bluuebunny/crossref_metadata_2025_split huggingface dataset:
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 &gt;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 &lt; 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&lt;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 &gt;= 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 &gt;8% for over 6 months (p &lt; 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 &lt; 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 (&gt;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&lt;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&lt;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&lt;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)
202-OR: Cell-Autonomous Impairment of BCAA Catabolism in White Adipocytes Leads to Systemic Metabolic Dysregulation
Authors: TZENG JOYCE , AGUILLARD ASHLEY , LORENZO DAMARIS 
Published: June 2021

Increased levels of serum branched-chain amino acids (BCAA) is associated with obesity, insulin resistance (IR), and type 2 diabetes (T2D). However, the mechanisms that trigger perturbations in BCAA homeostasis, and whether elevated BCAA causes obesity and other metabolic impairments or is a consequence of them is not clear. Young knock-in mice bearing the human T2D-linked R1788W variant in the cytoskeletal protein ankyrin-B (AnkB) show normal body weight and composition. These mice display increased glucose uptake by white adipose tissue (WAT) due to deficient internalization of the glucose transporter GLUT4. We reported that sustained elevation in glucose disposal in WAT leads to the onset of increased adiposity, lipotoxicity, systemic inflammation, and IR in AnkB mutant mice with age or in young animals fed Western diets. Non-obese R1788W AnkB mice also exhibit transcriptional changes consistent with lower BCAA catabolism in WAT. Here, we show that AnkB deficits impair BCAA catabolism in WAT prior to the onset of obesity. Lean R1788W AnkB mice show reduction in surface levels of the BCAA transporter Asct2 and BCAA uptake together with downregulation of BCAA catabolic enzymes in WAT. These deficits are concomitant with elevations in serum levels of BCAA and related acylcarnitines. Reduced expression of BCAA catabolic enzymes was also observed in WAT of lean WAT-specific AnkB KO mice. In contrast, AnkB deficiency did not alter BCAA oxidation in skeletal muscle (SKM), brown adipose tissue, or liver. Studies in control and R1788W AnkB mice fed isocaloric low and high fat (HFD) diets enriched in BCAA suggest that BCAA elevation triggers mitochondrial dysfunction, impairments in insulin secretion by the pancreas and in insulin signaling in SKM. Our data indicates that elevated circulating BCAA impair glucose tolerance and insulin sensitivity independently of obesity, and that these deleterious effects are potentiated by HFD.

Disclosure
J. Tzeng: None. A. Aguillard: None. D. Lorenzo: None.

Funding
American Diabetes Association (1-19-JDF-081 to D.L.)