bluuebunny/crossref_metadata_2025 huggingface dataset:
Siah2 Expression in Adipocyte Progenitor Cells
Authors: DANG THANH , KILROY GAIL E. , TAYLOR JESSICA L. , YU YONGMEI , FLOYD ELIZABETH
Published: June 2018

Obesity-related insulin resistance is associated with adipose tissue inflammation and visceral adipose tissue expansion via adipocyte hypertrophy and impaired recruitment of new progenitor cells to undergo adipogenesis (hyperplasia). Deletion of the ubiquitin ligase Seven-in-absentia homolog 2 (Siah2) in obese mice significantly reduced adipose tissue inflammation and insulin resistance compared to obese wild type mice. However, larger adipocyte size accompanied this phenotype and subsequent experiments with adipose tissue stromal vascular fraction (SVF) cells showed adipogenesis required Siah2. In an earlier study, we found Siah2 affects adipogenesis by enhancing gene expression of the PPARγ coactivator, Zfp423 via proteasome-dependent degradation of ZFP521, a transcriptional repressor of Zfp423. ZFP423 is an early marker of preadipocyte determination that is expressed in adipocyte progenitor cells. Although Siah2 mediates adipogenesis and is highly expressed in the adipose tissue stromal vascular cell fraction, cell-specific expression of Siah2 in adipose tissue is not well characterized. We found that Siah2 is highly expressed in macrophage. RNA-seq and microarray data from the Immunological Genome Project (Immgen.org) also reported Siah2 expression in lymphocytes. To identify Siah2 expression profile in adipose tissue, unsorted cells and magnetically sorted macrophage, T-cell, B-cell, and SCA-1 positive progenitor cells from mouse adipose tissues SVF were analyzed for Siah2 expression. In parallel, in situ hybridization RNAscope of fat pads was employed to inspect Siah2 mRNA localization in adipose tissue. Since our evidence indicates Siah2 acts upstream of ZFP423, we predict Siah2 is expressed in adipocyte progenitor cells as well as immune cells in adipose tissue. This work will provide the groundwork to better understand how Siah2 controls commitment of progenitor cells to the adipocyte lineage and links obesity to adipose tissue inflammation and insulin resistance.

Disclosure

T. Dang: None. G.E. Kilroy: None. J.L. Taylor: None. Y. Yu: None. E. Floyd: None.
Comprehensive Analysis of the Characteristics and Differences in Adult and Newborn Brown Adipose Tissue
Authors: ZHANG CHUANHAI , YIN RUILI , SHENG YAO , YANG CUI , HE XIAOYUN , XU WENTAO , HUANG KUNLUN
Published: June 2018

Brown adipose tissue (BAT) plays an important role in maintain body temperature, treating obesity and diabetes. However, the amount and activity of BAT in adults (a-BAT) is very low, while the BAT in infant (i-BAT) is abundant and with strong activation. The a-BAT and i-BAT vary greatly in activation, but the characteristics and differences at the molecular level have not yet been fully revealed. We examined the changes in the mRNA expression of UCP1 and thermogenic genes genes such as PRDM16, PGC1α, CPT1α and CPT1β in a-BAT and i-BAT of mouse. We found that, compared with i-BAT, both UCP1 and thermogenic genes were significantly decreased in a-BAT. Western blot data further confirmed the result. Transmission electron microscope (TEM) and scanning electron microscopy (SEM) also showed a clear distinction in a-BAT and i-BAT. Compared with a-BAT, the lipid droplet is less and mitochondrial density is higher in i-BAT. In addition, the characteristics and differences of a-BAT and i-BAT were comprehensively analyzed by mRNA, microRNA, LncRNA, circRNA, DNA methylation and proteome. Thousands of signifcantly changed lncRNAs and mRNAs as well as proteins were identifed. Compared with i-BAT, we found hyper 383 and hypo 503 DMR related genes in a-BAT by differentially methylated region (DMR) analysis. What’s more, we found 1221 new circRNA in i-BAT and 1991 new circRNA in a-BAT and there were significant higher expression of circRNA in a-BAT compared with i-BAT. Furthermore, we constructed correlated expression networks circRNA-mRNA-lncRNA-methylation with bioinformatics methods. Co-expression analysis showed lnc-NONMMUG024827 and lnc-NONMMUG020075 expression is correlated with Fatty acid metabolism genes, including FASN and ACADA. Taken together, these results provide a better understanding of BAT function and development, and show a novel perspective roles of i-BAT or making a-BAT achieve the better activation and dynamic state just like i-BAT through the epigenetic modification.

Disclosure

C. Zhang: None. R. Yin: None. Y. Sheng: None. C. Yang: None. X. He: None. W. Xu: None. K. Huang: None.
Adipose Tissue Transferrin and Insulin Resistance
Authors: MCCLAIN DON , SHARMA NEERAJ K. , LORENZO FELIPE , JAIN SHALINI , LANGEFELD CARL D. , COMEAU MARY E. , SALAYE LIPIKA , DAS SWAPAN K.
Published: June 2018

Iron is an important micronutrient involved in several metabolic processes, and excessive iron is a risk factor for insulin resistance (IR) and diabetes. To define the genetic regulation of iron metabolism and its role in IR, we used gene expression, genotype, and insulin sensitivity data from an African American cohort (AAGMEx, N=256). Among the genes in a manually curated list of 62 transcripts representing iron homeostasis genes, expression of 32 in adipose tissue showed significant correlation with SI (p<0.01). The expression levels of transferrin (TF, β= 0.29, p=7.84 x 10-6) and ferritin heavy chain 1 (FTH1, β= -1.2, p=3.75 x 10-13) in adipose tissue were the most positively and negatively associated with SI, respectively. Observations were replicated in independent adipose tissue data sets from individuals of European ancestry (ARCA, N=99; METSIM, N=720). Among these SI-associated transcripts, the strongest cis-regulatory genetic variant (cis-eSNP) was for TF (rs6785596, β= 0.962, p=7.84 x 10-18) in adipose, but not in muscle or liver. To identify the role of TF in adipocytes, we downregulated its expression in a human adipocyte cell model (SGBS). Gene specific shRNA knockdown of TF caused differential expression (log2FC +/-0.4, probability>70%) of 465 genes, involved in mitochondrial function (CPT1B, UCP2), glucose transport (GLUT4), Wnt-pathway/insulin sensitivity (SFRP4, SFRP1), chemokine activity/cell-cell interaction (CXCL1, CXCL12, ICAM1), and genes with possible roles in obesity (CES1, RARRES2). Knockdown of TF mRNA in differentiated SGBS cells impaired mitochondrial respiration (49±10% reduction of maximal oxygen consumption rate) and caused a 34±4% reduction in maximal insulin-stimulated glucose uptake (p<0.05).

In summary, genetic regulation of transferrin expression in adipose tissue plays a novel role in regulating insulin sensitivity.

Disclosure

D. McClain: None. N.K. Sharma: None. F. Lorenzo: None. S. Jain: None. C.D. Langefeld: None. M.E. Comeau: None. L. Salaye: None. S.K. Das: None.
A Positive Allosteric Modulator Enhances the Ability of Beta Cell M3 Muscarinic Receptors to Simulate Insulin Secretion In Vitro and In Vivo
Authors: ZHU LU , WESS JÜRGEN
Published: June 2018

Several studies have shown that activation of M3 muscarinic acetylcholine (ACh) receptors (M3Rs) expressed by pancreatic beta-cells leads to striking increases in glucose-stimulated insulin release. As a result, we hypothesized that agents that can promote signaling through beta-cell M3Rs might become useful in the treatment of type 2 diabetes. The M3R is a prototypic class A GPCR that is selectively coupled to G proteins of the Gq family. At present, selective M3R agonists that bind to the orthosteric ACh binding site are not available. However, the lab of Craig Lindsley (Bridges et al., 2010) recently described a compound (VU0119498) that binds to an allosteric site on the M3R, thus enhancing ACh-induced signaling through M3Rs. In this study, we tested the ability of this positive allosteric modulator (PAM) to stimulate insulin release in vitro and in vivo. The use of PAMs has the great advantage that it respects the spatio-temporal control of receptor activation, i.e., the PAM is only active upon receptor occupation by an endogenous orthosteric agonist. Studies with cultured MIN6 cells showed that VU0119498 enhanced ACh-induced insulin secretion in an M3R-dependent fashion. In vivo studies demonstrated that PAM treatment of WT mice caused a significant increase in plasma insulin levels, accompanied by a striking improvement in glucose tolerance. These VU0119498 effects were mediated by beta-cell M3Rs since they were absent in mutant mice selectively lacking M3Rs in beta-cells. In future studies, we will use mouse models of diabetes to examine whether this M3R-PAM is endowed with antidiabetic activity. This approach may lead to the development of a novel generation of antidiabetic drugs.

Disclosure

L. Zhu: None. J. Wess: None.
Polymorphic Role of P2Y6 Receptor in Insulin Sensitive Organs—Adipose Tissue and Skeletal Muscle
Authors: JAIN SHANU , WESS JÜRGEN , JACOBSON KENNETH A.
Published: June 2018

Adipose tissue and skeletal muscle are the two largest insulin-sensitive organs in the body. They play a major role in maintaining whole body glucose and energy homeostasis. Insulin action results in glucose disposal principally in skeletal muscle and to a lesser extent in adipose tissue. Dysregulation of this function promotes the development of obesity, insulin resistance and type 2 diabetes. Many G protein-coupled receptors (GPCRs) are expressed in insulin sensitive organs and thus have emerged as potential targets for novel antidiabetic drugs. P2Y purinergic receptors are a class of GPCRs activated by nucleotides and nucleotide sugars. The purinergic P2Y6 receptor (P2Y6R) is activated by uridine 5’-diphosphate. The potential role of P2Y6R in adipose tissue and skeletal muscle with respect to maintaining whole body glucose homeostasis remains unexplored. To address this issue, we used Cre/loxP technology to generate mice that lack P2Y6R selectively in adipose tissue (AT-Y6-KO) or skeletal muscle (SK-Y6-KO). Interestingly, AT-Y6-KO mice consuming a high fat diet gained less weight, while SK-Y6-KO mice gained more weight than the corresponding control mice. Body composition revealed that the difference in body weight was due to loss or gain in fat mass in AT-Y6-KO and SK-Y6-KO mice, respectively. Improved vs. impaired glucose tolerance and insulin sensitivity was observed in AT-Y6-KO and SK-Y6-KO mice, respectively. Moreover, fasting blood glucose and fed plasma insulin levels were decreased in AT-Y6-KO mice. SK-Y6-KO mice showed elevated blood glucose and plasma insulin levels under both fasting and fed conditions. Detailed mechanistic studies are required for understanding the role of P2Y6R in metabolic tissues and to alter its function for therapeutic purposes.

Disclosure

S. Jain: None. J. Wess: None. K.A. Jacobson: None.
Absence of Changes in Galectin-3 with Insulin Sensitization and Anti-inflammation
Authors: DANDONA PARESH , GHANIM HUSAM , SHAH MANASI S. , GREEN KELLY , MAKDISSI ANTOINE , CHAUDHURI AJAY
Published: June 2018

Galectin-3 (gal-3) has recently been shown to mediate insulin resistance in mice. Its deletion leads to insulin sensitization while its excess is associated with insulin resistance. We, thus, undertook an investigation into its role in the reversal of insulin resistance in three human models of insulin sensitization: (1) 6 months following bariatric surgery (RYGB) and weight loss in patients with morbid obesity; there was a reduction in BMI from 52.1±4.8 to 40.4±4.0 kg/m2 (p<0.001) and HOMA-IR fell from 7.1±1.1 to 2.1± 0.3 (p<0.001); (2) 12 weeks of pioglitazone (45mg/day) treatment in obese patients with type 2 diabetes, when HOMA-IR fell from 3.5±0.7 to 2.1±0.4; and (3) following 6 months of testosterone replacement in obese patients with type 2 diabetes and hypogonadotropic hypogonadism, when HOMA-IR fell from 4.2±0.9 to 2.7±0.4. Gal-3 levels at baseline were 7.6±1.1, 5.7±0.9 and 4.4±0.7ng/ml, respectively in the 3 groups. In all three models, there was no significant change plasma concentrations of gal-3 (8.0±1.2, 5.9±0.9 and 5.8±0.9ng/ml, respectively) following interventions. There was no change in the expression of gal-3 in peripheral blood mononuclear cells either. Thus, insulin sensitization in all three human models is not associated with any significant alteration in either plasma concentrations or cellular expression of gal-3. Our data do not support a key role for gal-3 in the pathogenesis of insulin resistance or its reversal.

Disclosure

P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. H. Ghanim: None. M.S. Shah: None. K. Green: None. A. Makdissi: 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..
Mechanism Mediated by S6 Kinase Resulting in both Sufficient Glucose Metabolism Improvement and Insufficient Weight Loss by Glucose Excretion against Fat Load
Authors: KIKUCHI TAKAKO , KUSHIYAMA AKIFUMI , FUJISHIRO MIDORI , SAKODA HIDEYUKI , ASANO TOMOICHIRO , IWAMOTO YASUHIKO
Published: June 2018

SGLT2 inhibitors have succeeded in improving prognosis in addition to blood glucose control and weight loss in T2D patients, but the reason is unclear, Systemic metabolic changes when improvement by glucose excretion is not sufficiently elucidated. Here, metabolic respiration balance and insulin signal change were analyzed when the high fat diet-induced insulin resistance was improved with the SGLT2 inhibitor tofogliflozin. 8-week-old male C57/Bl6 mice were divided into 3 groups; normal feed group (N group), 60% high fat (HF) feed group and 3 mg/kg/day tofogliflozin (Tofo) administered group on high fat diet. After 8 weeks of food loading, the body weight increased by 30% in the HF group compared to the N group and by 16% in the Tofo. Both IPGTT and IPITT were improved in the Tofo compared with HF group. In the calorimetric analysis, the heat production increased, the respiratory exchange ratio (RER) decreased, and the RER diurnal variation disappeared in the HF group, while the Tofo reduced the energy consumption to the same level as the N group while maintaining the RER equivalent to the HF group. UCP1 in brown fat was elevated in the HF group and improved in the Tofo. In liver, muscle and fat IRS-1 amount decreased in the HF group and revived in Tofo. Phosphorylation of the basal S6K was enhanced in the HF group and disappeared in the Tofo, while after insulin administration, pAkt and resulting pS6K were accelerated in the Tofo.

In conclusion, urinary glucose excretion against high fat load is resulting in improvement of IRS-1 degradation by basal S6Kinase promotes insulin Akt activation. Lipid synthesis is enhanced by insulin while energy expenditure is normalized. Inhibited fat burning compensation leaves weight gain, but since insulin signal has been improved enough, glucose metabolism is improved adequately. This suppression of catabolism might be involved in the improved prognosis by administration of SGLT2 inhibitors.

Disclosure

T. Kikuchi: None. A. Kushiyama: Research Support; Self; Teijin Pharma Limited, Sanwa Kagaku Kenkyusho Co., Ltd., Kowa Pharmaceutical Co., Ltd, StaGen. Consultant; Self; RIZAP. M. Fujishiro: Research Support; Self; Johnson & Johnson Services, Inc.. H. Sakoda: None. T. Asano: Research Support; Self; Teijin Pharma Limited, Sanwa Kagaku Kenkyusho Co., Ltd., Sanofi K.K. Y. Iwamoto: Board Member; Self; Japan Diabetes Foundation.
Impact of Blood Sugar Control on Metabolites and Carbohydrate Metabolism in Type 1 Diabetes
Authors: KUHTREIBER WILLEM , JANES SOPHIE E. , YANG MICHAEL W. , FAUSTMAN DENISE L.
Published: June 2018

In type 1 diabetes (T1D), long-term blood sugar control measured by HbA1c can vary over a wide range. Although metabolites are commonly studied in type 2 diabetes (T2D) as they relate to HbA1c, similar studies in T1D are few. Since the underlying etiologies of T1D and T2D are different, we explored the overall pathways of metabolism in T1D subjects with tight vs. poor blood sugar control. T1D subjects (n=50) were divided into two groups (n=25 each) based on low vs. high HbA1c (Screen 1, low: mean 6.7 ± 0.1%; high: mean 8.7 ± 0.3%). Serum samples were analyzed on a metabolomic GC/HPLC/MS platform and analyzed for differences in biochemicals between the groups. The screen was repeated with a second group of 50 patients for verification (Screen 2, mean 6.3 ± 0.1%; mean 8.0 ± 0.2%) and then both screens combined. For each detected biochemical, average scaled intensity was determined and statistical significance of differences was calculated using a two-tailed, unpaired Student’s T test (p-values) and False Discovery Rate (q-values). The platform distinguished 690 components in Screen 1 and 623 biochemicals in Screen 2. In Screen 1, two biochemicals, including glucose, showed significant differences (≦0.05) for both p and q value. In Screen 2, none of the biochemicals reached threshold. When the screens were combined (100 samples), 10 biochemicals were significant for both p and q. Three components (glucose, mannose and 1,5-AG) were carbohydrates related to blood sugar control and thus expected in a high and low HbA1c analysis. Significant biochemicals commonly found in T2D and related to blood sugar control were not significant in T1D for both p and q in the screens. We conclude that few metabolites are correlated in T1D with tight vs. poor blood sugar control compared to T2D. Unlike T2D, metabolites related to intracellular sugar utilization, the Krebs cycle and purine synthesis are unrelated to blood sugar control in T1D cohorts.

Disclosure

W. Kuhtreiber: None. S.E. Janes: None. M.W. Yang: None. D.L. Faustman: None.
Preserved Beta-Cell Function during Acute DKA in Ketosis-Prone Diabetes
Authors: MEHTA PARAS B. , MULUKUTLA SURYA N. , HSU JEAN W. , KEENE KELLY R. , RAM NALINI , BALASUBRAMANYAM ASHOK
Published: June 2018

Introduction: Ketosis prone diabetes (KPD) comprises heterogeneous syndromes characterized by presentation with DKA. “ß+” subgroups of KPD have substantial beta cell functional reserve measured ≥ 1 month after the index DKA episode, and can discontinue insulin therapy. Either acute beta cell dysfunction leading to DKA is reversible in these patients, or DKA is due to factors other than severe beta cell dysfunction. In a longitudinal study, we measured serum C-peptide, insulin and counter-regulatory hormones in patients with hyperglycemic crises upon admission to the emergency department (ED) to determine beta cell function during the acute DKA episode.

Methods: Among 57 adult patients assessed so far, 32 had DKA (anion-gap acidosis with elevated beta-hydroxybutyrate) and 25 had non-ketotic hyperglycemia. Blood was sampled prior to insulin administration in 24 patients (50% with DKA), and ≤9 h after starting the insulin infusion in 33.

Results: There was no significant difference in C-peptide, glucose, insulin, or cortisol levels in DKA vs. non-ketotic hyperglycemia groups. Mean C-peptide was 1.4 ± 0.5 ng/mL in the DKA group and 2.1 ± 0.4 ng/mL in the non-DKA group (p = 0.29). Among the 24 patients whose blood was sampled prior to administering insulin, there was no group difference in C-peptide levels (2.3 ± 1.2 vs. 2.6 ± 0.7 ng/mL, p = 0.83). C-peptide was >1.5 ng/mL in 22% of the DKA group.

Conclusions: Many adults with KPD have substantial beta cell function at the time of the index DKA episode, a finding that defies the concept that near-complete absence of endogenous insulin secretion is required to develop DKA. Longitudinal follow-up testing will determine whether these patients populate KPD subgroups that are formally defined as “ß+”; such an outcome would indicate that their proclivity to develop ketoacidosis may be due to factors other than absence of endogenous insulin, such as defective amino acid metabolism (Patel et al, Diabetes 62:912-922, 2013) or dysregulation of counter-regulatory hormones.

Disclosure

P.B. Mehta: None. S.N. Mulukutla: None. J.W. Hsu: None. K.R. Keene: None. N. Ram: None. A. Balasubramanyam: None.
MEDI0382, a GLP-1/Glucagon Receptor Dual Agonist, Shows Differential Brain Activation vs. Liraglutide in Mice
Authors: BURKE LUKE K. , BROWN LEE , LAPOINTE JEAN-MARTIN , SULIKOWSKI MICHAL GRZEGORZ , LEWIS ARTHUR R. , TREVASKIS JAMES , BAKER DAVID
Published: June 2018

MEDI0382 is under development for the treatment of type 2 diabetes. MEDI0382 reduces food intake and body weight in obese mice and primates. In rodents, the weight-reducing effects of MEDI0382 are superior to those of the GLP-1 analogue, liraglutide. The current study characterised the activation of distinct neuroanatomical areas following peripheral administration of MEDI0382, relative to liraglutide and the glucagon receptor agonist, G1432. C57Blk6 mice were fasted for 4 h and then injected with a single dose (3 nmol/kg; s.c) of test agent or vehicle (n=4 each). After 2 h, mice were sacrificed and brains were dissected out and immersion-fixed in formalin (24-48 h). The brains were then cut into 3 mm serial slices and processed to paraffin blocks. Each block was sectioned entirely, sampling a 4µm step section every 100µm. Each section was immunohistochemically stained for c-fos, using a rabbit anti-fos polyclonal, with haematoxylin counterstain. Stained sections were digitally scanned at 20x magnification (Aperio AT2). The appropriate brain sections containing the area postrema (AP), the nucleus of the solitary tract (NTS), and the hypothalamic parabrachial (PBN) and arcuate nuclei were selected. These areas were manually delimited using the online Allen mouse brain atlas. The number of positive and negative nuclei were automatically counted (Halo), and reported as % of total positive cells and number of cells per tissue area. MEDI0382 significantly increased c-fos activation in the AP and NTS vs. vehicle, whereas liraglutide and G1432 showed no difference from vehicle. There was no significant increase in c-fos activation in the arcuate nucleus or PBN in any treatment group when compared to vehicle.

In summary, the neuronal activation by MEDI0382 shows that distinct differences were observed compared to GLP-1 and glucagon agonists alone, suggesting that a different pattern of activation exists for the dual agonist, MEDI0382 vs. the monotherapies.

Disclosure

L.K. Burke: None. L. Brown: Stock/Shareholder; Self; AstraZeneca. J. Lapointe: Employee; Self; MedImmune. M. Sulikowski: None. A.R. Lewis: Employee; Self; MedImmune. Stock/Shareholder; Self; MedImmune. J. Trevaskis: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. D. Baker: Stock/Shareholder; Self; AstraZeneca.
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 >=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<0.001), but not at the first visit (03B2;=0.12, p003C;0.23) (interaction p<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<0.001), VAT (Std.β-Coeff.=0.18, p<0.05) and brain MRglu (Std.β-Coeff.=-0.33, p<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 (<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<0.05, ** p<0.01 for comparisons vs. C, or ¤ p<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<0.0001). NP was inversely correlated with body weight (r= -0.55; p<0.001). Six-months after RYGB, BMI was markedly reduced (34.3±1.6 kg/m2; p<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< 0.05). Post-OGTT GLP-1 levels increased (AUCOGTTfrom 5457±715 to 11215±1067 pmol/l×120min; P<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<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 <.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<.001.009.030Current Smoker.686.283.150.010.1821.305N=256; Duration of diabetes = <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<.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 < 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<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<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<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<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<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<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<0.05) on DOL6, but normalized by DOL14. C-peptide was abnormally increased (3.3 fold, p<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<0.01) whereas IR/IRS and PEPCK-C didn’t change. Skeletal muscle GLUT1 was 70% decreased in HYPER animals (p<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 < 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<0.vs STZ-CON

Disclosure

J.H. Parilla: None. S. Mongovin: None. B. Barrow: None. N. Esser: None. S. Zraika: None.
Retinol Binding Protein 4 Impairs Pancreatic Beta-Cell Function, Leading to the Development of Type 2 Diabetes
Authors: HUANG RONG , BAI XINXIU , LI XUEYAN , ZHAO LINA , XIA MIN
Published: June 2018

Circulating Retinol binding protein 4 (RBP4), the specific transport protein for vitamin A, has been implicated in insulin resistance and type 2 diabetes. Pancreatic beta cell failure plays a decisive role in the onset and the progression of type 2 diabetes. However, the effect of RBP4 on beta cell function and the molecular mechanisms are far from clear. The direct effect of RBP4 on islet function was assessed by treating primary isolated islets from C57BL/J mice with different dose of RBP4 (0, 20, 40, 60 μg/ml) for 24 hour or with 60ug/ml RBP4 for different time points (0, 12, 18,24 hours). We found that RBP4 could dose and time dependently inhibit the glucose stimulated insulin secretion (GSIS). To further identify the role of RBP4 on islet beta cell function. RBP4-overexpressing mice (RBP4-Tg) were generated. Compared to the wild type group, the islets isolated from RBP4-Tg mice showed a significant decrease of insulin secretion in response to glucose (∼50%) and KCl (∼70%). The Dynamic insulin secretion of the isolated islets of RBP4-tg mice in response to glucose was further characterized. RBP4 could dramatically inhibit first-phase GSIS by up to 80%. In consistent to these in vitro findings, RBP4-tg mice showed a progressive decrease of GSIS (8weeks, 12weeks, 16weeks) which appeared as early as 8weeks. While the glucose tolerance of these mice was not significantly impaired until 12 weeks by intraperitoneal glucose tolerance test and the insulin sensitivity was not changed until 16 weeks by intraperitoneal insulin tolerance test respectively.

In conclusion, RBP4 could impair pancreatic beta cell function which may lead to the onset and the development of T2DM.

Disclosure

R. Huang: None. X. Bai: None. X. Li: None. L. Zhao: None. M. Xia: None.