bluuebunny/crossref_metadata_2025 huggingface dataset:
311-LB: Gustatory Cortex Response to Sweet Taste Is Positively Correlated with Adiposity
Authors: CONSIDINE ROBERT V. , JANETSIAN-FRITZ SARINE S. , PICKLESIMER MAKAYLA D. , WAINSCOTT SARAH E. , DZEMIDZIC MARIO , KAREKEN DAVID A.
Published: June 2019

How sweet taste perception promotes excess caloric intake, obesity and diabetes is debated. There is little evidence for altered sweet taste in obesity, and adiposity does not predict sweet liking. However, overweight and obese subjects generally prefer high fat, sweet stimuli. The effect of adiposity on brain responses to sweet taste has not been systematically assessed, particularly in adults. In this ongoing study, 8 normal weight women (BMI 23.4±2.2 kg/m2, age 47±14 y) and 7 women with obesity (BMI 48.8±9.2 kg/m2, age 44±10 y), underwent functional magnetic resonance imaging (fMRI) on a Siemens 3T Magnetom Prisma using 32-channel head coil. fMRI assessed brain responses to 0.40M and 0.10M sucrose sprayed onto the tongue as compared to water (7 sucrose and 17 water trials in each 5:52 min long scan). Two scans were acquired at each concentration, where 0.40M and 0.10M scans alternated and the first scan sucrose concentration was counterbalanced across subjects. Across the whole sample, BOLD activation from [Sucrose (0.40M) > water] was detected (p<0.01, k>10) in gustatory insula, sensorimotor cortex/rolandic operculum, right ventral striatum, and bilateral posterolateral orbital cortex (the latter only in [Sucrose (0.10M) > water]). After including BMI as a covariate, a positive association of BMI and [Sucrose (0.40M) > water] contrast was present in the left gustatory insula area (peak, p<0.005), right rolandic operculum and sensorimotor cortex (ps<0.008). There were no negative correlations between BMI and the [Sucrose (0.40M) > water] contrast. BMI did not correlate with the [Sucrose (0.10M) > water] contrast. These preliminary findings suggest that women with obesity have greater responses in gustatory cortex to sweet taste compared to lean women. This is consistent with reports that overweight and obese subjects generally prefer sweet foods. The data might also suggest that gustatory cortex reactivity is altered by excess adiposity, possibly complicating diet compliance.

Disclosure

R.V. Considine: None. S.S. Janetsian-Fritz: None. M.D. Picklesimer: None. S.E. Wainscott: None. M. Dzemidzic: None. D.A. Kareken: None.

Funding

American Diabetes Association (1-18-ICTS-036 to R.V.C.)
311-OR: CREBZF as a Novel Target of Glucose Sensing Signaling in the Control of Adaptive Thermogenesis in the Adipose Tissue
Authors: CUI AOYUAN , LIU ZHENGSHUAI , MA FENGGUANG , BAI JINYUN , XUE YAQIAN , LIU YUXIAO , HU ZHIMIN , HAN YAMEI , ZHANG FEIFEI F. , GAO JING , GAO XIN , LI YU
Published: June 2019

Although glucose is generally considered to be required for generating heat during cold-induced nonshivering thermogenesis in the adipose tissue, whether it engages nutrient sensing pathways in the adipose tissue to negatively regulate thermogenesis and impairs metabolic homeostasis remains largely unknown. Here we report CREB/ATF bZIP transcription factor CREBZF as a key target of adipocyte glucose sensing signaling that exerts a negative effect on the adaptive thermogenesis in the adipose tissue. We found that CREBZF was significantly induced in inguinal white adipose tissue (iWAT) in response to cold exposure or β3AR agonist treatment, which was associated with an induced expression of glucose transporter genes such as GLUT1 and GLUT4. To elucidate the function of CREBZF, we generated adipose-specific CREBZF knockout (CREBZF FKO) mice. Compared with WT mice, CREBZF FKO mice exhibited enhanced browning of iWAT and thermogenic capacity in response to acute and chronic cold exposure. Moreover, CREBZF FKO mice were less cold sensitive. In the adipocyte, CREBZF was induced by glucose treatment, which was associated with increased acetylation of CREBZF. Interestingly, the protein stability of CREBZF was dynamically regulated by reversible acetylation mediated by transacetylase CREB-binding protein (CBP) and deacetylase HDAC. Deletion of CBP ameliorated glucose-induced CREBZF. Proteomic analysis was performed to identify potential acetylation sites of CREBZF. Furthermore, CREBZF associated with PGC-1α and inhibited its transcription activity. Together, we propose that in addition to its role as a fuel source to promote thermogenesis, glucose may act as a chemical signal to stimulate CREBZF activity and cause impaired browning and thermogenesis in the adipose tissue. This study uncovers an unknown mechanism of glucose sensing in the adipocyte that contributes to homeostasis of energy metabolism.

Disclosure

A. Cui: None. Z. Liu: None. F. Ma: None. J. Bai: None. Y. Xue: None. Y. Liu: None. Z. Hu: None. Y. Han: None. F.F. Zhang: None. J. Gao: None. X. Gao: None. Y. Li: None.

Funding

National Key Research and Development Program of China (2017YFC0909601); National Natural Science Foundation of China (31471129, 31671224); Chinese Academy of Sciences (KJZD-EW-G20-02); K.C. Wong Education Foundation (to Y.L.)
312-LB: Irisin, Meteorin-Like Protein, and Bone Remodeling Markers in T2D and Obesity
Authors: ABU-FARHA MOHAMED , CHERIAN PREETHI THOMAS , KHAIRI IRINA AL , JAMAL MOHAMMAD , AL-SABAH SULEIMAN , ALI HAMAD , DSOUZA CAROL , ALOTAIBI FATEMAH KULAIB , AL-ALI WALEED , AL-KHALEDI GHANIM MOHAMMAD , ABUBAKER JEHAD , AL-MULLA FAHD
Published: June 2019

Obesity and type 2 diabetes (T2D) are linked to metabolic dysregulation and chronic inflammation. Adipose tissue and skeletal muscles are key endocrine organs. Dysregulation in adipomyokines secreted by these organs could play a role in obesity-induced complications. Obesity, T2D and bone metabolism are interrelated. Our objective was to study the expression of two adipomyokines-Irisin and Meteorin-like protein (METRNL) in obesity and T2D and understand their association with various bone markers. Overall, 228 individuals were enrolled in this study, including 124 nondiabetic and 104 T2D . Plasma level of MTRNL and irisin were assessed by ELISA. Plasma level of METRNL and irisin were significantly higher in T2D (1263.5 ± 24.9 pg/ml and 623.0± 21.8 pg/ml respectively) compared to nondiabetic individuals (1198.5 ± 24.2 pg/ml for METRNL and 508.2 ± 15.3 pg/ml for irisin) p-Value < 0.05. METRNL and irisin were significantly higher in obese (1267.9 ± 24.8 pg/ml and 593.4 ± 18.1 pg/ml respectively) compared to non-obese individuals (1186.3 ± 24.2 pg/ml and 519.9 ± 19.1 respectively) p-Value < 0.05. Plasma level of bone markers Osteoactivin, Syndecan, OPG and SPARC were significantly higher in obese and T2D individuals compared to non-obese and nondiabetic individuals (P-values ≤0.01). Correlation analysis on nondiabetic population showed significant positive correlation between METRNL and irisin. Irisin showed a strong positive association with Osteoactivin, Syndecan, OPG, and SPARC. A strong positive association was observed between METRNL and Osteoactivin. The interplay between these bone markers is linked to bone remodeling. The strong positive association between the adipomyokines and bone markers suggests that, a dysregulation in the functional interaction between them may play a possible role in the development of bone related complications associated with obesity and T2D. We are currently conducting further experiments to understand mechanistically the significance of their interplay.

Disclosure

M. Abu-farha: None. P.T. Cherian: None. I. Al khairi: None. M. Jamal: None. S. Al-Sabah: None. H. Ali: None. C. Dsouza: None. F.K. AlOtaibi: None. W. Al-Ali: None. G.M. Al-Khaledi: None. J. Abubaker: None. F. Al-Mulla: None.

Funding

Dasman Diabetes Institute
317-LB: Optimal Weight Loss Effect of Short-Term Low Carbohydrate Diet with Calorie Restriction on Overweight/Obese Subjects in South China—A Multicenter Randomized Controlled Trial
Authors: SUN JIA , XU NINGNING , LIN NIE , WU PEILI , YUAN KUN , AN SHENGLI , ZHANG ZHEN , RUAN YUTING , ZHANG YING , XU GUGEN , MA WENJUN , LU ZEYUAN , CHEN XIAOMING , HUANG QIYA , ZHANG XIUWEI , LI YUZHONG , LI SHU , DENG GUOBAO , LIANG YONGQIAN , LIU LISHENG , CHEN HONG
Published: June 2019

Objective: This study aims to investigate whether there was a collaborative weight-loss effect or other metabolic benefits between low-carbohydrate (LCD) and calorie restriction (CR) on overweight/obese subjects from South China.

Methods: We enrolled 290 overweight/overweight adults with similar dietary habits from 13 hospitals in different areas of South China. Participants were randomly assigned into four diets for 12-week intervention, including normal diet, low-carbohydrate diet, calorie-restricted diet and calorie-restricted combined with low-carbohydrate diet. Covariance in quasi-factorial design was used to calculate the major effect as well as collaborative effect between low-carbohydrate and calorie restriction.

Results: A total of 259 participants completed the study for 12-week intervention. Participants in CR+LCD group lost weight by 7.99±3.57 kg, which was most significantly among 4 groups (P<0.001). Similarly, the results of body composition analysis showed that the visceral fat area and body fat rate was improved after intervention, especially in the CR+LCD group (P<0.001). Besides, fatty liver also alleviated substantially compared with control group (p=0.018). In addition, Significant effect of different diet intervention was shown on changes of triglycerides (P <0.001), which decreased by 0.73±1.26 mmol/L in the CR+LCD group. Furthermore, the results of covariance analysis showed no collaborative effects between calorie restriction and low carbohydrates (F=0.004, P=0.950).

Conclusions: Although our study indicated that low carbohydrate combined with calorie restricted diet have more significant effect on weight loss, it’s the first time to prove that no collaborative weight-loss effect of low carbohydrate diet and calorie restriction, which may possibly due to the carbohydrate based dietary habits in South China. (Registration number, ChiCTR1800015156).

Disclosure

J. Sun: None. N. Xu: None. N. Lin: None. P. Wu: None. K. Yuan: None. S. An: None. Z. Zhang: None. Y. Ruan: None. Y. Zhang: None. G. Xu: None. W. Ma: None. Z. Lu: None. X. Chen: None. Q. Huang: None. X. Zhang: None. Y. Li: None. S. Li: None. G. Deng: None. Y. Liang: None. L. Liu: None. H. Chen: None.
318-LB: Acanthosis Nigricans and Obesity among College Students on Guam
Authors: FLISCO VICTORIA D.C. , PAULINO YVETTE C.
Published: June 2019

Obesity has been associated to Acanthosis nigricans (AN), but there is a dearth in studies regarding this association in Pacific Islander populations. Data collected pertaining to health indicators of obesity in a cross-section of students—recruited to participate in the Pacific Islands Cohort on College Students (PICCS) during August to December 2017, was analyzed. The purpose of this analysis was to determine the relationship between obesity (obese and non-obese groups decided by using Body Mass Index (BMI)) and AN (presence/absence) of a non-random sample of 303 college students (CS) at the University of Guam. Of 299 CS, mean age was 21 ± 6 years and 45% were males and 55% were females. Anthropometric measurements were taken by undergraduate research students trained to use standardized stadiometer, weight scale, and measuring tape and ascertain AN presence/absence (neck area). Of 299 CS, height mean was 164 ± 32 cm and weight mean was 72 ± 20 kg. Of 294 CS, waist circumference mean was 88 ± 28 cm. The BMI mean of 299 CS was 27 ± 7. The relationship between presence/absence of AN in obese and non-obese groups was statistically significant, X2 (N = 282) = 16.37, (p = 0.000). Of 282 participants, 21.5% of the obese group had AN present while 5.1% of the non-obese group had AN present as well. These results may be further investigated and may assist in raising awareness regarding the association between obesity and AN presence/absence to the people of Guam; which may better assist in strategies of obesity screening.

Disclosure

V.D.C. Flisco: None. Y.C. Paulino: None.

Funding

National Institutes of Health
319-OR: Deficit of Retrograde Axonal Transportation Was Mediated via Activation of Macrophage RAGE Signaling in Experimental Diabetic Polyneuropathy
Authors: OSONOI SHO , MIZUKAMI HIROKI , TAKAHASHI KAZUHISA , KUDO KAZUHIRO , SANGO KAZUNORI , YAGIHASHI SOROKU
Published: June 2019

Activation of AGEs-RAGE signal at macrophage (Mφ) aggravates local inflammation in diabetic polyneuropathy (DPN). Mφ skewing toward pro-inflammatory phenotype (M1) is implicated in insulin resistance (IR) in fatty tissue, suggesting activation of RAGE at Mφ may similarly trigger IR in DPN. Generally, IR leads to axonal transport deficit in peripheral nerves. The aim of this study is to clarify the role of RAGE in the inflammation of DPN and its relationship to IR and axonal transport. Male C57BL/6 mice (W) and RAGE null mice (R) were recruited and rendered diabetic with streprozotocin (STZ) (D). DPN was confirmed by delay of nerve conduction velocities (NCVs) 8 weeks later of STZ injection. Polarization of Mφ in the sciatic nerve (SN) was determined by immunofluorescence (IF) and qPCR. IR of SN was evaluated by phospho (p)-AKT expression with stimulation of 5 unit insulin. Cell size of the dorsal root ganglia (DRG) neuron was morphometrically measured. For the retrograde axonal transport, DRG was quantitatively evaluated by IF for Fluoro-Gold (FG) 7 days after subcutaneous injection of FG into the hindlimb footpad. WD showed significant delay of NCVs (p<0.01, vs. W), while those were maintained in RD. Significant increase in the infiltration M1 in SN of WD (p<0.05, vs. W), whereas robust infiltration of anti-inflammatory Mφ (M2) was seen in RD (p<0.01, vs. R and WD). Increased nuclear translocation of NF-κB p65 and decreased pAKT expression were seen in SN of WD, but not in RD. The cell size in DRG neuron was significantly decreased in WD (p<0.05, vs. W), but that was similar in R and RD. The frequency of transported FG in DRG were significantly decreased in WD (p<0.05, vs. W), while maintained in RD. Taken together, our results suggest that RAGE induces inflammation in SN with skewing toward M1, which associates with IR and attenuation of the retrograde axonal transport in STZ DPN model. Those changes may contribute to the atrophic change of neuronal body in DRG of DPN.

Disclosure

S. Osonoi: None. H. Mizukami: None. K. Takahashi: None. K. Kudo: None. K. Sango: None. S. Yagihashi: None.

Funding

Japan Society for the Promotion of Science
32-OR: Coordination of Mitochondrial Uncoupling with Pyruvate Dehydrogenase Activation Safely Ameliorates Hyperglycemia through Preferential Glucose Oxidation
Authors: JIANG HAOWEN , LI JINGYA , LI JIA
Published: June 2019

Type 2 diabetes (T2D), which is characterized by hyperglycemia and insulin resistance, has become global epidemic. Uncoupling of mitochondria by chemical uncoupler, 2,4-dinitrophenol (DNP), is an efficient way to ameliorate hyperglycemia and insulin resistance. However, DNP use ceased in 1930s due to the systemic toxicities including hyperlactacidemia, hyperthermia and even death, which were mainly resulted from uncoupling actions induced excessive fat combustion and anaerobic glycolysis. To relieve the adverse effects derived from uncoupling activity, here we identified an effect-enhancing and toxicity-reducing way linking activation of pyruvate dehydrogenase (PDH) with DNP to T2D therapy. Activation of PDH by its classical activator, dichloroacetic acid (DCA), protected mice from DNP-derived hyperlactacidemia, hyperthermia and even death. Meanwhile, DCA combined with DNP further promoted glucose disposal in streptozotocin-induced hyperglycemic mice and enhanced insulin signaling in high-fat diet mice. Mechanistically, PDH activation corrected the excessive fatty acid oxidation and anaerobic glycolysis by DNP that was strongly associated with the adverse effects, and preferentially promoted glucose oxidation to improve hyperglycemia. Based on the beneficial effects of DNP combined with DCA, a novel compound possessing both mitochondrial uncoupling and PDH activation effects, named 6j, was identified and confirmed to promote glucose oxidation preferentially in vitro and in vivo. Therefore, our study suggested that combination of mitochondrial uncoupling and PDH activation might be a novel effective pharmacological approach for safely treating T2D.

Disclosure

J. Li: None. J. Li: None.

Funding

National Natural Science Foundation of China; Chinese Academy of Sciences; Shanghai Science and Technology Commission; K.C. Wong Education Foundation
320-LB: Metabolically Unhealthy Overweight Individuals Have High Lysophosphatide Levels, Phospholipase Activity, and Oxidative Stress
Authors: HAN YOUNGMIN , KIM MINJOO , JIN YOO HYE , HO LEE JONG
Published: June 2019

Background and Aims: Metabolically unhealthy overweight (MUO) individuals and metabolically healthy overweight (MHO) individuals differ in biomarkers of atherogenesis. Metabolomic approaches enable studies of the metabolic variables underlying these differences.

Methods: We determined the metabolomes in plasma samples from 34 MUO and 34 MHO individuals matched for sex, age, and body mass index (BMI) to identify potential metabolic markers or pathways associated with atherogenic traits.

Results: This analysis revealed that the MUO group had significantly higher levels of glycolic acid, 6 lysophosphatidylethanolamines (lysoPEs), and 12 lysophosphatidylcholines (lysoPCs). Although the two groups had similar total body fat percentages and lean body masses, MUO individuals had larger visceral fat areas (VFAs). They also had greater circulating lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and higher levels of oxidized low-density lipoprotein (ox-LDL) and urinary 8-epi-prostaglandin F2α (8-epi-PGF2α), reflecting higher risks for oxidative and lipid-related tissue damage. The following measures were positively correlated: VFA and ox-LDL; ox-LDL and Lp-PLA2 activity; and lysoPC, lysoPE, and 8-epi-PGF2α levels. Chronic plasma lysoPC increases were associated with atherogenic traits, higher levels of mean ox-LDL, 8-epi-PGF2α, Lp-PLA2, and visceral fat accumulation in MUO compared to MHO individuals.

Conclusions: This panel of plasma metabolites distinguishes MUO from MHO individuals and will enable future research on fat dysregulation and obesity.

Disclosure

Y. Han: None. M. Kim: None. H. Yoo: None. J. Lee: None.

Funding

National Research Foundation of Korea (NRF-2017R1C1B2007195, NRF-2012M3A9C4048762)
322-LB: Balancing Act: Atf6alpha Plays Positive and Negative Roles in the Pancreatic Beta-Cell Stress Response
Authors: SHARMA ROHIT B. , DARKO CHRISTINE O. , GABLASKI BRIAN , ALONSO LAURA C.
Published: June 2019

Diabetes is caused by loss or dysfunction of beta cells. Endoplasmic reticulum (ER) stress has been implicated in beta cell loss in both type 1 and type 2 diabetes. Hyperglycemia and increased insulin demand cause ER stress, activating the unfolded protein response (UPR). The initial beta cell response to stress increases cell number through proliferation, but prolonged stress leads to beta cell demise. Precisely characterizing the beta cell UPR could lead to a better understanding of how beta cells are lost in diabetes. In this study, mouse primary islet cells were treated with ER stressors Thapsigargin (Tg) or tunicamycin (Tm), which activate all three arms of the UPR: Atf6, Ire1 and Perk. In mouse beta cells, Tg (1uM) activated the Ire1 (tested by splicing of Xbp1) and Perk (tested by phosphorylation of eIF2-alpha) pathways within 1 hour, and induced Atf6 transcriptional targets by 4 hours. Specific roles of Atf6 in the beta cell ER stress response are not well understood, with both positive and negative roles reported in the literature. Therefore, we tested how Atf6 participates in the acute beta cell response to severe stress, including UPR pathway activation and cell death. We found that knockdown of Atf6 leads to a blunted ER stress response, with delayed activation of Atf6 target genes Grp78, Hyou1 and Pdia4, but not HerpUD1. The Ire pathway was also negatively impacted by Atf6 knockdown, with blunted activation of Xbp1 target genes Sec24D, Erdj4 and Ssr3. Perk pathway activation was not affected by knockdown of Atf6 (p-eIF2-alpha, Chop mRNA). Finally, acute knockdown of Atf6 increased beta cell death even in the absence of stress (n=4) and made beta cells more prone to stress-mediated cell death (n=2). On the other hand, overexpression of ATF6 had no impact on Tg-mediated beta cell death suggesting Atf6 was not sufficient to protect (n=2) against irreversible ER stress. In sum, our data suggest a nuanced role for Atf6 in the beta cell stress response and the cell fate choice between life and death.

Disclosure

R.B. Sharma: None. C.O. Darko: None. B. Gablaski: None. L.C. Alonso: None.

Funding

National Institutes of Health (R01DK114686); National Institute of Diabetes and Digestive and Kidney Disease (R01DK113300)
326-LB: BCL-xL/BCL2L1 Is a Critical Anti-Apoptotic Protein that Suppresses BAK to Promote Pancreatic Specification from Human Pluripotent Stem Cells
Authors: SAI WENG LOO LARRY , TEO ADRIAN , GHOSH SOUMITA , ALVIN PURNOMO SOETEDJO ANDREAS , NGUYEN LINH , KRISHNAN VIDHYA G. , HOON SHAWN
Published: June 2019

The differentiation of human pluripotent stem cells (hPSCs) into desired cell types such as the pancreatic cells involve cellular proliferation and apoptosis during cell fate transitions. Although different rates of cell growth and death are typically observed during differentiation, its implications for pancreatic tissue formation in humans remain unclear. Here, we profiled the expression of BCL-2 family of proteins during pancreatic specification from hPSCs and observed an upregulation of BCL- XL, downregulation of BAK and corresponding downregulation of cleaved CASP3 representative of apoptosis. The inhibition or downregulation of BCL-xL reciprocally increased apoptosis and resulted in a decreased gene expression of pancreatic markers despite a compensatory increase in companion anti-apoptotic protein BCL2. RNA-Seq analyses revealed a downregulation of multiple metabolic genes upon inhibition of BCL-xL function. Bioenergetics assays then revealed a broad downregulation of both glycolysis and oxidative phosphorylation when BCL-xL function was inhibited.

In conclusion, we have identified anti-apoptotic protein BCL-xL to be necessary for suppressing the expression of pro-apoptotic protein BAK to facilitate proper pancreas formation in human cells. This is the first report that links a member of the BCL-2 family with pancreatic specification. Therefore, modulation of these two BCL-2 family of proteins can potentially increase the survival and robustness of pancreatic progenitors that ultimately defines human pancreatic beta cell mass and function.

Disclosure

L. Loo: None. A. Teo: None. S. Ghosh: None. A. Soetedjo: None. L. Nguyen: None. V.G. Krishnan: None. S. Hoon: None.

Funding

Agency for Science, Technology and Research; Institute of Molecular and Cell Biology
326-OR: A Novel Machine Learning Analysis of Brain Multimodal Magnetic Resonance Imaging Classifies Painful Diabetic Neuropathic Pain Severity with High Accuracy
Authors: SELVARAJAH DINESH , TEH KEVIN , SLOAN GORDON P. , SHILLO PALLAI RAPPAI , WILKINSON IAIN D. , TESFAYE SOLOMON
Published: June 2019

Using advanced MR neuroimaging we have demonstrated altered brain structure and functional connectivity that could serve as a potential Central Pain Signature (CPS) for painful diabetic neuropathy (DN). However, the key challenge is how to apply this potential biomarker for routine diagnostic purposes. The aim of this study was to examine if the CPS can accurately classify painful DN patients based on a patient’s pain severity.

Methods: 53 painful DN patients underwent detailed clinical and neurophysiological assessments. The NTSS-6, a validated questionnaire that measures both the frequency and the intensity of neuropathic pain was used to assess pain severity. Patients were divided into high pain (NTSS-6 score >7) and low pain (<7). All subjects underwent brain volume and resting state functional MRI at 3T. We used novel and validated machine learning algorithms [support vector machines] to differentiate pain severity based on functional connectivity and structural/volume data. A nested cross validation method was used to determine the accuracy (sensitivity and specificity).

Results: There was no age or gender difference (p > 0.05) between the high and low pain groups. The CPS classified painful DN patients based on their pain intensity with 94% accuracy (AUC 0.98). The positive and negative predictive values were 0.80 and 1.00 respectively. The F1 scores for predicting high pain and low pain were 0.89 and 0.96 respectively. Brain regions identified as the best classifier were the left and right postcentral gyri, thalami, and anterior and posterior cingulate cortices.

Conclusions: This novel study demonstrates that a simple, 15-minute MR brain scan can accurately classify painful DN patients according to pain intensities with high accuracy. This assessment tool has a great potential as a biomarker of diabetic neuropathic pain and may serve as a target for future trials of analgesic compounds for painful DN.

Disclosure

D. Selvarajah: None. K. Teh: None. G.P. Sloan: None. P. Shillo: None. I.D. Wilkinson: None. S. Tesfaye: Advisory Panel; Self; Mitsubishi Tanabe Pharma Corporation, WÖRWAG Pharma. Speaker's Bureau; Self; AstraZeneca, Merck & Co., Inc., NAPP Pharmaceuticals Limited, Neurometrix, Novo Nordisk Inc., Pfizer Inc. Other Relationship; Self; Impeto Medical.

Funding

European Foundation for the Study of Diabetes
328-LB: Characteristic Features in the Intraislet Ductal Cells of Diabetic C414A-CRY1 Transgenic Mice
Authors: OKANO SATOSHI , YASUI AKIRA , KANNO SHIN-ICHIRO , SATOH KENNICHI , IGARASHI MASAHIKO , NAKAJIMA OSAMU
Published: June 2019

The transgenic mice ubiquitously expressing the zinc-binding site-mutant CRY1 (C414A-CRY1) show early onset diabetes mellitus similar to human MODY characterized by β-cell dysfunction. In the Tg mice with age, atypical ductal structures emerged inside islets, suggesting that islet cells can transdifferentiate to duct-like cells as we have reported at ADA Scientific Sessions in 2017 and 2018. To explore further molecular features of intra-islets ducts, we conducted staining experiments for Dolichos biflorus agglutinin (DBA) lectin in the pancreatic sections of well-matured mice. The results showed that high levels of staining for DBA lectin were observed in normal ducts of both wild type and Tg mice. In contrast, majority of intra-islet ductal structures especially still not fully developed small ones were weakly positive for DBA lectin, suggesting immaturity for ductal functions of the intra-islet ductal cells. Furthermore, the variation of the staining levels for DBA lectin in intra-islet ductal cells was evidently larger than that in other ductal cells, indicating heterogeneity in the cell functions among intra-islet ductal cells. We also found that remarkably high accumulation of FAM98A, an RNA-binding protein whose functions are still not decisive, was observed in the intra-islet ducts in the Tg mice. In normal ducts, moderate staining of FAM98A was observed. As for pancreatic endocrine cells, although as a whole the immunostaining levels were much weaker than those of acini and ductal cells, discernable staining of FAM98A is detected in both α and β cells of islets. Taken together, our results indicate that intra-islet ductal cells have unique feature distinct from normal ductal cells, and suggest that FAM98A may play important roles in the generation of atypical ductal cells from non-ductal cells in the islet.

Disclosure

S. Okano: None. A. Yasui: None. S. Kanno: None. K. Satoh: None. M. Igarashi: None. O. Nakajima: None.

Funding

Japan Society for the Promotion of Science; Tohoku University
330-LB: Using Human Induced Pluripotent Stem Cell-Derived Organoids to Identify New Pathologies in Patients with PDX1 Mutations
Authors: KRISHNAMURTHY MANSA , BRODA TAYLOR R. , ZHANG XINGHAO , PALERMO JOSEPH J. , THOMAS INAS H. , HEIDER AMER , STEIEN DANA B. , DAUBER ANDREW , WELLS JAMES
Published: June 2019

Pancreas and gastrointestinal (GI) tract development is guided by several transcription factors, including Pancreatic and duodenal homeobox gene-1 (PDX1). While it is well known that PDX1 is essential for pancreas development, its role in GI development and function in humans has not been investigated. We have identified two patients with a homozygous point mutation in PDX1 (c.188delC(p.P63fs)), causing total loss of protein function. These patients have additional GI complications however endoscopy and histological analysis of gastric and ?intestinal biopsies did not? reveal any pathologies. We used patient derived GI organoids from induced pluripotent stem cells (iPSCs) as a novel diagnostic approach and identified a myriad of undiagnosed GI pathologies. Analyses of human antral gastric organoids (HAGO) using immunofluorescence staining demonstrated a loss of gastric marker? claudin18 (CLDN18) and increased intestinal villin expression in PDX1-null? organoids, signifying that regions of the antrum are converting to an intestinal?phenotype. Similarly, human intestinal organoids (HIO) demonstrated a loss of intestinal marker ?Cadherin17 and an increase in gastric marker? CLDN18, indicating that regions of the intestine are undergoing gastric metaplasia. We also observed an increase in parietal cells in HAGOs, a lack of gastrin hormone in HAGO, and an increase in mucin production in HIOs. Based on this data we re-analyzed antral and duodenal biopsies of both patients and confirmed gastric and intestinal metaplasia increased parietal cells, decreased gastrin and increased mucin production. Because of our findings, these patients will have additional screening to monitor for development of gastric and intestinal cancer. This clearly demonstrates the utility of organoids in improving patient diagnoses and developing new clinical treatment plans.

Disclosure

M. Krishnamurthy: None. T.R. Broda: None. X. Zhang: None. J.J. Palermo: None. I.H. Thomas: None. A. Heider: None. D.B. Steien: None. A. Dauber: Consultant; Self; Novo Nordisk Inc. Research Support; Self; Novo Nordisk Inc. J. Wells: None.

Funding

American Diabetes Association (1-19-PDF-036 to M.K.)
331-OR: Glycemic Index and Postprandial Blood Glucose Excursions, Insulin Requirements, and Hunger in T1D
Authors: LENNERZ BELINDA S. , SIMONSON DONALD C. , STEIL GARRY M. , LUDWIG DAVID S.
Published: June 2019

High compared to low glycemic index (GI) foods elicit larger glycemic and insulinemic excursions, and are associated with lower satiety. However, it is unclear whether the satiety effect is attributable to differences in glycemia or insulinemia, and whether insulin delivery in individuals with T1D could be optimized for satiety per se. Fifteen men with T1D, BMI 25 (SD 3) kg/m2, aged 23 (5) years, HbA1c 7.4 (0.7)% underwent three experimental conditions in a randomized cross-over design: High GI, high insulin (HGI/HI): meal GI of 84 with intravenous insulin (IVI) to maintain euglycemia; Low GI (LGI): meal GI of 37 with IVI to maintain euglycemia (comparison condition); High GI, low insulin (HGI/LI): high GI meal as above with IVI matched to LGI. Test meals provided 25% of daily calories (60% carbohydrate, 15% protein, 25% fat). IVI was adjusted using a PID algorithm with blood glucose measurements every 5 minutes for 4.5 hr. When using matched insulin doses, blood glucose area under the curve (AUC) was 789 (145) vs. 493 (48) mg/dl*h (p<0.001) for HGI/LI vs. LGI. To maintain euglycemia (HGI/HI vs. LGI), 25 (9) vs. 17 (5) units of insulin were needed (p=0.005). Late postprandial (3.5-4.5 hr) free fatty acid (FFA) concentrations were higher for HGI/HI (0.62 [0.31] mmol/L) vs. LGI (0.26 [0.09] mmol/L p=0.008). Hunger was lower at peak glycemia (1 hr) for HGI/HI vs. LGI (2.3 vs. 3.2 on a 0-10 scale, p=0.01), but was greater in the late postprandial phase after either HGI/HI or HGI/LI vs. LGI (6.3 [p=0.05] or 6.3 [p=0.03] vs. 5.3, respectively). In a controlled feeding study, a high GI meal was associated with a 1.5-fold higher insulin requirement to obtain similar glycemia, or a 1.6-fold higher glucose AUC when using the same insulin dose. The high GI meal also increased late postprandial hunger regardless of insulin dose, and resulted in a greater rise in FFA (high insulin condition). These meal effects, with or without aggressive insulin management, may predispose to cardiovascular risk, metabolic dysfunction or weight gain.

Disclosure

B.S. Lennerz: None. D.C. Simonson: Stock/Shareholder; Self; GI Windows, Inc. Stock/Shareholder; Spouse/Partner; Phase V Technologies, Inc. G.M. Steil: Consultant; Self; Eli Lilly and Company, Profusa, Inc. D.S. Ludwig: Other Relationship; Self; Various publishers.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (K12DK094721, K24DK082730)
332-OR: Determining the Impact of Additional Macronutrients on the Glycemic-Insulin Dynamic Model
Authors: JIANG BOYI , ZHONG YUXIANG , AGRAWAL PRATIK , CORDERO TONI L. , VIGERSKY ROBERT
Published: June 2019

Background and Aims: Though many studies report that macronutrients such as lipids and protein significantly impact the absorption rate of carbohydrates and insulin requirement, there has not been wide adoption of simulators that take macronutrients into account. This may likely be due to lack of access to macronutrient records. This study evaluated the introduction of additional macronutrient components to a carbohydrate-only simulator.

Methods: Data uploaded between 05/15/2018-10/15/2018 by 114 individuals aged 38.1±14.2 years who used the Guardian Connect continuous glucose monitoring system with the Sugar.IQ application were analyzed. Information on 10 major macronutrients was collected on 4213 meals. Models fitting using 1) Only carb as input (“Carb-only”) and 2) Carbohydrate, lipids and protein as inputs (“Multi-macro”) were conducted and compared using the Mean Average Percent Error (MAPE) and Error Grid Analysis (EGA).

Results: The “Multi-macro” model predicts sensor glucose (SG) outcome 15% more accurately than the “Carb-only” model (MAPE: 11.3% vs. 13.5%, p<0.05). The “Multi-macro” model also improved points within the Clarke A region by 6.1% (EGA: 81.6% vs. 75.5%, p<0.05).

Conclusion: Lipids and protein are macronutrients that should be considered when creating glycemic-insulin dynamic models, as both appear to significantly impact the absorption of carbohydrates and improve SG prediction accuracy surrounding meal intake.

Disclosure

B. Jiang: Employee; Self; Medtronic. Y. Zhong: None. P. Agrawal: Employee; Self; Medtronic MiniMed, Inc. Stock/Shareholder; Self; Medtronic. T.L. Cordero: Employee; Self; Medtronic. R. Vigersky: Employee; Self; Medtronic MiniMed, Inc.
34-OR: Maladaptive Increases in Skeletal Muscle Ketone Body Oxidation Contribute to Dysglycemia in Mice Subjected to Experimental Obesity
Authors: BATRAN RAMI AL , GOPAL KESHAV , CHAHADE JADIN J. , USSHER JOHN R.
Published: June 2019

Type 2 diabetes (T2D) is a rapidly growing health epidemic, with intense investigation on whether perturbations in skeletal muscle carbohydrate and fatty acid metabolism contribute to obesity-induced insulin resistance and/or T2D. Conversely, whether perturbations in skeletal muscle ketone body oxidation take place in the pathology of obesity-induced insulin resistance/T2D remains unclear. Therefore, our goal was to investigate potential alterations in ketone body metabolism during the pathology of obesity-induced T2D, and to elucidate whether such changes are adaptive or maladaptive. C57BL/6J mice were subjected to low-fat (lean) or high-fat (obese) diet supplementation for 12 weeks. Obese mice exhibited glucose intolerance, which was associated with decreased circulating βOHB and elevated circulating glucose levels. In addition, obese mice demonstrated a marked increase in mRNA and protein expression of succinyl CoA:3-ketoacid CoA transferase (SCOT), the rate limiting enzyme of ketone body oxidation, within gastrocnemius muscles, which was associated with an increase in SCOT enzymatic activity. Of interest, SCOT activity requires succinyl-CoA as a substrate, which is also required for protein succinylation. Accordingly, siRNA knockdown of Oxct1 augmented lysine succinylation, whereas Oxct1 overexpression abolished lysine succinylation. Additionally, Oxct1 knockdown in C2C12 myotubes increased AMPK phosphorylation, which was recapitulated in mice with an Oxct1 skeletal muscle-specific deficiency (Oxct1SkM-/-). Intriguingly, Oxct1SkM-/- mice were protected against obesity-induced dysglycemia and insulin resistance. Our results suggest that ketone body metabolism is augmented in skeletal muscle during the pathology of obesity, which may contribute to dysglycemia and insulin resistance in T2D via potentially modifying protein succinylation and/or AMPK activity.

Disclosure

R.Al batran: None. K.Gopal: None. J.J.Chahade: None. J.R.Ussher: None.
342-OR: The Feasibility and Acceptability of a Diabetes Survival Skills Intervention for Incarcerated Persons Transitioning to the Community
Authors: REAGAN LOUISE A. , LAGUERRE RICK A. , GALLAGHER COLLEEN
Published: June 2019

Community evidenced-based diabetes self-management education (DSME) models have not been examined for feasibility, acceptability or effectiveness among incarcerated persons transitioning to independent DSM. In a non-equivalent control group design with repeated measures, we examined the feasibility, acceptability and preliminary effect of a 6-week 1-hour per week diabetes survival skills (DSS) intervention on diabetes knowledge, distress, self-efficacy and outcome expectancy for transitioning incarcerated males. Of the 92 participants (84% T2D, 83% using insulin, 40% black, 20% white,30% Latino, 66% high school or less, mean age 47.3 years, 84% length of incarceration ≤4 years), 41 completed the study (22 Control/19 intervention (TX). One-way repeated measures ANOVAs revealed significant changes in diabetes knowledge within each group (C, p=.002; TX, p=.027) at all time points; however, a two-way repeated measures ANOVA showed no differences between groups. Additionally, both groups showed improvement in diabetes-related distress and outcome expectancy with the treatment group experiencing greater and sustained improvement at the 12-week time point. Analysis of focus group data (Krippendorf) revealed acceptance of and enthusiasm for the DSS training and low literacy education materials, and the need for skill demonstration, and ongoing support throughout incarceration and before release. Our results highlight the complexity of working with incarcerated populations. We observed information-gathering strategies among incarcerated persons that may account for overall increases in diabetes knowledge. Due to high attrition, the power to detect effects was limited. Yet, results suggest that the intervention is feasible and acceptable with an increased sample size and refined recruitment procedure.

Disclosure

L.A. Reagan: None. R.A. Laguerre: None. C. Gallagher: None.

Funding

American Nurses Foundation
348-OR: Impact of Endocrinology ECHO on Utilization in Medicaid Patients with Complex Diabetes
Authors: BLECKER SAUL , LEMIEUX EMILY , PAUL MAGGIE , BERRY CAROLYN , BOUCHONVILLE MATTHEW F. , HAGER BRANT , ARORA SANJEEV , BILLINGS JOHN
Published: June 2019

Background: Poorly controlled diabetes can be difficult to manage, particularly in high-risk patients and in settings without an endocrinologist. Project ECHO is a case-based learning and tele-mentoring model that connects primary care providers (PCPs) with specialists. We evaluated the impact of the ECHO model on healthcare utilization and care for Medicaid patients with diabetes in New Mexico (NM).

Methods: Between January 2015 and April 2017, patients with complex diabetes from 10 federally qualified health centers in NM were recruited to receive diabetes care from a PCP and community health worker upskilled via weekly Endo ECHO sessions. We included patients with 6 months of continuous enrollment in the NM Medicaid claims database and performed 5:1 propensity matching of participants to comparison Medicaid beneficiaries. We used a difference-in-difference (DID) approach to compare utilization and processes of care between study participants and controls.

Results: Of 539 Medicaid patients enrolled in Endo ECHO, 235 met inclusion criteria and were successfully matched to comparison patients. Outpatient visits increased for study participants in the pre- versus post-enrollment period (801 vs. 1056 per 1,000 patients/month) but not for comparators (785 vs. 680 per 1000 patients/month, DID p<0.01). We observed no difference in inpatient (131 vs. 134 per 1,000 patients/month) or ED utilization (24 vs. 26 per 1,000) in the pre- versus post-enrollment period for study participants. The intervention was associated with increased metformin utilization (DID 15.2%, p=0.01), but had no effect on expenditures, statin utilization, or ACE inhibitor/ARB utilization for hypertension.

Discussion: Patient enrollment in Endo ECHO was associated with increased outpatient utilization and increased compliance with some, but not all, process measures. No impact was observed on hospitalizations or ED visits. Ongoing evaluation will determine the impact of the ECHO model on clinical outcomes.

Disclosure

S. Blecker: Advisory Panel; Self; Medtronic. E. Lemieux: None. M. Paul: None. C. Berry: None. M.F. Bouchonville: None. B. Hager: None. S. Arora: None. J. Billings: None.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust
349-OR: Major Cardiovascular Outcomes among At-Risk High-Deductible Health Plan Members
Authors: FRANK WHARAM J. , ZHANG FANG , LU CHRISTINE , HERNANDEZ ADRIAN F. , WALLACE JAMIE , ROSS-DEGNAN DENNIS , NEWHOUSE JOSEPH P.
Published: June 2019

High-deductible health plan (HDHP) effects on major cardiovascular outcomes are unknown. We studied a 2004-2014 national sample of 63,363 HDHP members aged 40-64 years with diabetes, cardiovascular disease, hypertension, or hyperlipidemia, who were continuously enrolled for 1 year in a low-deductible (≤$500) plan followed by 3 years in a HDHP (≥$1000) after an employer-mandated switch. We matched HDHP members to 539,445 contemporaneous controls who had the same cardiovascular risk factors and whose employers offered only low-deductible plans. Using a controlled interrupted-time-series design, we analyzed cumulative rates of myocardial infarction, stroke, and amputation. We modelled weighted cumulative event rates using aggregate-level segmented regression. HDHP members experienced no detectable absolute change in myocardial infarction (-0.9 events per 10,000 members, 95% confidence interval: -2.7, 0.8) at 3 years of follow-up relative to the end of the baseline year compared to controls. Stroke and amputation declined by 3.4 (-4.0, -2.9) and 6.7 (-9.0, -4.4) events per 10,000 members, respectively, among HDHP members versus controls over the same period. At-risk patients who were switched to HDHPs did not experience increases in major cardiovascular outcomes over 3 follow-up years. Future research should follow patients longer and examine outcomes among low-income populations.

Disclosure

J. Wharam: None. F. Zhang: None. C. Lu: None. A.F. Hernandez: Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation. Research Support; Self; AstraZeneca, GlaxoSmithKline plc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation. J. Wallace: None. D. Ross-Degnan: None. J.P. Newhouse: Board Member; Self; Aetna Inc.

Funding

National Institutes of Health
35-OR: Physiological Insulin Regulates Alternative mRNA Splicing in Liver and Muscle at Multiple Levels
Authors: BATISTA THIAGO M. , CAI WEIKANG , BRANDAO BRUNA , KAHN C. RONALD
Published: June 2019

Alternative splicing of mRNAs contributes importantly to proteome diversity and tissue identity. Work by us and others have suggested that alternative splicing and the spliceosome are dysregulated in diabetes, but the role of this under physiological conditions is not known. To gain more insight into alternative splicing regulation by physiological insulin in vivo, we performed RNA-seq of mRNAs in skeletal muscle and liver from mice undergoing euglycemic clamp with physiological insulin for 3h. In both tissues, insulin significantly regulated over 1000 transcripts, including known pathways related to glucose and fatty acid metabolism. In addition, insulin also regulated many components involved in mRNA splicing, including mRNAs of ribonucleoprotein particles (RNP) spliceosome components, splicing factors and CLK splicing kinases, many of which were down-regulated by insulin. This was associated with significant changes in 102 and 63 alternatively spliced mRNAs in muscle and liver in a variety of gene classes including those encoding proteins involved in tissue-structure, mitochondrial function, autophagy and transcription. Insulin also regulated the spliceosome at the post-translational level, with a 1.5- to 2-fold increase in the phosphorylation of the U2-RNP component SF3B1 and the splicing factor SRSF5. Phosphorylation of the splicing factors SRSF4, SRSF5 and SRSF6 was also increased by insulin in C2C12 myotubes, and this was prevented by pretreatment with the CLK inhibitor TG003. Myotubes treated with TG003 also showed dose-dependent decrease of insulin-stimulated glucose uptake and increased FCCP-uncoupled respiration. Taken together, these data demonstrate that regulation of alternative splicing at multiple mechanistic levels integrates the physiological response to insulin. Disruption of insulin signaling to the spliceosome could potentially shift isoform balance of metabolically relevant proteins and contribute to insulin resistance.

Disclosure

T.M. Batista: None. W. Cai: None. B. Brandao: None. C. Kahn: Advisory Panel; Self; MedImmune. Board Member; Self; Kaleido Biosciences. Consultant; Self; AntriaBio, Inc., Cobalt Therapeutics, Flagship Pioneering. Research Support; Self; Alnylam.

Funding

National Institutes of Health
351-OR: Continuous Glucose Monitoring in Pregnant Women with Type 1 Diabetes: Cost-Effectiveness Analyses of the CONCEPTT Randomized Controlled Trial
Authors: MURPHY HELEN R. , FEIG DENICE , PATEL NASHITA
Published: June 2019

Aims: To evaluate the cost-effectiveness of continuous glucose monitoring (CGM) in type 1 diabetes (T1D) pregnancy.

Methods: Decision analytical models to compare T1D antenatal care with and without use of CGM. Probabilities, maternal health state utilities and healthcare resource utilization were obtained from individual patient-trial data. Costs and neonatal health state utilities were obtained from the literature. Primary outcome of interest was neonatal quality adjusted life years (QALY). The willingness to pay threshold was £30,000/QALY.

Results: Direct costs of CGM use were £2,045. From a neonatal perspective, CGM during was cost saving (- £2,613), and effective (75.43 vs. 73.77 QALYs), with an incremental cost effectiveness ratio (ICER) - 1,570.57/QALY (Figure 1). Sensitivity analyses demonstrated robustness of the model across ranges of variables including varying NICU care for preterm and term neonates, and health state utilities. From a maternal perspective, CGM was associated with additional cost (£330), but remained effective; QALYs 61.33 vs. 61.27 and ICER £5,508.00/QALY. CGM remained efficacious and the favored treatment strategy in the sensitivity analyses performed.

Conclusions: CGM use during T1D pregnancy is cost saving from a neonatal perspective and associated with improved cost effectiveness for both mother and neonate.

Disclosure

H.R. Murphy: Advisory Panel; Self; Medtronic MiniMed, Inc. D. Feig: Advisory Panel; Self; Medtronic. Speaker's Bureau; Self; Medtronic. N. Patel: None.

Funding

JDRF (17-2011-533); JDRF Canadian Clinical Trial Network (80-2010-585)