bluuebunny/crossref_metadata_2025 huggingface dataset:
29-OR: Regulatory Loop of IR Signaling for Adipocyte Mitochondrial Homeostasis
Authors: SAKAGUCHI MASAJI , OKAGAWA SHOTA , OKUBO YUMA , FUKUDA KAZUKI , IGATA MOTOYUKI , KAWASHIMA JUNJI , KONDO TATSUYA , ARAKI EIICHI
Published: June 2021

Insulin and IGF1 signaling initiate Tyr phosphorylation of IR/IGF1R and adaptor IRSs, leading to Ser/Thr phosphorylation of PI3K/AKT and MAPK/ERK pathways essential for the maintenance of brown and white adipose tissues (BAT and WAT). Lack of insulin-signaling in adipose tissues caused metabolic disease in mice with hyperglycemia, hyperlipidemia, and fatty liver, but the mice recovered adipose tissues by regenerating adipocytes. We addressed the mechanism of how adipose tissues regenerate using adipocyte-specific and inducible IR/IGF1R knockout mice (Ai-DKO). We identified a reduction of protein phosphatase protector, α4, which can regulate Ser/Thr phosphorylation of down-stream insulin signaling. shRNA-mediated α4 knockdown (KD) in BAT affected not only insulin-stimulated down-stream Ser/Thr phosphorylation of AKT (S473) but also affected up-stream Tyr phosphorylation of IRβ (Y1162/1163) and IRS1 (Y612). Proteomics analysis of α4-binding molecule identified Y-box protein 1 (YBX1), which functions as a transcription factor for Tyr phosphatase PTP1B. We observed increased PTP1B expression in α4-KO preadipocytes. As the impact of α4 in vivo, inducible adipocyte-specific α4 KO (Ai-α4 KO) mice with tamoxifen-inducible Cre-ERT2 transgene showed cold intolerance, diabetes, ectopic lipid accumulation in the liver, and pancreatic islet hyperplasia, with an increase of C18: 0-ceramide in WAT and BAT. RNA-seq showed a marked reduction of genes associated with mitochondrial fatty acid oxidation and the increases in inflammatory cytokine pathways in Ai-α4 KO WAT and BAT, implicating the cause of fat tissue loss was the increased adipocyte apoptosis. The α4 to PTP1B loop is critical for fat tissue maintenance by regulating IR tyrosine phosphorylation.

Disclosure

M. Sakaguchi: None. S. Okagawa: None. Y. Okubo: None. K. Fukuda: None. M. Igata: None. J. Kawashima: None. T. Kondo: None. E. Araki: Other Relationship; Self; Daiichi Sankyo Company, Limited, Eli Lilly Japan K. K., Mitsubishi Tanabe Pharma Corporation, MSD K. K., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Sanofi K. K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca K. K., Kowa Company, Ltd.

Funding

Japan Society for the Promotion of Science; Merck Sharp & Dohme Corp; Takeda Foundation
291-OR: GPR31 Appears to Mediate the Downstream Actions of 12-Lipoxygenase in the Setting of Diabetic Inflammation
Authors: TERSEY SARAH A. , WALSH MELISSA , HERNANDEZ-PEREZ MARIMAR , DOWGIELEWICZ JONATHAN , KULKARNI ABHISHEK , ANDERSON RYAN , MIRMIRA RAGHAVENDRA G.
Published: June 2021

Inflammation in macrophages and pancreatic islets is a hallmark of both type 1 diabetes (T1D) and type 2 diabetes (T2D). The enzyme 12-lipoxygenase (12-LOX) is expressed in macrophages and β cells, produces the eicosanoid 12(S)-HETE and promotes inflammation. GPR31 has recently been identified as the 12(S)-HETE receptor. To clarify the role of GPR31 in diabetic inflammation, we generated Gpr31b-/- mice on the C57BL/6J background. Gpr31-/- mice are viable, with normal body weight, glucose tolerance, and β-cell mass, similar to 12-LOX knockout mice. Upon low dose streptozotocin treatment to induce β-cell inflammation, Gpr31b-/- mice remained normoglycemic unlike wildtype littermates, and exhibited no reductions in β-cell mass. Isolated islets treated with the insulin receptor antagonist S961 to mimic insulin resistance showed the expected decrease in Ins1, Pdx1, and Gpx1 mRNA levels. By contrast, in Gpr31b-/- islets, these genes remained unaltered. Additionally, Gpr31b-/- islets showed a trend towards a decrease in ER stress markers Ddit3 and spliced-Xbp1 expression. To examine GPR31 in macrophage inflammation, we first interrogated its role in the generation of proinflammatory macrophages upon polarization in vitro to the M1 state; under these conditions, we found no differences between Gpr31b-/- and wildtype macrophages, suggesting that GPR31 does not play a role in macrophage polarization. To test a role for GPR31 in proinflammatory macrophage function, we leveraged a zebrafish tailfin injury model, in which macrophages migrate to the site of tailfin injury. Compared to control fish, fish harboring knockdown of GPR31 showed reduced numbers of macrophages at the site of injury. Taken together, our data support the notion that the effects of 12-LOX are mediated through GPR31, and that GPR31 appears to promote proinflammatory responses in both macrophages and pancreatic islets.

Disclosure

S. A. Tersey: None. M. Walsh: None. M. Hernandez-perez: None. J. Dowgielewicz: None. A. Kulkarni: None. R. Anderson: None. R. G. Mirmira: Advisory Panel; Self; Hibercell Inc., Sigilon Therapeutics, Inc., Veralox Therapeutics, Employee; Spouse/Partner; Beta Bionics, Inc.

Funding

National Center for Advancing Translational Sciences (R03TR003381)
304-OR: Association of Eating Patterns and Diabetic Kidney Disease in Type 2 Diabetes
Authors: RODRIGUES CÍNTIA C.R. , RIBOLDI BÁRBARA P. , RODRIGUES TICIANA C. , SARMENTO ROBERTA A. , ANTONIO JULIANA P. , BORBA RAQUEL A. , VIEIRA ADRIELE P. , PASINI ISADORA S. , DE ALMEIDA JUSSARA C.
Published: June 2021

Evaluation of association of eating patterns with diabetes kidney disease (DKD) in patients with type 2 diabetes (T2DM) was performed. Cross-sectionally, T2DM patients underwent clinical, laboratory, and nutritional assessments. Dietary information was evaluated by a quantitative food frequency questionnaire validated for diabetes and converted into daily intakes. The eating patterns were identified by cluster analysis. DKD was defined as estimated glomerular filtration rate <60 mL/min/1.73m2 and persistently elevated urinary albumin excretion (≥14 mg/dL). A chi-square test, one-way analysis of variance (ANOVA/Bonferroni’s post hoc test) and Kruskal-Wallis test (Bonferroni post hoc correction) were used to test differences across the eating patterns. Poisson regression analysis was used to investigate the associations between eating patterns and DKD. IBM SPSS Statistics 25.0 (p<0.05). A total of 329 T2DM patients were evaluated: 10 years (5-19) diabetes duration; HbA1c=8.7±2.0%; 62±10 years old; BMI=30.9±4.2kg/m². Four eating patterns were identified: (1) high intake of dairy products, fruits, and vegetables; (2) ultra-processed foods; (3) high intake of refined carbohydrates, processed meats, and solids fats; and (4) high intake of red meat and sugary beverages. Age, sex, sedentary lifestyle, maximum doses of anti-glycemic agent in addition to fasting plasma glucose levels were different among the patterns. Poisson regression models confirmed the association of Pattern 2 (PR=1.48; 95% CI=1.10-1.99; P=0.010) and Pattern 4 (PR=1.93; 95% CI=1.29-2.89; P=0.001) with presence of DKD after adjusting for confounders.

In conclusion, eating patterns with higher consumption of ultra-processed foods or red meat and sugary beverages were associated with the presence of DKD when compared to patterns rich in dairy products, fruits, and vegetables in this sample of T2DM outpatients.

Disclosure

C. C. R. Rodrigues: None. B. P. Riboldi: None. T. C. Rodrigues: None. R. A. Sarmento: None. J. P. Antonio: None. R. A. Borba: None. A. P. Vieira: None. I. S. Pasini: None. J. C. De almeida: None.
325-OR: Genetic and Socioeconomic Factors Are Independently Associated with Type 2 Diabetes
Authors: CROMER SARA JANE , LAKHANI CHIRAG M. , MERCADER JOSEP M. , MAJARIAN TIM , FLOREZ JOSE C. , MANNING ALISA , MERINO JORDI , UDLER MIRIAM
Published: June 2021

Genetics and socioeconomic status (SES) are key drivers of increased type 2 diabetes (T2D) risk, but the extent to which they impact disease in an additive or non-additive manner is unknown. We examined T2D prevalence using cross-sectional electronic health record (EHR) data from 27,771 participants of European ancestry in the Mass General Brigham Biobank. A polygenic score for T2D was derived using a previously published globally expanded score (gePS). Multiple area-based socioeconomic risk estimates were evaluated (including deprivation indices and a machine learning model incorporating hundreds of census variables) with similar impact on T2D risk; here, an individual’s estimated SES risk was defined as the percent of residents in their census tract with less than high school education. T2D status was derived using a machine-learning algorithm validated by expert chart review to have 90% positive predictive value. The age and sex-adjusted odds of T2D was 1.72 (95% CI 1.63-1.81, p<0.001) per SD increase of T2D gePS and 1.36 (95% CI 1.31-1.42, p<0.001) per SD increase in socioeconomic risk. In a combined model of gePS and socioeconomic risk, these associations persisted, with no evidence of interaction. Persons in the highest quintile of both genetic and socioeconomic risk had an almost 3-fold risk of T2D compared to those of middle quintile risk for both (OR 2.67, 95% CI 2.08-3.44, p<0.001). Notably, the T2D risk of individuals in the highest quintile of genetic risk but lowest quintile of socioeconomic risk was indistinguishable from that of those in the middle quintile for both risk factors (OR 1.13, 95% CI 0.85-1.51). These data provide evidence for the independent associations of genetic risk and SES with T2D and suggest that living in a community with high SES is associated with reduced T2D risk, even among those at increased genetic risk. Our findings raise the hypothesis that interventions targeted at specific elements of SES, such as education, may reduce risk of T2D in those with high genetic risk.

Disclosure

S. Cromer: Employee; Spouse/Partner; Johnson & Johnson Medical Devices Companies. C. M. Lakhani: Consultant; Self; xy. ai. J. M. Mercader: None. T. Majarian: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk. A. Manning: Employee; Spouse/Partner; Emulate, Inc, Stock/Shareholder; Spouse/Partner; Invitae. J. Merino: None. M. Udler: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007028)
332-OR: Pharmacological Inhibition of CREBZF Improves Insulin Resistance by Altering Activation of Macrophage in Adipose Tissue of Diet-Induced Obese Mice
Authors: LIU YUXIAO , HU ZHIMIN , LIU ZHENGSHUAI , SU WEITONG , ZHENG ZENGPENG , DING DONG , MA FENGGUANG , XUE YAQIAN , CAI GENXIANG , WEI SHUANG , WANG ZIXUAN , SUN XIAOYANG , JIANG YANG , DAI XIAOZHEN , LI YU , CUI AOYUAN
Published: June 2021

Obesity and type 2 diabetes are associated with chronic inflammation response in adipose tissue, in which macrophage activation and infiltration are hallmark characteristics. However, the molecular mechanism of this association remains largely unknown. Here, we report that CREBZF, a newly characterized transcription factor for insulin-induced lipogenesis, functions as a key regulator in adipose tissue macrophage and couples inflammatory signals to systemic insulin resistance in obesity. Myeloid cell-specific CREBZF knockout (CREBZF MKO) mice were generated by crossing floxed CREBZF mice with LysM-Cre transgenic mice. A small molecule (LIC902) was identified as a CREBZF inhibitor using a luciferase reporter-based high-throughput screening, which is shown to repress expression levels of CREBZF in the macrophage, such as J774. We found that ablation of CREBZF in myeloid cells or administration of LIC902 attenuates insulin resistance and hyperglycemia in mice fed with high-fat high-sucrose (HFHS) diet. Intriguingly, myeloid CREBZF deficiency or LIC902 treatment causes a profound reduction of infiltrated macrophages and reverses M1/M2 imbalance in white adipose tissue of mice fed with HFHS diet, suggesting important roles of CREBZF in regulating macrophage polarization in adipose tissue. CREBZF is capable of potentiating NF-κB signaling in the macrophage as evidenced by increased phosphorylation of p65, whereas CREBZF deficiency or inhibition of CREBZF activity results in the opposite effect. These data indicate that CREBZF plays a critical role in the regulation of innate immune response in the macrophage and maintains whole-body glucose homeostasis. Pharmacological manipulation of CREBZF may provide novel opportunities for treating metabolic diseases such as insulin resistance and type 2 diabetes.

Disclosure

Y. Liu: None. S. Wei: None. Z. Wang: None. X. Sun: None. Y. Jiang: None. X. Dai: None. Y. Li: None. A. Cui: None. Z. Hu: None. Z. Liu: None. W. Su: None. Z. Zheng: None. D. Ding: None. F. Ma: None. Y. Xue: None. G. Cai: None.

Funding

National Key Research and Development Program of China (2019YFA0802502); National Natural Science Foundation of China (81925008); Shanghai Science and Technology Commission (19140903300)
34-LB: Vitamin D Supplementation and Risk of Type 2 Diabetes in Patients with Prediabetes: A Meta-analysis of Individual Participant Data from Randomized, Placebo-Controlled Trials
Authors: PITTAS ANASTASSIOS G. , KAWAHARA TETSUYA , JORDE ROLF , NELSON JASON P. , ANGELLOTTI EDITH , VICKERY ELLEN , DAWSON-HUGHES BESS , TRIKALINOS THOMAS , BALK ETHAN M.
Published: June 2021

Background: Individual randomized clinical trials have not shown conclusively that taking vitamin D can prevent type 2 diabetes.

Methods: We conducted a systematic review and meta-analysis of individual participant-level data to determine whether vitamin D supplementation lowers the risk of diabetes in people with prediabetes. Trials published through February 12, 2021, that compared oral vitamin D supplementation (alone) with placebo over a minimum 2-year follow up, and had new-onset diabetes as a primary outcome were included. Proportional hazards models were used to analyze individual participant data, with pre-specified intention-to-treat (ITT) and per-protocol analyses, without and after adjustment for baseline age, gender, BMI, race and hemoglobin A1c. Safety was also assessed.

Results: Three trials were eligible (testing D3 20,000 IU/week [Tromsø], D3 4,000 IU/day [D2d], and eldecalcitol 0.75 μg/day [DPVD] vs. matching placebos) and contributed data from 4190 randomized participants (mean age 60.4 years, 44.2% women). After a median 3.0 years of follow-up, new-onset diabetes occurred in 475/2097 participants assigned to vitamin D and 524/2093 assigned to placebo (8.42 and 9.50 events per 100 person-years, respectively). The unadjusted hazard ratio (95% CI) for vitamin D was 0.88 (0.77 to 0.99) in the ITT and 0.85 (0.75 to 0.97) in the per-protocol analyses. Adjusted hazard ratios were 0.85 (0.75 to 0.96) in the ITT and 0.83 (0.73 to 0.94) in the per-protocol analyses. There was no evidence of heterogeneity of treatment effect among the three trials. The incidence of hypercalcemia, hypercalciuria, or kidney stones did not differ between the vitamin D and placebo groups.

Conclusion: In adult patients with prediabetes, vitamin D supplementation is safe and effective for lowering the risk of diabetes by about 15%.

Disclosure

A. G. Pittas: None. T. Kawahara: None. R. Jorde: None. J. P. Nelson: None. E. Angellotti: None. E. Vickery: None. B. Dawson-hughes: None. T. Trikalinos: None. E. M. Balk: None.

Funding

American Diabetes Association (1-14-D2D-01 to A.G.P.); National Institutes of Health (U01DK098245)
366-P: Cystatin C Predicts Incident Diabetes in Angiographied Coronary Patients
Authors: MADER ARTHUR , SPRENGER LUKAS , VONBANK ALEXANDER , LARCHER BARBARA , MAECHLER MAXIMILIAN , MUTSCHLECHNER BEATRIX , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: June 2021

Cystatin C is an established marker of renal function, and has also been found to be associated with cardiovascular disease. There is substantial overlap between risk factors for cardiovascular disease and type 2 diabetes; however, it is unclear whether cystatin C predicts new onset diabetes. This issue is addressed in the present study. We prospectively followed 481 consecutive nondiabetic patients undergoing coronary angiography for the evaluation of established or suspected stable coronary artery disease over a follow-up period of 5.5 ± 3.5 years. Overall, 135 patients (28.1%) newly developed diabetes. Cystatin C proved to be a strong predictor of incident diabetes univariately (standardized HR=1.80 [1.14-2.28], p=0.011) and after adjustment for age, gender, hypertension, smoking, LDL cholesterol, HDL cholesterol and fasting glucose (HR=1.86 [1.07-3.21], p=0.027). We conclude that cystatin C is a strong predictor of incident diabetes in angiographied coronary patients.

Disclosure

A. Mader: None. C. H. Saely: None. L. Sprenger: None. A. Vonbank: None. B. Larcher: None. M. Maechler: None. B. Mutschlechner: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
37-OR: Mitofusins 1 and 2 Collaborate to Fuel Pancreatic Beta-Cell Insulin Release via Regulation of Both Mitochondrial Structure and DNA Content
Authors: SIDARALA VAIBHAV , ZHU JIE , PEARSON GEMMA , SOLEIMANPOUR SCOTT
Published: June 2021

Mitochondrial health and function are critical for coupling glucose metabolism to insulin secretion in pancreatic β-cells. Mitochondria are highly dynamic organelles, and mitochondrial fusion is essential for regulating mitochondrial architecture. To decipher the role of mitochondrial fusion in β-cell function, we investigated the roles of dynamin-like GTPases mitofusins 1 and 2 (Mfn1 and Mfn2) in the maintenance of functional mitochondria. We observe that while loss of Mfn1 or Mfn2 is dispensable for β-cell function, combined loss of both Mfn1 and Mfn2 (Mfn1/2) in β-cells results in impaired glucose tolerance and glucose-stimulated insulin secretion (GSIS). Our assessments indicate decreased respiratory capacity in Mfn1/2-deficient β-cells, coupled with increased mitochondrial fragmentation, loss of mtDNA content, and decreased expression of subunits comprising the electron transport chain. Gene dosage studies suggest that a single allele of Mfn2 is sufficient to maintain mtDNA content and glucose homeostasis, independent of maintenance of mitochondrial structure and reticular network. Further investigations revealed that Mfn1/2-deficiency reduced mtDNA copy number through decreased levels of Tfam, a critical regulator of mitochondrial nucleoid packaging and maintenance. Overexpression of Tfam rescued mtDNA levels and GSIS in Mfn1/2 deficient β-cells. Lastly, Mfn1/2 agonists restored mtDNA levels and β-cell function in db/db mouse islets, a model for type 2 diabetes. Together, our studies demonstrate concerted roles of Mfn1 and 2 in the maintenance of mitochondrial structure and mtDNA in β-cells, and therefore propose novel therapeutic targets to restore glucose homeostasis in diabetes.

Disclosure

V. Sidarala: None. J. Zhu: None. G. Pearson: None. S. Soleimanpour: None.
38-LB: Reduced Carbohydrate and Increased Protein and Fat during Weight Loss Improve the Atherogenic Lipid Profile in Type 2 Diabetes
Authors: THOMSEN MADS N. , SKYTTE MADS J. , SAMKANI AMIRSALAR , ASTRUP ARNE , FRYSTYK JAN , CHABANOVA ELIZAVETA , HARTMANN BOLETTE , HOLST JENS J. , LARSEN THOMAS M. , MADSBAD STEN , MAGKOS FAIDON , THOMSEN HENRIK S. , WALZEM ROSEMARY , HAUGAARD STEEN B. , KRARUP THURE
Published: June 2021

Objective: Elevated triglyceride-rich lipoproteins (TRL), excess small dense LDL particles (LDL5) and decreased HDL2/HDL3 ratio promote atherogenesis in type 2 diabetes (T2D). Carbohydrate restriction reduced intrahepatic triglyceride (IHTG) content beyond the positive effect of weight loss in a group of T2D patients, the present study sought to determine whether parallel improvements in lipoprotein density profiles occurred in these same patients.

Research Design and Methods: Seventy-two adult T2D patients with a mean BMI of 33 kg/m2 were assigned to 6 weeks of fully-provided hypocaloric dietary treatment aimed at ~6% weight loss, either with a carbohydrate-reduced high-protein (CRHP, C30E%/P30E%/F40E%) diet or a conventional diabetes (CD, C50E%/P17E%/F33E%) diet. Density profiles of lipoproteins were determined by ultracentrifugation of fluorescently labelled plasma. Magnetic resonance spectroscopy was used to assess IHTG.

Results: Body weight decreased by 5.8 kg (~6%) in both groups. Compared with the CD diet, the CRHP diet reduced TRL (mean [95% CI]) by -16 [-30;1]% (p=0.07) and LDL5 by -13 [-22;-3]% (p=0.01), and increased HDL2/HDL3 by 11 [1;22]% (p=0.04). The CRHP diet also decreased IHTG more than the CD diet (-26 [-45;0]%, p=0.05), and changes in IHTG including both groups correlated significantly with changes in TRL and LDL5 (Spearman’s ρ 0.39 and 0.38, p<0.01).

Conclusions: Carbohydrate restriction adds to the positive effect of weight loss in T2D patients by inducing greater improvements in atherogenic lipid profile, maybe facilitated by a reduction in intrahepatic fat.

Disclosure

M. N. Thomsen: None. S. Madsbad: Advisory Panel; Self; AstraZeneca; Boehringer Ingelheim; Eli Lilly; Merck Sharp & Dohme; Novo Nordisk; Sanofi, Research Support; Self; Novo Nordisk, Boehringer Ingelheim, Speaker’s Bureau; Self; AstraZeneca; Boehringer Ingelheim; Merck Sharp & Dohme; Novo Nordisk; Sanofi. F. Magkos: None. H. S. Thomsen: None. R. Walzem: None. S. B. Haugaard: None. T. Krarup: None. M. J. Skytte: None. A. Samkani: None. A. Astrup: Consultant; Self; Groupe Éthique et Santé, France, Employee; Self; Novo Nordisk Foundation, Other Relationship; Self; Flaxslim ApS, Denmark, Gelesis, Personalized Weight Management Research Consortium ApS (Gluco-Diet. dk). J. Frystyk: None. E. Chabanova: None. B. Hartmann: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. T. M. Larsen: None.

Funding

Arla Foods; Danish Dairy Research Foundation
39-LB: Estimating Basal Metabolic Rate in People with Diabetes
Authors: WEXLER YDO , GOLDNER DAN
Published: June 2021

Objective: Health care settings and self-care programs use Basal Metabolic Rate (BMR) to determine caloric need. BMR is difficult to measure directly, so many formulas have been published to estimate BMR, each derived from relatively small samples. We fit two regressions to a large sample of BMR estimates from the Apple Watch for people with diabetes and prediabetes, and compared the results to 10 common BMR formulas.

Method: Data included self-reported height, age, sex, weight, diabetes type, and over 500,000 daily values of BMR and caloric expenditures from Apple Watch, from 3,071 people (56% male, 14.5% female; 29.5% unreported; 11.4% type 1, 58.9% type 2, 15.3% prediabetes, 14.4% other diabetes). We regressed to Apple Watch BMR using 5-fold cross-validation, first with height, weight, age and sex only, then adding 30-day calorie expenditure, and measured the hold-out accuracy.

Results: The 10 published formulas we evaluated predicted Apple Watch BMR with an average RMSE of 354 ± 67 calories and an average R2 of 0.726 ± 0.074. The Harris-Benedict equation showed the closest correspondence to Apple Watch BMR, with RMSE 287 calories and R2 0.760. Our regression without energy expenditure yielded BMR = -112.2 + 1.08w + 3.89h - 51.6g + 0.13w2 + 0.0467h2 - 0.00041w3 - 0.00017h3, and with energy expenditure, BMR = -232 + 1.66w + 4.01h - 46.9g + 0.13w2 + 0.045h2 - 0.000417w3 - 0.00017h3 + 0.0091e, where w=weight (kg), h=height (cm), g=gender(-1=male, 1=female, 0=unreported) and e = 30-day energy burn (kcal). The accuracies were RMSE 280 calories, R2 0.766; without energy expenditure and RMSE 274 calories, R2 0.780 with energy expenditure.

Conclusion: Regressions to more than a half-million samples from over 3,000 people with diabetes predicted Apple Watch BMR estimates with lower error than common published formulas. The most accurate regression included 30-day energy burn, reducing RMSE by 13 calories (4.5%) and increasing R2 by .02 vs. the closest common formula. These results recommend consideration of activity measures when estimating BMR.

Disclosure

Y. Wexler: None. D. Goldner: Employee; Self; One Drop.
39-OR: Pancreatic Beta Cell SERCA2 Deficiency Impacts ER-Golgi Vesicle Trafficking and Ceramide Metabolism
Authors: KONO TATSUYOSHI , IIDA HITOSHI , LEE CHIH-CHUN , KRISHNAN PREETHI , ARVAN PETER , LINDBERG IRIS , EVANS-MOLINA CARMELLA
Published: June 2021

Alterations in endoplasmic reticulum (ER) calcium (Ca2+) levels arising from reduced activity of the Sarcoendoplasmic Reticulum Ca2+ ATPase (SERCA) pump are associated with impaired insulin secretion and reduce β-cell survival in both major forms of diabetes. However, at present, the mechanisms of how reduced ER Ca2+ impairs β-cell function remain incompletely understood. To test this, we analyzed mice with β-cell specific SERCA2 deletion (βS2KO mice) and S2KO INS1 cells. βS2KO mice exhibited age-dependent glucose intolerance, reduced glucose-stimulated insulin secretion, and increased proinsulin secretion without evidence of impaired insulin sensitivity. Immunoblot analysis of βS2KO islets and S2KO INS-1 cells revealed reduced active forms of the proinsulin processing enzymes, PC1/3, PC2, and CPE, while immunofluorescence analysis suggested impaired ER-Golgi trafficking of the convertase enzymes and proinsulin. Because the ER serves as the main site of cellular lipid synthesis and changes in the β-cell lipidome have been linked with diabetes pathophysiology, we hypothesized that ER Ca2+ loss may alter protein trafficking in the secretory pathway through changes in ER lipid content. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed on the ER fractions of control and S2KO INS1 cells and revealed increased levels of 16:0, 24:0, 24:1, and total ceramides in S2KO cells. SERCA2 restoration partially rescued convertase enzyme expression, proinsulin processing, and ceramide content. Consistent with these findings, RNA sequencing analysis of βS2KO islets revealed changes in pathways related to vesicle transport, protein processing, and lipid metabolism. We conclude that SERCA2 in the β-cell plays a central role in the maintenance of insulin biosynthesis as well as ceramide metabolism.

Disclosure

T. Kono: None. H. Iida: None. C. Lee: None. P. Krishnan: None. P. Arvan: None. I. Lindberg: None. C. Evans-molina: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; Dompe, Other Relationship; Self; Bristol-Myers Squibb Company, Nimbus Pharmaceuticals, Pfizer Inc.

Funding

National Institutes of Health (R01DK093954)
397-P: Insulin Dosing Adjustments in Patients with Diabetes on Peritoneal Dialysis or Hemodialysis: A Systematic Review of the Literature
Authors: TUMLINSON ROBIN , BLAINE EMILY , COLVIN MARION , HAYNES TYLER G. , WHITLEY HEATHER P.
Published: June 2021

Chronically uncontrolled hyperglycemia is the leading cause of end-stage renal disease (ESRD) necessitating dialysis. During times of transition to hemodialysis (HD) or peritoneal dialysis (PD), considerations must be given to insulin dosing adjustments for persons with diabetes (PWD) in efforts to maintain glycemic control. However, literature is sparse with few clear and direct practical clinical recommendations for therapeutic adjustments. The objective of this systematic review was to identify and report the evidence and gaps in the literature for adjustments in therapeutic insulin recommendations when initiating HD or PD in patients with ESRD and diabetes mellitus. A literature search using PubMed, CENTRAL, MEDLINE, CINAHL, Google Scholar, and ClinicalTrials.gov revealed 184 results. After removing duplicates and articles not reaching pre-specified criteria, 29 relevant articles remained for further analysis. The most common recommendation regarding HD was to reduce the basal insulin dose up to 25% on HD days to prevent hypoglycemia, although a lack of consensus exists on the percent reduction. Little information was found as to insulin management with continuous ambulatory PD (CAPD) or automated PD (APD). During PD, insulin may be administered subcutaneously, intraperitoneally, or with the dialysis fluid. Administration of insulin with dialysate may necessitate a dose increase of up to 30% due to a loss to tubing and dilution. Furthermore, the use of dextrose-based dialysate may require additional insulin to mitigate systemic impact of dextrose absorption on blood glucose. Overall, a gap exists in the primary literature regarding recommendations for prophylactically adjusting insulin therapy when initiating HD or PD, or when switching between the two. Greater research is needed to clarify ideal alterations in insulin dosing, administration techniques, and product selections for this patient population.

Disclosure

R. Tumlinson: None. E. Blaine: None. M. Colvin: None. T. G. Haynes: None. H. P. Whitley: None.
426-P: Sudomotor Dysfunction Is Associated with Decreased Cardiac Diastolic Function in Patients with Type 2 Diabetes
Authors: CHEN XUEYAN , YANG XUBIN , XU WEN , DENG HONGRONG , WU JINPING , YAN JINHUA , YAO BIN
Published: June 2021

Diabetic autonomic neuropathy has been proved to be associated with onset of heart failure in patients with diabetes. However, relationship between sudomotor dysfunction, the early manifestation of autonomic neuropathy, and cardiac diastolic function has not yet been investigated. This study aimed to explore the association between sudomotor function and cardiac diastolic function in patients with type 2 diabetes mellitus (T2DM).

A total of 63 patients (65% male, 50±13 years old) with T2DM were enrolled and divided into two groups according to mean feet electrochemical skin conductance (ESC) assessed by sudoscan device: sudomotor dysfunction group(SDF group: ESC≤60 μS) and normal sudomotor function group (NSF group: ESC>60 μS). Impaired cardiac diastolic function detected by tissue Doppler imaging echocardiography manifested as elevations of late atrial (A) transmitral peak flow velocity (LgA) and the early (E) transmitral peak flow velocity/early diastolic velocity (e’) (E/e’ratio).

The prevalence of sudomotor dysfunction was 30.2%. In SDF group, LgA and E/e’ ratio were significantly higher than those in NSF group (-0.2±0.2 m/s vs. -0.4±0.3 m/s, P=0.011 and 11.0±3.8 vs. 8.8±2.7, P=0.013, respectively). Pearson correlation analysis revealed that LgA was negatively correlated with mean feet ESC(r=-0.3, P=0.017). In logistic regression analyse, LgA (OR=0.05, 95%CI 0.004-0.585, P=0.017) and E/e‘ ratio (OR=0.79, 95%CI 0.641-0.970, P=0.025) were found to be independently associated with presence of sudomotor dysfunction.

Cardiac diastolic function significantly decreased in type 2 diabetic patients with sudomotor dysfunction.

Disclosure

X. Chen: None. X. Yang: None. W. Xu: None. H. Deng: None. J. Wu: None. J. Yan: None. B. Yao: None.

Funding

Natural Science Foundation of Guangdong Province (2018A030313915); Medical Scientific Research Foundation of Guangdong Province (A2018286)
451-P: Participants’ Satisfaction with the Support Online Self-Guided Educational Platform for Type 1 Diabetes Management: A Proof-of-Concept Study, Preliminary Results
Authors: XIE LI FENG , LEROUX CATHERINE , ROY-FLEMING AMÉLIE , RABASA-LHORET RÉMI , BRAZEAU ANNE-SOPHIE
Published: June 2021

Introduction: The development of the SUPPORT self-guided online educational platform was guided by the behavioral wheel framework and built by healthcare professionals specialized in type 1 diabetes (T1D) and patient-partners. It has 4 learning paths that are based on the mode of insulin delivering and blood glucose monitoring of the patient. The learning modules are divided into 6 groups (e.g., medication, nutrition) and have 3 levels of complexity. Features (e.g., quiz, glossary) are included. This proof-of-concept study aims to evaluate the satisfaction of adults with T1D using the SUPPORT platform after 6 months.

Methods: Adults (≥18 years old) living with T1D for ≥ 1 year, using ≥ 4 insulin injections per day or an insulin pump, and having access to the Internet were recruited from the BETTER registry in Quebec. People with ongoing pregnancy or illness limiting diabetes care were excluded. Usage data were collected with Google Analytics. A face-validated 10-item questionnaire was sent after 6 months of access to SUPPORT to evaluate participants’ satisfaction and feedback (e.g., top 3 preferred features).

Results: A total of 61 participants (38% men; age 50.3±13.3 years; T1D duration 24.3±14.6 years; mean viewing time per connected session: 12min56sec) completed the 6-month questionnaire. The mean satisfaction score was 39.6±7.8 (out of 49; higher score for a greater satisfaction). The most preferred features were access to downloadable PDF summaries, quizzes, and blogs on scientific updates. Providing certificates, virtual points, and glossary were the least appreciated. More than half reported being more confident to prevent (53%) and manage (53%) hypoglycemia.

Conclusion: The SUPPORT platform received a high level of satisfaction. Although further validation is needed, this platform may be a useful resource for widely and timely diabetes education and for reducing the hypoglycemia burden faced by patients.

Disclosure

L. Xie: None. C. Leroux: None. A. Roy-fleming: None. R. Rabasa-lhoret: Advisory Panel; Self; Bayer Inc., Covance Inc., Insulet Corporation, Pfizer Inc., Other Relationship; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Dexcom, Inc., Eli Lilly and Company, HLS Therapeutics Inc., Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Novo Nordisk, Sanofi-Aventis, Research Support; Self; Canadian Institutes of Health Research, Cystic Fibrosis Canada, Diabetes Canada, JDRF, National Institutes of Health, Prometic, Société Francophone du Diabète, Speaker’s Bureau; Self; CMS Canadian Medical&Surgical Knowledge Translation Research Group, CPD Network. A. Brazeau: None.

Funding

Canadian Institutes of Health Research (JT1-157204); JDRF (4-SRA-2018-651-Q-R)
476-P: Multidisciplinary Predialysis Team Education for Patients with Diabetic Nephropathy, Postponed Hemodialysis Induction, and Prolonged Survival after Hemodialysis Induction
Authors: HITOMI MAMIKO , SATO TERUKO , MORIYA TATSUMI
Published: June 2021

To determine whether a multidisciplinary team approach (MTA) improves the course of hemodialysis (HD), including clinical status, hospital admission costs, and prognosis after HD induction, in patients with diabetic nephropathy (DN), we compared the HD course of 36 patients who received MTA and 33 patients managed with a dietitian approach (DA) (n=69; 47 men: mean age, 59±12 years; 66 type 2 diabetic patients). HD started between January 2010 and June 2016. The observation period ended with death or in September 2018. MTA staff consisted of physicians, dietitians, nurses, laboratory technologists, and pharmacists. They provided broad education, including advice on nutrition, medication, medical examinations, and foot care. There were no significant differences in HbA1c, age, BMI, or eGFR between the groups when the baseline serum creatinine (S-Cr) was 2.0 mg/dL. There were no differences in the incidence of severe hypoglycemia or use of erythropoiesis-stimulating agents or RAS inhibitors. The MTA group was more likely to undergo 24-h urine collection than the DA group (likelihood ratio, 6.11; p=0.014). The MTA group had smaller CTR than the DA group (52.0% vs. 55.8%; p=0.024). Sodium intake based on 24-h urine collection was correlated with CTR (p=0.033). The MTA group had lower cost per admission for HD induction than the DA group ($20,580±14,170 vs. $14,804±8,397; p=0.023). Kaplan-Meier survival analysis showed that the MTA group had a longer duration from Cr 2.0 mg/dL to HD initiation (Wilcoxon 5.679; p=0.017) and from HD initiation to death than the DA group (Wilcoxon 3.860; p=0.050). MTA provided multiple broad effects with a longer duration before HD initiation, better clinical course, lower costs, and prolonged survival after HD induction compared with DA when observation started at the same S-Cr level. Future studies are needed to examine whether MTA has legacy effects after HD initiation.

Disclosure

M. Hitomi: None. T. Sato: None. T. Moriya: None.
481-P: Risk Assessment among Organizations Participating in the National Diabetes Prevention Program (National DPP) Lifestyle Change Program
Authors: JABRAH RAJAI , ELY ELIZABETH
Published: June 2021

The National DPP is a partnership of public and private organizations working to build a nationwide delivery system for a lifestyle change program (LCP) proven to prevent or delay onset of type 2 diabetes in adults with prediabetes. The CDC’s Diabetes Prevention Recognition Program (DPRP) recognizes organizations that deliver the 12-month LCP. Organizations can achieve three levels of recognition—pending, preliminary, or full—which reflect their ability to meet national quality standards. Identifying factors that impact organizations’ ability to meet these standards provides opportunities to strengthen their program delivery. This study aims to compare program enrollment and retention among in-person LCP participants in organizations that have achieved preliminary or full recognition to that of organizations that withdrew from the DPRP. Analysis was limited to the 109,201 eligible participants who had the opportunity to complete the 12-month program by March 2020. Among the 862 organizations that had achieved preliminary or full recognition, the average enrollment per 6-month period was 31 participants. However, the average enrollment per 6-month period among the 335 withdrawn organizations was 19 participants. Among organizations that achieved preliminary or full recognition, 60% of participants were retained for ≥9 months. Among withdrawn organizations, however, only 44% of participants were retained for ≥9 months. Among organizations that achieved preliminary or full recognition, the average number of sessions attended in the first and second 6-month phases was 14 and 6, respectively. For withdrawn organizations, however, the average number of sessions attended in the first and second phases was 13 and 3 sessions, respectively. Knowing that withdrawn organizations struggled with enrollment and retention provides a starting point for identifying strategies to assist these organizations.

Disclosure

R. Jabrah: None. E. Ely: None.
485-P: Insights from Type 2 Diabetes Patients Reveal Education- and Income-Based Disparities in Awareness Surrounding Kidney Disease Risk and Renoprotective Therapies
Authors: STEVENSON JULIA , YE EMILY , SUHL SARA , GOWEN REBECCA , TAIT JACQUELINE , FLORISSI CATERINA , WOOD RICHARD
Published: June 2021

Objective: Diabetes is a leading cause of chronic kidney disease (CKD), and new drug classes including SGLT-2 inhibitors and GLP-1 receptor agonists have shown renal benefits for those with type 2 diabetes (T2D). This study evaluated T2D patients’ awareness regarding CKD and renoprotective drugs across household income and educational attainment.

Method: In an online survey in September 2020, 2,008 adults with T2D not currently being treated for kidney disease rated their level of agreement with statements about CKD risk and renoprotective drugs. Demographic information was collected.

Result: The majority (58%) of patients strongly agreed that diabetes increases risk of CKD. Those with an income of <$50k and a high school diploma were less aware of the link between diabetes and CKD than those with the same income and a bachelor’s degree or higher (51%, vs. 62%) and those with an income of >$100k and a bachelor’s degree or higher (65%). Only 30% of patients indicated strong concern about CKD risk, and 25% were aware that some T2D drugs have renal benefits. Among those earning $50k-$100k, patients with a high school diploma were more concerned about their risk (44%) than those with some college (24%) or a bachelor’s degree or higher (29%). Those earning >$100k with a bachelor’s degree or higher were more likely to indicate strong awareness that some T2D drugs are renoprotective (34%) than those earning <$50k (high school diploma: 23%; some college: 24%), those earning $50k-$100k (some college: 24%; bachelor’s degree or higher: 25%), and those earning >$100k with some college (20%).

Conclusion: While few T2D patients are aware that some T2D drugs have renoprotective effects, those with higher education and income are more likely to be aware. These findings emphasize the importance of informing patients about renal health and therapeutic options, in efforts to increase accessibility of SGLT-2 and GLP-1 therapies to all who would benefit.

Disclosure

J. Stevenson: Other Relationship; Self; Abbott, Ascensia Diabetes Care, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, LifeScan, Medtronic, Roche Diabetes Care, Senseonics, Tandem Diabetes Care. E. Ye: Other Relationship; Self; dQ&A. S. Suhl: Other Relationship; Self; dQ&A has several clients (>10) in the diabetes field. R. Gowen: Other Relationship; Self; dQ&A. J. Tait: Other Relationship; Self; dQ&A Market Research Inc. C. Florissi: Other Relationship; Self; Abbott Diabetes, Ascensia Diabetes Care, Dexcom, Inc., Insulet Corporation, LifeScan, Lilly Diabetes, Medtronic, Roche Diabetes Care, Senseonics, Tandem Diabetes Care. R. Wood: Research Support; Self; Abbott Diabetes, American Diabetes Association, Ascensia Diabetes Care, Boehringer Ingelheim International GmbH, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk Inc., Sanofi.
487-P: Exploring the Research Experiences of American Indian Mother/Daughter Dyads and Site Coordinators after a GDM Risk Reduction and Preconception Counseling Randomized Controlled Trial
Authors: STOTZ SARAH A. , FISCHL ANDREA F. , TERRY MARTHA A. , GARROW HEATHER , O’BANION NANCY , CHALMERS LAURA , MOORE KELLY R. , CHARRON-PROCHOWNIK DENISE
Published: June 2021

Gestational diabetes mellitus (GDM) is the most common complication of pregnancy and contributes to increased risk for T2D in both the mother and offspring. American Indians are at higher risk of GDM and subsequent diagnosis of T2D than non-Hispanic white women. This project examined the experiences of American Indian mother-daughter (M-D) dyads as participants and the site coordinators who facilitated a GDM risk reduction and preconception counseling randomized controlled trial (RCT) to evaluate Stopping GDM (SGDM). The SGDM RCT included 4 visits over 9 months which dyads attended together but completed SGDM intervention (video and eBook) and questionnaires separately. SGDM content included GDM risk reduction (e.g., healthy nutrition), GDM risk awareness/health beliefs, preconception counseling, reproductive health communication, and family planning. For this study, dyads (n=22 dyads) were recruited from three of the five study sites and site coordinators from all sites participated (n=6). Mothers, daughters, and site coordinators were in separate focus groups. Focus groups were facilitated by trained qualitative researchers, conducted/recorded remotely using Zoom, transcribed verbatim, and analyzed using qualitative content analysis and Atlas.ti. Themes include: 1) SGDM provided valuable quality time and conversation about GDM and reproductive health among dyads; 2) GDM risk factors and risk reduction was largely new information for most dyads; 3) all sites experienced challenges to study engagement and recruitment; 4) recommendations for study improvement: personalized recruitment that is clinic-based and mother-focused; remote/asynchronous study visits; and significantly shorter content. These findings will be used to inform revisions of SGDM to improve the program and for a broader, more inclusive version of the program for other at-risk females.

Disclosure

S. A. Stotz: None. A. F. Fischl: None. M. A. Terry: None. H. Garrow: None. N. O’banion: None. L. Chalmers: None. K. R. Moore: None. D. Charron-prochownik: None.

Funding

National Institutes of Health (UL1TR001857 to D.C-P.); National Institute of Nursing Research (1R01NR014831-01A1 to D.C-P., K.R.M.)
505-P: Implementation of Nutrition Assessments to Evaluate and Improve Nutrition Knowledge at Initial Follow-up of New-Onset Type 1 Diabetes
Authors: THIVIERGE MEREDITH R. , SNOW SHANI , SEEL MAUREEN , BROWN ELIZABETH A. , AKHTAR YASMIN , WOLF RISA
Published: June 2021

Background: Carbohydrate counting is a key component of type 1 diabetes (T1D) management that is taught at the time of diagnosis, but it is hard to determine how much knowledge is retained during that stressful period. We hypothesize that implementation of a nutrition quiz at one of the first comprehensive diabetes follow-up visits will evaluate knowledge retained and increase carbohydrate counting knowledge in newly diagnosed T1D patients.

Methods: A quality improvement project was prospectively conducted to assess nutrition knowledge retained following new onset diagnosis of T1D. We implemented a 16-item nutrition assessment (at the 1st or 2nd outpatient visit), evaluating topics including nutrition label reading, hypoglycemia/hyperglycemia management, and insulin dose calculations. Data was collected from the medical record, and descriptive and summary statistics were performed.

Results: Quizzes were administered to 17 patients/caregivers, mean age of patient 8.9y (SD=3.5), 83% NH White, mean HbA1c 9% at time of assessment, and mean time of 2.5 months from diagnosis. Quizzes were completed by parents 53%, parents and child 35%, and child 12% of the time. Mean overall quiz score was 13.5/16, with scores related to questions about insulin of 4.18/5, general nutrition of 3.24/4, nutrition labels of 1.65/2, and symptoms and complications of 4.41/5. The dietitian spent on average 20 min (range 13-30 min) with patient/caregiver. Patient age was not associated with quiz score. Patients with private insurance scored higher on the quiz compared to those with Medicaid (p = 0.05). Ongoing recruitment may further elucidate this association.

Conclusions: Implementation of nutrition assessments is feasible and facilitates nutrition education with the patient and/or caregiver in an engaging manner. There is a vast amount of nutrition knowledge to be acquired at diagnosis of T1D, and reinforcement is important for long-term diabetes management and outcomes.

Disclosure

M. R. Thivierge: None. S. Snow: None. M. Seel: None. E. A. Brown: None. Y. Akhtar: None. R. Wolf: Consultant; Self; NEMA Research.