bluuebunny/crossref_metadata_2025_split huggingface dataset:
178-LB: Insights from the University of Chicago Monogenic Diabetes Registry on Diagnosis and Management of Monogenic Diabetes
Authors: HARRIS ANASTASIA , NAYLOR ROCHELLE N. , SANYOURA MAY , GREELEY SIRI ATMA W. , KANDASAMY BALAMURUGAN , PHILIPSON LOUIS H. , LETOURNEAU-FREIBERG LISA R. 
Published: June 2020

Monogenic diabetes (MDM), caused by a single gene or chromosomal abnormality, affects ~2% of people diagnosed with diabetes under 35 years of age, but is frequently misdiagnosed and mistreated. The Monogenic Diabetes Registry began in 2008, and has served to diagnose and longitudinally follow individuals with congenital diabetes and MODY. Research-based genetic testing and pragmatic cohort studies have clarified genotype-phenotype correlations and barriers to diagnosis and appropriate management. Interested participants complete a secure web-based registration form. They are screened and consented by phone or in-person. Participants provide medical and family history information at baseline and annually thereafter via REDCap, as well as DNA samples that are stored in laboratory databases. The Registry has grown exponentially from 430 total participants enrolled by 2009 to over 3,600 participants, from 1,900 families, with an average yearly increase of 38.5%. Fifty-seven percent were referred to the Registry through their diabetes provider. To date, 1,050 participants have a confirmed genetic diagnosis. The majority of testing has been completed through our lab (73%), followed by commercial labs (22%) and other research labs (5%). The average time for an MDM diagnosis is 10 years. The most common cause of MODY in the Registry is GCK-MODY (60%) while the most common cause of congenital diabetes is mutations in KCNJ11 (38%). Of those with baseline survey data on insulin use, 81% were found to have a genetic cause of MDM typically amenable to oral therapies or no treatment. The Registry provides a robust network of MDM resources and support to participants and providers throughout the United States. However, research-based diagnosis has constraints not faced by commercial labs. The long delay in diagnosis and high proportion of research-based testing suggests that broader access to clinical testing via insurance coverage is critically needed.

Disclosure
A. Harris: None. R.N. Naylor: None. M. Sanyoura: None. S.W. Greeley: None. B. Kandasamy: None. L.H. Philipson: None. L.R. Letourneau-Freiberg: None.

Funding
National Institutes of Health (R01DK104942, P30DK020595, K23DK094866, UL1TR000430)
1781-P: Remission of Type 2 Diabetes over 2 Years Normalizes Morphology of the Whole Pancreas
Authors: TAYLOR ROY , ZHYZHNEUSKAYA SVIATLANA V. , PETERS CARL , BARNES ALISON C. , HOLLINGSWORTH KIEREN G. , SATTAR NAVEED , LEAN MICHAEL E. , AL-MRABEH AHMAD 
Published: June 2020

In type 2 diabetes, the pancreas is 30% smaller with irregular borders. The lack of rapid postprandial rise in insulin may explain the loss of exocrine tissues mass was postulated to be reversible on remission of diabetes. 90 people (38/52 F/M, 52.8±7.9 years, initial weight 100.2±16.3kg, and BMI 34.7±4.3 kg/m2) were randomized (Diabetes Remission Clinical Trial) to low calorie diet or to continue with routine diabetes management. A group of nondiabetic controls (n=25) matched to the post-diet weight was studied in one occasion. MR techniques were used for anatomical and fat fraction images of the pancreas (3T Philips, Netherlands). Specifically developed methods were used to quantify intrapancreatic fat, change in pancreas volume and irregularity of the border. At baseline, pancreas volume was lower in diabetes (63.8±1.8 vs. 79.8±2.9cm3, p&lt;0.0001). It was unchanged after 5 months, increased at 12 months, and at 24 months had increased further by 12.6±1.5cm3 in responders compared with 4.5±1.3cm3 in non-responders (p&lt;0.0001). Over 24 months, pancreas fat content decreased only in responders (p&lt;0.0001) and responders lost 1.56±0.3% vs. 0.51±0.4% (p&lt;0.05). At 12 months, there were negative correlations between decrease in pancreas fat and increase of insulin secretion (r=-0.55, p&lt;0.0001), and increase in pancreas volume and the decrease of pancreas fat within the whole study (r=-0.35, p=0.02). Reflecting irregularity, Fractal Dimension (FD) of the pancreas borders was higher in the diabetic group (1.116±0.013 vs. 1.097±0.005, p&lt;0.0001) and decreased to 24 months only in those who achieved remission (1.097±0.008, p=0.0003). The low pancreas volume of type 2 diabetes is likely to be related to deficiency of acute insulin secretion over many years of disease progression. Fat removal from the pancreas can restore β cells function and may lead to restoration of exocrine tissues mass via trophic effects of insulin. Pancreas morphology appears to reflect the pathophysiology of type 2 diabetes.

Disclosure
R. Taylor: Speaker’s Bureau; Self; Novo Nordisk Foundation. 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. A. Al-Mrabeh: None.

Funding
Diabetes UK
1782-P: Impact of Treatment with Medication vs. Laparoscopic Gastric Banding (GB) on ß-Cell Function in Adults with Impaired Glucose Tolerance (IGT) or Type 2 Diabetes (T2D) in the Restoring Insulin Secretion (RISE) Study
Authors: EHRMANN DAVID A. , EDELSTEIN SHARON , XIANG ANNY , BUCHANAN THOMAS A. , ARSLANIAN SILVA A. , CAPRIO SONIA , MATHER KIEREN J. , NADEAU KRISTEN J. , KAHN STEVEN E. ,   THE RISE CONSORTIUM
Published: June 2020

The RISE Consortium conducted a study in adults with IGT or recently diagnosed T2D to determine if β-cell function can be conserved or improved. Participants were randomized to GB, metformin, liraglutide + metformin (L+M), or placebo. β-cell function was assessed at baseline (BAS) and at 12 mo (12M) on therapy. Hyperglycemic clamp measures of β-cell function were: acute C-peptide (CP) response to glucose (ACPRg), steady-state CP (SSCP) at a plasma glucose of 11.1 mmol/L and maximal CP response to arginine, a non-glucose secretogogue, at a plasma glucose &gt;25 mmol/L (ACPRmax). At BAS, BMI, ACPRg, SSCP, and ACPRmax were similar across groups. BMI was lower at 12M in all treatment groups and unchanged in those on placebo (Table). Analyses were adjusted for age, sex, and race. Participants randomized to L+M had significant increases in ACPRg and SSCP. There was also a modest but significant attenuation in ACPRmax in the L+M group. In contrast, participants who received GB or metformin alone had no change in β-cell function. Liraglutide appears to result in increased acute and steady-state responses, but greater β-cell “exhaustion” evidenced by a relative reduction in the CP response to arginine. Mechanisms responsible for this finding and its long-term implications are needed.

Disclosure
D.A. Ehrmann: None. S. Edelstein: None. A. Xiang: None. T.A. Buchanan: None. S.A. Arslanian: Research Support; Self; National Institutes of Health. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. S. Caprio: None. K.J. Mather: Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. K.J. Nadeau: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc. T. Consortium: None.

Funding
American Diabetes Association (1-14-RISE-01 to S.E.K.); National Institute of Diabetes and Digestive and Kidney Diseases
18-LB: Increased Acidosis and Free-Radical Production Causes Recurrent Hypoglycemia–Induced Increase in Post-ischemic ER Stress in Treated Diabetic Rats
Authors: REHNI ASHISH K. , CHO SUNJOO , DAVE KUNJAN R. 
Published: June 2020

Cerebral ischemia is a serious complication of diabetes. Treatment of diabetes causes recurrent hypoglycemia (RH). Prior RH exposure increases ischemic brain damage in insulin-treated diabetic (ITD) rats. However, the mechanism of this injury is not well understood. We showed that ischemic acidosis increases reactive oxygen species (ROS) production in RH-exposed ITD (ITD + RH) rats. As enhanced acidosis and ROS production in normal subjects activate PERK, we hypothesized that increased ischemic acidosis and ROS production in RH-exposed ITD rats activate PERK. Therefore, we determined if the administration of tris-(hydroxymethyl)-aminomethane (THAM; an alkalizing agent) and N-acetylcysteine (NAC; an antioxidant) decrease RH-induced post-ischemic PERK activation in ITD + RH rats. Wistar rats were treated with insulin 2-3 weeks after streptozotocin induced diabetes. After 2 weeks, hyperinsulinemic hypoglycemia was induced for 3 hours for 5 days. Following groups were employed: (I) ITD + vehicle (Veh) (n = 6); (II) ITD + RH + Veh (n = 7); (III) ITD + RH + THAM (0.3 M, 3 ml/kg/hr, i.v.) (n = 6); and (IV) ITD + RH + NAC (150 mg/kg, i.v.) (n = 6). Transient global cerebral ischemia was induced by bilateral carotid artery occlusion with hypotension a day after RH. THAM/Veh was infused from 15 min before to 88 minutes after ischemia. NAC/Veh was administered 5 min before and 12 h after ischemia. Based on Western blot analysis, pPERK to total PERK ratio in the ITD + RH + THAM and ITD + RH + NAC groups were significantly lower by 32% and 26%, respectively, when compared with ITD + RH + Veh group. CHOP levels in the ITD + RH + THAM and ITD + RH + NAC group were lower by 38% and 63%, respectively, when compared with ITD + RH + Veh group. Therefore, ischemic acidosis and ROS production may mediate RH-induced ischemic activation of PERK. Understanding the ischemic damage in RH-exposed ITD rats may help identify new treatments for diabetes induced increase in ischemic injury.

Disclosure
A.K. Rehni: None. S. Cho: None. K.R. Dave: None.

Funding
National Institutes of Health (NS073779); American Heart Association (18POST34070061)
18-OR: Joslin Home: An Innovative Integrated Digital-Health Model of Diabetes Care in the Technology Era
Authors: HAMDY OSAMA , MITRI JOANNA , BARRETT ALANA , GABBAY ROBERT A. 
Published: June 2020

Despite major advances in diabetes care and technology, the current clinic-based model is costly and at times inefficient with limited scalability. Joslin Home model (JH) includes 5 new pillars of diabetes interactions: short visits of 5-15 min conducted by telehealth, more frequent visits with a multidisciplinary team (MD, NP, RD, CDE, exercise physiologist (EP), and behavioral therapist (BT)), direct 2-way electronic scheduling, brief documentations and easy one-step billing.
In this 6-month pilot study, we tested the feasibility of JH among 17 patients with critically high A1C (average 9.5±1.6%), age 62±14 yrs, weight 225±35 lbs and 70.6% treated with insulin. Cellular glucose meter, body-weight scale and BP kit were delivered to subjects’ homes for self-reporting. Patients were instructed to self-schedule/cancel appointments using an electronic calendar. Five precise questions were asked before each encounter. Providers were asked to briefly document encounters.
Results: Virtual visits were completed in an average of 16 min, MDs and NPs concluded them in &lt;15 min (∼11 min), but BT needed the longest time (20-30 min). Patients had an average of one encounter/week. Higher visit frequency was only seen in &lt;25% of patients. Around 76% of scheduled encounters were completed (range 56-100%). Visit cancellation was the lowest with RD and EP (10-18%) and highest with BT and CDE (29-31%). A1C dropped significantly by 1.2% (to 8.2±1.5%, p&lt;0.001). Patients’ satisfaction was high and they were willing to pay out-of-pocket of $50-200/encounter. We conclude that JH model is potentially acceptable alternative to clinic-based model and that is potentially scalable for remote and underserved areas where multidisciplinary approach is lacking. Frequent and short encounters of &lt;20 min resulted in significant A1C improvement. JH may be ideal for high-risk patients who require frequent encounters with a diabetes team. Larger adoption in a randomized clinical study warrants consideration.

Disclosure
O. Hamdy: Consultant; Self; Abbott, AstraZeneca, Merck & Co., Inc., Sanofi-Aventis. Research Support; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Healthimation, LLC. J. Mitri: Consultant; Spouse/Partner; Janssen Pharmaceuticals, Inc., kymera. Consultant; Self; national dairy council/local dairy council. Research Support; Spouse/Partner; AbbVie Inc., beigene, Janssen Pharmaceuticals, Inc. Research Support; Self; Kowa Pharmaceuticals America, Inc., national dairy council. Research Support; Spouse/Partner; pharma cyclic, TG therapeutics. A. Barrett: None. R.A. Gabbay: Advisory Panel; Self; FormHealth, Health Reveal, Lark, Onduo, Vida Health.

Funding
Joslin Diabetes Center
1815-P: Dipeptidyl Peptidase-4 Inhibitor Improves Steatohepatitis by Targeting Trail Receptor-Mediated Apoptosis Under Modulation of Dipeptidyl Peptidase-4 Expression
Authors: LEE SEJEONG , LEE MINYOUNG , SHIN EUGENE , KIM YOUNG-EUN , KANG EUN SEOK , CHA BONG-SOO 
Published: June 2020

Dipeptidyl peptidase-4 inhibitors (DPP-4i) are useful antidiabetic medications that prevent cleavage of incretin hormones by dipeptidyl peptidase-4 (DPP-4). As DPP-4 targets diverse substrates besides incretin, DPP-4i may exert nonglycemic pleiotropic effects. Recent studies have reported that hepatic DPP-4 expression is upregulated under nonalcoholic steatohepatitis (NASH) condition in animals and humans. We investigated whether DPP-4i could ameliorate the pathological phenotype of NASH and evaluated the underlying mechanisms in a mouse model. Mice were randomly assigned to one of three groups: Group 1, chow-fed mice with vehicle treatment for 20 weeks; group 2, high-fat, high-fructose, and high-cholesterol AMLN diet-fed mice with vehicle treatment for 20 weeks; group 3, AMLN diet-fed mice with vehicle treatment for 10 weeks followed by DPP-4i (teneligliptin 20 mg/kg/day by oral gavage) treatment for 10 weeks. Serum and liver tissues were analyzed. Administration of DPP-4i significantly reduced the body weight, liver to body weight ratio, and serum liver enzyme levels in AMLN diet-induced NASH model. DPP-4i-treated AMMN diet-fed mice revealed a marked alleviation in liver steatosis and fibrosis compared with vehicle-treated AMLN-fed mice. NASH alleviation in vivo significantly correlated with the suppression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis and decreased DPP-4 expression in the liver. In vitro assay of palmitate-treated hepatocytes, treatment with DPP-4i significantly attenuated the hallmarks of TRAIL receptor-mediated lipoapoptosis, suppressing DPP-4 expression. DPP-4i may efficiently attenuate the pathogenesis of AMLN diet-induced NASH in mice by suppressing lipotoxicity-induced apoptosis, possibly through the modulation of hepatic DPP-4 expression.

Disclosure
S. Lee: None. M. Lee: None. E. Shin: None. Y. Kim: None. E. Kang: None. B. Cha: None.

Funding
Handok Inc. (2017-31-0006)
1816-P: Hepatic Mitochondrial Alterations in a Murine Model of Combined Diabetes and Fatty Liver Disease
Authors: DEWIDAR BEDAIR , ENGLISCH CORNELIA , PESTA DOMINIK , ROHBECK ELISABETH , RESS CLAUDIA , ESPOSITO IRENE , RODEN MICHAEL 
Published: June 2020

Nonalcoholic fatty liver disease (NAFLD) is tightly associated with obesity and type 2 diabetes. There is evidence that mitochondrial function is altered in both diseases. Here, we examined hepatic mitochondria during different stages of NAFLD in mice with experimental diabetes.
Two-days old male C57BL/6j mice received 200 µg streptozotocin (STAM) or vehicle (CTRL). From 4 weeks on, they were on high-fat diet for either 4 w or 8 w to induce steatosis or nonalcoholic steatohepatitis (NASH). Liver histology was performed to quantify steatosis, inflammation and fibrosis. Mitochondrial respiration was assessed in liver tissues using high-resolution respirometry with different substrate protocols. Citrate synthase activity (CSA) served as a surrogate marker for mitochondrial content. Immunoblotting was used to quantify mitochondrial complexes.
Compared to CTRL, STAM mice showed 140% and 54% higher blood glucose and liver/body weight. Hepatic steatosis increased from 2% to 15% at 4 w and decreased to 5% at 8 w. NAFLD activity score was 0.25 in CTRL and increased to 2.5 at 4 w and 8 w in STAM. STAM mice had lower CSA, indicating lower mitochondrial content at both time points, whereas complex III protein content was decreased only at 8 w. Of note, maximal uncoupled β-oxidation-associated respiration, normalized to CSA, was 1.7- and 2.7-fold higher in livers of STAM mice after 4 w and 8 w, respectively, as compared to CTRL.
In conclusion, combined diabetes and NASH decreased mitochondrial content but resulted in greater maximal oxidative capacity per mitochondrion, possibly reflecting an adaptation of mitochondrial function during NAFLD progression in adult mice.

Disclosure
B. Dewidar: None. C. Englisch: None. D. Pesta: None. E. Rohbeck: None. C. Ress: None. I. Esposito: None. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S.

Funding
German Federal Ministry of Health and Ministry of Culture and Science of the State North Rhine-Westphalia; German Federal Ministry of Education and Research by the European Regional Development Fund (KomIT, EFRE-0400191); German Research Foundation (DFG; SFB 1116/2)
182-OR: A Novel Dual-Acting Glucokinase Activator (GKA) Dorzagliatin (HMS5552) Achieved Primary Efficacy Endpoint with Good Safety Profiles in T2DM Patients after 24 Weeks of Treatment in a Phase III Monotherapy Trial
Authors: ZHU DALONG , ZHANG YI , CHEN LI 
Published: June 2020

GK acts as a ’glucose sensor’ to regulate glucose homeostasis. Dorzagliatin is a novel dual-acting allosteric GKA targeting both pancreatic and liver GK. The study aimed to confirm the efficacy and safety of dorzagliatin as a monotherapy in Chinese T2D patients. It is the first successful Phase III trial for a GKA. It was a multicenter, randomized, double-blind, placebo-controlled trial. 463 drug-naïve adult subjects were randomized to 75 mg dorzagliatin or placebo (2:1) BID for 24 wks. The primary endpoint was the change in HbA1c from baseline to wk 24. Secondary endpoints included 2h PPG and other glycemic variables. Safety assessment included AE, hypoglycemia, laboratory tests, ECG, etc. The MMRM results suggested the LS mean change in HbA1c from baseline at wk 24 was -1.07% in dorzagliatin group, significantly lower than the placebo group (P&lt;0.0001). The homeostatic control rate (HbA1c &lt;7% without hypoglycemia), was 45.0% in dorzagliatin group compared to 21.5% in placebo group (P&lt;0.0001). At wk 24, the mean change of 2h PPG (mM) from baseline was -3.05 and -0.78 for the dorzagliatin and placebo groups (P&lt;0.0001). The mean change of FPG (mM) from baseline at wk 24 was -0.70 in dorzagliatin group and -0.34 in placebo group with no significant difference. The change of HbA1c from baseline at each study visit was significantly lower (P&lt;0.001) in dorzagliatin group compared with the placebo group. Dorzagliatin was well-tolerated during the 24 wks and had a good safety profile. Fewer than 1% of patients experienced incident of hypoglycemia over 24 wks. There were no death, drug-related SAEs, and severe hypoglycemia in subjects treated with dorzagliatin. Overall, dorzagliatin had a favorable effect on glycemic control and a good safety profile over 24 wks in Chinese T2D patients. It brings the reality a step further in developing a novel T2D drug with GKA mechanism of action.

Disclosure
D. Zhu: None. Y. Zhang: None. L. Chen: None.
1826-P: Dietary Models of Nonalcoholic Fatty Liver Disease in Normal and Diabetic Nonhuman Primates
Authors: GAO JIAJUN , WANG DAVEY , JI YANQIN , ZHANG XIAOYU , YANG CHEN , ZHANG JIAPING , YE WEIWEI , SHI FENG , JIANG MENGNAN , JIN QIAN , ZHANG DUNWEI , WANG XIAOLI , SONG WEIHUA , CHNG KEEFE , JIANG HAISHAN , WANG YIXIN , XIAO YONG-FU 
Published: June 2020

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome as an arising health issue globally. Obesity and diabetes seem coherent with high NAFLD occurrence. Currently, its underlying mechanism of cause and progression remains to be elicited and effective therapy is unavailable. Huge investment on studying its pathogenesis and innovative therapy is underway. As mechanistic studies are more difficult or unethical to be performed in humans, animal model that recapitulates the human disease is urgently needed. Nonhuman primates (NHPs) with NAFLD can highly mimic the human disease. This study aimed to induce NAFLD by various diets (Table 1) in normoglycemic and diabetic NHPs with biomarker and histopathology assays to quantify NAFLD occurrence. Our data show that diabetic monkeys with high-fat-high-fructose (HFHF) diet developed NAFLD which could assemble to the human disease and be highly valuable for NAFLD research. However, low choline (LC), LC+10% fructose, LC+low methionine (LCM)+10% fructose diets for 31 weeks had no significant effects on liver function, except significant decrease in body weight and food intake in LCM+10%F group and some increase in liver histological scores in LC+10%F group (Table 1).
In summary, normal diet with LC or LCM ± high fructose is hardly to induce NAFLD in normoglycemic NHPs, at least in 31 weeks. HFHF could induce or enhance NAFLD in diabetic NHPs.

Disclosure
J. Gao: Employee; Self; Crown Bioscience. D. Wang: Employee; Self; Crown Bioscience. Y. Ji: Employee; Self; Crown Bioscience. X. Zhang: Employee; Self; Crown Bioscience. C. Yang: None. J. Zhang: Employee; Self; Crown Bioscience. W. Ye: Employee; Self; Crown Bioscience. F. Shi: Employee; Self; Crown Bioscience. M. Jiang: Employee; Self; Crown Bioscience. Q. Jin: Employee; Self; Crown Bioscience. D. Zhang: None. X. Wang: None. W. Song: Employee; Self; Crown Bioscience. K. Chng: None. H. Jiang: Employee; Self; SYSE Bio-tec Co., Ltd. Y. Wang: None. Y. Xiao: Employee; Self; Crown Bioscience.
1829-P: Aggravating Liver Lipid Accumulation and Fibrosis in Nonalcoholic Steatohepatitis Model of MS-NASH Mice by a Modified Amylin Diet
Authors: ZHANG GUODONG , CHNG KEEFE , WANG YIXIN 
Published: June 2020

MS-NASH mouse is a leptin pathway intact model of spontaneous metabolic diseases. Our previous work developed a nonalcoholic steatohepatitis (NASH) model in MS-NASH mice fed with western diet and fructose drinking water (WDF). This study showed aggravated liver cholesterol content and fibrosis score by using a modified Amylin diet (GAN). Liver Cholesterol was increased from 10.11±1.58 mg/g to 14.07±0.81 mg/g and fibrosis score increased from 1.5±0.3 to 2.1±0.2 when comparing GAN with WDF and with C57Bl/6 mice. Administration of 30 mg/kg Obeticholic Acid (OCA, QD, PO) or 30 mg/kg Elafibranor (GFT-505, QD, PO) for 8 weeks significantly reduced serum liver enzymes, liver lipids and fibrosis scores.
Conclusion: The GAN diet fed MS-NASH mice can be a better NASH model for novel compound efficacy.

Disclosure
G. Zhang: None. K. Chng: None. Y. Wang: None.