bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incident Silent Myocardial Infarction among People with Prediabetes—Results from Four Longitudinal Cohort Studies
Authors: ZGIBOR JANICE C. , MALMI MARKKU , WANG WEI , KIP KEVIN E. , SCHOCKEN DOUGLAS D. , ALMAN AMY C. , STACEY RICHARD B. 
Published: June 2018

Approximately 45% of first of myocardial infarctions (MI) are silent. People with diabetes are more likely to have MIs than those without diabetes. Little is known, however, about silent MIs (SMIs) among those with prediabetes. The prognosis of SMIs is similar to clinical MIs making timely detection imperative. We aimed to assess the association between prediabetes and incident SMI in four long duration cohort studies. We pooled data from the following studies: Cardiovascular Health, Atherosclerotic Risk in Communities, Health Aging and Body Composition, and Multi-Ethnic Study of Atherosclerosis (n=30,898). Population characteristics were: mean age 61.3 years, 45% male, 66.4% white, 40.0% had hypertension and 35.3% had hyperlipidemia. Diabetes status was based on fasting glucose (100-125mg/dL=prediabetes and &gt;=126mg/dL=diabetes). Participants were also defined as having diabetes if they were taking medications for diabetes or reported a previous diagnosis. At baseline, 36% did not have diabetes, 50% had prediabetes and 14% had diabetes. Among participants with prediabetes, 3% experienced SMI over a mean follow-up of 9.6 years compared with 2% among those without diabetes. In Cox Proportional Hazards Models, we found an increased risk of incident SMI among those with prediabetes compared to those without diabetes (Hazard Ratio=1.25; 95% CI: 1.04-1.5, p=0.02), adjusting for age, sex, race, smoking status, hypertension, and high cholesterol. Significant baseline predictors of SMI in addition to having prediabetes included being male, older age, current smoking, and hypertension. People with prediabetes, comprising 50% of these cohort study populations, may be at increased risk for SMI, and could benefit from increased focus on prevention and treatment of cardiovascular risk factors.

Disclosure
J.C. Zgibor: None. M. Malmi: None. W. Wang: None. K.E. Kip: None. D.D. Schocken: None. A.C. Alman: None. R.B. Stacey: None.
Adiposity and Cardiovascular Markers in Offspring of Women with Diabetes during Pregnancy—The EPOCH Study
Authors: HOCKETT CHRISTINE , STARLING ANNE P. , BELLATORRE ANNA , AALBORG JENNY , SAUDER KATHERINE A. , GARG KAVITA , RINGHAM BRANDY , GLUECK DEBORAH H. , DABELEA DANA 
Published: June 2018

We previously showed that exposure to maternal diabetes mellitus (DM) affects adiposity and cardiovascular (CV) markers in pre-pubertal children. After further follow-up, we are now testing whether DM exposure continues to affect these markers throughout adolescence. Data on 381 youth (313 unexposed, 68 exposed) were collected at two research visits, on average at 10.4 and 16.6 years, respectively. Measures included BMI, waist circumference, height, visceral (VAT) and subcutaneous adipose tissue (SAT), systolic and diastolic blood pressure and fasting lipid levels. Linear mixed models were used to assess the longitudinal relationship between DM exposure and offspring outcomes, adjusting for child age, sex, race/ethnicity, and Tanner stage. BMI, VAT and SAT were log-transformed. We tested for effect modification of exposure by visit. Exposure to DM was associated with markers of adiposity and CV risk throughout adolescence (Table), and for most outcomes effects were not different across visits. Youth exposed to DM had higher non-HDL cholesterol at the second visit (β=0.30, p&lt;0.001), but not at the first visit (03B2;=0.12, p003C;0.23) (interaction p&lt;0.045). Adjustment for SES, child’s total calories and physical activity did not influence the results. Our data provides novel evidence that exposure to maternal DM has persistent effects on offspring adiposity and CV markers throughout adolescence.

Disclosure
C. Hockett: None. A.P. Starling: None. A. Bellatorre: None. J. Aalborg: None. K.A. Sauder: None. K. Garg: Research Support; Spouse/Partner; Eli Lilly and Company, MannKind Corporation. Advisory Panel; Spouse/Partner; Novo Nordisk A/S, Sanofi, Senseonics. Research Support; Spouse/Partner; Dexcom, Inc., Medtronic. B. Ringham: None. D.H. Glueck: None. D. Dabelea: None.
Glucose Uptake in Muscle, Visceral Adipose Tissue, and Brain Strongly Predict Whole-Body Insulin Resistance in the Development of Type 2 Diabetes
Authors: BOERSMA GRETHA J. , HEURLING KERSTIN , PEREIRA MARIA J. , JOHANSSON EMIL , LUBBERINK MARK , KATSOGIANNOS PETROS , SKRTIC STANKO , KULLBERG JOEL , AHLSTRÖM HÅKAN , ERIKSSON JAN W. 
Published: June 2018

We aimed to elucidate tissue-specific glucose uptake in the development of whole-body insulin resistance and type 2 diabetes (T2D). We recruited 13 T2D(D), 12 prediabetes (IFG/IGT) (P), and 10 control (C) subjects, matched for age and BMI. Integrated whole-body 18F-FDG PET and MRI was performed during a hyperinsulinemic euglycemic clamp to assess glucose uptake rate (MRglu) in several tissues.
MRglu in skeletal muscle, subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and liver correlated positively with the M-value. Muscle and adipose tissue MRglu was lower in both P and D. D had lower liver MRglu than P and C. Brain MRglu was higher in D and P and it was inversely correlated with M-values. The M-value was best predicted by a multivariate model (adjusted r2= 0.85) including muscle (Std.β-Coeff.=0.64, p&lt;0.001), VAT (Std.β-Coeff.=0.18, p&lt;0.05) and brain MRglu (Std.β-Coeff.=-0.33, p&lt;0.001).
In the development of T2D, brain glucose uptake is enhanced during hyperinsulinemia in parallel with an impairment in peripheral organs. Impaired glucose uptake in skeletal muscle and VAT together with elevated brain MRglu were independently associated with whole-body insulin resistance. This suggests that these alterations may contribute to T2D development.Table 1.Table 1M-Value (g/kg lbm/min)MRglu Muscle (μmol/100g/min)MRglu Liver (&lt;μmol/100g/min)MRglu VAT (μmol/100g/min)MRglu SAT (μmol/100g/min)MRgluHeart (μmol/100g/min)MRgluBrain (μmol/100g/min)Control10.82 ± 1.1415.4 ± 1.96.2 ± 0.73.4 ± 0.52 ± 0.480.5 ± 4.815.8 ± 1.4Prediabetes6.33 ± 0.96 **8.8 ± 1.2**6.6 ± 0.82.5 ± 0.4*1.8 ± 0.176.7 ± 9.418.4 ± 0.9*T2D5.12 ± 0.69 **6.7 ± 1.2**3.7 ± 0.6*¤2.1 ± 0.3*1.4 ± 0.2*79.7 ± 7.419.3 ± 1.1* M-ValueMuscleLiverVATSATHeartBrainMuscler=0.884**r=0.335*r=0.712**r=0.596**r=0.156r=-0.437**Liverr=0.403*r=0.335*r=0.462**r=0.557**r=-0.166r=-0.167VATr=0.707**r=0.712**r=0.462**r=0.683**r=0.126r=-0.259SATr=0.574**r=0.596**r=0.557**r=0.683**r=0.064r=-0.058Heartr=0.149r=0.156r=-0.166r=0.126r=0.064r=-0.007Brainr=-0.616**r=-0.437**r=-0.167r=-0.259r=-0.058r=-0.007* p&lt;0.05, ** p&lt;0.01 for comparisons vs. C, or ¤ p&lt;0.for comparison vs. P.

Disclosure
G.J. Boersma: None. K. Heurling: None. M.J. Pereira: None. E. Johansson: None. M. Lubberink: None. P. Katsogiannos: None. S. Skrtic: Employee; Self; AstraZeneca. J. Kullberg: Stock/Shareholder; Self; Antaros Medical. Board Member; Self; Antaros Medical. Employee; Self; Antaros Medical. H. Ahlström: Stock/Shareholder; Self; Antaros Medical AB. J.W. Eriksson: Employee; Spouse/Partner; Amgen Inc.. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Consultant; Self; Novo Nordisk A/S, Merck Sharp & Dohme Corp.. Research Support; Self; Bristol-Myers Squibb Company.
Effect of Bariatric Surgery on Neuroplasticity in Humans
Authors: DANIELE GIUSEPPE , DARDANO ANGELA , LUNGHI CLAUDIA , BINDA PAOLA , CICCARONE ANNAMARIA , SANTINI FERRUCCIO , CECCARINI GIOVANNI , GIUSTI LAURA , BELLINI ROSARIO , SEGHIERI MARTA , GUERRA SILVIA DEL , MORETTO CARLO , MORRONE MARIA CONCETTA , PRATO STEFANO DEL 
Published: June 2018

Background and Aim: Obesity and diabetes are associated to increased risk of cognitive impairment, neurodegenerative disorders, neuroinflammation and synaptic plasticity abnormalities. The aim of the study was to evaluate the effect of obesity and bariatric surgery on neural plasticity (NP).
Methods: We recruited 20 normal weight subjects (NS; age 26±10 years, BMI 21.7±2.6 kg/m2) and 31 obese subjects (OB; 40±11 years; BMI: 41.6±6.7 kg/m2) in whom NP in the visual cortex was measured as change in ocular dominance after 120 min of monocular deprivation obtained by ocular patch. To explore the effect of body weight reduction on NP, 14 OB (BMI=45.7±1.6 kg/m2) underwent metabolic surgery (RYGB) and NP was measured 6 months after surgery. Hormonal and metabolic parameters were obtained before and after administration of 75g glucose (OGTT).
Results: At baseline NP was lower in OB than in NS (0.04±0.vs. 0.12±0.05, p&lt;0.0001). NP was inversely correlated with body weight (r= -0.55; p&lt;0.001). Six-months after RYGB, BMI was markedly reduced (34.3±1.6 kg/m2; p&lt;0.001 vs. baseline) and glucose metabolism improved (HOMA-IR from 4.7±0.9 to 1.6±0.4; P=0.0and Disposition Index from 0.07±0.02 to 0.81±0.30 mUI × ml-1/ mg × dl-1× 1/ mUI × ml-1; p&lt; 0.05). Post-OGTT GLP-1 levels increased (AUCOGTTfrom 5457±715 to 11215±1067 pmol/l×120min; P&lt;0.002). NP showed a 10-fold increase (0.01± 0.03 to 0.10±0.04; p=0.008) indicating restoration of visual plasticity. The NP increase was correlated to increase in active GLP-1 (r=0.86; p&lt;0.007) and BMI reduction (r=0.10; p=0.07).
Conclusion: NP is markedly altered in OB, and it is restored to normal after RYGB. The relationship between NP increase and circulating GLP-1 levels suggests a potential role of this hormone in the NP restoration in humans.

Disclosure
G. Daniele: None. A. Dardano: None. C. Lunghi: None. P. Binda: None. A. Ciccarone: None. F. Santini: None. G. Ceccarini: None. L. Giusti: None. R. Bellini: None. M. Seghieri: None. S. Del Guerra: None. C. Moretto: None. M. Morrone: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Intarcia Therapeutics, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Servier, Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Takeda Pharmaceuticals U.S.A., Inc.. Advisory Panel; Self; Janssen Biotech, Inc., Abbott.
Current Smoking—An Independent Predictor of Elevated A1C in Adults with Type 2 Diabetes
Authors: CHASENS EILEEN R. , SEREIKA SUSAN M. , DINARDO MONICA , WEINZIERL VALARIE A. , HOENSTINE AMY L. , KORYTKOWSKI MARY T. 
Published: June 2018

While the cardiovascular risk of smoking is well documented in persons with type 2 diabetes (T2D), less is known about the impact of smoking on glycemic control in this population. The purpose of this study was to determine predictors, including smoking status, of elevated A1C in a sample of adults with T2D. This secondary analysis used baseline data from adults (N=256; 48% male) recruited for the Diabetes Sleep Treatment Trial. Participants were queried on demographics, diabetes-related distress (Problem Areas in Diabetes), diabetes knowledge (Diabetes Knowledge Test), and smoking behavior (never/former/current). A clinical assessment obtained height and weight to calculate BMI (kg/m2) and A1C. Non-smokers (53%; n=136) and former smokers (28%; n=72) were similar (p ≥.05) in terms of age, A1C, BMI, diabetes-related distress and knowledge; however, current smokers (19%; n=48) were less obese (BMI 33.3 [SD 6.5] vs. 36.1 [SD 6.9] kg/m2, p=.016), more likely to be non-Caucasian, have lower education, more financial difficulty, higher diabetes-related distress, and lower diabetes knowledge than non-smokers (all p-values &lt;.05). Using hierarchical regression diabetes duration, diabetes distress, and current smoking status were identified as predictors of higher A1C. We conclude smoking is associated with lower BMI and higher A1C, providing further support for counseling for smoking cessation in adults with T2D.Final model of regression to predict glucose control (A1C)VariableUnstandardized bStd. ErrorBetaSig.95% CI for bLowerUpperDuration of diabetes-.458.220-.126.038-.890-.026Diabetes-related distress.020.005.230&lt;.001.009.030Current Smoker.686.283.150.010.1821.305N=256; Duration of diabetes = &lt;10 years vs.10 or more years; Diabetes-related distress= scores on Problem Areas in Diabetes (PAID) questionnaire; Current smoker compared with non-smoker or former smoker.Sex, race, financial difficulty, education, and former smoking status not significant; removed from final modelModel Summary: Adj. R2= .098; p&lt;.001

Disclosure
E.R. Chasens: None. S.M. Sereika: None. M. DiNardo: None. V.A. Weinzierl: None. A.L. Hoenstine: None. M.T. Korytkowski: Advisory Panel; Self; Novo Nordisk Inc.. Other Relationship; Self; JAEB Center For Health Research.
Central KATP Channels Modulate Glucose Effectiveness
Authors: MITCHELL WILLIAM G. , LONTCHI-YIMAGOU ERIC , REDA SARAH A. , CAREY MICHELLE , ZHANG KEHAO , ALEKSIC SANDRA , HUFFMAN DEREK , HAWKINS MEREDITH 
Published: June 2018

Glucose effectiveness describes the restraining effect of hyperglycemia on endogenous glucose production (EGP), which is lost in type 2 diabetes (T2D). Since central nervous system KATP channels likely regulate EGP in humans and rats, we examined whether these channels contribute to glucose effectiveness. Paired 4-hour hyperglycemic ’pancreatic clamp’ studies were performed in 9 healthy humans (age 37 ± 15 years; BMI 26 ± 4 kg/m2) 3 hours following glyburide 10 mg (GLB) or placebo (PLC). With PLC, hyperglycemia suppressed EGP by 59% (euglycemia: 2.38 ± 0.229 vs. hyperglycemia: 0.98 ± 0.17, p &lt; 0.001). GLB resulted in 46% less suppression of EGP by hyperglycemia from baseline euglycemia compared to PLC (GLB: 1.56 ± 0.29 mg/kg/min vs. PLC: 0.98 ± 0.17 mg/kg/min, p = 0.047). To confirm that GLB’s effects were centrally mediated, parallel hyperglycemic studies were conducted in normal rats after oral gavage of normal saline (NS) (n=8), GLB (n=14), and oral GLB with intracerebroventricular (ICV) infusion of KATP channel agonist diazoxide (DZX) (n=8). GLB attenuated hyperglycemia’s suppressive effect on EGP (GLB: 9.4 ± 0.3 mg/kg/min vs. NS: 6.9 ± 0.3 mg/kg/min; p = 0.047), while ICV DZX abolished the effects of GLB (DZX + GLB: 5.5 ± 0.5 mg/kg/min vs. GLB, p = 0.003)(Figure 1). This suggests that ∼50% of the suppression of EGP by hyperglycemia is mediated by central KATP channels. Targeting these channels may offer a new therapeutic approach to improve glycemic control in T2D.

Disclosure
W.G. Mitchell: None. E. Lontchi-Yimagou: None. S.A. Reda: None. M. Carey: None. K. Zhang: None. S. Aleksic: None. D. Huffman: None. M. Hawkins: None.
Neuronal Deletion of the Mammalian Indy Homolog (Slc13a5) Increases Energy Expenditure in Mice
Authors: KURZBACH ANICA , WILLMES DIANA M. , SCHUMANN TINA , HENKE CHRISTINE , EL-AGROUDY NERMEEN , KLEINRIDDERS ANDRE , BIRKENFELD ANDREAS L. 
Published: June 2018

INDY (I’m Not Dead Yet) is a transporter of TCA cycle intermediates, mediating cellular citrate uptake and is highly expressed in liver and brain. Reduced expression of Indy in lower organisms extended lifespan, reduced whole body fat content and increased mitochondrial biogenesis. In mammals, whole body deletion of the mammalian Indy homolog (mIndy, Slc13a5) increased energy expenditure and protected mice from diet and aging induced obesity and insulin resistance. Here, we address the role of neuronal mIndy in energy homeostasis. We generated a neuronal mIndy knockout (NINKO) mouse model by crossing mIndy-floxed to NestinCre mice. Deletion of mIndy in neurons led to an increase in energy expenditure compared to NestinCre mice after 8 weeks of high fat diet (HFD) feeding (average 24h EE: NestinCre: 11.5±0.5 kcal/h/kg lean mass (lm); NINKO: 13.6±0.6 kcal/h/kg lm; p&lt;0.001). The respiratory exchange ratio decreased from 0.78±0.01 in NestinCre mice to 0.77±0.01 in NINKO mice during the light phase (p&lt;0.001), indicating augmented lipid oxidation in NINKO mice. Body temperature increased in NINKO compared to NestinCre mice (NestinCre: 37.0±0.1°C, NINKO: 37.3±0.1°C at 6pm; p&lt;0.05). Fat mass was reduced and lean mass increased significantly in NINKO mice (NestinCre: 60±1% lm, 31±1% fat mass; NINKO: 63±1% lm, 27±1% fat mass after 8 weeks of HFD feeding; p&lt;0.05). Hyperinsulinemic-euglycemic clamp studies showed improved insulin sensitivity in NINKO mice (steady state GINF NestinCre: 26±2 mg/kg/min; NINKO: 34.6±2 mg/kg/min; p&lt;0.05). Together, these data suggest that neuronal mIndy is a critical regulator of energy and glucose homeostasis in mammals. Further studies will address the mechanisms involved in the effect.

Disclosure
A. Kurzbach: None. D.M. Willmes: None. T. Schumann: None. C. Henke: None. N. El-Agroudy: None. A. Kleinridders: None. A.L. Birkenfeld: None.
Transient Hyperglycemia Alters Pancreatic Function and Peripheral Insulin Signaling in Preterm Baboons
Authors: BLANCO CYNTHIA , QUINN AMY , WINTER LAURYN A. , VALENTINE JOE , MUSI NICOLAS , DEFRONZO RALPH A. 
Published: June 2018

Background: Premature infants develop transient hyperglycemia and insulin resistance. Hyperglycemia is not treated by intensivists to avoid caloric restriction and promote growth.
Objective: To determine the effects of transient hyperglycemia on endocrine pancreas, skeletal muscle and liver at early stages of development in preterm baboons.
Methods: Baboons were delivered prematurely (67% gestation; n=6) via c-section and ventilated for 14 days or sacrificed immediately after birth (n=6). Preterm ventilated animals were randomly assigned to tight glucose control (EUG; serum glucose 50-100mg/dL) or hyperglycemia (HYPER; serum glucose 150-250 mg/dL) from day of life (DOL) 0-5; tight glucose control thereafter. Hyperglycemic (HG) clamps were performed on DOL6 and DOL14. IHC was done for α-β-δ cells in pancreas tissue. Muscle and liver mRNA expression and protein content of key insulin signaling molecules were measured.
Results: HYPER baboons had higher serum glucose compared to EUG (183±61 vs. 69±24 mg/dL, p&lt;0.01) from DOL 0-5, and similar glucose from DOL 6-14. During the HG clamps, HYPER baboons had abnormally increased insulin secretion (2.7 fold, p&lt;0.05) on DOL6, but normalized by DOL14. C-peptide was abnormally increased (3.3 fold, p&lt;0.05) on DOL6; by DOL14 the same HYPER animals had a 38% decrease in c-peptide as compared to EUG (p=0.07). The α/β cell area was decreased in HYPER animals. Akt content was increased in the liver of HYPER baboons (2.8 fold, p&lt;0.01) whereas IR/IRS and PEPCK-C didn’t change. Skeletal muscle GLUT1 was 70% decreased in HYPER animals (p&lt;0.01); INSR, IRS-1, Akt and mitochondrial oxygen consumption were similar.
Conclusion: Premature baboons exposed to transient hyperglycemia have an initial abnormal increase in insulin/c-peptide secretion followed by a decrease in c-peptide secretion a week later; alterations in α and β cell percent area are found at necropsy. Insulin signaling molecules are altered in liver/skeletal muscle of HYPER preterm baboons.

Disclosure
C. Blanco: None. A. Quinn: None. L.A. Winter: None. J. Valentine: None. N. Musi: None. R.A. DeFronzo: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc..
Relative Pancreas Volume Is Reduced in Autoantibody Negative First-Degree Relatives and Subjects with Pre–Type 1 Diabetes
Authors: CAMPBELL-THOMPSON MARTHA , ATKINSON MARK A. , FILIPP STEPHANIE L. , GURKA MATTHEW J. , BEEGLE RICHARD , SCHATZ DESMOND , HALLER MICHAEL J. ,   TYPE 1 DIABETES STUDY GROUP
Published: June 2018

Pancreatic size is significantly reduced in new-onset type 1 diabetes (T1D) patients and one study reported decreased weight in T1D-related autoantibody (AAb) positive nondiabetic organ donors. We proposed that pancreas volume (PV) could provide important information regarding progression to T1D onset. The relationship between PV and autoantibody status was determined. Study design included 4 groups: T1D patients &lt; 1 year of diagnosis; AAb+ first-degree relatives (FDR); AAb- FDR; and AAb- controls. Fasting subjects underwent pancreas magnetic resonance imaging (MRI) and images were analyzed by radiologists blinded to group. Relative PV (RPV=PV/BMI) was analyzed utilizing a linear mixed model accounting for age, gender, and family clustering with Tukey correction for multiple comparisons. A total of 223 subjects were enrolled with overall age of 19.6±10.5 years (45% males). RPV was significantly higher in controls (n=49) than AAb- FDR (n=60), AAb+ FDR (n=62 (single AAb+ n=30, multiple AAb+ n=32)) and recent onset T1D (n=52) (Figure). RPV was also significantly higher in AAb- FDR and AAb+ FDR vs. recent onset T1D (Figure). Pancreas MRI demonstrates smaller RPV in AAb- FDR than age-matched controls and patients with recent onset T1D have lower RPV than those FDR with established autoimmunity. Pancreas MRI may improve our understanding of the natural history of T1D.

Disclosure
M. Campbell-Thompson: None. M.A. Atkinson: Other Relationship; Self; Patent Issued. S.L. Filipp: None. M.J. Gurka: None. R. Beegle: None. D. Schatz: None. M.J. Haller: None.
Pharmacological Neprilysin Inhibition Improves Glucose Homeostasis in a Mouse Model of Type 2 Diabetes
Authors: PARILLA JACQUELINE H. , MONGOVIN STEVE , BARROW BREANNE , ESSER NATHALIE , ZRAIKA SAKENEH 
Published: June 2018

Neprilysin (NEP) is a ubiquitous peptidase whose plasma activity in humans and rodents increases in conditions associated with type 2 diabetes (T2D). In high fat-fed mice, increased plasma NEP activity correlates with insulin resistance and impaired beta-cell function, and we’ve shown genetic ablation of NEP ameliorates these deleterious effects, thereby decreasing glucose levels. Thus, we sought to determine whether clinically relevant, pharmacological inhibition of NEP also confers beneficial effects on glycemic status in a mouse model of T2D. Five-week old C57BL/6 mice were fed high fat diet for 3 weeks, followed by injection of low-dose beta-cell toxin streptozotocin (30 mg/kg i.p. once daily for 3 consecutive days; STZ) to induce diabetes, or vehicle (VEH) as a control. Mice were continued on high fat diet alone (CON) or supplemented with the NEP inhibitor sacubitril (48 mg/kg/day; SAC) for 8 weeks. Body weight did not differ among the 3 groups of mice at baseline (Table), and increased to a similar extent in all groups after 8 weeks of treatment. Further, both fasting and fed glucose levels were higher in STZ-CON vs VEH-CON mice after 8 weeks, but significantly lower in STZ-SAC vs STZ-CON mice.
Together, these data show that pharmacological NEP inhibition improves both fasting and fed glucose levels in a mouse model of T2D, and thus may be a useful treatment strategy in human T2D.VEH-CON (n=3)STZ-CON (n=5)STZ-SAC (n=7)Body weight (g)Baseline19.9±0.220.9±0.418.6±0.5Post-Treatment35.1±3.532.1±1.331.0±1.9Plasma glucose levels post-treatment (mg/dl)fasting145±5*314±38184±21*fed292±6*459±41317±29**p&lt;0.vs STZ-CON

Disclosure
J.H. Parilla: None. S. Mongovin: None. B. Barrow: None. N. Esser: None. S. Zraika: None.