bluuebunny/crossref_metadata_2025 huggingface dataset:
333-OR: DMHCA Reduces the Development of Diabetic Retinopathy (DR) in db/db Mice by Lowering Cholesterol Levels and Altering the Transcriptomic Profile of Hematopoietic Stem Cells
Authors: VIEIRA CRISTIANO P. , FORTMANN SETH D. , LONGHINI ANA LEDA , LYDIC TODD A. , BUSIK JULIA V. , GRANT MARIA B.
Published: June 2020

Diabetic dyslipidemia, common in type 1 and type 2 diabetes (T2D), contributes to the pathogenesis of DR. LXR activation enhances cholesterol removal by reverse cholesterol transport (RCT) and reduces inflammatory gene expression. Systemic inflammation in diabetes is mediated, in part, by myeloidosis in the bone marrow (BM), which contributes to the pathogenesis of DR. We sought to test whether the progression of DR could be reduced by administering the novel LXR modulator, DMHCA (8mg/kg/body weight/day), in a T2D mouse model for 6 months. Retinal tissue was assessed by flow cytometry and Mass spectroscopy. LXR activation by DMHCA reduced cholesterol levels through the conversion to oxysterols and demosterol and was associated with a reduction of inflammatory cells in the retina and systemic circulation. Increased levels of long-term (17±1 vs. 11±2 db/db) and decrease levels of multipotent progenitors (MPP) (35±1 vs. 41±2 db/db) were noted in total bone marrow cells from db/db mice. DMHCA reduced the production of granulocyte-progenitors (GMP) (16 ± 1 vs. 22±3 db/db) and restored levels of NRF-2 (1±0.2 vs. 3±1 db/db) in bone marrow (BM) of db/db. DMHCA increased the number of myeloid angiogenic cells in the systemic circulation of db/db (0.04%±0.003 vs. 0.01%±0.002 db/db). Single cell RNA-seq analysis was performed using hematopoietic stem cells (HSCs) from untreated db/db and DMHCA treated db/db bone marrow. DMHCA treated HSCs showed upregulated genes associated with the activator protein 1 (AP-1) complex. AP-1 complexes regulate different stages of HSC differentiation along most of the myeloid lineage. Together, these findings reveal that LXR activation, via DMHCA treatment, decreases systemic and tissue-specific inflammation by controlling the production of pro-inflammatory stem cells and reducing oxidative injury in the BM of T2D mice.

Disclosure

C.P. Vieira: None. S.D. Fortmann: None. A. Longhini: None. T.A. Lydic: None. J.V. Busik: None. M.B. Grant: None.

Funding

National Institutes of Health (EY025383, EY012601)
335-OR: A Successful Diabetes Management Model of Care in Long-Term Care Facilities
Authors: SY SARAH L. , MUNSHI MEDHA
Published: June 2020

Objectives: The management of diabetes in long-term care (LTC) facilities requires facility staff to perform most diabetes self-care activities on the behalf of the residents. We describe a practical model of care to improve diabetes management in LTC facilities.

Design and Methods: A diabetes management model of care was developed and implemented at six LTC facilities over 4-year period. The components of the program included: 1) developing individualized curriculum, and educating interdisciplinary staff members, 2) educating patients and families, and 3) developing a practical clinical care algorithm. Staff members were trained to identify the most likely reasons for hypo- or hyperglycemic episodes and intervention strategies based on the causes.

Results: Over 500 LTC staff members were educated and achieved competence during the program implementation. The patients and families received on an average 12.5 education sessions per month in skilled nursing facilities, and 1.5 education sessions per month in nursing homes. A total of 1031 residents were screened to assess risk of hypo- or hyperglycemia on admission to LTC. During the first 2 weeks of stay, hypo- and hyperglycemic episodes occurred in 31.4% and 29.2% of residents respectively. Overall, 245 residents (23.8%) experienced ≥1 episode of hypoglycemia (glucose <70mg/dl). Of those 245 residents, 66.5% had 1 event, 15.5% had 2 events, and 18.0% had ≥3 events. Similarly, 240 residents (23.3%) experienced ≥1 episode of hyperglycemia (≥3 consecutive glucose readings >200 mg/dl) with 63.7% having 1 event, 17.9% with 2 events, and 18.4% having ≥3 events. The most common cause of either hypo- or hyperglycemia was found to be medication related. The hypoglycemia episodes resolved without recurrence in 73-90% cases and interventions reduced the number of events over time.

Conclusion: Implementation of a practical model of diabetes management in LTC facilities can improve staff education leading to improved diabetes management for all residents.

Disclosure

S.L. Sy: None. M. Munshi: Consultant; Self; Eli Lilly and Company, Sanofi.
344-OR: Slowed Metabolic Decline after Oral Insulin (OI) in Relatives at High Risk for Type 1 Diabetes (T1D)
Authors: SOSENKO JAY , PALMER JERRY P. , HALLER MICHAEL J. , SKYLER JAY S. , PUGLIESE ALBERTO , SCHATZ DESMOND
Published: June 2020

We assessed whether OI slowed metabolic decline after 1 yr of treatment among highest risk relatives who participated in the Diabetes Prevention Trial-Type 1 (DPT1) and TrialNet (TN) T1D prevention trials for OI. As published, with a diagnosis of T1D as the endpoint, both OI trials (7.5 mg/day) were negative overall. However, subgroup analyses suggested efficacy for those at high risk in each trial (DPT1: higher titer of insulin autoantibodies; TN: lower first-phase insulin response). Thus, we assessed whether OI slowed metabolic decline among the OI trial participants at highest risk, defined by DPT1 Risk Scores over a 6.75 threshold (DPTRS; OGTT C-peptide and glucose, age, and BMI), above which T1D risk increases sharply as DPTRS increases. Of 73% in DPT1 and 89% in TN with 1 yr OGTTs, 32% in DPT1 (90/282; age: 8.7±4.8 yrs) and 35% in TN (118/340; age: 6.9±3.3 yrs) were in the highest risk groups (3 yr risks: 56% in DPT-1; 55% in TN). In the analysis, area under curve (AUC) C-peptide increased from baseline to 1 yr in both OI groups (DPT1: p<0.01; TN: p<0.05) but not in the placebo groups, while AUC glucose increased more in the placebo groups (DPT1: p<0.01; TN: p<0.01) than in the OI groups (DPT1: p<0.05; TN: n.s.). Consistent with those changes, in both trials the 1 yr AUC C-peptide/AUC glucose ratio (x100; AUC ratio) was greater in the OI group than in the placebo group [DPT1: 2.86±1.06 vs. 2.42±1.03 (ng/ml)/(mg/dl); TN: 3.06±1.13 vs. 2.57±0.96 (ng/ml)/(mg/dl); p-value<0.05 for each (baseline adjusted)]. For DPT1 and TN combined (no interaction for treatment between trials), the p-value for the AUC ratio difference was <0.001. Of those with DPTRS <6.75 (3 yr risk: 24% for both DPT1 and TN), the AUC ratio did not differ between OI and placebo.

In conclusion, when DPTRS was >6.75 metabolic outcomes at 1 yr appeared similarly favorable for OI in the DPT1 and TN trials, suggesting OI slows insulin decline in those at high risk for T1D. Moreover, metabolic measures could be useful endpoints for T1D prevention trials.

Disclosure

J. Sosenko: None. J.P. Palmer: None. M.J. Haller: Advisory Panel; Self; SAB Biotherapeutics, Inc. J.S. Skyler: Advisory Panel; Self; Abvance Therapeutics, ADOCIA, Avotres, Boehringer Ingelheim Pharmaceuticals, Inc., Dance Biopharm Holdings, Inc., Immunomolecular Therapeutics, Intrexon, Oramed Pharmaceuticals, Orgenesis Inc., Sanofi, Tolerion, Inc., Viacyte, Inc. Board Member; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics. Consultant; Self; Novo Nordisk A/S. Research Support; Self; Tolerion, Inc. Stock/Shareholder; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics. A. Pugliese: None. D. Schatz: None.
347-OR: Trends in Glycemic Control among Youth with Diabetes: The Search for Diabetes in Youth Study
Authors: MALIK FAISAL , SAUDER KATHERINE A. , ISOM SCOTT , ROBERTS ALISSA J. , MAYER-DAVIS ELIZABETH J. , DOLAN LAWRENCE M. , DABELEA DANA , LAWRENCE JEAN M. , PIHOKER CATHERINE
Published: June 2020

Objective: To describe temporal trends in glycemic control in youth-onset diabetes.

Methods: The study included 6399 SEARCH for Diabetes in Youth participants with diabetes >1 year. Visit data was categorized into 3 time periods: 2002-2007, 2008-2013, and 2014-2019 and 3 groups of diabetes duration: 1-4, 5-9, and 10+ years. Participants contributed one randomly selected data point to each duration group. Stratified multivariable regression models were used to test differences in hemoglobin A1c (A1c) over time, adjusted for site, age, sex, race/ethnicity, health insurance status, and disease duration, both overall (with repeated measures) and for each duration group.

Results: Estimated mean A1c among individuals with type 1 diabetes (T1D) was different over the three periods with a higher mean A1c in 2014-2019 and 2008-2013 versus 2002-2007 (p<0.01; Table). There was a temporal difference in mean A1c for T1D participants with diabetes for 5-9 years (p<0.01) and for T2D participants with diabetes 10+ years (p<0.01).

Conclusions: Despite increased availability of diabetes technology, newer therapies, and more aggressive glycemic targets over time, current youth and young adults with T1D in the U.S. have worse glycemic control than earlier cohorts. Similarly, participants with T2D diagnosed in childhood and diabetes duration of 10+ years exhibit the temporal trend of worse glycemic control in recent years.

Disclosure

F. Malik: None. K.A. Sauder: None. S. Isom: None. A.J. Roberts: None. E.J. Mayer-Davis: None. L.M. Dolan: None. D. Dabelea: None. J.M. Lawrence: None. C. Pihoker: None.

Funding

Centers for Disease Control and Prevention (1U18DP006131, U18DP006133, U18DP006134, U18DP006136, U18DP006138, U18DP006139, U18DP006136, U58/CCU019235-4, U01 DP000244, U18DP002710-01); National Institute of Diabetes and Digestive and Kidney Diseases (1UC4DK108173)
350-OR: A Novel Long-Acting GLP-1 Agonist (GL0034) Demonstrates Remarkable Efficacy on HbA1c, Weight Loss, and Triglycerides in a Model of Type 2 Diabetes, the db/db Mouse
Authors: THENNATI RAJAMANNAR , BURADE VINOD S. , VILSBØLL TINA , THORENS BERNARD , RUTTER GUY A.
Published: June 2020

Glucagon-like peptide-1 receptor agonists (GLP-1RA) provide substantial reductions in HbA1c and significant body weight loss in patients with type 2 diabetes (T2D). GL0034 is a novel long-acting, human GLP-1RA. In cellular cAMP assays GL0034 has a half-maximal effective concentration of 80 pM on GLP-1R expressing cells, but no effect on cells expressing the GIPR or the glucagon receptor. Upon SC dosing in the db/db mouse every other day for 4 weeks, GL0034 doses of 1.5, 3, and 6 nmol/kg lowered HbA1c by 1.6%, 3.2%, and 3.4%, respectively; demonstrating greater activity than that achieved with a higher dose of semaglutide (2.8%) or dulaglutide (2.0%) (Table). At 6-nmol/kg dose, GL0034 also induced a significant decrease in body weight; furthermore, plasma triglycerides and glucagon were significantly reduced by ∼74% and ∼41%, respectively. These effects of GL0034 treatment were greater than those induced by semaglutide or dulaglutide. Together, our study demonstrates that GL0034 is a potent, selective, long-acting GLP-1RA, which displays improved control of glucose homeostasis, body weight, and dyslipidemia in diabetic mice as compared with GLP-1RAs currently used for the treatment of T2D. GL0034 may serve as a promising new GLP-1RA for T2D and obese patients with T2D.

Disclosure

R. Thennati: None. V.S. Burade: Employee; Self; Sun Pharmaceutical Industries Ltd. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. B. Thorens: Other Relationship; Self; Servier. G.A. Rutter: Consultant; Self; Sun Pharmaceutical Industries Ltd. Research Support; Self; Servier, Sun Pharmaceutical Industries Ltd.
354-OR: Cotadutide (medi0382), a Dual Receptor Agonist with Glucagon-Like Peptide-1 and Glucagon Activity, Modulates Hepatic Glycogen and Fat Content
Authors: ROBERTSON DARREN , HANSEN LARS , AMBERY PHILIP , ESTERLINE RUSSELL L. , JERMUTUS LUTZ , CHANG YI-TING , PETRONE MARCELLA , JOHANSSON EDVIN , JOHANSSON LARS , SJÖBERG FOLKE B. , PARKER VICTORIA
Published: June 2020

Background and Aims: Cotadutide, a dual receptor agonist with glucagon-like peptide-1 (GLP-1) and glucagon activity, is being researched for the potential treatment of nonalcoholic steatohepatitis. Given the known effects of glucagon on hepatic glycogen and lipid metabolism, the aim of this phase 2a study was to investigate the effect of cotadutide on hepatic glycogen.

Methods: In this double-blind, placebo-controlled study, 21 overweight or obese adults with type 2 diabetes mellitus (HbA1c ≤ 8%) were randomized to receive once-daily subcutaneous cotadutide (n = 12) or placebo (n = 9) for 28 days. Following 48 hours of standardized meals, serial magnetic resonance spectroscopy scans relying on signals from naturally abundant 13C were performed to measure glycogen, and liver fat was also estimated. Fasting amino acid and ketone levels were also assessed.

Results: Significant reductions from baseline in postprandial hepatic glycogen content were observed with cotadutide (-100.2 mmol/L; 90% CI: -150.2, -50.1) vs. placebo (+5.5 mmol/L; 90% CI: -47.2, 58.3; P = 0.023). Statistically significant reductions in hepatic glycogen content were observed across serial measures and after a 14-hour fast (P < 0.05), with an overall change in glycogen AUC24h of -27.3% (P = 0.003) vs. placebo. In addition, a relative reduction in liver fat of 33.2% vs. placebo was reported (P = 0.006), and significant reductions in fasting alanine, glutamate, glycine, lysine, and threonine levels were also observed with cotadutide vs. placebo (all P ≤ 0.05). Beta-hydroxybutyrate and acetoacetate levels were not significantly different between the two arms.

Conclusions: Cotadutide promoted a generalized reduction in hepatic glycogen and selected amino acid levels. Substantial reductions in liver fat were also observed with cotadutide, suggesting glucagon receptor engagement.

Disclosure

D. Robertson: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. L. Hansen: Employee; Self; AstraZeneca. P. Ambery: Employee; Self; AstraZeneca. R.L. Esterline: Employee; Self; AstraZeneca. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. Y. Chang: None. M. Petrone: Employee; Self; AstraZeneca. E. Johansson: None. L. Johansson: Employee; Self; Antaros Medical AB. Stock/Shareholder; Self; Antaros Medical AB. F.B. Sjöberg: None. V. Parker: None.

Funding

AstraZeneca
36-LB: Linoleic Acid Derived Oxylipins, Memory, and Microvascular Retinal Complications in Patients with Type 2 Diabetes Mellitus
Authors: WONG SOPHIE K. , NGUYEN MICHELLE M. , MAJOR-ORFAO CHELSI , LANCTÔT KRISTA L. , HERRMANN NATHAN , OH PAUL , SHAH BAIJU R. , GILBERT JEREMY , ASSAL ANGELA , HALPERIN ILANA , YANG PEARL , PEDERSEN THERESA , TAHA AMEER , SWARDFAGER WALTER
Published: June 2020

Introduction: Memory decline is accelerated in type 2 diabetes mellitus (T2DM), and it is thought that microvascular disease may be a contributor. Oxylipins, bioactive lipid species derived from polyunsaturated free fatty acids such as linoleic acid, can act on small vessels. Cytochrome p450 derived epoxides may be immunologically active, whereas their hydrolysis into diols by soluble epoxide hydrolase (sEH) may render them inactive or cytotoxic. We examine linoleic acid epoxide and diol concentrations in peripheral blood and their associations with memory performance and retinal microvascular disease in patients with T2DM or prediabetes.

Methods: Patients with T2DM or prediabetes were recruited from 3 sites. Memory was assessed via California Verbal Learning Test 2nd Edition (CVLT-II). Patient history of retinopathy was recorded. Serum oxylipin concentrations were measured via ultra-high-performance liquid chromatography tandem mass-spectrometry.

Results: In people with T2DM or prediabetes (n=76, 55% women, 63±9 years old, HbA1C=7.4±1.2% mmol/mol, duration of diabetes 8±10 years), 9.2% had retinopathy, and the mean CVLT-II was -0.07±1.01 Z-score units (indicating generally average performance). The linoleic acid derived epoxide 12(13)-epoxyoctadecenoic acid concentration was negatively correlated with CVLT-II performance (β=-0.298, p=0.003), whereas the diol derived from that species (12,13-dihydroxyoctadecenoic acid) was elevated in people with retinopathy (9.1±4.1 nM vs. 6.5±11.5 nM, U=72.0, p=0.008).

Discussion: Oxylipins generated by cytochrome p450 and sEH should be explored as potential biomarkers for cognitive complications and microvascular disease in T2DM. The observed relationships might suggest the presence of a cytochrome p450-mediated response that may generate differential response and lack benefit in T2DM, possibly due to sEH-mediated conversion of epoxides into diols, warranting further study.

Disclosure

S.K. Wong: None. M.M. Nguyen: None. C. Major-Orfao: None. K.L. Lanctôt: None. N. Herrmann: None. P. Oh: None. B.R. Shah: None. J. Gilbert: Speaker’s Bureau; Self; Abbott, Amgen, Ascensia Diabetes Care. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Dexcom, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. A. Assal: None. I. Halperin: Advisory Panel; Self; Tandem Diabetes Care. Speaker’s Bureau; Self; Abbott, Boehringer Ingelheim (Canada) Ltd., Dexcom, Inc., Novo Nordisk Inc., Sanofi. P. Yang: None. T. Pedersen: None. A. Taha: None. W. Swardfager: None.

Funding

Canadian Institutes of Health Research (410010992)
363-OR: Comprehensive Assessment of Glycemic Control after Pancreas Transplantation
Authors: KAUR RAVINDER JEET , REID COREY , THAPA PRABIN , RIZVI SHAFAQ RAZA , MCCRADY-SPITZER SHELLY K. , BATTHULA SREEDHAR , SMITH BYRON H. , DEAN PATRICK , KREMERS WALTER K. , KUKLA ALEKSANDRA , STEGALL MARK D. , KUDVA YOGISH C.
Published: June 2020

Introduction: Limited data are available about comprehensive metabolic evaluation after Pancreas transplantation (PT) for type 1 diabetes (T1D).

Methods: After IRB approval, we prospectively studied 15 PT recipients at least 1 year post transplant. After a screening visit, subjects underwent Dexcom G4 CGM for one week and Mixed Meal Test (MMT) according to standard procedure.

Results: PT recipient were 53.1 ± 10.6 years old, F/M 12/3, BMI (Kg/m2) 30.8 ± 6 and mean duration of diabetes was 33 ± 12.3 years with 6 ± 5 (1-17) years mean interval from PT to the study. Twelve patients underwent pancreas transplant alone and three underwent simultaneous pancreas kidney transplantation. Baseline values were Hemoglobin 12.3 ± 1.4 (g/dl), HbA1c 5.4 ± 0.6 %, Albumin 4.0 ± 0.3 g/dl, Fructosamine 233 ± 27 (µmol/L), Fasting Glucose 94.3 ± 17.5 mg/dl, C-peptide 2.5 ± 0.9 (ng/ml), eGFR 56.3 ± 25.5 ml/min and AST 23.4 ± 8.5 U/L. MMT revealed Glucose concentration increased from 90.9 ± 9.6 mg/dl at baseline to 140.6 ± 41.5 mg/dl at 30min followed by 123.2 ± 48.0 mg/dl and 115.2 ± 34.6 mg/dl at 60mins and 120 mins respectively. C-peptide was 2.4 ± 0.7 ng/ml at baseline, peaked to 7.5 ± 5.4 ng/ml at 60 mins and was 6.0 ± 3.6 mins and 5.9 ± 2.4 at 30 and 120 mins respectively with insulin peaking from 13.5 ± 5.5 uIU/ml at baseline to 107 ± 81.6 uIU/ml at 30 mins and 85.8 ± 78 uIU/ml and 42.2 ± 23.2 uIU/ml at 60 mins and 120 mins respectively. CGM analysis revealed mean CGM glucose was 120.4 ± 14.8 with SD 26.2 ± 7.7. Glucose control was excellent with 94 ± 9.2% of readings within 70-180mg/dl and 79.8 ± 17.6% within 70-140 mg/dl. Percentage time < 70 mg/dl and < 54 mg/dl were 1.1 ± 1.1% and 0.1 ± 0.4% respectively. Percentage time > 180 and > 250 mg/dl were 4.8 ± 9.3% and 0.4 ± 0.7% respectively. HBGI, LBGI and ADRR were 1.3 ± 1.6, 0.7 ± 0.5 and 17.4 ± 8.9 respectively.

Conclusion: PT recipients demonstrate excellent glucose control on comprehensive assessment one or more years after the procedure. CGM and MMT data are different from normal people.

Disclosure

R. Kaur: None. C. Reid: None. P. Thapa: None. S. Rizvi: None. S.K. McCrady-Spitzer: None. S. Batthula: None. B.H. Smith: None. P. Dean: None. W.K. Kremers: Research Support; Self; AstraZeneca. A. Kukla: None. M.D. Stegall: None. Y.C. Kudva: Research Support; Self; Dexcom, Inc., Roche Diabetes Care. Other Relationship; Self; Abbott.
370-OR: Hepatic FGF21 Expression Is Under the Regulation of the Canonical Wnt Signaling Pathway
Authors: BADAKHSHI YASAMAN , SHAO WEIJUAN , TIAN LILI , JIN TIANRU
Published: June 2020

The metabolic hormone FGF-21 is mainly produced and released from the liver in response to nutritional stresses such as starvation, alcohol or ketogenic diet consumption. Body weight lowering and insulin signaling sensitization effects of FGF-21 and its analogues have been demonstrated in animal models or in human subjects. We show here that hepatic FGF-21 mRNA and FGF-21 protein levels were reduced in male LTCFDN, a transgenic mouse line in which canonical Wnt signaling cascade is functionally attenuated due to the expression of dominant negative transcription factor TCF7L2 in the liver, and the reduction is not associated with reduced expression of PPARα, a key transactivator of FGF-21. Furthermore, starvation-induced plasma FGF-21 elevation was also attenuated in male LTCFDN mice.

Utilizing mouse primary hepatocytes, we found that FGF-21 mRNA and FGF-21 protein expression can be increased by Wnt-3a or LiCl treatment. Two evolutionarily conserved TCF binding motifs (TCFB) were then located within the mouse FGF-21 gene promoter. Luciferase and ChIP results suggest that one of them is responsible for β-cat/TCF mediated activation on FGF-21 transcription.It has been shown recently that in mouse brain tanycytes, FGF-21 secretion can be induced by palmitate treatment. We found that in mouse primary hepatocytes, palmitate but not oleate treatment increased expression of the Wnt target gene Ccnd1, which encodes cyclin D1.

Our observations hence suggest that Wnt signaling cascade is involved in hepatic FGF-21 production and secretion, and the positive regulation is likely independent of fibrate/PPARα-mediated induction. Investigations on this novel hepatic signaling axis will strengthen our knowledge on the physiologically significant hormone FGF-21, leading to novel therapeutic avenues in treating impaired metabolism.

Disclosure

Y. Badakhshi: None. W. Shao: None. L. Tian: None. T. Jin: None.

Funding

Canadian Institutes of Health Research (PJT159735)
375-P: Missed Bolus Doses (MBDs) Are Associated with Reduced Time-in-Range (TIR): The Influence of Hypoglycemic Fear
Authors: EDWARDS STEPHANIE S. , HE XUANYAO , JOHNSON JENNAL , MEADOWS ERIC , WANG WENJIE , WOLPERT HOWARD , POLONSKY WILLIAM
Published: June 2020

Connected insulin pens have potential utility as diagnostic tools to objectively assess MBDs and their impact on glycemic outcomes. This cross-sectional study enrolled 68 people with T1D or insulin-using T2D (A1C ≥ 8%, ≥ 3 insulin boluses/day reported at enrollment). Mean (± SD) age of participants was 48 years (± 12), 44% female, 59% T1D, 51% BMI ≥ 30 and 65% with A1C ≥ 9.0%. Connected pen and blinded CGM data (21 days collected) were used to calculate MBDs (no insulin dose from 2 hrs prior to and 4 hrs after the start of a glucose excursion [defined as > 70 mg/dl rise within 2 hrs, not preceded by a value < 70 mg/dl]). On average, participants had 21.6 MBDs/30 days (range 0-55.8); time-in-range (TIR) was relatively low, 42.6% (± 18.8%) while time-above-range (TAR) was high, 52.8% (± 21.3%). MBD daily frequency was significantly associated with TIR (Spearman’s correlation coefficient [rS] = -0.28, p = 0.02) and TAR (rS = 0.26, p = 0.03). Baseline predictors of MBD included A1C (incidence rate ratio, IRR = 1.118, p = 0.003) and BMI (IRR = 0.969, p = 0.008). Due to differences between T1D and T2D populations (age: 42.5 vs. 55.2 yrs, p < 0.001; BMI: 27.7 vs. 34.1, p < 0.001; diabetes duration: 22.7 vs. 16.0 yrs, p = 0.015, respectively), the groups were analyzed separately. For T2D, MBDs were associated with the Worry, Avoidance, and Maintain High subscales of the Hypoglycemic Fear Survey (HFS-W, A, and MH). MBDs were significantly more common among those with lower HFS-W (IRR = 0.940, p = 0.004), but with higher HFS-A (IRR = 1.140, p = 0.004) and higher HFS-MH (IRR = 1.075, p = 0.040). For T1D, none of the HFS subscales were significantly associated with MBDs. Given the differences in behavioral factors associated with MBDs in T1D and T2D, customized therapeutic approaches to reduce MBDs and improve TIR are likely needed.

Disclosure

S.S. Edwards: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. X. He: Employee; Self; Eli Lilly and Company. J. Johnson: Employee; Self; Eli Lilly and Company. E. Meadows: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. W. Wang: None. H. Wolpert: Employee; Self; Eli Lilly and Company. W. Polonsky: Advisory Panel; Self; Intarcia Therapeutics, Roche Diabetes Care. Consultant; Self; Abbott, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Novo Nordisk Inc., Onduo, Sanofi US, Xeris Pharmaceuticals, Inc.

Funding

Eli Lilly and Company
378-P: Real-Time Inpatient Hypoglycemia Intervention Reduces the Rate of Recurrent Severe Hypoglycemia
Authors: GORANTLA YAMUNA , YAP SARA ELIZABETH T. , GUERRA YANNIS , FOGELFELD LEON
Published: June 2020

Hypoglycemic events are a common inpatient safety issue; over half are preventable. There are no studies of real-time detection/response to prevent recurrence of hypoglycemia. We evaluated the effectiveness of real-time electronic hypoglycemia surveillance program (REHSP) to reduce the rate of recurrent severe hypoglycemic events (RHE) in hospitalized patients.

REHSP is driven by a multidisciplinary team of endocrinologists and nurse practitioners who review an electronic database of all inpatient hypoglycemia events in the last 24hrs. Recommendations to reduce RHE are given to primary teams and appropriate response is monitored.

We compared recurrence rates of severe hypoglycemia (BG <50 mg/dL) in inpatients with at least one severe hypoglycemic event (index event) 1 year Pre-REHSP vs. 1 year Post-REHSP implementation. RHE were defined as severe hypoglycemia occurring 20 hours and more after the index event (based on CMS criteria). The primary outcomes were rates of RHE and appropriate response by the primary teams.

The Table shows that demographic and clinical characteristics were similar in both groups. In the Post-REHSP group the rates of RHE and length of stay declined significantly and the appropriate response of the teams significantly increased.

This study highlights the potential of reducing recurrent hypoglycemia through real-time intervention.

Disclosure

Y. Gorantla: None. S.T. Yap: None. Y. Guerra: None. L. Fogelfeld: Research Support; Self; Bayer Healthcare Pharmaceuticals Inc., Gan & Lee Pharmaceuticals, Gilead Sciences, Inc., Merck & Co., Inc., Sanofi.
388-P: Real-World Associations between Glucose Management Indicator and CGM-Derived Metrics of Hypoglycemia
Authors: WALKER TOMAS C. , DOWD ROBERT , WELSH JOHN , NORMAN GREGORY J. , PARKER ANDREW SCOTT , PRICE DAVID A.
Published: June 2020

Early randomized controlled trials (RCTs) showed a strong inverse relationship between A1C and severe hypoglycemia (SH) risk, which could potentially limit therapy intensification and resulted in some guidelines suggesting increased A1C goals in at-risk patients. Subsequently, RCTs demonstrated that real-time continuous glucose monitoring (CGM) alters this relationship and attenuates SH risk associated with low A1C values ≥6.5%. The glucose management indicator (GMI) reflects average CGM glucose and correlates with A1C. This analysis uses real-world evidence to explore the relationship between GMI and hypoglycemia exposure. Data were from an anonymized convenience sample of 151,315 U.S.-based Dexcom G6 CGM app users with good device adherence evidenced by having uploaded ≥80% of possible CGM values in 3Q 2019. Hypoglycemia exposure was reported as the percentage of glucose values <70 or <54 mg/dL (level 1 or level 2 hypoglycemia, respectively). The Figure shows hypoglycemia and the number of users in six GMI categories. Although there are small, incremental increases in hypoglycemia until GMI is <6.5%, time spent in level 1 and level 2 hypoglycemia remains below the consensus goals of <4% and <1% for users with GMI values ≥6.5%. On average, CGM users with GMI values ≥6.5% have acceptably low rates of hypoglycemia, obviating the need to relax GMI goals as a strategy to reduce the risk of SH.

Disclosure

T.C. Walker: Employee; Self; Dexcom, Inc. J. Welsh: Employee; Self; CSL Behring. G.J. Norman: Employee; Self; Dexcom, Inc. A. Parker: Employee; Self; Dexcom, Inc. Stock/Shareholder; Self; Dexcom, Inc. D.A. Price: Employee; Self; Dexcom, Inc.
413-P: The New Myokine Myonectin Is Significantly Associated with Type 2 Diabetes in Patients with Peripheral Artery Disease
Authors: MUENDLEIN AXEL , GEIGER KATHRIN , LEIHERER ANDREAS , ZACH CHRISTINA , VONBANK ALEXANDER , SAELY CHRISTOPH H. , HEINZLE CHRISTINE , FRAUNBERGER PETER , DREXEL HEINZ
Published: June 2020

The novel myokine myonectin is predominantly expressed in skeletal muscle and is involved in the regulation of metabolic homeostasis. A putative association between myonectin and type 2 diabetes mellitus (T2DM) has been discussed controversially in current literature. The association between myonectin and T2DM in subjects peripheral artery disease (PAD) has not been investigated at all and is addressed in the present study. We measured myonectin in 224 patients with sonographically proven PAD, of whom 93 had T2DM (41.5%). Myonectin concentrations were significantly decreased in PAD patients with T2DM compared to nondiabetic PAD patients (median 2.00, interquartile range [1.19-3.35] versus 2.63 [1.58-3.88] ng/ml; p=0.030). Analysis of covariance revealed that the association between myonectin and T2DM remained significant after adjusting for age, sex, body mass index, LDL-cholesterol, smoking, as well as systolic and diastolic blood pressure (F=5.42; p=0.021). Further, plasma myonectin significantly correlated with HbA1c (spearman’s rho=-0.164; p=0.015), but not with levels of fasting glucose or 2-hour glucose in oral glucose tolerance tests (rho=-0.059; p=0.387 and rho=-0.148; p=0.053, respectively). We conclude that plasma myonectin levels are significantly associated with T2DM in patients with PAD.

Disclosure

A. Muendlein: None. K. Geiger: None. A. Leiherer: None. C. Zach: None. A. Vonbank: None. C.H. Saely: None. C. Heinzle: None. P. Fraunberger: None. H. Drexel: None.
423-P: The A Body Shape Index and Type 2 Diabetes Are Mutually Independent Predictors of Cardiovascular Events and Mortality in Patients with Established Cardiovascular Disease
Authors: VONBANK ALEXANDER , LARCHER BARBARA , MADER ARTHUR , MAECHLER MAXIMILIAN , SPRENGER LUKAS , LEIHERER ANDREAS , PURIN DANIELA , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: June 2020

The A Body Shape index (ABSI) is a validated measure of visceral adiposity that is calculated based on waist circumference, height and BMI. Its power to predict cardiovascular events and mortality in patients with established cardiovascular disease (CVD) is unclear and is addressed in the present study. We prospectively recorded cardiovascular events in a large cohort of 1546 patients with established CVD (1299 patients with angiographically proven stable coronary artery disease and 247 patients with sonographically verified PAD) over a mean follow-up time of 9.7±4.6 years. At baseline, the ABSI was higher in patients with type 2 diabetes (T2DM; n=502) than in those who did not have diabetes (8.4±0.6 vs. 8.3±0.5; p<0.001). Prospectively, the ABSI significantly predicted the incidence of cardiovascular events (n=749) and death (n=619) after adjustment for age, gender, smoking, hypertension, LDL cholesterol, HDL cholesterol, and T2DM (standardized adjusted HRs 1.11 [1.03-1.19]; p=0.006 and 1.18 [1.09-1.27]; p<0.001, respectively). T2DM in turn also significantly predicted cardiovascular events and death in this fully adjusted model independently from the ABSI, with adjusted HRs of 1.37 [1.17-1.0]; p<0.001 and 1.40 [1.18-1.6]; p<0.001, respectively. We conclude that the ABSI and T2DM are mutually independent of cardiovascular events and mortality in patients with PAD.

Disclosure

A. Vonbank: None. B. Larcher: None. A. Mader: None. M. Maechler: None. L. Sprenger: None. A. Leiherer: None. D. Purin: None. A. Muendlein: None. H. Drexel: None. C.H. Saely: None.
440-P: Decreased Peripheral Perfusion Measured by Perfusion Index Is a Novel Indicator for Cardiovascular Death in Patients with Type 2 Diabetes and Established Cardiovascular Disease
Authors: OKADA HIROSHI , OKADA YUKI , FUKUI MICHIAKI
Published: June 2020

We investigated the role of peripheral perfusion as an indicator for cardiovascular death in patients with type 2 diabetes and established cardiovascular disease (CVD). This retrospective cohort study included 1080 patients with type 2 diabetes and history of CVD recruited from the outpatient clinic at Matsushita Memorial Hospital in Osaka, Japan. Peripheral perfusion is assessed using the perfusion index (PI), which represents the level of circulation through peripheral tissues. PI was measured using a Masimo SET Radical-7 (Masimo Corporation, Irvine, CA) instrument. The median age and PI values were 74 years (range: 67-79 years) and 2.6% (range: 1.1-4.3%), respectively. The average duration of follow up was 871 ± 265 days. During follow-up duration, 60 patients died due to CVD. The adjusted Cox regression analysis demonstrated that the risk of developing cardiovascular death was higher in the first quartile (HR, 5.84; 95% CI, 2.23 to 20.16) or second quartile (HR, 3.00; 95% CI, 1.05 to 10.81) of PI than that in the highest quartile (fourth quartile) of PI. PI (per 1% decrease) was associated with the development of cardiovascular death (HR, 1.38; 95% CI, 1.15 to 1.64). PI could be a novel indicator of cardiovascular death in patients with type 2 diabetes and established CVD.

Disclosure

H. Okada: None. Y. Okada: None. M. Fukui: None.
445-P: Network Meta-analysis of Seven Glucagon-Like Peptide-1 Receptor Agonists: A Focus on Cardiovascular Outcome Trials Data
Authors: ALFAYEZ OSAMAH , ALKHEZI OMAR , ALMUTAIRI ABDULAALI R.
Published: June 2020

Objective: To indirectly compare glucagon like peptide-1 receptor agonists (GLP-1RA) cardiovascular outcome trials (CVOTs) using network meta-analysis (NMA).

Methods: We searched Medline to retrieve CVOTs that involved GLP-1RA. We conducted NMAs using binomial likelihood logit link model for the following outcomes: CV death, myocardial infarction (IM), stroke, and death from any cause. After running both fixed effects and random effects models for each outcome, we identified the best fit model that has the smallest deviance information and the average posterior residual deviance. We followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA-NMA) in reporting this NMA.

Results: After screening, a total of seven GLP-1RA CVOTs were included. The NMA results showed that oral semaglutide was statistically better than exenatide (HR 0.47, CI: 0.21-0.99), dulaglutide (HR 0.46, CI: 0.20-0.97), albiglutide (HR 0.45, CI: 0.19-0.97), and lixisenatide (HR 0.43, CI: 0.19-0.92) in reducing CV death events. No significant differences were detected between most of the treatments regarding reducing death from any cause, MI and stroke events. The ranking results showed that oral semaglutide had the highest probability to be ranked first (>90%) in reducing CV death and death from any cause. Moreover, once weekly semaglutide had the highest probability to be ranked first in reducing MI and stroke events.

Conclusion: The indirect comparison of GLP-1RAs using CVOTs data showed that oral semaglutide is preferred over most of the GLP-1RAs in reducing CV death and death from any cause events. The ranking probability showed that once weekly semaglutide and oral semaglutide are the most likely to be ranked first in reducing the outcomes of interest.

Disclosure

O. Alfayez: None. O. Alkhezi: None. A.R. Almutairi: None.
447-P: Bone Mineral Density Is Associated with Subclinical Atherosclerotic Cardiovascular Disease in Elderly Men with Type 2 Diabetes
Authors: CHEN YAO , WANG XINGCHUN , MA BINGWEI , QU SHEN , WEI DONG
Published: June 2020

The incidence of osteoporosis is controversial in type 2 diabetes(T2DM). There have been few studies to explore the influencing factors of bone mineral density (BMD) in old diabetic men. This study aimed to investigate the association of BMD with subclinical atherosclerotic cardiovascular disease in diabetic men. 295 diabetic men over 55 years old were enrolled divided into two groups: subclinical PAD and non-subclinical PAD group with age-, BMI-, and duration of diabetes- matched. The subclinical PAD was defined by ankle brachial index (ABI)≤0.9. BMD (at right hip, femoral neck and lumbar spine1-4 (L1-L4) by dual-energy X-ray absorptiometry), bone metabolic markers, ABI and routine anthropometric parameters were measured. Results showed that the incidence of osteoporosis had no difference(37.6% vs. 36.4 %,P=0.865). BMD at right hip were significantly lower in subclinical PAD group than non-subclinical PAD group (0.83±0.27g/cm2 vs. 0.92±0.16g/cm2, P=0.004). The T-score and Z-score at right hip, and T-score at femoral neck were significantly lower(-1.10±0.88vs. -0.69±0.97, P=0.005; -0.39±0.82 vs. -0.07±0.96, P=0.03;-1.36±0.92 vs. -0.99±1.04, P=0.02). BMD, T-score and Z-score at right hip were significantly associated with ABI(r=0.165,P=0.004; r=0.174,P=0.003, r=0.133,P=0.022).

In conclusion, BMD was associated with subclinical PAD in elderly men with type 2 diabetes. It suggests that vascular health, even in its early stages, is linked to bone health in elderly men with type 2 diabetes.

Disclosure

Y. Chen: None. X. Wang: None. B. Ma: None. S. Qu: None. D. Wei: None.
45-LB: Introduction of the Diabetes Exercise Perception (DEEP-1) Questionnaire for Assessing Perceived Attitudes and Challenges in Athletes with Type 1 Diabetes
Authors: SCOTT SAM N. , FONTANA FEDERICO Y. , HAYES CHARLOTTE A. , LAGROU PETER H. , ZUEGER THOMAS , SOUTHERLAND PHIL , STETTLER CHRISTOPH
Published: June 2020

Background and Aims: Little is known about individual perspectives and challenges faced by elite-level athletes living with type 1 diabetes and where they turn to for advice. Currently, there is no validated tool to assess this. We aimed to generate and pilot test the Diabetes ExErcise Perception (DEEP-1) questionnaire in a group of professional endurance athletes with type 1 diabetes to investigate perceived attitudes and challenges.

Methods: The online questionnaire consists of a range of open and closed questions, focusing on 4 key areas related to diabetes management and exercise: 1) Technology; 2) Sleep and Recovery; 3) Glucose Management; and 4) Nutrition. Sixteen professional cyclists with type 1 diabetes (age 27 ± 4 years; HbA1c 6.8 ± 0.5%) were asked to anonymously complete the questionnaire using SurveyMonkey.com. Data were then analyzed descriptively.

Results: Fifteen participants responded. In this cohort, 90% showed an interest in using technology for improved exercise performance and 89% for glucose management, although 28% felt unaware of newer technologies. Glucose was perceived as being generally well regulated; however, according to the responses, more attention needs to be focused overnight and pre/during exercise. Sleep quality was rated as an important factor affecting exercise performance by 80% of respondents. 93% of participants identified nutrition as an area for improved performance, with 25% reporting a lack of education in this area.

Conclusions: This pilot study highlights the importance of an individualized approach to diabetes management and high-level exercise performance. Future work should validate the DEEP-1 questionnaire in a larger sample size using individuals with a range of physical activity levels. Such a tool may provide a useful and time-efficient means for health care professionals to gain deeper insight into their patients’ attitudes and challenges regarding exercise.

Disclosure

S.N. Scott: None. F.Y. Fontana: None. C.A. Hayes: Other Relationship; Self; Novo Nordisk A/S. P.H. Lagrou: None. T. Zueger: None. P. Southerland: None. C. Stettler: None.
456-P: Targeted Deletion of Insulin Receptor in Vascular Smooth Muscle Cells Accelerated Thinning of Plaque Cap and Apoptosis and Atherosclerosis
Authors: LI QIAN , FU JIALIN , PARK KYOUNGMIN , ZAITSU YUMI , ST-LOUIS RONALD , RASK-MADSEN CHRISTIAN , KING GEORGE L.
Published: June 2020

Vascular smooth muscle cells (VSMCs) play an important role in the development of the stability of atherosclerotic plaque. We reported that knockout of insulin receptor (IR), but not IGF1 receptor, in VSMCs reduced intimal hyperplasia of femoral artery after wire injury. To investigate the role of IR in VSMCs on atherosclerotic plaque, ApoE and smooth muscle cells IR double knockout (SMIRKO/ApoE-/-) mice were generated. Extent of lipid deposition and atherosclerosis were increased in the aorta of SMIRKO/ApoE-/- mice compared to control mice (p<0.05). However, total cell numbers and proliferation of VSMCs, cap thickness and collagen of the plaque were decreased, whereas VSMCs apoptosis, macrophage content and necrotic area were increased in the aortic plaques of SMIRKO/ApoE-/- mice compared to ApoE-/- mice. VSMCs cultured from SMIRKO/ApoE-/- mice exhibited more apoptosis by withdrawing growth factors which were inhibited by insulin compared to VSMCs from ApoE-/- mice. Analysis of genes in VSMCs subsets which were reported to be increased in aortic plaques showed MMP2, decorin, thrombospondin 1 and 5, sFRP3 and IGFBP4 were increased in the aortic media of SMIRKO/ApoE-/- mice vs. ApoE-/- mice, with MMP2, thrombospondin 1 and 5 and sFRP3 were also increased in the aortic media of mice fed with high fat diet or diabetic mice due to streptozotocin injection. Insulin downregulated MMP2 and thrombospondin 1 in cultured VSMCs, whereas overexpression of Foxo1 in VSMCs increased the expression of thrombospondin 1. Reanalysis of existed microarray data base and found MMP2 and thrombospondin 1 were also elevated in internal mammary artery of diabetic compared to nondiabetic people. Thus, insulin receptor action on VSMCs can change expression of extracellular genes and its turnover to increase the stability of atherosclerotic plaque.

Disclosure

Q. Li: None. J. Fu: None. K. Park: None. Y. Zaitsu: Employee; Self; Sunstar Group. R. St-Louis: None. C. Rask-Madsen: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc.

Funding

National Institutes of Health (R01DK053105)
468-P: PDK1 Is a Key Regulator of Podocyte Viability and Maintenance of Glomerular Function
Authors: IWATA WAKIKO , UNOKI-KUBOTA HIROYUKI , KATO HIDEKI , MATSUMOTO MICHIHIRO , NANGAKU MASAOMI , KABURAGI YASUSHI
Published: June 2020

In diabetic states, altered activity of insulin signaling pathway is likely to play key roles in insulin resistance and in kidney dysfunction. Since the 3-phosphoinositide-dependent protein kinase 1 (PDK1) serves as a major signaling molecule in the regulation of cellular responses in multiple organs by mediating the phosphoinositide 3-kinase signaling pathway, we tested the hypothesis that podocyte-specific deletion of PDK1 leads to podocyte injury and proteinuric kidney disease. PDK1 was selectively silenced in podocytes using Cre-mediated recombination controlled by the podocin promoter. Mice with a podocyte-specific deletion of PDK1 (PDK1 KO) developed proteinuria, and died due to end-stage renal disease by 5 weeks after birth. Histologically, features characteristic of glomerulosclerosis, including podocyte foot process effacement, mesangial sclerosis, and protein casts, were observed in PDK1 KO at 3 weeks of age. We also examined podocyte distribution in glomeruli using the podocyte markers synaptopodin and WT-1, and found that their expressions were lost in some glomeruli of PDK1 KO at 3 weeks of age although their expression patterns at 1 weeks of age PDK1 KO were almost comparable with control mice. We next examined a possible role of forkhead transcription factor, forkhead box O1 (FoxO1) in linking PDK1 of podocytes to kidney function. For this, we generated podocyte-specific PDK1 and FoxO1 double knockout mice (DKO) by introducing Foxo1-flox gene into PDK1 KO mice. DKO exhibited a reduced level of proteinuria compared with age-matched PDK1 KO, and the maximal survival time of DKO had extended to 6.6 weeks after birth. Taken together, PDK1-FoxO1 pathway may be one of the critical signal transduction pathways that links podocyte injury and kidney dysfunction in diabetic states.

Disclosure

W. Iwata: None. H. Unoki-Kubota: None. H. Kato: None. M. Matsumoto: None. M. Nangaku: Consultant; Self; Akebia Therapeutics, Astellas Pharma Inc., Bayer AG, Boehringer Ingelheim International GmbH, Daiichi Sankyo, GlaxoSmithKline plc., Japan Tobacco Inc., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Otsuka Pharmaceutical Co., Ltd., Scohia Pharma Inc. Research Support; Self; Takeda Pharmaceutical Company Limited. Speaker’s Bureau; Self; AstraZeneca, Torii Pharmaceutical Co. Ltd. Y. Kaburagi: None.
469-P: ROCK1/AMPK Axis Regulates the Development of Diabetic Kidney Disease via Modulation of Fatty Acid Metabolism
Authors: NAGAI YOSUKE , MATOBA KEIICHIRO , TAKEDA YUSUKE , AKAMINE TOMOYO , KAWANAMI DAIJI , UTSUNOMIYA KAZUNORI , NISHIMURA RIMEI
Published: June 2020

The small GTPase Rho and its effector Rho-kinase are involved in the pathogenesis of diabetic kidney disease. Accumulating evidence shows that renal dysfunction in diabetic patient is associated with abnormal fatty acid oxidation in the kidney. However, the interaction of Rho-kinase and fatty acid oxidation in diabetic kidney remain unclear. Glomeruli isolated from type 2 diabetic db/db mice demonstrated decreased gene expression of fatty acid oxidation mediators such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), CD36, carnitine palmitoyltransferase 1A (CPT1A). Chemical inhibition of Rho-kinase restored expression of fatty acid oxidation-related genes in both isolated glomeruli and cultured mesangial cells. An investigation of mechanisms underlying this observation revealed activated Rho-kinase functions through the phosphorylation of AMPK and increased expression of PGC-1α. Extracellular flux analyzer demonstrated that Rho-kinase inhibition improves TGF-β-induced mitochondrial dysfunction. Furthermore, fluorescence histochemistry showed that Rho-kinase inhibitors suppresses ROS production as a result of mitochondrial damage due to abnormal fatty acid metabolism. Knockdown by small interfering RNA against two Rho-kinase isoforms, ROCK1 and ROCK2, showed that ROCK1 but not ROCK2 controls this metabolic machinery. Consistent with this result, mesangial cells isolated from ROCK1 deficient mice were protected from TGF-β-mediated downregulation of fatty acid metabolism. These observations indicate that ROCK1 is a key player in the development of diabetic renal injury. Glomerular ROCK1 may be a potential therapeutic target for the treatment of diabetic kidney disease.

Disclosure

Y. Nagai: None. K. Matoba: Research Support; Self; Sanofi K.K., Takeda Pharmaceutical Company Limited. Y. Takeda: None. T. Akamine: None. D. Kawanami: None. K. Utsunomiya: None. R. Nishimura: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly Japan K.K., Medtronic, Merck & Co., Inc., Novo Nordisk Inc., Sanofi K.K., Takeda Pharmaceutical Company Limited.