bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
A UCP1 Near-Infrared Reporter System for Monitoring Adipose “Browning” In Vivo Using Photoacoustic Imaging
Authors: CHAN DERRYN XIN HUI , SUGII SHIGEKI , HAN WEIPING
Published: June 2018

Obesity has reached pandemic proportions in the developed world. The discovery that white adipocytes have the capacity to undergo browning to become metabolically-active beige cells has generated significant interest in the field of metabolic medicine. However, the study of adipose tissue browning has been hampered by a lack of imaging modalities that permit longitudinal and non-invasive monitoring of this process. To this end, we designed near infra-red (NIR) fluorescence protein iRFP720-Ucp1 reporter construct, in which the expression of iRFP720 is driven by a mini UCP1 promoter. Non-invasive assessment of adipose beiging during adrenergic stimulation was performed by viral transduction of mouse white adipocytes, followed by multi-spectral optoacoustic imaging technology with ultrasound tomography (MSOT-US). We observed increased iRFP720 fluorescence coupled with attenuated lipid signals upon stimulation. As proof of concept, we validated our approach against the hybrid positron emission tomography combined with magnetic resonance (PET/MR) imaging modality, and quantified the extent of adipose browning by MRI-guided segmentation of PET signals. Notably, the browning extent detected by the iRFP720 reporter system with MSOT-US and the 18-FDG uptake in PET/MR are well correlated with Ucp1 induction. Together, these systems provide platforms for preclinical screening of compounds aimed to promote adipose browning and facilitate the translation of these discoveries into pharmacological treatments for obesity.

Disclosure

D. Chan: None. S. Sugii: Stock/Shareholder; Self; Celligenics. W. Han: None.
Maternal Dietary Manipulation Programs Offspring’s Metabolism
Authors: KANG MINSUNG , ANTIPENKO JESSICA P. , LIU XIAOBING , HABEGGER KIRK M. , TIMOTHY GARVEY W.
Published: June 2018

There is emerging evidence supporting fetal metabolism is determined in utero, and the programmed metabolism persists into adulthood. Understanding how metabolic dysfunction is transmitted through generations will help identify the biological mechanisms underlying obesity and cardiometabolic disease, and provide insight regarding rational strategies for treatment and prevention.

Metabolic parameters were assessed in offspring from dams fed different diets for 4 weeks before pregnancy and during pregnancy and lactation; open standard (OSD), isocaloric low protein (LPD, 8% protein) and high-fat diets (HFD, 60% fat). After weaning, offspring had OSD.

Offspring from dams fed LPD showed 31% reduced birthweights compared to offspring from dams fed OSD, and the difference persisted into 6 months of age. At 3 and 6 months, they exhibited significantly smaller perigonadal fat pad than offspring from dams fed OSD. In addition, they showed significantly higher blood glucose concentration than offspring from dams fed OSD at birth (52.35mg/dl vs. 63.71 mg/dl). In case of offspring from dams fed HFD, they exhibited significantly higher body weights (5.99g vs. 6.56g) and blood glucose level at birth (52.35mg/dl vs. 64.64 mg/dl) compared to offspring from dams fed OSD. The difference of body weights continued to 3week-old at weaning, and they showed significantly impaired glucose tolerance compared to offspring from dams fed OSD at the same age.

Maternal dietary manipulation strongly influenced metabolic phenotypes such as birthweight, blood glucose concentration at birth and glucose tolerance, and the programed phenotypes persisted into adulthood. Therefore, maternal nutrition programs a glucose intolerant phenotype in offspring indicating that in utero stress augments diabetes risk not only childhood but also adulthood. We expect our findings in this study to help clarify the mechanism how the utero environment affects offspring’s metabolism, which would explain in part the intergenerational transmission of obesity.

Disclosure

M. Kang: None. J.P. Antipenko: None. X. Liu: None. K.M. Habegger: Consultant; Self; Glyscend, Inc.. Research Support; Self; Glyscend, Inc.. Consultant; Self; Intarcia Therapeutics, Inc. W. Garvey: Advisory Panel; Self; Novo Nordisk Inc., Merck & Co., Inc.. Research Support; Self; Sanofi, Pfizer Inc., Novo Nordisk Inc., AstraZeneca, Merck & Co., Inc., Elcelyx Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Eisai Inc..
Ablation of Galectin-1 Reduces Adipogenesis and Obesity
Authors: BAEK JUNGHWAN
Published: June 2018

Galectin-1 is a member of the animal lectin family that contains a carbohydrate-recognition binding domain (CRD) that binds a B-galactoside. Many studies are reported about the role of galectin-1 in cancer and immune disorders. But, the role of galectin-1 in metabolic dysfunction is not fully understood. We were interested in the role of galectin-1 on metabolic diseases and investigated the mechanism how galectin-1 regulates adipocyte differentiation and high fat diet (HFD) induced obesity. The level of galectin-1 increased during adipocyte differentiation and was predominantly expressed in mouse fat tissues. Galectin-1 knockdown significantly reduced adipocyte differentiation in 3T3-L1 cells and also decreased the expression of peroxisome proliferator-activated receptor (PPAR)-γ, ccaat enhancer binding protein (C/EBP)-α. fatty acid binding protein (FABP) 4 and fatty acid synthase (FASN). When lactose was treated to inhibit function of extracellular galectin-1, there was no effect on adipocyte differentiation. After 10-week high-fat diet (60% fat), lgals1-/- mice had lower body weight and WAT mass than wild type (lgals1+/+) mice. The expression levels of lipogenic genes were significantly down-regulated in liver and gonadal WAT of lgals1-/- mice. In addition, lgals1-/- mice had elevated expression of genes involved in thermogenesis in inguinal WAT and BAT. These data suggest that galectin-1 is an important regulator of adipogenesis. We also suppose that galectin-1 might be potential therapeutic target in obesity and fat liver diseases and further study is needed for clinical application.

Disclosure

J. Baek: None.
Inhibition of Adipose Tissue Angiogenesis Prevents Rebound Weight Regain after Calorie Restriction Independent of Hypothalamic Melanocortin System in Obese Mice Fed a High-Fat Diet
Authors: LEE HYE-JIN , SONG MUN-GYU , HA NA-HEE , JIN BO-YEONG , CHOI SANG-HYUN , KIM DONG-HOON
Published: June 2018

Prevention of rebound weight gain after dieting is essential to treat obesity. However, its attempts have been unsuccessful and the underlying mechanism remains unclear. In this study, we sought to investigate the role of adipose tissue (AT) vasculature in rebound weight gain after calorie restriction in obese mice fed a high-fat diet (HFD). Obese mice were randomly assigned to 4 groups including mice fed HFD ad libitum (CON), mice under 40% calorie restriction for 5 weeks (CR), 3 days of HFD ad libitum after CR (CRAL), or CRAL treated with TNP-470, an angiogenesis inhibitor (TNP). We compared parameters of energy balance, AT morphometry and remodeling, and hypothalamic neuropeptides gene expression among the groups. Rebound weight gain and food intake were significantly lower and the level of brown AT UCP-1 gene expression was higher in TNP group than CRAL group. Fat mass was significantly lower in TNP group than CRAL group and it was similar to CR group while lean mass was not different between TNP and CRAL groups. Notably, the CD31-positive area was not different in AT between CON, CR, and CRAL groups, indicating that AT vasculature was maintained independently of nutritional status. However, that tended to be lower in AT of TNP group compared to other groups, implicating that inhibition of AT vasculature might be crucial to suppress rebound weight gain after calorie restriction. Consistently, circulating leptin levels were significantly lower in TNP group than CRAL group. However, the pattern of hypothalamic neuropeptides gene expression was different from the changes in food intake among the groups, suggesting an existence of novel regulatory signals independent of melanocortin system. Taken together, these results suggested a critical role of AT vasculature in regulating rebound weight gain and hyperphagia after calorie restriction independent of hypothalamic melanocortin system.

Disclosure

H. Lee: None. M. Song: None. N. Ha: None. B. Jin: None. S. Choi: None. D. Kim: None.
Modified Mesenchymal Stromal Cells Promote Multiple Metabolic Benefits in Obese Diabetic Mice
Authors: DOMINGUES CLEYTON C. , KUNDU NABANITA , KROPOTOVA YANA , AHMADI NEEKI , SEN SABYASACHI
Published: June 2018

Background: Mesenchymal stromal cells (MSCs) are multipotent cells that can home-in to the sites of inflammation. Therefore, antioxidant-upregulated MSCs delivered intra-peritoneally can home-in to local inflamed fat pockets which may reduce inflammation and improve glucose tolerance in diet-induced obese and diabetic mouse model.

Methods: GFP-containing adenoviral constructs were used to upregulate antioxidants Sod2 (mitochondrial) and Catalase (cytosolic) in human adipose-derived MSCs. Modified MSCs were delivered (IP) into mice subjected to 45% and 60% high-fat diet for 8-16 weeks.

Results: Glucose tolerance was improved at week 4 in the antioxidant upregulated MSC-receiving groups with concomitant reduction in hyperplasia in omental fat. A reduction in plasma levels of TNFa, an well-known inflammatory marker, was found for all treated animal groups in comparison to control (null-MSCs). RT-PCR analysis of omental and pericardial fat showed significant up-regulation in mRNA expression of brown fat marker, Ucp1 (∼1000-fold and 10-100-fold, respectively) which was confirmed by Ucp1-staining and concomitant increases in down-stream genes such as Pgc1a and Prdm16 mRNA expression. Remarkably, the treatment showed a significant reduction in liver fat content (by histology) and triglyceride content measurement.

Conclusion: Delivery of Sod2 and Catalase upregulated MSCs improved glycemic control by reducing systemic inflammation, promotes browning of white adipose tissue and reverses hepatic lipid accumulation. These results indicate that antioxidant upregulated MSCs can help to improve glucose homeostasis, adipocyte energetics and hepatic lipid metabolism. Modified MSC therapy can be a promising therapy for type 2 diabetes, obesity and fatty liver disease.

Disclosure

C.C. Domingues: None. N. Kundu: None. Y. Kropotova: None. N. Ahmadi: None. S. Sen: None.
Loss of Insulin Actions on Arterial Smooth Muscle Cells May Enhance Unstable Atherosclerotic Plaque Formation
Authors: LI QIAN , FU JIALIN , PARK KYOUNGMIN , CHRISTIAN RASK-MADSEN , KING GEORGE L.
Published: June 2018

Formation of unstable atherosclerotic plaque, a major cause of cardiovascular mortality, is accelerated in insulin resistance and diabetes. Previous studies have suggested that endothelial dysfunction and systemic hyperlipidemia due to loss of insulin actions can accelerated its formation. However, the mechanism for insulin resistance to accelerate the various pathologies of unstable plaque, such as decreases in VSMC and extra cellular matrix (ECM) and increased inflammatory cells, have not been defined. Since insulin actions on the vascular wall are diminished in insulin resistant states, we assessed the loss of insulin action in VSMC and its effect on the formation of atherosclerotic plaque. Insulin receptor (IR) was specifically deleted from VSMC by breeding SM22 a promoter Cre and IR Flox mice to produce SMIRKO mice which were mated with ApoE-/- mice to generate SMIRKO/ ApoE-/- mice. Cultured VSMC from SMIRKO/ApoE-/- mice showed decreased insulin signaling and stimulated proliferation by >50%, but not to PDGF. Weight, blood pressure, glucose, and systemic insulin tolerance were comparable between ApoE-/- and SMIRKO/ApoE-/- mice; which were fed with normal chow to mimic pathophysiological hyperlipidemia encountered clinically. Surprisingly, SMIRKO/ ApoE-/- mice developed significantly more atherosclerotic aortic plaques (Sudan IV staining for lipid content) compared to ApoE-/- mice with parallel increases of macrophage content and inflammatory cytokines such as IL18 and ICAM1. In contrast, SMC as measured by SM22α staining was decreased with elevation of necrotic plaques (p<0.05). Further, proliferative index of VSMC as measured by Ki67 staining and expression of hyaluronan synthase-2 were decreased. Thus, surprisingly, the loss of insulin’s specific actions on VSMC to increase proliferation increased inflammatory cell influx as observed in insulin resistance, may accelerated formation of unstable plaques in diabetes.

Disclosure

Q. Li: None. J. Fu: None. K. Park: None. C. Rask-Madsen: Research Support; Self; Novo Nordisk A/S. G.L. King: Research Support; Self; Sanofi-Aventis.
Differences in Energy Expenditure between Respiratory Chamber and Metabolic Ward in Inpatient Men and Women
Authors: ZHOU MEGAN S. , HOWARD REBECCA E. , RABEL ANTOINETTE , SEDMAK CAROLINE , CAI HONGYI , WALTER PETER J. , BRYCHTA ROBERT , FLETCHER LAURA , LEITNER BROOKS , GUO JUEN , SIKDER SHANAZ , COURVILLE AMBER B. , BERNSTEIN SHANNA , GREWAL SHIVRAJ , MUNIYAPPA RANGANATH , CHEN KONG Y. , HALL KEVIN
Published: June 2018

We previously investigated 16 men with overweight or class I obesity who were admitted to a metabolic ward and engaged in 90 minutes of daily cycle ergometry at a fixed resistance. Subjects resided in a respiratory chamber for 2 days per week. The remaining days were spent in their inpatient rooms. Total expenditure was measured over 2 weeks via doubly labeled water (DLW). We found a surprisingly large (∼500 kcal/day) decrease in expenditure when subjects resided in the respiratory chamber as compared to the days spent in their rooms. Here, we attempted to reproduce this finding in non-exercising healthy volunteers.

Purpose: To measure differences in daily energy expenditure between days spent on a metabolic ward vs. days spent in a respiratory chamber.

Methods: 10 adults (2 M, 8 F) aged (mean ± SE) 34 ± 3.5 years with BMI 27.9 ± 2.3 kg/m2 completed a 7-day inpatient stay on the metabolic ward at the NIH Clinical Center. Two days were spent residing in a respiratory chamber. Study participants received a controlled diet and refrained from exercise. Temperature and clothing were kept constant. Energy expenditure on days spent on the ward was calculated using DLW over 6 days after accounting for the energy expended during the 2 respiratory chamber days.

Results: Average energy expenditure on the ward was 2122 ± 155 kcal/day, with an average of 1996±130 kcal/day expended during the two respiratory chamber days. Therefore, energy expenditure on the metabolic ward was 126 ± 55 kcal/day (p= 0.048) greater than in the respiratory chamber.

Conclusion: Participants expended ∼126 kcal/day more on the metabolic ward than in the respiratory chamber. This was a much smaller discrepancy than previously found in exercising men. Failure to reproduce our previous results may have been due to the lack of exercise, the inclusion of women, or the wider range of BMIs in the current study. Further studies are needed to investigate the determinants of energy expenditure differences between ward and respiratory chamber days.

Disclosure

M.S. Zhou: None. R.E. Howard: None. A. Rabel: None. C. Sedmak: None. H. Cai: None. P.J. Walter: None. R. Brychta: None. L. Fletcher: None. B. Leitner: None. J. Guo: None. S. Sikder: None. A.B. Courville: None. S. Bernstein: None. S. Grewal: None. R. Muniyappa: None. K.Y. Chen: None. K. Hall: None.
Sustained Improvement of Obesity in Hypogonadal Men with Type 2 Diabetes (T2DM) Receiving Long-Term Treatment with Injectable Testosterone Undecanoate (TU)—Real-Life Evidence from a Urological Registry Study
Authors: SAAD FARID , HAIDER KARIM S. , HAIDER AHMAD
Published: June 2018

Background: Hypogonadism is highly prevalent in men with obesity as well as T2DM.

Methods: Of 805 hypogonadal men in a urological registry, 311 men (39%) had T2DM diagnosed and treated elsewhere. 141 received TU 1000 mg/12 weeks (T-group), 170 opted against treatment (CTRL). Mean changes over time between groups were compared by mixed effects model for repeated measures with random effect for intercept and fixed effects for time, group and their interaction. Changes were adjusted for age, weight, waist circumference, HbA1c, blood pressure (BP), lipids to account for baseline differences between the two groups.

Results: Mean age:T-group: 61.8±5.3, CTRL: 63.5±4.9 years. Follow-up: mean: 7.5, median: 8 years. T-group: 89.4% were obese, 9.9% overweight, and 0.7% had normal weight. Weight decreased progressively from 113.4±13.9 to 90.7±8.6 kg at 10 years (p<0.0001) with statistical significance vs. previous year for the first 9 years. CTRL: 70% were obese, 26.5% overweight, and 3.5% had normal weight. Weight remained stable. Estimated adjusted difference between groups: -25.7 kg (p<0.0001). T-group: waist circumference decreased from 112.6±10.7 to 99.6±5.2 cm (p<0.0001) with statistical significance vs. previous year for the first 9 years. CTRL: Waist circumference remained stable. Estimated adjusted difference between groups: -17.9 cm (p<0.0001). T-group: BMI decreased from 36.3±4.4 to 29.3±2.7 kg/m2 at 10 years (p<0.0001) with statistical significance vs. previous year for the first 9 years. CTRL: BMI remained stable. Estimated adjusted difference between groups: -8.3 kg/m2 (p<0.0001). Since injections were administered in the doctor’s office and no patient dropped out, there was a 100% adherence to testosterone therapy (TTh).

Conclusions: Long-term TTh with TU in hypogonadal men with T2DM improved anthropometric measures compared to untreated controls.

Disclosure

F. Saad: Employee; Self; Bayer AG. Stock/Shareholder; Self; Bayer AG, Novo Nordisk A/S. K.S. Haider: Other Relationship; Self; Bayer AG. A. Haider: Research Support; Self; Bayer AG.
The CCR4-NOT Complex Maintains ß-Cell Identity through the Repression of ß-Cell Disallowed Genes
Authors: MOSTAFA DINA , TAKAHASHI AKINORI , YANAGIYA AKIKO , YAMAMOTO TADASHI
Published: June 2018

Loss of β-cell identity, dedifferentiation and reprogramming are recognized as mechanisms of β-cell dysfunction in diabetes. Molecular β-cell identity is not only defined by the expression of signature functional β-cell specific genes but also the repression of several genes recently identified in β-cell research as β-cell disallowed genes. The molecular mechanisms involved in the repression of β-cell disallowed genes are largely unknown. Here, we show that the CCR4-NOT complex, a major deadenylase conserved in eukaryotes, is involved in post-transcriptional regulation of β-cell disallowed genes. β-cell specific depletion of CNOT3 (CNOT3βKO), a CCR4-NOT complex subunit, in mice promotes deceased insulin secretion, early impaired glucose tolerance and the development of overt diabetes at 12 weeks of age. CNOT3βKO islets display decreased insulin content and decreased glucose responsiveness. Furthermore, CNOT3 depleted ß cells exhibit ultrastructural abnormalities including: degranulated β cells, increased immature insulin granules and abnormal mitochondria. RNAseq and qRT-PCR analyses revealed that CNOT3βKO islets have decreased expression of β-cell functional genes: (Ins1, Ins2, MafA, Pcsk2 and Cpe) and increased expression of 9 of the 11 core β-cell disallowed genes: (Slc16A1, Ldha, Pdgfra, Cxcl12, Igfbp4, Oat, Maf, Smad3 and Cd302) and progenitor-like cells genes: (Nanog and Ngn3) supporting the loss of β-cell identity. Using the total RNAseq data, we assessed mRNA stability by calculating the relative amounts of introns and exons for a given mRNA. RNA immunoprecipitation revealed that the CCR4-NOT complex directly binds several upregulated stabilized β-cell disallowed genes: Slc16A1, Tgm2, Cat and Parp3 genes. The present data highlight deadenylation as a novel molecular mechanism regulating β-cell disallowed genes. Thus, we further propose that the CCR4-NOT complex is essential for maintaining β-cell identity by repressing β-cell disallowed genes.

Disclosure

D. Mostafa: None. A. Takahashi: None. A. Yanagiya: None. T. Yamamoto: None.
The Relationship of Acculturation to Cardiometabolic Risk Factors among U.S. South Asians—Findings from the MASALA Study
Authors: AL-SOFIANI MOHAMMED , LANGAN SUSAN J. , KANAYA ALKA M. , KANDULA NAMRATHA R. , NEEDHAM BELINDA , KIM CATHERINE , BECKER DIANE M. , VAIDYA DHANANJAY , GOLDEN SHERITA , LEE CLARE , KALYANI RITA RASTOGI
Published: June 2018

Background: Immigration and the process of acculturation can lead to behavioral changes that exacerbate or reduce diabetes development. We investigated the association between acculturation strategies and cardiometabolic risk (CMR) factors among South Asian (SA) immigrants living in the U.S.

Methods: Participants (n=849) in the Mediators of Atherosclerosis in SA Living in America (MASALA) study were categorized into 3 acculturation strategy classes based on self-reported questionnaire responses: separation (preference for SA culture), assimilation (preference for U.S. culture), and integration (similar preference for SA and U.S. cultures). Adjusted linear regression models examined associations of acculturation strategies with fasting and 2 hour glucose, lipids, blood pressure, waist circumference (WC), and body composition.

Results: Overall, 22.4, 19.6, and 58% of men and 23.7, 26.2, and 50.1% of women were in separation, assimilation, and integration classes; respectively. Participants in the assimilation class had significantly lower levels of obesity, 2 hour glucose, insulin, HOMA-IR, triglycerides (TG), visceral fat, and higher HDL than those in the separation class (all p<0.05). In sex-stratified analyses, after adjusting for education, income, other socioeconomic variables, physical activity, caloric intake, depression, smoking, and alcohol intake, women in the assimilation class continued to have significantly lower TG and higher HDL levels compared to women in the separation class [β (95% CI): -23.7 (-41.9, -5.5) and 7.5 (2.9, 12.1); respectively]. There was no significant association between acculturation and CMR factors in men.

Conclusion: SA women who employed an assimilation strategy had a more favorable CMR profile compared to women using a separation strategy. Future research should investigate the behavioral pathways linking acculturation strategies with CMR and potential incorporation into prevention interventions.

Disclosure

M. Al-Sofiani: None. S.J. Langan: None. A.M. Kanaya: None. N.R. Kandula: None. B. Needham: None. C. Kim: None. D.M. Becker: None. D. Vaidya: None. S. Golden: None. C. Lee: None. R. Rastogi Kalyani: None.
Longevity of Beta Cells and Protein Complexes Revealed by Isotope Imaging
Authors: E DRIGO RAFAEL ARROJO , TOYAMA BRANDON H. , TYAGI SWATI , LEV-RAM VARDA , DEERINCK THOMAS J.J. , BUSHONG ERIC A. , RAMACHANDRA RANJAN , LECHENE CLAUDE , ELLISMAN MARK H. , HETZER MARTIN
Published: June 2018

We discovered recently that long-lived cells (LLCs), such as neurons, contain long-lived proteins (LLPs) in the nucleus that can last a lifetime, and their decline during aging impairs nuclear function. Beta cells are LLCs with a slow cell replication process, yet it is unknown whether individual beta cells have different lifespans. We tested this hypothesis by using a hybrid microscopy and mapping platform (MIMS-EM) to identify beta cells and quantify cell and protein turnover in the islets of Langerhans. This is achieved by pulse-labelling mice with an 15N-rich diet followed by a chase period with a control 14N-rich diet for up to 2 years. Here, old cells and protein structures retain 15N while those that turnover incorporate 14N. The levels of 15N and 14N were measured with multi-isotope mass spectroscopy (MIMS) and the 15N-to-14N ratio reports on cell and protein turnover. Importantly, the MIMS data is correlated with scanning electron microscopy (EM) to create high-resolution maps of cells and intra-cellular structures overlaid with age information. Here we report the use of MIMS-EM on mouse islets to discover that beta cells have vastly different ages. In fact, while approximately 75% of beta cells replicate between 2-4 times, almost 25% of all beta cells does not replicate at all after weaning and remain quiescent for an entire lifetime, and therefore, are as old as cortical neurons. Such longevity was also found in other islet cell-types and at the protein super-complex level, where 15N accumulation on the primary cilium of beta cells strongly indicates that this important signaling structure is exceptionally long-lived. Strikingly, and similar to what is found in old rat neurons, beta cells from humans aged >60-years-old lose specific nuclear LLPs and show signs of impaired nuclear function. Together, our data shows that beta cell longevity is heterogeneous and identifies the loss of nuclear LLPs in human beta cells as a potential contributing factor to age-dependent loss of beta cell function.

Disclosure

R. Arrojo e Drigo: Stock/Shareholder; Self; VTV Therapeutics, Novo Nordisk A/S. B.H. Toyama: None. S. Tyagi: None. V. Lev-Ram: None. T.J.J. Deerinck: None. E.A. Bushong: None. R. Ramachandra: None. C. Lechene: None. M.H. Ellisman: None. M. Hetzer: None.
Socioeconomic Profiles as Predictors of Glycemic Control in Youth with Type 1 Diabetes
Authors: SUTHERLAND MELANIE W. , MA XIAONAN , MENDOZA JASON A. , BELL BETHANY A. , REBOUSSIN BETH A. , KAHKOSKA ANNA R. , SAUDER KATHERINE A. , PIHOKER CATHERINE , LIESE ANGELA D.
Published: June 2018

Various measures of socioeconomic status (SES) predict glycemic control in youth and young adults (YYA) with type 1 diabetes; however, rarely have multiple SES factors been considered simultaneously, including parental education and income, food security, health insurance status, and food assistance. The purpose of this study was to identify multidimensional SES profiles in YYA with type 1 diabetes and to assess the association between these profiles and glycemic control. Data from 257 YYA with type 1 diabetes enrolled in the SEARCH Food Insecurity Ancillary Study in South Carolina and Washington between the years 2013 and 2015 were included. We identified SES profiles utilizing latent class analysis and used multivariable logistic regression to compare the profiles’ glycemic control, with HbA1c > 9% defined as poor glycemic control. Two profiles were identified: Profile 1 (74%) included YYA that were of higher parental income and education, and less likely to have government-funded health insurance, to receive food assistance, and to be food insecure. Profile 2 (26%) included YYA who were categorized opposite to that of profile 1. In profile 2, 60% of YYA had poor glycemic control compared to 44% of YYA in profile 1. After adjustment for age, sex, race/ethnicity, site, diabetes duration, and diabetes medication, YYA in profile 2 were significantly more likely to have poor glycemic control relative to YYA in profile 1 (OR = 1.94, 95% CI = 1.01-3.71). Membership to a lower SES profile is associated with poor glycemic control among YYA with T1D. Strategies to improve glycemic control, particularly in YYA who belong to lower SES profiles, are needed.

Disclosure

M.W. Sutherland: None. X. Ma: None. J.A. Mendoza: None. B.A. Bell: None. B.A. Reboussin: None. A.R. Kahkoska: None. K.A. Sauder: None. C. Pihoker: None. A.D. Liese: None.
Saturated Fatty Acids Impair Organellar Trafficking in Dorsal Root Ganglion (DRG) Sensory Neurons
Authors: LOGRASSO GIOVANNI , RUMORA AMY , HAIDAR JULIA A. , LENTZ STEPHEN I. , FELDMAN EVA L.
Published: June 2018

Diabetic neuropathy (DN) is a highly prevalent complication of type 2 diabetes that is associated with dyslipidemia and causes length-dependent sensory nerve damage in the lower extremities. The primary sensory neurons, dorsal root ganglion (DRG) neurons, extend bundles of axons into the peripheral nerves and transmit sensory information from the limbs. These neurons require a constant supply of mitochondrial derived energy maintained by trafficking of the mitochondria throughout the length of the DRG axon. We have shown that dyslipidemia-associated saturated fatty acid (FA) palmitate impairs mitochondrial trafficking whereas unsaturated FA oleate prevents this impairment. In the current study, we assessed whether FAs alter trafficking of synaptic vesicles in DRG axons to determine whether palmitate impairs mitochondrial trafficking specifically or global organellar transport. Primary DRG neurons were treated with physiological concentrations of FAs ranging from 31.25-250 µM saturated FA palmitate, unsaturated FA oleate, and oleate/palmitate mixtures. Mitochondria and synaptic vesicles showed a significant dose-dependent reduction in motility with increasing concentrations of saturated FA palmitate. However, mitochondria and synaptic vesicles retained motility with treatments of unsaturated FA oleate compared to the controls. Similarly, palmitate induced a trending decrease in velocity of bi-directional motile mitochondria and synaptic vesicles, whereas oleate treatments did not alter mitochondrial and synaptic vesicle velocity. Finally, co-incubation of oleate prevents palmitate-induced inhibition of mitochondrial and synaptic vesicle trafficking. These results suggest that high concentrations of saturated FAs lead to the dysfunction of global organellar transport throughout the DRG axon associated with the development and progression of DN.

Disclosure

G. LoGrasso: None. A. Rumora: None. J.A. Haidar: None. S.I. Lentz: None. E.L. Feldman: None.
Dextrose-Sulfonylurea Challenge as a Screening Test for Monogenic Diabetes in Patients Diagnosed with Type 1 Diabetes
Authors: WOOD AURELIA C.H. , REMEDI MARIA S. , NICHOLS COLIN , MARSHALL BESS A.
Published: June 2018

Monogenic diabetes due to ABCC8, KCNJ11, HNF1A and HNF4 can be treated with sulfonylurea (SU). The SEARCH for Diabetes in Youth confirmed most patients with monogenic diabetes are misdiagnosed with T1DM, and that family history and fasting C-peptide do not reliably increase pre-test probability for diagnosis. Confirmatory genetic testing is expensive and methods to improve cost-benefit ratio do not exist. As such, we developed a dextrose-SU challenge to assess C-peptide response to SU as indication of clinically significant underlying β-cell excitation defects. We postulate negative response to hyperglycemia with positive response to SU indicates presence of a genetic defect in glucose-stimulated insulin secretion. This challenge has been completed on 42 subjects with TIDM on insulin therapy. Blood glucose (BG) and C-peptide were obtained at regular intervals prior to and after a 0.5 g/kg IV dextrose bolus, a single dose of glipizide was given 20 minutes after dextrose (0.3 mg/kg max 15mg if <50 kg; 40 mg if >50 kg) and BG and C-peptide were obtained until study completion. Twenty of the 42 subjects had undetectable C-peptide. Twenty-two subjects had detectable C-peptide, 13 of which showed preferential C-peptide response to glipizide (ΔC-peptide 0.41 ± 0.45 ng/mL) compared to hyperglycemia (Δ 0.05 ± 0.03 ng/mL). This suggests islets may show modest but specific response to SU in TIDM. Nine of the 13 who showed preferential response to glipizide completed a dextrose-only challenge 6 months later and retained marginal C-peptide response to hyperglycemia alone (Δ 0.05 ± 0.04 ng/mL). Whole exome sequencing is pending on these subjects. These data suggest the challenge may serve to elicit and stratify C-peptide response to SU, assist in categorizing residual β-cell function, support screening for monogenic diabetes, and increase consideration of SU therapy for appropriate patients.

Disclosure

A.C.H. Wood: None. M.S. Remedi: None. C. Nichols: None. B.A. Marshall: None.
Racial and Socioeconomic Disparities in Meeting Goals of Care in Adults with Type 1 Diabetes
Authors: HAW J. SONYA , PENG LIMIN , PASQUEL FRANCISCO J. , VELLANKI PRIYATHAMA , FAYFMAN MAYA , DAVIS GEORGIA , UMPIERREZ GUILLERMO E.
Published: June 2018

Racial and socioeconomic (SES) disparities exist in youth with type 1 diabetes (T1D). Black youth have worse glycemic control, higher frequency of DKA, and less use of insulin pump therapy. However, data is sparse on whether racial and SES disparities in meeting ABC (A1c, Blood pressure, Cholesterol) goals of care exist in adulthood, when financial independence, access to healthcare, and cognitive maturity change.

We used T1D Exchange Network data, which enrolled youth and adults with T1D from 73 practices. We include adults (≥ 18 years) with available race/ethnicity data. Of 12,746 adults, 90% where white, 4.8% black and 5.7% Hispanic; annual household income in 13% was <$25K, 20% was $25-50K, 34% was $50-100K, and 33% was >$100K. Logistic regression showed increased probability of poor glycemic control (A1c >7%) with annual income <$25K (OR 2.29, 95% CI [1.92,1.74]), being black (OR 3.05, 95% CI [2.09,4.43]) or Hispanic (OR 1.42, 95% CI [1.10, 1.82]). Outcomes were similar in achieving SBP <140mmHg and LDL <100mg/dL. Data stratified by income showed significant disparities among races, with fewer black and Hispanic adults achieving ABC goals compared to whites. There were no differences in mortality.

Racial and SES disparities exist in adults with T1D. Racial disparities are evident after adjusting for income, suggesting socio-ecological factors play a role in achieving optimal diabetes care in minority populations.

White, non-HispanicBlack, non-HispanicHispanicp-value>$100K N=2924N=45N=77A1c <7%, n (%)920 (32)4 (9.1)14 (22)<0.001SBP <140 mmHg, n (%)2736 (95)34 (79)69 (92)<0.001LDL <100 mg/dL, n (%)1690 (69)24 (57)43 (67)0.23No smoking, n (%)2218 (95)37 (95)63 (90)0.19$50K-100KN=2914N=99N=105A1c <7%, n (%)751 (26)13 (14)27 (26)0.02SBP <140 mmHg, n (%)2695 (93)88 (89)99 (95)0.20LDL <100 mg/dL, n (%)1607 (65)53 (63)48 (57)0.27No smoking, n (%)2103 (90)87 (97)84 (97)0.01$25K-50KN=1590N=96N=134A1c <7%, n (%)333 (21)8 (8.4)16 (12)<0.001SBP <140 mmHg, n (%)1439 (91)84 (88)124 (93)0.37LDL <100 mg/dL, n (%)828 (65)43 (62)56 (59)0.49No smoking, n (%)1049 (83)76 (87)101 (85)0.52<$25KN=964N=125N=149A1c <7%, n (%)159 (17)6 (5.1)19 (13)0.001SBP <140 mmHg, n (%)890 (93)97 (81)141 (96)<0.001LDL <100 mg/dL, n (%)460 (65)55 (60)61 (53)0.04No smoking, n (%)565 (75)93 (79)123 (89)0.001

Disclosure

J. Haw: None. L. Peng: None. F.J. Pasquel: Consultant; Self; Merck Sharp & Dohme Corp., Sanofi, Boehringer Ingelheim Pharmaceuticals, Inc. P. Vellanki: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. M. Fayfman: None. G. Davis: None. G.E. Umpierrez: Research Support; Self; Sanofi US, Merck & Co., Inc., Novo Nordisk Inc., AstraZeneca. Advisory Panel; Self; Sanofi, Intarcia Therapeutics, Inc..
Mechanistic Role of IP3R Calcium Release Channel in Pancreatic Beta-Cell Function
Authors: SHU JUN , GAMBARDELLA JESSICA , SORRIENTO DANIELA , SANTULLI GAETANO
Published: June 2018

Background: According to the classic paradigm, insulin secretion is triggered by the influx of extracellular Ca2+ via voltage-dependent channels, leading to the fusion of insulin granules. Instead, the mechanisms involved in Ca2+ mobilization from internal stores are less defined. The main intracellular Ca2+ release channels are inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR), whereas Ca2+ is returned to the ER primarily by the activity of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) pump. We recently demonstrated the importance of RyR in type 2 diabetes mellitus (T2DM), showing that it is essential in glucose-stimulated insulin secretion (GSIS). Conversely, the exact role of IP3R in GSIS remains not fully understood.

Methods and Results: Three isoforms of IP3R have been identified in mammalian cells. Channel opening is stimulated by the binding of second messenger IP3 and by changes in Ca2+ concentrations. Studies in rodent and human samples indicate that β cells express all IP3R isoforms. We demonstrated that the expression of all isoforms is significantly increased in human islets from T2DM cadaveric donors T2DM compared with nondiabetic individuals. These results were also confirmed in diabetic db/db mice and in mice fed high-fat diet. Moreover, pancreatic β cells from T2DM patients exhibited dysmorphic and dysfunctional mitochondria, with markedly altered Ca2+ uptake. Similar features were found in clonal β cells chronically exposed to high glucose. In vitro, overexpression of IP3Rs was associated with impaired GSIS, whereas IP3R silencing improved β cell function, mitochondrial Ca2+ uptake and function, ER stress, and insulin release in response to different secretagogues.

Conclusions: Taken together, our data indicate that IP3Rs are upregulated in human islets from T2DM donors, leading to mitochondrial dysfunction and pancreatic β cell failure, identifying in these intracellular Ca2+ release channels a novel therapeutic target to treat T2DM.

Disclosure

J. Shu: None. J. Gambardella: None. D. Sorriento: None. G. Santulli: None.
Ethnicity and Common Genetic Variants Modulate Nonalcoholic Fatty Liver Disease (NAFLD) Metabolic Phenotype in Obese Youth
Authors: TRICO DOMENICO , CAPRIO SONIA , UMANO GIUSEPPINA R. , GALDERISI ALFONSO , MATA MARIANA M. , NOUWS JESSICA , PIERPONT BRIDGET , KIM GRACE , SANTORO NICOLA
Published: June 2018

Background: Pediatric Nonalcoholic Fatty Liver Disease (NAFLD) represents a major risk factor for insulin resistance and type 2 diabetes in adolescents.

Methods: To characterize the clinical and genetic features associated with the development of pediatric NAFLD, 503 obese adolescents (191 Caucasians, 134 African Americans, and 178 Hispanics) underwent a MRI to quantify hepatic fat content, an oral glucose tolerance test to assess glucose tolerance and insulin sensitivity, and the genotyping of three SNPs associated with NAFLD (PNPLA3 rs738409, GCKR rs1260326, and TM6SF2 rs58542926). MRI and metabolic assessments were repeated in 133 patients after 2.27±1.44 years.

Results: The prevalence of NAFLD was 42.9% in Caucasians, 15.7% in African Americans, and 59.6% in Hispanics (p<0.0001). Compared to Caucasians and Hispanics with NAFLD, African Americans adolescents with NAFLD had higher fasting glucose (p=0.03), insulin (p=0.0004), C-peptide (p=0.04), 2-h-glucose (p=0.04), HbA1c (p<0.0001), and lower insulin sensitivity (p=0.03), despite similar age (p=0.34) and gender distribution (p=0.37). This translated in a higher prevalence of prediabetes and type 2 diabetes in African Americans (66.6%) compared to Caucasians (24.4%) and Hispanics (31.1%) with NAFLD (p=0.0003). Analysis of the patients without NAFLD at baseline showed that ethnicity (p=0.02), high C-peptide levels (p=0.0006), changes in z-score BMI over time (p=0.0006) and common gene variants were strong predictors of NAFLD development at follow-up (AUROC curve 0.976).

Conclusions: African American obese adolescents are relatively protected from NAFLD, but are more susceptible to the deleterious effects of NAFLD on glucose metabolism. The combination of ethnicity, markers of insulin resistance and genetic factors are strong predictors of pediatric NAFLD.

Disclosure

D. Trico: None. S. Caprio: None. G.R. Umano: None. A. Galderisi: None. M.M. Mata: None. J. Nouws: None. B. Pierpont: None. G. Kim: None. N. Santoro: None.
Pancreatic Alpha-Cell Function and Identity in Human T2D
Authors: DAI XIAOQING , SOLER JOAN CAMUNAS , BRIANT LINFORD , SPIGELMAN ALIYA F. , HANG YAN , RORSMAN PATRIK , KIM SEUNG , MACDONALD PATRICK
Published: June 2018

Glucagon is synthesized and released by pancreatic α-cells and, along with insulin, maintains blood glucose levels within the physiological range. We seek to understand the impact of glucose on the biophysical properties of α-cells in T2D. We studied α-cells from human donors (34 nondiabetic, and 14 T2D) and from mice fed a high fat diet (HFD) by whole-cell patch-clamp electrophysiology, with and without combined single-cell RNA sequencing (patch-seq). We found that, opposite to what is observed in β-cells, depolarization-induced exocytosis and Ca2+-channel function is enhanced at low glucose (LG, 1 mM G) and suppressed at high glucose (HG, 5-20 mM G) in nondiabetic (ND) α-cells. This is reversed in α-cells from T2D donors, which display a β-cell-like phenotype where HG amplifies exocytosis and LG inhibits it. Using pharmacological antagonists of Ca2+ channels, we found that LG increases P/Q-type Ca2+ currents in human α-cells, which are specifically linked to glucagon exocytosis. Similar results were obtained from α-cells of HFD mice for 10-14 weeks, where α-cell exocytosis and glucagon secretion were both enhanced, while exocytosis shifted from a dependency on P/Q-type (α-cell-like) to L-type (β-cell-like) Ca2+ channels. Finally, given that the Ca2+ responsiveness of α-cells is variable (suggesting cell- to-cell heterogeneity) and the function of α-cells is dysregulated in diabetes, we applied combined computational approaches and single-cell RNA sequencing with patch-clamp analysis (patch-seq) to link single human α-cell function with transcriptomic profiles. We found distinct α-cell sub-populations in human islets that are either resistant to, or sensitive to, dysfunction in the form of a shift towards a more ’β-cell like’ functional phenotype in T2D. In all, we provide new information to understand normal function of α-cells and important determinants of glucagon secretion in health and diabetes.

Disclosure

X. Dai: None. J. Camunas Soler: None. L. Briant: None. A.F. Spigelman: None. Y. Hang: None. P. Rorsman: None. S. Kim: None. P. MacDonald: None.
CD19+IgM+ Cells from NOD Mice Demonstrate Enhanced Therapeutic Efficacy in Type 1 Diabetes Mellitus
Authors: VONBERG ANDREW D. , PIETROPAOLO MASSIMO
Published: June 2018

We describe a protective effect on autoimmune diabetes and a reduced destructive insulitis in NOD.scid recipients following splenocyte injections from diabetic NOD donors and sorted CD19+ cells compared to NOD.scid recipients receiving splenocytes alone. This protective effect was age-specific (only CD19+ cells from young NOD donors exerted this effect; p < 0.001). Furthermore, we found that CD19+IgM+ cells is the primary cell subpopulation of B cells that delayed adoptive transfer of diabetes mediated by diabetogenic T cells from NOD mice (p = 0.002). In fact, removal of IgM+ cells from the CD19+ pool did not result in diabetes protection. Blockade of IL-10 with neutralizing antibodies at the time of CD19+ cell co-transfers also abrogated the therapeutic effect, suggesting that IL-10 secretion was an important component of the protective effect. These results were strengthened by ex vivo incubation of CD19+ cells with IL-5, which resulted in enhanced IL-10 production and significantly delayed diabetes progression compared to controls (p = 0.0005). To the best of our knowledge, this is the first study demonstrating that CD19+IgM+ cells is the primary cell subpopulation of regulatory B cells delaying diabetes mediated by diabetogenic T cells from NOD mice. The potential to expand CD19+IgM+ cells, especially in response to increased stimulation using IL-5 or by pharmacologic agents, may be a new therapeutic option for type 1 diabetes.

Disclosure

A.D. Vonberg: None. M. Pietropaolo: None.