bluuebunny/crossref_metadata_2025 huggingface dataset:
300-OR: Individualized Hemoglobin A1C: A New Glycemic Marker Determined Using Continuous Glucose Monitoring
Authors: BERGENSTAL RICHARD M. , DUNN TIMOTHY , XU YONGJIN , AJJAN RAMZI
Published: June 2019

Glycation of hemoglobin (Hb) measured by A1C depends on red blood cell (RBC) lifespan, thus may misrepresent intracellular glucose exposure in other tissues, and may explain observed dissociations between A1C and microvascular complications. A kinetic model that accounts for rates of RBC turnover and intracellular glucose transport was evaluated for A1C individualization using continuous glucose monitoring data (CGM) and laboratory A1C from 58 individuals with diabetes (type 1/type 2 = 5/53, mean age 58 years (range 27 to 77, M/F=38/20). A1C was performed at 0, 3, and 6 months with concurrent CGM for 6 months, having a minimum of 80% coverage and no gaps >36 hours. The adjustment required to calculate individualized A1C is expressed as follows: A1C/(A1C+(1-A1C)*KTR/KT), where KT is the Hb and RBC turnover rate, and KTR is the reference Hb and RBC turnover rate. The mean (±SD) rate of Hb and RBC turnover was 1.18±0.20%/day as depicted in the Figure, showing the individualized A1C calculation. These data suggest that laboratory A1C does not only underestimate cellular glucose exposure in some patients but can also overestimate average glucose levels making the individual prone to hypoglycemia through unnecessary escalation of antidiabetic therapies. Quantitative individualization of A1C derived from A1C and CGM readings has the potential to more accurately assess intracellular glycemic exposure.

Disclosure

R.M. Bergenstal: Research Support; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Dexcom, Inc., Glooko, Inc., Hygieia, JDRF, Johnson & Johnson Medical Devices Companies, Lilly Diabetes, Medtronic MiniMed, Inc., Merck & Co., Inc., National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk Inc., Roche Diabetes Care, Sanofi. Other Relationship; Self; Abbott, Helmsley Charitable Trust, Hygieia, Lilly Diabetes, Novo Nordisk Inc., Onduo LLC, Sanofi, UnitedHealth Group Inc. T. Dunn: Employee; Self; Abbott Laboratories. Y. Xu: Employee; Self; Abbott Laboratories. R. Ajjan: Consultant; Self; Abbott. Research Support; Self; Abbott, LifeScan, Inc.

Funding

Abbott Diabetes Care
301-LB: Effects of Amino Acid Restriction on Development of Type 2 Diabetes in NZO Mice by FGF21 Secretion
Authors: CASTAÑO-MARTINEZ TERESA , JONAS WENKE , WEBER DANIELA , WEIKERT CORNELIA , LAEGER THOMAS
Published: June 2019

Dietary protein restriction (PR) is emerging as an alternative approach to treat obesity and glucose intolerance since it increases plasma fibroblast growth factor 21 (FGF-21) levels. Also, dietary methionine restriction (MR) is known to mimic the metabolic effects of PR by increasing FGF-21 and inducing beneficial effects. Therefore, we tested in New Zealand Obese (NZO) mice, a model of polygenic obesity and type 2 diabetes, whether a moderate PR or a MR protects against diabetes. Moreover, we investigated whether a decreased methionine intake caused by vegetarian and vegan diets modulates plasma FGF-21 in humans.

NZO mice were placed on high-fat diets that provided protein at control (18 gm%), low levels (4 gm%), or on high-fat diets (protein, 18 gm%) that provided methionine at control (0.86 gm%) or low levels (0.17 gm%) for up to 9 weeks. Changes in glucose homeostasis and energy expenditure were assessed. Among humans, plasma FGF-21 levels were investigated by comparing vegetarians and vegans to omnivores, and the effect of short-term vegetarian diet on FGF-21 induction was evaluated.

PR prevented the onset of hyperglycemia only when protein was substituted by fat. When protein was substituted by carbohydrates, mice developed hyperglycemia two weeks later than the control, despite elevated plasma FGF-21 levels and increased energy expenditure. MR elevated plasma FGF-21 levels and prevented the onset of hyperglycemia. Human plasma FGF-21 levels were higher in vegans and vegetarians compared to omnivores. Interestingly, already a short-term switch to a vegetarian diet increased plasma FGF-21 in omnivores.

Thus, restriction of dietary protein and methionine elevates plasma FGF-21 levels, which protect from hyperglycemia, an effect compromised by high dietary carbohydrates in NZO mice. Patients at high risk of developing type 2 diabetes may benefit from dietary changes in favor of methionine restriction, via increased circulating levels of FGF-21, without protein and calorie restriction.

Disclosure

T. Castaño-Martinez: None. W. Jonas: None. D. Weber: None. C. Weikert: None. T. Laeger: None.

Funding

Deutsche Forschungsgemeinschaft
301-OR: The Impact of Continuous Glucose Monitoring in Youth with Type 1 Diabetes, Aged 16-21
Authors: LEE MYRON , HOLMES-WALKER JANE , FARRELL KAYE
Published: June 2019

Background: People with T1DM under 21 are eligible for subsidised continuous glucose monitoring (CGM) products under the Australian National Diabetes Services Scheme. There are few “real world” published studies to evaluate the benefits of CGM in young adults.

Aim: To determine whether CGM is associated with improvement in glycaemic markers amongst eligible T1DM patients.

Methods: Patients at the Westmead Hospital young adult diabetes clinic aged 16-21 who commenced CGM prior to July 2018 were followed-up for 6 months after CGM commencement. Differences in HbA1c and glucose metrics at baseline and follow-up are compared between those started on CGM and those who were not.

Results: There were 115 eligible patients, of which 38% (n=44) commenced CGM. There were no differences in age, gender or baseline HbA1c of those started on CGM vs. those who were not. CGM users were more likely to use CSII than MDI (n=27 vs. 17, P=0.02), and came from post code areas which had higher median household incomes, despite fully subsidised CGM costs. At 6 months follow-up, only 41% (n=18/44) were confirmed to still be using CGM, with common reasons for dropout being discomfort, inconvenience, and disruptive alarms. Of those who continued, there was no change from baseline to 6 months in HbA1c (8.2±1.3% vs. 8.3±1.5%, P=0.7), coefficient of variation of glucose (0.39 vs. 0.38, P=0.5), or % time in range (54% vs. 58%, P=0.3), with average CGM wear time 65% in the 4 weeks prior to follow-up visit. At 6 months there was a weak correlation between percentage use of CGM and HbA1c reduction (R=0.46, P=0.07). Mean hypoglycaemia fear scores (worry scale) was significantly decreased from baseline at 6 months (33 vs. 18, P<0.01).

Conclusion: There are high rates of discontinuation in CGM use amongst T1DM patients aged 16-21. At six months of use there was no significant improvement in glycaemic control, although higher CGM usage was weakly correlated with increased time in range. Worry of hypoglycaemia was significantly decreased amongst those who continued CGM.

Disclosure

M. Lee: None. J. Holmes-Walker: None. K. Farrell: None.
308-OR: Genome-Wide Association Study of Food Frequency Questionnaire Single Nutrients and Dietary Patterns Uncover Hundreds of Genetic Associations
Authors: COLE JOANNE B. , LEONG AARON , HIRSCHHORN JOEL , FLOREZ JOSE C.
Published: June 2019

Unhealthy dietary habits are leading risk factors for type 2 diabetes (T2D) and related traits. However, there has been limited success in the use of traditional dietary measures in genetic, epidemiological, and clinical translation studies thus far, highlighting the potential for exploring complex and genetically based dietary habits. We leveraged quantitative traits and extensive correlation structure from food frequency questionnaires in UK Biobank, one of the largest cohorts of diet and genetics collected to date (N~500K), to derive dietary habits that encompass both single nutrients and principal component (PC) dietary patterns. Dietary patterns summarize correlated food intake into single factors that better represent true dietary habits and thus can translate well into diabetes care and prevention. For example, dietary pattern PC1, similar to “prudent” and “Western” factors as have been previously described, separate individuals that consume more whole meal bread, produce, fish, and water from those that consume more white bread, processed meat, and butter and oil spreads. Overall, we found that 84% of 170 derived dietary habits had a significant genetic component, and genome-wide association studies of 143 significantly heritable dietary habits identified 814 independent genetic loci surpassing genome-wide significance (5.0×10-8). Among these include genetic loci previously associated with T2D, BMI, HDL cholesterol and triglyceride levels, coronary artery disease, physical activity, and macronutrient intake as well as several novel loci. A better understanding of the genetic architecture of diet will undoubtedly be of value to the diabetes community, for which these discoveries lay the foundation for research on biological mechanisms of diet, interaction with known genetic and environmental diabetes risk factors, and advancement on dietary intervention and prevention plans for diabetes.

Disclosure

J.B. Cole: None. A. Leong: None. J. Hirschhorn: Board Member; Self; Camp4 Therapeutics. J.C. Florez: None.

Funding

American Diabetes Association (1-19-PDF-028 to J.B.C.); National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK110919-02)
312-OR: Functional Decline in Brown Adipose Progenitors during BAT Remodeling
Authors: HUANG ZAN , ZHANG ZENGDI , RUAN HAI-BIN
Published: June 2019

In humans, there is a striking decrease in the prevalence and activity of brown adipose tissue (BAT) with age and obesity; however, the cellular and molecular mechanisms of BAT remodeling are almost completely unknown. Rodent models have been widely used to study BAT but they possess constitutively active BAT throughout life even at thermoneutrality; therefore, complementary animal models that possess characteristics of human BAT remodeling are needed. Here, we found that BAT progressively whitened in rabbits in a similar manner as in humans. As rabbits mature, preadipocytes in BAT displayed reduced capacity to be differentiated into brown adipocytes, when transplanted into immune-deficient mice. RNA-sequencing of brown preadipocytes identified that, during BAT remodeling, genes enriched for muscle contraction and mitochondrial function were down-regulated, while genes involved in lipid and amino acid metabolism were up-regulated. Single-cell RNA sequencing discovered a unique population of stromal vascular fraction cells specifically expressing genes regulating muscle and mitochondrial function. Knocking down these genes in rabbit brown preadipocytes blunted their ability to become mature brown adipocytes. We also identified follistatin like 1 (FSTL1) as a novel “batokine” that is specifically expressed by brown preadipocytes but not mature brown adipocytes. FSTL1 gradually reduced its expression when BAT whitens in rabbits, but was stably expressed in mouse BAT during life. Deleting FSTL1 specifically in the Myf5 lineage in mice reduced BAT size, UCP1 expression, and body temperature in newborns, suggesting the constitutive expression of FSTL1 prevents BAT whitening in mice. Taken together, we identify potential molecular mechanisms underlying functional decline in the browning ability of preadipocytes that contribute to BAT remodeling in rabbits and possibly humans.

Disclosure

Z. Huang: None. Z. Zhang: None. H. Ruan: None.

Funding

American Diabetes Association (1-18-IBS-167 to H-B.R.)
316-OR: Suppressing Adipose Tissue Inflammation Promotes Insulin Resistance in Mice
Authors: ZHU QINGZHANG , SCHERER PHILIPP E.
Published: June 2019

Obesity is frequently concomitant with chronic adipose inflammation, although its role in the pathophysiology of obesity remains inconclusive. We previously described that constitutively suppressing adipose inflammation indeed impairs adipose development and leads to profound systemic metabolic disturbances. RIDα/β is an adenoviral protein complex that inhibits several inflammatory pathways, including TNFα and IL1β. To avoid developmental issues, we generated a tet-responsive promoter-driven RIDα/β (“TRE-RID”) mouse and crossed it to an adiponectinP-rtTA mouse to achieve doxycycline(dox)-inducible, adipocyte-specific expression of this transgene (referred to as fatRID mice).

We induced RIDα/β expression with dox-chow diet at 8-weeks of age. Upon induction, RIDα/β is specifically expressed in adipocytes, but not in the liver. LPS-stimulated inflammatory markers, such as TNFα, IL1β and Saa3 are significantly decreased in transgenic mice. Under dox-chow fed conditions, fatRID mice display higher levels of glucose and insulin upon refeeding. FatRID mice exhibit glucose intolerance and insulin resistance. Under obesogenic condition with high-fat-diet (HFD, supplement with dox) feeding, fatRID mice gain less weight, but also display insulin resistance. Moreover, to precondition the mice with inflammation and obesity, mice were pre-fed with HFD without dox for 30 days, and then switched to dox-containing HFD. Under these conditions, fatRID mice exhibit similar body weights, but still display glucose intolerance, insulin resistance, massive fatty liver and reduced adiponectin levels. These metabolic impairments were seen despite the fact that inflammatory pathways (including TNFα and IL1β) are effectively reduced.

Combined, suppressing adipose inflammation under either normal or obese conditions promotes insulin resistance, despite beneficial (or minimally no negative) effects on body weight.

Disclosure

Q. Zhu: None. P.E. Scherer: None.

Funding

National Institutes of Health
319-LB: GLP-1 Receptor Agonist Promotes Brown Remodeling in? Human Adipose-Derived Stromal Cells Isolated from Omentum through Foxc2
Authors: HE XIAOYING , LIU LIEHUA , KE WEIJIAN , LI YANBING
Published: June 2019

Background: Brown adipose tissue (BAT) can disperse stored energy as heat. Promoting BAT-like features in white adipose tissue (WAT) is an attractive therapeutic approach to oppose obesity, glucose intolerance and insulin resistance. Accumulating evidence has revealed the significant role of glucagon-like peptide-1 (GLP-1) in improving insulin resistance in adipose tissue by reducing fat mass and adipocyte hypertrophy. Forkhead box C2 (FOXC2) plays a vital role in the regulation of lipid metabolism.

Objects: Here, we investigated the effect of brown remodeling induced by the GLP-1 receptor (GLP-1R) agonist exenatide (exendin-4) in human adipose-derived stromal cells (hADSCs) isolated from omentum. We also looked at the role of FOXC2 in this process.

Methods: hADSCs were isolated, cultured and differentiated as previously described. The effect of Exendin-4 on brown remodeling during differentiation of hADSCs was examined. The knockdown by siRNA was performed to determine the roles of FOXC2 in brown remodeling during differentiation of hADSCs.

Results: In our study, oil red O test showed that Exendin-4 significantly increased the number of smaller lipid droplets, which is more similar to the morphological characteristics of brown fat. QPCR showed that Exendin-4 treatment could significantly up-regulate mRNA levels of some pro-brown adipogenic genes (UCP-1, FOXC2, PPARGC1A, PRDM16 and DIO2). Western blot also indicated that Exendin-4 could increase the protein levels of FOXC2 and UCP-1. Exendin-4-induced responses were partially blocked by GLP-1 receptor antagonist exendin9-39. The pro-brown adipogenic effects and increased expression of adipocyte specific markers caused by Exendin-4 was significantly reversed by the knockdown of FOXC2.

Conclusions: Our data highlight that a GLP-1R agonist promotes brown remodeling of WAT in a FOXC2-dependent manner, this might be one of the mechanisms underlying its effect on weight loss.

Disclosure

X. He: None. L. Liu: None. W. Ke: None. Y. Li: None.
32-LB: Variations of Sole Images on Hard and Soft Floors Are Useful in the Prediction of Diabetic Peripheral Neuropathy and Diabetic Foot Diseases
Authors: CHOU SHENGPU , HARAGUCHI MIKIKO , KOMORI HIROYA , WATANABE KOUHEI , TSUICHIHARA SATOKI , NAKAMURA SUNAO , TAKEMURA HIROSHI
Published: June 2019

Background: Diabetic peripheral neuropathy (DPN) is one of the major risks to diabetic foot diseases (DFD). Currently, there are few quantitative methods to assess progression of DFD if no obvious ulcerations, microtraumas, and other skin lesions are presented. We investigated the differences of sole images (SI) on hard and soft floors in patients with or without diabetes and evaluated the availability to predict DPN and severity of DFD.

Material and Methods: We prospectively recruited 104 patients from December 2017 to December 2018. Both SI on hard and soft floors were taken by the specific device with a camera underneath and were analyzed according to total area, shape, distal and proximal variations and bilateral differences. Severity of DFD was defined and calculated according to classical neurological and hemodynamic assessments.

Results: SI variations were significantly increased in diabetic patients with DPN compared with those without DPN (p<0.01). A weak but positive correlation was presented significantly between diabetes duration and SI variations (r=0.247, p<0.05). Moreover, SI variations also showed positive correlation with severity of DFD (r=0.462, p<0.001). The area under the ROC (receiver operating characteristic) curve of SI variations for diagnosing probable DPN was 0.722 with the optimal cut-off value of 0.591. The sensitivity, specificity was 67.9% and 72.9%, respectively. Logistic regression analysis showed that SI variation was a significant factor to predict DPN.

Conclusion: Variations of SI on hard and soft floors increase along with diabetes duration and have significantly positive correlation with severity of DFD. Because of good sensitivity and specificity for screening of DPN, this approach may be effective and useful in daily practice to diabetic patients.

Disclosure

S. Chou: None. M. Haraguchi: None. H. Komori: None. K. Watanabe: None. S. Tsuichihara: None. S. Nakamura: None. H. Takemura: None.
324-LB: A Novel Link between Mig6 and PP2a in Beta-Cell Apoptosis
Authors: REZAEIZADEH ALIREZA , BAUER BRANDON M. , FUEGER PATRICK T.
Published: June 2019

Hyperglycemia in both type 1 and 2 diabetes is toxic to pancreatic beta cells and exacerbates the decline in functional beta cell mass in both diseases. Thus, identifying the molecular mechanism for how this glucotoxicity negatively impacts beta cells is essential for identifying new therapeutic targets to treat both forms of diabetes. We identified that EGF receptor feedback inhibitor Mig6 is induced in islets cultured in glucotoxic conditions and that Mig6 promotes apoptosis in beta cells. To define how the adaptor protein Mig6 promotes apoptosis, we sought to identify its interacting partners. Following immunoprecipitation of flag-tagged Mig6 in Ins1-derived 832/13 cells cultured in normal and toxic conditions, mass spectrometric analysis revealed protein phosphatase 2A (PP2A). PP2A controls many cellular functions ranging from metabolism, cell cycle, DNA replication, growth and apoptosis, and PP2A can be exploited by tumor cells to promote cell survival. Thus, we hypothesized Mig6 interacts with PP2A to regulate beta cell apoptosis. We cultured 832/13 cells and mouse islets in low (5 mM) or high glucose (HG, 20 mM) for up to 48h and validated that glucotoxicity increased methylation and decreased phosphorylation of PP2A (indicating activation). HG also increased expression of Mig6, CHOP (ER stress), γH2AX (DNA damage response), and cleaved caspase 3 (CC3; apoptosis). Compared to controls, siRNA-mediated suppression of Mig6 in 832/13 cells increased methylated PP2A and decreased γH2AX and CC3, suggesting Mig6 antagonizes beta cell survival. We generated mice lacking Mig6 in beta cells (Mig6βKO) by crossing Mig6-floxed mice (Mig6fl/fl) with RIP-Cre mice. Beta cell mass and glucose homeostasis were similar between Mig6βKO and control Mig6fl/fl littermates. Islets from Mig6βKO mice had increased methylated PP2A during HG compared to controls. We speculate the Mig6-PP2A interaction limits PP2A activation; hence, disrupting Mig6-PP2A or inhibiting Mig6 could promote compensatory beta cell survival by activating PP2A.

Disclosure

A. Rezaeizadeh: None. B.M. Bauer: None. P.T. Fueger: None.
332-LB: Mir-132 Controls Pancreatic Beta-Cell Proliferation and Survival through the Pten/Akt/Foxo3 Signaling
Authors: KERSTING STEPHAN , MZIAUT HASSAN
Published: June 2019

Aim and Hypothesis: microRNAs (miRNAs) play an integral role in maintaining beta cell function and identity. We aimed to identify miRNAs and their downstream targets involved in regeneration of islet beta cells following partial pancreatectomy (pP) in mice.

Methods: RNA from laser capture microdissected islets of pP and sham-operated mice were profiled with microarrays to identify miRNAs implicated in control of beta cell regeneration. Altered expression of selected miRNAs, including miR-132, was verified by RT-PCR. Potential targets of miR-132 were selected through bioinformatic data mining. Predicted miR-132 targets were validated for their changed RNA and protein expression levels and signaling upon miR-132 knockdown and overexpression in mouse MIN6 cells and human EndoC-βH1 insulinoma cells. The ability of miR-132 to foster beta cell proliferation in vivo was further assessed in pP miR-132-/-and control mice.

Results: pP significantly increased the number of BrdU+/insulin+ positive islet cells. Microarray profiling revealed 14 miRNAs, including miR-132, to be significantly upregulated in LCM islets of partially pancreatectomized mice and confirmed by RT-PCR. Downregulation of miR-132 in MIN6 cells reduced proliferation while enhancing the levels of pro-apoptotic cleaved caspase-9. Microarray profiling, RT-PCR and immunoblotting revealed downregulated expression of Pten, with concomitant increased levels of pro-proliferative factors as well as inactivation of pro-apoptotic Foxo3. Overexpression of miR-132 in human insulinoma cells EndoC-βH1 validated the findings. In vivo regeneration of beta cells was reduced in pP miR-132-/- mice compared to control mice.

Conclusions: Our study provides compelling evidence for miR-132 being critical for regeneration of mouse islet beta cells in vivo through downregulation of its target Pten. Hence, the miR-132/Pten/Akt/Foxo3 signaling pathway may represent a suitable target to enhance beta cell regeneration.

Disclosure

S. Kersting: None. H. Mziaut: None.

Funding

German Center for Diabetes Research (to S.K.)
333-LB: Impact of Aging on Mitochondrial Respiratory Chain Expression and Pancreatic Islet Cell Composition by Using a Mitochondrial DNA Mutator Mouse Model
Authors: YU XUEFEI , ARDEN CATHERINE , CHEN CHUN , BRADSHAW CARLA , WHITEHALL JULIA , WHITE MICHAEL G. , ANDERSON SCOTT J. , SHAW JAMES A. , TURNBULL DOUG , GREAVES LAURA , WALKER MARK
Published: June 2019

Introduction: Age-related cumulative mitochondrial mutations can cause mitochondrial dysfunction. The mitochondrial DNA mutator mouse (PolgAmut/mut) is a model of premature ageing and has been previously shown to develop impaired insulin secretion with age.

Methods: Immunofluorescence was used to study mitochondrial respiratory chain protein expression (complex I and IV) and the cell composition in islets. Experiments were conducted on pancreas tissue from PolgAmut/mut mice and age-matched wild type (WT) mice at two ages: 12 weeks (young) and 44 weeks (old).

Results: (1) Comparing young WT mice versus old WT mice, there was no difference in islet complex I expression, while islet size and beta cell number increased with age (both P<0.01). (2) Comparing young PolgA mut/mut mice versus young WT mice, complex I expression was significantly lower (P<0.01) in islets from young PolgA mut/mut mice. However, there were no significant differences in islet size and cell composition between young PolgA mut/mut and young WT mice. (3) Comparing old PolgA mut/mut mice versus old WT mice, complex I expression was significantly lower (P<0.01) and complex IV expression was significantly higher (P<0.01) in islets from the old PolgA mut/mut mice. Old PolgA mut/mut islets had a lower beta cell percentage (mean ± SEM; 71.8 ± 4 % vs. 89.3 ± 4% P<0.01) but a higher alpha cell percentage (mean ± SEM; 29.6 ± 4 % vs. 12.5 ± 5%; P<0.01) versus old WT mice (both P<0.01).

Conclusions: In PolgA mut/mut mice, complex I deficiency was already present in the islets of young mice and persisted with age. This was associated with a proportional increase in alpha cells and decrease in beta cells in islets from old PolgA mut/mut versus the old WT mice. We conclude that complex I deficiency in PolgA mut/mut mice is linked to altered islet cell composition with increasing age.

Disclosure

X. Yu: None. C. Arden: None. C. Chen: None. C. Bradshaw: None. J. Whitehall: None. M.G. White: None. S.J. Anderson: None. J.A. Shaw: Advisory Panel; Self; Sanofi. Other Relationship; Self; Novo Nordisk A/S. D. Turnbull: None. L. Greaves: None. M. Walker: None.
334-LB: Dapagliflozin, a SGLT2 Inhibitor, Therapy Improves ß-Cell Function in Neonatal Diabetes by Reducing Oxidative and ER Stress, and Loss of ß-Cell Identity
Authors: YAN ZIHAN , SHYR ZEENAT A. , REMEDI MARIA S.
Published: June 2019

Loss of pancreatic β-cell identity, rather than β-cell death, has been recently demonstrated in both neonatal and type-2 diabetes. However, the underlying mechanisms and temporal progression remains elusive. By using an insulin secretory-deficient KATP-GOF mouse model of human neonatal diabetes, we demonstrate normal insulin content at day 7 despite severe diabetes, but a dramatic decrease (55%) in content at day 15 of diabetes. Loss of content was accompanied by a marked increase in proinsulin protein, a striking increase in oxidative- and ER-stress markers such as ROS, TXNIP, sXBP1 and ATF6, distended ER and decreased number of insulin granules. These changes lead to later loss of β-cell identity and increased α-cell identity (ARX increased 50%), glucagon content and secretion. We hypothesized that lowering blood glucose alone will be sufficient to reverse this process and improve β-cell function. Therefore, diabetic KATP-GOF mice were treated with dapagliflozin (DAPA), a sodium-glucose transporter-2 (SGLT2) inhibitor clinically used to reduce blood glucose by preventing renal glucose reabsorption. As expected, DAPA therapy significantly reduced blood glucose without changing circulating insulin levels. Ten days DAPA therapy markedly improved insulin content, reduced proinsulin/insulin ratio and enhanced β-cell function by reducing oxidative and ER stress and preventing loss of β-cell identity. Together, we clearly demonstrate that loss of insulin content, increased oxidative and ER stress, and changes in calcium dynamics underlie later loss of β-cell identity in diabetes, and that these features can be prevented/reversed by normalization of blood glucose alone with SGLT2 inhibitors. From the therapeutic perspective, these results have important implications indicating that early alleviation of β-cell stress may prevent loss of β-cell mass and preserve islet-cell identity, architecture and function.

Disclosure

Z. Yan: None. Z.A. Shyr: None. M.S. Remedi: None.

Funding

National Institutes of Health (DK098584 to M.S.R.), (T32DK108742 to Z.A.S.)
335-LB: Towards Generating Spatiotemporal Multiscale Models of Pancreatic ß Cells
Authors: WHITE KATE L. , SINGLA JITIN , STEVENS RAYMOND C.
Published: June 2019

To characterize biology, we must consider how molecular machines and organelles within a cell interact and traffic, similar to the importance of understanding traffic patterns in major cities. We use an imaging across scales approach to understand architectural changes that occur in pancreatic β-cells during insulin secretion. β-cells produce and release insulin in response to glucose and are therefore a target for diabetes therapies. Diabetes is a worldwide problem affecting hundreds of millions of people with increasing patient numbers every year. To acquire cellular architectural information, we are integrating data from cryo-electron tomography, soft x-ray tomography (SXT), and fluorescence microscopy. We used multiple glucose and GPCR agonist concentrations to investigate the cellular organization changes induced during insulin vesicle biogenesis and trafficking. The SXT method allows for investigating the 3D cellular architecture and is an ideal method for investigating cell-to-cell variabilities. Additionally, we are using machine learning methods for image analysis and autosegmentation which increased the number of conditions and samples we can analyze rapidly. Furthermore, we can use the information from cryo-ET and SXT along with with live cell imaging to assemble a data-driven, dynamic model of insulin granules within pancreatic β-cells. Furthermore, the SXT method provides a unique opportunity for comparing cell-to-cell heterogeneity and will be a useful technique for comparing differences between rodent and human primary cell architectures. The integration of data from different time and spatial scales represents a sophisticated convergence of our understanding of cellular structure and function, which will revolutionize biological discovery, open new dimensions of research, and accelerate advancements in healthcare.

Disclosure

K.L. White: None. J. Singla: None. R.C. Stevens: Board Member; Self; BirdRock Bio, Danaher Corp.

Funding

University of Southern California
337-OR: Injection Technique (IT) Training in Subjects Injecting into Lipohypertrophy (LH)—The Tianjin Randomized Controlled Trial (RCT)
Authors: CHEN LIMING , XING QIULING , LI JING , ZHOU JIANXIN , YUAN YI , XU HAIYAN , WAN YING , PFLUG BRIAN K. , STRAUSS KENNETH , HIRSCH LAURENCE
Published: June 2019

Rationale: LH is a common local complication of insulin injection. We conducted a 6-month prospective RCT to assess effects of intensive IT training vs. usual care on HbA1c, TDD insulin, LH lesions, injection behavior and BG variability.

Methods: Adult subjects injecting into LH lesions were randomized to usual care (N=104), or intensive IT training (N=106): stop LH injections, lower TDD insulin 10-20%, properly rotate injections within and between sites, and reduce needle reuse. The 2 groups saw different study staff to avoid injection practice contamination in Controls.

Results: Subjects were well matched for (mean ± SD) insulin injection duration (7.0 ± 5.0 years); HbA1c (8.5 ± 1.1%); TDD insulin (46.2 ± 21.2 IU); LH lesion count (1.9 ± 0.4), strict correct site rotation (2.9%), and factors such as age, BMI, needle reuse (% and frequency), daily number and sites of injections. Subjects did not perform adequate SBGM to assess BG variability. Due to protocol non-adherence (not lowering TDD in initial IT subjects), and injection behavior contamination in 63 Controls, both ITT and Per Protocol (PP) results are shown.

Conclusion: Intensive IT training in subjects who inject into LH lesions can safely lower HbA1c even as TDD insulin is reduced. Conduct of LH RCTs with behavioral education is difficult for both investigators and subjects. Control contamination is likely multi-factorial.

Disclosure

L. Chen: Research Support; Self; Becton, Dickinson and Company. Q. Xing: Research Support; Self; Becton, Dickinson and Company. J. Li: Research Support; Self; Becton, Dickinson and Company. J. Zhou: Research Support; Self; Becton, Dickinson and Company. Y. Yuan: Employee; Self; Becton, Dickinson and Company. H. Xu: Employee; Self; Becton, Dickinson and Company. Y. Wan: Employee; Self; Becton, Dickinson and Company. B.K. Pflug: Employee; Self; Becton, Dickinson and Company. K. Strauss: Employee; Self; Becton, Dickinson and Company. L. Hirsch: Employee; Self; Becton, Dickinson and Company. Stock/Shareholder; Self; Merck & Co., Inc.

Funding

Becton, Dickinson and Company
338-OR: Leveraging the Project ECHO Model for Type 1 Diabetes (T1D) in California and Florida: Democratizing Knowledge in Underserved T1D Communities
Authors: CUTTRISS NICOLAS , ANEZ-ZABALA CLAUDIA , BAER LINDA G. , BERNIER ANGELINA , BASINA MARINA , FILIPP STEPHANIE L. , HOOD KOREY K. , GURKA MATTHEW J. , LAL RAYHAN , HALLER MICHAEL J. , MAAHS DAVID M. , HU HUI , TOWN MARISSA , SHEEHAN ELENI , WANG C. JASON , YABUT KATARINA , WALKER ASHBY F. ,   FOR THE ECHO T1D STUDY GROUP
Published: June 2019

T1D care for many patients in both the pediatric and adult populations in the U.S. falls on primary care providers (PCPs). Persistently suboptimal outcomes for people with T1D and a lack of access to subspecialty care mandates the development of innovative healthcare delivery models. Using the Project ECHO (Extension for Community Healthcare Outcomes) model, Stanford University and the University of Florida partnered to develop and pilot a “ECHO T1D” teleECHOTM clinic. The goal of the pilot was to demonstrate the feasibility of an ECHO model for T1D and improve the ability of PCPs to manage patients with T1D. Utilizing a “Hub-and-Spoke” model, we recruited and partnered with PCPs at non-specialty diabetes practices across Florida and California and held weekly hour teleECHO sessions consisting of didactic presentations and case reviews. Precision recruitment methods to target clinics in remote and medically underserved regions included: (1) geocoding to identify high-need areas, (2) claims data to identify PCPs treating T1D, (3) survey data from PCPs. The 18-month pilot program is ongoing and enrollment demonstrated extremely high interest amongst PCPs as the pilot program filled beyond capacity. In California, 11 Spoke sites enrolled with 37 clinics serving roughly 900 adult and pediatric patients with T1D who do not receive specialty T1D care. In Florida, 12 Spoke sites enrolled with 67 clinics who serve roughly 1,300 patients with T1D. PCPs and their clinic staff have become local experts in T1D, providing a more informed level of care for the many patients who lack access to endocrinologists. Project ECHO T1D is an innovative healthcare delivery model which appears capable of building capacity for diabetes management education in the medically underserved. Having demonstrated proof-of-concept for ECHO T1D, future efforts will focus on replicating the model and on designing studies to demonstrate improvements in patient level outcomes.

Disclosure

N. Cuttriss: None. C. Anez-Zabala: None. L.G. Baer: None. A. Bernier: None. M. Basina: None. S.L. Filipp: None. K.K. Hood: Consultant; Self; Lilly Diabetes. Research Support; Self; Dexcom, Inc. Speaker's Bureau; Self; Johnson & Johnson Diabetes Institute. M.J. Gurka: None. R. Lal: Consultant; Self; Abbott. M.J. Haller: Advisory Panel; Self; Pancreum, SAB Biotherapeutics. D.M. Maahs: Advisory Panel; Self; Novo Nordisk Inc. Consultant; Self; Abbott, Sanofi. Research Support; Self; Dexcom, Inc., Tandem Diabetes Care. H. Hu: None. M. Town: None. E. Sheehan: None. C. Wang: None. K. Yabut: None. A.F. Walker: None.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust
340-OR: Supports for Using Retail Pharmacists in Delivering Diabetes Education in Saudi Arabia
Authors: KHAN YASMIN , TURKISTANI SARAH , BAYOUMI ALY H. , MCNAMARA MAURA J. , LEBLANC JENNIFER , POBER DAVID M. , HSU WILLIAM C.
Published: June 2019

The aim of this program evaluation was to assess the effectiveness of retail pharmacists in providing diabetes education in Saudi Arabia. Following an earlier pilot showing feasibility, the program was expanded to 50 community pharmacies. Joslin Diabetes Center collaborated with Nahdi Medical Company that operates a large network of retail pharmacy chains in Saudi Arabia to offer a diabetes program called “Let’s Talk About Diabetes” (LTAD). Pharmacists identified potential participants as having diabetes by the medication and supplies they purchased and then invited them to join the LTAD program. LTAD consists of four 1:1 educational sessions on topics such as medications, lab results, glucose monitoring, and doctor visits. Each session lasts approximately 20 minutes each, scheduled over a 2-4 month period. The entire program spanned approximately a 4-year period including the pilot. Among the 2066 participants who had paired results at baseline and follow-up, HbA1c improved from 8.5 ±1.6 to 7.6 ±1.5%. This change remained significant (p<0.001) after adjustment for change in diabetes distress, age, gender, diabetes duration, insulin treatment, baseline awareness of HbA1c baseline HbA1c result, and number of sessions participated in. This change was associated with a shift in the proportion of individuals meeting target HbA1c <7.0 from 22% at baseline to 37% at follow (p<0.0001 by McNemar’s test). There were additional significant improvements in exercise, diet, medication adherence, and other diabetes self-care behaviors, attitudes and beliefs, suggesting that retail pharmacists were effective in delivering diabetes education programs in Saudi Arabia.

Disclosure

Y.Khan: None. S.Turkistani: Employee; Self; Nahdi Medical Company. A.H.Bayoumi: Employee; Self; Al Nahdi Pharmacy. M.J.Mcnamara: None. J.Leblanc: None. D.M.Pober: None. W.C.Hsu: Consultant; Self; Onduo LLC.
343-OR: Trends in A1C and Lipid Testing, Antilipid Therapy, and Target Attainment following First-Time Glucose-Lowering Drug Treatment in Type 2 Diabetes, Denmark, 2000-2017
Authors: KNUDSEN JAKOB S. , WITTE DANIEL R. , HULMAN ADAM , RØNN PERNILLE F. , LAURITZEN TORSTEN , SÔRENSEN HENRIK T. , THOMSEN REIMAR W.
Published: June 2019

Objective: To examine 18-year trends in early A1C and lipid control among patients initiating first-time glucose-lowering drug therapy (GLD) for type 2 diabetes.

Materials and Methods: Population-based sequential cross-sectional study using healthcare databases covering Northern Denmark (∼1.8 million persons). For all 94,175 GLD initiators during 2000-2017, we examined likelihood of A1C and lipid testing, antilipid therapy, and 1-year glycemic and LDL cholesterol target achievement.

Results: The proportion of patients with at least one A1C test increased from 53% in 2000 to 95% in 2017 (Figure, Panel A). Lipid testing increased from 82% to 98% and lipid lowering therapy initiation quintupled from 12% to 61%. Mean pre-treatment A1C declined substantially, from 9.2% (77 mmol/mol) to 7.3% (56 mmol/mol) in 2011, then rose to 7.9% (63 mmol/mol) in 2017 (Panel B). Post-treatment A1C decreased less; pre- and post-treatment LDL cholesterol declined similarly. The proportion of patients achieving glycemic and cholesterol targets increased substantially over time (Panel C).

Conclusion: Monitoring and treatment of A1C and cholesterol in early type 2 diabetes have improved considerably over the past 18 years, while quality improvement was somewhat flat after the 2011 change in diagnostic criteria.

Disclosure

J.S. Knudsen: None. D.R. Witte: None. A. Hulman: None. P.F. Rønn: Research Support; Self; Amgen AB. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. T. Lauritzen: Advisory Panel; Self; AstraZeneca. Board Member; Self; Novo Nordisk A/S. H.T. Sôrensen: None. R.W. Thomsen: None.

Funding

Aarhus University
344-OR: Persistent Treatment Gaps and Disparities in U.S. Diabetes Mellitus Care in 2005-2016
Authors: KAZEMIAN POOYAN , SHEBL FATMA M. , MCCANN NICOLE , WALENSKY ROCHELLE , WEXLER DEBORAH J.
Published: June 2019

We sought to evaluate whether diabetes mellitus (DM) diagnosis, linkage to care, and meeting individual and combined treatment targets improved over time and to investigate potential disparities in U.S. DM care.

To do so, we derived percentages of diagnoses, linkage, and treatment goal achievement from NHANES in 2005-08, 2009-12, and 2013-16, and developed a logistic regression model adjusting for period, demographics, education, and health insurance.

In 2013-16, 74% of U.S. adults with DM were aware of their diagnoses; 70% were linked to DM care, 70% met HbA1c, 70% met blood pressure, 51% met cholesterol target, and 84% did not smoke. Twenty-one percent of patients achieved all treatment goals (Figure).

None of the individual and combined outcomes improved over the 3 study periods (p=0.08-0.98). Compared to middle-aged adults with DM (45-64y), older adults (≥65y) were more likely (OR 1.64, 95% CI 1.20-2.24) and younger adults (18-44y) were less likely (OR 0.50, 95% CI 0.28-0.90) to meet the combined goals. Women achieved the combined goals less often (OR 0.59, 95% CI 0.46-0.76). Reporting non-Hispanic black race (vs. non-Hispanic white race) was associated with reduced likelihood of achieving the combined goals (OR 0.59, 95% CI 0.42-0.82).

Despite major advances in DM medications and new care models, U.S. DM care has not significantly improved between 2005 and 2016.

Disclosure

P. Kazemian: None. F.M. Shebl: None. N. McCann: None. R. Walensky: Other Relationship; Spouse/Partner; Aileron. D.J. Wexler: Other Relationship; Spouse/Partner; APOLO1BIO.

Funding

Boston Area Diabetes Endocrinology Research Center; Steve and Deborah Gorlin MGH Research Scholar Award
350-OR: Disparities in Uptake of Guideline-Recommended Postpartum Diabetes Screening after GDM
Authors: BROWN SUSAN D. , TSAI AI-LIN , HEDDERSON MONIQUE M. , QUESENBERRY CHARLES , FERRARA ASSIAMIRA
Published: June 2019

For women with GDM, ADA guidelines urge screening at 4-12 weeks postpartum via OGTT, given its superior sensitivity to detect diabetes. Yet data on screening uptake according to these guidelines is scarce. In a large California integrated health system, we evaluated uptake and predictors of guideline-recommended screening among 2,207 women (77% racial/ethnic minorities) diagnosed with GDM in 2011-2012. Overall screening uptake was 47.9% but varied by race/ethnicity (Figure). In a multivariable adjusted model, black race/ethnicity (odds ratio [OR], [95% CI]: 0.64 [0.44-0.95]) vs. white; having less than a college degree (0.67 [0.56-0.81]) vs. having at least a college degree; parity ≥2 (0.58 [0.45-0.74]) vs. 0; and higher pre-pregnancy BMI (0.97 [0.95-0.98] per unit increase) were associated with lower odds of screening uptake. In the same model, attending a postpartum medical visit (7.96 [4.36-14.5]); Chinese race/ethnicity (2.03 [1.41-2.92]) vs. white; greater years of age (1.04 [1.02-1.06] per unit increase); and greater gestational weeks at delivery (1.06 [1.02-1.10] per unit increase) were associated with higher odds of screening uptake. Postpartum screening uptake varies by patient characteristics in an integrated health system setting. Strategies to reduce barriers, especially among black and non-college educated women, present an opportunity to reduce downstream diabetes health disparities.

Disclosure

S.D. Brown: None. A. Tsai: None. M.M. Hedderson: None. C. Quesenberry: None. A. Ferrara: None.

Funding

Kaiser Permanente Northern California
352-OR: Maternal Triglycerides in Gestational Diabetes Are Strongly Associated with Increased Newborn Hepatic Fat Independent of Subcutaneous Fat
Authors: HERNANDEZ TERI L. , FARABI SARAH S. , HIRSCH NICOLE , DUNN EMILY Z. , HAUGEN ELIZABETH A. , BRUMBAUGH DAVID , BROWN MARK S. , FRIEDMAN JACOB E. , BARBOUR LINDA (LYNN) A.
Published: June 2019

The incidence of childhood obesity continues to rise and alarmingly, 40% are already estimated to have nonalcoholic fatty liver disease (NAFLD), the leading cause of liver transplantation. An early origin exposure that contributes to NAFLD may be maternal obesity, diet, triglycerides (TG) and free fatty acids (FFA) in-utero, particularly in offspring of mothers with diabetes or gestational diabetes (GDM) who are at high risk for childhood metabolic disorders. In this pilot study, we explored the hypothesis that maternal TG in diet-controlled GDM (A1GDM) is associated with offspring intrahepatic lipid (IHL) accumulation. We randomized newly diagnosed A1GDM women (n=13, BMI 32±2 [mean±SEM]) to eucaloric diets at 32 weeks. Fasting and postprandial (PP) glucose, insulin, TG, FFA, and glycerol were measured in a breakfast test meal study (hourly x5) at baseline and 37 weeks. Newborn IHL content (Magnetic Resonance Spectroscopy; MRS) and body composition (%fat, PEAPOD) were measured at ~10 days. At 32 weeks, but not at 37 weeks, maternal fasting TG (199±17 mg/dL) and the 5-hour TG area-under-the-curve (AUC) were strongly associated with newborn IHL (r=0.69, p=0.01; r=0.75, p=0.003, respectively). The 1-hour and 2-hour PPTG (205-206±19-20 mg/dL) were highly associated with IHL (r=0.69-0.73; p≤0.01) as was the 5-hour glycerol AUC (r=0.65, p=0.01). There was no relationship between IHL and subcutaneous %fat by PEAPOD. We found no associations between maternal pre-pregnancy BMI, gestational weight gain (11±1.6 kg), glucose, insulin, or FFA and IHL. These data are the first in humans to support that maternal TG exposure at the time of GDM diagnosis, when fetal subcutaneous fat depots are early in development, may result in increased liver lipid deposition. If confirmed, MRS newborn liver fat measures and early interventions targeting maternal TG may be indicated to lower fetal liver fat deposition that could potentially be a developmental risk for pediatric NAFLD.

Disclosure

T.L. Hernandez: None. S.S. Farabi: None. N. Hirsch: None. E.Z. Dunn: None. E.A. Haugen: None. D. Brumbaugh: None. M.S. Brown: None. J.E. Friedman: Consultant; Self; Janssen Research & Development. L.A. Barbour: None.

Funding

National Institutes of Health
353-OR: Comparison of Methods for Classifying Heterogeneity in Gestational Diabetes (GDM) and Association with Outcomes
Authors: MCINTYRE DAVID , MADSEN LENE R. , GIBBONS KRISTEN S. , SACKS DAVID A. , MA RONALD C. , TAM WING H. , CATALANO PATRICK
Published: June 2019

An underlying principle of the IADPSG GDM classification is that women at similar risk of adverse pregnancy outcomes related to hyperglycemia should be classified similarly. Powe et al have described heterogeneous GDM phenotypes related to impaired insulin secretion and/or insulin sensitivity and reported that pregnancy complications relate primarily to impaired insulin sensitivity. However, their Gen3G cohort was largely Caucasian and GDM women received treatment. Our study was designed to further examine this hypothesis in a diverse population of 6128 untreated women from 5 centers in the blinded epidemiologic HAPO study. Following similar methodology (Impairment = parameter value <25th centile for non GDMs), women with IADPSG GDM were classified as (1) GDMsecr - impaired insulin secretion - using either HOMA β (Hβ) or Insulinogenic index (II); (2) GDMsens - impaired insulin sensitivity - using Matsuda index; (3) Both 1 and 2; (4) GDMND - No Defect. Analyses compared neonatal outcome frequencies (LGA, excess neonatal (NN) adiposity, NN hypoglycemia, NN hyperinsulinemia) with non GDM women and between GDM groups using χ2 tests and logistic regression analyses adjusted for multiple confounders including maternal age, height, smoking, FH of diabetes, BMI at the OGTT visit, ethnicity and HAPO study center. Hβ and II gave divergent results for GDMsecr, with only 25% concordance. GDMND women (10% of all GDM by Hβ, 6% by II) showed outcome frequencies similar to non GDM women. NN hypoglycemia was unrelated to GDM group. In all adjusted analyses, using either Hβ or II, Groups 1-3 showed higher odds (aORs 1.6-3.1; p < 0.01 vs. non GDM) for LGA, NN adiposity and NN hyperinsulinemia. Although Hβ and II identify different women as having defects in insulin secretion, both may contribute to detection of a lower risk group of GDMND women. Beyond this, the division of women according to insulin secretion and insulin sensitivity status did not permit additional risk stratification.

Disclosure

D. McIntyre: None. L.R. Madsen: None. K.S. Gibbons: None. D.A. Sacks: None. R.C. Ma: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Research Support; Self; AstraZeneca, Bayer AG, Pfizer Inc. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca. W.H. Tam: None. P. Catalano: None.