.0±0.3* in HFFD-PoG). Thus, in the Chow vs. HFFD groups, the impact of hyperglycemia on overall net hepatic glucose balance was 3.1±0.5 vs. 0.4±0.4* (13% of normal) in the absence of portal glucose delivery and 4.3±0.9 vs. 1.6±0.5* (37% of normal) in its presence. Hyperglycemia suppressed Ra by 75±12 vs. 22±6%* (last h) in Chow vs. HFFD-PeG, respectively, and by 81±14 vs. 34±7%* in Chow vs. HFFD-PoG.

In summary, HFFD induced a severe impairment in hepatic glucose effectiveness but did not affect the liver’s response to the portal glucose signal. (*P<0.05).

Disclosure

D.S. Edgerton: None. G. Kraft: None. B. Farmer: None. M. Scott: None. M.S. Smith: None. A.D. Cherrington: Advisory Panel; Self; Biocon, Fractyl Laboratories, Inc., Metavention, Sekkei Bio, Sensulin, LLC., vTv Therapeutics, Zafgen, Inc. Consultant; Self; Thetis Pharmaceuticals LLC. Research Support; Self; Diasome Pharmaceuticals, Inc. Other Relationship; Self; Abvance Therapeutics, Novo Nordisk Inc.

Funding

National Institutes of Health (R01DK18243)
374-P: External Validation and Clinical Application of the Risk Prediction Model for Severe Hypoglycemia in Type 2 Diabetes
Authors: AHN YU-BAE , YUN JAE-SEUNG , LEE JUNG-MIN , SONG KI-HO , KO SEUNG-HYUN
Published: June 2020

We previously developed and internally validated a one-year risk prediction model for SH in type 2 diabetes using the National Health Insurance Service database and analyzing data from 1,173,820 subjects with type 2 diabetes. In this study, we planned external validation to verify the performance of the previously-developed risk prediction model in a tertiary hospital setting. From January 2018 to December 2018, 2,724 patients over 30 years old who visited the diabetes center were enrolled. The Harrell C-statistics were compared to identify the discrimination of the developed model. The predicted incidence and actual incidence of SH at 1 year in the development and validation cohort were compared by ranking subjects into deciles of predicted risk. External validation was performed with a total of 2,757 patients. The incidence rate of severe hypoglycemia was 12.6 per 1000 patient-year. The concordance index for SH was 0.854 in the external validation cohort. The sensitivity and specificity of this model prediction in the external validation cohort were 0.714 and 0.853, respectively. However, compared with the model for the development cohort, the incidence rate of SH in each decile group was three times higher than the predicted value. SH risk scores increased in proportion to the age and the duration of diabetes (P for trends <0.001, respectively). The HbA1c distribution was distributed in the form of a J-shape according to the decile group of SH risk score. The risk score for SH was higher in the subjects with chronic kidney disease, heart failure, and dementia than those with other major comorbidities. Our SH prediction model showed excellent discrimination when applied to type 2 diabetes subjects in the tertiary hospital. The results of this study confirm that the risk of hypoglycemia can be accurately predicted using this model. The actual number of SH events is higher than expected, which might be due to the characteristics of the subjects in the tertiary hospital.

Disclosure

Y. Ahn: None. J. Yun: None. J. Lee: None. K. Song: None. S. Ko: None.
379-P: Glucagon Use by U.S. Adults with Type 1 and Type 2 Diabetes
Authors: KAHN PETER , LIU SHULING , MCCOY ROZALINA G. , GABBAY ROBERT A. , LIPSKA KASIA J.
Published: June 2020

The American Diabetes Association recommends that patients at high risk for hypoglycemia be prescribed glucagon.

Using de-identified administrative claims from OptumLabs® Data Warehouse (OLDW) for commercial and Medicare Advantage enrollees, we examined glucagon prescriptions filled between 1/1/2014 and 12/31/2014 among pharmacologically treated type 1 and 2 diabetes patients. We examined association of glucagon fills with demographic, clinical, and laboratory-based factors. HbA1c levels were available for a subsample. Model performance was assessed with AUC and calibration plots.

Among 12,338 patients with type 1 and 323,244 with type 2 diabetes, 14.5% and 0.7% filled glucagon in 2014, respectively. Among type 1 diabetes patients, the multivariable model had poor discriminative performance (AUC=0.61). Among patients with type 2 diabetes, the model AUC was 0.89. Factors associated with glucagon use are shown in Figure. HbA1c level was not independently associated with glucagon fills.

In this national study, glucagon was rarely filled.

Among patients with type 1 diabetes, glucagon fills were unpredictable and not targeted to highest risk patients. Patients with type 2 diabetes were more likely to fill glucagon in the setting of prior hypoglycemia, higher income, and endocrinology care. These findings suggest opportunities to improve care, including better prescribing practices to target high-risk patients.

Disclosure

P. Kahn: None. S. Liu: None. R.G. McCoy: None. R.A. Gabbay: Advisory Panel; Self; FormHealth, Health Reveal, Lark, Onduo, Vida Health. K.J. Lipska: None.

Funding

National Institutes of Health (K23AG048359)