bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Mitochondrial Pyruvate Carrier Modulators to Treat Diabetes
Authors: MCCOMMIS KYLE S. , HODGES WESLEY T. , CHEN YANA , CHAMBERS KARI , FINCK BRIAN N.
Published: June 2018

Recent work conducted in knockout mouse models or using small molecule modulators of the mitochondrial pyruvate carrier (MPC) have suggested that targeting this protein complex may have efficacy for treating diabetes as insulin sensitizers. To begin to identify other small molecules that interact with the MPC and could potentially be new therapeutic leads, we used a BRET-based MPC reporter assay (reporter sensitive to pyruvate; RESPYR) system that responds to molecules that interact with the pyruvate binding site of the complex. Screening of a 1600 molecule chemical library generated a number of hits for compounds that activated RESPYR activity. Some hits in this unbiased screen confirmed previous reports of MPC interacting drugs, including the insulin-sensitizing thiazolidinediones, pioglitazone and rosiglitazone. Another hit in this screen was Zaprinast, an inhibitor of phosphodiesterase 5 (PDE5). Zaprinast affected RESPYR activity in a dose-dependent manner and at high nM concentrations. Zaprinast also potently inhibited pyruvate-mediated respiration in isolated WT, but not MPC-deficient mitochondria, demonstrating a direct mitochondrial effect and MPC-dependence for this inhibition of pyruvate metabolism. Analyses conducted using other PDE5 inhibitors (Sildenafil, Tadalafil, and Vardenafil) showed no effect on RESPYR activity or mitochondrial respiration. Consistent with the concept that hepatic gluconeogenesis from pyruvate requires mitochondrial pyruvate import, Zaprinast reduced production of glucose from pyruvate in WT, but not MPC-deficient hepatocytes in vitro. Studies are ongoing to determine whether Zaprinast treatment will lower blood glucose in vivo.

In conclusion, these data demonstrate the feasibility of screening for novel MPC interacting compounds to identify novel therapeutics for treating diabetes and other metabolic diseases and also suggests that the orphan drug Zaprinast may be a novel antidiabetic agent.

Disclosure

K.S. McCommis: None. W.T. Hodges: None. Y. Chen: None. K. Chambers: None. B.N. Finck: Board Member; Self; Cirius Therapeutics.
One-Year Follow-Up of Medicare Advantage Enrollees with Type 2 Diabetes and an Initial Elevated HbA1c Value
Authors: CORDIER TRISTAN A. , CHIGULURI VINAY , HINES HUYI , CLARK SARA H. , HAUGH GIL , GUMPINA RAJIV , GOPAL VIPIN , PREWITT TODD G.
Published: June 2018

Introduction: Blood glucose control is critical to slowing the onset of T2DM complications for individuals. National guidelines encourage clinicians and payers to ensure patient HbA1c lab results are less than 8.0%. Understanding the longitudinal patterns of HbA1c control among individuals with lab results over 8.0% is therefore an important undertaking. This study aims to characterize the proportion of individuals returning to HbA1c control within a one year period after an uncontrolled result.

Population and Study Design: Medicare Advantage (MA) patients with a large, national health and wellness company residing in Florida with a diagnosis of type 2 diabetes were included if they had an HbA1c lab value greater than or equal to 8.0% in 2016. Patients had at least one year of continuous coverage prior to the uncontrolled result and were followed until disenrollment, death, or a controlled HbA1c lab value, up to a maximum of one year. Cox regression stratified by initial HbA1c value (8.0-8.9%, 9.0-9.9%, 10.0-10.9%, 11.0-11.9%, 12.0%+) was used to assess the adjusted proportion of persons returning to control over the one year follow-up period. Confounders in the model included: demographic factors, supply of insulin, and comorbidities.

Results: The study cohort consisted of 28,026 persons who met the inclusion criteria (50.7% female, 57.4% white, mean age 71.9 years). Overall, 50.5% (95% CI: 50.0%, 51.1%) of persons achieved HbA1c control within the 1 year follow-up. Inability to return to control was driven by higher initial Hba1c [8.0-8.9% return rate: 61.6% (60.9%, 62.4%) vs. 9.0-9.9%: 39.4% (38.1%, 40.7%) vs. 12.0+%: 27.7% (25.1%, 30.2%)].

Implications: MA patients with HbA1c results greater than 9.0% experienced challenges resuming controlled status suggesting increased attention to this population may be warranted.

Disclosure

T.A. Cordier: Employee; Self; Humana Inc.. Stock/Shareholder; Self; Humana Inc.. V. Chiguluri: None. H. Hines: None. S.H. Clark: None. G. Haugh: None. R. Gumpina: None. V. Gopal: None. T.G. Prewitt: None.
Diabetes and Liver Cancer Risk—A Stronger Effect in Whites than Blacks?
Authors: CONWAY BAQIYYAH , BLOT WILLIAM J
Published: June 2018

Both diabetes and liver and biliary tract cancer are overrepresented among African Americans, but limited information is available on the interrelationship of these two diseases among African Americans. We tested the relationship of diabetes with the incidence of liver cancer and whether this relationship varied between blacks and whites. Using the Southern Community Cohort Study, we conducted a cancer follow-up (2002-2015) of a cohort of mostly low income black and white participants aged 40-79 with (n=17,644) and without diabetes (n=64,870) at cohort entry. Mean age and diabetes duration of those with diabetes was 55.0 and 9.5 years, respectively. Mean age of those without diabetes was 51.6 years. Logistic regression was used to compute ORs (95% CIs) for the risk of incident liver and biliary tract cancer. There were 429 incident cases of these cancers. In univariate analyses, diabetes was associated with an increased risk of liver and biliary tract cancer (OR=1.73, 95% CI=1.36-2.21). Upon further controlling for age, sex, race, BMI, current and former smoking, total alcohol consumption, and any hepatitis infection, diabetes remained a significant risk factor for liver and biliary tract cancer (OR=1.49, 95% CI= 1.18-1.89). However, when stratified by race, risk associated with diabetes was significantly greater among whites (OR = 2.67, 95% CI = 1.71-4.19) than blacks (OR= 1.28, 0.98-1.68) (pinteraction=.002). Furthermore, controlling for diabetes greatly attenuated the higher risk of liver and biliary tract cancer among blacks; indeed, while the cancer risk among those without diabetes was twice as high among blacks than whites (OR=2.01, 95% CI = 1.50-2.69), no racial disparity was observed among those with diabetes (OR = 0.95, 95% CI= 0.62-1.45). The findings raise the possibility of markedly different impacts of diabetes on hepatic carcinogenesis between blacks and whites.

Disclosure

B. Conway: None. W.J. Blot: None.
Persistence with Insulin Glargine 300 IU/ml Compared with Other Basal Insulins—A Canadian Retrospective Cohort Study
Authors: QUANSAH KOBINA A. , SAURIOL LUC , KUKASWADIA ATIF A. , BREMNER SAMANTHA , MILLSON BRADLEY
Published: June 2018

Introduction: Insulin glargine (300 units/mL) is a long-acting insulin approved in Canada on 28-May-2015 for once-daily administration in the treatment of T1DM or T2DM requiring basal insulin therapy. Made of the identical molecule as insulin glargine (100 unit/mL), insulin glargine (300 units/mL) delivers the same amount of insulin in one third of the dose. Four pivotal trials compared GLA-300 to GLA-100 with changes in HbA1C from baseline to 6 months. However, persistence is another important medication metric. Persistence with antihyperglycemic therapies have been associated with positive clinical outcomes and reduced health care costs.

Objective: To assess 12-month persistence on neutral protamine Hagedorn (NPH), insulin detemir, and insulin glargine using Canadian private claims data.

Methods: The study utilized longitudinal private drug plan claims data from IQVIA’s Canadian Private Drug Plan Database. The study was performed looking at persistence for T1DM and T2DM patients combined, without any treatment cessation or change to a different basal insulin. Patients were indexed on their first claim for any of the basal insulins of interest between May 28th 2014 and June 30th 2016, patients’ basal insulin therapy was tracked for 12 months plus a 3 month look-forward period. Patients who did not have continuous coverage or with fewer than 3 claims for an insulin were excluded from the analysis.

Results: At 12 months using a 90 day grace period, 63% of insulin glargine 300 IU/ ml (Toujeo®) patients persisted with therapy compared to 54% of insulin glargine 100 IU/ml (Basaglar), 50% for insulin glargine 100 IU/ml (Lantus), 45% insulin detemir 100 IU/ml (Levemir) and 29% of NPH patients.

Conclusion: A retrospective cohort study of real-world claims data demonstrated insulin glargine 300 IU/ml (Toujeo ®) had the highest persistence among all basal insulins.

Disclosure

K.A. Quansah: Consultant; Self; Sanofi. Employee; Self; Allergan. L. Sauriol: Employee; Self; Sanofi. A.A. Kukaswadia: Consultant; Self; Sanofi. S. Bremner: Consultant; Self; Sanofi. B. Millson: Consultant; Self; Sanofi.
Insulin Acutely Regulates Gene Expression in Brain–A New Potential Major Level of Control of Metabolism and Neurotransmission
Authors: CAI WEIKANG , RAMIREZ ALFRED , DREYFUSS JONATHAN , BATISTA THIAGO M. , MARTIN RUBEN GARCIA , PAN HUI , LI MENGYAO E. , O'NEILL BRIAN T. , KIM JASON K. , RONALD KAHN C.
Published: June 2018

While the brain is now recognized as an insulin sensitive tissue, and impaired insulin signaling in brain can lead to many metabolic and behavioral abnormalities, effects of insulin on gene expression in the brain remain largely unknown. To understand now this aspect of insulin action may impact physiology in vivo, we performed hyperinsulinemic-euglycemic clamps at low (4 mU/kg/min) and high (12 mU/kg/min) physiological doses of insulin in C57BL/6 mice, and after 3 hours collected different brain regions and analyzed their transcriptomes using RNA Seq. In response to low dose insulin infusion, 1851 genes were up- or down-regulated in the hypothalamus by at least 50% (all P < 0.01). This was more than 4-fold as the number of genes regulated in liver or muscle under the same conditions. Other regions showed different responses with 2significantly regulated by at least 50% in hippocampus and 131 regulated in nucleus accumbens. The most upregulated pathway in all three regions was that for very long chain fatty acyl-CoA synthesis, indicating an important role of insulin action on brain fatty acid metabolism. Most other insulin responsive genes in these three brain regions were distinct. In the hypothalamus, insulin played a key role in modulating genes involved in neurotransmission in the hypothalamus, including enhancing the GABA-A receptor signaling pathway and suppressing neuropeptide signaling pathways. Insulin also modulated metabolism in the hypothalamus by suppressing the glycolysis and pentose phosphate pathways, while increasing the pyruvate dehydrogenase complex and cholesterol biosynthesis. Thus, insulin action in the brain acutely and potently regulates expression of genes involved in brain metabolism, neurotransmission and neuromodulation. In this way, insulin re-routes the carbon source to the biogenesis of plasma membrane for neuronal and glial function and synaptic remodeling.

Disclosure

W. Cai: None. A. Ramirez: None. J. Dreyfuss: None. T.M. Batista: None. R. Garcia Martin: None. H. Pan: None. M.E. Li: None. B.T. O'Neill: None. J.K. Kim: None. C. Kahn: Advisory Panel; Self; CohBar, ERX Therapeutics, AntriaBio, Inc.. Board Member; Self; Kaleio Biosciences.
Lack of Brain Insulin Receptor Substrate-1 (IRS1) Causes Growth Retardation via Growth Hormone Releasing Hormone
Authors: HAYASHI TAKANORI , KUBOTA NAOTO , KUBOTA TETSUYA , KADOWAKI TAKASHI
Published: June 2018

Background and Purpose: We previously revealed that systemic Irs1 deficient mice showed growth retardation, indicating that Irs1 plays an important role in growth. Irs1 is main substrate of not only insulin receptor (IR) but also IGF-1 receptor (IGF-1R) tyrosine kinase. Recently, brain specific IGF-1 receptor knockout mice were reported to become growth impairment. We hypothesized that brain Irs1 may regulate growth via IGF-1.

Methods: We generated NIrs1KO mice and analyzed growth related parameter and immunohistochemistry (IHC) study.

Result: The body weight of NIrs1KO mice was significantly smaller than control mice. NIrs1KO mice also showed shorter body length and bone length. On the other hand food intake and gene expression of appetite-related neuropeptides (POMC, AgRP and NPY) were not different between two groups. We next confirmed that plasma IGF-1 and growth hormone (GH) levels of NIrs1KO mice were lower than control mice. Hypothalamic GHRH mRNA expression levels of NIrs1KO mice were also lower than those of control mice although hypothalamic somatostatin mRNA expression was not different between two groups. These data strongly suggest that lack of brain Irs1 causes growth retardation via GHRH. IHC study indicated that Irs1 colocalized with GHRH neuron in hypothalamus. We next investigated the IGF-1-induced proliferation in hypothalamic neural cells by using siIrs1. Downregulation of Irs1 significantly inhibited IGF-1-induced neural cell proliferation.

Conclusion: Our results suggest that IGF-1-Irs1 pathway promotes the proliferation of GHRH neurons and regulate growth.

Disclosure

T. Hayashi: None. N. Kubota: None. T. Kubota: None. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.
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<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<0.05), insula (CBF 67.5 ml/100g/min ANOVA p<0.005), and frontal lobes (CBF 71.8 ml/100g/min, ANOVA p<0.005). Pearson’s correlation revealed significant correlations between ACE-R score and regional CBF measurements in the medial temporal lobes, (p<0.05, r=.25) thalamus (p<0.05, r=.23) and insula (p<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<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 <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 (<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 >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: <65, 65-75, >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 (>2 ADL/IADL dependencies), death.

At <65 years 1,283 respondents developed diabetes, 1,440 at 65-75, and 1,149 at >75; 21,994 never developed DM. Adults diagnosed with DM at <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<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 <35) GI diet, high (HGI >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 <7%, fasting blood glucose [BG] <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 >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 >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<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<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 < 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..
Mild Physiologic Hyperglycemia Impairs Beta-Cell Function and Induces Insulin Resistance in Healthy Normal Glucose Tolerant Subjects
Authors: MEROVCI AURORA , MALDONADO CORCHADO ENRIQUE R. , TRIPATHY DEVJIT , DEFRONZO RALPH A.
Published: June 2018

The aim of the present study was to evaluate effect of a physiologic increase (+45 mg/dl) in plasma glucose concentration on insulin secretion in healthy NGT individuals. 20 NGT subjects: 12 without family history of T2DM (FH-) (9M/3F, age = 50± 4 years, BMI = 27 ± 1 kg/m2) and 8 with FH (FH+) (4M/4F, Age = 48±2, BMI = 26±1) received an OGTT and 2-step hyperglycemic (+125 and +300 mg/dl) clamp (duration of each step = 80 minutes) followed by IV arginine (5g) bolus. The acute insulin response (AIR0-10min), 2nd phase (SP) insulin secretion (IR) (SPIS10-80 and SIS90-160 minutes during each hyperglycemic step and following arginine (AIRArg) were assessed. Insulin sensitivity was assessed as the glucose infusion rate/steady state plasma insulin (M/I) during the hyperglycemic clamp. FPG concentration increased from 97±4 to 140±4 mg/dl for 48 hours by a variable IV glucose infusion. First phase insulin secretion (0-10 min) and 2nd phase insulin secretion (10-80 and 90-60 min) increased by 59% and 78%, respectively, following chronic glucose infusion while insulin sensitivity (M/I) during both hyperglycemic clamp steps declined (15± 3.5 to 12±2.8 and 20.8 ± 4.7 to 8.1 ± 2.0, both p<0.02). Consequently, the insulin secretion/insulin resistance (disposition) index declined by 85± 18% (1st clamp step) and 81±45% (2nd clamp step) (both p<0.05) following chronic glucose infusion. Similar changes were observed when indices of insulin secretion were measured using C-peptide. There was no difference in the effect of chronic glucose infusion on insulin secretion and insulin sensitivity between subjects with and without FH of T2DM. These results demonstrate that: (i) sustained physiologic hyperglycemia impairs insulin sensitivity (glucotoxicity); (ii) increases absolute insulin secretion; (iii) impairs beta cell function as measured with the disposition index (glucotoxicity).

Disclosure

A. Merovci: None. E.R. Maldonado Corchado: None. D. Tripathy: 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..
Insulin Resistance Impairs Cognitive Performance Even in Healthy Subjects at Risk for Diabetes Mellitus
Authors: SORICE GIAN PIO , IMPROTA ILARIA , MEZZA TERESA , GRIONI SARA , IACOBUCCI GIOVANNA MASONE , MOFFA SIMONA , MARI ANDREA , MARRA CAMILLO , GIACCARI ANDREA
Published: June 2018

Increasing scientific evidences support the hypothesis that type 2 diabetes mellitus (T2D) increases the risk of developing dementia and cognitive impairment. Experimental data, although still conflicting, show that insulin resistance (IR) is able to influence cognitive performance (CP). The objective of our study, therefore, was to verify the relationship between insulin resistance and cognitive performance (PC) in subjects at risk for DM2.

For this reason 134 (111 F) volunteers, healthy at risk for diabetes mellitus (overweight and/or fasting hyperglycemia and/or family history for T2D), 39.0±12.3 year old, BMI 25.2±4.8 kg/m2, were enrolled; they underwent to metabolic study (OGTT for glycemia, insulinemia and c-peptide), and neuropsychological tests to evaluate global cognitive function, verbal learning, memory, visual attention and executive functions.

The results of the neuropsychological tests were subsequently normalized by age and education; each test was standardized with a score from 0 (worst) to 4 (best performance). The equivalent scores of each test were summed to obtain a composite endpoint (Cognitive Performance Index), from 0 to 16, with increasing gradient for better CP.By dividing the subjects recruited into quartiles on the basis of PCI, the IR indexes gradually worsened as PCI became worse, particularly HOMA-IR, Matsuda, basal insulin secretion and basal insulin clearance (p <0.04, <0.005, <0.and <0.001, respectively). After multiple regression analysis, basal insulin secretion was more related to CP worsening. No correlation with fasting blood glucose, 1 hour and 2 hours glucose after oral load, was found.

These data seem to reinforce the hypothesis that insulin resistance, independently of glycemia, can worsen performance even in Health subjects, at risk for diabetes mellitus.

Disclosure

G. Sorice: None. I. Improta: None. T. Mezza: None. S. Grioni: None. G. Masone Iacobucci: None. S. Moffa: None. A. Mari: None. C. Marra: None. A. Giaccari: Advisory Panel; Self; Sanofi-Aventis. Speaker's Bureau; Self; AstraZeneca, Merck Sharp & Dohme Corp., Amgen Inc..
Hepatic Lipid Profiling in Fatty Liver Disease—Degree of Saturation Matters
Authors: ERICKSON MELISSA L. , HAUS JACOB M. , FLASK CHRIS , KIRWAN JOHN P.
Published: June 2018

Introduction: Hepatic lipids can take on several storage forms, which vary by degree of saturation. The health consequences of hepatic lipids may vary by storage type, in that polyunsaturated lipids may be favorable, while saturated lipids may be detrimental. The purpose of this study was to determine if the degree of hepatic lipid saturation is related to hallmark characteristics of obesity-related nonalcoholic fatty liver disease, including low exercise capacity and insulin resistance.

Methods: Hepatic lipid profiles were measured using 1H-MRS in 30 adults (55 ± 13.4 years, 31 ± 5.5 kg/m2). Methyl, allylic, methylene, and diallylic peaks were quantified. Hepatic lipids were categorized by storage form, including polyunsaturation, unsaturation, and saturation indices. Explored health correlates include exercise capacity, 40 mU/m2 euglycemic-hyperinsulinemic clamps, and abdominal CT scans.

Results: 20 participants met the diagnostic criteria for nonalcoholic fatty liver disease (total hepatic fat > 5%). Hepatic polyunsaturation index was positively related to absolute maximal oxygen uptake (r=0.41, P=0.04). In addition, hepatic saturation index was inversely related to clamp-derived skeletal muscle insulin sensitivity (r=-0.48, P=0.007).

Discussion/Conclusion: We found that the hepatic polyunsaturation index was positivity related to exercise capacity, independent of body weight. Conversely, saturation index was inversely related to insulin sensitivity. These data show that the health consequences of hepatic fat vary by storage type. Insulin resistance is associated with a higher degree of saturation and a consequential lower degree of polyunsaturation. Thus, effective treatment strategies for nonalcoholic fatty liver disease should not only aim to reduce total hepatic lipid content, but also promote a shift in storage type, from saturation to polyunsaturation, in order to maximize metabolic benefit.

Disclosure

M.L. Erickson: None. J.M. Haus: None. C. Flask: None. J.P. Kirwan: None.
Liver-Specific Overexpression of NOS1AP Alleviates Hepatic Insulin Resistance in Obese Mice
Authors: WANG CHEN , MU KAIDA , ZHAO TIANXUE , ZHU HUI , JIA WEIPING
Published: June 2018

Objective: Nitric oxide synthase 1 adaptor protein (NOS1AP) controls a number of different signaling complexes. We reported previously that the NOS1AP SNP rs12742393 was associated with type 2 diabetes (T2D). T2D and nonalcoholic fatty liver disease (NAFLD) are closely associated, in which NAFLD contributes to the development of liver insulin resistance in T2D. Thus, we investigated whether NOS1AP plays a role in regulating hepatic insulin sensitivity.

Methods: Liver-specific NOS1AP overexpression and knockout mice were fed a high-fat diet (HFD).

Results: NOS1AP protein is highly expressed in mouse liver. Its expression is downregulated in livers of obese rodents. Overexpression of NOS1AP in liver of ob/ob or HFD-induced obese mice improved pyruvate and/or glucose and insulin tolerance, and attenuated liver lipid accumulation in these mice. Conversely, liver specific deletion of NOS1AP impaired pyruvate, glucose and insulin tolerance in the mice, and increased lipid accumulation in the liver. Moreover, overexpression of NOS1AP resulted in reduced expression of Pck1 and increased insulin-induced p-Akt in HepG2 cells. Furthermore, the insulin sensitizing effect of NOS1AP could be mimicked by overexpression of C-terminal domain of NOS1AP in ob/ob mice.

Conclusion: Our data demonstrate a novel role of NOS1AP in regulating hepatic insulin sensitivity and lipid accumulation in liver, which implicates NOS1AP a therapeutic target for treatment of NAFLD and prevention of T2D.

Disclosure

C. Wang: None. K. Mu: None. T. Zhao: None. H. Zhu: None. W. Jia: None.
A Novel Role for SerpinB1, a Protease Inhibitor, in Hepatic Biology
Authors: ORIME KAZUKI , DE JESUS DARIO F. , KULKARNI ROHIT
Published: June 2018

SerpinB1, a protease inhibitor that is secreted from the liver in response to insulin resistance, was recently reported to promote pancreatic β cell proliferation. We focused on investigating the significance of SerpinB1 in the liver to gain insights into its role in regulating whole body metabolism. We determined SerpinB1 gene expression in multiple metabolic tissues harvested under fasting or fed states from ∼34-week-old male Liver-specific insulin receptor knockout (LIRKO) mice and littermate controls. While in controls SerpinB1 expression was reduced by ∼50% after feeding when compared to the fasting state, (P=0.02, n=4-5), the LIRKOs, in contrast, exhibited a 2.3-fold higher (P=0.01, n=5-6) expression in the fed vs. fasting states and the higher levels were consistent with earlier observations in the LIRKO livers. We next took advantage of the availability of liver samples from 18 to 24-week-old male SerpinB1 KO mice and littermate controls and subjected them to RNA-sequencing. As expected, SerpinB1 gene expression was absent in the KO samples, and interestingly, was associated with a significant decrease in gene expression related to cell cycle, NF-kappa B signaling, and inflammatory pathways. Independent validation of these data by RT-qPCR confirmed a decrease in cell cycle-related genes such as Ccna2 (-60%, P=0.04), Ccnb2 (-54%, P=0.04), Ccnd1 (-46%, P=0.03), and Ccne1 (-51%, P=0.07), and the cell proliferation marker, Mki67 (-60%, P=0.00) (n=5). Furthermore, knockdown of SerpinB1 in the human hepatocyte cell line, HepG2, exhibited significantly decreased expression of Ccnb1 (-36%, P=0.01), Ccnb2 (-44%, P=0.00), Ccne1 (-21%, P=0.00), MKi67 (-30%, P=0.00), and MCM2 (-29%, P=0.00) genes, and increased expression of P21 (+165%, P=0.00) (n=3 for control vs. knockdown groups). These novel data implicate endogenous SerpinB1 in cell proliferation in hepatocytes and warrant further investigation of its role in hepatocyte function and the overall impact on glucose homeostasis.

Disclosure

K. Orime: None. D.F. De Jesus: None. R. Kulkarni: None.