bluuebunny/crossref_metadata_2025 huggingface dataset:
147-LB: Targeted Intervention for At-Risk Patients with Diabetes to Reduce Readmissions
Authors: HARRIS ASHLEY , GRDINOVAC KRISTINE
Published: June 2021

With benefits to patient outcomes, provider burden, and health system costs, the goal of reducing hospital readmissions for patients with diabetes mellitus (DM) is multifaceted. Current studies have neither elucidated a clear approach to accurately identify at-risk patients nor implemented reliable interventions to significantly reduce readmissions. We trialed a Quality Improvement project utilizing a diabetes Nurse Practitioner (NP)/Certified Diabetes Care and Education Specialist (CDCES) to see at-risk patients during initial hospitalization and in close clinic follow-up after discharge with an endpoint of reducing future readmissions. Over 21 months, 79 hospitalized patients with DM were identified as high-risk for readmission. Identifying factors included previous admission, DKA/HHS, new DM diagnosis, new to insulin, high-dose steroid use, or provider discretion. The NP/CDCES provided DM management, education, and coordinated discharge. Patients were called shortly after discharge and had a 2-4 week clinic follow-up with the NP/CDCES. The primary endpoint was number of readmissions 180 days post-discharge after NP/CDCES intervention versus number of previous readmissions pre-intervention. Change in hemoglobin A1C, time to post-hospital phone call, and time to outpatient follow-up were also evaluated. Pre- and post-intervention readmission rates remained unchanged; average pre-intervention readmissions per patient was 1.7 versus 1.88 post-intervention readmissions (p=0.74). However, a secondary endpoint of reduction in A1C was statistically significant, with a mean decrease in A1C of 0.97% per patient (p=0.0025). Time to post-hospital phone call and early follow-up did not affect readmission rates. While targeted inpatient-to-outpatient intervention for high-risk patients with DM did not reduce readmission rates, our data suggests coordinated inpatient intervention with close hospital follow-up may improve A1C in high-risk patients with diabetes.

Disclosure

A. Harris: None. K. Grdinovac: None.
15-OR: The COVID-19 Pandemic and New-Onset Pediatric Type 2 Diabetes
Authors: MARKS BRYNN E. , KHILNANI ANEKA , MEYERS ABBY , ESTRADA DORIS E. , BOUGHTON JENNIFER , GAI JIAXIANG , STREISAND RANDI , MONAGHAN MAUREEN
Published: June 2021

Introduction: Reports are emerging about the impact of the COVID-19 pandemic on pediatric T1D, however few studies have explored pediatric T2D. We aimed to investigate changes in T2D initial clinical presentation and patient demographic characteristics during COVID-19.

Methods: A retrospective cross-sectional review of youth diagnosed with T2D during the COVID-19 pandemic (3/11/2020-11/30/2020) and in the time matched period in 2019 was conducted at a pediatric tertiary care center. BMI Z-score (>1.64), age (>8) and the absence of DKA and autoantibodies at diabetes diagnosis (A1c >6.5%) were used to screen for T2D, with confirmation by chart review. Chi-square, Fisher’s exact, and independent samples t-tests were used for analyses.

Results: During the pandemic, cases of T2D increased 233% from 2019 (n=36, Mage=14.1±2.6 years, 56% F) to 2020 (n=84, Mage=14.6±2.2 years, 42% F). Rates of new onset T2D increased as the pandemic continued, from 4-8 per month in April-June to 20 and 16 cases, respectively, in October and November. Only 3 youth were actively infected with COVID-19 at T2D diagnosis. Rates of DKA at diagnosis increased from 6% in 2019 to 21% in 2020 (p=0.03), with 6 cases of hyperosmolar DKA during the pandemic as compared to none in 2019. Before the pandemic, 53% of youth diagnosed with T2D were Black, compared to 77% during the pandemic (p=0.03). Similar increases were seen among those with public insurance, rising from 67% to 86% (p=0.02).

Conclusions: Cases of T2D and severity of initial presentation increased during the first 9 months of the COVID-19 pandemic, particularly among Black and publicly insured youth. These findings align with prior reports highlighting the disproportionate impact of the COVID-19 pandemic on racial/ethnic and socioeconomically disadvantaged communities. As few youth were infected with COVID-19 at T2D diagnosis, pandemic-related social distancing measures may also have disproportionate impacts on these communities and serve to worsen pre-existing health disparities.

Disclosure

B. E. Marks: None. A. Khilnani: None. A. Meyers: None. D. E. Estrada: None. J. Boughton: None. J. Gai: None. R. Streisand: None. M. Monaghan: None.
153-LB: Initial Presentation of Children with Type 2 Diabetes during the COVID-19 Pandemic
Authors: HSIA DANIEL S. , LIM MARIA , BEYL ROBBIE A. , HASAN HIRA A. , GARDNER JAMES
Published: June 2021

Stay at home orders due to the COVID-19 pandemic have exacerbated risk factors for type 2 diabetes. These orders have limited opportunities for daily physical activity, encouraged more screen time and sedentary behaviors, led to disturbed sleep, and promoted consumption of ultra-processed foods. Even modest weight gain over a short period of time can increase the risk for long-term consequences such as type 2 diabetes and cardiovascular disease. During the COVID-19 pandemic, there has been little data on the incidence or severity of new-onset type 2 diabetes in the pediatric population. We conducted a retrospective chart review of admissions for new onset type 2 diabetes from March to December 2019 and for the same period in 2020 at a tertiary care children’s hospital. Eligible patients were identified using ICD-10 codes for type 2 diabetes (E11.*); hyperglycemia (E72.51, E11.65, R73.9, R73.09); and hyperosmolar hyperglycemic syndrome (E13.*, E11.01). Each admission was carefully reviewed, and those with type 1 diabetes or hyperglycemia unrelated to diabetes were excluded. In 2019 the hospitalization rate for new onset type 2 diabetes was 0.27% (8 cases out of 2964 hospitalizations) compared to 0.62% (17 out of 2729) in 2020, p<0.048. In total 23 of 25 children were African American and 19 children were male. Three children in 2019 versus 8 children in 2020 met criteria for DKA while 2 children met criteria for HHS in 2020. The mean admission HbA1c was 12.4% in 2019 vs. 13.1% in 2020; while the mean admission glucose was 441 mg/dL in 2019 vs. 669 mg/dL in 2020. Furthermore, the admission serum osmolality was 314 mmol/kg in 2019 compared to 335 mmol/kg in 2020. Our study found that the incidence of hospitalization for new onset type 2 diabetes was higher in 2020 during the COVID-19 pandemic compared to the same period in 2019. While the labs presented were not statistically different due to the limited number of participants, further studies are warranted to better understand the clinical implications of these findings.

Disclosure

D. S. Hsia: None. M. Lim: None. R. A. Beyl: None. H. A. Hasan: None. J. Gardner: None.

Funding

National Institute of General Medical Sciences (U54GM104940)
16-OR: Endocrine Manifestations of Pediatric HNF1B-MODY (MODY 5)
Authors: CRAVEN MEGHAN E. , BAMBA VANEETA , CALABRIA ANDREW C. , PINNEY SARA E.
Published: June 2021

Objective: Mutations in hepatocyte nuclear factor 1B (HNF1B), are often identified based on a history of renal disease and diabetes mellitus, but other endocrine manifestations including dyslipidemia and hyperparathyroidism have not been well-defined in the literature. Given HNF1B-MODY is rare, there have been few case series defining the disease spectrum. This study analyzes the clinical characteristics of HNF1B-related endocrine disorders in 9 pediatric patients identified at a single pediatric tertiary care center.

Methods: Data was collected through the Atypical Diabetes Registry and Biorepository at the Children’s Hospital of Philadelphia.

Results: Of the 9 pediatric patients with HNF1B mutations or deletions, 7/9 (78%) have diabetes mellitus, 8/9 (89%) have renal disease, 8/9 (89%) have dyslipidemia, and 5/9 (55%) have hyperparathyroidism. Over half (55%) initially presented with diabetes mellitus, while the remaining 45% were diagnosed either based on family history or a genetic workup secondary to renal disease. No patients presented with diabetic ketoacidosis and only two presented with ketosis. Of the 4/9 with previously identified HNF1B-mutations, two have subsequently developed diabetes mellitus. Lipid profiles demonstrated: 7/9 with total cholesterol >170 mg/dL, 8/9 with triglycerides >100 mg/dL, 3/9 with LDL > 110 mg/dL and 3/9 with HDL < 40 mg/dL. In regards to calcium homeostasis, 55% have an elevated PTH (>65 pg/mL) with high-normal calcium levels. Autism spectrum disorder was diagnosed in 3/9 patients (2 with 17q12 deletion and 1 with HNF1B mutation).

Conclusion: This study represents one of the largest series of pediatric patients with HNF1B-MODY at a single center. The majority of patients have had progressively declining beta-cell function resulting in diabetes mellitus. Nearly all had elevated lipids with hypertriglyceridemia predominating. Over half of the patients had elevated PTH levels preceding the decline in renal function concerning for primary hyperparathyroidism.

Disclosure

M. E. Craven: None. V. Bamba: None. A. C. Calabria: None. S. E. Pinney: None.
162-OR: Food Insecurity and Glycemic Control among Youth and Young Adults with Type 2 Diabetes
Authors: REID LAUREN A. , MENDOZA JASON A. , MERCHANT ANWAR , GERACI MARCO , REBOUSSIN BETH A. , ELLYSON ALICE M. , MALIK FAISAL , DABELEA DANA , MERJANEH LINA , MARCOVINA SANTICA M. , LUSTIGOVA EVA , LIESE ANGELA D.
Published: June 2021

Screening for household food insecurity (HFI) is recommended because of its impact on diabetes management. While HFI has been shown to be associated with poor glycemic control in adults with type 2 diabetes (T2D) and youth and young adults (YYA) with type 1, the association between HFI and glycemic control in YYA with T2D is not known.

This cross-sectional study included T2D YYA (n=395) from the 2015-2020 SEARCH for Diabetes in Youth Study (14-35 yrs; median age: 25.2 yrs). HFI was defined as affirming ≥3 items on the US Household Food Security Survey Module. HbA1c values were available for 271 participants. It was measured in a sample of whole blood and analyzed as a continuous variable. Glycemic control was dichotomized into optimal/suboptimal (≤9 %) vs. high risk (> 9.0%) based on HbA1c. Survey data on experiencing severe hypoglycemia or diabetic ketoacidosis (DKA) in the last 12 months was available for 292 participants. Logistic and linear regression were used for modeling the association of HFI with binary and continuous outcomes, respectively.

Approximately 34% of YYA with T2D reported HFI in the past 12 months. The mean HbA1c of the YYA with HFI was 9.2%, 54% had HbA1c >9.0%, and 19% reported experiencing DKA or hypoglycemia. YYA who were food secure had a mean HbA1c of 9.5%, 54% had HbA1c >9.0%, and 8% reported acute complications. No associations were observed between HFI and HbA1c or glycemic control. YYA with HFI had 2.3 (CI: 1.1-5.2) times the odds of experiencing DKA or hypoglycemia as those without HFI, after adjusting for age, gender, race, parent education, household income, insurance, clinic, diabetes duration, use of continuous glucose monitoring, and medication regimen. Our data suggests that HFI among YYA with T2D is a quite common, affecting more than a third of our sample and is associated with acute diabetes-related complications. These results warrant longitudinal studies in this particularly vulnerable group to establish if alleviating HFI reduces frequency of DKA and hypoglycemia episodes.

Disclosure

L. A. Reid: None. S. M. Marcovina: None. E. Lustigova: None. A. D. Liese: None. J. A. Mendoza: None. A. Merchant: None. M. Geraci: None. B. A. Reboussin: None. A. M. Ellyson: None. F. Malik: None. D. Dabelea: None. L. Merjaneh: None.

Funding

National Institutes of Health (R01DK117461, 1UC4DK108173)
167-OR: Long-Term Follow-up after Total Pancreatectomy and Islet Cell Autotransplantation in Patients with Chronic Pancreatitis Utilizing Off-Site Islet Isolation
Authors: LAD SALONI U. , ALI KHAWLA F. , JOHNSTON PHILIP C. , MARTIN VICENTE SAN , LIN YU KUEI , BOTTINO RITA , WALSH MATTHEW , STEVENS TYLER , HATIPOGLU BETUL
Published: June 2021

Context: Total pancreatectomy (TP) with islet-cell auto transplantation (IAT) is an option for pain management for patients with chronic pancreatitis (CP). IAT allows the preservation of beta cell function to reduce or prevent long-term diabetes.

Objective: We performed a follow-up study up to 12 years after TPIAT surgery with an off-site isolation laboratory, to determine the efficacy and durability of the procedure.

Methods: Data (August 2008 to August 2020) were obtained from a TPIAT database which included information from medical records, clinic visits, questionnaires, and follow-up telephone calls. Patient demographics were collected. Additionally, each patient was assessed with a 4-hour mixed meal tolerance test for metabolic measurements, serial glycosylated hemoglobin (HbA1c), and insulin requirements prior to surgery and during their most recent follow-up appointment.

Results: Seventy-seven patients with a median age of 45.0 years underwent TP-IAT for CP due to different etiologies. At a median follow-up time of 422.5 days 12 patients were insulin independent and 65 patients were on at least one insulin injection a day. Post-operative C-peptide area under the curve (AUC) measurements (P=0.008) were a better indicator of procedure success compared to the number of islet cells transplanted (P=0.225). Patients who were insulin-dependent post-surgery demonstrated increased insulin resistance prior to surgery, by their median pre-surgery insulin AUC; insulin-independent, 626 (241, 3803); insulin-dependent, 1591 (325, 4803), HOMA-IR values 9.02.

Conclusions: TPIAT improves intractable pain for patients with CP. IAT decrease insulin requirement and improve blood glucose control after TP. Insulin resistance prior to surgery may be a predictor for insulin-dependence. Intervention studies using insulin sensitizer prior surgery may be considered in evaluating long-term outcomes for these patients.

Disclosure

S. U. Lad: None. K. F. Ali: None. P. C. Johnston: None. V. San martin: None. Y. Lin: None. R. Bottino: None. M. Walsh: None. T. Stevens: Speaker’s Bureau; Self; AbbVie Inc. B. Hatipoglu: None.
173-OR: Medial Amygdala Projections Regulate the Metabolic Responses to Internal and External Signals
Authors: DEVARAKONDA KAVYA , ALVARSSON ALEXANDRA , GONZALEZ MARIA JIMENEZ , LI ROSEMARY , LEHMANN VANESSA E. , STANLEY SARAH
Published: June 2021

Medial amygdala projections regulate the metabolic responses to internal and external signals

The brain is a crucial part of the complex system that controls blood glucose in response to internal signals and external stressors. However, we do not know whether distinct CNS circuits regulate metabolism in response to internal state (fed vs. fasted) and environmental cues. Here we used detailed mapping of activated neurons, circuit tracing and projection-specific neural manipulation to determine the contribution of medial amygdala (MeA) neurons and circuits to the metabolic response to internal and external signals. Fasting, refeeding and stressors that increase blood glucose significantly activate MeA neurons. MeA neurons are synaptically connected to organs crucial to metabolic control and chemogenetic activation of MeA neurons significantly increased blood glucose, independent of pancreatic hormone release, and suppressed feeding. We identified the bed nucleus of the stria terminalis (BNST) and ventromedial hypothalamus (VMH) as major downstream projections from the MeA. MeA neurons projecting to BNST and to VMH are distinct neural populations activated by metabolic and emotional stress. Targeted activation of MeA neurons projecting to VMH but not to BNST MeA neurons mimicked the glycemic responses to fasting and stress with significantly impaired glucose tolerance, increased hepatic gluconeogenesis and a more rapid recovery from hypoglycemia, without increased corticosterone or epinephrine. Conversely, targeted ablation of MeA neurons projecting to VMH significantly reduced blood glucose and blunted the hyperglycemic response to stress. These data reveal a critical role for the MeA-VMH circuit in glucose regulation in response to internal and external signals. Future work will assess how this pathway is disrupted in diabetes and its contribution to the associations between diabetes and mental health disorders.

Disclosure

K. Devarakonda: None. A. Alvarsson: None. M. Jimenez gonzalez: None. R. Li: None. V. E. Lehmann: None. S. Stanley: None.

Funding

American Diabetes Association/Pathway to Stop Diabetes (1-17-ACE-31 to S.S.); National Institutes of Health (R01NS097184, OT2OD024912); U.S. Department of Defense (W81XWH-20-1-0345, W81XWH-20-1-0156); Charles H. Revson Foundation (18-25); Swedish Society
176-OR: STIM1 Deletion Leads to Loss of Beta-Cell Identity in High-Fat Diet-Fed Female Mice
Authors: SOHN PAUL , KRISHNAN PREETHI , LEE CHIH-CHUN , KONO TATSUYOSHI , EVANS-MOLINA CARMELLA
Published: June 2021

STIM1 is an endoplasmic reticulum (ER) calcium (Ca2+) sensor that replenishes ER Ca2+ stores in a process known as store operated calcium entry (SOCE). Previously, we have shown that SOCE is impaired in the diabetic pancreatic β cell; however, the consequences of reduced β cell SOCE have not been well studied. To this end, mice with pancreatic β cell specific deletion of STIM1 (STIM1Δβ) were generated by crossing STIM1flox/flox with Ins-Cre mice and fed a high fat diet (HFD) beginning at 8 wk of age. Male STIM1Δβ mice did not show changes in glucose tolerance or body composition. In contrast, female HFD-fed STIM1Δβ mice were heavier (25.1 vs. 28.3 g, p<0.05), had increased fat mass (4.9 vs. 8.2g, P<0.01), and exhibited significant glucose intolerance (AUC IPGTT 22461 vs. 29245 mg/dL*min; p<0.0001) with impaired insulin secretion by in-vivo GSIS (p<0.05) without differences insulin tolerance, energy expenditure or food intake. Bulk RNA-sequencing of wild-type and STIM1Δβ female islets revealed reduced expression of MafA, UCN3, and Ins1 and Ins2 in STIM1Δβ islets, indicating potential loss of β cell identity. Pathway analysis showed modulation of pathways related to 17-beta estradiol (E2) signaling, with downregulation of a G-protein coupled estrogen receptor 1 (GPER), while differentially expressed genes were enriched for functions related to apoptosis, lipid metabolism, and epithelial cell differentiation. Consistently, STIM1Δβ female mice had lower β cell mass (2.984 mg vs. 1.349 mg, p<0.05) and higher alpha cell mass (0.1822 mg vs. 0.4463 mg, p<0.05). Proteomics analysis performed in STIM1-deficient INS-1 cells revealed significantly increased glucagon expression. Further, lower mobilization of intracellular cAMP levels was noted in response to treatment with E2 or G1, an agonist of GPER. These findings suggest a role for STIM1 in the maintenance of pancreatic β cell identity and indicate a potential interaction between SOCE and E2 signaling in female mice.

Disclosure

P. Sohn: None. P. Krishnan: None. C. Lee: None. T. Kono: 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 (5T32DK064466-17, 5F30DK123996); U.S. Department of Veterans Affairs (2-I01BX001733); National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK093954-06A1); Indiana University School of Medicine; Gates Millennium Scholars Program
178-LB: Food Insecurity and Dietary Intake Adequacy in Youth and Young Adults with Type 1 and Type 2 Diabetes
Authors: BERCAW HOPE D. , REID LAUREN A. , MENDOZA JASON A. , FRONGILLO EDWARD A. , SAUDER KATHERINE A. , REBOUSSIN BETH A. , MAYER-DAVIS ELIZABETH J. , DABELEA DANA , MARCOVINA SANTICA M. , MERCADO CARLA , LIESE ANGELA D.
Published: June 2021

Household food insecurity is associated with poor dietary intake in the general population, but little is known about persons with diabetes. We examined dietary intake among youth and young adults (YYA) with diabetes in relation to food security (FS) to identify differences in intake quantity and adherence to recommendations. The SEARCH for Diabetes in Youth cross-sectional study includes 1,134 YYA with type 1 diabetes (T1D, mean age: 21 years ± 5) and 274 YYA with type 2 diabetes (T2D, 25 years ± 4.2). Participants (or parents if <18 years) completed the USDA Household FS Survey Module, wherein ≥3 affirmations indicate food insecurity. Diet was assessed via food frequency questionnaire and compared to age- and sex-specific 2020-25 Dietary Guidelines for Americans (DGA) nutritional goals for daily energy, added sugar, saturated fat, calcium, fiber, iron, magnesium, potassium, sodium, vitamins C, D, and E. Associations of FS with daily intake and meeting guidelines were assessed with sex-stratified multivariate linear regression. No intake differences by FS were observed, except females with T1D consumed more sodium (+155 mg, p = .01) and percent of kilocalories from saturated fat (+0.7%, p = .04) when FS was absent. Males with T2D consumed more vitamin E (+1 mg, p = .03) when FS was present. Crude guideline adherence was poor across the board (i.e. below 60%). After multivariate adjustment for demographic, socioeconomic, clinical and diabetes characteristics, females with T1D and T2D, regardless of FS, on average met vitamin C and males met iron guidelines. Males with T2D met percent of kilocalories from saturated fat guidelines in the absence of FS. DGA adherence among YYA with diabetes is of grave concern given that diet is crucial to diabetes management. FS reflects very little enhancement in diet quality. YYA with diabetes consume excessive sodium, added sugars, and inadequate micronutrients except for vitamin C and iron, increasing risk for deficiency, weight gain, heart attack and stroke.

Disclosure

H. D. Bercaw: None. C. Mercado: None. A. D. Liese: None. L. A. Reid: None. J. A. Mendoza: None. E. A. Frongillo: None. K. A. Sauder: None. B. A. Reboussin: None. E. J. Mayer-davis: None. D. Dabelea: None. S. M. Marcovina: None.
183-OR: Pyruvate Kinase M2 (PKM2) Enzymatic Activity Is Necessary to Improve Podocyte Mitochondrial Function and Glomerular Fuel Metabolism and Diabetic Nephropathy
Authors: FU JIALIN , SHINJO TAKANORI , LI QIAN , ST-LOUIS RONALD , PARK KYOUNGMIN , YOKOMIZO HISASHI , YU MARC GREGORY , SHAH HETAL , WU I-HSIEN , KING GEORGE L.
Published: June 2021

Diabetic nephropathy (DN) is the result of abnormal systemic and local changes in metabolism and hemodynamics. We have reported that many glycolytic enzymes, such as pyruvate kinase M2 (PKM2), were elevated in the renal glomeruli of type 1 and type 2 diabetic patients who were protected from DN. TEPP46, a small-molecule which activates PKM2 by inducing oligomerization, reversed glomerular pathology in diabetic mice. After 7 months of STZ induced diabetes, mice with PKM2 specific overexpression in podocytes (PPKM2Tg) with podocin promoter, exhibited lower albumin-creatinine ratio (ACR), kidney-body weight ratio, mesangial expansion, basement membrane thickness and podocyte foot process effacement vs. WT diabetic littermates. PPKM2Tg mice exhibited lower expression of fibrotic (FN, TGFβ1 and Col4a) and oxidative stress (p47phox, NOX2 and NOX4) genes and improvement in endothelial function with increased eNOS and VEGF expressions in the glomeruli, compared to diabetic WT mice. Glycolytic and mitochondrial metabolisms as measured by oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using Seahorse showed striking improvement of impaired mitochondrial maximal respiration capacity and glycolytic rate in isolated glomeruli of diabetic PPKM2Tg mice, in concordance with elevated expressions of mitochondrial related-genes, such as PGC1α. Knocking-down PKM by shRNA in podocyte cell line (pPKMKD) replicated metabolic findings induced by diabetes with dramatic decline of both OCR and glycolytic rate. Re-expressing human PKM1 or PKM2 in pPKMKD cell line reversed impaired mitochondrial function and glycolysis, which were not improved in pPKMKD cells re-expressing with enzymatically inactive human PKM2 gene. These results indicate that PKM2 and its enzymatical function are both necessary in podocytes to improve glomerular mitochondrial abnormalities and delay the progression of DN.

Disclosure

J. Fu: None. G. L. King: Consultant; Self; Agios, Inc., Medtronic, Other Relationship; Self; Janssen Pharmaceuticals, Inc. T. Shinjo: None. Q. Li: None. R. St-louis: None. K. Park: None. H. Yokomizo: None. M. Yu: None. H. Shah: None. I. Wu: None.

Funding

Iacocca Family Foundation
186-OR: Risk Prediction of Early Decline in Renal Function in Diabetic Kidney Disease with Algorithm Including Fractional Excretion of Glycated Amino Acids
Authors: THORNALLEY PAUL , FUENTE ALBERTO DE LA , RABBANI NAILA
Published: June 2021

Diabetic kidney disease occurs in ca. 40% patients with diabetes. Approximately 1 in 5 patients with type 1 diabetes mellitus (T1DM) develop early decline in renal function (EDRF), requiring renal dialysis after 5 - 20 years. Currently, it is uncertain which patients are at high risk of EDRF. With Joslin Kidney Study investigators, we found patients with T1DM with and without microalbuminuria who later develop EDRF (Decliners) have higher fractional excretion (FE) of 6 glycated amino acids - fructosyl-lysine and 5 advanced glycation endproducts (AGEs), compared to patients with stable renal function (Non-decliners) (Perkins et al., Sci Rep 10, 12709, 2020). No individual FE could classify patients. In this study, we applied artificial intelligence machine learning to develop diagnostic algorithms to classify Decliners and Non-decliners, exploring A1C, log(ACR), 14 glycated and oxidized amino acids in plasma, urine, related FEs and other features. Data from patients with T1DM with stable renal function (n = 52) and EDRF (n = 33) were available. Algorithms were trained and tested on 90%/10% data split, repeated 1000 times, using Extreme Gradient Boosting. Optimum classification required measurement of 3 AGEs: Nꞷ-carboxymethylarginine (CMA) and glyoxal-derived hydroimidazolone (G-H1) in plasma and urine, and N-carboxymethyl-lysine (CML) in plasma; measured in 15 min by liquid chromatography-tandem mass spectrometry. Optimum algorithm features were: A1C, log[ACR], FECMA, FEG-H1 and plasma CML free adduct. The diagnostic performance for risk prediction of future EDRF was (mean ± SD): sensitivity 0.74 ± 0.09, specificity 0.91 ± 0.04 and accuracy 87 ± 4%. The positive likelihood ratio LR+ of 11.0 indicates that this method gives strong, often conclusive evidence of future EDRF in patients with T1DM. With further validation, including in patients with type 2 diabetes mellitus, this method may markedly improve risk prediction of EDRF.

Disclosure

P. Thornalley: None. A. De la fuente: None. N. Rabbani: None.

Funding

Qatar Foundation; Qatar University
188-LB: Type 2 Diabetes Is Genetically Correlated with Multiple Long-Term Conditions but These Correlations Are Only Partly Explained by BMI
Authors: PILLING LUKE C. , DUDBRIDGE FRANK , MELZER DAVID , BOWDEN JACK , FRAYLING TIMOTHY M.
Published: June 2021

People with Type 2 diabetes (T2D) are at high risk of many other long term conditions (LTC). These LTCs include Osteoarthritis, Alzheimer’s disease and Depression as well as cardiovascular conditions but the causes of these higher risks are uncertain and hard to study in trials or observational studies. We aimed to use a genetic approach to test the hypothesis that type 2 diabetes shares disease pathways with other LTCs and that BMI would account for some of the sharing. We used data from large (14,000 - 120,000 cases) genome wide association studies to calculate genetic correlations (Rg) between T2D and 16 LTCs. We then used Genomic structural equation models to test the extent to which the genetic component to BMI accounted for the correlations. This genetic approach has the advantage that type 2 diabetes can be compared to co-morbidities across databases. Eight of 16 LTCs were genetically correlated (Rg) with T2D. These were Heart failure (HF; Rg 0.49, p=1x10-50), coronary artery disease (CAD; 0.40, p=6x10-75), gastroesophageal reflux (GORD, 0.36, p=3x10-58), stroke (0.32, p=4x10-20), osteoarthritis (OA; 0.32, p=4x10-28), depression (0.14, p=4x10-11), hearing aid use (0.13, p=2x10-3) and asthma (0.13, p=9x10-9). The genetic component to BMI accounted for a large proportion of the genetic correlations between T2D and osteoarthritis (87% of Rg), hearing aid use (68%) and asthma (64%), but a smaller proportion of T2D’s genetic correlations with stroke (32%), CAD (35%), HF (47%), depression (39%) and GORD (44%). T2D shares a genetic component with multiple long term conditions and excess body weight is only partly responsible. We hypothesize that where the genetic correlation between T2D and another LTC dramatically diminishes upon adjustment for BMI, lifestyle interventions on BMI may successfully reduce the burden of both LTCs. Where there is less such attenuation, alternative risk factors, such as body fat distribution, need to be considered.

Disclosure

L. C. Pilling: None. F. Dudbridge: None. D. Melzer: None. J. Bowden: None. T. M. Frayling: None.

Funding

Medical Research Council (MR/V005359/1)
188-OR: Inflammatory and Insulinemic Dietary Patterns Associate with Nephropathy in Type 1 Diabetes (T1D)
Authors: SHAH HETAL , ADAM ATIF , BOUMENNA TAHANI , YU MARC GREGORY , LI JUN , HU FRANK , TABUNG FRED K. , KING GEORGE L.
Published: June 2021

Diabetic nephropathy (DN) causes much morbidity and mortality in T1D, necessitating better mechanistic insights for improved prevention and therapy. In addition to hyperglycemia, DN pathogenesis may involve inflammation or insulin resistance, and diets modulating these pathways may impact DN risk. In this cross-sectional study, we examined associations of inflammatory and insulinemic potentials of whole diets with DN in a subset of the Joslin 50-year Medalist Study, comprising 570 individuals with T1D >50 years and food frequency questionnaire data. Empirical dietary inflammatory pattern (EDIP) and empirical index for hyperinsulinemia (EDIH) scores were separately derived as weighted sums of foods and beverages previously shown to be predictive of circulating inflammatory biomarkers or C-peptide levels, respectively. In multivariable-adjusted logistic regression models, including age, sex, BMI, exercise, lipids, HbA1c, and hypertension as covariates, 1 S.D. increments in EDIP and EDIH associated with 0.46 (95% CI 0.26-0.84, p=0.01) and 0.31 (95% CI 0.15-0.68, p=0.003) reduced odds of being protected against DN (167 events, CKD-EPI eGFR < 60 ml/min/1.73 m2), respectively. Both scores inversely correlated with continuous eGFR (p=0.03 and 0.0003, respectively). Neither index associated with HbA1c, retinopathy severity, neuropathy or cardiovascular diseases. Both scores positively correlated (p<0.05) with C-reactive protein, which correlated to HbA1c but did not offset the effects of EDIP or EDIH on DN. These findings show that dietary patterns with higher inflammatory and insulinemic potentials are associated with DN in T1D, independent of glycemic control, inflammation or hypertension, suggesting the involvement of a metabolic and renal-selective pathway underlying DN pathogenesis. Future studies will focus on whether consumption of diets with low EDIP and EDIH can protect against DN onset and progression, and the potential pathways through which they do this.

Disclosure

H. Shah: None. A. Adam: None. T. Boumenna: None. M. Yu: None. J. Li: None. F. Hu: None. F. K. Tabung: None. G. L. King: Consultant; Self; Agios, Inc., Medtronic, Other Relationship; Self; Janssen Pharmaceuticals, Inc.
19-OR: Maternal Diabetes Is Associated with Adverse Diabetes Characteristics and Accelerated Onset of Complications in Youth with Type 2 Diabetes (T2D) in TODAY
Authors: ISGANAITIS ELVIRA M. , SHAH RACHANA , CHERNAUSEK STEVEN , FARRELL RYAN M. , GEFFNER MITCHELL , KEADY JOYCE , KELSEY MEGAN M. , TESFALDET BEREKET , TRYGGESTAD JEANIE B. , VAN NAME MICHELLE A.
Published: June 2021

Background: Prenatal exposures, including parental nutrition and diabetes (DM) status, are increasingly viewed as risk factors for future cardiometabolic health. There are currently no data on effects of parental DM on disease progression or complications in youth-onset T2D.

Aims: To analyze effects of parental history of DM on glycemic outcomes and complications in the TODAY study.

Methods: Participants (n=699) aged 10-14 yr with newly diagnosed T2D were enrolled at 14 U.S. centers and followed for up to 15 yr. Subjects had negative islet autoantibodies and BMI >= 85th %. Information about DM diagnosis in mothers of participants was available for 621 participants [Never (MN) =301; During pregnancy (MD) =218; After pregnancy (MA)=102)] and in biological fathers in 519 (No DM=352; Paternal DM=167).

Results: Maternal, but not paternal, DM was associated with accelerated loss of glycemic control, defined as HbA1c >8% for over 6 months (p < 0.0001). Participants whose mothers had diabetes had 60% higher risk of loss of glycemic control [MD vs. MN hazard ratio (HR): 1.58 (1.28, 1.95), p < 0.0001; MA vs. MN HR: 1.57 (1.20, 2.04), p = 0.0009]. Similarly, maternal, but not paternal, diabetes was associated with glomerular hyperfiltration [MD vs. MN HR: 1.58 (1.18-2.1), p = 0.0021; MA vs. MN HR: 1.56 (1.08, 2.24), p = 0.0170;], diabetic retinopathy (MD: 50.0%; MA: 59.7%; MN: 41.8%, p=0.0439), and pulse wave velocity indices reflecting heart rate variability, including SD of normal R-R interval [(SDNN), MD: 42 ± 26 ms; MA: 41 ± 26 ms; MN: 54 ± 31 ms; p = 0.0005] and proportion of successive NN intervals greater than 50 ms [(pNN50%), MD: 14.1 ± 19.4; MA: 16.2 ± 21.5; MN: 21.9 ± 23.5; p = 0.0069], after 10 to 15 yr of follow-up. Associations were maintained after adjusting for multiple confounders.

Conclusions: Maternal, but not paternal, diabetes is associated with adverse diabetes outcomes and accelerated onset of complications in their offspring with T2D in TODAY.

Disclosure

E. M. Isganaitis: None. M. A. Van name: None. R. Shah: None. S. Chernausek: None. R. M. Farrell: Stock/Shareholder; Self; Tandem Diabetes Care. M. Geffner: Advisory Panel; Self; Daiichi Sankyo, Novo Nordisk, Pfizer Inc., Consultant; Self; Gilead Sciences, Inc., Other Relationship; Self; Ascendis Pharma A/S, McGraw-Hill, UpToDate, Research Support; Self; Novo Nordisk. J. Keady: None. M. M. Kelsey: Other Relationship; Self; Boehringer Ingelheim (Canada) Ltd., Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp. B. Tesfaldet: None. J. B. Tryggestad: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (U01DK61212, U01DK61230, U01DK61239, U01DK61242, U01DK61254)
194-LB: Case of Pembrolizumab-Induced Type 1 Diabetes Mellitus
Authors: SPYROPOULOS STAVROULA , MANESSIS ANASTASIOS
Published: June 2021

Immune checkpoint inhibitors, anti-PD1 and anti-CTLA-4, have become widely utilized and proven effective in treating various forms of cancer. Although the discovery of immunotherapy has been a major advancement in the field of oncology, a series of endocrinopathies have been described and research is still ongoing. We would like to report a case of diabetes mellitus with positive glutamic acid decarboxylase (GAD) antibodies secondary to pembrolizumab therapy for locally advanced Merkle Cell Carcinoma. A 70-year-old male with no history of diabetes presented to the ER with severe hyperglycemia after his fifth cycle of pembrolizumab. His labs revealed a blood glucose of 659 mg/dL, an A1c of 8.5%, creatinine of 1.45 mg/dL, and urine negative for ketones. He demonstrated elevated anti-GAD antibodies (>250 IU/mL), suggesting type 1 diabetes. The patient was started on both long acting insulin glargine and prandial short acting insulin with improved glycemic control. The first case reports of pembrolizumab induced diabetes and diabetic ketoacidosis were published in 2015. During the initial clinical trials, only 0.1% of patients using pembrolizumab developed type 1 DM, but a review of current literature suggests that it has become more prevalent with rates as high as 2%. The rise in cases has also demonstrated that the majority of immunotherapy induced diabetes results primarily in patients receiving anti-PD1 therapy. A study done on mice demonstrated PD-L1 expression in inflamed pancreatic beta cells of mice that had developed diabetes. These results suggest that pembrolizumab causes destruction of insulin producing cells, releasing intracellular proteins such as GAD, and triggering the immune system to create autoantibodies. This emphasizes the need for further studies investigating the relationship between immunotherapy and autoimmune diabetes. In addition, it is essential that clinicians become aware and remain vigilant of this potentially life-threatening complication.

Disclosure

S. Spyropoulos: None. A. Manessis: Advisory Panel; Self; Medtronic, Research Support; Self; IQVIA, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., MannKind Corporation, Sanofi US.
199-LB: ATF4 Deletion in Brown Adipose Tissue Impairs Adaptive Thermogenesis but Attenuates Diet-Induced Insulin Resistance
Authors: BJORKMAN SARAH , MARTI ALEX A. , WEATHERFORD ERIC T. , GARCÍA-PEÑA LUIS M. , POTTHOFF MATTHEW J. , ABEL EVAN D. , PEREIRA RENATA
Published: June 2021

Short-term cold exposure induces the integrated stress response (ISR) and its main effector, the activating transcription factor 4 (ATF4), in brown adipose tissue (BAT). Furthermore, induction of ATF4 in BAT in response to mitochondrial stress is required for systemic metabolic adaptations mediated by BATokine secretion. To test the hypothesis that ATF4 in BAT is required for cold-induced thermogenesis and to promote BATokine secretion, we selectively deleted ATF4 in BAT by crossing Atf4 floxed mice with mice harboring the Cre recombinase under the control of the Ucp1 promoter (ATF4 BAT KO). KO mice experienced a significant reduction in core body temperature after 3 days of cold exposure relative to wild type (WT) mice. Impaired thermogenesis correlated with reduced BAT mass, and decreased UCP1 and tyrosine hydroxylase protein levels. In addition, KO mice had impaired cold-induced browning of white adipose tissue (WAT) and reduced expression of fibroblast growth factor 21 (Fgf21) and growth and differentiation factor 15 (Gdf15), BATokines shown to be induced in response to BAT thermogenic activation. Surprisingly, although KO mice had equivalent weight gain and fat mass relative to WT mice after 12 weeks of high-fat feeding, glucose and insulin intolerance were ameliorated, and fasting insulin levels were significantly reduced, indicating increased insulin sensitivity. Improved glucose clearance correlated with increased levels of glucose transporters 1 and 4 (GLUT1 and GLUT4) in BAT, but not in WAT or skeletal muscle. Taken together, our data indicate that Atf4 expression is required for full thermogenic activation of BAT and to regulate FGF21 and GDF15 release as BATokines, likely coordinating BAT thermogenesis with systemic adaptations. Finally, our data suggest that in diet-induced obesity, ATF4 downregulation may increase glucose utilization in BAT, contributing to improved glucose homeostasis and insulin sensitivity.

Disclosure

S. Bjorkman: None. A. A. Marti: None. E. T. Weatherford: None. L. M. García-peña: None. M. J. Potthoff: None. E. D. Abel: Board Member; Self; MyoKardia, Other Relationship; Self; AstraZeneca. R. Pereira: None.

Funding

National Institutes of Health (R01DK125405)
20-LB: A M1/M2-Macrophages Regulating New Drug in an International Phase 3 Study
Authors: KUO MIN-LIANG
Published: June 2021

The healing of diabetic foot ulcers (DFUs) stalled in inflammation stage due to overabundance of inflammatory macrophages and the dysregulated M1/M2 macrophages in the lesion. Restoring the balance of M1/M2 macrophages plays a critical role in orchestrating the healing process of DFUs. By recognizing the therapeutic potential in M1/M2-macrophage-regulation for DFUs, we aim to evaluate the efficacy and safety of ON101, a topical new drug with M1/M2-macrophage-regulating mechanism versus a hydrocolloid dressing in an international, multicenter, randomized, controlled, evaluator-blind phase 3 study in 21 clinical/medical centers across the US, China, and Taiwan by following Guidance for Industry Chronic Cutaneous Ulcer and Burn Wounds — Developing Products for Treatment. 236 eligible patients with post-debrided DFU(s) between 1 - 25 cm2, present for ≥4 weeks and Wagner Grade 1 or 2, were randomized 1:1 to receive ON101 or comparator for up to 16 weeks followed by a 12-week follow-up. Baseline demography and medical history between the two groups were well balanced. The incidence of complete healing as the primary endpoint in full analysis set was 60.7% by ON101 and 35.1% by the comparator during the treatment period (p=0.0001). Time to complete ulcer healing as the secondary endpoint was noted faster in the ON101 group (p=0.002). No significant changes or differences between the two treatment groups in hematology, biochemistry (including HbA1c and fasting glucose), or vital signs. Related treatment of emergent adverse events was reported in 7 patients (5.7%) in the ON101 group and 5 (4.4%) from the comparator group. None of the serious adverse events was related to ON101 while there was a case of osteomyelitis reported to be related to the comparator. ON101, recently approved by Taiwan Food and Drug Administration, was shown with clinically significant efficacy and well-tolerated safety profile in DFUs which provides not only a new prospect in DFU management but a differentiated approach towards active-healing.

Disclosure

M. Kuo: Employee; Self; Oneness Biotech Co., Ltd.
201-LB: Arx and Nr2f6 Transcriptionally Regulate Visceral and Brown Fat Phenotype
Authors: MAGANTI AARTHI , CHI JINGYI , COHEN PAUL
Published: June 2021

Mammals possess fat in three distinct depots- brown, subcutaneous and visceral fat depots. While brown fat contains thermogenic brown fat cells, the subcutaneous and visceral fat depots contain lipid-storing white fat cells. Excess visceral fat is associated with increased insulin resistance and type 2 diabetes, whereas the presence of brown fat corelates with lower odds of type 2 diabetes. These differences likely arise due to distinct developmental origins of brown and white fat cells. Expression of co-factors such as PRDM16 and PGC1α is limited to brown fat cells. Brown and white fat cells also have distinct sets of open chromatin. I hypothesize that epigenetic variations between brown and white fat can reveal fat depot-enriched factors that are essential to establishing fat identity and phenotype, and therefore, influence obesity and type 2 diabetes. Adipoq-NuTrap mice, that have labeled adipocytes, were used to isolate adipocyte nuclei from brown and visceral fat. ATAC-sequencing of these nuclei uncovered fat cell-specific open regions, which were then subjected to bioinformatic analysis to identify depot-enriched transcription factors. These analyses resulted in the discovery of two factors: Arx and Nr2f6. Arx is dramatically enriched in visceral gonadal fat, compared to brown and subcutaneous fat. Pathway analysis of Arx target genes reveal that Arx may regulate inflammation, cell shape and motility. Adipose-specific Arx knockout mice have lesser visceral fat and will be used to study the role of Arx in insulin tolerance and obesity. On the other hand, Nr2f6 expression is enriched in brown fat, increases with cold exposure and is dependent on PRDM16 expression. Pathway analysis of Nr2f6 target genes show that Nr2f6 regulates mitochondrial, thermogenic and lipolytic genes, genes central to brown fat function. Nr2f6 overexpression dampened thermogenic response, suggesting a novel regulatory mechanism in brown fat function. Nr2f6-null mice will be used to assess the role of Nr2f6 in brown fat function.

Disclosure

A. Maganti: None. J. Chi: None. P. Cohen: None.

Funding

American Diabetes Association (1-19-PDF-024 to A.M.)
202-LB: Reduced Glucose Effectiveness Exacerbates Impaired Glucose Tolerance in Prediabetic Dogs
Authors: KOLKA CATHRYN M. , PORTER JAY , ADER MARILYN , BERGMAN RICHARD N.
Published: June 2021

The prodromal prediabetic state is characterized by glucose intolerance. Both insulin-dependent (sensitivity, secretion, clearance) and -independent factors (“glucose effectiveness”) contribute to glucose homeostasis. The relative importance of glucose effectiveness is not known. Healthy dogs (n=18) were tested at baseline (BL), after 6 wk on a high-fat diet (HFD), and 2 wk, after a sub-diabetogenic dose of streptozotocin (STZ, 18.5 mg/kg); HFD was continued. We performed intravenous glucose tolerance tests (IVGTTs)at 0, 6, and 8 wks. Minimal model analysis quantified insulin sensitivity (SI), acute insulin response to glucose (AIRg), disposition index (DI, = SI x AIRg), and glucose tolerance (KG). Glucose effectiveness (SG) was measured both by minimal model analysis and directly by multi-step hyperglycemic clamps at basal insulin in a subset of the dogs (n=5). Consumption of HFD induced 7.7±1.0% weight gain (P<0.001) and reduced SI (BL: 3.33±0.35; HFD: 2.01±0.38 x 104 min-1 per µU/ml; P=0.02). HFD elicited an increased AIRg (BL: 596±42; HFD: 1865±476 µU/ml, P=0.03) while maintaining KG (BL: 3.33±0.25; HFD: 3.67±0.33 min-1, P=0.69) as well as β-cell function expressed as DI (BL: 1939±236; HFD: 1882±199, P=0.97). SG was not changed by fat feeding per se (P=0.88). Prediabetes (STZ) conserved fasting glucose, but KG deteriorated (-45% from HFD to STZ) due to sustained insulin resistance with compromised β-cell function (DI decreased by 45±8%, P<0.01). Additionally, minimal model-based SG declined 37±8% from HFD to STZ (0.044±0.003 vs. 0.027±0.003 min-1, P<0.01), a result confirmed by glucose clamps (-30%). Impairments in both insulin-dependent and insulin-independent factors contribute to the glucose intolerance of experimental prediabetes. Rather than compensating for insulin resistance and beta-cell dysfunction, glucose effectiveness also declines, demonstrating that it exacerbates and contributes to glucose intolerance in the canine model of prediabetes.

Disclosure

C. M. Kolka: Research Support; Self; AstraZeneca. J. Porter: None. M. Ader: None. R. N. Bergman: None.

Funding

National Institutes of Health (DK27619, DK29867)