bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cerebral Blood Flow Abnormalities in Brain Regions Responsible for Cognitive Function in Type 2 Diabetes
Authors: HUNT LEANNE , SELVARAJAH DINESH , TESFAYE SOLOMON , WILKINSON IAIN D. 
Published: June 2018

Aim: The risk of developing mild cognitive impairment (MCI) increases with type 2 diabetes (T2DM). Brain morphometric changes associated with MCI have been described. However Cerebral Blood Flow (CBF) changes in relation to MCI has not been fully investigated. This study aims to investigate regional CBF changes in subjects with T2DM and MCI.
Method: Seventy-four age and gender matched subjects [28, T2DM (T2DM); 17, T2DM+MCI (T2DM/MCI) and 29, healthy volunteers (HV)] were recruited. All subjects underwent clinical and questionnaire (Addenbrooke’s Cognitive Assessment [ACE-R]) assessment along with Arterial Spin Labelling (ASL) perfusion Magnetic Resonance Imaging (MRI) of the brain. The ASL data was modelled to yield quantitative arterial CBF maps in neuroanatomical regions involved with cognitive function.
Results: Demographic data revealed aged-matched participants between all three groups (mean age 69.3-71.5 years, ANOVA, p = 0.164). Mean age of last education was significantly lower in the T2DM/MCI group (mean±SD;15.1 ±0.9 when compared to the other groups (HV 19.3±5.6, T2DM 17.1±2.9) Kruskal-Wallis, p=0.003. T2DM/MCI ACE-R score (mean±SD; 83±4) was significantly lower compared to other groups (HV=96±2, T2DM=94±3; ANOVA p&lt;0.001). There was significantly lower CBF in T2DM/MCI compared to T2DM and HV in the medial temporal lobes (CBF 76.8 ml/100g/min, ANOVA p&lt;0.05), insula (CBF 67.5 ml/100g/min ANOVA p&lt;0.005), and frontal lobes (CBF 71.8 ml/100g/min, ANOVA p&lt;0.005)&lt;bold&gt;. &lt;/bold&gt;Pearson’s correlation revealed significant correlations between ACE-R score and regional CBF measurements in the medial temporal lobes, (p&lt;0.05, r=.25) thalamus (p&lt;0.05, r=.23) and insula (p&lt;0.05, r=.29).
Conclusion: This study demonstrates significantly lower CBF in T2DM MCI subjects in neuroanatomical regions responsible for cognitive function. This may be essential to help understand the pathological mechanisms that occur behind the increased risk of developing cognitive impairment in T2DM.

Disclosure
L. Hunt: None. D. Selvarajah: None. S. Tesfaye: Speaker's Bureau; Self; Pfizer Inc.. Other Relationship; Self; Janssen Pharmaceuticals, Inc., Takeda Development Centre Europe Ltd.. Advisory Panel; Self; Wörwag Pharma GmbH & Co. KG. I.D. Wilkinson: None.
Sympathetic Innervation of Human Alpha Cells
Authors: BUTTERWORTH ELIZABETH A. , NASIF LITH H. , NASIF KAMAL , CARTY KATELYN N. , MATHEWS CLAYTON E. , ATKINSON MARK A. , GERLING IVAN C. , CAMPBELL-THOMPSON MARTHA 
Published: June 2018

Autonomic input is critical for the regulation of glucagon secretion to maintain blood glucose levels. Glucagon secretion is abnormal in patients with type 1 diabetes (T1D) and we hypothesize this results from dysfunctional sympathetic innervation of alpha-cells and may be present in at-risk autoantibody positive (AAb+) individuals. To characterize alpha-cell sympathetic innervation, pancreas tail samples were used from age-matched organ donors in three groups: controls (n=6), AAb+ (4), and T1D (4). Fresh frozen 40μm sections or 1-2 cm optically cleared samples were stained with markers for neuroendocrine cells (GCG, INS), total (NCAM)/ sympathetic nerves (tyrosine hydroxylase (TH)), and vascular smooth muscle cells (SMA) followed by confocal and Lightsheet imaging. To determine whether sympathetic fibers were decreased in AAb+ and/or T1D donors, TH+ fiber numbers were counted within islets and the percentage (%) of TH+ fibers/NCAM+ fibers determined. The TH+ fibers/islet were not significantly different between controls (1.5 ± 0.36, n=6), AAb+ (1.2 ± 0.27 (4)), and T1D (1.8 ± 0.57 (4)) donors (p = 0.07, ANOVA) with similar results for TH+ %. TH+ fibers were observed at alpha-cells in all donors. TH+ nerve densities were also similar between islets and exocrine regions between groups. Microarray analysis of single islet transcriptomes obtained using laser microdissection (n=120 islets, 13 control, 12 T1D) showed decreased expression of VMAT2 in insulin+ islets from T1D donors compared to control islets (p=0.047) while insulin- islets in T1D donors had significantly reduced VMAT2 levels compared to control islets (p&lt;0.0001). These data indicate a potential direct mechanism by which the sympathetic nervous system may regulate alpha-cell glucagon secretion with dysregulation of a vesicular monoamine transporter that accumulates monoamines in synaptic vesicles in islets without beta-cells in T1D donors. Sympathetic innervation of alpha-cells could play a direct role in exacerbation of dysregulated glucagon secretion in T1D.

Disclosure
E.A. Butterworth: None. L.H. Nasif: None. K. Nasif: None. K.N. Carty: None. C.E. Mathews: None. M.A. Atkinson: Other Relationship; Self; Patent Issued. I.C. Gerling: None. M. Campbell-Thompson: None.
Shared Genetic Influence on Early Growth and Type 2 Diabetes in Adulthood
Authors: TEKOLA-AYELE FASIL , LEE ANTHONY , WORKALEMAHU TSEGASELASSIE , SHRESTHA DEEPIKA 
Published: June 2018

Background: There is a strong evidence of association between birthweight (BW) and type 2 diabetes (T2D) in adulthood. Although shared genetics has been suggested to be a significant contributor to these associations, to date, we know very few shared genetic loci. We conducted a systematic genome-wide investigation of shared genetic effects (pleiotropy) and enrichment of biologically functional loci implicated in BW-T2D associations.
Methods: We evaluated pleiotropy, enrichment of functional annotation, and association of single nucleotide polymorphisms (SNPs) using genome-wide summary statistics of 2,893,797 SNPs for BW from the Early Growth Genetics Consortium, and T2D from the DIAbetes Genetics Replication And Meta-analysis Consortium. Analyses were conducted using the Genetic analysis incorporating Pleiotropy and Annotation (GPA). Tests for enrichment of annotations from functional datasets were performed in loci associated with pairs of traits.
Results: We found significant enrichment of genetic pleiotropy (P &lt;10-30) and biologically functional loci jointly associated with BW and T2D (enrichment fold of shared vs. BW-specific vs. T2D-specific loci: 1.45 vs. 1.24 vs. 0.57; P=1.73x10-21). A total of 178 independent SNPs in genes NYAP2-IRS1, ADCY5, ST6GAL1, CDKAL1, ANK1, HHEX-ECOC6, FAT3-MTNR1B, and MPHOSPH9 were associated with both BW and T2D at a false discovery rate of 5%. The locus at NYAP2-IRS1 (rs1515098 C) associated with reduced BW and increased T2D risk was novel. Functional analysis showed that rs62188784, in strong LD with rs1515098 (r2=0.91), has potential regulatory (cis-eQTL) effect on expression of the IRS1 gene in adipose tissues.
Conclusions: We found shared genetic loci that influence early growth and type 2 diabetes, including novel shared variant in the insulin receptor substrate 1 gene. Findings suggest that genetic regulation of insulin signaling in adipose tissue potentially influences the associations of early growth and type 2 diabetes later in life.

Disclosure
F. Tekola-Ayele: None. A. Lee: None. T. Workalemahu: None. D. Shrestha: None.
Hypothalamic HSP10 Impacts Mitochondrial Dynamics, Insulin Signaling, and Liver Glycogen Content
Authors: WARDELMANN KRISTINA , CASTRO JOSÉ PEDRO , RATH MICHAELA , WEIß JÜRGEN , SCHUERMANN ANNETTE , KLEINRIDDERS ANDRE 
Published: June 2018

The mitochondrial chaperones heat shock protein 10 (HSP10) and 60 enable proper protein folding and thereby facilitate mitochondrial function. Previously, we demonstrated a reduction of hypothalamic Hsp60 gene expression in type 2 diabetic mice and patients which caused mitochondrial dysfunction and central insulin resistance. Mitochondrial HSP10 is also reduced in brains of db/db mice. However, the effects of reduced HSP10 expression in brain on metabolism and insulin sensitivity are unknown. Thus, we generated a shRNA-mediated knockdown (KD) of Hsp10 in the hypothalamic murine cell line Clu183 and investigated cellular stress responses, mitochondrial function and insulin signaling. 50% KD of HSP10 in vitro causes impaired mitochondrial dynamics and reduced mitochondrial count, but increases mitochondria-endoplasmatic reticulum (ER) contact sites. These cells exhibit reduced mitochondrial respiration and mild oxidative stress represented by a 35% decrease of protein amount of SOD2 along with about 20% decreased protein amounts of subunits of the electron transport chain complexes IV and II. Notably, HSP10 KD induces ER stress shown by the increased gene expression of Chop and increased phosphorylation of IRE1(S724). Most importantly, KD of HSP10 induces acute insulin resistance shown by reduced phosphorylation of IRS-1(Y612) and AKT/PKB(S473) after 5 min of 10 nM insulin stimulation. Preliminary data of a lentiviral-mediated KD approach of Hsp10 in the mediobasal hypothalamus in C57BL/6N mice revealed an unexpected 11% reduction in liver weight partly due to reduced hepatic glycogen content compared to control mice. Consistently, hepatic gene expression of Pepck, which is suppressed by insulin, was increased in Hsp10 KD mice by 60%.
In conclusion, we identified an unexpected role of Hsp10 in regulating hypothalamic mitochondrial function, insulin sensitivity and liver function. Thus, hypothalamic Hsp10 may present a novel regulator of the brain-liver crosstalk.

Disclosure
K. Wardelmann: None. J. Castro: None. M. Rath: None. J. Weiß: None. A. Schuermann: None. A. Kleinridders: None.
Elevated Glucose Concentrations 60 Minutes after an Oral Challenge in Subjects with Normal Glucose Tolerance Are Not Explained by the Rate of Meal-Derived Glucose Appearance
Authors: ADAMS J.D. , TREIBER GERLIES , HURTADO MARIA D. , LAURENTI MARCELLO C. , MAN CHIARA DALLA , COBELLI CLAUDIO , RIZZA ROBERT A. , VELLA ADRIAN 
Published: June 2018

Glucose concentrations 60 minutes after an oral glucose tolerance test (OGTT) ≥155 mg/dL (8.6 mmol/L) identify an increased risk of progression to type 2 diabetes even in those with normal glucose tolerance (NGT). Recent data suggests that these differences can be explained by increased intestinal glucose absorption due to increased expression of the sodium/glucose cotransporter 1 (SGLT1) in the intestine. To examine the contribution of meal appearance to postprandial glucose concentrations we studied 36 subjects with NGT using a 75g OGTT, and a labelled mixed meal. Insulin secretion and action, endogenous glucose production (EGP), meal-derived glucose appearance (Meal Ra) and glucose disappearance (Rd) were subsequently calculated. Participants were grouped according to 60 minute glucose into HI (≥155 mg/dl) or LO (&lt;155mg/dl). No differences in age (47±3 vs. 50±2 years, LO vs. HI respectively, p=0.59) or BMI (28±1 vs. 28±1 Kg/M2, p=0.95) were observed. Fasting (11.9±0.6 vs. 12.6±0.6 μmol/kg/min, p=0.44) and nadir (2.0±0.8 vs. 3.3±0.3 μmol/kg/min, p=0.21) EGP did not differ. Similarly, peak (86±10 vs. 92±6 μmol/kg/min, p=0.59) and integrated (9.8±1.3 vs. 10.6±1.1 mmol per 6 hour, p=0.69) Meal Ra did not differ between groups. On the other hand, when β-cell responsivity (ϕ) was expressed as a function of insulin action (Si), the resulting Disposition Index (DI) was lower in the HI group (1862±409 vs. 893±103 10-14 dl/kg/min2 per pmol/l, p=0.01). When analyzed as a continuous variable, 60 minute glucose was inversely related to DI (r = -0.37, p=0.02) but did not correlate with peak (r=0.03, p=0.96) and integrated (r=0.02, p=0.91) Meal Ra. Taken together, these data indicate that increased 60 minute glucose concentrations, even in subjects with NGT, are explained by decreased β-cell function not by an increased systemic rate of appearance of meal-derived glucose.

Disclosure
J. Adams: None. G. Treiber: None. M.D. Hurtado: 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. A. Vella: Research Support; Self; Novo Nordisk Inc., XOMA Corporation. Advisory Panel; Self; VTV Therapeutics, Bayer AG.
Impact of Diabetes Age of Onset and Duration on Outcomes
Authors: ZHONG JUDY , HA JINKYUNG , BLAUM CAROLINE , KABETO MOHAMMED , CIGOLLE CHRISTINE 
Published: June 2018

Older adults vary in age of onset and duration of diabetes (DM) but are treated similarly. We hypothesized that age of DM-onset has differential impact on distal outcome risk.
0057e analyzed waves 1993-2014 of the Health and Retirement Study, a nationally-representative health survey where we can study people before and after DM diagnosis for ∼ 20 years. Our sample included adults &gt;50 years (n=27,975) without DM at entry. Age of DM-onset was defined as age when respondent first reported DM diagnosis. We classified adults who developed DM into 3 groups: &lt;65, 65-75, &gt;75. For each group, we constructed a propensity-score-matched control group of respondents who never develop DM. We compared risks of outcomes for each onset-age group and control: cardiac disease, stroke, mild disability (1-2 ADL/IADL dependencies), severe disability (&gt;2 ADL/IADL dependencies), death.
At &lt;65 years 1,283 respondents developed diabetes, 1,440 at 65-75, and 1,149 at &gt;75; 21,994 never developed DM. Adults diagnosed with DM at &lt;65 years had substantial increased relative risk of: cardiac 1.3, stroke 1.5, mild disability 1.5, severe disability 1.7, death 1.5, (p&lt;0.001 for each). Respondents diagnosed at older ages had moderate increases with similar duration. (Table)
Age of DM diagnosis differentially impacts key outcome risks in older adults and has more impact than duration. Findings reinforce clinical heterogeneity in DM and the focus to improve DM management in middle aged adults.

Disclosure
J. Zhong: None. J. Ha: None. C. Blaum: None. M. Kabeto: None. C. Cigolle: None.
Altering Glucose Variability with Low- or High-Glycemic–Index Diets in Adults with Prediabetes Does Not Affect Beta-Cell Function or Markers of Oxidative Stress
Authors: UTZSCHNEIDER KRISTINA , JOHNSON TONYA N. , BREYMEYER KARA , NEUHOUSER MARIAN L. 
Published: June 2018

High glycemic variability has been associated with increased oxidative stress and β-cell dysfunction. To test whether changes in glycemic variability impact β-cell function and oxidative stress markers in adults with prediabetes, we conducted an RCT where we provided study subjects controlled diets varying in glycemic index (GI) to experimentally manipulate post-prandial glucose excursions. After 2 weeks on a control diet (mean GI= 55-58), subjects were randomized to 1 of 3 groups for 4 weeks: low (LGI &lt;35) GI diet, high (HGI &gt;70) GI diet plus the anti-oxidant N-acetylcysteine (HGI/NAC) 600 mg BID or HGI diet plus placebo (HGI/PLAC). Subjects underwent CGMS (iPro), fasting markers of oxidative stress (GSH/GSSG and TBARS) and an IVGTT at the end of each diet. Independent t-test was used to test the intervention effect on the change in disposition index (DI), a marker of β-cell function. Fifty-two subjects (26M/26F, age 53±10 y, BMI 32.1±6.2 kg/m2) with IFG and/or IGT completed the study (18 LGI, 17 HGI/NAC, 17 HGI/PLAC). The 3 groups did not differ by sex, age, BMI, A1c, fasting or 2 h glucose (ANOVA). On the control diet, DI was inversely correlated with CGMS mean daily glucose (r=-0.33, p=0.02) and daily SD glucose (r=-0.31, p=0.03) and the GSH/GSSG ratio (r=-0.35, p=0.01), but not TBARS (r=0.13, p=0.4). Compared to LGI, HGI/PLAC increased mean CGMS glucose (change -1.4±1.9 LGI vs. 4.6±2.4 HGI/PLAC mg/dl, p=0.05) and SD (change -2.6±1.3 vs. 5.0±2.2, p=0.005). Results did not differ between HGI/PLAC and HGI/NAC. There were no significant intervention effects on DI, TBARS or GSH/GSSG ratio. Changes in CGMS mean glucose and SD and oxidative stress markers did not correlate with changes in DI.
In conclusion, GI diet-induced changes in glucose concentrations and variability did not impact β-cell function or oxidative stress markers. These results suggest that glucose variability may be a consequence of β-cell dysfunction rather than a cause.

Disclosure
K. Utzschneider: Consultant; Self; Novo Nordisk Inc.. T.N. Johnson: None. K. Breymeyer: None. M.L. Neuhouser: None.
Normal Glucose Tolerance (NGT) in Obese African-Americans (AA) with Ketosis-Prone Diabetes (KPDM)
Authors: VELLANKI PRIYATHAMA , STEFANOVSKI DARKO , NARWANI VISHAL , ANZOLA ISABEL , PENG LIMIN , SMILEY-BYRD DAWN , UMPIERREZ GUILLERMO E. 
Published: June 2018

KPDM is characterized by new-onset DKA and near-normoglycemia remission (HbA1c &lt;7%, fasting blood glucose [BG] &lt;130 mg/dl, and maintain glycemic control for at least one week off insulin) with intensive insulin treatment. Glycemic status at insulin remission varies from NGT, prediabetes or diabetes on OGTT. We hypothesized that patients with NGT at near-normoglycemia remission will have higher insulin sensitivity (Si) and secretion and longer hyperglycemia relapse-free survival. Obese AA who presented with DKA (n=33) and severe hyperglycemia (n=42) (BG &gt;400 mg/dl with no DKA) underwent 2 hour 75-gm OGTT a week after insulin remission. NGT, prediabetes and diabetes were defined as per ADA criteria. At near-normoglycemia remission, Si was calculated using the OGTT minimal model analysis. Insulin secretion was calculated as incremental area under the curve of insulin (IncreAUCi) with insulin levels from OGTT. Disposition index (DI) was calculated as Si x IncreAUCi. Hyperglycemia relapse was defined as fasting BG ≥ 130 mg/dl, HbA1c &gt;7% or 2 random BG ≥ 180 mg/dl. There were no differences in baseline characteristics among patients with NGT (12%), prediabetes (45%) and diabetes (43%). DI was higher in patients with NGT vs. prediabetes vs. diabetes (1.88±1.63 vs. 1.05±1.14 vs. 0.35±0.92, p&lt;0.001). The difference in DI was explained by higher Si than IncreAUCi in NGT compared to prediabetes and diabetes (Si:4.2±4.4 vs. 2.4±3.5 vs. 1.2±2.5 10-4.(mU/l)-1.min-1, p&lt;0.001; IncreAUCi: 6571±3451 vs. 6585±4947 vs. 4450±3051, p=0.14 mU/ml2). Multivariate Cox regression showed that age, sex, DKA presentation, OGTT status, and DI were not associated with long-term relapse-free survival. There were no differences in any variables between patients presenting with DKA or severe hyperglycemia. NGT at near-normoglycemia remission is characterized by higher insulin sensitivity than higher insulin secretion. However, none of these markers were associated with long-term hyperglycemia-free survival.

Disclosure
P. Vellanki: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. D. Stefanovski: None. V. Narwani: None. I. Anzola: None. L. Peng: None. D. Smiley-Byrd: Speaker's Bureau; Self; Sanofi, Merck & Co., Inc., Novo Nordisk Inc. G.E. Umpierrez: Research Support; Self; Sanofi US, Merck & Co., Inc., Novo Nordisk Inc., AstraZeneca. Advisory Panel; Self; Sanofi, Intarcia Therapeutics, Inc..
Association of Pancreas Fat with Impaired Insulin Secretion Depends on Liver Fat and Circulating Fatty Acids
Authors: JAGHUTRIZ BENJAMIN , WAGNER ROBERT , MACHANN JÜRGEN , STEFAN NORBERT , PETER ANDREAS , SIEGEL-AXEL DOROTHEA I. , GERST FELICIA , ULLRICH SUSANNE , FRITSCHE ANDREAS , HAERING HANS-ULRICH , HENI MARTIN 
Published: June 2018

Objective: Beta cell failure is a crucial factor in the pathogenesis of type 2 diabetes. Fat accumulation within the pancreas is associated with impaired insulin secretion only in the context of prediabetes. In vitro evidence suggests an underlying mechanism that depends on the crosstalk between fatty liver and pancreatic fat via circulating factors, including free fatty acids. We now addressed the existence of such an inter-organ crosstalk in humans. We therefore tested for interaction between pancreatic fat content, liver fat, and circulating free fatty acids on insulin secretion.
Methods: We metabolically characterized 296 individuals (93 males/203 females) at increased risk of type 2 diabetes by an 75g oral glucose tolerance test. Insulin sensitivity, insulin secretion, and free fatty acid levels were assessed. Pancreatic fat accumulation was measured by MR-imaging, liver fat was determined by MR-spectroscopy.
Results: There was a significant interaction between pancreatic fat content, liver fat, and free fatty acids on insulin secretion (e.g., p &lt; 0.03 for insulinogenic index). Pancreatic fat was negatively associated with insulin secretion when liver fat content and levels of free fatty acids were markedly elevated. In contrast, at median liver fat and free fatty acid levels, no such relation was detectable.
Conclusion: Pancreatic fat accumulation appears to be harmful for human beta cell function only when additional factors, i.e., fatty liver and elevated levels of circulating free fatty acids are present. These results can explain why the impact of pancreas fat on insulin secretion is only detectable in a prediabetic context and point towards liver fat and circulating factors as possible targets to indirectly improve beta cell function.

Disclosure
B. Jaghutriz: None. R. Wagner: None. J. Machann: None. N. Stefan: Consultant; Self; Merck Sharp & Dohme Corp.. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca, OmniaMed Ltd.. A. Peter: None. D.I. Siegel-Axel: None. F. Gerst: None. S. Ullrich: None. A. Fritsche: Advisory Panel; Self; Sanofi-Aventis Deutschland GmbH, Novo Nordisk A/S, Eli Lilly and Company, Boehringer Ingelheim GmbH. H. Haering: None. M. Heni: Research Support; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Merck Sharp & Dohme Corp., Novo Nordisk Inc..