bluuebunny/crossref_metadata_2025 huggingface dataset:
1330-P: Ethnic Differences in Insulin Clearance: Relationship with Admixture Scores, Diet, and Physical Activity
Authors: PICCININI FRANCESCA , GOWER BARBARA , FERNANDEZ JOSE R. , BERGMAN RICHARD N.
Published: June 2019

Recent studies showed that hepatic insulin clearance is lower in African Americans (AA) than European Americans (EA). The aim of this work is to elucidate the possible genetic/epigenetic versus lifestyle causes. The frequently-sampled intravenous glucose tolerance test (FSIGT) was performed in 142 children [38 AA, 69 EA, 28 HA (Hispanic Americans), both sexes, age 7-13 years, mean BMI = 19 kg/m2, basal plasma glucose = 99 mg/dL, insulin = 78 pmol/L, C-peptide = 511 pmol/L]. Mathematical modeling provided hepatic (FEL) and extra-hepatic (CLP) insulin clearance values. Two-way analysis of covariance was done (groups: sex and ethnicity, covariates: age, Tanner stage and body fat from DXA). Data are mean (standard error). FEL was lower in AA than EA (18% (2%) vs. 31% (3%), p=0.001), but no difference was observed in HA. CLP was not different among ethnicities. Partial correlation was calculated between FEL, CLP and 1) diet composition (energy intake, % of calories from carbohydrate, fat, protein), 2) physical activity (PA: light, moderate, hard, very hard), 3) admixture scores (African, European, Amerindian). FEL was positively correlated with the European admixture score (r=0.3, p<0.01), and negatively with the African one (r=-0.3, p=0.001); FEL was negatively associated with moderate PA in all the subjects (r=-0.2, p=0.01), and with hard PA in EA (r=-0.4, p<0.01). CLP was positively correlated with moderate PA in AA (r=0.4, p=0.02). Concerning diet, FEL was only correlated with % of calories from fat in EA (r=0.3, p=0.01). Because of its negative association with the African admixture, but positive with the European one, the lower hepatic insulin clearance might be genetic in origin, possibly resulting in hyperinsulinemia and diabetes risk. Our data also suggest that detrimental effects of lower insulin clearance might be mitigated by lifestyle changes such as exercise: moderate PA in AA could lead to a normalization of insulinemia by increasing extra-hepatic insulin clearance.

Disclosure

F. Piccinini: None. B. Gower: None. J.R. Fernandez: None. R.N. Bergman: Consultant; Self; Zafgen, Inc.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (DK067426); Nutrition Obesity Research Center (DK56336); National Institutes of Health (M01RR00032)
1334-P: Structural Brain Differences between Adolescents with Type 2 Diabetes and Obese Controls
Authors: REDEL JACOB M. , DIFRANCESCO MARK W. , LEE GREGORY R. , DOLAN LAWRENCE M. , SHAH AMY SANGHAVI
Published: June 2019

Recent studies have shown differences in brain structure between adolescents with type 2 diabetes (T2D) and their nondiabetic peers. Compared to obese controls (OCs), global white matter (WM) and regional gray matter (GM) differences have been found. Our aim was to evaluate further for global and regional differences in GM, WM, and parenchymal (GM and WM combined) brain volume between youth with T2D and nondiabetic OCs. We compared 11 youth with T2D (mean age 17.1 ±2.0 years, mean HbA1c 8.6 ±2.5%) and 11 age, race and sex similar OCs (mean HbA1c 5.3 ±0.2%). Participants underwent high-resolution T1-weighted MRI scans, analyzed using voxel-based morphometry. Tissue volumes were normalized across participants by dividing by each individual’s intracranial volume (ICV). The normalized global volumes were compared between the two groups, and statistical significance was determined at p<0.05. For regional analyses, statistical significance for each voxel was established at p <0.05 using a family-wise error rate procedure, reporting only clusters with ≥200 contiguous voxels. Compared to OCs, adolescents with T2D had significantly lower parenchymal brain volume (parenchymal/ICV ratio 0.843 in T2D vs. 0.856 in OC, p=0.04). There were no significant differences in global GM (GM/ICV ratio 0.514 in T2D vs. 0.517 in OC, p=0.76) or global WM (WM/ICV ratio 0.329 in T2D vs. 0.340 in OC, p=0.10), although global WM did trend toward significance. In addition, there were 3 brain regions in the T2D group that had lower GM volume than OCs, and 2 regions in which the T2D group had greater GM volume. Adolescents with T2D show significantly lower parenchymal brain volume compared to age, race, and sex similar OCs. This difference may be attributable to lower WM volume, but a larger sample size is needed. No global GM differences were found between groups, but regional differences in GM were identified. These data support the hypothesis that, independent of obesity, structural brain differences may exist in adolescents with T2D.

Disclosure

J.M. Redel: None. M.W. DiFrancesco: None. G.R. Lee: None. L.M. Dolan: None. A.S. Shah: None.

Funding

Endocrine Fellows Foundation; Cincinnati Diabetes and Obesity Center; Cincinnati Children's
1341-P: Association of NAFLD with Diabetes and the Impact of Waist Circumference and BMI Changes in Subjects with Prediabetes
Authors: LEE JIWOO , KANG YU MI , PARK JOONG-YEOL , LEE WOO JE
Published: June 2019

Background: Nonalcoholic fatty liver disease (NAFLD) and prediabetes are well-known risk factors for diabetes. However, few studies have been performed about the risk of diabetes in subjects with prediabetes in the presence of NAFLD. In addition, little information was known about the impact of waist circumference (WC) and body mass index (BMI) changes on the development of diabetes. In this study, we examined the association of NAFLD with diabetes and the impact of WC and BMI changes in subjects with prediabetes.

Methods: We enrolled 6,240 subjects with prediabetes who underwent general routine health evaluations in 2007 and returned for follow-up examinations in 2008 -2013 at least one time. Subjects were stratified by WC and BMI changes into three groups. The relative ratios (RRs) of NAFLD for diabetes was evaluated.

Results: The prevalence of NAFLD in study participants was 45.4% (2,830/6,240). Subjects with NAFLD had higher BMI, WC, HbA1c levels, blood pressure levels, blood lipid levels, and also higher ALT levels (P < 0.001). During the follow-up, the total incidence of diabetes was 8.093%. Subjects with NAFLD at baseline had a higher incidence of diabetes and the adjusted RRs were 2.181 [95% confidence interval (CI), 1.778 to 2.674]. Furthermore, the RRs were closely related to WC changes. The adjusted RRs for diabetes according to WC change (≤ 0.0 cm, 0 cm to 3.0 cm, and > 3.0 cm) were 1.953 (95% CI, 1.365 to 2.794), 1.996 (95% CI, 1.407 to 2.833), and 2.302 (95% CI, 1.598 to 3.314), respectively. Furthermore, the RRs were also closely related to BMI changes and the adjusted RRs for diabetes according to BMI change (< -0.35 kg/m2, -0.35 kg/m2 to 0.35 kg/m2, and > 0.35 kg/m2) were 1.633 (95% CI, 1.121 to 2.380), 1.995 (95% CI, 1.415 to 2.811), and 2.924 (95% CI, 2.053 to 4.165), respectively.

Conclusion: There was a strong and independent association between NAFLD and diabetes in Korean subjects with prediabetes, and this relationship was closely related to WC and BMI changes.

Disclosure

J. Lee: None. Y. Kang: None. J. Park: None. W. Lee: None.
1364-P: Parent and Physician Preferences for Screening in Type 1 Diabetes (T1D)
Authors: DUNNE JESSICA L. , SUTPHIN JESSIE , BUSHMAN JESSE S. , FONTANALS-CIRERA BARBARA , COULTER JOSHUA R. , HUTTON CAMPBELL T. , KORALOVA ANNE , ERVIN CLAIRE M. , MANSFIELD CAROL
Published: June 2019

Purpose: Qualitative interviews were conducted and a survey instrument was developed to inform the implementation of a general population screening program for T1D in children and to quantify screening-test attributes relevant to parents and physicians in the United States.

Methods: Semi-structured qualitative interviews were conducted with parents and physicians to understand views on general population screening for T1D and identify important attributes of screening programs. Using the results, a discrete-choice experiment (DCE) survey instrument was developed to quantify preferences over multiple options. The survey was pretested using interviews to confirm attribute relevance and respondent comprehension.

Results: In the qualitative interviews (10 parents, 10 physicians), test accuracy and the availability of treatments to delay onset or lessen T1D-associated health risks ranked as important. Parents’ concerns included the need for venipuncture and the cost of the test. Physicians’ concerns included the emotional impact of positive results on families and test reimbursement. A DCE survey was developed with 5 attributes covering when, where, and how the sample for screening is obtained; cost; monitoring and education to reduce the risk of DKA; and availability of an optional treatment to delay T1D. In the pretest interviews (15 parents, 15 pediatricians), the relevance of the attributes was confirmed. The pretest sample placed the most value on reducing the risk of DKA and the availability of a treatment to delay T1D onset. Low cost and convenience were considered key to widespread adoption by pediatricians.

Conclusions: Two sets of interviews confirmed an interest in general population T1D screening, but follow-up treatment for a positive result was the key driver for acceptance. The survey will be administered to 1,000 parents and 500 pediatricians to quantify the importance of screening attributes with the goal of informing the implementation of a general population T1D screening program.

Disclosure

J.L. Dunne: None. J. Sutphin: Other Relationship; Self; Multiple Companies. J.S. Bushman: None. B. Fontanals-Cirera: None. J.R. Coulter: Other Relationship; Self; Multiple companies. C.T. Hutton: None. A. Koralova: Research Support; Spouse/Partner; Bristol-Myers Squibb Company. C.M. Ervin: Other Relationship; Self; Multiple companies. C. Mansfield: Other Relationship; Self; Multiple companies.

Funding

JDRF; The Leona M. and Harry B. Helmsley Charitable Trust
137-OR: The Selective Human Beta 3 Adrenergic Receptor Mirabegron Potently Activates Lipolysis in Human White Adipocytes
Authors: CERO CHERYL , JOHNSON JAMES W. , O’MARA ALANA , LINDERMAN JOYCE D. , CYPESS AARON M.
Published: June 2019

Human obesity is an increasing burden worldwide. Lipids stored as metabolic fuel in white adipose tissue (WAT) can be rapidly mobilized through lipolysis. In rodent adipocytes, activation of the β3-adrenergic receptors (β3-ARs) leads to lipolysis. The physiological role of the β3-AR in human adipocytes remains controversial due to its reported low expression and previous access only to partial β3-AR agonists. Mirabegron, an FDA-approved drug for overreactive bladder, is a highly-selective human β3-AR agonist. In clinical trials, mirabegron treatment led to activation of human brown adipose tissue (BAT) thermogenesis and increased plasma NEFA’s. Therefore, we investigated if mirabegron directly mediates lipolysis in human white adipocytes. We found similar gene expression of the three β-ARs in human immortalized and primary white adipocytes, with β2-AR being the most expressed, followed by β1-AR and β3-AR. Next, to assess the functionally of the β3-AR in human adipocytes, we established dose-response curves and found that mirabegron increased the release of glycerol, a lipolytic product, in the picomolar range. To identify the molecular mechanism controlling mirabegron-induced lipolysis, we assessed the regulation of key downstream lipolytic proteins. Mirabegron mediated lipolysis by rapidly phosphorylating hormone sensitive lipase (HSL), as well as the mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). Moreover, acute inhibition of either the PKA or MAPK/ERK pathways decreased lipolysis.

In summary, we identify a major role played by the β3-AR in the regulation of human WAT lipolysis. Mirabegron acts as a potent pro-lipolytic effector, signaling through the canonical adrenergic receptor pathway as well as the MAPK/ERK pathway. Due to the comparatively minimal effects previously reported of mirabegron on the cardiovascular system, mirabegron may be the optimal choice for targeted lipid mobilization in human WAT.

Disclosure

C. Cero: None. J.W. Johnson: None. A. O’Mara: None. J.D. Linderman: None. A.M. Cypess: None.

Funding

National Institutes of Health
1371-P: Continuing Improvement of Diabetes Control after the Establishment of the Population-Based Childhood Diabetes Register ČENDA
Authors: SUMNIK ZDENEK , PAVLÍKOVÁ MARKÉTA , CINEK ONDREJ ,   ČENDA STUDY GROUP
Published: June 2019

Objectives: The Czech National Childhood Diabetes Register (ČENDA) is a web-based nationwide database that collects treatment and outcome data in children and adolescents with diabetes. Here we present data from the first five years of ČENDA (2013-2017).

Methods: Data include characteristics of disease onset and annual summaries of key clinical care parameters from every patient treated by participating pediatric diabetes outpatient clinics.

Results: The database contains data from 4361 children (aged 0 to 19 years) from 52 centers, which is estimated to be 85% of all Czech pediatric patients. Of these, 94% had type 1 diabetes (T1D), 4.5% had genetically proven monogenic or secondary, and 1.5% had type 2 diabetes. In children with T1D, median HbA1c decreased throughout the observed period from 66.3 to 61.0 mmol/mol (p < 0.0001, 95% confidence interval for change -6 to -5). Consequently, the proportion of children reaching the ADA target therapeutic goal of 58.5 mmol/mol increased from 28% in 2013 to 40% in 2017. This improvement was significant for all categories of age and diabetes duration and was independent of gender. The overall proportion of children treated with continuous subcutaneous insulin infusion (CSII) remained stable over the observed period (25%). The main predictors associated with lower HbA1c were treatment with CSII, male sex and care provided at a large diabetes center (with >100 patients in regular care).

Conclusions: A significant continuous decrease in HbA1c was observed in Czech children over the past five years. As this improvement was not accompanied by appreciable changes in the mode of therapy, we assume that the establishment of our nationwide register has itself constituted a stimulus towards improvement in the care process.

Disclosure

Z. Sumnik: None. M. Pavlíková: None. O. Cinek: None.

Funding

Ministry of Health of the Czech Republic
138-OR: Ablating Adipose CREB3l3 Preserves Metabolic Health during Obesity
Authors: MCCANN MAXIMILIAN A. , LI SHENGXIAN , LI YANLIANG , GIL VICTORIA , LIEW CHONG WEE
Published: June 2019

During obesity, the adipose tissue becomes supersaturated with lipids, leading to inflammation, the release of free fatty acids into the bloodstream, and the development of metabolic syndrome. However, a small obese subpopulation does not develop metabolic syndrome and has been deemed to have “metabolically healthy” obesity (MHO). Our lab has created a mouse model that mimics MHO, via adipose-specific ablation of the ER-bound transcription factor cyclic-AMP Responsive Element Binding Protein 3-like-3 (CREB3L3). We have discovered that CREB3L3 is not only expressed in adipose tissue, but selectively downregulated in the “metabolically protective” subcutaneous fat in obese mice and human patients. We hypothesized that CREB3L3 downregulation could contribute to the healthier metabolic profile of subcutaneous fat during obesity, so we created a CREB3L3 fat-specific knockout (KO) mouse. CREB3L3 KO mice had enhanced diet-induced obesity following 12 weeks of high-fat diet feeding and significantly larger inguinal white adipose tissue (iWAT) and epididymal white adipose tissue (eWAT) compared to wild type controls. Unexpectedly, the KO mice do not exhibit the reduction in glucose tolerance or insulin sensitivity that would be expected with their more obese phenotype, which is likely due to the enlarged adipose tissues. The KO mice do not exhibit the expected dyslipidemia or hepatic steatosis, suggesting that the KO adipose tissue sequesters lipids away from these spaces. Additionally, the KO iWAT and eWAT have reduced inflammatory marker expression, suggesting that CREB3L3 plays a role in adipose inflammation. Indeed, we observed that obese mice overexpressing CREB3L3 via direct injection of a CREB3L3 adeno-associated virus into the iWAT and eWAT had marked upregulation of IL-1B and MCP1 in both of these tissues. Together, these data suggest that adipose ablation of CREB3L3 preserves metabolic health during obesity by allowing the adipose tissue to meet the body’s lipid storage demands via healthy expansion.

Disclosure

M.A. McCann: None. S. Li: None. Y. Li: None. V. Gil: None. C. LIew: None.

Funding

National Institutes of Health (R01DK109015)
1385-P: Associations between Maternal Metabolomic and Lipidomic Profiles across Gestation with Neonatal Birthweight in Type 1 Diabetes Pregnancy
Authors: STEWART ZOE A. , YAMAMOTO JENNIFER M. , MEEK CLAIRE L. , SANCHEZ J. JOHANNA , FEIG DENICE , MURPHY HELEN R.
Published: June 2019

Aims/Objectives: To describe the maternal-fetal metabolomic and lipidomic profiles and examine associations with neonatal birthweight in type 1 diabetes pregnancy.

Methods: A longitudinal prospective study of 162 CONCEPTT mothers. 1049 maternal metabolites and 1041 lipids were analyzed at 12, 24 and 34 weeks gestation, in addition to 93 cord-blood samples using ultra-performance liquid chromatography-tandem mass spectroscopy. The effects on neonatal birth weight, classified as appropriate for gestational age (AGA) 10-90th percentile, large for gestational age (LGA) >90th percentile and extreme LGA (ELGA) >97.7th percentile were examined through ANOVA, principle component analysis and hierarchical clustering, adjusting for maternal BMI.

Results: Significant gestational changes in the maternal metabolome and lipidomic profiles were observed. Metabolite changes associated with birthweight were modest in LGA, albeit more apparent in ELGA. At 24 and 34 weeks, glucose levels were significantly elevated and 1,5-anhydroglucitol (1,5-AG) significantly reduced in ELGA mothers. Triglycerides did not differ between AGA and LGA. Throughout pregnancy, many lipid classes were lower in LGA mothers, with modest increases in free fatty acids and acylcarnitine species at 34 weeks in ELGA. The distribution of lipid classes was significantly different between maternal and cord-blood samples, with most cord-blood lipids comparable between AGA, LGA and ELGA. There were some differences in the cord-blood steroid hormones and acylcarnitine species of ELGA neonates.

Conclusions: Gestational changes in maternal-fetal metabolomic and lipidomic profiles are largely conserved across birthweight categories. Some differences in glucose handling, lipid homeostasis, steroid hormones and acylcarnitine species were apparent in maternal-fetal samples of ELGA neonates.

Disclosure

Z.A. Stewart: None. J.M. Yamamoto: None. C.L. Meek: None. J. Sanchez: None. D. Feig: Advisory Panel; Self; Medtronic. Speaker's Bureau; Self; Medtronic. H.R. Murphy: Advisory Panel; Self; Medtronic MiniMed, Inc.

Funding

Diabetes UK; JDRF
1387-P: Genotyping Cell-Free Fetal DNA to Decide whether to Treat Hyperglycemia during Pregnancy in Women with GCK Monogenic Diabetes—A Case Study
Authors: KWAK SOO HEON , JANG SE SONG , KANG SUNYOUNG , JANG HAK CHUL , LEE SEUNG MI , CHAE JONG HEE , PARK KYONG SOO
Published: June 2019

Patients with inactivating glucokinase (GCK) mutation usually do not require treatment except for during pregnancy. The decision to treat hyperglycemia during pregnancy would depend on the fetal GCK genotype. However, it has not been able to noninvasively investigate the fetal genotype antenatally. In this study, we developed a method to determine cell-free fetal genotype of GCK and applied it in a case of pregnant woman with GCK mutation. A 40 years old woman in her second pregnancy presented with hyperglycemia. She was diagnosed with GCK p.Gly411Ser (chr7:44185121C>T; NM_000162 c.G1228A) mutation prior to her second pregnancy. We used targeted linked-read deep sequencing to resolve the haplotypes of GCK for both the women and her husband. Cell-free DNA was extracted from maternal plasma at week 24 of gestation and were subjected to massively parallel sequencing. The allelic fraction of the heterozygous variants that were in maternal mutant-linked haplotype were analyzed. The fetal fraction of the maternal plasma cell-free DNA was 21.8%. In maternal plasma cell-free DNA, a total of 12 heterozygous variants, that were homozygous in paternal genomic DNA, were identified within 40 kb of the disease-causing mutation. The average allelic fraction of the 12 variants in the mutant-linked haplotype and the wild type-linked haplotype in the cell-free DNA was 44.1% and 55.9%, respectively. This significant difference in allelic fraction of the haplotypes suggested that the fetus did not inherit the GCK mutant-linked haplotype (P 0.0081). The inferred fetal genotype was available at week 30 of gestation and the patient was treated with basal-bolus insulin therapy until term at 38 weeks. The fetal birth weight was 2,980 g (25th percentile). The fetal genotype of GCK was confirmed by Sanger sequencing postnatally. This was the first study to use cell-free DNA to determine fetal genotype to guide treatment of hyperglycemia in pregnant women with GCK mutation.

Disclosure

S. Kwak: None. S. Jang: None. S. Kang: None. H. Jang: None. S. Lee: None. J. Chae: None. K. Park: None.

Funding

Korean Ministry of Health and Welfare (HI15C3131, HI13C1468)
1388-P: Umbilical Cord Blood-Derived Exosomal LRG1 and ECM1 Induce Abnormal Placental Angiogenesis in Women with Gestational Diabetes Mellitus
Authors: YAO JULEI , DUAN TAO , WANG KAI
Published: June 2019

Background: Gestational diabetes mellitus (GDM) is characterized by a high risk of fetal macrosomia and placenta hypervascularization. There is a need to investigate the underlying mechanism to explain these associate complications. Exosomes had been known participating in the regulation of various angiogenic processes. However, the effects of exosomes from cases of GDM on placental vascular network formation remain unclear.

Methods and Results: Capillary branching per placental villi and protein level of CD31 were identified to be increased in GDM. Exosomes derived from umbilical cord blood (UE) enhanced endothelial cell vascularization significantly, especially in GDM pregnancies. The proteome of 10 normal exosomes and 10 GDM exosomes showed different profiles and uncovered two up-regulated proteins in GDM cases, namely leucine-rich alpha-2-glycoprotein-1 (LRG1) and extracellular matrix protein 1 (ECM1). Genetically engineered exosomes that overexpressed LRG1 or ECM1 resulted in hyper vascularization, including proliferation and migration.

Conclusions: Our results demonstrate for the first time the expression of LRG1 and ECM1 in normal and GDM UE and their role in regulating pathological placental angiogenesis. These findings support the potential role of LRG1 and ECM1 in monitoring placental pathologies in this increasingly prevalent condition and novel insights into the causes.

Disclosure

J. Yao: None. T. Duan: None. K. Wang: None.

Funding

National Natural Science Foundation of China; National Key Research and Development Program of China
1398-P: Augmented Insulin Secretory Response in Early Pregnancy Is Independent of Gestational Insulin Resistance
Authors: POWE CAMILLE E. , PRESLEY LARRAINE , LOCASCIO JOSEPH J. , CATALANO PATRICK
Published: June 2019

Background: Augmentation of insulin secretory response (ISR) in pregnancy has been attributed to a pregnancy-associated reduction in insulin sensitivity. We hypothesized that ISR in pregnancy increases prior to and independent of decrements in insulin sensitivity.

Methods: In 34 women, ISR (by intravenous glucose tolerance test) and insulin sensitivity (by euglycemic clamp) were assessed prior to pregnancy, in early pregnancy (12-14 weeks gestation), and in late pregnancy (34-36 weeks gestation). In a secondary analysis of data from a prior study, we used mixed effects models to compare ISR and insulin sensitivity in early pregnancy to the same parameters prior to pregnancy and in late pregnancy, with adjustment for age, obesity, and GDM status. We next explored the relationship between ISR and circulating hormones.

Results: ISR increased from prior to pregnancy to early pregnancy (unadjusted mean [standard deviation] 1st phase insulin response 465.1 [268.5] to 720 [358.2], P<0.001) and from early pregnancy to late pregnancy (to 924 [494.6], P=0.01). Insulin sensitivity increased from prior to pregnancy to early pregnancy (insulin sensitivity index 0.10 [0.04] to 0.12 [0.05], P=0.001) and decreased in late pregnancy (to 0.06 [0.03], P<0.001). Adjustment for insulin sensitivity did not attenuate observed augmentation in ISR in early pregnancy (P <0.001), but did eliminate the augmentation of ISR between early pregnancy and late pregnancy (P=0.30). Adjustment for age, obesity, and GDM status did not affect longitudinal changes in physiologic parameters. Leptin was positively associated with ISR, independent of insulin sensitivity and adiposity (P=0.004). Adjustment for leptin attenuated the augmentation of ISR in early pregnancy (adjusted mean change 121.5, P=0.13).

Conclusion: ISR increases markedly in early pregnancy, prior to and independent of the late pregnancy decrement in insulin sensitivity. Circulating hormones may mediate this metabolic adaptation.

Disclosure

C.E. Powe: None. L. Presley: None. J.J. Locascio: None. P. Catalano: None.

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD22965); National Center for Research Resources (UL1RR024989); National Institute of Diabetes and Digestive and Kidney Diseases (K23DK113218); Robert Wood Johnson Foundation; National Center for Advancing Translational Sciences (UL1TR002541)
140-OR: Dermal Adipose Tissue—A Unique Fat Pad Undergoes Dynamic Changes by Reversible Dedifferentiation
Authors: ZHANG ZHUZHEN , SHAO MENGLE , GUPTA RANA K. , SCHERER PHILIPP E.
Published: June 2019

Dermal adipose tissue is a layer of adipocytes residing under the reticular dermis. Recent data have revealed a difference between the dermal adipose tissue and subcutaneous adipose tissue. Dermal adipocytes show dramatic changes in synchrony with hair cycling. Beyond hair cycling, many additional stimuli can modulate the volume of dermal adipose tissue. However, dermal adipose tissue remains poorly characterized. The fate of the mature dermal adipocytes and the origin of the re-appearing dermal adipocytes after they de-differentiate are still unclear. Here we isolated dermal adipocytes and characterized dermal fat as a fat pad with unique identity. Using pulsed lineage tracing of dermal mature adipocytes, as well as single cell sequencing, we reveal that mature dermal adipocytes can de-differentiate into fibroblast-like cells or even myofibroblast-like cells. Upon various stimuli, the de-differentiated fibroblasts proliferate and re-differentiated into adipocytes. Similar to other skin fibroblasts, the de-differentiated fibroblast-like cells showed two distinct clusters, and totally lose their mature adipocyte characteristics. In addition, manipulation of dermal adipose tissue highlights an important role of adipocytes for hair cycling and wound healing. This study advances our knowledge of dermal adipose tissue and implicates dermal adipocytes as essential components for normal skin morphology and function.

Disclosure

Z. Zhang: None. M. Shao: None. R.K. Gupta: None. P.E. Scherer: None.
1400-P: Adverse Perinatal and Long-Term Outcomes Differ among Physiologic Subtypes of Gestational Glucose Intolerance
Authors: EDELSON PAULA , CORELLI KATIE , JAMES KAITLYN , HIVERT MARIE-FRANCE , THADHANI R. , ECKER JEFFREY L. , POWE CAMILLE E.
Published: June 2019

Background: Gestational diabetes mellitus (GDM) is associated with adverse perinatal and long-term outcomes; it is unclear if these outcomes are equally distributed among all affected women. We aimed to define physiologic subtypes of gestational glucose intolerance using beta-cell (BC) function and insulin sensitivity (IS) parameters and characterize adverse outcomes associated with each subtype.

Methods: We used homeostasis model assessment to estimate BC function and IS from fasting glucose and insulin levels at 16-20 weeks gestation. We defined BC and IS defects using the 50th percentile in 1369 women with normal subsequent 50g glucose load tests (GLTs, performed at 24-30 weeks gestation). We categorized 158 women whose GLTs were abnormal (1-hour glucose ≥130 mg/dl) according to the predominant physiologic defect. We compared hyperglycemia-associated adverse outcomes across physiologic subtypes. We used logistic regression to adjust for potential confounders.

Results: Among 158 women, 59 (37%) had BC defects, 83 (53%) had IS defects, 10 (6%) had both, 6 (4%) had neither. Women with IS defects (vs. those with BC defects) were more likely develop GDM (13% vs. 2% by Carpenter-Coustan criteria, P=0.03), while women with BC defects were more likely to develop pregnancy-associated hypertension (20% vs. 7%, P=0.02). Women with IS defects (vs. women with BC defects) were more likely to develop postpartum glucose intolerance (prediabetes/type 2 diabetes) (29% vs. 3%, P<0.001) during a mean follow-up of 12 years. Differences persisted after adjustment for BMI, age, and GDM. There were no differences in other pre-specified outcomes (macrosomia, cesarean delivery, neonatal intensive care unit admission) across subtypes.

Conclusion: Distinct underlying physiologic mechanisms leading to gestational glucose intolerance are associated with distinct hyperglycemia-associated adverse outcomes. This may inform risk stratification and allow for targeted management approaches.

Disclosure

P. Edelson: None. K. Corelli: None. K. James: None. M. Hivert: None. R. Thadhani: Consultant; Self; Thermo Fisher Scientific. J.L. Ecker: None. C.E. Powe: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (K23DK113218); Robert Wood Johnson Foundation; Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD094150)
1406-P: Associations between Indices of Glycemic Variability (GV) and Gestational Outcomes among Pregnant Women with Type 1 Diabetes (T1D)
Authors: POLSKY SARIT , PYLE LAURA , GARCETTI RACHEL , JOSHEE PRAKRITI , DEMMITT JAMIE K. , VIGERS TIM B. , SNELL-BERGEON JANET K.
Published: June 2019

Pregnancies associated with diabetes are at high risk of adverse health outcomes. We examined associations between indices of glycemia and GV, assessed by continuous glucose monitoring, and maternal and fetal outcomes in women with T1D.

Women with T1D were stratified to groups during preconception or the 1st trimester: (1) CGM Alone (n=13): women without Apple devices, or (2) CGM Share (n=15, DexCom, San Diego, CA): women with iPhone and followers with data viewing devices. Association between change in GV indices over time and gestational outcomes were measured with linear mixed models.

Preeclampsia developed in 28.6% (8/28) of women. Preeclampsia was significantly associated with higher estimated A1C, mean sensor glucose, and time spent >140 mg/dL, and with lower time spent <65 mg/dL and 65-140 mg/dL (Table 1). Gestational age at delivery was 36.7 ± 1.7 weeks (mean ± SD). Gestational age at delivery was associated with lower estimated A1C (0.11% decrease A1C per 1 week increased gestational age, p=0.02), mean sensor glucose, and time spent >140 mg/dL, and with higher time in range (Table 2). There were no associations found between GV indices and cesarean delivery, delivery <37 weeks, large-for-gestational age infants, birth weight, and neonatal hypoxemia.

Preeclampsia and gestational age at delivery were associated with worse A1C and CGM metrics, but not with GV indices.

Disclosure

S. Polsky: Consultant; Self; Jaeb Center for Health Research. Research Support; Self; Barbara Davis Center for Diabetes, Children's Diabetes Foundation, Dexcom, Inc., Eli Lilly and Company, JDRF, Leona & Harry Helmsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases, Sanofi US. L. Pyle: None. R. Garcetti: None. P. Joshee: None. J.K. Demmitt: None. T.B. Vigers: None. J.K. Snell-Bergeon: None.

Funding

Dexcom, Inc.; National Center for Research Resources/Colorado Clinical and Translational Science Institute (UL1RR025780)
1408-P: Seasonal Variations in Incidence and Neonatal Outcomes of Gestational Diabetes: A Retrospective Cohort Study
Authors: MEEK CLAIRE L. , DEVOY BENJAMIN O. , SIMMONS DAVID , PATIENT CHARLOTTE , MURPHY HELEN R. , AIKEN CATHERINE
Published: June 2019

Objective: Gestational diabetes (GDM) incidence reportedly demonstrates seasonal variation. We aimed to assess if season also affects maternal-fetal outcomes in GDM.

Methods: 23,735 women who consecutively delivered singleton, live-born, term infants in a tertiary obstetrics center (2004-08; 4.6% GDM) were included. Additive dynamic regression models (age, BMI, parity, ethnicity adjusted) compared GDM incidence and outcomes (GDM diagnosis, birth weight, delivery mode) over annual cycles.

Results: GDM incidence varied by 30% from peak (October births) to nadir (March births; p<0.05). Temperature at time of test (28 weeks) was strongly positively associated with diagnosis (p<0.001). Birth weight in GDM-affected pregnancies showed marked seasonal variation (mean: 58th centile June - Sept; 67th centile Dec-Mar; p<0.05; fig). Emergency Caesarean rates (50% variation, p<0.05), closely temporally correlated with birth weight.

Conclusions: Substantial seasonal variation exists in GDM diagnoses and maternal-fetal outcomes in GDM-affected pregnancies. Birth weight is highest when GDM diagnoses are lowest, implying either over-diagnosis in summer or more challenging glycemic control in winter. Considering seasonal variation gives new opportunities for intensive individualized therapy to improve outcomes.

Figure: Effect of season on birthweight centiles in GDM; p<0.05.

Disclosure

C.L. Meek: None. B.O. Devoy: None. D. Simmons: Speaker's Bureau; Self; Sanofi-Aventis. Other Relationship; Self; Medtronic. C. Patient: None. H.R. Murphy: Advisory Panel; Self; Medtronic MiniMed, Inc. C. Aiken: None.

Funding

Diabetes UK (17/0005712 to C.L.M.)
1410-P: High Prevalence of Gestational Diabetes among Women in Rural District of North-Eastern Tanzania
Authors: GRUNNET LOUISE , HJORT LINE , NIELSEN BIRGITTE B. , MINJA DANIEL T. , MSEMO OMARI ABDUL , LUSINGU JOHN P. , PRASAD RASHMI B. , GROOP LEIF , THEANDER THOR G. , SCHMIEGELOW CHRISTENTZE , BYGBJERG IB C. , CHRISTENSEN DIRK L.
Published: June 2019

Background and Aims: The prevalence of gestational diabetes mellitus (GDM) is increasing world-wide and it complicates around 1-10% of all pregnancies. GDM is associated with increased risk of long-term metabolic health consequences for both mother and child. In Tanzania, GDM prevalence increased from 0% in 1991 to 19.5% in 2016. Furthermore, the prevalence seems to be dependent on the living conditions, thus an overall GDM prevalence of 5.9% was found in urban areas and 1.0% in rural areas in Tanzania. We aimed to examine the prevalence of GDM in a rural district of North-Eastern Tanzania based upon an oral glucose tolerance test (OGTT) with subsequent fasting blood samples.

Methods: The participants were included in a large population-based pre-pregnancy study named ”FOETALforNCD - Foetal Exposure and Epidemiological Transition: The Role of Anaemia in Early Life for Non-Communicable Diseases in Later Life." In total, 538 women were included in the pregnancy study; hereof 403 women were screened with an OGTT at week 32-34 of gestation, after 12 hours of fasting. GDM was diagnosed according to the WHO 2013 guidelines.

Results: The OGTT results showed that 153 women had GDM, i.e., a prevalence of 39.0%. The majority (94.1%) were diagnosed based on the fasting blood sample. When examine the blood samples from the follow-up of the 153 women diagnosed with GDM, 41 had a confirmed GDM diagnosis (39 had repeated fasting blood sample and 2 had a repeated OGTT. In the remaining 112 women. GDM could not be validated. 40 women had repeated fasting blood samples, 43 had random blood samples, 3 had a repeated OGTT and 26 had no further blood samples taken.

Conclusion: A very high prevalence of GDM was found in this part of Tanzania. In view of the laborious, costly and patient unfriendly OGTT, in low and middle-income countries alternative methods should be considered to be used to diagnose GDM.

Disclosure

L. Grunnet: None. L. Hjort: None. B.B. Nielsen: None. D.T. Minja: None. O.A. Msemo: None. J.P. Lusingu: None. R.B. Prasad: None. L. Groop: None. T.G. Theander: None. C. Schmiegelow: None. I.C. Bygbjerg: None. D.L. Christensen: None.

Funding

Danish Council for Strategic Research (1309-00003B)
1411-P: Glycated Hemoglobin A1c Levels during Pregnancy and Risk of Autism in Offspring
Authors: XIANG ANNY , CHOW TING , MARTINEZ MAYRA P. , GETAHUN DARIOS , PAGE KATHLEEN A. , BUCHANAN THOMAS A. , FELDMAN R. KLARA
Published: June 2019

Children exposed in utero to pre-existing type 1, type 2 diabetes or gestational diabetes diagnosed by second trimesters are at increased risk of developing autism spectrum disorders (ASD). Here we assessed the role of maternal glycemic levels using hemoglobin A1c. Data were from 35,819 singleton children born in 2012 and 2013 with maternal HbA1c measured during the first two trimesters of pregnancy (median=9.0 weeks, interquartile range (IQR) 6.7-11.4 weeks). All children were from an integrated healthcare system and enrolled in the health plan by age one. Children were tracked from age one until December 31, 2017. Risk of ASD associated with maternal HbA1c levels were estimated by hazard ratio (HR) using Cox regression. Potential confounding by maternal age, maternal obesity, parity, education, race/ethnicity, history of comorbidity, and sex of the child were assessed. During a median of 4.5 (IQR of 4.0-5.0) years after birth, 707 (2.0%) children were diagnosed with ASD. Univariately, the HR of ASD associated with each 1% increase of HbA1c was 1.23 (95% CI 1.08-1.41; p=0.002). When analyzed categorically, compared to exposure to HbA1c <5.7% (n=30,419), the HR (95% CI) associated with exposure to HbA1c 5.7% to 5.9% (n=4,172), 6.0% to 6.5% (n=871) and >6.5% (n=357) were 1.24 (1.01-1.54; p=0.04), 0.98 (0.61-1.59; p=0.94) and 2.17 (1.30-3.62; p=0.003) respectively. None of the potential confounders changed the model estimates by more than 10% except for maternal pre-pregnancy BMI and race/ethnicity. Adjusting for both reduced the corresponding HRs to 1.08 (0.87-1.35; p=0.46), 0.79 (0.48-1.28; p=0.33) and 1.79 (1.06-3.00; p=0.03) respectively. Thus, exposure to hyperglycemia defined by HbA1c >6.5% in the first two trimesters was associated with an increased ASD risk in offspring. Improving glycemic control during pregnancy may reduce the risk of ASD in children, and monitoring HbA1c may assist in identifying at-risk children for early intervention to reduce ASD disabilities.

Disclosure

A. Xiang: None. T. Chow: None. M.P. Martinez: None. D. Getahun: Research Support; Self; Bayer AG. K.A. Page: None. T.A. Buchanan: Research Support; Self; Allergan, Apollo EndoSurgery. R. Feldman: None.
1416-P: Impact of Birth Weight Category on Early Childhood Growth in the Offspring of Women with Diabetes
Authors: FEGHALI MAISA N. , CARITIS STEVE , SCIFRES CHRISTINA M.
Published: June 2019

Maternal diabetes mellitus (DM) affects fetal growth and we sought to examine the impact of birth weight category on growth in the first 3 years of life. We conducted a retrospective cohort study of 787 women with gestational (n=629) or pre-gestational DM (n=158). Maternal characteristics and perinatal outcomes, as well as childhood height and weight through age 3, were collected. Bivariate and multivariable linear regression analyses were used to assess factors associated with early childhood growth.

We compared weight z-scores and BMI at 6 months, 1, 2, and 3 years of age among those born small for gestational status (SGA) (n=71), adequate for gestational age (AGA) (n=619) and large for gestational age (LGA) (n=97). Weight z-scores and BMI at all time points were higher in infants born LGA and lower among those with SGA birth weight. BMI >85th percentile at age 3 was more common in offspring born LGA compared to those born AGA or SGA (44.57 vs. 21.09 vs. 12.9%, p<0.001). After adjusting for covariates, birth weight category remained significantly associated with BMI at ages 2 and 3 (Table).

Our findings suggest that birth weight category is a significant predictor of early childhood growth, and interventions that reduce the prevalence of LGA birth weight or optimize early childhood nutrition may impact long-term obesity risks.

Disclosure

M.N. Feghali: None. S. Caritis: None. C.M. Scifres: None.

Funding

National Institutes of Health (K23HD092893)
142-OR: Unique Role of the a4 Component for S6-Kinase Activity in Metabolic Regulation and Anti-apoptotic Effect in Brown Adipose Tissue
Authors: SAKAGUCHI MASAJI , OKAGAWA SHOTA , KITANO SAYAKA , KONDO TATSUYA , ARAKI EIICHI
Published: June 2019

Insulin and IGF1 signaling regulate function of brown and white adipose tissues. Recently we created adipocyte-specific inducible IR/IGF1R knockout mouse (Ai-DKO) and demonstrated the critical role of insulin signaling in maintenance of BAT and WAT. To further investigate downstream targets of these hormones regulating adipose tissue mass in adult animals, we compared gene expression patterns in WAT and BAT by using Ai-DKO mice, and found α4 expression was significantly reduced in Ai-DKO BAT but not in WAT compared with those of control. Knockdown of α4 in brown preadipocytecell lines using shRNA did not affect insulin-stimulated phosphorylation of IR, IRS1 or Akt; however, phosphorylation of ribosomal S6 protein was significantly increased in α4 KD cells after insulin stimulation. To investigate the impact of α4in mature adipocytesin vivo, we created inducible adipocyte-specific knockout of α4 gene (Ai-α4 KO) using floxed mice and mice carrying a tamoxifen-inducible Cre-ERT2transgene on the adiponectin promoter. Within 7 days, Ai-α4KO displayed an apparent decrease in SC-WAT and BAT mass, but not a significant effect on PG-WAT mass. Ai-α4 KO revealed extensive losses of adipocytes in SC-WAT and BAT depots with a significant increase in stromovascular cells in histological analysis with elevation of F4/80, TNF-α and IL-6, while no apparent changes were observed in PG-WAT. This appears to be due to a rapid development of an apoptotic process with increased TUNEL and cleaved caspase-3.Interestingly, Ai-α4KO showed marked reduction of BAT-associated functional gene UCP1 as well as PRDM16, Tfam and PGC1α mRNA compared to control. Consistent with these changes in mRNA and the decrease in BAT mass, Ai-α4 KO mice showed marked cold intolerance, glucose intolerance and insulin resistance. Thus, α4 is one of the components in control of insulin signaling and preferentially BAT mass, and has a unique role in regulating anti-apoptotic effect in brown adipocytes.

Disclosure

M. Sakaguchi: None. S. Okagawa: None. S. Kitano: None. T. Kondo: None. E. Araki: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Merck & Co., Inc., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi.

Funding

Japan Society for the Promotion of Science; Takeda Foundation; MSD Foundation; Kenzou Suzuki Foundation; Ono Foundation; Motida Foundation
1420-P: Improvements in Contraception Uptake and Reduced Pregnancy Rates in Women with Type 1 Diabetes after Changes to the Running of a Tertiary Centre Diabetes Transition Clinic
Authors: SIMMONS DAVID , OSUAGWU UCHECHUKWU L. , GUPTA AKHIL , RATNAWEERA MANJULA
Published: June 2019

Objective: Unplanned pregnancies among young women with diabetes are associated with hyperglycaemia related fetopathy. We have evaluated whether introducing a structured approach to contraception and pregnancy planning in the clinic was associated with greater uptake of contraception and reduced pregnancy rates.

Methods: Repeat retrospective reviews before (2012-2016) and after (2017- 2018) the introduction of a proforma including documentation of contraception uptake, provision of educational materials, reserved waiting area space and early evening clinic slots in a tertiary hospital diabetes transition clinic (for those aged 17-25 years). Between clinic telephone support continued unchanged.

Results: The pre-/post-change reviews included 43 and 48 women with type 1 diabetes (T1DM) respectively. Age at diagnosis (10-11 years), time between first and last clinic attendance (25-26 months), diabetes duration (10-12 years), CSII use (23%) and HbA1c (9.5-9.7%) on first attendance were similar. Number of clinic attendances dropped from 6.8±4.1 to 5.0±3.7 (p=0.01). HbA1c reduction since first attendance (0.1±1.8 vs. 1.2±3.0%, p<0.001) was greater, and episodes of diabetic ketoacidosis (55.8% vs. 14.6% p<0.001) and severe hypoglycaemia (18.6% vs. 2.1% 0.01) were less, in the ‘after’ group. Metformin use increased from 2.3% to 18.4% (p<0.05). Use of CGMS increased from 0% to 39.6% (p<0.001). Documented advice on contraception increased from 0% to 95.8% (p<0.001). Use of contraception increased from 25.6% to 43.8% (p<0.001: implants 7 to 15%, OCPs 16 to 27%). Prior/current pregnancy rates were less (18.6% vs. 8.3% respectively; p=0.03).

Conclusions: Introduction of more proactive approaches to diabetes management including contraception awareness and advice were associated with improved glycaemia and a reduced risk of pregnancy in younger women with T1DM.

Disclosure

D. Simmons: Speaker's Bureau; Self; Sanofi-Aventis. Other Relationship; Self; Medtronic. U.L. Osuagwu: None. A. Gupta: None. M. Ratnaweera: None.
1423-P: Diagnostic Performance of Fasting Glucose, Insulin, and HOMA-IR in the First and Second Trimesters in Predicting Gestational Diabetes
Authors: ZHU YEYI , HEDDERSON MONIQUE M. , FENG JUANRAN , QUESENBERRY CHARLES , FERRARA ASSIAMIRA
Published: June 2019

The International Association of Diabetes and Pregnancy Study Groups recommend early testing for gestational diabetes (GDM) using fasting glucose (FG) of 5.1-6.9 mmol/L at the first prenatal visit. Nonetheless, the optimal approach to diagnosing GDM remains debatable given the limited data on glycemia in the first half of pregnancy. We evaluated the diagnostic performance of FG, insulin, and HOMA-IR in the first and second trimesters in prediction of GDM diagnosis in the third trimester. In a nested case-control study within the prospective Pregnancy Environment and Lifestyle Study (PETALS) pregnancy cohort, 193 GDM cases were diagnosed at gestational weeks 24-28 using the Carpenter-Coustan criteria and matched to 386 controls on age and race/ethnicity. FG, insulin and HOMA-IR were assessed at gestational weeks 10-13 and 16-19, respectively. The mean (SD) of FG and insulin were 4.4 (0.4) mmol/L and 8.4 (10.9) µU/mL at weeks 10-13, and 4.4 (0.5) mmol/L and 11.5 (18.3) µU/mL at weeks 16-19, respectively. The sensitivity of GDM diagnosis using FG of 5.1-6.9 mmol/L was 0.25 (95% CI 0.19-0.32) at gestational weeks 10-13, 0.29 (0.22-0.36) at weeks 16-19, and 0.39 (0.32-0.47) at either weeks 10-13 or 16-19; the corresponding specificity was 0.97 (0.94-0.98), 0.94 (0.91-0.96), and 0.91 (0.88-0.94). By lowering the cutoff to 4.9 mmol/L (90th percentile among controls) for FG, the corresponding sensitivity was 0.38 (0.31-0.45), 0.42 (0.35-0.49), and 0.54 (0.46-0.61) at gestational weeks 10-13, 16-19, or either, with specificity ranging from 0.81-0.90. Diagnostic performance of GDM was not enhanced by using fasting insulin or HOMA-IR. Our data show that only 25% or 29% of GDM can be diagnosed using FG ≥5.1 mmol/L at gestational weeks 10-13 or 16-19 and thus do not support a single FG value of 5.1-6.9 mmol/L in the first or second trimester as the criteria for GDM diagnosis. It is still imperative to conduct an OGTT at gestational weeks 24-28 to confirm or rule out GDM.

Disclosure

Y. Zhu: None. M.M. Hedderson: None. J. Feng: None. C. Quesenberry: None. A. Ferrara: None.

Funding

National Institutes of Health