bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monogenic Diabetes in the Progress for Diabetes Genetics in Youth (ProDiGY) Collaboration
Authors: TODD JENNIFER , KLEINBERGER JEFFREY W. , SRINIVASAN SHYLAJA , TOLLEFSEN SHERIDA E. , LEVITSKY LYNNE L. , KATZ LORRAINE E.L. , TRYGGESTAD JEANIE B. , BACHA FIDA , IMPERATORE GIUSEPPINA , LAWRENCE JEAN M. , PIHOKER CATHERINE , DIVERS JASMIN , FLANNICK JASON , DABELEA DANA , FLOREZ JOSE C. , POLLIN TONI I. 
Published: June 2018

Monogenic diabetes, including maturity-onset diabetes of the young (MODY), is frequently misdiagnosed as type 1 or type 2 diabetes. Correct diagnosis can result in a change in clinical treatment and impacts prediction of complications and familial risk. Clinical algorithms can select individuals for genetic testing; however, up to half of youth with MODY do not meet clinical criteria. Other barriers also limit access to genetic testing.
To assess the prevalence of MODY in youth with a clinical diagnosis of type 2 diabetes, we evaluated whole-exome sequence data from ProDiGY, a collaboration of the TODAY, SEARCH for Diabetes in Youth, and T2D-GENES studies. Focusing on 14 genes previously identified as causal for MODY (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, KCNJ11, ABCC8, and APPL1) we considered patients to have MODY if they carried one or more variants classified as likely pathogenic (LP) or pathogenic (P) according to current guidelines. We found 77 of 3650 patients carried an LP/P variant in HNF4A (14 individuals), GCK (22), HNF1A (32), PDX1 (4), INS (3), and PAX4 (2). Compared to those with no LP/P variants, youth with MODY had a younger age at diagnosis (12.9 ± 0.3 vs. 13.6 ± 0.1, P=0.01) and lower fasting C-peptide levels (3.0 ± 0.2 vs. 4.5 ± 0.1, P=0.0001), although for both measures, the range of values overlapped between the two groups. Youth with MODY were less likely to have hypertension (6.9% vs. 18.2%, P=0.03) and less likely to be on insulin (32.0% vs. 51.1%, P=0.001). Parental history of diabetes was not significantly different. MODY was found in all race/ethnic groups.
Using a comprehensive set of MODY genes, we identified MODY in 2% of youth with clinically diagnosed type 2 diabetes; in 88% (n=68) the specific diagnosis would direct management. While these individuals differed significantly on several clinical characteristics, no criterion reliably separated the two groups. Further study is needed to find ideal criteria to select individuals for genetic testing.

Disclosure
J. Todd: None. J.W. Kleinberger: None. S. Srinivasan: None. S.E. Tollefsen: None. L.L. Levitsky: Consultant; Self; Eli Lilly and Company. L.E.L. Katz: None. J.B. Tryggestad: None. F. Bacha: Research Support; Self; AstraZeneca, JAEB Center For Health Research, National Institutes of Health, Pediatric Diabetes Consortium. G. Imperatore: None. J.M. Lawrence: None. C. Pihoker: None. J. Divers: None. J. Flannick: None. D. Dabelea: None. J.C. Florez: Consultant; Self; Intarcia Therapeutics, Inc.. Consultant; Spouse/Partner; Santen. T.I. Pollin: Research Support; Self; Regeneron Pharmaceuticals, Inc..
Digenic Mutations in the FGF-21 Signaling Pathway Found in an Adolescent with Extreme Insulin Resistance
Authors: STONE STEPHEN I. , ADESANYA ELIZABETH A. , WEGNER DANIEL J. , WAMBACH JENNIFER A. , COLE F. SESSIONS , ORNITZ DAVID M. , URANO FUMIHIKO 
Published: June 2018

Fibroblast Growth fFactor-21 (FGF-21) is a secretory molecule that has multiple metabolic functions. However, its role in human insulin resistance remains unclear. Here we report a 12 year old female presenting to pediatric diabetes clinic with acanthosis nigricans, hirsutism, and acromegalic features. The subject was noted to have extremely elevated insulin (2446 uIU/mL) and elevated free testosterone (16 pg/mL). Due to her unique presentation, we hypothesized that she may have a genetic insulin resistance syndrome and whole exome sequencing was performed. 2 variants were identified in genes critical for FGF-21 signaling, Fibroblast Growth Factor Receptor 1 (FGFR1) and beta Klotho (KLB). These mutations were inherited in trans from each parent. FGFR1 and KLB are transmembrane co-factors that bind FGF-21, leading to activation of intracellular tyrosine kinases, and subsequent intracellular signaling. Fasting serum FGF-21 was elevated in the subject (391.3 pg/mL) compared to her father (104.3 pg/mL) and mother (225.2 pg/mL). A bicistronic expression plasmid was created recapitulating the above mutations found in this family. These plasmids were transiently transfected into L6 myoblasts, a cell line known to have low levels of FGF receptor expression. ERK phosphorylation (pERK), the major downstream signal of FGF-21, was measured after the cells were treated with FGF-21. pERK was strongly upregulated in the cells transfected with wild type FGFR1 and KLB (43,463 AU). However, mutations in either FGFR1 or KLB greatly attenuated pERK (13,601.5 and 15,526 AU respectively). The combination of mutations in both FGFR1 and KLB led to the lowest level of pERK (10,148.3 AU). We hypothesize that these digenic mutations in both FGFR1 and KLB are acting in a synergistic fashion leading to FGF-21 resistance. This helps explain the severe insulin resistance found in this subject and may represent a novel category of insulin resistance syndromes related to FGF-21.

Disclosure
S.I. Stone: Speaker's Bureau; Self; AbbVie Inc.. Research Support; Self; National Institutes of Health, Pediatric Endocrine Society. E.A. Adesanya: None. D.J. Wegner: None. J.A. Wambach: None. F. Cole: None. D.M. Ornitz: None. F. Urano: Research Support; Self; Eli Lilly and Company. Stock/Shareholder; Self; CytRx.
Predicting Insulin Secretion Profiles for Immunoisolating Devices with Transplanted Islets
Authors: BUCHWALD PETER , TOMEI ALICE A. , STABLER CHERIE L. 
Published: June 2018

Avascular islets or stem cells transplanted under immunoisolating conditions offer considerable hope in overcoming the challenges of islet transplantation; however, because of diffusional limitations, implants face long-term viability and efficiency-of-response problems. To quantitatively characterize the glucose-stimulated insulin release of pancreatic islets, we conducted parallel dynamic perifusion experiments with free and hydrogel encapsulated islets. Perifused human islets secreted less insulin than murine islets per unit mass (IEQ) and had a less pronounced first-phase peak. The data was used to develop a computational model of insulin secretion. Our model couples hormone secretion and nutrient consumption kinetics with diffusive and convective transport, fits well the experimental data, and can be used to predict insulin release profiles for arbitrary geometries and glucose challenges. We found that larger diffusion distances (larger capsules) unavoidably dampen the first-phase insulin response, resulting in a sustained-release type insulin secretion that sluggishly responds to changes in glucose concentration. Hence, bioartificial pancreas devices can provide long-term and physiologically desirable solutions only if immunoisolation and biocompatibility considerations are considered together with optimized nutrient diffusion and insulin release characteristics.

Disclosure
P. Buchwald: None. A.A. Tomei: Consultant; Self; EyePharma. Research Support; Self; Semma Therapeutics, Inc.. Stock/Shareholder; Self; Converge Biotech Pvt. Ltd.. C.L. Stabler: None.
STAT5 Deficiency in Mature Adipocytes Results in Metabolically Healthy Adiposity, Reduced Growth Hormone Signaling in Adipose Tissue, and Decreased Energy Expenditure
Authors: RICHARD ALLISON J. , HANG HARDY , ALLERTON TIMOTHY D. , ELKS CARRIE M. , STEPHENS JACQUELINE M. 
Published: June 2018

STAT5 proteins promote adipocyte development and regulate adipose tissue function in vitro and in vivo. To further elucidate the role of STAT5 proteins in adipocytes, we used adiponectin-Cre and floxed STAT5 A/B mice to generate mice that lack both STAT5A and STAT5B in mature fat cells (STAT5AKO). Studies on several cohorts of both sexes of mice have revealed that STAT5AKO mice have increased adiposity. Notably, the adiposity phenotype disappears upon high fat feeding when growth hormone (GH) levels and GH signaling are diminished. Another striking observation is that obese STAT5AKO female mice are highly resistant to weight loss induced by low fat feeding when compared to floxed control mice that exhibit significantly enhanced weight loss and reduced adiposity. The adiposity of STAT5AKO mice is not a result of alterations in food intake or lean body mass. Furthermore, the increased adiposity in STAT5AKO mice is uncoupled from insulin resistance and metabolic dysfunction. It is well known that chronic elevation of GH is associated with insulin resistance. However, in most mammals a disruption of the IGF-1 axis accompanies altered GH signaling. Notably, STAT5AKO mice do not have alterations in circulating IGF-1 levels. In addition, the adiposity phenotype of STAT5AKO mice does not appear to be associated with alterations in basal or stimulated lipolysis. However, STAT5AKO female mice have a significant reduction in energy expenditure and fat oxidation.
In summary, our extensive phenotypic characterization of STAT5AKO mice has shifted our understanding of the metabolic actions of growth hormone and functions of STAT5 proteins.

Disclosure
A.J. Richard: None. H. Hang: None. T.D. Allerton: None. C.M. Elks: None. J.M. Stephens: None.
Individual and Combined Glucose-Lowering Effects of Glucagon Receptor Antagonism and Dipeptidyl Peptidase-4 Inhibition
Authors: HAEDERSDAL SOFIE , LUND ASGER B. , NIELSEN-HANNERUP ELISABETH , MAAGENSEN HENRIK , HOLST JENS J. , KNOP FILIP K. , VILSBØLL TINA 
Published: June 2018

Type 2 diabetes is characterized by absolute or relative hypoinsulinemia and hyperglucagonemia. Dipeptidyl peptidase 4 inhibitors (DPP-4i) augment insulin secretion and decrease glucagon secretion, but if glucagon is removed from the metabolic equation, the effect of DPP-4i is unknown. In a randomized, placebo-controlled, double-dummy, double-blinded, cross-over study, patients with type 2 diabetes (n=12, age [mean (SD)]: 60.9 (7.8) years, BMI 34.6 (7.1) kg/m2; HbA1c 50.3 (10.5) mmol/mol) underwent four 4-hour liquid mixed meal tests preceded by single-dose administration of 1) placebo, 2) DPP-4i (5 mg linagliptin) 2 hours before the meal, 3) glucagon receptor antagonist (GRA) (300 mg LY2409021) 12 hours before the meal, and 4) GRA + DPP-4i. Compared to placebo, fasting plasma glucose (FPG) was lowered by GRA but not DPP-4i. Adding DPP-4i to GRA did not lower FPG further. Compared to placebo, DPP-4i increased insulin responses to the meal (C-peptide AUC) (P&lt;0.01), but did not result in a difference in plasma glucose excursions (Figure). GRA alone lowered glucose AUC, and the combination of GRA and DPP-4i lowered glucose AUC further.
In conclusion, the combination of DPP-4i and GRA has additive effects on postprandial glucose excursions. This seems to be driven by the efficient reduction in FPG by GRA combined with additional reduction in postprandial glucose excursions by DPP-4i.

Disclosure
S. Haedersdal: None. A.B. Lund: Other Relationship; Self; Novo Nordisk A/S. E. Nielsen-Hannerup: None. H. Maagensen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.
Sirt5 Plays a Critical Role in Mitochondrial Protein Acylation and Mitochondrial Metabolic Homeostasis in Brown Fat
Authors: WANG GUOXIAO , MEYER JESSE G. , CAI WEIKANG , LI MENGYAO E. , SOFTIC SAMIR , KAHN C. RONALD 
Published: June 2018

Brown adipose tissue (BAT) is rich in mitochondria and plays important roles in energy expenditure, thermogenesis and glucose homeostasis. Recent studies have shown that mitochondrial activity can be regulated by protein succinylation and malonylation, processes that are in part controlled by Sirt5, the major mitochondrial desuccinylase and demalonylase. Compared to other tissues, brown fat has high levels of protein malonylation and succinylation, which were further increased in mice lacking Sirt5. BAT specific Sirt5 KO mice (Sirt5-BKO) are intolerant to acute cold. Furthermore, when stressed with high fat diet or aging, Sirt5-BKO mice develop impaired glucose homeostasis. Mass Spec analysis reveals that this correlates with an increase in succinylation of a variety of mitochondria enzymes and proteins, including succinate dehydrogenase (SDH), glutamate dehydrogenase (GDH), and UCP1. Lysine to glutamine mutations of UCP1 at the two target sites, which mimic acylation, resulted in significantly decreased UCP1 activity. Likewise, hyperacylation of SDH and GDH secondary to Sirt5 deficiency also impaired their activities. The reduced function of these and other proteins in Sirt5KO BAT resulted in decreased mitochondrial membrane potential and increased accumulation of PINK1, a mitochondrial serine/threonine kinase that protect cells from stress-induced mitochondrial dysfunction. Depolarized mitochondria are often smaller in size. Consistent with this, mitochondria from BAT of Sirt5KO mice had higher Fis1 expression during fasting, leading to increased mitochondrial fission and smaller mitochondria. Thus, succinylation and malonylation of key metabolic enzymes in mitochondria is regulated by Sirt5 and plays an important role in BAT activity. Over-acylation impairs mitochondrial protein function and results in depolarized mitochondria and disturbed systemic metabolic homeostasis.

Disclosure
G. Wang: None. J.G. Meyer: None. W. Cai: None. M.E. Li: None. S. Softic: None. C. Kahn: Advisory Panel; Self; CohBar, ERX Therapeutics, AntriaBio, Inc.. Board Member; Self; Kaleio Biosciences.
Soluble RAGE Sequesters Advanced Glycation End Products following an Overnight Fast in T1DM Patients
Authors: MIRANDA EDWIN R. , FULLER JR. KELLY N. , PERKINS RYAN , BEISSWENGER PAUL J. , FARABI SARAH S. , QUINN LAURIE T. , HAUS JACOB M. 
Published: June 2018

Context and Objectives: Advanced glycation end products (AGEs) promote the development of diabetic complications through activation of their receptor (RAGE). Isoforms of soluble RAGE (sRAGE) sequester AGEs and thus protect against RAGE-mediated diabetic complications. Low cellular energy, such as during fasting, activates sRAGE production. We investigated the effect of an overnight fast on circulating substrates, hormones, AGEs, and sRAGE isoforms in 26 individuals with type 1 diabetes (T1DM).
Participants and Methods: Blood was collected from young (18-30 years) T1DM patients on insulin pumps before and after an overnight fast. Circulating AGEs were measured via LC-MS/MS and sRAGE isoforms were analyzed via ELISA. eGFRcystatin-c was calculated based on circulating cystatin-c measured via ELISA.
Results: Glucose, insulin, glucagon, and eGFRcystatin-c decreased while cortisol increased following the overnight fast (p&lt;0.05). NEFAs and cholesterol did not change (p&gt;0.05). AGEs (CML, CEL, 3DG-H, MG-H1, and G-H1) decreased (21-58%, p&lt;0.0001) while total sRAGE, cleaved RAGE (cRAGE), and endogenous secretory RAGE (esRAGE) increased (22-24%, p&lt;0.0001) following the overnight fast. The changes in sRAGE isoforms were inversely related to MG-H1 (rho=-0.493 to -0.589, p&lt;0.05) and the change in esRAGE was inversely related to the change in G-H1 (rho=-0.474, p&lt;0.05). Multiple regression analysis revealed a 1 pg/mL increase in total sRAGE, cRAGE, and esRAGE independently predicted a 0.42-0.52 nM decrease in MG-H1.
Conclusions: Following an overnight fast, sRAGE isoforms were increased and sequestered MG-H1. Sequestration of AGEs by sRAGE has been shown to attenuate AGE/RAGE-mediated complications. Energy restriction appears to be important for protection against AGE/RAGE-mediated complications.

Disclosure
E.R. Miranda: None. K.N. Fuller: None. R. Perkins: None. P.J. Beisswenger: Employee; Self; PreventAGE Health Care, LLC.. S.S. Farabi: None. L.T. Quinn: None. J.M. Haus: None.
Resistance to Diet-Induced Obesity in Mice Lacking OPA1 in Adipose Tissue Occurs Independently of Fat-Derived FGF-21 and BAT Function
Authors: PEREIRA RENATA , OLVERA ANGELA C. , MARTI ALEX A. , HEWEZI RANA , BUI TRAN WILLIAM A. , POTTHOFF MATTHEW J. , DALE ABEL E. 
Published: June 2018

Optic Atrophy 1 (OPA1) is a mitochondrial protein that regulates mitochondrial dynamics and function. The role of OPA1 in adipose tissue physiology and systemic metabolism is incompletely understood. We generated mice lacking OPA1 in adipose tissue (OPA1 Ad-KO) and demonstrated that OPA1 deletion in adipose tissue completely prevents diet-induced obesity (DIO). This metabolic protection occurs concomitantly with increased levels of FGF-21 in adipose tissue and the circulation and higher energy expenditure. In the present study, we sought to determine the contribution of fat-derived FGF-21 and brown adipocyte function to the phenotype observed in OPA1 Ad-KO mice. To test whether changes in BAT function are responsible for the resistance to DIO, soon after weaning, OPA1 Ad-KO mice were fed either 60% high-fat diet (HFD) or 10% fat diet (control diet) for 8 weeks at thermoneutral conditions (30oC), when BAT function is dampened. To test whether fat-derived FGF-21 is required for the resistance to DIO in OPA1 Ad-KO mice, we generated mice lacking both OPA1 and FGF-21 in adipose tissue, by using the cre recombinase under the control of the adiponectin promoter (DKO). We, then, fed 4-week old DKO mice either 60% HFD or 10% control diet for 4 weeks. OPA1 Ad-KO mice fed a HFD under thermoneutral conditions failed to gain weight. Diet-induced increases in total fat mass was completely prevented. Although BAT mass was equally increased in WT and Ad-KO mice, gonadal and inguinal fat pads were significantly reduced in OPA1 Ad-KO mice fed HFD. Likewise, after 4 weeks of high-fat feeding, DKO mice had significantly reduced body weight and total fat mass compared to WT mice.
In conclusion, our data suggest that reducing BAT function is not sufficient to induce fat expansion in OPA1 Ad-KO mice in response to HFD. Additionally, here we show that adipose tissue-derived FGF-21 is dispensable for the resistance to DIO observed in OPA1 Ad-KO mice.

Disclosure
R. Pereira: None. A.C. Olvera: None. A.A. Marti: None. R. Hewezi: None. W.A. Bui Tran: None. M.J. Potthoff: None. E. Abel: None.
Endoplasmic Reticulum Membrane Protein Complex 10 (EMC10), a Novel Circulating Factor for Systemic Energy and Metabolic Homeostasis
Authors: WANG XUANCHUN , QIANG GUIFEN , LI YANLIANG , CAO XINYI , GIL VICTORIA , LI SHENGXIAN , CHEN KUANGYANG , WANG XINRU , BLUHER MATTHIAS , LIEW CHONG WEE 
Published: June 2018

Proteins secreted from metabolic organs play critical roles in fine-tuning and maintenance of systemic metabolic and energy homeostasis. In this study, we identified a novel obesity-regulated circulating protein, EMC10, that regulates systemic energy homeostasis. We initially observed that EMC10 is modulated in adipose tissues in diet-induced obesity (DIO) models and subsequently in obese patients. Using an in-house-developed chemiluminescent immunoassay, we found that circulating EMC10 is significantly upregulated in overweight and obese patients. To determine the role of EMC10, we subjected Emc10 KO mice to dietary treatment. We observed that ablation of Emc10 protects mice from DIO and associated metabolic dysregulation including glucose intolerance, insulin resistance, hyperinsulinemia, hyperleptinemia, and hyperlipidemia. Conversely, enhanced circulating EMC10 by expression of secretable AAV-hEMC10 in the liver promotes obesity and associated metabolic dysfunctions in mice fed with either chow or high fat diet. Subsequent metabolic analysis revealed that Emc10 KO mice on HFD have elevated whole body energy expenditure compared to WT controls via an increase in oxygen consumption in both the brown and inguinal subcutaneous fat. We showed that ablation of Emc10 not only promotes basal UCP1 and PGC1a expression but also sensitized adipocytes to beta-adrenergic stimulated thermogenic markers activation. Finally, our preliminary data showed that activation of the transcription factor CREB and p38 MAPK could potentially mediate EMC10 regulation of thermogenesis. Our findings implicate EMC10 as a novel therapeutic target for counteracting the development of obesity and obesity-induced metabolic dysfunction.

Disclosure
X. Wang: None. G. Qiang: None. Y. Li: None. X. Cao: None. V. Gil: None. S. Li: None. K. Chen: None. X. Wang: None. M. Bluher: Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; Bayer AG. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Novartis AG, Novo Nordisk A/S, Sanofi-Aventis Deutschland GmbH, Amgen Inc., Boehringer Ingelheim GmbH. C. Liew: None.
Comparison of Xenogeneic Encapsulated Islet Transplantation in Nonhuman Primates With and Without Immunosuppression
Authors: LEE EUN YOUNG , PARK HEON SEOK , KIM JIWON , YANG YEOREE , LIM JAYOUNG , KIM HUN-SUNG , LEE SEUNG-HWAN , CHO JAE HYOUNG , CHA BONG YUN , YOON KUN-HO 
Published: June 2018

Previously, we have shown the long-term efficacy and biocompatibility of chitosan-coated alginate capsule in allogeneic islet transplantation with canine models of diabetes. In this study, we compared the efficacy and immune response of chitosan-coated alginate capsule in xenogeneic islet transplantation with non-human primates (NHPs). Porcine islets were encapsulated alginate crosslinked with BaCl2, followed by suspension in chitosan solution. Encapsulated porcine islets were transplanted intraperitoneally in NHPs with and without immunosuppressants. Anti-αGal IgM and IgG was measured from the day of transplantation. After transplantation of encapsulated porcine islets, hyperglycemia and exogenous insulin requirements were decreased in the NHP recipients. Porcine C-peptide was detected in plasma after transplantation, but decreased with time. Anti-αGal IgM and IgG began to increase a week after transplantation in NHP without immunosuppressants, while they showed little increase in NHP with immunosuppressants. Exogenous insulin began to be administered to the NHP recipients from 3 to 5 days after transplantation regardless of immunosuppressants. However, daily insulin requirement increased earlier in NHP without immunosuppressants than those with immunosuppressants. Retrieved encapsulated porcine islets from showed fibrosis more than 70% in NHP without immunosuppressants, whereas only 5% of retrieved capsules showed fibrosis in NPH with immunosuppressants. In addition, in NPH with immunosuppressants, dithizone positive islets were observed over a month after transplantation. The use of immunosuppressants in xenogeneic encapsulated islet transplantation in NHP may help reduce fibrosis and improve islet function by modulating immune reaction.

Disclosure
E. Lee: None. H. Park: None. J. Kim: None. Y. Yang: None. J. Lim: None. H. Kim: None. S. Lee: None. J. Cho: None. B. Cha: None. K. Yoon: None.