bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Relationship of Fasting Free Fatty Acids, Adipose Tissue, Insulin Resistance, and Fasting Glucose Concentrations with Subsequent ß-Cell Function in Nondiabetic Subjects
Authors: HURTADO MARIA D. , ADAMS J.D. , LAURENTI MARCELLO C. , MAN CHIARA DALLA , COBELLI CLAUDIO , RIZZA ROBERT A. , JENSEN MICHAEL D. , VELLA ADRIAN 
Published: June 2018

Elevations in both plasma free fatty acids (FFA) and glucose concentrations during fasting are associated with impaired β-cell function and predict progression from prediabetes to diabetes. Their interaction and subsequent effect on β-cell function as quantified by Disposition Index (DI) is unknown. We therefore measured total, saturated, mono-unsaturated and poly-unsaturated FFA concentrations using LC/MS in 120 nondiabetic subjects (across a range of fasting glucose &lt; 6.9 mmol/l) who underwent a 2 hour oral glucose tolerance test (OGTT). Insulin secretion and action were quantified using the oral minimal model. The adipose tissue insulin resistance index (Adipo-IR) was calculated for each subject. Subjects were categorized by normal (NFG) or impaired (IFG) fasting glucose and by 2-hour glucose into normal (NGT) or impaired (IGT) glucose tolerance. Fasting total FFA were increased (p &lt; 0.01) in IFG/IGT (835 ± 47 μmol/L) and in NFG/IGT (835 ± 30 μmol/L) but, intriguingly, not in IFG/NGT (593 ± 26 μmol/L) when compared to NFG/NGT (652 ± 29 μmol/L). These differences were no longer apparent within 60 minutes of OGTT and all groups suppressed FFA to the same nadir (166 ± 12 vs. 191 ± 18 vs. 184 ± 12 vs. 174 ± 17μmol/L, p = 0.59). On the other hand, an inverse relationship (p &lt; 0.01) of fasting FFA (r = -0.33) and of Adipo-IR (r = -0.28) was observed with insulin action (Si). Fasting FFA did not correlate with β-cell responsivity (ϕ, r = 0.04). However, higher Adipo-IR was associated with higher values of ϕ (r = 0.36, p &lt; 0.01). Fasting glucose concentrations did not alter these relationships; specifically no interaction of glucose with FFA during the fasting state to influence DI was evident. It remains to be ascertained whether the elevation in FFA reflects defects in production or in uptake, and whether the effect of changes in fasting glucose concentrations on DI is modulated by fasting FFA concentrations.

Disclosure
M.D. Hurtado: None. J. Adams: None. M.C. Laurenti: Other Relationship; Self; GlySens Incorporated. C. Dalla Man: None. C. Cobelli: Research Support; Self; Sanofi-Aventis. Advisory Panel; Self; Novo Nordisk Inc.. R.A. Rizza: None. M.D. Jensen: Other Relationship; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. A. Vella: Research Support; Self; Novo Nordisk Inc., XOMA Corporation. Advisory Panel; Self; VTV Therapeutics, Bayer AG.
Effects of GLP-1 and GIP on Insulin Secretion in Glucose Intolerant, Pancreatic Insufficient Cystic Fibrosis
Authors: EIEL JACK N. , NYIRJESY SARAH , PELECKIS AMY J. , LEON DIVA DE , HADJILIADIS DENIS , KUBRAK CHRISTINA , TAMI ABIGAIL , SHEIKH SABA , RUBENSTEIN RONALD C. , KELLY ANDREA , RICKELS MICHAEL R. 
Published: June 2018

Individuals with pancreatic insufficient cystic fibrosis (PI-CF) and glucose intolerance demonstrate impaired incretin and insulin secretion. The goal of this study was to assess β-cell responsiveness to the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) during glucose potentiated arginine (GPA) testing in adults with PI-CF and abnormal glucose tolerance. Participants were randomized to receive either GLP-1 (n=15) or GIP (n=15) and then underwent GPA testing during either incretin or placebo infusion in a randomized, cross-over fashion. OGTT was similar between groups (1hr: 214±8 vs. 208±7 mg/dL; 2hr: 141±18 vs. 150±18 mg/dL). During GPL-1 infusion, fasting glucose was lower after 30 min vs. placebo (p&lt;0.001), and during the 230 mg/dL glucose clamp the glucose infusion rate (GIR) was higher (p&lt;0.001). Second phase insulin levels were substantially increased prior to arginine administration under 230 mg/dL clamp conditions vs. placebo (p&lt;0.001), but no difference in the acute insulin response (AIR) to GPA was present. At 230 mg/dL, proinsulin and C-peptide were increased under GLP-1 vs. placebo (both p&lt;0.001), but the proinsulin secretory ratio (PISR) was unchanged. During GIP infusion, fasting glucose was slightly lower after 30 min vs. placebo (p&lt;0.05), but no difference in the GIR required to achieve 230 mg/dL was found. Second phase insulin levels were not different during the 230 mg/dL glucose clamp. The AIR to GPA was lower during GIP vs. placebo (p&lt;0.01). Second phase proinsulin and C-peptide levels were higher with GIP vs. placebo (both p&lt;0.01) with an increased PISR (p&lt;0.05). These results indicate that GLP-1 augments glucose-dependent insulin secretion while GIP may lead to disproportionate proinsulin secretion in glucose intolerant PI-CF. Further studies should determine whether GLP-1 may provide a therapeutic benefit in this population.

Disclosure
J.N. Eiel: None. S. Nyirjesy: None. A.J. Peleckis: None. D. De Leon: Employee; Spouse/Partner; Merck & Co., Inc.. Research Support; Self; Zealand Pharma A/S. Consultant; Self; XOMA Corporation, ProSciento. Research Support; Self; Biomarin Corporation. D. Hadjiliadis: None. C. Kubrak: None. A. Tami: None. S. Sheikh: None. R.C. Rubenstein: None. A. Kelly: None. M.R. Rickels: Consultant; Self; Hua Medicine, Xeris Pharmaceuticals, Inc..
Glucose Metabolism after Overnight and Prolonged Fasting in Healthy Subjects
Authors: TRIPOLT NORBERT J. , STEKOVIC SLAVEN , URL JASMIN , ABERER FELIX , PFERSCHY PETER N. , RIEDL REGINA , OBERMAYER-PIETSCH BARBARA M. , PIEBER THOMAS R. , MADEO FRANK , SOURIJ HARALD 
Published: June 2018

Background: It is well known that the metabolic regulation of glucose can be influenced by dietary interventions, including alterations in meal timing. Aim of our analysis was to examine the glucose metabolism after an overnight fast (10 hours) and after prolonged fasting (36 hours of fasting).
Material and Methods: Glucose metabolism was assessed by a 75 g oral glucose tolerance test after an overnight fasting period of 10 hours and a fasting period of 36h. Beta-cell function was quantified by 1st and 2nd phase insulin secretion indices.
Results: We included 37 healthy subjects (mean age 48±10 years; 54% women) with a mean body mass index (BMI) of 25.2±3.4 kg/m2. After prolonged fasting mean 2h-glucose and AUC for glucose value were significantly higher than after 10h fasting (2h-glucose: 110±27 mg/dL vs. 89±24 mg/dL; p&lt;0.001) (AUCglucose: 5336±3302 mg/dL/min vs. 3692±2266 mg/dL/min; p=0.002). First (745±500 vs. 982±573; p=0.012) and second phase insulin secretion (211 ± 115 vs. 266 ± 132; p=0.011) were significantly lower after 36h of fasting as compared to an overnight fast. Estimates for insulin sensitivity are similar after 10 and 36 hours of fasting.
Conclusion: Our data demonstrate higher glucose excursions and a reduced insulin response after a 36 hour fasting period as compared to an overnight fasting period in healthy subjects.After 10h fastingAfter 36h fastingp-valueFasting c-peptide (ng/mL)1.39 ± 0.651.09 ± 1.030.025Fasting insulin (mU/L)7.9 ± 5.15.7 ± 5.80.042Fasting glucose (mg/dL)88 ± 988 ± 180.830Insulin after 60min (mU/L)87.6 ± 85.853.4 ± 51.80.0361st phase insulin secretion982 ± 573745 ± 5000.012HOMA-IR1.75 ± 1.181.39 ± 2.070.303Stumvoll index (ISI)0.10 ± 0.030.09 ± 0.03 0.230

Disclosure
N.J. Tripolt: None. S. Stekovic: None. J. Url: None. F. Aberer: None. P.N. Pferschy: None. R. Riedl: None. B.M. Obermayer-Pietsch: None. T.R. Pieber: Consultant; Self; Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Employee; Self; CBmed. Research Support; Self; Novo Nordisk A/S, AstraZeneca. F. Madeo: None. H. Sourij: Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Novo Nordisk A/S, Amgen Inc., Sanofi, MSD K.K.. Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH, MSD K.K., GI Dynamics Inc..
Beta-Cell Function after Gastric Bypass
Authors: SHAH ANKIT , LEVESQUE KIARRA , AHLERS MICHAEL , HOLTER MARLENA M. , ALAM FATIMA , PIERINI ESMERALDA , ROJAS BETSY L. , MARK VICTORIA , PATEL KAPILA , DUTIA ROXANNE , HARVEY EUGENIUS J. , PARK KOJI , KOSHY NINAN , BELSLEY SCOTT J. , MCGINTY JAMES J. , LAFERRERE BLANDINE 
Published: June 2018

β-cell glucose sensitivity (BCGS) improves after gastric bypass (RYGB) in individuals in diabetes (DM2) remission. We sought to assess BCGS (pmol/kg/min/mM) after an oral glucose test (OGT) and an IV graded glucose infusion (GGI) in subjects with and without DM2 remission after RYGB.
Twenty five subjects with DM2 were studied with GGI and 75g-OGT before and 3 months after RYGB. Glucose, insulin, C-peptide, insulin secretion rate, GLP-1 and BCGS were assessed during the OGT and the GGI. Data are presented as mean±SD. Within and between group comparisons with paired and unpaired t-test; GLM with repeated measure to assess change during OGT or GGI were (SPSS 24).
Of the 25 subjects studied pre-surgery, 10 experienced DM2 remission (REM), 9 remained with DM2 (N-REM) at 3 months; 6 remained glucose intolerant and were not included in the analysis. Pre-surgery BMI (41.5±4.7 kg/m2), weight (108.3±15.9 kg), age (43.8±8.8 years), gender (95% female), HOMA-IR (12.1±6.7) and Matsuda index did not differ between groups; N-REM had longer DM2 duration (14 vs. 2.5 y p&lt;0.001), higher HbA1c (8.2±1.0 vs. 7.0±0.8%, p=0.01) and more likely to be taking insulin (7/9 vs. 0/10 p&lt;0.001). Prior to RYGB, OGT-BCGS was 4x greater (0.83±0.60 vs. 0.22±0.24, p=0.01) and GGI-BCGS was 2.5x greater (0.48±0.30 vs. 0.18±0.15, p=0.04) in REM vs. N-REM.
Weight loss did not differ for REM and N-REM (17±5%). HOMA-IR, GLP-1 and GGI-BCGS improved similarly in both groups. OGT-BCGS increased in both groups, but more in REM vs. N-REM (+1.31±1.0 vs. +0.30±0.28, p=0.01). The difference between OGT-BCGS and GGI-BCGS observed pre-RYGB (0.58±0.54 vs. 0.38±.035, p=ns) was exaggerated at 3 months by 4x in REM (2.13±1.vs. 0.58±0.15, p=0.001) and ∼2.5x in N-REM (0.60±.0.43 vs. 0.24±0.17, p=0.07).
In conclusion, β-cell function assessed during an IV GGI improves by the same magnitude regardless of DM2 remission status after RYGB. However, β-cell function improved more in REM than N-REM after oral glucose, suggesting a greater incretin effect, or other gut-related mechanisms, in REM after RYGB.

Disclosure
A. Shah: Employee; Spouse/Partner; Daiichi Sankyo Company, Limited. K. Levesque: None. M. Ahlers: None. M.M. Holter: None. F. Alam: None. E. Pierini: None. B.L. Rojas: None. V. Mark: None. K. Patel: None. R. Dutia: None. E.J. Harvey: None. K. Park: None. N. Koshy: None. S.J. Belsley: None. J.J. Mcginty: None. B. Laferrere: None.
Beta-Cell SCHAD Deficiency Causes Hypoglycemia in Mice
Authors: LUDEKE JOHANNA , VELASCO KELLY M. , DE JESUS DARIO F. , SLIPP BRITTANY A. , HU JIANG , STEINE SOLRUN J. , HELGELAND GEIR , NJØLSTAD PÅL RASMUS , KULKARNI ROHIT , MOLVEN ANDERS 
Published: June 2018

Congenital Hyperinsulinism of Infancy (CHI) is a group of rare, inheritable disorders with persistent hypoglycemia due to hyperinsulinemia. CHI is caused by mutations in genes that affect regulation of insulin secretion in β-cells. One such gene is HADH, which encodes short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), a metabolic enzyme of the fatty acid beta-oxidation pathway. Mutations resulting in SCHAD deficiency cause protein-sensitive CHI and increased systemic levels of some fatty acid oxidation metabolites.
To test the hypothesis that SCHAD-CHI is caused by a specific deficiency of this ubiquitously expressed protein in β-cells we created β-cell-specific SCHAD knock-out (β-SCHADKO) mice by crossing Hadh-floxed animals with mice expressing Cre under the regulation of the Ins1 promoter. Validity of the β-SCHADKO model was confirmed by PCR, Western Blot and immunofluorescence staining of pancreas tissue. Growth and development of β-SCHADKO mice was similar to littermate controls. Plasma glucose in the KOs was significantly reduced in the random fed state (♂ 158 ± 15 vs. 115 ± 28 mg/dL, p=0.0016; ♀ 143 ± 8 vs. 97 ± 19 mg/dL, p&lt;0.0001) and after overnight fasting (♂ 82 ± 14 vs. 56 ± 13 mg/dL, p&lt;0.0002; ♀ 62 ± 7 vs. 42 ± 4 mg/dL, p&lt;0.0001). Insulin and C-peptide levels were elevated in female KOs after overnight fasting (insulin: 0.25 ± 0.15 vs. 0.38 ± 0.21 ng/mL, p=0.0507; C-peptide: 0.15 ± 0.07 vs. 0.26 ± 0.16 ng/mL, p=0.05), but unchanged in the fed state. GSIS and overall glucose homeostasis, as assessed by insulin and glucose tolerance tests, were not significantly altered. Overall, these data indicate that the β-SCHADKO mouse is a suitable model to investigate the hypoglycemic phenotype of underlying SCHAD deficiency.

Disclosure
J. Ludeke: None. K.M. Velasco: None. D.F. De Jesus: None. B.A. Slipp: None. J. Hu: None. S.J. Steine: None. G. Helgeland: None. P. Njølstad: None. R. Kulkarni: None. A. Molven: None.
Metabolic Clearance Rate of Insulin Is Not Saturable within the Physiological Range
Authors: BEDIAKO ISAAC ASARE , PASZKIEWICZ REBECCA L. , WOOLCOTT ORISON O. , BERGMAN RICHARD N. 
Published: June 2018

The plasma concentration of insulin is determined by pancreatic beta cell secretion and the metabolic clearance of the hormone. It has been suggested that the concentration of insulin determines its metabolic clearance rate. Also, some reports suggest that clearance is saturable and insulin kinetics are non-linear even within physiologic ranges. We assessed the metabolic clearance rate of insulin at different physiologic concentrations to access if clearance changes with concentration. Using the dog model (n=12), insulin was infused peripherally at 3 incremental rates (dose-response) during the euglycemic clamp. Each infusion rate spanned 90mins, and the last 30mins was considered the steady state. The metabolic clearance rate of insulin was calculated as the ratio of the infusion rate to the steady state plasma concentration. The 3 infusion rates, 1.5, 3.0 and 4.5pmol/kg/min yielded steady state plasma insulin concentrations of 92 ± 8, 165 ± 12 and 256 ± 18pM respectively. The metabolic clearance rate of insulin was consistent and independent of dose (17.8 ±1.7, 19.1 ±1.2 and 18.6 ±1.4 ml/kg/min; p = ns) across the different plasma insulin infusion rates. Also, we found a strong linear correlation (r = 0.99) between the infusion rates and steady state insulin concentrations. Insulin kinetics are linear and the metabolic clearance of insulin is not saturable within physiologic ranges in the conscious dog. Though it’s possible that the site of degradation (i.e., liver vs. periphery) may change with dose.These data demonstrate that changing concentrations of plasma insulin within physiologic concentrations does not change the rate of insulin removal from the plasma.

Disclosure
I. Asare Bediako: None. R.L. Paszkiewicz: None. O.O. Woolcott: None. R.N. Bergman: Advisory Panel; Self; Ingredion, Inc.. Research Support; Self; AstraZeneca. Consultant; Self; GI Dynamics Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Consultant; Self; Novo Nordisk A/S.
Hemoglobin A1c (A1c) Genetics Contributes to A1c/Glucose Mismatches in the Multiethnic VA Million Veteran Program (MVP)
Authors: LEONG AARON , POSNER DANIEL , CHAREST BRIAN R. , RHEE MARY , MEIGS JAMES B. , WILSON PETER W. , COHEN ROBERT M. , MILLER DONALD R. , SUN YAN V. , CHO KELLY , PHILLIPS LAWRENCE S. 
Published: June 2018

A1c accuracy is important for diabetes management but mismatches in A1c relative to underlying glucose can impede care. Since the basis for mismatches is poorly understood, we assessed the contributions of 22 A1c variants identified in GWAS that were associated with erythrocytic traits but not glycemia. 73,128 MVP patients had continuity of care and monitoring: &gt;1 PCP visit, &gt;1 outpatient random plasma glucose (RPG) and &gt;1 A1c within each of 3 consecutive two-year periods. They had mean age 67 years and BMI 31 kgm-2; 71% were white and 21% were black; 51% had diabetes (ICD 9 codes and diabetes Rx). Mismatches were defined by the hemoglobin glycation index (HGI) calculated from regression residuals of mean A1c on mean RPG within each period, averaged over the 3 periods. We evaluated the associations with HGI of each A1c variant and a genetic risk score (GRS; sum of alleles weighted by their reported A1c effect sizes) by race. Mean HGI was -0.07% A1c units in whites and 0.2% in blacks. Of the 22 variants, 15 at 13 loci were associated with HGI (P&lt;5 x 10-8, ANK1, CNTN5, ERAL1, G6PD, HBS1L/MYB, HK1, HIST1H4A/HFE, MYO9B, SENP1, SPTA1, SYN2, TMPRSS6 and PEIZO1). GRS was associated with HGI (whites P=2 x 10-189, blacks P=1 x 10-233) and explained HGI variance (whites 1.7%, blacks 5.1%), especially in those without diabetes (whites 3.5%, blacks 11.4%). People in the lowest 10% of GRS had a glucose-independent fall in A1c (mean HGI, whites -0.19%, blacks -0.31% A1c units) while those in the highest 10% of GRS had the opposite (mean HGI, whites 0.06%, blacks 0.29%). The variants with the largest effects on HGI were rs1800562/HIST1H4A/HFE [mean HGI, AA: -0.37%, GG: -0.06% A1c units] in whites and rs1050828/G6PD [mean HGI, T: -0.31%; C: 0.29% A1c units] in black men.
Conclusions: HGI is higher in blacks than whites - a glucose-independent higher A1c. Common genetic variation explains 2-11% of the variance in HGI. Accounting for genetic variation in A1c may improve its accuracy in guiding diabetes care.

Disclosure
A. Leong: None. D. Posner: None. B.R. Charest: None. J.B. Meigs: None. P.W. Wilson: None. R.M. Cohen: Stock/Shareholder; Self; Bristol-Myers Squibb Company. D.R. Miller: None. Y.V. Sun: None. K. Cho: None. L.S. Phillips: Other Relationship; Self; DIASYST Inc.. Research Support; Self; Amylin Pharmaceuticals, Eli Lilly and Company, Novo Nordisk Inc., Sanofi-Aventis, PhaseBio Pharmaceuticals, Inc., Roche Diabetes Care Health and Digital Solutions, AbbVie Inc., Vascular Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., GlaxoSmithKline plc., Pfizer Inc.. Other Relationship; Self; Novartis Pharmaceuticals Corporation, Merck & Co., Inc..
The Postprandial C-peptide–to–Glucose Ratio Correlated with Beta-Cell Function in Japanese Patients with Type 2 Diabetes Mellitus
Authors: MATSUHASHI YUKI , CHIKAZAWA SHINJI , NAKAYAMA HIROFUMI , MURABAYASHI MASAYA , MIZUSHIRI SATORU , OSONOI SHO , TAKAHASHI KAZUHISA , OTAKA HIDEYUKI , YANAGIMACHI MIYUKI , MURAKAMI HIROSHI , DAIMON MAKOTO 
Published: June 2018

The onset of type 2 diabetes mellitus(T2DM) is based on the insulin resistance and decreasing of insulin secretion. Residual β-cell function is a key factor in achieving optimal glycemic control in patients with type 2 diabetes. Glucagon induces insulin secretion by direcdtly stimulating β-cells, therefore glucagon stimulaton test(GST) is a reliable marker for β-cell function. Fasting C-peptide(CPR)-index(CPR[ng/ml] to glucose[mg/dl] ratio x100; F-CPRI) is used as a marker of insulin secretion. We evaluated the efficacy of postprandial CPR to glucose ratio(P-CPRI) as a tool for evaluating β-cell function. Japanese T2DM patients with inadequte glycemic control(HbA1c&gt;7.0%) were enrolled in the study(n=333, insulin therapy =217). HbA1c, fasting CPR and glucose were measured, and F-CPRI was calculated. Postprandial(120 min after breakfast) CPR and glucose were measured, and P-CPRI was calculated. For the GST, CPR was determinated before and 6 min after 1mg of glucagon injection. GSTδCPR(CPR[6 min] - CPR[0 min]) was calculated. Factors correlated with GSTδCPR were analyzed using simple and multiple stepwise regression analysis. P value&lt;0.was defined as statistically different. F-CPR-index, P-CPR-index and GSTδCPR were 1.42±0.85, 2.26±1.59 and 1.85±1.15, respectively. Simple regression analysis showed that GSTδCPR was significantly correlated with age, height, body weight(BW), BMI, gender, duration of diabetes, diebetic retinopathy, diabetic nephropathy, insulin therapy, F-CPRI and P-CPRI. Multiple stepwise regression analysis revealed that independent factors contributing to GSTδCPR were BW(β=0.331, p&lt;0.001), P-CPRI(β=0.451, p&lt;0.001), duration of diabetes(β= -0.104, p=0.025), diabetic retinopathy(β= -0.127, p=0.004), DPP-4 inhibitor(β= -0.089, p=0.036) and biguanide(β= -0.144, p=0.001). Our date demonstrated that P-CPRI was valuable in assessing β-cell function and can help clinicians in clinical practice.

Disclosure
Y. Matsuhashi: None. S. Chikazawa: None. H. Nakayama: None. M. Murabayashi: None. S. Mizushiri: None. S. Osonoi: None. K. Takahashi: None. H. Otaka: None. M. Yanagimachi: None. H. Murakami: None. M. Daimon: None.
Heparan Sulfate of ß Cells Regulates Insulin Secretion and Contributes to Normal Glucose Homeostasis
Authors: MATSUZAWA TAKURO , YOSHIKAWA TAKEO , SUGAWARA AKIRA , YANAI KAZUHIKO 
Published: June 2018

Heparan sulfate (HS) is a linear polysaccharide and abundantly distributes around cell surface. HS can interact with various bioactive molecules and enhance their signal transduction. Thus, HS is involved in diverse biological functions including development, maturation and proliferation of various tissues. Previous reports demonstrated the expression of HS in β-cells and suggested the possible involvement of HS in functions of β-cells. However, the importance of HS for β-cells remains largely unknown. In the present study, we generated mice with β-cell specific deletion of Ext1 (cKO), which encodes an essential enzyme for HS synthesis, to investigate the detailed roles of HS in β-cell development and function. cKO mice had decreased body weight despite increased food intake compared to control mice. cKO mice showed impaired glucose tolerance associated with decreased insulin secretion upon glucose challenge, without insulin resistance. Glucose-induced insulin secretion from isolated islets of cKO mice was also significantly reduced. These results indicate the contribution of HS in β-cells to insulin secretion and glucose homeostasis. The expression of several genes essential for glucose-induced insulin secretion was decreased in cKO islets. Pdx1 and MafA, which are important transcriptional factors for β-cell development and maturation, were reduced in cKO islets, indicating HS promotes development and maturation of β-cells. Immunohistochemical analysis of the cKO pancreas revealed reduced β-cell mass and islet number. The percentage of BrdU- or Ki67-positive β-cells was decreased in cKO islets, suggesting the involvement of HS in the proliferation of β-cells. Insufficient vascularization in cKO islets might contribute to the abnormal islet architecture. These data demonstrate that HS plays diverse roles in β-cell development and maturation, and that loss of HS leads to insufficient insulin secretion and dysregulation of glucose homeostasis.

Disclosure
T. Matsuzawa: None. T. Yoshikawa: None. A. Sugawara: None. K. Yanai: None.