bluuebunny/crossref_metadata_2025_split huggingface dataset:
29-LB: Physicians’ Chronic Kidney Disease (CKD) Awareness over Time in Type 2 Diabetes (T2D)
Authors: SCHEMPF JOHN , FREESE REBECCA L. , CARAMORI LUIZA , HARINDHANAVUDHI TASMA 
Published: June 2020

Background: Data indicate lack of CKD awareness in T2D. Our study aimed to determine whether physician awareness of CKD in T2D is associated with CKD severity, and whether this changed over time.
Methods: Retrospective study of adults (≥ 18 years) with an electronic health record (EHR) T2D diagnosis (Dx), seen in clinic in 3 sequential periods: 1/1/11-6/30/13, 7/1/13-12/31/15, and 1/1/16-6/30/19. CKD stages were defined by estimated glomerular filtration rate (eGFR; CKD-EPI creatinine-based) and albumin-to-creatinine ratio (ACR, spot urine). G1-G5 indicates eGFR CKD stages (mL/min/1.73m2) G1 &gt;90, G2 89-60, G3a 45-59, G3b 30-44, G4 15-29, and G5 &lt;15. A1-A3 indicates ACR stages (mg/g) A1 &lt;30, A2 30-300, and A3 &gt;300. The frequency of CKD stages was determined for all participants, regardless of EHR CKD Dx.
Results: From 136,157 eligible patients (62±15 years; 53% male) seen during the study period, 77.9% had eGFR measured, 60.6% ACR, and 58.8% both. ACR was measured more often in less severe CKD stages (Chi-Square, p&lt;0.001). For example, in period 1, ACR was assessed in 82.1%, 80.2%, 76.7%, 76.2%, 66.9%, and 48.1% from G1-5, respectively. Patients in G3a less often had a CKD Dx on their problem list than those in G3b-5 (Chi-Square, p&lt;0.001). Among patients in G3a an EHR CKD Dx was present in 53.8%, 58.4%, and 60.1%, while among those in G3b-5 an EHR CKD Dx was present in 79.8%, 85.6%, and 84.9% in periods 1-3, respectively. Considering all patients in A2-3, an EHR CKD Dx was present in 44.9%, 44.5%, and 45.7% in periods 1-3, respectively.
Conclusions: Consistent with published data, most patients with T2D and lab-diagnosed CKD do not have a CKD Dx in the EHR. Our study indicates that physician’s CKD awareness is associated with CKD severity as related to eGFR but not to ACR. Our data also indicates that despite an initial increase in eGFR-driven CKD awareness between periods 1 and 2, this has leveled off. Not having an EHR CKD Dx suggests lack of physician (and patient) CKD awareness and can potentially lead to suboptimal care.

Disclosure
J. Schempf: None. R.L. Freese: None. L. Caramori: Speaker’s Bureau; Self; Bayer Inc. Other Relationship; Self; Bayer Inc., Novartis Pharmaceuticals Corporation. T. Harindhanavudhi: None.
297-OR: ß-Catenin Facilitates Skeletal Muscle Insulin-Stimulated Glucose Transport through the Regulation of Actin Remodeling
Authors: MASSON STEWART W. , MERRY TROY L. 
Published: June 2020

Skeletal muscle insulin-resistance is a major risk factor for type 2 diabetes. During the early stages of insulin-resistance the proximal insulin-signalling proteins are activated by insulin despite GLUT4 vesicle translocation and glucose transport being impaired. There is growing evidence that the dual function protein β-catenin can support vesicle trafficking, and is dysregulated in insulin resistance. Here we investigate the potential role of β-catenin in facilitating skeletal muscle glucose transport. We report that novel adult-induced skeletal muscle-specific β-catenin knockout mice are insulin resistant and have impaired skeletal muscle glucose transport. Furthermore, the mutation of β-cateninS552 in muscle cells impairs insulin-stimulated GLUT4 translocation and glucose uptake, an effect that appears to be independent of β-catenin’s WNT-signalling transcriptional role. Using immunoprecipitation coupled to proteomics we identify M-cadherin as an insulin-sensitive binding partner of β-catenin, which we confirmed to be required for normal insulin-stimulated glucose transport. Consistent with the role of cadherins in regulating actin filament organization, β-cateninS552 mutant muscle cells have impaired insulin-stimulated actin remodelling. This suggests that insulin-mediated phosphorylation of β-cateninS552 promotes the binding of β-catenin to M-cadherin which then provides support for actin polymerisation at the plasma membrane, a critical step for GLUT4 trafficking. We therefore propose that the dysregulation of β-catenin may play a role insulin resistance independent of proximal insulin signalling.

Disclosure
S.W. Masson: None. T.L. Merry: None.

Funding
Rutherford Discovery Fellowship (RDF-15-UOA-020)
300-OR: The Transcriptional Coregulator CITED2 Suppresses Expression of IRS-2 in Endothelial Cells and Impairs Vascular Insulin Signaling In Vivo
Authors: KUNKEMOELLER BRITTA , CHEN KUANGYANG , WANG XUANCHUN , RASK-MADSEN CHRISTIAN 
Published: June 2020

Endothelial insulin signaling regulates perfusion, leukocyte adhesion, and angiogenesis, and its impairment may contribute to the development of vascular complications in diabetes. Hypoxia-inducible factors (HIF) are known modulators of insulin signaling and we have recently shown that a negative regulator of HIF activity, CBP/p300 interacting transactivator-2 (CITED2), is increased in the vasculature of people with type 2 diabetes. Therefore, we examined the role of CITED2 in endothelial insulin signaling by generating a mouse model with endothelial-specific loss of Cited2. We found that in the aorta and isolated endothelial cells, loss of Cited2 markedly enhanced insulin-stimulated Akt phosphorylation at Ser473 without altering ERK1/2 phosphorylation. Consistent with this observation, Cited2 deletion in endothelial cells increased insulin-stimulated Vegfa expression, endothelial nitric oxide synthase phosphorylation, and cell proliferation. Endothelial cells lacking CITED2 exhibited a 3.6-fold increase in insulin receptor substrate (IRS)-2 protein, a key mediator of the insulin signaling cascade, and 66% increase in Irs2 mRNA expression while IRS-1 was unchanged. Similarly, overexpression of CITED2 in endothelial cells decreased IRS-2 levels by 55% without altering IRS-1. Expression of HIF-2α significantly increased transcription of the Irs2 promoter and co-expression of CITED2 abolished this increase. Moreover, ChIP showed that loss of CITED2 increases occupancy of p300, a key component of the HIF transcriptional complex, on the Irs2 promoter. Together, these results suggest that loss of CITED2 enhances endothelial insulin signaling through de-repression of HIF-dependent Irs2 expression. The CITED2-p300 interaction can likely be interrupted by a small-molecule drug, and is thus a potential target to improve insulin action on endothelial cells in order to prevent vascular complications of diabetes.

Disclosure
B. Kunkemoeller: None. K. Chen: None. X. Wang: None. C. Rask-Madsen: None.

Funding
National Institutes of Health (5T32DK007260)
301-OR: Lipin 1–Mediated Phosphatidic Acid Phosphatase Activity in Adipocytes Regulates Systemic Insulin Sensitivity on High-Fat Diet
Authors: LUTKEWITTE ANDREW J. , FINCK BRIAN N. 
Published: June 2020

Emerging evidence suggests that the capacity of adipocytes to appropriately store lipids and prevent their ectopic accumulation in liver and skeletal muscle may be an important regulator of systemic insulin sensitivity. Lipin 1 is a lipid phosphatase that is highly expressed in adipocytes and catalyzes the conversion of phosphatidic acid (PA) to diacylglycerol (DAG); the penultimate step in triglyceride synthesis. Adipose tissue lipin 1 expression positively correlates with insulin sensitivity in obese humans and mouse models. To test the role of adipose tissue lipin 1 in systemic insulin sensitivity, we generated mice lacking lipin 1 in adipocytes (Adn-Lpin1-/- mice). On normal chow, loss of lipin 1 in adipocytes modestly reduced white and brown adipose tissue mass, but did not affect glucose tolerance or insulin sensitivity. However, in response to 2 weeks high fat diet (HFD; 60% fat) feeding, Adn-Lpin1-/- mice remained lean, but developed hyperglycemia compared to littermate wild type (WT) mice. Lipidomic analyses demonstrated an increase in liver lipids (PA, DAG, and triglyceride) in HFD-fed Adn-Lpin1-/- mice compared to WT controls, whereas only PA accumulated in skeletal muscle. Plasma triglyceride concentration was not different, but free fatty acids and glycerol were significantly reduced in Adn-Lpin1-/- vs. WT mice fed HFD, suggesting that lipolysis may be decreased. Plasma adiponectin and resistin were significantly reduced in HFD-fed Adn-Lpin1-/- vs. WT control mice while leptin concentrations were not different. Lastly, with 5 weeks of HFD feeding, despite being leaner, Adn-Lpin1-/- mice became markedly hyperglycemic and glucose intolerant compared to littermate WT controls. Collectively, these data suggest that loss of lipin 1 in adipocytes leads to insulin resistance on HFD, likely due to an impaired capacity to store lipids appropriately in adipose tissue.

Disclosure
A.J. Lutkewitte: None. B.N. Finck: Advisory Panel; Self; Cirius Therapeutics. Stock/Shareholder; Self; Cirius Therapeutics.
307-OR: Activation of Mitochondrial Activities by Pyruvate Kinase M2 (PKM2) in Podocytes Improved Glomerular Metabolism and Diabetic Nephropathy
Authors: FU JIALIN , SHINJO TAKANORI , ST-LOUIS RONALD , LI QIAN , PARK KYOUNGMIN , YOKOMIZO HISASHI , ZAITSU YUMI , YU MARC GREGORY , WU I-HSIEN , SHAH HETAL , KING GEORGE L. 
Published: June 2020

Diabetic nephropathy (DN) is the result of systemic and local changes in metabolism and hemodynamics. We have found that the elevation of glycolytic enzymes, such as pyruvate kinase M2 (PKM2) in the renal glomeruli is correlated with preservation of renal function in human type 1 and type 2 diabetes. A small-molecule PKM2 activator, TEPP46, prevented or reversed glomerular pathology in diabetic mice of chronic duration. Mice with PKM2 overexpression specifically in podocytes (PPKM2Tg) were generated, which after 7 months of diabetes induced by streptozotocin, exhibited significantly lower albumin-creatinine ratio (ACR), kidney weight-body weight ratio, and glomeruli pathology such as reduced glomeruli size, mesangial expansion, and basement membrane thickness compared to diabetic WT mice. Furthermore, the glomeruli of diabetic PPKM2Tg mice exhibited lower expressions of fibrotic (FN, TGFβ1 and Col4a) and oxidative stress (p47phox, NOX2 and NOX4) genes compared to WT diabetic mice. Interestingly, the decreased expression of endothelial-trophic genes and mitochondrial-related genes were improved in the whole glomeruli of diabetic PPKM2Tg mice. Oxygen consumption rate (OCR) of glomeruli as measured by Seahorse showed significant improvement in diabetic PPKM2Tg mice versus WT mice (p &lt; 0.05). In vitro studies showed that the activation of PKM2 in mouse podocyte cell line by TEPP-46 decreased high glucose-induced ROS production, improved mitochondrial membrane potential (MMP) by increased the level of mitochondrial OCR and enhanced glycolytic rate. Furthermore, PKM-knockdown stable podocyte cell line, mimicking diabetic conditions, showed dramatical decline of OCR and glycolytic rate. These results showed that PKM2 specific overexpression in podocytes can significantly reduce diabetes-induced mitochondrial abnormalities and oxidative stress in the whole glomeruli, and delay the progression of diabetic nephropathy.

Disclosure
J. Fu: None. T. Shinjo: None. R. St-Louis: None. Q. Li: None. K. Park: None. H. Yokomizo: None. Y. Zaitsu: Employee; Self; Sunstar Group. M. Yu: None. I. Wu: None. H. Shah: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc.
308-OR: Deficiency of Mitochondrial Glycerol 3-Phosphate Dehydrogenase Accelerates the Progression of Diabetic Glomerular Pathology
Authors: QU HUA , ZHENG YI 
Published: June 2020

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease with limited therapeutic options. Although dysfunction of podocytes has been proved to critically associated with DKD, the mechanism underlying remains unclear. Here we identify mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) as a critical regulator of podocyte function during diabetic conditions. Specifically, its expressions were significantly decreased in the glomerular of diabetic mice, and it co-expressed with podocyte marker-WT1. By generating podocyte-specific mGPDH KO mice via breeding mGPDHfl/fl with podocin-Cre mice, we found significant higher levels of albuminuria in KO mice compared to WT during diabetes. Histological analysis showed greater mesangial expansion and decreased WT1 expressions in KO mice with diabetes. In keeping with this, the expressions of renal fibrosis genes were increased and mitochondrial contents and OXPHOS functions were decreased in KO mice with diabetes (Figure 1). Further molecular mechanism exploration showed that mGPDH regulates podocyte function might through AGEs/RAGE pathway. Rescuing mGPDH in STZ mice via AAV led to a significant improvement in their glomerular pathology and renal function. Our findings suggest that targeting mGPDH may be beneficial to attenuate diabetes-induced podocyte dysfunction and kidney injury.

Disclosure
H. Qu: None. Y. Zheng: None.
314-OR: The Effect of Inhibition of Fatty Acid Spillover from Adipose Tissues on Organ-Specific Distribution of Dietary Fatty Acids
Authors: MONTASTIER EMILIE , NOLL CHRISTOPHE , YE RUN ZHOU , AMRANI MEHDI , FRISCH FRÉDÉRIQUE , FORTIN MÉLANIE , BOUFFARD LUCIE , SARRHINI OTMAN , PHOENIX SERGE , GUERIN BRIGITTE , TURCOTTE ERIC E. , CARPENTIER ANDRÉ C. 
Published: June 2020

Excessive exposure of lean tissues to fatty acids leads to insulin resistance. Proper dietary fatty acids (DFA) storage in white adipose tissue (WAT) is thought to prevent lean tissue lipotoxicity. We showed that WAT storage of DFA was impaired in IGT (impaired glucose tolerance) and was associated with greater cardiac DFA uptake and subclinical left-ventricular dysfunction. Whether WAT DFA storage directly impacts cardiac DFA uptake in IGT subjects is not known. We aimed at investigating how inhibition of intracellular lipolysis affected WAT DFA storage, spillover, and cardiac DFA uptake. We recruited 23 participants: 12 IGT, 5 women/7 men, aged (mean ± sem) 64±2.5, BMI= 34.9±3.1 kg/m2 and 11 NGT, 7 women/4 men, aged 62±2, BMI= 30.4±1.6 kg/m2. Cardiac DFA uptake and whole-body organ-specific DFA partitioning were assessed using PET/CT method with oral administration of 18FTHA. NEFA appearance and WAT DFA spillover were measured using stable isotope tracer methods. Nicotinic acid (NA) was used to inhibit WAT DFA spillover. In both groups, NA decreased AUC DFA spillover rate (-31%±19, p=0.014) and AUC NEFA appearance rate (-28%±10, p=0.0002). In NGT group, NA decreased muscle and liver DFA distribution by 30%±8 (p=0.007) and 25%±8 (p=0.024), respectively, and increased WAT DFA distribution by 48%±8 (p=0.001). The same trend was observed in IGT group, but with blunted differences in WAT DFA storage vs. NGT (p=0.73). NA-induced increase in visceral WAT DFA distribution was correlated negatively with change in AUC. Nonesterified fatty acids (NEFA) appearance rate (ρ=-0.58, p=0.004). In both groups, NA did not significantly affect cardiac DFA distribution. In both groups, we estimated that DFA spillover may account for 31%±23 of DFA reaching lean organs over a 6-hour period after meals. Inhibition of WAT DFA spillover enhances DFA WAT storage and reduces liver and skeletal muscle, but not cardiac DFA partitioning.

Disclosure
E. Montastier: None. C. Noll: None. R. Ye: None. M. Amrani: None. F. Frisch: None. M. Fortin: None. L. Bouffard: None. O. Sarrhini: None. S. Phoenix: None. B. Guerin: None. E.E. Turcotte: None. A.C. Carpentier: Advisory Panel; Self; HLS Therapeutics, Inc.
317-OR: Assessing Sarcopenia in T2D: Results from the Large UK Biobank Imaging Study
Authors: LINGE JENNIFER , LEINHARD OLOF DAHLQVIST 
Published: June 2020

Background: A recent study on UK Biobank showed today’s sarcopenia definitions (using functional measures and muscle quantity) are highly BMI dependent and consequently underestimates sarcopenia within obesity. As obesity is common in T2D, this should also affect sarcopenia diagnosis and management in T2D patients. In addition, combined magnetic resonance imaging (MRI) based muscle assessment including sex and body size adjusted fat-free muscle volume (FFMV) and muscle fat infiltration (MFI) showed high diagnostic performance for detecting individuals with low function across BMI classes.
Methods: 9724 participants were included. Prevalence of low functional performance and sarcopenia was assessed using hand grip strength, dual energy X-ray absorptiometry and questionnaire data in T2D (N=434) and controls (N=9154 without diabetes). FFMV and MFI were quantified using MRI. For each participant, a matched virtual control group (VCG) was created to calculate an individualized z-score (sex and body size specific) for FFMV (FFMVVCG). Adverse muscle composition was defined as low FFMVVCG (below 25th percentile, whole cohort) and high MFI (above 75th percentile (sex specific), whole cohort).
Results: Although prevalence of sarcopenia was not different comparing T2D to controls (3.5 vs. 2.4 %, p=0.24), prevalence of low functional performance was higher in T2D: low hand grip strength 10.6 vs. 6.1 %, slow walking pace 14.8 vs. 3.9 %, no stair climbing 11.8 vs. 7.7 %, more than one fall last year 8.1 vs. 4.7 %, (all p&lt;.003). FFMVVCG was lower, mean -0.31 (SD 1.03) vs. 0.02 (0.98) SDs from sex and body size matched reference VCG, MFI higher 8.62 (2.37) vs. 7.34 (1.81) % (1.66 (2.24) pp from sex matched reference) and adverse muscle composition more common in T2D (26.0 vs. 9.5 %) (all p&lt;.001).
Conclusion: Sarcopenia related problems were much more common in T2D as compared to controls. This was not reflected in higher prevalence of sarcopenia within T2D but more accurately described using MRI-based muscle composition.

Disclosure
J. Linge: Employee; Self; AMRA Medical. O. Dahlqvist Leinhard: Employee; Self; AMRA Medical. Stock/Shareholder; Self; AMRA Medical.
32-LB: Early Selective Loss of CGRP Sensory Innervation to Cutaneous Arterioles May Be an Early Prediabetic Feature Developing prior to the Onset of Overt Type 2 Diabetes (T2D) in Rhesus Monkeys and Humans Instead of Being a Consequence
Authors: RICE FRANK , HOUK GEORGE , HANSEN BARBARA C. , TIGNO XENIA , ALBRECHT PHILLIP 
Published: June 2020

Vasculopathy complications of T2D cause limited tissue perfusion, ulcers, and often amputation. Mechanisms underlying T2D vasculopathy remain ambiguous. Compare to normal controls, multi-molecular immunofluorescence of glabrous hand and foot skin biopsies from 12T2D monkeys and 35 humans revealed a consistent depletion of CGRP containing sensory innervation (CGRPsens) that normally mediates local vasodilatation of cutaneous resistance arterioles. By contrast, arteriole vasoconstricting noradrenergic sympathetic innervation (NAsymp) remained largely intact. Thus, a vasoconstrictive imbalance could potentially impede arteriole blood flow contributing to hypertension and reduced capillary perfusion. Further analyses of monkeys indicated that this neurovascular pathology may begin during prediabetic metabolic syndrome. Surprisingly, the NAsymp and a separate set of CGRPsens to precapillary arterioles and capillaries initially remained intact in the T2D monkeys and humans and may even be increasing. This may be a maladaptive response to dilate and increase capillary perfusion to compensate for a reduced arteriole supply. As such, dilatation of the capillaries may increase their blood volume, but inadvertently reduce the rate of blood flow resulting in anoxia. In advanced T2D, a de novo superficial shunt pathology appears and capillaries begin to deteriorate. In contrast to this neurovascular pathology occurring early or before overt T2D onset, we and others have non-painful and painful T2D neuropathies involving other types of tactile sensory innervation typically occur after T2D hyperglycemia is well established. Thus, the early stage neurovascular pathology may be a direct contributor to the onset of 2TD instead of being a consequence of TD2 hyperglycemia, and may be a potential target for early detection and pre-emptive treatment.

Disclosure
F. Rice: None. G. Houk: None. B.C. Hansen: None. X. Tigno: None. P. Albrecht: None.
324-OR: The Incretin Action of GIP Is Mediated through Both Alpha and Beta Cells
Authors: EL KIMBERLEY M. , CAPOZZI MEGAN , GRAY SARAH M. , BROWN JENNIFER L. , WILLARD FRANCIS S. , EMMERSON PAUL , SLOOP KYLE , D’ALESSIO DAVID , CAMPBELL JONATHAN 
Published: June 2020

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are the principal incretins connecting nutrient intake to postprandial insulin secretion. Both GIP and GLP-1 directly stimulate insulin secretion in β-cells through cognate receptors (GIPR; GLP-1R) in a glucose-dependent manner. The GIPR is also expressed on α-cells and GIP stimulates glucagon secretion. α- to β-cell communication, manifest as activation of β-cell GLP-1R by proglucagon peptides (PGDP), dictates the magnitude of the insulin response. We hypothesized that GIPR-stimulation of PGDP enhances insulin secretion through α- to β-cell communication, and that GIPR activity in α-cells is nutrient dependent, similar to β-cells. Mouse islets perifused with GIP or alanine alone doubled their secretion of glucagon, but the combination produced ∼10x glucagon secretion, a synergistic effect that was present at both 2.8 and 10 mM glucose. At 10 mM glucose, GIP plus alanine also had a synergistic effect on insulin secretion. This synergy was abolished by the GLP-1R antagonist exendin-(9-39) indicating that amino acid enhancement of GIP-stimulated insulin secretion is dependent on α- to β-cell communication. In vivo, mice with α-cell deletion of GIPR had normal intraperitoneal and oral glucose tolerance, but impaired glycemic control and reduced insulin secretion in response to a mixed nutrient stimulus, a condition that enhances α-cell activity. Together, these results demonstrate that GIPR activity in α-cells is dependent upon amino acid activation and contributes significantly to insulin secretion through α- to β-cell communication.

Disclosure
K.M. El: None. M. Capozzi: None. S.M. Gray: None. J.L. Brown: None. F.S. Willard: None. P. Emmerson: None. K. Sloop: None. D. D’Alessio: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Intarcia Therapeutics. Research Support; Self; Ansh Labs, Eli Lilly and Company, Merck Sharp & Dohme Corp. Other Relationship; Self; Novo Nordisk A/S. J. Campbell: Research Support; Self; Eli Lilly and Company, Novo Nordisk Inc. Speaker’s Bureau; Self; Merck Sharp & Dohme Corp.

Funding
American Diabetes Association (1-17-JDF-074 to J.C.)