bluuebunny/crossref_metadata_2025 huggingface dataset:
172-LB: Identification of Specific Risk Factors for Mortality in Patients with Diabetes Mellitus Hospitalized with COVID-19
Authors: PINÉS-CORRALES PEDRO J. , MOLINA MARIA , GARCÍA-BLASCO LOURDES , TOBOSO ROSA QUILEZ , ALCARAZ MARINA , GUTIÉRREZ LUIS VICENTE , MELLINAS GEMA PATERNA , CALBO MAYO JUAN MARIA , ALFARO-MARTÍNEZ JOSÉ-JOAQUÍN
Published: June 2021

Introduction: Several studies have shown that diabetes mellitus (DM) is a risk factor for in hospital mortality due to COVID-19. The aim of our study was to analyze if prior clinical characteristics among DM patients affected the risk of in hospital mortality compared with nondiabetic patients hospitalized with COVID-19.

Material and Methods: The study was based on a retrospective, observational design and was conducted at two hospitals located in Albacete (Spain). All patients hospitalized with COVID-19 since the start of the pandemic until 7 July 2020 were included.

Results: During the study period, 1468 patients were hospitalized due to COVID-19; 402 of them had DM prior to hospitalization. DM was associated with higher in hospital mortality (28.6% versus 17.5%) in the univariate analysis. But, in a multivariate logistic regression analysis, after adjusting for age, presence of hypertension, smoking, presence of COPD, ACEI, ARB, antiplatelet, or anticoagulant therapy, DM was not a significant risk factor for death. Patients with DM2 receiving insulin treatment had a higher risk of in hospital death than nondiabetic patients (OR 1.78 [1.13-2.81], p=0.0126) after age was considered. The age-associated relative risk was 1.06 (1.05-1.07, p<0.001) per year, whereas the relative risk associated with DM2 treated with insulin compared with no DM was 1.57 (1.11-2.23, p=0.0111) suggesting that DM2 treated with insulin entails a risk of in hospital COVID-19 death equivalent to being 9 years older. When previous logistic regression models included other variables related to personal history and prior nondiabetic treatments, the risks described showed no change.

Conclusion: This study confirms that pre-admission need for insulin therapy before hospitalization in patients with DM2 are associated with higher in hospital mortality due to COVID-19 in a large sample of DM inpatients with COVID-19.

Disclosure

P. J. Pinés-corrales: None. M. Molina: None. L. García-blasco: None. R. Quilez toboso: None. M. Alcaraz: None. L. Vicente gutiérrez: None. G. Paterna mellinas: None. J. Calbo mayo: None. J. Alfaro-martínez: None.
174-LB: Severe Hypoglycemia, High Anxiety, and Depressive Symptoms Are Associated with Erectile Dysfunction in Male Adults with Type 1 Diabetes in a Brazilian Tertiary Hospital
Authors: JASKULSKI PAULA R. , PAVIN ELIZABETH J. , SILVEIRA MÔNICA S. , KOELLE MARIA B.
Published: June 2021

DM is the comorbidity that exerts the greatest risk for erectile dysfunction (ED). Studies have demonstrated a higher prevalence of sexual hormones’ disorders and depression in this population. There are few studies evaluating these aspects in persons with T1D (PWT1D). This study aimed to describe the frequency of ED in male adults with T1D (MAWT1D) followed in a Brazilian tertiary hospital and verify which sociodemographic, clinical, and laboratory factors were related to ED. In a cross-sectional study, 48 MAWT1D were evaluated. Inclusion criteria were T1D diagnosis for ≥ 5 years and age ≥ 18 years. We excluded MAWT1D in which other clinical conditions were present (e.g. COVID-19 infection, alcohol abuse). Patients’ characteristics were evaluated through medical records and a standard questionnaire displayed by Google Forms. Severe hypoglycemia was defined when PWT1D required another person assistance. Sexual hormones were measured by electrochemiluminescence and free androgen index (FAI) was calculated by multiplying total testosterone (ng/ml) by 347, then dividing by the sex hormone binding globulin (nmol/L). The scale 5-Item Version of the International Index of Erectile Dysfunction (IIEF-5) assessed ED. The Hospital Anxiety and Depression Scale - HAD measured anxiety and depressive symptoms (Cut point ≥ 8 indicated clinically relevant symptoms). Continuous and categorical measures were analyzed by Mann-Whitney, Kruskal-Wallis, chi-square, or Fisher’s exact test (p<5%). The participants’ average age was 35.5 ± 12.6 years, and mean years of T1D diagnosis was 22.08 ± 11.2 years. The ED frequency was 52.08%. The associated factors were: severe hypoglycemia (p= 0.0007), HAD/D and HAD/A ≥ 8 (p=0.0184 and p = 0.0042, respectively). FAI was lower in ED group (0.0410).

Conclusion: ED frequency is high in MAWT1D and its associated factors should be mitigated to improve ED and quality of life in this population.

Disclosure

P. R. Jaskulski: None. E. J. Pavin: None. M. S. Silveira: None. M. B. Koelle: None.
174-OR: ADA Presidents’ Select Abstract: Epigenetic Regulation of Functional Beta-Cell Mass by Cohesin Smc3
Authors: WANG JEAN K. , PANDEY APARAMITA , HAM ALEXANDER P. , PARVEEN NAZIA , DHAWAN SANGEETA
Published: June 2021

Both type 1 and type 2 diabetes are caused by insulin insufficiency due to inadequate functional beta-cell mass. The demise of beta-cells in diabetes is preceded by progressive impairment of beta-cell function. Several studies have shown that the regulation of beta-cell function and survival is tightly linked. However, the precise molecular mechanisms that link beta-cell function and survival remain far from clear. In this study, we report that the cohesin Smc3 is a novel epigenetic regulator of functional beta-cell mass. Smc3 is an ATPase that regulates the 3D chromatin architecture and chromatid cohesion, and plays an important role in cellular self-renewal, differentiation, and survival. Smc3 exists in a tripartite ring complex with proteins Smc1 and Rad21, and the association of this complex to the chromatin is regulated by Stag1. Our chromatin immunoprecipitation data suggest that the cohesin complex regulates beta-cell maturation and survival programs. Using transcriptomic profiling combined with histological and physiological analyses, we show that that the beta-cell specific Smc3 knockout mice (Smc3-BKO) become diabetic by 3 months of age, due to a progressive loss of beta-cell maturity and viability. Islets from the Smc3-BKO mice display impaired glucose stimulated insulin secretion (GSIS) around 1-2 months of age, with gene expression signatures that resemble functionally immature neonatal beta-cells. This is followed by progressive decline of beta-cell mass. At a molecular level, disruption of Smc3 leads to reduced protein levels of the other two subunits of the cohesin ring complex, Smc1 and Rad21. On the other hand, the mRNA levels of Stag1 are increased in the Smc3-BKO islets. Finally, we show that the cohesin regulatory program is disrupted in islets from humans with type 2 diabetes. Taken together, these studies provide a novel insight into the integrative epigenetic regulation of functional beta-cell mass.

Disclosure

J. K. Wang: None. A. Pandey: None. A. P. Ham: None. N. Parveen: None. S. Dhawan: None.
175-LB: Stress Hyperglycemia Predicts Mechanical Ventilation and Death in COVID-19 Infected Adults
Authors: MCDONNELL MARIE E. , SIMONSON DONALD C. , CROMWELL GRACE , GOPALAKRISHNAN GEETHA , GREENFIELD MARGARET , JOHNSON MATTHEW , KATTA SAI R. , LEBASTCHI JASMIN , MITRI JOANNA , PALERMO NADINE E. , RADHAKRISHNAN RAMYA , WESTCOTT GREGORY P. , WEINSTOCK RUTH S. , GARG RAJESH
Published: June 2021

People with diabetes (DM) hospitalized with COVID-19 infection have a 2-3 fold higher risk of death compared with those without DM, and mechanical ventilation (MV) has been identified as a major risk factor for death. While stress hyperglycemia (StH) has been established as a risk factor for death in some critically ill cohorts, it is not a well-established risk factor for MV in COVID-19. The COVIDEastDM consortium pooled data from 5 academic hospitals on the East Coast of the US to study the relationship between hyperglycemia and COVID-19 outcomes. Data were obtained retrospectively from electronic records of adults with COVID-19 and either DM or StH (defined in this cohort as day-1 admission blood glucose >180 mg/dl and A1c <6.5%). This analysis included 3,435 individuals, of which 1,001 (29.1%) required MV and 748 (21.8%) died. The mean age was 67 ± 15 yrs., BMI 30.4 ± 7.7 kg/m2, A1c 7.98 ± 2.21 % and glucose 184 ± 104 mg/dl. Additionally, 57% were male, 4 % Asian,19% Black, 52% White, and 28% Hispanic. In a univariate analysis, risk factors for MV included younger age (OR 0.98 [95% CI 0.97, 0.99] per year older), male sex (OR 1.4 [1.2, 1.7]), BMI (OR 1.013 [1.003, 1.023] per kg/m2), Hispanic ethnicity (OR 1.16 [1.07, 1.28]) and the presence of diabetic ketoacidosis (n=38) at admission (OR 3.9 [2.0, 7.5]). Patients with StH were more likely to require MV (OR 1.93, [1.10, 3.39]). In a multivariate analysis, this relationship was continuous, with both lower A1c and higher glucose increasing risk of MV (p< 0.01 for higher glucose, p<0.001 for lower A1c). Patients who required MV were more likely to die than those who did not require MV (OR 5.1, [4.3, 6.1]) and StH predicted mortality in the multivariate analysis. Thus, in patients hospitalized with COVID19 infection, StH is a strong predictor of both MV and death in COVID-19 infected adults. While it is unclear if StH is a cause or effect of severe COVID-19, its presence early in the hospital course identifies higher risk patients and could potentially impact management.

Disclosure

M. E. Mcdonnell: Stock/Shareholder; Spouse/Partner; Abbott Diabetes. N. E. Palermo: None. R. Radhakrishnan: None. G. P. Westcott: None. R. S. Weinstock: Research Support; Self; Boehringer Ingelheim International GmbH, Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Insulet Corporation, Kowa Research Institute, Inc., Medtronic, Tolerion, Inc. R. Garg: None. D. C. Simonson: Stock/Shareholder; Spouse/Partner; Phase V Technologies, Inc. G. Cromwell: None. G. Gopalakrishnan: None. M. Greenfield: None. M. Johnson: None. S. R. Katta: None. J. Lebastchi: None. J. Mitri: Consultant; Self; L-Nutra.

Funding

TechFoundation; Brigham Education Institute
175-OR: The Mitochondrial Life Cycle Determines ß-Cell Maturity through Activation of the Integrated Stress Response
Authors: PEARSON GEMMA , LAWLOR NATHAN , ZHU JIE , WALKER EMILY M. , RECK EMMA C. , STITZEL MICHAEL L. , SOLEIMANPOUR SCOTT
Published: June 2021

Mitochondrial function is pivotal to β-cell competence. The mitochondrial life cycle balances mitochondrial biogenesis and turnover (mitophagy) to ensure optimal metabolic function. Human type 2 diabetic (T2D) β-cells are known to develop mitochondrial structural/functional defects, suggestive of a defective mitochondrial life cycle. However, it is unclear if these defects are a cause or consequence of T2D. Here, we observed that human T2D β-cells had reduced mitophagic flux, mtDNA content, and expression of mitochondrially encoded genes. To test the importance of the mitochondrial life cycle to drive β-cell failure in T2D, we developed 2 distinct β-cell specific mouse models: βTfamKO (to deplete mtDNA) and βClec16aΚΟ (to impair mitophagy). We observed age dependent loss of glucose tolerance, glucose stimulated insulin secretion and β-cell mass in both models, which was exacerbated by obesity in βClec16aΚΟ mice. Loss of β-cell mass was largely independent of changes in proliferation or apoptosis but rather, due to an induction of β-cell immaturity. Using lineage tracing approaches, we confirmed that βClec16aKO and βTfamKO mice induce formation of both insulin-negative immature β-cells and β-to-α cell transdifferentiation. Further, high-throughput gene expression profiling, biochemical, and metabolic assays highlighted that either Clec16a or Tfam deficiency induces an aberrant retrograde signaling program, manifested by reductions in cellular ATP and activation of the integrated stress response (ISR). Importantly, inhibition of the ISR in vivo ameliorated glucose intolerance, defective insulin secretion, β-cell immaturity, and loss of β-cell mass, suggesting that aberrant retrograde signaling may directly lead to loss of β-cell identity. Taken together, our studies illustrate that a unified mitochondrial lifecycle is necessary to maintain β-cell mass and identity and may be targeted to prevent β-cell failure in T2D.

Disclosure

G. Pearson: None. N. Lawlor: None. J. Zhu: None. E. M. Walker: None. E. C. Reck: None. M. L. Stitzel: None. S. Soleimanpour: None.

Funding

American Diabetes Association (1-19-PDF-063 to G.P.)
179-OR: Defining Circadian Clock Dependency of Pancreatic Islet Transcriptional and Epigenetic Identity
Authors: BROWN MATTHEW , MATVEYENKO ALEKSEY
Published: June 2021

The circadian regulation of pancreatic β-cell function and identity is critical for the maintenance of glucose homeostasis. The circadian clock is entrained by rhythmic environment cues (e.g., light/dark and feeding/fasting cycles) that coordinate expression of the molecular circadian machinery. Nevertheless, the relative contribution of the aforementioned components in maintaining circadian β-cell identity remains unclear. Therefore, we set out to test the hypothesis that the molecular clockwork is required for the circadian regulation of β-cell transcriptional and epigenetic identity. To address this question, we performed diurnal RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) in pancreatic islets isolated from adult wild type (WT) and β-cell-specific Bmal1 (requisite circadian clock transcription factor) deficient (β-Bmal1-/-) mice. Time-dependent RNA-seq of β-Bmal1-/- islets revealed >95% decrease in the number of rhythmic transcripts compared to WT islets. Of the remaining rhythmic genes in β-Bmal1-/- islets, they predominately encoded for GO pathways regulating protein folding (FDR<.05). Correspondingly, ATAC-seq analysis found that there was >50% decrease in rhythmic chromatin accessibility in β-Bmal1-/- islets compared to WT. In line with transcriptomic findings, the remaining rhythmically accessible regions in β-Bmal1-/- islets annotated to regions regulating protein folding and insulin processing (FDR<.05). Interestingly, these regions were enriched for transcription factor motifs critical for insulin processing and biosynthesis including RFX and FOXA1. This study suggests that although the circadian clockwork is critical for entrainment of circadian β-cell identity, environmental stimuli (e.g., feeding) may maintain rhythmicity of insulin biosynthesis and protein folding in lieu of the circadian clock.

Disclosure

M. Brown: None. A. Matveyenko: None.

Funding

National Institutes of Health (DK098468 to A.M.), (DK123834 to M.B.)
180-OR: Single-Cell RNA Sequencing Reveals a Role for ROS Signaling in Nutrient-Induced ß-Cell Proliferation
Authors: VIVOLI ALEXIS , GHISLAIN JULIEN , CASTELL ANNE-LAURE , FILALI ALI , SLADEK ROBERT M. , POITOUT VINCENT
Published: June 2021

In nondiabetic obese individuals, β-cell mass accretion maintains glucose homeostasis by balancing levels of circulating insulin and insulin resistance. Type 2 diabetes appears when these compensatory mechanisms fail. Deciphering the pathways controlling β-cell proliferation may help to identify therapeutic targets to expand β-cell mass and prevent or delay the onset of diabetes. Previously we demonstrated that the monounsaturated fatty-acid oleate potentiates glucose-induced rat β-cell proliferation.

Aim: To identify the transcriptional mechanisms underlying oleate-induced rat β-cell proliferation.

Methods: Rat islets were exposed to 16.7mM glucose (Glu) with or without 0.5 mM oleate (Glu+Ol) or palmitate (Glu+Pal) for 48h. Proliferation was assessed by flow cytometry (C-peptide staining and EdU incorporation). Single-cell cDNA libraries were generated using 10X Genomics technology and sequenced on the Illumina platform. Bioinformatic analyses were performed using Seurat package.

Results: β-cell proliferation was potentiated by Ol, but not Pal. Following single-cell RNA sequencing, UMAP plots revealed several β-cell sub-populations, including proliferating β-cells. A number of differences in gene expression were identified between groups in non-proliferating sub-populations. Among these, gene sets involved in ER-stress and β-cell differentiation were significantly up- and down-regulated, respectively, in response to Pal, but not Ol. Gene set enrichment analyses comparing proliferative vs. non-proliferative β-cells revealed an up-regulation of reactive oxygen species (ROS) and oxidoreductase activity-related pathways in both Glu and Glu+Ol groups. The antioxidant N-acetyl cysteine or the peroxiredoxin inhibitor Conoidin A inhibited Glu+Ol-induced β-cell proliferation.

Conclusion: Our results suggest the involvement of ROS signaling through a redox relay via peroxiredoxin activation in nutrient-induced β-cell proliferation.

Disclosure

A. Vivoli: None. J. Ghislain: None. A. Castell: None. A. Filali: None. R. M. Sladek: None. V. Poitout: None.
184-LB: Lipid and HbA1c Profiles among People with Lean and Overweight Type 2 Diabetes in the Peruvian Amazon
Authors: ROBBINS DAVID C. , DEAN BARTHOLOMEW C. , GERHOLD CHAD , MOSHER M J , CAMARGO JULIANA
Published: June 2021

Type 2 DM in patients with BMIs > 25 is well defined. Gaps exist in understanding lean diabetes (LD), those with BMI < 25. In the US, LD presents in < 12% of patients and most prevalent in minorities. Childhood malnutrition, low socioeconomic status, and early age of onset contribute to this disease variant in developing countries. In Peru, diabetes is estimated to be prevalent in 7% of the population and may be, contrary to some publications, more widespread in remote Amazonian communities where poverty is common and access to health care is lacking. This study identifies characteristics in LD in comparison to individuals with overweight/obese (OOD) type 2 diabetes in Peru. A subsample of individuals with diabetes from a larger pilot study were profiled [F/M = 42/24, age ≥ 18 yrs] in the Amazonian town of Yurimaguas, Peru. We collected glycated hemoglobin (HbA1c), fasting blood lipids panels, height and weight from participants. Diabetes was determined using American Diabetes Association guidelines for HbA1c. In our sample (n = 64), 31.3% of individuals (n = 20) had BMI < 25. HbA1c percentages were significantly higher for LD compared to OOD (11.51%, 9.97% res, p = 0.034). We found no mean difference in age and lipid biomarkers for LD and OOD; for age (54.50 yrs, 53.89 yrs res, p = 0.841), triglycerides (223.56 mg/dL, 218.58 mg/dL res, p = 0.886), LDL (111.97 mg/dL, 114.85 mg/dL res, p = 0.731), HDL (48.12 mg/dL, 48.25 mg/dL res, p = 0.954). The proportion of LD with triglyceride levels > 150mg/dL was less than expected compared to OOD (χ2 = 4.30, df = 1, p = 0.038). We found a larger than expected portion of LD. Consistent with other studies, LD had higher HbA1c levels and less incidences of elevated triglycerides. Elevated blood lipids may be more important when screening OOD. For LD the focus should center on controlling HbA1c levels. Cause for concern is the high number of LD concealed in this study, in a population with a low prevalence of diabetes, and regional physicians could overlook screening in this population.

Disclosure

D. C. Robbins: None. B. C. Dean: None. C. Gerhold: None. M. Mosher: None. J. Camargo: None.

Funding

KU Diabetes Institute
19-LB: Statin Use as a Primary Prevention in Patients with Type 1 Diabetes: Where Do We Stand?
Authors: ALI DALAL S.A. , GRIFFIN TOMAS P. , CROWLEY RACHEL , CANAVAN RONAN
Published: June 2021

Type 1 diabetes (T1D) carries a high cardiovascular risk (CVD). Statins reduce risk of non-fatal myocardial infarction when used as primary prevention in selected patients[1]. We reviewed 205 electronic records of patients with T1D at our center from July 2019 to September 2019. We followed 2018 NICE guidelines for statin use as a primary prevention for our analysis (1)age ≥40 years (2)diabetes duration ≥10 years (3)established nephropathy (4)established other CVD risks.

Our cohort consisted of 119 males (58%) with a mean BMI of 25.5±4.4 kg/m2 and mean age of 43±16 years. The median duration of diabetes was 16 [IQR 8 - 27] years. More than 50% of our patients had attended “Dose Adjustment For Normal Eating, DAFNE” course. Approximately 71% had T1D for ≥10 years and 56% were ≥40 years. Mean systolic and diastolic blood pressures were 128 (±15.3) mmHg and 77 (±10) mmHg, respectively. Mean LDL was 2.4 (±0.74) mmol/L. In total 24.8% were on statin therapy, 2.4% on fibrates and 4.4% declined statin. Of the patients reviewed, 180 (87.8%) met the criteria for primary prevention; however, of those 51/180 (28.3%) were on statin, 44/146 (30.1%) with diabetes ≥10 years, 46/115 (40.0%) ≥40, 34/93 (36.6%) with established retinopathy. Regarding macro and microvascular complications, 3.4% had CAD, 6.8% chronic kidney disease (eGFR<60) and 47.8% retinopathy. Patients with T1D have higher CVD risk, for which statin therapy is advised[2, 3]. Our patients are undertreated with statins as primary prevention.

References: 1.Cholesterol Treatment Trialists’, C., et al., Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet (London, England), 2010. 376(9753): p. 1670-1681.2.De Ferranti, S.D., et al., Type 1 Diabetes Mellitus and Cardiovascular Disease. Circulation, 2014. 130(13): p. 1110-1130.3.Sharma, H., et al., Cardiovascular disease in type 1 diabetes. Cardiovascular endocrinology & metabolism, 2019. 8(1): p. 28-34.

Disclosure

D. S. A. Ali: None. T. P. Griffin: None. R. Crowley: None. R. Canavan: None.
192-LB: Human CD4+CD25+CD226- Regulatory T Cells Demonstrate High Purity and Lineage Stability following In Vitro Expansion for Adoptive Cell Therapy
Authors: BROWN MATTHEW E. , HANBALI SEIF R. , RODRIGUEZ LUZ MARINA GOMEZ , ARNOLETTI JUAN M. , CARPENTER EMMA B. , BRUSKO TODD M.
Published: June 2021

Human regulatory T cells (Tregs) are essential for the suppression of autoimmunity and adoptive cell therapy has been proposed as a means for restoring durable immune tolerance in T1D. The rare nature of this subset requires the isolation and in vitro expansion of thymic-derived Tregs (tTregs) for adoptive cell therapies to attenuate autoimmunity or islet transplant rejection. Current approaches involve the isolation of a subset with the marker profile of CD4+CD25+CD127-/lo. This strategy yields a population of Tregs that contains both naïve and peripheral Tregs (pTregs), with peripheral Tregs tending to lose lineage stability over time. Here, a novel gating strategy is presented for obtaining tTregs with high purity and extended lineage stability involving the elimination of the effector costimulatory molecule CD226. Tregs were obtained by fluorescence-activated cell sorting (FACS). This allows for the isolation of CD4+CD25+CD226- Tregs for comparison to classically sorted CD4+CD25+CD127-/lo Tregs over a 28-day culture period. Throughout the expansion, assessment of the lineage’s canonical transcription factors (FOXP3 and Helios), along with functional characteristics and epigenetic markers of the lineage occurred. Isolation of CD226- Tregs as compared to CD127- Tregs yields a Treg population with a higher proportion of tTregs (9.35%, p=0.0016), increased expression of CD25 (1.13-fold, p=0.0023), Helios (1.21-fold, p=0.0419), and CD45RA (1.24-fold, p=0.0017), equally low expression of CD127, and decreased expression of CD226 (2.27-fold, p=0.0001). Overall, this study suggests CD226- Tregs possess an increased therapeutic potential for adoptive transfer immunotherapies, including a more naïve phenotype and increased suppressive capabilities - both of which are critical factors for suppressing autoimmune destruction in vivo.

Disclosure

M. E. Brown: None. S. R. Hanbali: None. L. Gomez rodriguez: None. J. M. Arnoletti: None. E. B. Carpenter: None. T. M. Brusko: Consultant; Self; OneVax, LLC.

Funding

National Institutes of Health (1R01DK106191-01A1, UG3DK122638)
193-LB: A Puzzling Case of Hypoglycemia in a Patient with Type 1 Diabetes Mellitus and Cushing Syndrome
Authors: AMINI MEHDIA , KHINE AYE H. , LAMBA SIMARJEET S. , MISHRA SHREELA , NAING SOE , BABU VARSHA
Published: June 2021

Introduction: Exogenous insulin antibodies are common in patients with type 1 diabetes mellitus (T1DM) on insulin. However, they are clinically irrelevant as a cause of hypoglycemia. We report a unique case of exogenous insulin antibody-mediated severe hypoglycemia in a patient with T1DM and Cushing syndrome.

Case Report: A 55-year-old woman with T1DM on insulin pump presented with proximal muscle weakness and myalgia. She was diagnosed with Cushing syndrome due to an adrenal adenoma. Despite high serum cortisol, she had severe symptomatic episodic hypoglycemia with glucose levels <10 mg/dL requiring intermittent prolonged suspension of insulin pump. Surprisingly, she did not develop hyperglycemia or ketosis when off the insulin pump. During a witnessed hypoglycemic episode, serum insulin was 20.8 uIU/mL (NRR <19.7 uIU/mL), C-peptide <0.10 ng/mL (NRR 0.80-2.85 ng/mL), glucagon 11 pg/nl (NRR 8-57 pg/nl), and insulin antibody 4.1 U/mL (NRR <0.4/U/mL). She eventually underwent right adrenalectomy and was started on prednisone post-operatively resulting in a marked decrease in frequency of hypoglycemia. She was discharged on prednisone with plan for outpatient taper.

Discussion: Our case highlights the complex nature of glycemic dysregulation in insulin antibody-mediated hypoglycemia. Literature review suggests that binding capacity and affinity to insulin, rather than the quantity of insulin antibodies, determines the severity of hypoglycemia. We hypothesize that high binding capacities in our patient resulted in rapid sequestration of exogenous insulin through formation of immunoglobulin-insulin complexes. The low affinity allowed for subsequent rapid release of insulin in a physiologically dyssynchronous manner resulting in hyperinsulinemic hypoglycemia. A distinctive aspect of our patient is the presence of severe hypoglycemia despite endogenous hypercortisolism, although she responded to prednisone. This finding may have implications for future research.

Disclosure

M. Amini: None. A. H. Khine: None. S. S. Lamba: None. S. Mishra: None. S. Naing: None. V. Babu: None.
193-OR: Memory Advancement with Intranasal Insulin in Type 2 Diabetes: Randomized Control Trial
Authors: NOVAK VERA , MANTZOROS CHRISTOS , NOVAK PETER , MCGLINCHEY REGINA , DAI WEIYING , LIOUTAS VASILEIOS , BUSS STEPHANIE , FORTIER CATHERINE B. , KHAN FAIZAN , BECERRA LAURA APONTE , NGO LONG H.
Published: June 2021

Type 2 diabetes mellitus (T2DM) increases the risk of dementia. Intranasal insulin (INI) has emerged as treatment for T2DM-related cognitive impairment. This randomized, doubled blind trial consisted of 24-week treatment with 40 IU of intranasal insulin (Novolin® R) or placebo (sterile saline) once daily and 24-week follow-up period. T2DM and control participants > 50 years old and able to walk for 6 minutes, were enrolled. The primary outcomes were INI effect on cognition and normal and dual task walking. A total of 244 participants (122 women; 65.8 ± 9.1 years old) were randomized in the four groups (57 DM-INI, 58 DM-Placebo, 65 Control-INI, 64 Control-Placebo). Of 223 at baseline, 174 completed treatment (84 DM [70% of planned enrollment] and 90 controls [100%]), and 156 (69 DM) completed the follow-up. In T2DM, INI did not improve cognitive outcomes or depression as compared to placebo. In controls, INI improved verbal learning during on-treatment (p=0.03) and post-treatment (p=0.03) periods (Mixed Models). DM-INI group had faster normal walking at baseline and on-treatment (p<0.05), and dual task walking at baseline, on-treatment and post-treatment (p<0.05), as compared to DM-placebo. In T2DM, INI treatment increased perfusion in medio-prefrontal cortex (n=8) (p<0.001) measured using pseudo-continuous arterial spin labeling on 3T MRI. There were no clinically significant adverse events related to treatment. This was the Phase 2 Trial, thus the research design was not sufficiently powered to determine efficacy. On-INI improvement of normal and dual-task walking of ~ 5cm/s in T2DM participants and improvement of cognitive function in INI-treated controls are clinically significant and warrant further investigation (NCT02415556).

Disclosure

V. Novak: Advisory Panel; Spouse/Partner; Endonovo Therapeutics, Inc., Consultant; Spouse/Partner; Dysimmune Foundtation, Other Relationship; Spouse/Partner; Oxford University Press. L. Aponte becerra: None. L. H. Ngo: Consultant; Self; Five Islands Consulting, Other Relationship; Self; Radiological Society of America. C. Mantzoros: Advisory Panel; Self; Amgen Inc., GENFIT, Intercept Pharmaceuticals, Inc., Novo Nordisk, Regeneron Pharmaceuticals Inc. P. Novak: Other Relationship; Self; Dysimmune Foundation, Endonovo Therapeutics, Oxford Press. R. Mcglinchey: None. W. Dai: None. V. Lioutas: Consultant; Self; QMetis. S. Buss: Consultant; Self; Kinto Care. C. B. Fortier: None. F. Khan: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK103902); U.S. Food and Drug Administration (IND107690); Novo Nordisk (ISS-001063), Medtronic (NERP15-0310); World Health Organization (UTN-U111-1175-1588)
198-LB: A Novel Heterozygous Mutation in Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) Gene in a Woman with Familial Partial Lipodystrophy
Authors: WANDERLEY PATRÍCIA V. , DIAS JOAO C. , VIEIRA MARTA W. , GARCIA GIANE , FILHO ITUO T. , CHAMMA RAYSSA F. , GUGONI LILIAN S. , GIORGI RAFAEL B. , BARCELLOS CRISTIANO R.G.
Published: June 2021

Background: The nuclear peroxisome proliferator-activated receptor gamma (PPAR-γ) plays a role in the regulation of glucose and lipid metabolism in adipocytes by regulating their differentiation, distribution and function. Heterogeneous mutations of PPAR-γ can cause loss of gene function or reduce its expression leading to a clinical variety of phenotypes that characterize type 3 familial partial lipodystrophy syndrome. The most common features of this syndrome are abnormal body fat accumulation, muscle hypertrophy, insulin resistance, hypertriglyceridemia, polycystic ovary syndrome and hepatic steatosis.

Case report: A 32-year-old-woman was referred to the Endocrinology Division of PUC-SP for treatment of a severe hypertriglyceridemia diagnosed 4 years ago with recurrent episodes of acute pancreatitis and eruptive xanthomas since then. Also, diabetes mellitus (DM) was diagnosed 1 year ago with poor glycemic control. Her sister also had severe hypertriglyceridemia, recurrent episodes of acute pancreatitis and died in 2016. No DM was reported in her family. On physical examination, we found the presence of lipodystrophy, acanthosis nigricans on the neck and eruptive xanthomas on trunk, upper limbs, and thighs. BMI=24.9kg/m2; waist circumference=96cm. Abdominal CT scan revealed splenomegaly and fatty liver disease. Genetic sequencing showed a heterozygous (autosomal dominant inheritance) in the PPAR-γ of a Chr3 variant: 12.416.957 T> C (or alternatively c.1073T> C - ENST000002287820), promoting the substitution of leucine in codon 358 by proline (p.Leu358Pro).

Conclusion: The substitution of the amino acid leucine in codon 358 for proline is highly conserved in several species, and computer programs for predicting in silico of pathogenicity, suggesting that this new heterozygous mutation in the PPAR-γ gene is probably related to the type 3 familial partial lipodystrophy syndrome.

Disclosure

P. V. Wanderley: None. J. C. Dias: None. M. W. Vieira: None. G. Garcia: None. I. T. Filho: None. R. F. Chamma: None. L. S. Gugoni: None. R. B. Giorgi: None. C. R. G. Barcellos: None.
201-OR: Remission of Type 2 Diabetes and Decreased Inflammatory Markers with a High-Protein Diet
Authors: STENTZ FRANKIE B. , AMMONS ANN , CHRISTMAN JOHN V.
Published: June 2021

The purpose of this study was to determine if remission of type 2 diabetes(T2D) and a decrease in inflammatory cytokines (IC) can be achieved by macronutrients dietary changes without diabetes medications. High Protein (HP)(30% protein, 30% fat, 40% carbohydrates) or High Carbohydrate (HC)(15% protein, 30% fat, 55% carbohydrates) diets were used to study remission of type 2 diabetes(T2D) to Normal Glucose Tolerance(NGT), inflammatory cytokines, weight loss, body composition, and metabolic parameters in this randomized controlled clinical trial feeding study for 6 month(mo). Obese, age 20-65 years subjects withT2D were randomized to a HP or HC diet for 6 mo with all food provided. Caloric need for weight loss was determined by Resting Metabolic Rate-500 calories/day. Oral Glucose Tolerance Tests (OGTT) were performed at Baseline (BL) and 6 mo to determine T2D/NGT status. Glucose BL≥126 mg/dl and HbA1c≥6.5% and 2 hr glucose >199mg/dl was considered T2D and remission at 6 mo was glucose BL<126 mg/ml and HbA1c<6.5% and 2 hr glucose <140 mg/dl. DXA was done at BL and 6 mo. Food pick up and weight checks were weekly.T2D subjects on HP diet had 100% remission to NGT while HC diet subjects had 16% remission. IC were significantly decreased in HP compared to HC subjects at 6 mo for TNFa pg/ml (p=0.001) [HP 3.9±0.7 vs. HC 12.6±1.9] and IL-6 pg/ml (p=0.005) [HP 4.7±0.5 vs. HC 9.1±0.9]. Both diet groups had improvement in insulin sensitivity: HOMA IR [HP(BL 5.3±0.29; 6 mo 2.1±0.13)], [HC(BL 5.2±0.27; 6 mo 4.4±0.26)] and decrease in HbA1c [HP(BL 7.7±.05; 6 mo 5.6±.02)], [HC(BL 7.8±.04; 6 mo 6.6±.06)]. While both HP and HC groups has similar weight loss (HP =15.4±5 lb, HC=19.9±5 lb), HP group had a 2.7± 0.4% increase in lean body mass(LM) and 2.9± 0.4% decrease in fat mass(FM) while the HC group had a 1.9±0.3% LM and 3.3±0.9 % FM decrease respectively. The HP diet demonstrated improvement in glucose tolerance and insulin sensitivity with 100% remission of T2D to NGT and a significant decrease in inflammatory cytokines.

Disclosure

F. B. Stentz: None. A. Ammons: None. J. V. Christman: None.

Funding

AD Baskin (R073316012)
203-LB: Boosted Beta-Cell Function with Selective Deletion of the Adaptor Protein Mig6
Authors: BAUER BRANDON M. , BLOOM-SALDANA ELIZABETH A. , IRIMIA-DOMINGUEZ JOSE M. , FUEGER PATRICK T.
Published: June 2021

Type 1 and type 2 diabetes (T1D and T2D) are characterized by absolute and relative insulin deficiency, respectively. Thus, fortifying functional beta cell mass is essential for preventing or reversing either form of diabetes. We have investigated the impact of the adaptor protein mitogen inducible gene 6 (Mig6), a feedback inhibitor of epidermal growth factor receptor (EGFR) signaling induced in the diabetic milieu, on functional beta cell mass in the context of T1D and T2D. Given the importance of EGFR signaling in establishing and maintaining functional beta cell mass, we hypothesized that a selective loss of Mig6 in beta cells would increase functional beta cell mass. To this end, we generated mice lacking Mig6 in beta cells (BKO) using Mig6 floxed and Ins1-Cre knock-in mice and conducted extensive phenotyping, including quantifying beta cell function in vivo with hyperglycemic clamps. Compared to control littermates (CON), BKO mice had comparable beta cell mass, glucose tolerance, and post-prandial blood glucose or insulin concentrations when fed a standard chow diet. Mice underwent surgical catheterization of a carotid artery and jugular vein, and were allowed to recover for 4 days. Following a 5-h fast, mice were administered a primed and subsequent variable glucose infusion designed to clamp blood glucose at 15 mM (270 mg/dl). Target glycemia was achieved by 60 min and remained constant for the duration of the experiment. During the clamp, blood glucose or glucose infusion rates were not different between groups. Whereas beta cell mass was not different between groups, BKO had enhanced beta cell function in vivo, as exhibited by increased insulin secretion; compared to CON, the cumulative circulating insulin during the clamp in BKO was substantially larger (AUC: 340 ± 24 vs. 545 ± 70 ng/ml*120 min). Thus, a loss of Mig6 in beta cells enhances functional beta cell mass by increasing beta cell insulin secretory capacity in vivo. Therefore, Mig6 should be considered as a therapeutic target for diabetes.

Disclosure

B. M. Bauer: None. E. A. Bloom-saldana: None. J. M. Irimia-dominguez: None. P. T. Fueger: Consultant; Self; Protomer Technologies.

Funding

National Institutes of Health (R01DK099311)
204-LB: GADD45b Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of FoxO1
Authors: KIM HYUNMI
Published: June 2021

Increased hepatic gluconeogenesis is one of the main contributors to the development of type 2 diabetes. Recently, it has been reported that growth arrest and DNA damage-inducible 45 beta (GADD45β) is induced under both fasting and high-fat diet (HFD) conditions that stimulate hepatic gluconeogenesis. Here, this study aimed to establish the molecular mechanisms underlying the novel role of GADD45β in hepatic gluconeogenesis. Both whole-body knockout (KO) mice and adenovirus-mediated knockdown (KD) mice of GADD45β exhibited decreased hepatic gluconeogenic gene expression concomitant with reduced blood glucose levels under fasting and HFD conditions, but showed a more pronounced effect in GADD45β KD mice. Further, in primary hepatocytes, GADD45β KD reduced glucose output, whereas GADD45β overexpression increased it. Mechanistically, GADD45β did not affect Akt-mediated forkhead box protein O1 (FoxO1) phosphorylation and forskolin-induced cAMP response element-binding protein (CREB) phosphorylation. Rather it increased FoxO1 transcriptional activity via enhanced protein stability of FoxO1. Further, GADD45β colocalized and physically interacted with FoxO1. Additionally, GADD45β deficiency potentiated insulin-mediated suppression of hepatic gluconeogenic genes, and it were impeded by the restoration of GADD45β expression. Our finding demonstrates GADD45β as a novel and essential regulator of hepatic gluconeogenesis. It will provide a deeper understanding of the FoxO1-mediated gluconeogenesis.

Disclosure

H. Kim: None.
206-OR: RAGE-Dependent Macrophage Activation Aggravates Retrograde Axonal Transport via Attenuated Insulin Signaling of Peripheral Nerves in Experimental Diabetic Polyneuropathy
Authors: OSONOI SHO , MIZUKAMI HIROKI , KUDO KAZUHIRO , YAMAMOTO YASUHIKO
Published: June 2021

Advanced glycation end products (AGEs) activates its receptor, RAGE, resulting in a skewing of macrophage (Mϕ) polarity toward inflammatory phenotype (M1) and an impairment of the insulin signaling (IS) in adipose tissue. IS also regulates axonal transport (AT) in the peripheral nervous system. Although impaired IS and AT are assumed to be pathophysiology of diabetic polyneuropathy (DPN), the implication of Mϕ induced inflammation with RAGE activation in those factors is not fully understood. To this end, we generated bone marrow specific RAGE deficient mice to investigate the influence of RAGE signaling in Mϕ on the development of DPN. Bone marrow cells from C57BL/6 mice (W) or RAGE deficient mice (R) were transplanted into irradiated W (BMW and BMR). After 8 weeks of diabetes (D) induced by streptozotocin, nerve conduction velocities were delayed in BMWD compared to BMW, while those of BMRD were comparable to BMR. An increased infiltration of M1 was observed in the sciatic nerve (SN) in BMWD. Western blotting (WB) showed a lower phosphorylation of AKT in response to insulin in SN of BMWD, which suggested impaired IS, while it was maintained in BMRD. Retrograde AT (RAT) was evaluated with Fluoro-gold (FG) transportation from hindlimb-footpad to the dorsal root ganglion (DRG). Immunofluorescence revealed a lower positivity of FG in DRG of BMWD which suggested a deficit of RAT, while it was maintained in BMRD. Neuronal cells isolated from mice DRG were cocultured with a Mϕ cell line RAW264, which was polarized into M1 by AGEs. Intra-axonal vesicles were labeled fluorescently. Subsequently, AT was visualized by time-lapse imaging. The ratio and the velocity of RAT was decreased in the axon of the neurons cocultured with M1 compared with naïve Mϕ.

In summary, our data suggested that the activation of RAGE signaling skewed Mϕ polarity toward M1, impairing IS and RAT through inflammation, which might trigger and develop DPN.

Disclosure

S. Osonoi: None. H. Mizukami: None. K. Kudo: None. Y. Yamamoto: None.

Funding

Japan Society for the Promotion of Science (18K16220)
207-OR: Cardiac Autonomic Neuropathy (CAN) and HDL Proteomics in Type 1 Diabetes (T1D)
Authors: TOYOSHIMA MARCOS T. , SILVA AMANDA , SANTANA MONIQUE DE FATIMA M. , RONSEIN GRAZIELLA E. , CORREA-GIANNELLA MARIA LUCIA , PASSARELLI MARISA
Published: June 2021

CAN is a common complication of diabetes mellitus (DM) strongly related to cardiovascular (CV) disease, contributing to high morbidity and mortality. HDL is inversely related to CV disease due to its ability in removing excess cholesterol from cells and antioxidant, anti-inflammatory and vasodilation actions. Apart from plasma HDL cholesterol (HDLc) and apoA-I levels that are not invariably changed in T1D, HDL proteomics may contribute to understand HDL functionality and its association with CAN. A total of 50 individuals with T1D with or without CAN were selected to assess the proteome of HDL subfractions (HDL2 and HDL3). CAN evaluation was performed by Ewing test using the Poly-Spectrum software. HDL subfractions were isolated by ultracentrifugation and proteomics analyzed by parallel reaction monitoring (PRM). Subjects with T1D with (n = 15) and without CAN (n = 35) did not differ in age, sex, body mass index, age at DM diagnosis, duration of DM, and fructosamine, HbA1c, total cholesterol, HDLc and triglycerides values. A total of 45 proteins were found in association with HDL2 and HDL3; three proteins were highlighted because they were more abundant in HDL2 from T1D with CAN: α1-microglobulin/bikunin precursor (AMBP), α1-acid glycoprotein (Orm1) and transthyretin (TTR) (Mann-Whitney test; P values <0.01, 0.03, 0.04, respectively). Orm1 is an acute inflammatory phase protein that regulates sphingolipid homeostasis related to the pathogenesis of diabetic neuropathy. TTR carries thyroid hormones and retinol binding protein and mutations in the TTR gene causes amyloidosis that includes motor and sensory polyneuropathy, neuropathic pain and autonomic dysfunction. The AMBP gene encodes α1microglobulin and bicunin that relates to T1D complications.

In conclusion, three proteins with potential for involvement in the pathophysiology of CAN were more abundant in HDL2 in T1D presenting this chronic complication.

Disclosure

M. T. Toyoshima: None. A. Silva: None. M. M. Santana: None. G. E. Ronsein: None. M. Correa-giannella: None. M. Passarelli: None.

Funding

FAPESPCNPq
23-LB: Economic Outcomes and Health Care Utilization of DSMES Interventions: A Systematic Review and Recommendations for Research
Authors: WHITEHOUSE CHRISTINA , SRIVASTAVA SNEHA B. , TUITAMA ADONICA I. KAUWE , BLANCHETTE JULIA E. , HAYDON-GREATTING STARLIN A. , BRADY VERONICA J. , SMITH TIERRA , LITCHMAN MICHELLE L. , YEHL KIRSTEN E. , BZOWYCKYJ ANDREW
Published: June 2021

Value-driven outcomes are important, especially when health systems are determining sustainability of Diabetes Self-Management Education & Support (DSMES). We conducted a systematic review to synthesize existing research of the economic outcomes and healthcare utilization for interventions that incorporate DSMES in the US. Seven databases were searched for relevant published studies that included of at least one component of the Association of Diabetes Care and Education Specialists 7 Self-Care Behaviors (ADCES7). Reviewers independently selected articles, extracted data and assessed the methodological quality of included studies. In total, 14,804 records were identified, 25 articles met the inclusion criteria. Three articles were determined to have poor quality and were not included in the final analysis. Our findings are based on a total of 22 articles describing 21 studies. DSMES interventions varied widely, including face-to-face education, group classes, home visits with community health workers, telemedicine visits, education modules, and/or visits with registered dietitians, nurses and/or pharmacists. A majority of the studies were not specifically designed for health economic evaluation. Seven studies reported a statistically significant decrease in either total health care costs, hospital or emergency utilization, outpatient medical costs, and/or medication costs. Four of the seven studies utilized all components of the ADCES7. Clinical impact across studies varied. Studies that measured HbA1c found a decrease over their study time frame. The methodological heterogeneity among studies was considerable; therefore, a meta-analysis was not conducted. Our review highlights DSMES interventions may positively impact economic outcomes and/or healthcare utilization, though not all studies showed consistent benefit. This review highlights an evidence gap and future full health economic evaluations are warranted.

Disclosure

C. Whitehouse: None. A. Bzowyckyj: None. S. B. Srivastava: None. A. I. Kauwe tuitama: None. J. E. Blanchette: Board Member; Self; JDRF, Consultant; Self; Insulet Corporation, Other Relationship; Self; Insulet Corporation, Tandem Diabetes Care, Research Support; Self; Association of Diabetes Care and Education Specialists. S. A. Haydon-greatting: None. V. J. Brady: None. T. Smith: None. M. L. Litchman: Research Support; Self; Abbott Diabetes. K. E. Yehl: None.
232-OR: Replacing Sedentary Time by Different Types of Physical Activity and the Risk of Type 2 Diabetes
Authors: LI XIANG , ZHOU TAO , MA HAO , HEIANZA YORIKO , QI LU
Published: June 2021

Background: Sedentary behaviors have been associated with an increased risk of type 2 diabetes (T2D). The newly released Physical Activity Guidelines for Americans also recommend replacing sedentary behaviors by physical activity. However, it is largely unknown which types of physical activity would be the healthy alternatives to sedentary behaviors, and to what extent it may reduce the risk of T2D.

Methods: We prospectively analyzed the association between sedentary time and risk of T2D among 475,502 participants free of T2D in the UK Biobank. Sedentary time was quantified by summing up the time spent on television watching, computer using, and driving.

Results: During a median follow-up of 11 years, we documented 18,169 incident T2D. Sedentary time were significantly associated with an increased risk of T2D (≥6 hours/day vs. <2 hours/day: hazard ratio [HR]: 1.58; 95% confidence interval (CI): 1.47~1.71). Such associations were more profound among women or obese participants (p-interaction<0.001 for both). Replacing 30 minutes/day sedentary time with different types of physical activities were significantly associated with a 6-31% lower risk of T2D, with strenuous sports (exercise making sweat or breathing hard) showing the strongest risk reduction (per 30 minutes/day: HR: 0.69; 95% CI: 0.63~0.76). Replacing sedentary time by structured exercise showed greater reduction (26%, 23-28%) of T2D risk than by daily-life activity (9%, 8-10%).

Conclusions: Our study indicates that sedentary time combining watching TV, using computer and driving are independently associated with an increased risk of T2D; and replacing sedentary time with the structured exercise is related to greater reduction than with daily activity on T2D risk.

Disclosure

X. Li: None. T. Zhou: None. H. Ma: None. Y. Heianza: None. L. Qi: None.