bluuebunny/crossref_metadata_2025 huggingface dataset:
Endothelial/Nitric Oxide Regulation of Brown Adipose Tissue Activating Lipokine, 12, 13-diHOME and Its Antiatherogenic Actions
Authors: PARK KYOUNGMIN , LI QIAN , LYNES MATT , YOKOMIZO HISASHI , SHINJO TAKANORI , ST-LOUIS RONALD , FU JIALIN , RASK-MADSEN CHRISTIAN , TSENG YU-HUA , KING GEORGE L.
Published: June 2018

Activation of brown adipose tissue (BAT) has been shown to decrease atherosclerosis due to its systemic actions to improve insulin sensitivity and facilitate weight loss. However, the direct effect of BAT cytokines on vascular arterial function and atherosclerosis has not been studied. We have reported that enhancing insulin’s action on the endothelial cells (EC) by overexpressing IRS1 to the EC on ApoE-/- background (ECIRS1/ApoE-/- mice) greatly increased insulin induced NO production and decreased atherosclerosis. ECIRS1 mice exhibited significant increases in BAT mass and activation when exposed to cold temperature (5°C), in parallel with elevation of BAT lipokine, 12,13-diHOME levels at basal, regular chow (RD) or high fat diet (HFD) compared to wild type mice (WT) by 188±33% and 187±39%, respectively, (P<0.01). Recently, 12,13 diHOME has been reported to activate BAT (Nat. Med, 2017. Elevation of 12, 13 diHOME induced by cold temperature was inhibited by L-NAME, an inhibitor of NO. In EC, the addition of 12,13-diHOME increase pAkt from 1-100nM, but without affecting peNOS and pErk. However, oxLDL-induced pErk activity and VCAM-1 expression were reduced in 12,13-diHOME (1nM) treated EC. Further, 12,13-diHOME also increased intracellular calcium concentration with parallel elevation in NO production in EC. Functionally, 12,13-diHOME(1nM-10nM) increased vascular relaxation in myography experiments significantly by 7.5%-24%. Using antibody arrays for assessing the effects of 12,13-diHOME on NO production in EC, signaling studies showed 12,13-diHOME activated mTOR, CREB and HSP27 (by 50, 2.5, and 4 fold, respectively) and down-regulated tyrosine-protein kinase (HCK) and GSK3α/β (by 30% and 26%, p<0.05) in EC. These studies for the first time showed that insulin’s action in EC can regulate BAT lipokine 12,13-diHOME expression in a positive feedback loop to increase NO and increase vasodilation with associated decrease in atherosclerosis.

Disclosure

K. Park: None. Q. Li: None. M. Lynes: None. H. Yokomizo: None. T. Shinjo: None. R. St-Louis: None. J. Fu: None. C. Rask-Madsen: Research Support; Self; Novo Nordisk A/S. Y. Tseng: Other Relationship; Self; Chugai Pharmaceutical Co., Ltd.. Research Support; Self; MedImmune. G.L. King: Research Support; Self; Sanofi-Aventis.
Fructose Consumption Induces Strain-Specific Transcriptomic Response Perturbing Different Pathways in Genetically Diverse Mouse Strains
Authors: ZHANG GUANGLIN , BYUN HYAE RAN , YING ZHE , ZHAO YUQI , GOMEZ-PINILLA FERNANDO , YANG XIA
Published: June 2018

Metabolic syndrome (MetS) predisposes individuals to type 2 diabetes mellitus and cardiovascular diseases. Epidemiological and clinical studies support fructose intake as an environmental risk for MetS and the associated metabolic diseases. To explore the role of genomic variability in determining metabolic responses to fructose, we fed three strains of mice, namely C57/B6 (B6), DBA and FVB, with 8% fructose for 12 weeks. Fructose-fed DBA mice gained a significantly higher amount of body weight and glucose intolerance from the 4th to the 12th week, while B6 and FVB showed no differences in these phenotypes over 12 weeks. In addition, elevated insulin levels were found in fructose-fed DBA and FVB mice, and cholesterol levels were uniquely elevated in B6 mice. To explore the molecular underpinnings, we applied RNA sequencing to investigate the effect of fructose on the transcriptional profiles of liver, adipose and hypothalamus tissues. Different strains showed distinct patterns of transcriptional and pathway perturbations in a tissue-specific manner. Among pathways altered in the liver tissue, fatty acid and cholesterol metabolic pathways were prominent in B6 mice, while DBA mice showed unique over-representation of pathways related to PPAR signaling pathway. In adipose tissue, pathways are more related to fatty acid metabolism and oxidation in B6 mice, whereas no metabolic pathways were found to be enriched for differential genes in DBA and FVB mice. In hypothalamus tissue, only B6 showed significant enrichment for pathways involved in protein folding, pancreatic secretion and fatty acid beta-oxidation. Using network modeling, we predicted potential key regulators of fructose response such as FGF-21 and Sqle in the liver, Cav1 and DPP-4 in adipose tissue and Fmod in the hypothalamus. Our findings provide molecular insights into the mechanisms by which fructose contributes to the development of MetS and metabolic diseases.

Disclosure

G. Zhang: None. H. Byun: None. Z. Ying: None. Y. Zhao: None. F. Gomez-Pinilla: None. X. Yang: None.
Iron-Overload Evaluation by Noninvasive Methods in Patients with Nonalcoholic Fatty Liver Disease, Overweight, and Hyperferritinemia
Authors: BRANISSO PAULA P.F. , OLIVEIRA CLAUDIA P. , LEÃO FILHO HILTON M. , SANTOS ARITANIA , LIMA FABIANA R. , MANCINI MARCIO , CARRILHO FLAIR JOSÉ , ROCHA MANOEL , CERCATO CINTIA
Published: June 2018

Introduction: Hyperferritinemia (HF) may reflect the inflammatory status of patients with NAFLD and obesity, but about 33% reflects a real hepatic iron overload. The dysmetabolic iron overload syndrome (DIOS) definition is HF, normal transferrin saturation, and mild hepatic iron overload in a patient with metabolic disorders. The gold standard for diagnosis of iron overload is the liver biopsy. As it is an invasive method, new methods are necessary. Among them, magnetic resonance imaging (MRI) is the most available one.

Methods: This study evaluated patients with HF, overweight and NAFLD. All patients were submitted to liver biopsy. MRI relaxometry (Fat/Iron analysis - 3T machine), measurement of inflammatory markers (TNF α and IL-6), analysis of the expression of ferritin light and heavy chain subunits (FTL and FTH) and serum hepcidin were held. Data were correlated with liver biopsy.

Results: 152 biopsy-proven NAFLD patients were screened but only 67 were included in this study. DIOS frequency was 37%. The cut off of ferritin levels were correlated with iron overload in liver biopsy was 284,3 ng/ml (sensibility of 74% and specificity of 84%). Hepcidin levels were higher in DIOS patients, correlating with hepatic siderosis. IL-6 and TNF α were similar among the groups. The expression of FTH and FTL were similar in role sample, although there was a tendency of FTL in iron overload group. In the other hand, FTL correlates with metabolic syndrome and abdominal circumference, while FTH correlates with in higher fat scores. The MRI was able to identify mild iron overload. The R2 * cut off level was 58,9 s -1.

Conclusions: HF may reflect iron overload when above 284,3 ng/ml; MRI using relaxometry method is accurate to evaluate mild iron overload in DIOS patients; Hepcidin correlates with iron and serum ferritin in NAFLD patients; FTL correlates with metabolic syndrome and abdominal circumference while FTH correlates with in higher fat scores.

Disclosure

P.P.F. Branisso: None. C.P. Oliveira: None. H.M. Leão Filho: None. A. Santos: None. F.R. Lima: None. M. Mancini: None. F. Carrilho: None. M. Rocha: None. C. Cercato: None.
Acute Insulin Secretory Effects of a Classic Ketogenic Meal in Healthy Subjects
Authors: BERTOLI SIMONA , SPADAFRANCA ANGELA , DE AMICIS RAMONA , LEONE ALESSANDRO , MARI ANDREA , BATTEZZATI ALBERTO
Published: June 2018

Classic Ketogenic Diet (KD) is a high-fat, low-carbohydrate diet that induces ketone body production through fat metabolism with the goal of mimicking a starvation state without depriving the body of necessary calories. KD is an established treatment of glucose transporter type 1 deficiency syndrome and drug-resistant epilepsy, and it is currently evaluated in the management of insulin resistant states as metabolic syndrome, obesity and type 2 diabetes. Insulin is required for effective storage of meal substrates, but insulin secretory rate (ISR) response after a classic ketogenic meal (cKDm) has never been investigated

We measured ISR after a cross-over administrations of a cKDm and of a Mediterranean meal (Mm) providing 2%vs60% carbohydrates, 88%vs25%fat and 10%vs15% protein, respectively of 40% of individual’s total energy requirement in 12 healthy subjects (6F/6M, 19-31 year. Venous blood was sampled at 0, 10, 20, 30, 45, 60, 90, 120 and 180min to measure glucose, insulin and C-peptide concentrations. ISR was calculated from c-peptide deconvolution and normalized to estimated body surface area

Glucose and insulin concentrations and ISR responses were markedly reduced (p<0,001 al parameters) after cKDm with respect to Mm (Figure).

For the first time we have shown that cKDm is disposed with only a minimal ISR compared to a Mm. This finding may be of interest for patients with insulin resistance and or insulin secretory defects.

Disclosure

S. Bertoli: None. A. Spadafranca: None. R. De Amicis: None. A. Leone: None. A. Mari: None. A. Battezzati: None.
Lifestyle Intervention in Senior Diabetics (LISD) Subanalysis—Autoimmune Profile in the Overweight/Obese Elderly
Authors: CUBB TRISHA , ACEVEDO-CALADO MARIA J. , CELLI ALESSANDRA , COLLELUORI GEORGIA , PHADNIS UMA D. , PIETROPAOLO MASSIMO , VILLAREAL DENNIS
Published: June 2018

Introduction: The LISD trial assesses the effects of intensive lifestyle intervention (ILI) in older adults w/T2D on glycemic control, physical function, and QoL. Within the LISD framework, we examined the autoimmune profile before and after intervention.

Methods: The LISD study is a RCT of 100 individuals w/T2D that are ≥65 year old w/BMI ≥27 who were randomized to healthy control vs. ILI. ILI included 6m of 3x weekly supervised exercise and dietary counseling followed by 6m of community exercise and dietary monitoring. The following were performed at baseline, 6m, and 12m: GAD ab, ZnT8 ab, IA-2FL ab, serum cytokines via MESO QuickPlex, and 2 hour frequently sampled OGTT.

Results: 4/100 participants were + for IA-2FL ab (M: 0.369±0.104) and none for GAD or ZNT8 ab. Compared to IA-2FL - participants, IA-2FL + participants had lower age (68 vs. 71yo; p=0.001), BMI (32 vs. 35; p=0.001), and insulin secretion (Homa-β 68.7 vs. 227.6; p=0.02 Disposition Index: 729 vs. 6049; p=0.009). There was no difference (p>0.05) in insulin sensitivity (Homa-IR 7.2 vs. 12.1; Matsuda: 2.9 vs. 2.3), hgbA1c (7.3 vs. 7.7), DM duration (15.2 vs. 13.5yr), or need for insulin therapy (1/4 vs. 38/96). 3/4 IA-2FL + participants were randomized to ILI (weight loss of -9.5 and -11.1% at 6m/12m). Changes in IA-2FL titers did not correlate w/changes in body weight or metabolic parameters.

Conclusion: It is thought that the incidence of autoimmune DM in adults has been underestimated, which has led to focus on LADA pathogenesis/prevalence in recent literature. However, the obese elderly population has yet to be examined. Some postulate that obesity/aging leads to inflammation that could be a nidus for autoimmune DM. Interestingly in this understudied population, we found that ab+ status correlates w/a lower BMI, age, and insulin secretion for the same level of glycemic control. Our study serves as a pilot to further investigate autoimmunity in terms of prevalence, phenotype, and pathogenesis of this process in the obese elderly with T2D.

Disclosure

T. Cubb: None. M.J. Acevedo-Calado: None. A. Celli: None. G. Colleluori: None. U.D. Phadnis: None. M. Pietropaolo: None. D. Villareal: None.
Continuous Remote Care Model Utilizing Nutritional Ketosis Improves Type 2 Diabetes Risk Factors in Patients with Prediabetes
Authors: MCKENZIE AMY , HALLBERG SARAH , BHANPURI NASIR H. , ATHINARAYANAN SHAMINIE J. , MCCUE JACKSON , MCCARTER JAMES P. , VOLEK JEFF , PHINNEY STEPHEN
Published: June 2018

Prediabetes (preT2D) is a major U.S. public health concern, as over 84 million adults are at greater risk of cardiovascular disease and progression to type 2 diabetes (T2D). Abnormal glucose, BMI, blood pressure, and blood lipids are risk factors for progression to T2D. The purpose of this single-arm prospective longitudinal investigation was to assess change in risk factors after one year of treatment with a continuous remote care model utilizing nutritional ketosis, behavior change, and support from a health coach, medical provider, and peers provided via an online clinic. Patients with preT2D enrolled (n=116); at 1 year, 95 participants (82%) remained active.

Results are reported for participants with measurements completed at 1 year and baseline; n varied across measures (range: 77-95). Changes from baseline to 1 year included: weight -13.1±9.5 kg (from 110.6±23.5 kg, p<0.0001), BMI -5.0±3.5 kg/m2 (from 38.9 kg/m2, p<0.0001), HbA1c -0.3±0.3% (from 5.9±0.2%, p<0.0001), fasting glucose -9±14 mg/dL (from 110±15 mg/dL, p<0.0001), systolic BP -6±14 mmHg (from 130±13 mmHg, p=0.0003), diastolic BP -3±9 mmHg (from 83±8 mmHg, p=0.0032), triglycerides -43±55 mg/dL (from 148±67 mg/dL, p<0.0001), and HDL-C +7±9 mg/dL (from 52±14 mg/dL, p<0.0001). Seventy percent (54/77) of participants lost >7% body weight. At 1 year, 51.1% (45/88) participants achieved fasting glucose <100 mg/dL (up from 24/94, 25.5% at baseline). No completer progressed to T2D, and 60.7% (54/89) achieved HbA1c <5.7% (up from 14/94, 14.9% at baseline). Most participants (56.3%, 54/96) maintained mean blood beta-hydroxybutyrate concentrations ≥0.5 mmol/L, indicating moderate adherence to nutritional advice.

These results demonstrate that patients with preT2D can be supported remotely with this continuous care model to improve risk factors associated with progression of preT2D to T2D. Ongoing research will evaluate the continued sustainability of this intervention and prevention of T2D.

Disclosure

A. McKenzie: Employee; Self; Virta Health Corp.. Stock/Shareholder; Self; Virta Health Corp. S. Hallberg: Board Member; Spouse/Partner; Atkins Nutritionals, Inc.. Employee; Self; Virta Health. Stock/Shareholder; Self; Virta Health. N.H. Bhanpuri: Employee; Self; Virta Health Corp.. Stock/Shareholder; Self; Virta Health Corp. S.J. Athinarayanan: Employee; Self; Virta Health Corp. J. McCue: Employee; Self; Virta Health Corp.. Stock/Shareholder; Self; Virta Health Corp. J.P. McCarter: Employee; Self; Virta Health Corp.. Stock/Shareholder; Self; Virta Health Corp. J. Volek: Stock/Shareholder; Self; Virta Health Corp.. Advisory Panel; Self; Atkins Nutritionals, Inc.. Other Relationship; Self; Beyond Obesity. S. Phinney: Employee; Self; Virta Health Corp.. Advisory Panel; Self; Atkins Nutritionals, Inc..
Measurement of Liver Size by Imaging Methods Unveils Fatty Liver and Hepatomegaly in Overweight Mexican-American Children
Authors: QUINTANA FERNANDO G. , CERVANTES-GONZALEZ FRANCISCO J. , WANG HONGWEI
Published: June 2018

The aim of this study was to analyze the relationship between BMI percentile and liver size and to predict the probabilities of fatty liver and hepatomegaly for overweight and obese boys and girls. 1161 records from children visiting a South Texas pediatric clinic from 2003 to 2018 were assessed. Ultrasonography was requested for patients whenever the patient was gaining excessive weight and the readings for alkaline phosphatase levels were 2 SD above the normal population or when liver enzymes were elevated, SGOT above 50/46, SGPT above 47/41, and GGT above 32/28 for boys and girls respectively. The data analysis was processed under TAMIU IRB approval #2012-01-13. The data was analyzed using logistic regression. The results were as follows. a) Boys and girls logistic regression of BMI percentile vs. Fatty Liver (n=1161, a=-11.83, Wald=49.01, df=1, p<0.05; b=0.12, Wald=43.39, df=1, p <0 .05), b) boys and girls logistic regression of BMI Percentile vs. Hepatomegaly (n=1161, a=-9.42, Wald=33.47, df=1, p<0.05; b=.085, Wald=25.73, df=1, p<0.05), c) girls logistic regression of BMI percentile vs. fatty Liver (n=450, a=-8.10, Wald=17.88, df=1, p<0.05; b=.07, Wald=13.53, df=1, p<0.05) d) girls logistic regression of BMI percentile vs. Hepatomegaly (n=450, a=-5.67, Wald=12.04, df=1, p<0.05; b=0.041, Wald=5.65, df=1, p<0.05) e) boys, Logistic regression of BMI percentile vs. Fatty Liver (n=840, a=-22.98, Wald=51.27, df=1, p<0.05; b=.23, Wald=50.58, df=1, p<0.05), f) boys logistic regression of BMI percentile vs. Hepatomegaly (n=840, a=-16.58, Wald=31.79, df=1, p <0 .05; b=.16, Wald 29.43, df=1, p<0.05). A cubic curve was also fitted between liver size and BMI percentile for each group. The results of the analysis support that the probability of fatty liver and hepatomegaly increase exponentially as BMI percentile increases, there is also a positive relationship between liver size and BMI percentile.

Disclosure

F.G. Quintana: None. F.J. Cervantes-Gonzalez: None. H. Wang: None.
Dietary Rapeseed Oil Supplementation Reduces Hepatic Steatosis in Obese Men
Authors: KRUSE MICHAEL , KEMPER MARGRIT , GANCHEVA SOFIYA , DANNENBERGER DIRK , MARKGRAF DANIEL F. , RODEN MICHAEL , PFEIFFER ANDREAS F.
Published: June 2018

Obesity is associated with nonalcoholic fatty liver disease (NAFLD) leading to increased hepatic glucose production. NAFLD is one of the most frequent liver diseases however, effective treatment is limited. Animal studies showed a reduction in hepatic steatosis with dietary alpha linoleic acid, which is highly enriched in rapeseed oil (RA). In this study we used a nutritional therapeutic approach and investigated the effect of an isocaloric diet supplemented with RA or olive oil (OL) on liver fat content, endogenous glucose production, total body insulin sensitivity and serum lipids in obese humans suffering from NAFLD. 27 obese men (BMI 30-35, age 18-65) consumed an isocaloric diet including 50 g of either RA (n=12) or OL (n=15) daily for eight weeks. Hepatic MRI, hyperinsulinemic-euglycemic clamp studies with isotope labelled glucose and blood tests were performed prior to and at the end of the study to assess liver fat content, endogenous glucose production and cholesterol and free fatty acid levels, respectively. Body fat content and BMI did not change over the time of intervention for RA and OL. At the end of the study a significant reduction in hepatic fat content (P=0.038) could be observed for RA (13.09±1.61 before vs. 11.14±1.58% after intervention) vs. OL (13.29±2.52 before vs. 15.73±2.74% after intervention). For RA, a 21% reduction (P<0.02) in serum free fatty acids was observed after eight weeks of oil consumption whereas no significant changes were seen for OL. Consuming RA resulted in a slight reduction in basal endogenous glucose production (1.71±0.15 before vs. 1.49±0.mg/kg/min after intervention, P=n.s.) compared to OL (1.66±0.before vs. 1.65±0.mg/kg/min after intervention, P=n.s.). There were no significant changes in total body insulin sensitivity and serum cholesterol levels in RA or OL. Our results demonstrate a beneficial effect of the fatty acid composition of RA on hepatic lipid production as shown by reduced hepatic fat content and free fatty acid levels.

Disclosure

M. Kruse: None. M. Kemper: None. S. Gancheva: None. D. Dannenberger: None. D.F. Markgraf: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. A.F. Pfeiffer: None.
Gut Microbiota Metabolites, Amino Acid Metabolites, and Improvements in Diabetes-Related Traits—The POUNDS Lost Trial
Authors: HEIANZA YORIKO , SUN DIANJIANYI , BRAY GEORGE , QI LU
Published: June 2018

Gut microbiota alterations may be related to insulin resistance, diabetes, and the impaired amino acid metabolism. We investigated whether changes in gut microbiota metabolite of trimethylamine N-oxide (TMAO) and its precursors (choline and L-carnitine) were associated with improvements of diabetes-related traits and diabetes-risk-related amino acids in a weight-loss diet intervention. This study included 504 obese adults who were randomly assigned to 1 of 4 energy-reduced diets varying in the macronutrient composition. We calculated changes (Δ) in TMAO, choline, and L-carnitine from baseline to 6 months after the diet intervention. Greater decreases in choline and L-carnitine were significantly (p <0.05) associated with greater improvements in fasting insulin levels and the Homeostatic Model Assessment of Insulin Resistance of insulin resistance (HOMA-IR) at 6 months. Particularly, the reduction of choline was predictive of long-term (2-year) improvements in fasting glucose (p=0.007), insulin (p=0.002), and HOMA-IR (p <0.001). We found significant interactions between dietary fat intake and ΔTMAO for changes in fasting glucose, insulin, and HOMA-IR (Pinteraction <0.05); among participants who consumed a high-fat diet, greater increase in TMAO was related to less improvements of the outcomes. In addition, ΔL-carnitine and Δcholine were also significantly related to changes in amino acids (including branched-chain and aromatic amino acids). However, the associations of ΔTMAO, Δcholine, and ΔL-carnitine with the diabetes-related traits were independent of the changes in amino acids.

In conclusion, weight-loss-diet-induced changes in TMAO, choline, and L-carnitine were significantly associated with the improvements in glycemia and insulin sensitivity, regardless concurrent changes in diabetes-risk related amino acids. Dietary fat intake may modify the associations of changes in TMAO with the improvements of diabetes-related traits.

Disclosure

Y. Heianza: None. D. Sun: None. G. Bray: Advisory Panel; Self; Herbalife International of America, Inc., Novo Nordisk A/S. L. Qi: None.
Lipocalin Prostaglandin D2 Synthase (LPGDS) Levels following Sleeve Gastrectomy and a Very-Low-Calorie Diet (VLCD)—A Pilot Study
Authors: LAU RAYMOND G. , KUMAR SUNIL , LEE JENNY , HALL CHRIS , PALAIA THOMAS , ISLAM SHAHIDUL , BRATHWAITE COLLIN , RAGOLIA LOUIS
Published: June 2018

Background: Lipocalin prostaglandin D2 synthase (LPGDS) is a bile acid binding protein that has been found to have a significant role in glucose metabolism and appetite. In performing sleeve gastrectomy (SG) and gastric bypass in rodent models, we have also demonstrated LPGDS appears to have an important role in the beneficial metabolic effects seen after surgery. We have sought to correlate if LPGDS has a significant clinical effect in humans for surgical weight loss.

Methods: Serum LPGDS levels were obtained in patients undergoing SG before, and then one month following surgery. Serum LPGDS was also measured in subjects undergoing a very low calorie diet (VLCD) program before, and then one month following the start of the program. LPGDS levels were measured by ELISA and analyzed.

Results: Subjects that underwent surgical loss went from 304.45 +/-74 pounds before surgery to 271.4 +/- 70 pounds one month following surgery. Subjects that underwent VLCD went from 273.1 +/- 65 pounds before the program to 255 +/-61 pounds one month after starting the program. LPGDS levels for surgical weight loss increased from 579.9 +/-161 ng/mL before the program to 694.6 +/- 448 ng/mL one month after surgery. LPGDS for VLCD was 583.1 +/- 187 ng/mL before the program and 598.4 +/- 165 ng/mL one month after starting the program.

Conclusion: LPGDS levels appear to increase after sleeve gastrectomy but not VLCD, although this trend is not statistically significant. Further study is needed to confirm this trend.

Disclosure

R.G. Lau: None. S. Kumar: None. J. Lee: None. T. Palaia: None. S. Islam: None. C. Brathwaite: None. L. Ragolia: None.
Liraglutide as an Additional Treatment to Insulin in Patients with Type 1 Diabetes Mellitus—A 52-Week Randomized Double-Blinded Placebo-Controlled Clinical Trial
Authors: DANDONA PARESH , GHANIM HUSAM , KUHADIYA NITESH D. , SHAH TANVI , HEJNA JEANNE M. , MAKDISSI ANTOINE , BATRA MANAV , CHAUDHURI AJAY
Published: June 2018

We have previously demonstrated that a 12-week addition of liraglutide to insulin therapy in patients with type 1 diabetes (T1D) results in an improvement in glycemic control, weight loss and a reduction in systolic blood pressure (SBP). We have now conducted a 1 year randomized study investigating effects of liraglutide in patients with T1DM. All patients had T1D for at least one year, were on insulin therapy and had no detectable c-peptide in plasma (mean BMI: 28.9±1.4kg/m2, mean HbA1c: 7.82±0.16%, mean age: 46.7±1.9 years, mean age of T1D diagnosis: 22.3±1.7 years). They were randomized to receive placebo, (n=20) or 1.8mg Liraglutide (n= 26) daily for 52 weeks. Continues glucose monitoring (CGM) was performed for 4 weeks before and at end of treatment. At the end of 52 weeks treatment with liraglutide, placebo adjusted HbA1c fell significantly by 0.57±0.17% (p=0.006 vs. placebo) from 7.920.15± to 7.45±0.12% (p=0.009). Weekly placebo adjusted average blood glucose fell by 15±4mg/dl (p=0.014 vs. placebo) from 174±5 to 156±6mg/dl (p=0.021) and fasting weekly glucose fell by 8±7mg/dl (p=0.075 vs. placebo) from 165±7 to 153±9mg/dl (p=0.032). There was no change in reported incidences of hypoglycemia and no change in percent time spent below 70mg/dl based on CGM. Total insulin dose did not alter. There was a significant weight loss by 2.5±0.9kg (placebo adjusted, p=0.041 vs. placebo) from 83.6±4.1 to 80.5±4.0kg (p=0.01) in the liraglutide group. Placebo corrected SBP also fell following liraglutide treatment by 9±3mmHg (p=0.031) from 128±3 to 122±3 mmHg while placebo adjusted diastolic BP fell by 5±1mmHg from (79±2 to 75±2mmHg). We conclude that the addition of liraglutide to insulin treatment in type 1 diabetes significantly reduced HbA1c, mean and fasting blood glucose, blood pressure and body weight without significant increase in hypoglycemia.

Disclosure

P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. H. Ghanim: None. N.D. Kuhadiya: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk A/S, Janssen Scientific Affairs, LLC.. Advisory Panel; Self; AstraZeneca. Consultant; Self; Dexcom, Inc.. T. Shah: None. J.M. Hejna: None. A. Makdissi: Speaker's Bureau; Self; Eli Lilly and Company. M. Batra: Speaker's Bureau; Self; Eli Lilly and Company. A. Chaudhuri: Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc..
Prolongation of Allograft Survival by Intrathymic Introduction of Allogeneic Thymic Epithelial Cells
Authors: PRADHAN ISHA , WONG-NOONAN STEPHANIE , BERTERA SUZANNE , LAKOMY ROBERT J. , COHEN HENRY , WELLS DERRICK , TRUCCO MASSIMO , FAN YONG
Published: June 2018

Thymic epithelial cells (TECs), the primary stromal population in the thymus, are critical to establish the microenvironments required for generating self-tolerant, pathogen-responsive T cells. However, due to the inaccessibility of the thoracic cavity and the fragility of TECs, manipulating the thymus to modulate adaptive immune responses remains challenging. We developed a novel surgical procedure that allowed access to thymus glands for intrathymic injection (ITI), without the need to cut the manubrium of the sternum bone. Horizontal cuts of the muscle layers between the first and second bones of the rib cage expose the thymus with minimal side effects. This novel ITI procedure enabled us to implant 16.5-day embryonic TECs into an adult syngeneic recipients’ thymus. Long-term survival and colonization of the implanted TECs was observed via live imaging, flow cytometry, and immunohistochemistry. We further investigated if introduction of allogeneic TECs in the thymus promote negative selection against allo-reactive T cells and induce donor-specific immune tolerance. We engrafted B6 islets under the kidney capsules of chemically induced diabetic Balb/C mice, preconditioned with T-cell depletion sera and intrathymic injection of B6 16.5-day embryonic TECs. Prolonged survival of the transplanted islets was observed compared to sham-operated controls. Mixed lymphocyte reaction experiments further showed dampened T cell proliferation responses against donor B6 antigens. Moreover, increased levels of Foxp3+ T-regulatory cells were detected in Balb/C recipients with ITI of B6 TECs, suggesting that implanted TECs could also promote the generation of alloantigen-specific T regulatory cells in addition to facilitating negative selection of donor antigen-reactive T cells. Our results suggest that intrathymic transplantation of TECs could be an effective way to induce donor-specific immune tolerance with limited general immune suppression.

Disclosure

I. Pradhan: None. S. Wong-Noonan: None. S. Bertera: None. R.J. Lakomy: None. H. Cohen: None. D. Wells: None. M. Trucco: None. Y. Fan: None.
Elevated ANGPTL5 Level in the Circulation of Obese and Type 2 Diabetic People
Authors: ABU-FARHA MOHAMED , ALHASAWI NOUF , QADDOUMI MOHAMMAD , ALMULLA FAHD , TUOMILEHTO JAAKKO , ALANBAEI MUATH , ABUBAKER JEHAD
Published: June 2018

Angiopoetin like protein family is composed of eight members that are involved in regulating various metabolic processes. ANGPTL5 is one of the members of this family that is mainly expressed in the heart and was showed to stimulate the expansion of human cord blood hematopoietic stem cell ex-vivo. This study was designed to investigate the expression level of this protein in the plasma of obese and diabetic people.

Methods: A total of 204 people were enrolled in this study including 109 nondiabetic and 95 type 2 diabetics. The nondiabetic people included 70 non-obese (BMI<30 Kg/m2) and 39 obese people (BMI<30 Kg/m2), while the diabetic people included 34 non-obese and 61 obese people. ANGPTL5 plasma level was measured by ELISA.

Results: In this study we showed that ANGPTL5 level was increased in the plasma of diabetic people (5.78±2.59 ng/mL) compared to nondiabetics (4.42 ± 2.32 ng/mL) (p-Value<0.0001). Obese nondiabetics had a significantly higher level of ANGPTL5 (5.12±2.23 ng/mL) compared to non-obese people (4.02 ± 2.27 ng/mL) (p-Value=0.029). Obese diabetic had higher level of ANGPTL5 compared non-obese yet did not reach significance (p-Value=0.064). ANGPTL5 was significantly associated with glycated haemoglobin 1C and insulin resistance as measured by HOMA-IR.

Conclusion: Our data shows for the first time that ANGPTL5 was increased in diabetic and obese people. Given its unique tissue expression in the heart, ANGPTL5 might modulate its response to insulin resistance through its interaction with other proteins including other ANGPTL proteins. Further analysis will be required to better understand the interaction between ANGPTL5 and other metabolic related biomarkers to shed more light on its role in diabetes and obesity.

Disclosure

N. Alhasawi: None. M. Qaddoumi: None. F. Almulla: None. J. Tuomilehto: None. M. Alanbaei: None. J. Abubaker: None.
Lactogens Prevent ER Stress-Induced ß-Cell Death and Diabetes
Authors: LI ROSEMARY , HAMPTON ROLLIE F. , KONDEGOWDA NAGESHA GUTHALU , FENUTRIA RAFAEL , VASAVADA RUPANGI C.
Published: June 2018

ER stress is highly relevant in the context of diabetes, as inducers of β cell death and dysfunction implicated in the disease - including proinflammatory cytokines and glucolipotoxicity - are known to impair ER function. Previous work has shown that prolactin (Prl) and placental lactogen (PL), which bind to the same receptor (Prl-R), are important for β cell function and proliferation, and enhance survival against cytokines and glucolipotoxicity. Here, we examine the effect of Prl/PL directly on ER stress and the associated unfolded protein response (UPR) in the β cell. ER stress was induced in vitro via tunicamycin in INS1, primary mouse, and primary human β cells, concurrent with Prl/veh treatment. Expression of ER stress and UPR associated genes was measured via qRT-PCR and preliminarily via WB, and insulin-TUNEL co-staining was used to assay for β cell death. As an in vivo model, heterozygous Akita mice - a well-established β cell ER stress model which becomes diabetic by 4 weeks of age - were bred to single-transgenic mice overexpressing PL in the β cell. Prl increases survival of INS1, primary mouse and human β cells against ER stress-mediated cell death in vitro (2.34±0.19% TM vs. 0.73±0.19% TM+Prl, human). Differences in mRNA expression point towards modulation of the PERK/IRE1 UPR arms. Non-Tg Akita mice quickly become and remain hyperglycemic/diabetic, while overexpression of PL in the β cells of these mice significantly improves glycemia in males (663±29mg/dL non-Tg vs. 327±37mg/dL Tg, 12 weeks) and results in normoglycemia in females. In vivo GSIS at 12 weeks shows a trend towards restoration of β cell function in Tg compared to non-Tg Akita mice. Males at this age exhibit improved β cell mass (0.28±0.12mg non-Tg vs. 2.29±0.44mg Tg), with similar trends in β cell proliferation. Taken together, these data demonstrate that Prl/PL can prevent and protect against ER stress in the β cell, in vitro and in vivo. As ER stress is highly relevant to diabetes, modulation of the lactogenic pathway could present a novel therapy for this disease.

Disclosure

R. Li: None. R.F. Hampton: None. N. Guthalu Kondegowda: None. R. Fenutria: None. R.C. Vasavada: None.
A Phase 3 Comparison of a Novel Liquid Glucagon Autoinjector to Glucagon Emergency Kit for the Symptomatic Relief of Severe Hypoglycemia
Authors: CHRISTIANSEN MARK P. , CUMMINS MARTIN J. , STEVEN J. PRESTRELSKI , STRANGE POUL
Published: June 2018

Objective: A novel ready-to-use stable liquid glucagon autoinjector (GAI; Xeris Pharmaceuticals), was evaluated for relief of symptoms during rescue treatment of severe hypoglycemia.

Research Design and Methods: A randomized, controlled, double-blind, crossover clinical trial was conducted in 80 adults with T1D (mean age 43.6 years) to compare subcutaneous 1 mg doses of GAI vs. Glucagon Emergency Kit (GEK; Eli Lilly) for the treatment of insulin-induced severe hypoglycemia. Serial assessments of 4 autonomic and 4 neuroglycopenic symptoms and sensation of hypoglycemia were performed at each treatment visit.

Results: The mean time to symptom relief was comparable between GAI and GEK for both autonomic symptoms (15.4±12.1 min and 14.2±9.7 min, p=NS), and neuroglycopenic symptoms (16.3±10.9 min and 13.9±9.4 min, p=NS). Mean time to resolution of the global feeling of hypoglycemia was also similar between groups. The incidence of all AEs was low in both groups; the most commonly reported AE was nausea (GAI 20.5%, GEK 12.7%, p=NS).

Conclusions: The prompt relief of neurologic symptoms is critical in the rescue of severe hypoglycemic emergencies. GAI achieved both autonomic and neuroglycopenic symptom relief during induced severe hypoglycemia, and was safe and well tolerated. These results demonstrate that ready-to-use GAI is a viable alternative to GEK.

Disclosure

M.P. Christiansen: Research Support; Self; Dexcom, Inc., Insulet Corporation, Medtronic MiniMed, Inc., Abbott, Novo Nordisk Inc., Senseonics, REMD Biotherapeutics, Xeris Pharmaceuticals, Inc. M.J. Cummins: Employee; Self; Xeris Pharmaceuticals, Inc. S.J. Prestrelski: Employee; Self; Xeris Pharmaceuticals, Inc. P. Strange: Other Relationship; Self; AstraZeneca. Consultant; Self; Valeritas, Inc.. Stock/Shareholder; Self; Valeritas, Inc..
BioChaperone Glucagon (BCG), a Stable Ready-to-Use Liquid Glucagon Formulation, Is Well Tolerated and Quickly Restores Euglycemia after Insulin-Induced Hypoglycemia
Authors: GLEZER STANISLAV , HOVELMANN ULRIKE , TENG SOPHIE , LAMERS DANIELA , ODOUL MARION , CORREIA JOSÉ , ZIJLSTRA ERIC , GAUDIER MARTIN , SOULA OLIVIER , DURACHER DAVID
Published: June 2018

BCG is a stable, ready-to-inject, aqueous formulation of human glucagon for hypoglycemia rescue therapy. In this randomized, double-blind, crossover trial we investigated the safety and efficacy of two BCG formulations vs. a commercially available glucagon (GlucaGen® HypoKit, GEN) in 27 patients with type 1 diabetes who received single subcutaneous doses of 1 mg of BCG1, BCG2 or GEN under insulin-induced hypoglycemic conditions (plasma glucose (PG)<60 mg/dl). Both BCG formulations were safe and well tolerated with the most frequent adverse event being mild nausea with both BCGs and GEN. Both BCGs quickly restored PG of ≥ 70 mg/dl after hypoglycemia (BCG1 11.5±5.0 min; BCG2 10.0±3.5 min; GEN 7.3±1.8 min, p<0.001 vs. BCG1 and BCG2). PG≥70 mg/dl was reached within 30 minutes by all but one patient with both BCGs and the mean PG increase at 15 minutes was 29±17 mg/dl with BCG1, 36±16 mg/dl with BCG2 and 47±11 mg/dl with GEN (p<0.001 vs. BCG1 and BCG2).

In conclusion, the BioChaperone technology allows the formulation of stable ready-to-use liquid formulations of human glucagon suited for rescue therapy of severe hypoglycemia with only slightly slower effects than GEN.

Disclosure

S. Glezer: Stock/Shareholder; Self; Sanofi. Stock/Shareholder; Spouse/Partner; Sanofi. Employee; Self; ADOCIA, Novo Nordisk Inc.. Employee; Spouse/Partner; Pfizer Inc., Teva Pharmaceutical Industries Ltd.. Stock/Shareholder; Spouse/Partner; Teva Pharmaceutical Industries Ltd.. U. Hovelmann: None. S. Teng: Employee; Self; ADOCIA. D. Lamers: None. M. Odoul: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. J. Correia: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. E. Zijlstra: Speaker's Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Novo Nordisk A/S. M. Gaudier: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. O. Soula: Board Member; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. Employee; Spouse/Partner; ADOCIA. D. Duracher: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA.
Mediators of the Racial Disparity in Diabetes Incidence—The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study
Authors: CARSON APRIL P. , LONG D. LEANN , CHERRINGTON ANDREA , DUTTON GARETH R. , HOWARD VIRGINIA J. , BROWN TODD , MOY CLAUDIA , CUSHMAN MARY , SAFFORD MONIKA , HOWARD GEORGE
Published: June 2018

Objective: To identify the contribution of individual and neighborhood factors to the racial disparity in diabetes incidence among older adults.

Methods: This study included 7,304 black and white adults, aged 45-91 years at baseline (2003-07), without prevalent diabetes. Incident diabetes was assessed at the 2nd in-home exam (2014-16) using plasma glucose or use of diabetes medications. Modified Poisson regression, stratified by sex, was used to obtain risk ratios. Mediation analyses using the change in beta coefficient method and bootstrapping were done to evaluate the contribution of socioeconomic, anthropometric, lifestyle, clinical and neighborhood factors, grouped separately and all factors combined.

Results: The risk of diabetes was 75% higher for black women compared with white women and 35% higher for black men compared with white men (Table). Among men, only lifestyle factors were significant mediators of the racial disparity. In contrast, among women, all grouped factors, except clinical, were significant mediators. When taking into account all factors combined, only 4.2% and 28.1% of the racial disparity was explained for men and women, respectively.

Conclusion: Although the factors underlying the racial disparity varied by sex, the excess diabetes risk for black vs. white adults remained after accounting for individual and neighborhood factors.

Disclosure

A.P. Carson: Research Support; Self; Amgen Inc.. D. Long: None. A. Cherrington: Advisory Panel; Self; AstraZeneca. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Novo Nordisk Inc.. G.R. Dutton: None. V.J. Howard: None. T. Brown: Research Support; Self; Amgen Inc., AstraZeneca. C. Moy: None. M. Cushman: None. M. Safford: None. G. Howard: None.
Analysis of Transcriptome Data from 261 Individual Laser-Captured Islets from Nondiabetic, Autoantibody-Positive, and Type 1 Diabetic Organ Donors
Authors: CAMPBELL-THOMPSON MARTHA , BUTTERWORTH ELIZABETH A. , LENCHIK NATALIYA I. , ATKINSON MARK A. , MATHEWS CLAYTON E. , GERLING IVAN C.
Published: June 2018

The purpose of this study was to obtain comprehensive gene expression datasets from a large number of individual islets, with defined pathological phenotypes, from organ donors with different clinical stages of type 1 diabetes. Here we will present results from an analysis that compared “normal” (Ins+CD3-) islets from the 3 clinical phenotypes: Autoantibody negative nondiabetic (C), Autoantibody positive nondiabetic (AB) and type 1 diabetic (T1D). We obtained pancreatic tissue from 43 male and female nPOD donors with the 3 clinical phenotypes (C=16, AB=11, T1D=16). Staining of islets for both insulin and CD3 resulted in the following histologic subtypes of the 261 islets collected and analyzed for gene expression: Ins+CD3- (n=147), Ins+CD3+ (n=78), Ins-CD3+ (n=12), and Ins-CD3- (n=23). The gene expression profiles of these 261 individual islets were obtained using Affymetrix HTA 2.0 arrays. We compared gene expression profiles of the 147 islets that were Ins+CD3- from each of the 3 organ donor types. The number of transcripts differentially expressed by >1.5 fold and p<0.001 (Student’s t-test with FDR<0.05) were as follows: C vs. AB=448; C vs. T1D=240; AB vs. T1D=387. Those gene lists were subjected to a data mining workflow. The 448 transcripts differing between Ins+CD3- islets of C and AB organ donors were dominated by non-coding RNA (33%). Islets from AB donors had reduced transcripts associated with islet regeneration, cell replication, and immune responses. The 387 transcripts differing between Ins+CD3- islets of AB and T1D organ donors expressed increased levels of beta cell specific transcripts and markers of immune responses in T1D islets. A number of oxidative phosphorylation gene transcripts were lower in T1D islets. The 240 transcripts differing between Ins+CD3- islets of C and T1D organ donors demonstrated reduced levels of beta cell specific transcripts but increased HLA class II transcripts in T1D islets

Disclosure

M. Campbell-Thompson: None. E.A. Butterworth: None. N.I. Lenchik: None. M.A. Atkinson: Other Relationship; Self; Patent Issued. C.E. Mathews: None. I.C. Gerling: None.
Food Insecurity in Older Adults with Diabetes
Authors: SCHROEDER EMILY B. , ZENG CHAN , STERRETT ANDREW , KIMPO TINA K. , PAOLINO ANDREA R. , STEINER JOHN
Published: June 2018

Background: Food insecurity (FI) among individuals with diabetes has been associated with both hypoglycemia and worse glycemic control, but studies of elderly insured populations are lacking.

Methods: As part of its Medicare Annual Wellness Visit, Kaiser Permanente Colorado (KPCO) initiated a member survey in January 2012 that included a question about FI (“Do you always have enough money to buy the food you need?”). We combined this survey with electronic health record data and other data to conduct a nested case-control study of FI among KPCO members ≥ 65 years with diabetes. Of 32,666 members with diabetes, 10,052 (31%) completed a survey. Of those, the 742 (7.4%) who had FI were matched 1:3 based on date of the survey (± 7 days) to 2,226 individuals without FI.

Results: Individuals with FI were slightly younger (mean age ± SD of 73.2 ± 6.1 vs. 73.9 ± 6.8), and were more likely to be female (60.6% vs. 46.8%), non-white (36.8% vs. 21.8%), living without a partner (49.6% vs. 33.0%), have less than high school education (21.2% vs. 9.0%), and have Medicaid (16.4% vs. 3.2%). Individuals with FI reported higher frequency of fair or poor general health (29.2% vs. 16.7%) and quality of life (23.6% vs. 10.5%), and were more likely to eat ≤ 2 meals a day (19.0% vs. 8.9%). Rates of hypertension and chronic kidney disease were similar, but individuals with FI were more likely to have depression on PHQ2 screening (24.8% vs. 9.1%). Individuals with FI were more likely to be taking any diabetes medication (70.5% vs. 63.6%) or insulin (25.4% vs. 19.4%), have an emergency department (ED) visit (19.0% vs. 13.9%) or hospitalization in the prior year (8.6% vs. 7.0%), and have an A1c ≥ 9% (11.2% vs. 5.8%). Mean A1c for those with FI was 7.4 ± 1.4 and those without FI was 7.1 ± 1.1. ED visits or hospitalizations for hypoglycemia or hyperglycemia were infrequent (≤10) in both groups.

Conclusions: In this insured elderly population with diabetes, food insecurity was associated with higher health care utilization and A1c levels. Strategies to address FI in individuals with diabetes deserve further evaluation.

Disclosure

E.B. Schroeder: None. C. Zeng: None. A. Sterrett: None. T.K. Kimpo: None. A.R. Paolino: None. J. Steiner: None.
Selectively Agonizing Treg in Type 1 Diabetes with IL-2 Muteins
Authors: KHORYATI LILIANE , KUMARI SWARNIMA , NGUYET PHAM THI MINH , BOGDANI MARIKA , GAVIN MARC
Published: June 2018

Regulatory T cells (Treg) play a pivotal role in maintaining self-tolerance. For their development and function, Treg rely on interleukin-2 (IL-2) and efficiently compete with other immune cells for IL-2 by expressing the highest levels of the IL-2 receptor alpha-chain (IL-2Ra or CD25). Treg deficiencies and alterations of the IL-2 pathway have been reported in several autoimmune diseases including type 1 diabetes (T1D) where the loss of self-tolerance leads to the destruction of insulin-producing beta cells in the pancreas. Low-dose IL-2 therapy has been shown to be successful in several autoimmune and inflammatory conditions; however, the potential for IL-2 to activate pro-inflammatory immune cells raises concerns regarding its widespread utility, particularly in type 1 diabetes (T1D) where pathogenic autoreactive T cells are activated by IL-2. Hence, there is a need to develop novel IL-2 based therapeutics with enhanced Treg-specificity. We have generated a series of Fc-fused murine IL-2 muteins (Fc.IL-2 mutein) to optimize Treg-selectivity, tissue distribution and PK. Twenty-eight Fc.IL-2 muteins were screened for their signaling potency and surface retention on Treg. Eight of the mutein candidates, showing a reduced signaling in Treg but prolonged association with CD25, were further characterized in vitro. Two of the weakest muteins were tested in vivo and showed a greater enrichment and Ki-67 induction in Treg compared to wild type (WT) IL-2, and less effect on CD4+ T effector cells, CD8+ cells and NK cells. Finally, in the non-obese diabetic mouse model of T1D, we observed a significantly improved protection in mice treated infrequently with Fc.IL-2 mutein compared to WT IL-2, and, unexpectedly, differences in efficacy between WT and mutein were more pronounced at a very high dose level. Altogether, our data suggest that Fc.IL-2 mutein treatment represent a safer and more efficient alternative for the WT IL-2 therapy, allowing a selective Treg enrichment and a targeted control of the autoimmune response.

Disclosure

L. Khoryati: None. S. Kumari: None. T. Pham: None. M. Bogdani: None. M. Gavin: None.