bluuebunny/crossref_metadata_2025 huggingface dataset:
238-OR: A Single Hypoglycemic Event Causes a Prolonged Immune Response
Authors: VERHULST CLEMENTINE E. , VAN HECK JULIA , FABRICIUS THERESE W. , STIENSTRA RINKE , TACK CORNELIS , PEDERSEN-BJERGAARD ULRIK , DE GALAN BASTIAAN E. , CONSORTIUM HYPO-RESOLVE
Published: May 2022

Hypoglycemia acutely activates the immune system and is associated with an increased risk for atherosclerotic disease. Since atherosclerosis is driven by inflammation, we set out to determine the duration of the pro-inflammatory response to a hypoglycemic event in people with and without diabetes. Adults with type 1 diabetes (n = 47) or insulin-treated type 2 diabetes (n = 15) , and age-matched controls without diabetes (n = 32) underwent a hyperinsulinemic-euglycemic (5.2 ± 0.4 mmol/L) -hypoglycemic (2.8 ± 0.1 mmol/L) glucose clamp. Before, during and up to a week thereafter, blood was drawn to determine circulating immune cell composition and function combined with measurements of and circulating hs-CRP concentrations. At baseline, participants with diabetes had higher counts of produced cytokines and hs-CRP compared to individuals without diabetes (all p < 0.01) . In response to hypoglycemia, absolute numbers of lymphocytes (1.57 ± 0.53 vs. 2.69 ± 0.95·103/µL) and monocytes (0.40 ± 0.14 vs. 0.62 ± 0.22·103/µL) increased acutely and remained elevated for one week in all subgroups (all p < 0.001) . During hypoglycemia, the proportion of pro-inflammatory CD16+-monocytes increased from 26.9 ± 13.3% to 38.1 ± 14.9% and the proportion of phagocytotic CD14+-monocytes decreased from 65.2 ± 14.4% to 54.5 ± 15.9% in all subgroups (all p < 0.01) . Stimulated monocytes released more TNF-α and IL-1β, and less IL-during hypoglycemia. Similarly, hs-CRP concentrations increased from 2.± 3.20 µg/mL to 2.71 ± 3.57 µg/mL 1 day after the clamp (p < 0.001) and remained elevated for one week (p < 0.001) thereafter to similar extent in all subgroups.

In conclusion, a single hypoglycemic event induces a prolonged immune response in humans independent of the presence of diabetes.

Disclosure

C.E.Verhulst: None. J.Van heck: None. T.W.Fabricius: None. R.Stienstra: None. C.Tack: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. B.E.De galan: Research Support; Novo Nordisk. Hypo-resolve consortium: n/a.

Funding

The Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement 777460. The JU receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA and T1D Exchange, JDRF, International Diabetes Federation (IDF) , The Leona M. and Harry B. Helmsley Charitable Trust.
240-LB: Adipogenesis in Weight Regain Does Not Accelerate Adiposity in Mice
Authors: GERSTENBERG MARINA K. , BOOKOUT ANGIE , CASTORENA CARLOS M. , TORZ LOLA , DOVMARK TOBIAS H. , LUNDH SOFIA , MADSEN SUZI H. , ANDERSEN BIRGITTE S. , PEDERSEN THOMAS A. , KUHRE RUNE E. , PETERSEN NATALIA
Published: May 2022

Weight loss and regain are associated with profound cytoskeleton changes in collapsing and re-expanding adipocytes. These drastic changes in the adipose tissue may drive proinflammatory signalling and fibrotic processes during weight regain. It remains unclear how adipose tissue re-expansion affects adipose tissue function and thereby the comorbidities related to obesity. The aim of this study was to characterize structural and metabolic changes in subcutaneous adipose tissue after weight loss and regain in diet-induced obesity (DIO) mice. DIO mice underwent calorie restriction to achieve a 25% weight loss and then returned to ad libitum high fat diet feeding to regain weight. Inguinal adipose tissue was collected and analysed from five groups of mice during the experiment: before high fat diet feeding (Lean) , before weight loss (DIO 1) , after weight loss (WL) , after 3 weeks of weight regain (WR) and age-matched ad libitum DIO mice (DIO 2) . We found that WR group had lower weight and fat mass compared to DIO2 group (31.9±1.6 vs. 23.9±1.9 %) and lower basal lipolysis measured ex-vivo. We detected a larger population of small adipocytes in WR mice compared to DIO2 group, resulting in smaller average adipocyte size (81.6±1.4 vs. 52.5±0.9 µm) and increased expression of cell renewal markers Cidea, Antrx1 and Prkaa in adipose tissue, indicating activation of adipogenesis. Expression of cytokines Il2, Ccl19, Cdc3 in adipose tissue in WR compared to DIO was reduced as well as plasma levels of cytokines Il2, KC/GRO and Inf-γ.

In conclusion, our study does not support that increased adipogenesis in weight regain results in accelerated fat accumulation in mice. Weight regain is accompanied by reduced systemic and adipose inflammation. This suggests in general a beneficial effect of regain-induced adipogenesis resulting in potentially healthier adipose tissue in mice. Weather these findings represent the human situation with weight loss and regain is unknown and is currently under investigation.

Disclosure

M. K. Gerstenberg: Employee; Novo Nordisk. R. E. Kuhre: Employee; Novo Nordisk. N. Petersen: Employee; Novo Nordisk A/S. A. Bookout: Employee; Novo Nordisk. C. M. Castorena: Employee; Novo Nordisk. L. Torz: Other Relationship; Novo Nordisk A/S. T. H. Dovmark: None. S. Lundh: Employee; Novo Nordisk A/S. S. H. Madsen: None. B. S. Andersen: Employee; Novo Nordisk A/S. T. A. Pedersen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S.
241-LB: Significant Worsening of Preexisting Obesity in South Texas Children during COVID-19 Lockdown
Authors: CERVANTES FRANCISCO J.
Published: May 2022

Background: Obesity has been on the rise for the past several decades, which is associated with increased risk for comorbidities and severe consequences to the individual. In the Mexican American community, obesity has become a serious problem in children. The COVID-19 lockdown order issued in February 2020 caused further challenges for children to engage in regular physical activity.

Objective: To determine if the COVID-19 lockdown impacted the weight of 95% Medicaid-insured Mexican American children at a pediatric clinic in South Texas.

Design and Methods: We identified 417 new patients from March 2019 to February 2020 (with exclusion of 104 newborns) and followed them until December 2021. Height and weight were measured to estimate Body Mass Index (BMI) . The percentage of overweight or obese (OW/OB) children was calculated at the first and last visit.

Results: We had a total of 346 children at the end of the study. The average stature of the whole group was at the 48th percentile with 60% of the children at or below the 50th percentile based on CDC growth charts. Boys increased BMI from the 62.7th to 71.8th percentile (p<0.01) and girls increased from the 60th to the 70th percentile (p<0.02) . The distribution of BMI of the whole group indicated that 34.5% of children were OW/OB on the first visit and 49% were OW/OB at the last visit.

Conclusion (s) : Our study exemplifies that the lockdown during the COVID-19 pandemic, which was associated with decreased physical activity, increased the BMI of children and increased associated comorbidities based on lab values. We have shown in previous studies that when BMI is in the OW/OB category, children have increased blood pressure, decreased high density lipoproteins, elevated liver enzymes, increased insulin resistance, larger kidneys, and fatty liver. These indicators place children at a higher risk for early development of hypertension, renal function decline, diabetes, and cardiovascular disease.

Disclosure

F. J. Cervantes: None.
245-OR: Age and Diabetes Interact to Decrease Muscle Mitochondrial Function
Authors: ABUSHAMAT LAYLA , SCALZO REBECCA L. , RAMIREZ DAVID , SCHAUER IRENE E. , KNAUB LESLIE , CLARK ETHAN , REYES YESENIA GARCIA , CREE-GREEN MELANIE , REUSCH JANE , REGENSTEINER JUDITH G.
Published: May 2022

People with T2D have lower cardiorespiratory fitness (CRF) than those without diabetes contributing to increased cardiovascular morbidity and mortality. People with T2D have impaired oxidative flux associated with lower CRF. Yet, reports on muscle mitochondrial dysfunction in T2D are mixed. As diabetes duration and age are predictors of poor outcomes, we hypothesized that T2D and increased age associate with impaired mitochondrial function. We assessed post-exercise calf mitochondrial function in overweight sedentary participants (45 with and 54 without T2D) ages 30-50 and 51-70y. Mitochondrial function was measured in vivo by 31Phosphorous magnetic resonance spectroscopy (31P-MRS) before, during and after 90 seconds of isotonic calf press at 70% maximal force and ex vivo by mitochondrial respiration in muscle fibers using the Oroboros Oxygraph-2k. There was no significant effect of age or T2D on ex vivo measures. MRS-measured phosphocreatine synthesis, apparent maximum rate of oxidative ATP synthesis and ADP time constant were worse in those with T2D or age >50 (Figure) . Age and T2D interact to significantly decrease apparent maximum rate of oxidative ATP synthesis. These data suggest that age and T2D decrease in vivo oxidative capacity. Given that impairment is only found in in vivo mitochondrial measures, factors such as micro- and macrovascular function and blood flow, combined with cardiac function, are likely implicated.

Disclosure

L.Abushamat: None. J.G.Regensteiner: None. R.L.Scalzo: None. D.Ramirez: None. I.E.Schauer: None. L.Knaub: None. E.Clark: None. Y.Garcia reyes: None. M.Cree-green: None. J.Reusch: Advisory Panel; Medtronic.

Funding

American Diabetes Association (1-21-CMF-003) (1-12-CT-64) ; Department of Veterans Affairs (BX002046, CX001532)
246-LB: Neonatal Microbes Stimulate Beta-Cell Development
Authors: HILL JENNIFER H. , GUILLEMIN KAREN , MURTAUGH CHARLES L. , ROUND JUNE
Published: May 2022

Newborns are exposed to environmental microbes that colonize the gut and increase in diversity during childhood to establish the resident microbiota. Concurrently, insulin-producing β-cells enter a postnatal window of proliferation and maturation. We found that germ-free animal models exhibit significant reductions in β-cell mass compared to their microbe-carrying counterparts, revealing a role for microbes in the establishment of these cells. By mining this unique source, we uncovered mechanisms of bacterially driven β-cell development.

Neonatal mice given strategically timed doses of broad-spectrum antibiotics incurred lasting reductions in β-cell mass, revealing a critical period of microbial influence on β-cells. Though reconstituted with a normal microbiota after antibiotic treatment, as adults these animals had reduced glucose tolerance and insulin secretion, and were more susceptible to metabolic disease. Treatment of neonatal mice with selective antibiotics resulted in variations in β-cell mass, blood glucose, and insulin levels, suggesting unique bacterial taxa or products influence these traits. Sequencing revealed that distinct microbes were enriched within each antibiotic treatment, allowing us to identify candidate bacterial taxa that we show are sufficient to stimulate β-cell expansion and restore insulin function. Further, we have identified multiple islet associated cell types that respond to these microbial cues. Previously, we identified the bacterial protein, BefA, that directly stimulates β-cell proliferation, and we anticipate finding additional bacterial modulators of this important tissue.

Reduced microbiota diversity can be predictive of diabetes in susceptible children, suggesting that early life microbial exposures are critical to prevent disease. Our results indicate loss of specific bacteria may result in reduced insulin production capacity prior to autoimmunity. If we can reinstate these lost microbes, we may be able to bolster the β-cell population against loss.

Disclosure

J. H. Hill: None. K. Guillemin: None. C. L. Murtaugh: None. J. Round: None.

Funding

Junior Diabetes Research Foundation (3-PDF-2019-747-A-N)
246-OR: Role of Skeletal Muscle Branched-Chain Amino Acid Metabolism in Exercise Training–Induced Insulin Sensitivity
Authors: PATAKY MARK W. , KUMAR ARATHI PRABHA , ROBINSON MATTHEW M. , KLAUS KATHERINE , DASARI SURENDRA , NAIR K. SREEKUMARAN
Published: May 2022

Insulin sensitivity is enhanced by 3 months of either aerobic (high-intensity interval training, HIIT) or resistance exercise (RET) , but mechanisms leading to improved insulin sensitivity are not identical between modes of exercise. We sought to identify common predictors of exercise training-induced insulin sensitivity. Using RNAseq we found that branched chain amino acid (BCAA) and general amino acid metabolism were the only common pathways associated with enhanced insulin sensitivity by HIIT and RET in skeletal muscle. We explored the BCAA metabolism pathway and other amino acid metabolites as related to insulin sensitivity in response to HIIT and RET. Skeletal muscle and plasma were obtained from our previously published study which showed significantly enhanced insulin sensitivity following 12-weeks of either HIIT (n=19) or RET (n=18) . Immunoblotting was used to measure the abundance and phosphorylation of the key rate limiting enzyme in BCAA metabolism, branched chain ketoacid dehydrogenase (BCKDH) , in skeletal muscle. Liquid chromatography-mass spectrometry was used to measure amino acids and their metabolites before and after exercise training. Skeletal muscle BCKDH abundance and activity (indicated by reduced phosho/total BCKDH) were significantly increased (P<0.05) by both HIIT and RET. HIIT significantly increased (P<0.05) all three BCAAs (Ile +7.7 ± 2.2, Leu +18.9 ± 5.6, Val +24.5 ± 7.3 pmol/mg muscle) , as well as multiple other amino acids and metabolites in skeletal muscle. Although we did not detect an increase in amino acids or metabolites following RET in skeletal muscle, in plasma there was a significant increase (P<0.05) in all three aromatic amino acids (Phe +5.1 ± 2.2, Trp +5.6 ± 2.5, Tyr +4.8 ± 1.7 µM) as well as Pro (13.0 ± 4.6 µM) , Ala (+29.3 ± 12.1 µM) , and Met (2.1 ± 0.5 µM) following RET. These results suggest activation of amino acid metabolism pathways, contributing to enhanced insulin sensitivity following different modes of exercise training.

Disclosure

M.W.Pataky: None. A.Prabha kumar: n/a. M.M.Robinson: Stock/Shareholder; GE Healthcare Systems. K.Klaus: None. S.Dasari: None. K.Nair: None.

Funding

National Institutes of Health (RAG09531) National Institutes of Health (T32 DK007352)
25-OR: Machine Learning for Early Detection of Nonresponders to Lifestyle Intervention for Prediabetes
Authors: FOPPIANI ANDREA , DE AMICIS RAMONA , LEONE ALESSANDRO , BERTOLI SIMONA , BATTEZZATI ALBERTO
Published: May 2022

Introduction: Lifestyle intervention is the first-line treatment for prediabetes. More intensive intervention usually follows for those patients that fail to improve glycemia. We explored the possibility to early detect non-responders to lifestyle intervention from a single baseline evaluation.

Methods: The sample was composed of 738 pre-diabetic (fasting glucose 100-125 mg/dl) patients (median age 54 IQR 45-62, 57% female, median BMI 30.4 IQR 27.5, 34.2) , that were prescribed a lifestyle intervention, and were re-evaluated within 12 months. Lifestyle intervention consisted of a hypocaloric diet (based on resting energy expenditure measured by indirect calorimetry, with a Mediterranean pattern, tailored on patient habits) and WHO physical activity guidelines. The outcome was normalization of fasting glucose at follow-up (0: ≥100 mg/dl, 1: <100 mg/dl) , with an historical failure rate of 44%. Baseline evaluation consisted of anthropometry, indirect calorimetry, abdominal fat ultrasound, laboratory exams, structured medical and nutritional interview, and psychological questionnaires, with a total of 114 predictors. Statistical and machine learning models were screened to select the best classifier for the outcome.

Results: The best model was a random forest model (a machine learning model) , with a validation-set accuracy of 72%, ROC AOC of 0.64, sensitivity of 55%, and specificity of 86%.

Discussion: The best developed model is able to identify more than half non-responders on the basis of a single baseline evaluation, while including few responders as false-positives. The model accuracy resulted higher than the historical rate of failure, so integrating the model suggestion in the clinical decision process should allow to more promptly treat future patients and improve the overall success rate. Machine learning models show potential in leveraging high-dimensional multi-domain routinely-collected clinical data to aid in clinical decision.

Disclosure

A.Foppiani: None. R.De amicis: None. A.Leone: None. S.Bertoli: None. A.Battezzati: None.
252-LB: GRK2 Participates in Islet Function and Glucose-Stimulated Insulin Secretory Responses
Authors: SNYDER JONATHAN W. , MONTGOMERY SARAH K. , DOLIBA NICOLAI M. , ROMAN JEFFREY , TIAN YUZHEN , SATO PRISCILA Y. , HOLLAND WILLIAM L. , HEE CHOI RAN
Published: May 2022

Insulin deficiency is central to diabetes and diabetes-related cardiac dysfunction. GPCRs are known modulators of insulin secretion and a main pharmacological target in various tissues, including the heart. GPCR kinase 2 (GRK2) phosphorylates activated GPCRs, targeting receptors for recycling or degradation. Notably, we and others have shown that GRK2 can also localize to the cardiac mitochondria where it participates in substrate utilization, particularly in response to cellular stress. GRK2 is downregulated in the pancreas of diabetogenic mice, and we have shown that pancreatic loss of GRK2 impairs insulin secretion in normal and high fat diet. Mice with pancreatic-specific GRK2 KO showed glucose intolerance (AUC WT 8691 vs. KO 14766 mg/dl*min, n=22/group, p<.05) due to significant decrease in insulin secretion following glucose administration (after 15 minutes WT 2.35 vs. KO 1.616 ng/ml, N=16-19/group, P<.0001) without changes in islet size or cell distribution. Using a model of high fat diet, we observed an impairment in glucose-stimulated insulin release in pancreatic GRK2 KO animals when compared to control animals without significant changes in fasting insulin secretion or insulin sensitivity. To further dissect the role of islet GRK2 in α- or β-cells, we have constructed two novel mouse models of inducible cell type-specific GRK2 KO. Our preliminary studies reveal that β-cell GRK2 deficient animals are prone to glucose intolerance and decreased glucose-induced insulin secretion when exposed to high fat high sucrose diet. This suggests that GRK2 plays a role in islet adaptation to metabolic challenge. Further studies will delineate the mechanistic role of GRK2 in mediating metabolism and calcium influx in β-cells regulating insulin secretion, and subsequently the impact to the heart in the presence or absence of TAC. Our studies will provide new GRK2 mechanistic insight that could be explored as new pharmacological strategies to delay diabetes disease progression.

Disclosure

J. W. Snyder: None. S. K. Montgomery: None. N. M. Doliba: None. J. Roman: None. Y. Tian: None. P. Y. Sato: None. W. L. Holland: None. R. Choi: None.

Funding

National Institutes of Health (1R56HL149887) ; University of Pennsylvania Diabetes Research Center Pilot and Feasibility Grant (P30-DK019525) ; American Heart Association Scientist Development Grant (17SDG33660407)
254-OR: Glucose Response Patterns Based on 75g OGTTS during Pregnancy and Their Association with the Risk of Macrosomia: A Latent Class Analysis of TWO Cohort Studies
Authors: FRITSCHE LOUISE , HULMAN ADAM , PRYSTUPA KATSIARYNA , HENI MARTIN , BIRKENFELD ANDREAS L. , PETER ANDREAS , FRITSCHE ANDREAS , KUN ATTILA , TABAK ADAM , WAGNER ROBERT
Published: May 2022

Background and Aims: People with different glucose response patterns during the 2-h oral glucose tolerance test (OGTT) have substantially different clinical characteristics and risk for long-term outcomes in the general population. We aimed to identify comparable glucose response patterns in pregnancy and their association with maternal and fetal outcomes.

Materials and Methods: We used latent class trajectory modelling to identify glucose response patterns using 5-point 75g OGTT in 470 pregnant women at 27.3±2.2 weeks of gestation. We assessed these classes and investigated pregnancy outcomes in an independent cohort of 7073 pregnant women with 3-point OGTTs.

Results: We identified five different glucose response patterns (classes) . Rate of gestational diabetes (GDM) was lowest in class 1 (< 7%) and highest in class 5 (100%) for both cohorts. Class 3 was characterized by transient hyperinsulinemia at 30 minutes but the prevalence of GDM was only 25-36%. Compared to class 1, women in class 3 had an increased gestational weight gain (GWG, β=0.85 SE: 0.31kg, p=0.0065, adjusted for age, gestational age, pre-gestational BMI, GDM treatment and AUCGlucose) . New-borns in class 3 had the highest risk of macrosomia (OR 1.47 95% CI: [1.12, 1.93] vs. class 1) after adjustment for maternal age, parity and smoking, but this was attenuated by additional adjustment for pre-pregnancy BMI and GWG.

Conclusion: We found an easily identifiable group of pregnant women who have an increased risk of macrosomia without formally meeting GDM diagnosis. These women would most likely benefit from a therapy (e.g. nutritional counselling) aiming at preventing excessive glucose excursions and GWG.

Note: LF and AH contributed equally to this work.

Disclosure

L.Fritsche: None. R.Wagner: Advisory Panel; Akcea Therapeutics, Daiichi Sankyo, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. A.Hulman: None. K.Prystupa: None. M.Heni: Advisory Panel; Boehringer Ingelheim International GmbH, Research Support; Boehringer Ingelheim International GmbH, Sanofi, Speaker's Bureau; Amryt Pharma Plc, Boehringer Ingelheim International GmbH, Novo Nordisk. A.L.Birkenfeld: None. A.Peter: None. A.Fritsche: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. A.Kun: None. A.Tabak: Consultant; 77 Elektronika Kft., Boehringer Ingelheim International GmbH, Speaker's Bureau; 77 Elektronika Kft., AstraZeneca, Sanofi_aventis Zrt.

Funding

The PREG study is supported in part by a grant from the Federal Ministry of Education and Research (BMBF) (01GI0925) to the German Center for Diabetes Research (DZD)
257-LB: A Novel MODY-Associated Gain-of-Function Mutation in TALK-1 Leads to Islet Dysfunction and Glucose Intolerance
Authors: NAKHE ARYA Y. , DADI PRASANNA , ZABORSKA KAROLINA E. , JACOBSON DAVID
Published: May 2022

The most islet-restricted and abundantly expressed K+ channel of the human ꞵ-cell, TALK-1, regulates electrical activity and glucose-stimulated insulin secretion (GSIS) . Recently we identified a gain-of-function (GOF) mutation near the pore domain of TALK-1 (Leu114Pro) that causes Maturity-Onset Diabetes of the Young (MODY) in an autosomal dominant manner, but only in a single family. To confirm TALK-1-Leu114Pro as the mutation that causes the MODY phenotype and investigate the impact of TALK-1 GOF on glucose homeostasis, a mouse model containing the TALK-1-Leu114Pro mutation was generated. Interestingly, mice with TALK-1-Leu114Pro mutation show neonatal lethality which may be due to alterations of islet hormone secretion during neonatal development (this was observed in heterozygous TALK-1-Leu114Pro C57BL/6J and homozygous TALK-1-Leu114Pro CD-1 (ICR) mice) . We first confirmed that TALK-1-Leu114Pro mutation resulted in a GOF in β-cell whole-cell K+ currents. On the ꞵ-cell plasma membrane the resulting TALK-1-Leu114Pro hyperpolarizing current blunted glucose-stimulated Ca2+ entry and subsequent Ca2+ oscillations, whereas on the endoplasmic reticulum membrane TALK-1-Leu114Pro enhanced IP3-induced Ca2+ release. TALK-1-Leu114Pro+/- islets also showed decreased GSIS and reduced plasma insulin levels in TALK-1-Leu114Pro+/- mice when compared to controls. TALK-1-Leu114Pro+/- mice exhibit a significant impairment in glucose homeostasis which is likely due to reduced islet Ca2+ influx and GSIS. However, TALK-1 activity in other islet cell types may also contribute to glucose dyshomeostasis in TALK-1-Leu114Pro+/- mice. For example, pancreatic α-cell area and islet glucagon secretion are increased TALK-1-Leu114Pro+/- mice. Taken together, these data prove that the MODY-associated TALK-1-Leu114Pro mutation disrupts glucose homeostasis and suggests that TALK-1 is an islet-restricted target for the treatment for diabetes.

Disclosure

A. Y. Nakhe: None. P. Dadi: None. K. E. Zaborska: None. D. Jacobson: None.
258-LB: ICAM-1 Abundance Is Increased in Pancreatic Islets of Hyperglycemic NOD Mice and Is Rapidly Upregulated by NF-kB in Pancreatic Beta Cells
Authors: MARTIN THOMAS , BURKE SUSAN , GHOSH SUJOY , KARLSTAD MICHAEL D. , COLLIER JASON
Published: May 2022

Type 1 diabetes (T1D) is an autoimmune disease strongly associated with immune cell targeting of pancreatic β-cells, which ultimately produces insulin insufficiency. We identified the Icam1 gene and ICAM-1 protein, which facilitate interaction with immune cells, as elevated in female NOD mice relative to male mice. This observation is consistent with a greater frequency of diabetes onset in female mice in this well-established model of T1D. In addition, ICAM-1 protein abundance was greater in hyperglycemic female NOD compared with age-matched normoglycemic female NOD mice. Upon examining islet β-cell responses to immune cell-derived cytokines, we discovered that the Icam1 gene was rapidly (within 3h) and strongly (> 20-fold) upregulated in mouse, rat, and human islets as well as 832/13 rat insulinoma cells in response to IL-1β (p < 0.01) . Using chromatin immunoprecipitation (ChIP) assays, we identified rapid recruitment (within 30 minutes) of the p65 transcriptional subunit of NF-κB to κB genomic elements within the Icam1 gene promoter (3-fold; p < 0.05 relative to isotype control) . ChIP assays also revealed elevated RNA polymerase II recruitment to the Icam1 gene promoter (within 30 min) in response to IL-1β (7-fold, p < 0.05) . Finally, using single-cell RNA-Sequencing, we discovered that only a few clusters of β-cells expressed Icam1 at very low abundance in the basal (unstimulated) condition, while the majority of β-cell clusters in the IL-1β (3 h) stimulated condition presented with strong Icam1 positive (mRNA expressing) cells. Thus, we conclude that most, if not all, β-cells undergo rapid genetic reprogramming by IL-1β to enhance expression of the Icam1 gene and promote accumulation of the ICAM-1 protein. These findings illustrate the importance of pancreatic β-cell communication with the immune system and reveal inducible events at the β-cell level that are linked with onset and progression of T1D.

Disclosure

T. Martin: None. S. Burke: None. S. Ghosh: None. M. D. Karlstad: None. J. Collier: None.

Funding

National Institutes of Health (R03 AI151920-02)
266-OR: Dexamethasone-Induced Hyperglycemia in Nondiabetic Patients with COVID-19
Authors: RHOU YOON JI J. , HOR AMANDA , WANG MAWSON , WU YU-FANG , CHIPPS DAVID R. , CHEUNG N. WAH
Published: May 2022

Background: Dexamethasone improves COVID-outcomes. Detailed glycemic profile for patients receiving dexamethasone for COVID-is lacking.

Methods: Our hospital recommends routine blood glucose monitoring for patients with COVID-receiving dexamethasone 6mg daily. Subjects without prior history of diabetes admitted in a non-critical care setting over a 1-month period were identified and evaluated. The primary outcome was hyperglycemia post-dexamethasone, defined as glucose ≥10mmol/L.

Results: Of 277 subjects (52% male, age 52±18 yrs, weight 90±26 kg, 7% with newly diagnosed diabetes [HbA1c ≥6.5%]) , hyperglycemia post-dexamethasone occurred in 51%, with peak glucose 12.4±2.3 (mean 2.2 tests/day) . Glucose excursions peaked 7-9 hours post-dexamethasone (figure) . Hyperglycemic subjects were older (58±17 vs. 45±7 yrs, p<0.001) , had higher HbA1c (6.1±1.0 vs. 5.6±0.9%, p<0.001) , higher initial venous glucose (6.7±1.7 vs. 6.0±1.5mmol/L, p<0.001) , lower initial eGFR (80±18 vs. 84±15mL/min/m2, p=0.02) , higher initial CRP (969±640 vs. 791±558nmol/L, p=0.01) and greater mortality (7.7 vs. 1.5%, p=0.01) . Age, HbA1c and CRP were independent predictors of hyperglycemia.

Conclusions: Dexamethasone led to hyperglycemia in half of patients without prior diabetes admitted with COVID-19, with peak occurring 7-9 hours after dexamethasone. Older age, higher HbA1c and initial CRP predicted development of hyperglycemia.

Disclosure

Y.J.Rhou: None. A.Hor: None. M.Wang: None. Y.Wu: None. D.R.Chipps: None. N.Cheung: None.
267-OR: Diabetes, COVID-19, and All-Cause Mortality among People with Diabetes during the COVID-Pandemic in Minnesota: Population-Based Study
Authors: MCCOY ROZALINA G. , MULLAN AIDAN F. , JEFFERY MOLLY M. , BUCKS COLIN M. , CLEMENTS CASEY M. , CAMPBELL RONNA
Published: May 2022

People with diabetes have been profoundly impacted by the COVID-pandemic. Diabetes and its comorbidities are strong risk factors for severe, including fatal, COVID-disease. People with diabetes may also have limited or delayed routine and non-emergent medical services, potentially increasing their risk of death from causes unrelated to COVID-19. Granular population-level data on rates, causes, and places (i.e. home vs. hospital) of death among people with diabetes during the COVID-pandemic is scarce. We examined Minnesota death certificates from 2020 (COVID-year) and 2018-20 (comparator years) among people with diabetes to compare changes in population-adjusted rates of diabetes-specific mortality (diabetes as a primary cause of death) , and all-cause and other disease-specific mortality (other primary causes with diabetes as a contributing cause of death) . We also assessed COVID-mortality (COVID-as a primary cause and diabetes as a contributing cause) . Analyses were adjusted for multiple comparisons using the false discovery rate correction. COVID-accounted for 246 deaths per 100,000 people with diabetes. There was no significant change in diabetes-specific mortality from 2018-20to 2020 (328 to 353 per 100,000; 2020 vs. 2018-20IRR 1.[95% CI 1.01-1.15]; p=0.08) . All-cause mortality among people with diabetes increased from 1,484 to 1,922 per 100,000 (IRR 1.30 [95% CI 1.26-1.33]; p<0.001) , while non-COVID mortality among increased from 1,484 to 1,675 per 100,000 (IRR 1.13 [95% CI 1.10-1.16]; p<0.001) . Deaths for cardiovascular diseases, cancers, and infectious diseases (not including COVID-19) also increased significantly, suggesting that people may have deferred care for these conditions with deadly consequences. Our findings underscore the need for uninterrupted comprehensive care for people living with diabetes to ensure that access for acute and chronic health concerns remains prioritized.

Disclosure

R.G.Mccoy: Consultant; Emmi. A.F.Mullan: None. M.M.Jeffery: Stock/Shareholder; Goodness Growth Holdings. C.M.Bucks: None. C.M.Clements: Consultant; Vail Scientific LLC. R.Campbell: Consultant; Bryn Pharma.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (K23DK114497)
273-OR: Postprandial Dysfunction in Metabolic Associated Fatty Liver Disease (MAFLD)
Authors: GRANDT JOSEPHINE , JENSEN ANNE-SOFIE H. , WERGE MIKKEL P. , RASHU ELIAS B. , JUNKER ANDERS , HOBOLTH LISE , MORTENSEN CHRISTIAN , VYBERG MOGENS , SERIZAWA REZA , MØLLER SØREN , GLUUD LISE , WEWER ALBRECHTSEN NICOLAI J.
Published: May 2022

Metabolic dysfunction in patients with metabolic fatty liver disease (MAFLD) may increase the risk for diabetes development. The liver is essential for the postprandial control of our metabolism and hormonal response, yet most studies focus on fasting conditions. We therefore studied the fasting and postprandial phase in individuals with biopsy-proven nonalcoholic fatty liver disease (NAFLD, (n = 9, mean age 50 y, mean BMI 35 kg/m2, no/mild fibrosis) , cirrhosis (n = 10, age 62 y, BMI 32 kg/m2, CHILD A/B) and healthy controls (n = 10, age 23, BMI 25 kg/m2) , randomized 1:1 to fasting or Nutridrink (Nutricia, 300 kcal) . None of the postprandial patients had type 2 diabetes (T2D) . In the NAFLD/cirrhosis groups, 17/classified as MAFLD. Peripheral blood samples were collected at 0, 15, 45, 60, 90 and 120 minutes. At time point 60, a transjugular liver biopsy and liver vein blood were taken. Levels of glucose, insulin, C-peptide, glucagon, and fibroblast growth factor 21 (FGF21) were measured in peripheral blood, glucagon and FGF21 also in liver vein blood. Postprandial peak glucose and C-peptide was increased in NAFLD and cirrhosis compared with healthy (mean peak glucose (mM) 7, 10, 6; mean peak C-peptide (pM) 2675, 3340, 1689, respectively) . The postprandial incremental AUC for insulin was significantly increased in patients with NAFLD compared to healthy. Patients with NAFLD and cirrhosis had hyperglucagonemia, a phenotype related to prediabetes. FGF21 was increased in NAFLD and cirrhosis and correlated to age (r= .61, P = .001) and fasting glucose (r = .54, P = .006) . Glucagon levels were higher in liver vein compared to peripheral blood, while FGF21 levels were similar in both compartments.

In summary, patients with NAFLD and cirrhosis without T2D showed significant metabolic dysfunction after a standardized meal compared to healthy controls. We found impaired glucose tolerance, hyperinsulinemia and hyperglucagonemia in both NAFLD and cirrhosis, suggesting a condition of prediabetes in patients with MAFLD.

Disclosure

J. Grandt: None. A.H. Jensen: None. M.P. Werge: None. E.B. Rashu: None. A. Junker: None. L. Hobolth: None. C. Mortensen: None. M. Vyberg: None. R. Serizawa: Consultant; Merck Sharp & Dohme Corp. L. Gluud: Advisory Panel; Novo Nordisk. Consultant; Pfizer Inc. Research Support; Alexion Pharmaceuticals, Inc., Gilead Sciences, Inc., Novo Nordisk, Sobi. N.J. Wewer Albrechtsen: Research Support; Mercodia AB, Novo Nordisk, Regeneron Pharmaceuticals Inc. Speaker's Bureau; Merck & Co., Inc., Mercodia AB.

Funding

Nicolai J. Wewer Albrechtsen was financed by NNF Excellence Emerging Investigator Grant – Endocrinology and Metabolism (Application No. NNF19OC0055001) , EFSD Future Leader Award (NNF21SA0072746) and DFF Sapere Aude.
274-OR: The Malic Enzyme-1 Links Pyruvate Carboxylase–Mediated Anaplerosis to Redox State in Liver
Authors: INIGO MELISSA MAE R. , FLETCHER JUSTIN A. , KUCEJOVA BLANKA , SHARMA GAURAV , DEJA STANISLAW , FU XIAORONG , BURGESS SHAWN C.
Published: May 2022

Redox balance is critical for numerous cellular functions, including substrate oxidation, biosynthesis, and antioxidant defenses. Redox homeostasis is dysregulated in many metabolic diseases, including obesity and Type 2 diabetes. In addition to its role in replenishing TCA cycle intermediates, we previously showed that pyruvate carboxylase (PC) -mediated anaplerosis is necessary to regulate redox state, including the NADPH/NADP+ ratio and antioxidant capacity in liver, though the mechanism is unclear. We hypothesized that PC elicits effects on redox by modifying ratios of metabolites involved in redox mediated exchange reactions. Malic enzyme-1 (Me1) catalyzes the reversible, NADPH dependent, decarboxylation of malate to pyruvate. This enzyme plays a vital role in recycling malate and providing NADPH during lipogenesis. We show here that Me1 mediates redox by sensing TCA cycle function through the mass action of malate and pyruvate. We tested the role of Me1, as a sensor of anaplerosis in the TCA cycle and regulator of redox, using acute Me1 knockdown (Me1KD) in liver-specific PC knockout (LPCKO) mice. Stable isotope tracers were used to examine anaplerosis, gluconeogenesis, and pyruvate cycling fluxes, and targeted metabolomics were used to evaluate tissue energy status and redox. Anaplerosis, pyruvate cycling, and gluconeogenesis were lower in the absence of liver PC but were unaffected by Me1KD. Loss of PC decreased the malate/pyruvate ratio, congruent with impaired conversion of pyruvate to TCA cycle intermediates, which resulted in a concomitant decrease in the NADPH/NADP+ ratio. Acute removal of Me1 in LPCKO mice normalized NADPH/NADP+ and restored the malate/pyruvate ratio. Additionally, mitochondrial NAD+/NADH and FAD+/FADH redox states were more oxidized in LPCKO liver and were normalized by loss of Me1. Thus, despite not altering the aforementioned fluxes, Me1 transmits redox state in response to TCA cycle function by sensing alterations in the malate/pyruvate ratio.

Disclosure

M.R.Inigo: None. J.A.Fletcher: None. B.Kucejova: None. G.Sharma: None. S.Deja: None. X.Fu: None. S.C.Burgess: n/a.

Funding

Robert A. Welch Foundation Grant (I-1804)
275-OR: Inhibition of Hepatic ACC Decreases Ketogenesis during Fasting due to Elevated Amino Acid Availability
Authors: DEJA STANISLAW , FLETCHER JUSTIN A. , KUCEJOVA BLANKA , MIZERSKA MONIKA N. , FU XIAORONG , KIM CHAI-WAN , BROWNING JEFFREY , YOUNG JAMEY , HORTON JAY D. , BURGESS SHAWN C.
Published: May 2022

Activation of fatty acid oxidation is a promising therapy for NAFLD. Lowering acetyl-CoA carboxylase (ACC) activity depletes malonyl-CoA, activates CPT1, and increases mitochondrial fatty acid delivery. ACC1/2 liver double KO mice (LDKO) are protected from hepatic steatosis and have elevated ketogenesis in the prandial state. However, fasted LDKO mice exhibit an unexpected inhibition of ketogenesis, indicated by lower blood ketones and reduced in vivo ketone turnover of [3,4-13C2]acetoacetate and [U-13C4]β-hydroxybutyrate. Despite impaired fasting ketogenesis in vivo, perfused livers isolated from fasted mice and starved primary hepatocytes had normal or elevated ketone production, suggesting that a substrate-mediated mechanism inhibits ketosis in vivo. There were no differences in plasma NEFAs, but hepatic lactate was elevated during fasting in LDKO mice. The increase in lactate was sufficient to suppress ketone production in isolated perfused liver. An in vivo [U-13C3]lactate/pyruvate challenge was more rapidly diluted in fasted LKDO mice, indicating that alternative endogenous sources of pyruvate were available. Indeed, essential amino acids were elevated in fasted LDKO liver, but not plasma, suggestive of hepatic proteolysis as a source of amino acids. Liver size was 20% larger in LDKO mice, independent of glycogen storage or triglyceride content, but was consistent with increased insulin action and activation of Nrf2 which have been linked to hepatomegaly. Autophagy during fasting was normal or increased, suggesting that hepatomegaly supplies excess amino acids in the fasted state. Injection of exogenous alanine or glutamine in fasted WT mice recapitulated the fasted LDKO phenotype by increasing plasma glucose and lactate and decreasing ketone concentrations. Thus, hepatic growth is increased in the absence of malonyl-CoA synthesis, which provides a surplus of amino acids, anaplerotic maintenance of the TCA cycle and lower ketogenesis during fasting.

Disclosure

S.Deja: None. S.C.Burgess: n/a. J.A.Fletcher: None. B.Kucejova: None. M.N.Mizerska: None. X.Fu: None. C.Kim: None. J.Browning: None. J.Young: Consultant; Pfizer Inc., Research Support; Merck & Co., Inc., Stock/Shareholder; Metalytics, Inc. J.D.Horton: Board Member; Draupnir Bio, Consultant; Eli Lilly and Company, ESPERION Therapeutics, Inc., Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Pfizer Inc., Regeneron Pharmaceuticals Inc.

Funding

National Institutes of Health (R01DK078184, P41EB015908)
280-OR: Updated Diabetes Family Conflict Scale (DFC) Includes Continuous Glucose Monitoring (CGM) Items
Authors: CHEN CHARLOTTE , SHAPIRA AMIT , VOLKENING LISA K. , LAFFEL LORI M.
Published: May 2022

Introduction: With increased CGM use in youth with T1D, it is timely to assess diabetes-specific family conflict related to CGM use. We aimed to evaluate the psychometric properties of an updated DFC measure that includes CGM items.

Methods: Youth with T1D and their parents completed youth and parent versions, respectively, of the DFC that included 6 CGM-specific items (e.g., responding to CGM alarms) . Higher scores indicate more conflict. Item-to-total correlations and Cronbach’s α assessed internal consistency; correlations determined concurrent and predictive validity.

Results: The sample comprised 1youth (51% male) aged 13.2±2.7 years, with T1D duration 6.6±3.5 years. The final survey had 16 items after removal of those with outdated features, low response variability, or low item-to-total correlation. Cronbach’s α was .91 for youth and .81 for parents. Youth and parent scores were highly correlated (r=.48, p<.0001) . Higher DFC scores were associated with younger youth age (youth: r=-.23, p=.02; parent: r=-.27, p=.004) . Higher youth and parent DFC scores were also associated with adverse psychosocial outcomes: more depressive symptoms (youth: r=.38, p<.0001; parent: r=.35, p=.0002) , more diabetes burden (youth: r=.31, p=.0008; parent: r=.44, p<.0001) , more anxiety traits (youth: r=.23, p=.02; parent: r=.45; p<.0001) , lower youth general quality of life (QoL) (youth: r=-.30, p=.002; parent: r=-.45, p<.0001) and lower youth diabetes-specific QoL (youth: r=-.21, p=.02; parent: r=-.44, p<.0001) . Higher youth and parent DFC scores were associated with lower CGM satisfaction (youth: r=-.36, p<.0001; parent: r=-.28, p=.004) and with less CGM use at the time of DFC scale completion (youth: r=-.33, p=.0004; parent: r=-.31, p=.001) and 3 months later (youth: r=-.19, p=.05; parent: r=-.28, p=.003) .

Conclusion: The updated youth and parent DFC scales demonstrate strong psychometric properties and predictive validity and may be useful in clinical and research settings.

Disclosure

C.Chen: None. A.Shapira: None. L.K.Volkening: None. L.M.Laffel: Advisory Panel; Medtronic, Roche Diabetes Care, Consultant; Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompé, Insulet Corporation, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk, Provention Bio, Inc.

Funding

National Institutes of Health (P30DK036836, R01DK089349, T32DK007260)
281-OR: Psychosocial Benefits of Using Control-IQ Technology: Long-Term Outcomes from a Multiethnic Adult Cohort with Type 1 Diabetes
Authors: SINGH HARSIMRAN , ALENCAR GABRIEL , SANCHEZ HAIDEE , MANNING MICHELLE L. , WHITE KIRSTIN N. , WHEATCROFT ALEX , CARMELO KAREN , GRAHAM RISHI , MUELLER LARS , ARONOFFSPENCER ELIAH S. , PINSKER JORDAN E. , HABIF STEPHANIE
Published: May 2022

There is mounting evidence supporting the benefits of hybrid closed loop systems for type 1 diabetes (T1D) management. However, published studies lack long-term evaluation of these technologies in ethnically diverse patients including patient-reported outcomes (PROs) assessing lived experiences with these devices. As part of the Control-IQ Observational (CLIO) study, we evaluated psychosocial outcomes in T1D adults using the Tandem Diabetes Care t:slim X2 insulin pump with Control-IQ technology. Participants completed PRO measures including open-ended items at baseline (pre) , 3, 6, and 12 months (post) . Wilcox signed rank-test was used to assess differences and qualitative data was analyzed using thematic analysis. In all, 13adult study completers (57.6% female) (White=1084, Hispanic=86, Black=38, Asian=16, Mixed=42) were included in the analysis. Overall, there was a 25.2% improvement in satisfaction with insulin delivery device (IDD) using Control-IQ technology at post (mean=8.83±1.15) vs. pre (i.e., previous IDD) (7.06±2.04) (p<0.001) . The Asian cohort reported greater improvement (33.2%) than others. A significant reduction in diabetes impact (33.6%) was noted overall at post (p<0.001) with Hispanic participants reporting greater reduction in diabetes burden (42.8%) than others. For perceived impact of diabetes on quality of life, there was an overall reduction in diabetes impact at post (p<0.001) with Asians showing greater reduction (26.3%) vs. others, specifically in the “freedom to eat as you wish” aspect of life. At post, 71% reported improved sleep quality using Control-IQ technology. Thematic analysis supported these findings highlighting improved diabetes control, quality of life, and ease of use as valuable experiences supporting long-term use of Control-IQ technology. These data demonstrate substantial and sustained psychosocial improvements using Control-IQ technology in diverse ethnic cohorts with T1D.

Disclosure

H.Singh: Employee; Tandem Diabetes Care, Inc. E.S.Aronoffspencer: Research Support; Tandem Diabetes Care, Inc. J.E.Pinsker: Employee; Tandem Diabetes Care, Inc., Stock/Shareholder; Tandem Diabetes Care, Inc. S.Habif: Employee; Tandem Diabetes Care, Inc. G.Alencar: Employee; Tandem Diabetes Care, Inc. H.Sanchez: Employee; Tandem Diabetes Care, Inc. M.L.Manning: Employee; Tandem Diabetes Care, Inc. K.N.White: Employee; Tandem Diabetes Care, Inc. A.Wheatcroft: Employee; Tandem Diabetes Care, Inc. K.Carmelo: None. R.Graham: Research Support; Tandem Diabetes Care, Inc. L.Mueller: Employee; Tandem Diabetes Care, Inc., Research Support; Dexcom, Inc., Stock/Shareholder; Tandem Diabetes Care, Inc.

Funding

Tandem Diabetes Care
283-OR: Neighborhood Disadvantage for Teens with Type 1 Diabetes (T1D) : Associations with Glycemic and Psychosocial Outcomes
Authors: O'DONNELL MAEVE B. , DURAN BRENDA , ZHOU CHUAN , MALIK FAISAL , PIHOKER CATHERINE , SCOTT SAMANTHA R. , ELLISOR BRITNEY M. , PEREZ SAMANTHA GARCIA , DESALVO DANIEL , HILLIARD MARISA E. , YI-FRAZIER JOYCE
Published: May 2022

Background: For teens with T1D, stress related to neighborhood disadvantage may exacerbate diabetes distress and contribute to disparities in care and outcomes.

Objective: We explored associations among neighborhood disadvantage and clinical/psychosocial outcomes to identify patterns to inform future stress-resilience interventions.

Methods: At baseline of a 2-site psychosocial intervention trial, 173 teens aged 13-18 years with T1D ≥1 year and elevated diabetes distress (57% Female, 2% American Indian/Alaska Native, 4% Asian, 15% Black, 11% Hispanic White, 6% Hispanic Non-White, 63% Non-Hispanic White, mean A1c= 8.7±2.1, 66% pump use) completed a demographics form and measures of resilience, diabetes distress, diabetes quality of life and family conflict.. We retrieved area deprivation index (ADI) scores for home addresses; this measure of neighborhood disadvantage considers factors related to income, education, employment, and housing quality at the census block group level and provides a state-relative decile score (higher scores indicate more disadvantage) . Fisher’s exact tests and regression analyses were used to examine associations of ADI with A1c and survey data.

Results: Participant ADI spanned all deciles, M = 3.7± 2.4. Hispanic White/Non-White and Black teens and those not using pump had higher mean ADI. Higher ADI was associated with higher A1c (β=.18 [.06, 0.29], p=.003) and higher family conflict (β=.63 [.12, 1.1], p=.015) . ADI was not significantly related to resilience, diabetes distress, or quality of life.

Conclusions: In a diverse sample of distressed teens with T1D, neighborhood disadvantage was associated with Hispanic ethnicity and Black race, lower pump use, poorer glycemic control and greater family conflict. Considering neighborhood disadvantage may help providers deliver personalized care to target systemic sources of stress, ultimately improving clinical and psychosocial outcomes.

Disclosure

M.B.O'donnell: None. M.E.Hilliard: None. J.Yi-frazier: None. B.Duran: None. C.Zhou: None. F.Malik: n/a. C.Pihoker: None. S.R.Scott: None. B.M.Ellisor: None. S.Garcia perez: None. D.Desalvo: Consultant; Dexcom, Inc., Insulet Corporation, Research Support; Insulet Corporation.

Funding

US National Institutes of Health R01DK121224