bluuebunny/crossref_metadata_2025 huggingface dataset:
255-LB: Impaired Gsa/cAMP Signaling Exclusive to Pancreatic ß-Cells Exhibits a Unique Urinary Metabolome via Nontargeted Metabolomics in a Murine Model of Diabetes In Vivo
Authors: ILAIWY AMRO , CAPOZZI MEGAN , BROWN JENNIFER L. , D’ALESSIO DAVID , CAMPBELL JONATHAN
Published: June 2020

Background: β-cell dysfunction is a hallmark feature of diabetes mellitus. G protein a-subunit (Gsa) mediates receptor-stimulated intracellular cAMP production In β cells in order to increase glucose-stimulated insulin secretion, cell proliferation and survival. Growing interest in urinary metabolome has emerged as many drugs aim to improve outcomes by targeting kidney function. Given clinical significance of the Gsa pathway, we aimed to study changes of urinary metabolome as a result of Gsa deficiency.

Methods: Mice with Gsα deficiency limited to β cells (Gsa βcell-/-) were generated by mating Gsα-floxed mice with MIPcreERT mice in order to directly examine Gsα/cAMP signaling role in β cells, in a similar method to Xie et.al. Urine was collected from (Gsa βcell-/-) mice and controls and stored at -80C until processed for non-targeted metabolomics using GCMS.

Results: In a small cohort, 17 metabolites were significantly altered between the two groups (P<0.05). While pathway analysis somewhat echoed findings described in other models of diabetes (urea cycle, Malate-Aspartate shuttle, and amino acid metabolism), 4 metabolites were completely undetectable in (Gsa βcell-/-) urine including 3-Oxoglutaric acid and Methylglutarate. In addition, some changed in a different direction to what was previously described in other models of diabetes (e.g: Gsa βcell-/- mice exhibited decreased urinary adipic acid). Enrichment analysis of disease associated metabolite sets of the urine mimicked changes seen in enzymatic defects of 3-Hydroxy-3-Methylglutaryl-Coa Lyase, Kynureninase Deficiency, 2-Ketoglutarate Dehydrogenase and Wolcott-Rallison Syndrome (P<0.05).

Conclusion: Gsa pathway deficiency in β cells produced a model of diabetes with unique metabolome. Studying changes of urine metabolome after treatment with antiglycemics in the future might highlight the drugs renal impact in the setting of Gsa deficiency.

Disclosure

A. Ilaiwy: None. M. Capozzi: None. J.L. Brown: 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.
255-OR: ADA Presidents’ Select Abstract: Glucagon Receptor Antagonism Stimulates Beta-Cell Proliferation in Mouse and Human Islets
Authors: COATE KATIE C. , SPEARS ERICK , DAI CHUNHUA , WISNIEWSKI SCOTT , POFFENBERGER GREG , SHULTZ LEONARD D. , GREINER DALE L. , DRUCKER DANIEL J. , YAN HAI , SLOOP KYLE , POWERS ALVIN C. , DEAN DANIELLE
Published: June 2020

Interrupting glucagon signaling (IGS) elicits robust alpha cell proliferation in an amino acid-dependent manner in mouse and human pancreatic islets. To determine whether IGS triggers beta cell proliferation in mouse and human islets in vivo, we quantified the percentage of Ki67-positive beta cells in adult mouse and human islets after IGS. Wild type (WT) mouse islets transplanted into liver-specific glucagon receptor (GCGR) knockout (LKO) mice exhibited a 4.1-fold increase in beta cell proliferation (WT to LKO: 0.98±0.34%, WT to WT: 0.24±0.19%, P=0.008, n=8). Likewise, treatment of C57BL6 mice with an anti-GCGR monoclonal antibody (GCGR-Ab) elicited a 3.6-fold increase in beta cell proliferation (GCGR-Ab: 1.09±0.21%, control (CTR): 0.30±0.14%, P=0.004, n=10). Given that the cationic amino acid transporter, Slc7a2, is one of the most highly expressed amino acid transporters in pancreatic islets and required for IGS-induced alpha cell proliferation, we assessed GCGR-Ab-induced beta cell proliferation in adult mice with inactivation of Slc7a2. There was a 3.2-fold increase in beta cell proliferation in WT mice treated with GCGR-Ab (GCGR-Ab: 1.45±0.46%, CTR: 0.46±0.15%, P=0.001, n=10). Notably, this effect was absent in Slc7a2 knockout mice (GCGR-Ab: 0.35±0.35%, CTR: 0.41±0.28%, n=10), suggesting that GCGR antagonism induces beta cell proliferation in an amino acid-dependent manner in mice. Furthermore, transplanted human islets from normal donors (ages 10-55, n=8) into immunodeficient mice exhibited a 2.8-fold increase in beta cell proliferation (GCGR-Ab: 0.61±0.60%, CTR: 0.22±0.21%, P=0.05, n=8) following GCGR-Ab treatment. These data indicate that IGS stimulates beta cell proliferation in mouse and human islets and that in mouse islets, this is Slc7a2-dependent.

Disclosure

K.C. Coate: None. E. Spears: None. C. Dai: None. S. Wisniewski: None. G. Poffenberger: None. L.D. Shultz: None. D.L. Greiner: None. D.J. Drucker: Advisory Panel; Self; Merck Sharp & Dohme Corp. Consultant; Self; Eli Lilly and Company, Intarcia Therapeutics. Research Support; Self; Novo Nordisk Inc. H. Yan: Stock/Shareholder; Self; REMD Biotherapeutics Inc. K. Sloop: None. A.C. Powers: None. D. Dean: None.

Funding

National Institutes of Health (DK117147)
258-OR: DNA Methylation Regulates the Identity of Pancreatic Beta Cells
Authors: PARVEEN NAZIA , WANG JEAN K. , DHAWAN SANGEETA
Published: June 2020

Diabetes is associated with the loss of beta-cell identity and function. Thus, understanding the mechanisms that simultaneously regulate beta-cell function and identity is critical for developing beta-cell replacement therapies. In this study, we show that the de novo DNA methyltransferase, Dnmt3a, orchestrates beta-cell identity and function. Previously, we have shown that loss of Dnmt3a in pancreatic beta-cells prevents the developmental metabolic reprogramming, resulting in loss of glucose stimulated insulin secretion (GSIS). To gain insights into the role of new DNA methylation patterns established in early pancreas development, we deleted Dnmt3a in the embryonic pancreatic progenitors in mice. RNA sequencing of Dnmt3aKO and control islets in adult life revealed that loss of Dnmt3a in progenitors leads to dysregulation of key genes involved in the maintenance of beta-cell identity and function. Notably, loss of Dnmt3a led to the upregulation of Tyrosine Hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, along with dysregulation of several genes involved in Dopamine signaling. Specifically, a large proportion of beta-cells in KO was marked by TH expression, compared to controls. Bisulfite sequencing analysis revealed that TH expression is repressed in beta-cells due to DNA methylation during differentiation of endocrine progenitors. In addition, the TH positive beta-cells displayed G2/M cell cycle arrest, along with elevated ER-stress markers. This alteration of cell identity was accompanied by impaired glucose tolerance and a GSIS profile resembling functionally immature beta-cells in the KO mice. The Dnmt3aKO mice did not show any significant change in beta-cell mass, while delta- and alpha- cell masses were increased at 7 month. Taken together, our results show that de novo methylation during early pancreatic development is critical for the establishment of beta-cell identity and function.

Disclosure

N. Parveen: None. J.K. Wang: None. S. Dhawan: None.

Funding

National Institutes of Health (R01DK120523)
275-OR: The Association between the Biological Disease-Modifying Antirheumatic Drugs and Incidence of Diabetes
Authors: LIN CHU , JI HONGYU , CAI XIAOLING , YANG WENJIA , JI LINONG
Published: June 2020

Purpose: To evaluate the association between the biological disease-modifying anti-rheumatic drugs (bio-DMARDs) and the incidence of diabetes.

Methods: Studies recording the incidence of new-onset diabetes in subjects treated with bio-DMARDs were included.

Results: In total, 23 relevant studies were included. The pooled analysis suggested that bio-DMARDs treatment did not reduce the incidence of diabetes (RR= 0.87, 95% CI, 0.69 to 1.08, P = 0. 21) compared with non-bioDMARDs. However, subgroup analyses revealed incidence of new-onset diabetes was significantly reduced in patients with abatacept treatment (RR = 0.61, 95% CI, 0.38 to 0.99, P = 0.04).

Conclusions: The utilization of bio-DMARDs in general was not associated with the incidence of diabetes while the abatacept treatment may reduce the risk of diabetes.

Disclosure

C. Lin: None. H. Ji: None. X. Cai: None. W. Yang: None. L. Ji: None.

Funding

National Natural Science Foundation of China (81970698); National Key Research and Development Program of China (2016YFC1304901)
276-OR: A 2-Dimensional (2D) Analysis of Glucose and C-Peptide Shows a Teplizumab Effect in Individuals at Risk for Type 1 Diabetes (T1D) 3 Months after Treatment
Authors: SIMS EMILY K. , WARNOCK MEGAN V. , HEROLD KEVAN C. , SOSENKO JAY
Published: June 2020

We sought to determine whether a measure combining changes in C-peptide and glucose could show efficacy 3 months after teplizumab treatment among multiple islet autoantibody+ dysglycemic individuals (n=44, age 19.2± 11.9 yrs on teplizumab and n=32, age 17.5± 11.1 yrs on placebo) in the recent TrialNet teplizumab prevention trial (teplizumab delayed T1D onset). In the 2D analysis assessing changes in glucose and C-peptide below (Figure), mean glucose and C-peptide from 30 to 120 minutes are plotted from baseline and 3-month OGTTs. For each OGTT, centroids (central point of OGTT shape) are connected by vectors, showing opposite directionality from baseline to 3 months between groups. Since AUC C-peptide/AUC glucose (AUC Ratio) correlates highly with centroid C-peptide/centroid glucose (r=0.99), to quantify the differences in directionality, we compared AUC Ratio (x1,000; adjusted for baseline) change from baseline to 3 months. The teplizumab group showed a positive change in AUC Ratio: 1.5±2.9 vs. a negative change in placebo: - 0.78±2.7; p=0.001). This difference was sustained after 6 months of treatment (p=0.004).

In summary, a 2D analysis of glucose and C-peptide change provided visual and quantitative evidence of an early treatment effect. As a centroid correlate, the AUC Ratio can be a useful endpoint for performing shorter prevention trials.

Disclosure

E.K. Sims: None. M.V. Warnock: None. K.C. Herold: Consultant; Self; Provention Bio, Inc. J. Sosenko: None.

Funding

National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; JDRF
277-OR: Teplizumab Reverses the Loss of C-Peptide in Relatives at Risk for Type 1 Diabetes (T1D)
Authors: SIMS EMILY K. , BUNDY BRIAN N. , STIER KENNETH D. , SERTI ELISAVET , LIM NOHA , NEPOM GERALD T. , EVANS-MOLINA CARMELLA , HEROLD KEVAN C.
Published: June 2020

We demonstrated that a 2-week course of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) delayed T1D progression by a median of 24 months in high risk relatives of patients with T1D (76 multiple islet autoantibody positive dysglycemic relatives; 912 day median follow-up). Over the study 72% of the placebo-treated and 43% of the teplizumab-treated participants were diagnosed with T1D. We hypothesized that teplizumab treatment would also result in a secondary outcome of improved C-peptide responses to oral glucose tolerance tests (OGTT) compared to placebo. The C-peptide, 1 hr insulin secretory rate (early ISR), and glucose area under the curve (AUC) means were calculated for each study timepoint. Results were modeled using ANCOVA, regressing on treatment group, age and the baseline value of the dependent variable. Teplizumab treatment was associated with a greater on-study C-peptide AUC (teplizumab vs. placebo adjusted means: 1.94 vs. 1.73 nmol/L; p=0.009). For both groups, C-peptide AUC mean slopes over a mean of 7.9 months preceding study entry were similar and significantly less than zero (declining; p=0.03). In the placebo group, this decline continued over the 6 months after study entry. By contrast, the teplizumab-treated group showed an increased C-peptide AUC over this period (p=0.003 relative to study entry). Insulin secretion during the 1st hr of the OGTT also declined in participants treated with placebo, but increased in those treated with teplizumab at 6 months (p=0.007). Increases in C-peptide AUC were correlated with increases in partially exhausted KLRG1+TIGIT+ CD8+ T cells (r=0.403; p=0.018). Although rates of diabetes were reduced in teplizumab-treated participants, OGTTs showed persistent dysglycemia.

In conclusion, we found declines in C-peptide responses to OGTTs in high risk individuals prior to study treatment that were abrogated in the 6 month period after immunomodulation with teplizumab.

Disclosure

E.K. Sims: None. B.N. Bundy: None. K.D. Stier: None. E. Serti: None. N. Lim: None. G.T. Nepom: None. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. K.C. Herold: Consultant; Self; Provention Bio, Inc.

Funding

National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; JDRF
280-OR: Medical Nutrition Therapy and Glycemic Control in Youth-Onset Diabetes: SEARCH for Diabetes in Youth Study
Authors: SAUDER KATHERINE A. , STAFFORD JEANETTE M. , THE NATALIE S. , MAYER-DAVIS ELIZABETH J. , THOMAS JOAN , LAWRENCE JEAN M. , KIM GRACE , SIEGEL KAREN R. , JENSEN ELIZABETH T. , SHAH AMY S. , DAGOSTINO RALPH , DABELEA DANA
Published: June 2020

Medical nutrition therapy (MNT) is integral to diabetes (DM) management, but little is known about MNT use in youth and young adults. The SEARCH for Diabetes in Youth study assessed MNT use among 1476 participants with type 1 DM (T1D) and 245 with type 2 DM (T2D) who had up to 3 research visits over 5.2 years (range 1.7-11.5). Participants reported often, sometimes, or never using each of 10 MNT strategies, which we categorized with 5 mutually exclusive groups: often using across visits; start using at later visits; sometimes using across visits; stop using at later visits; or never using at every visit. We used general linear models to examine A1c levels at the most recent visit (mean 11.0 [range 6.3-17.0] years after DM diagnosis) for each MNT strategy, adjusting for sociodemographic and DM-related variables. Most participants with T1D reported often counting carbs (n=1080, 75%), while half (n=107, 47%) of those with T2D reported often limiting sweets. Table presents significant associations of A1c levels with MNT use by DM type. In T1D, mean A1c differed significantly across MNT use of 7 strategies, but only for 2 strategies in T2DM. For both T1D and T2D, A1c did not differ by use of dietary exchanges, drinking more milk, or eating more fruits/vegetables. Our data suggest that often using most MNT strategies is related to relatively better glycemic control in T1D, but this applies to fewer MNT strategies for T2DM.

Disclosure

K.A. Sauder: None. J.M. Stafford: None. N.S. The: None. E.J. Mayer-Davis: None. J. Thomas: None. J.M. Lawrence: None. G. Kim: None. K.R. Siegel: None. E.T. Jensen: None. A.S. Shah: None. R. Dagostino: Consultant; Self; Amgen, AstraZeneca, Celgene, Daiichi Sankyo. D. Dabelea: None.

Funding

National Institutes of Health
283-OR: Changes in HbA1c between 2011-2017 in Austria/Germany, Sweden, and the United States: A Lifespan Perspective
Authors: ALBANESE-O’NEILL ANASTASIA , HERMANN JULIA , SVENSSON ANN-MARIE , MILLER KELLEE , RAILE KLEMENS , AKESSON KARIN , CALHOUN PETER , EEG-OLOFSSON KATARINA , MAAHS DAVID M. , HOLL REINHARD W. , HANAS RAGNAR
Published: June 2020

This study assessed HbA1c across the lifespan in people with T1D in Austria/Germany, Sweden, and the United States (U.S.) between 2011 and 2017. Data extracted from the DPV, Austria/Germany (n = 25651 in 2011, n = 29442 in 2017); SWEDIABKIDS/NDR, Sweden (n = 44474 in 2011, n = 53690 in 2017); and T1D Exchange, U.S. (n = 16198 in 2011, n= 17087 in 2017) registries were included in the analysis. Mean HbA1c across the lifespan in 2017 and changes in mean HbA1c between 2011 and 2017 overall and by age cohorts were analyzed. In 2017 mean HbA1c for adults ≥45 years converged across registries; HbA1c levels for subjects <25 years were highest in the U.S. (Figure). Controlling for age, sex, and T1D duration, overall HbA1c increased in the U.S. between 2011 and 2017 (2011=8.02%, 2017=8.26%, p<.01); decreased in Sweden (8.06%, 7.74%, p<.01); and did not change in Austria/Germany (7.84%, 7.84%, p=.49). Controlling for sex and T1D duration, mean HbA1c decreased between 2011 and 2017 in all age cohorts in Sweden (all p<.01). In the U.S., HbA1c increased in subjects <45 years and ≥65 years (all p<.05) and did not change in subjects 45-<65 years (p=.06). In Austria/Germany, HbA1c decreased in subjects 13-<19 years (p<.01), did not change in subjects <13 years (p=.26) and 19-<25 years (p=.88), and increased in subjects ≥25 years (all p<.05). Further research is warranted to better understand causes of geographic disparities in glycemic control.

Disclosure

A. Albanese-O’Neill: Consultant; Self; American Diabetes Association. J. Hermann: None. A. Svensson: None. K. Miller: None. K. Raile: None. K. Akesson: None. P. Calhoun: Stock/Shareholder; Self; Dexcom, Inc. K. Eeg-Olofsson: None. D.M. Maahs: Advisory Panel; Self; Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk A/S. Consultant; Self; Abbott, Sanofi. Research Support; Self; Bigfoot Biomedical, Dexcom, Inc., Roche Diabetes Care, Tandem Diabetes Care. R.W. Holl: None. R. Hanas: Advisory Panel; Self; Abbott, Novo Nordisk A/S. Speaker’s Bureau; Self; Sanofi. Other Relationship; Self; AstraZeneca.

Funding

German Center for Diabetes Research; The Leona M. and Harry B. Helmsley Charitable Trust (G-2016PG-T1D053)
288-OR: Myeloid-Specific Deletion of Alox15 Decreases Pancreatic Inflammation and Protects from Spontaneous Diabetes Development in Nonobese Diabetic (NOD) Mice
Authors: PINEROS ANNIE , KULKARNI ABHISHEK , ORR KARA , GLENN LINDSEY , REISSAUS CHRISTOPHER A. , HERNANDEZ-PEREZ MARIMAR , MCDUFFIE MARCIA J. , NADLER JERRY , MORRIS MARGARET A. , MIRMIRA RAGHAVENDRA , TERSEY SARAH A.
Published: June 2020

The pathogenesis of type 1 diabetes (T1D) involves the interaction of the immune system with β cells. 12/15-lipoxygenase (12/15-LOX), an enzyme involved in arachidonic acid metabolism, is highly expressed in both β cells and macrophages. Global deletion of the gene encoding 12/15-LOX (Alox15) prevents diabetes in the NOD mouse (animal model for T1D) via reduction of proinflammatory cytokines produced by macrophages and islets. However, the role of 12/15-LOX in the macrophages during T1D development remains unclear. To address this issue, we generated myeloid lineage-specific Alox15 knockout mice (Alox15∆myel) on the NOD background and evaluated immune cell infiltration into the pancreas and in pancreatic lymph nodes, as well as diabetes outcome in these animals. Pancreas sections of Alox15∆Myel mice showed a decrease of lymphocyte infiltration compared to control littermates. Alox15∆Myel mice also showed a decreased frequency of IL-1β produced by macrophages (F480+IL1β+) and dendritic cells (CD11c+IL1β+) in the pLNs when compared to control mice. To clarify if Alox15 in myeloid cells mediates proinflammatory cytokines production by T cells, we performed a co-culture assay of Alox15-/- macrophages with naïve T cells. Alox15 deletion in macrophages impaired IFN-γ production from CD4+ T cells compared to WT macrophages. Furthermore, Alox15∆Myel mice showed a significant decrease in the incidence of spontaneous type 1 diabetes (<10%) compared to control mice (80%) (P<0.05). Alox15 deletion in macrophages led to increased β-cell mass and decreased insulitis in nondiabetic mice. Gene expression analysis in the islets showed increased expression of Pdx1 and Il-10 in islets of Alox15∆Myel mice. Together, these data suggest that myeloid-derived Alox15 promotes immune cell infiltration and inflammation in the pancreas leading to β-cell destruction and development of T1D.

Disclosure

A. Pineros: None. A. Kulkarni: None. K. Orr: None. L. Glenn: None. C.A. Reissaus: None. M. Hernandez-Perez: None. M.J. McDuffie: None. J. Nadler: None. M.A. Morris: Stock/Shareholder; Spouse/Partner; Becton, Dickinson and Company, Bristol-Myers Squibb, Johnson & Johnson, Medtronic, Sanofi. R. Mirmira: Advisory Panel; Self; Hibercell, Sigilon Therapeutics, Veralox Therapeutics. Employee; Spouse/Partner; Eli Lilly and Company. S.A. Tersey: None.

Funding

National Institutes of Health (R01DK105588, P30DK097512 to R.M.)
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 >90, G2 89-60, G3a 45-59, G3b 30-44, G4 15-29, and G5 <15. A1-A3 indicates ACR stages (mg/g) A1 <30, A2 30-300, and A3 >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<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<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 < 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<.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<.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.)
325-OR: ß-Arrestin 1 Regulates Glucagon-Like Peptide-1 Receptor Mediated Insulin Secretion in a Ligand-Dependent Manner
Authors: DOUROS JONATHAN D. , SLOOP KYLE , CAMPBELL JONATHAN , D’ALESSIO DAVID
Published: June 2020

Incretin-based drugs are widely thought to act via a Gαs/adenylate cyclase (AC)/cAMP pathway in β-cells. This model has been challenged by data demonstrating various glucagon-like peptide 1 receptor (GLP-1R) ligands differentially activate multiple signaling pathways including Gαs, Gq, ERK, and β-arrestins. This ligand-mediated signaling bias implicates an array of intracellular mechanisms that regulate GLP-1R action and raises the possibility GLP-1R agonists can be optimized to enhance insulin secretion. We tested the hypothesis that β-arrestin 1 (βarr1), a critical GPCR effector, is necessary for the full insulinotropic action of GLP-1R agonists. The β-cell βarr1 knockout mice (βarr1βcell-/-) used here have reduced Arrb1 expression in the β-cell, but not α- or Δ-cells; Arrb2 expression was unaffected. Islets isolated from βarr1βcell-/- mice have increased glucose stimulated insulin secretion (GSIS) compared to controls. The enhanced GSIS in the knockout islets was ablated by the GLP-1R antagonist exendin-9. In addition, βarr1βcell-/-islets treated with GLP-1 or exendin 4 (Ex4) have increased insulin release compared to controls. Conversely, βarr1 deletion did not impact the insulinotropic actions of glucagon, which signals through both the GLP-1R and the glucagon receptor (GCGR). Moreover, control and βarr1βcell-/- islets produced similar insulin secretion in response to a GCGR specific agonist that does not signaling through GLP-1R and to glucose-dependent insulinotropic polypeptide. Together, these results indicate that βarr1 in β-cells selectively dampens the insulinotropic actions of the GLP-1R, but not the GCGR or GIP receptor. Thus, there is a specific interaction between the GLP-1R and βarr1 that points to divergent regulation between the insulinotropic class B G-protein coupled receptors in β-cells. This data implies that GLP-1R agonists that bias away from βarr1 may be more effective at stimulating insulin secretion.

Disclosure

J.D. Douros: None. K. Sloop: None. J. Campbell: Research Support; Self; Eli Lilly and Company, Novo Nordisk Inc. Speaker’s Bureau; Self; Merck Sharp & Dohme Corp. 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.

Funding

1F32DK115031-01
33-LB: Role of Cav3.2 Channels in Sensory Neuron Abnormalities during Early Hyperglycemia
Authors: NEAPETUNG JOSEPH T. , CAMPANUCCI VERONICA A.
Published: June 2020

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes. It is characterized by a constellation of sensory abnormalities, including numbness, tingling, burning, and painful sharp, shooting sensations in the extremities. Patients with DPN are also at high risk for infection and amputation. Traditionally, neuropathy has been considered to result from peripheral nerve damage after long term diabetes, however more recent indicate that functional changes take place in early stages of diabetes. One of those changes is the increased expression and signalling of the receptor for advance glycation end-product (RAGE), which is known to have a pivotal role in the development of diabetic complications. In the current study we concentrate on T-type (Cav 3.2) channels, which are low voltage-activated calcium channels that play a key role in cellular excitability, and have been reported to contribute to pain abnormalities in rat models of DPN. The goal of this project is to elucidate the role of Cav 3.2 during early stages of diabetes in sensory neurons from the dorsal root ganglion (DRG) of mice, and its possible regulation through the RAGE pathway. We used cultured DRG neurons from wilt-type (WT) and RAGE knock-out (RAGE KO) mice maintained in control (5mM) or high glucose (25 mM) for up to 14 days, as well as intact DRG ganglia from streptozotocin (STZ)-induced diabetic mice (WT and RAGE KO) for 4 weeks. Using whole cell patch-clamp electrophysiology and protein biochemistry we revealed changes in the activation kinetics and expression levels of Cav 3.2 channels. Our data suggest that RAGE-dependent changes in Cav 3.2 expression and function may contribute to functional abnormalities in sensory neurons during early hyperglycemia.

Disclosure

J.T. Neapetung: None. V.A. Campanucci: None.