bluuebunny/crossref_metadata_2025 huggingface dataset:
Maintenance of ß-Cell Heterogeneity Is Required for Normal Islet Function
Authors: NASTESKA DANIELA , RUTTER GUY A. , ZHOU QIAO , HODSON DAVID
Published: June 2018

Aim: Recent studies have shown the existence of discrete β-cell subpopulations with differing levels of maturity and function. We sought here to understand how this diversity may influence islet function and insulin secretion using a ‘loss of heterogeneity‘ model.

Material and Methods: Overexpression was achieved using an adenoviral polycistronic construct for Pdx1, MafA, Ngn3 and mCherry (Ad3-NPM). Pdx1 was silenced using short hairpin RNAs (shRNA). Gene and protein levels were detected by qPCR and immunohistochemistry (IHC), respectively. Ca2+ fluxes, ATP/ADP ratios and cAMP levels were analysed using dyes/biosensors and high-speed spinning disk microscopy. Glucose- (GSIS) and incretin-stimulated insulin secretion (ISIS) were measured using HTRF assays.

Results: Ad3-NPM increased Pdx1 (12-fold vs. CT; P<0.01) and MafA levels (2-fold vs. CT) without affecting Ngn3. IHC showed that Pdx1 overexpression occurred predominantly in Pdx1low β-cells, forcing higher uniformity throughout the β-cell complement. The α/β-cell ratio did not change, indicating absence of transdifferentiation. Ca2+ responses to glucose were markedly blunted (ΔF=0.81 vs. 0.44 AU, CT vs. Ad3-NPM; P<0.01), and this was accompanied by a decrease in β-cell-β-cell cell connectivity and hub number (12.6 vs. 5.6 % hubs, CT vs. Ad3-NPM; P<0.05), the latter previously shown to be relatively immature cells with pacemaker features. ATP/ADP ratios and cAMP levels were unaffected. Glucose- and incretin-stimulated insulin secretion was impaired (% content secreted = 8.7 vs. 5.2 for GSIS and 56.4 vs. 29.02 for ISIS, CT vs. Ad3-NPM; both P<0.01). Similar results for Ca2+ dynamics, cellular connectivity and insulin secretion were obtained in islets treated with Pdx1 shRNA to increase the size of the Pdx1low population.

Conclusion: Loss of β-cell heterogeneity, whether due to increased or decreased maturity, leads to islet failure and impaired insulin secretion. Thus, cellular diversity appears necessary for normal islet function.

Disclosure

D. Nasteska: None. G.A. Rutter: Research Support; Self; Servier. Q. Zhou: None. D. Hodson: None.
Circulating ANGPTL8 and ANGPTL4 Levels Are Increased in Patients with Hyperglycemia Combined Dyslipidemia
Authors: YU XUEFENG , LU PUHAN , CHEN XI
Published: June 2018

Context: Angiopoietin-like protein 8 (ANGPTL8) and Angiopoietin-like protein 4 (ANGPTL4) are regarded as protein regulating triglyceride (TG) metabolism in mice. However, whether ANGPTL8/4 are involved in glucose and/or lipid metabolism in human remain unclear.

Objective: To examine circulating ANGPTL8/4 levels in subjects with hyperglycemia and/or dyslipidemia and their correlation with glucose and lipid metabolism. Design, Setting and Participants: Serum ANGPTL8/4 levels were measured using ELISA in age-, sex-, and BMI- matched healthy control subjects (CON) (n=92), subjects with isolated hyperglycemia (IHG) (n=87), with isolated dyslipidemia (IDL)(n=86) and hyperglycemia combined dyslipidemia (HCD)(n=99) from the Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal (REACTION) study.

Results: Serum ANGPTL8 and ANGPTL4 levels were both elevated in patients with HCD compared to CON subjects. After controlling for age, sex and blood lipid, ANGPTL8 levels positively correlated with fasting plasma glucose (FPG) (partial r = 0.154), HbA1c (partial r = 0.110) and triglycerides and glucose (TyG) index (age, sex adjusted)(partial r = 0.224). After controlling for age, sex and FPG, ANGPTL8 levels positively correlated with TG (r = 0.163), TG/HDL (r = 0.147) and non-HDL/HDL (r = 0.134). ANGPTL4 were positively correlated with FPG, 2h-glucose, HbA1c and TyG index. Among lipid-related variables, ANGPTL4 were positively correlated with TG, TG/HDL, non-HDL/HDL and negatively correlated with HDL-cholesterol. After controlling for related variables, the correlations were the same.

Conclusion: Circulating ANGPTL8 and ANGPTL4 levels were increased in patients with HCD and might play an important role in linking glucose and lipid metabolism.

Disclosure

X. Yu: None. P. Lu: None. X. Chen: None.
Hypertriglyceridemia per se Is Not an Independent Risk Factor for Beta-Cell Dysfunction
Authors: YAMAUCHI JUN , ZHANG TING , LEE SOJIN , DONG HENRY
Published: June 2018

Hypertriglyceridemia results from increased production and decreased clearance of triglyceride-rich very low-density lipoproteins, a pathological condition that accounts for heightened risk of ischemic vascular diseases in obesity and type 2 diabetes. Despite its intimate association with insulin resistance, whether hypertriglyceridemia constitutes an independent risk for beta-cell dysfunction in diabetes is unknown. Answering this fundamental question is stymied by the fact that hypertriglyceridemia is intertwined with hyperglycemia and insulin resistance in obese and diabetic subjects. To circumvent this limitation, we took advantage of apolipoprotein C3 (ApoC3)-transgenic mice, a model with genetic predisposition to hypertriglyceridemia without alterations in glucose metabolism. We showed that ApoC3-transgenic mice, as opposed to age/sex matched wild type littermates, develop hypertriglyceridemia with concomitant elevations in plasma cholesterol and non-esterified fatty acid levels. Anti-insulin and anti-glucagon dual immunohistochemistry in combination with morphometric analysis revealed that ApoC3-transgenic and wild type littermates had similar beta-cell and alpha-cell masses as well as islet size and architecture. These effects correlated with similar amplitudes of glucose-stimulated insulin secretion and similar degrees of postprandial glucose excursion in ApoC3-transgenic vs. wild type littermates. ApoC3-transgenic mice did not visualize lipid infiltration into islets, correlating with the lack of ectopic triglyceride and cholesterol depositions in the pancreata. ApoC3-transgenic mice, despite persistent hypertriglyceridemia, maintained euglycemia under both fed and fasting conditions without manifestation of insulin resistance and fasting hyperinsulinemia. We concluded that hypertriglyceridemia per se is not an independent risk factor for beta-cell dysfunction.

Disclosure

J. Yamauchi: None. T. Zhang: None. S. Lee: None. H. Dong: None.
Effect of a New Type of Nanomaterial on Glucose and Lipid Metabolism
Authors: WU JIN , CHEN YINGBO , LIU LIPING , YAO QING , LIU XIAOCEN , WU YINGJIE
Published: June 2018

Diabetes mellitus is a systemic metabolic disease characterized by disrupted glucose and lipid metabolism. With an alarming rise of incidence each year, there is therefore a pressing need to find more efficient medicines and methods for its treatment. Using the obese type 2 diabetes db/db mouse model, in our pervious work we found that a new type of nanomaterial could inhibit the formation of insulin resistance. The underlying mechanisms of its therapeutic effect in the glucose and lipid metabolism are further investigated in the present study. Compared with the control mice, the blood glucose of the mice decreased significantly after the nanomaterial injection, accompanied by a dose-dependent hypoglycemic effect. The impaired glucose tolerance and insulin resistance were significantly improved in mice treated with the material. We found that the expression of PCK1 and G6Pc were reduced at both RNA and protein levels, whilst p-AKT was stimulated at the protein level after the nanomaterial injection, which indicated its positive impact on glucose metabolism. Reductions in total, adipose and liver weight were also present in db/db mice treated with the material, compared with the control. In the aspect of lipid metabolism, H and E and oil red O staining of liver tissue revealed an amelioration of fatty liver symptoms in mice injected with the material. Consistent with the observed phenotype, the mRNA expression of the FA synthesis enzymes ACC and FAS were decreased significantly after the treatment, as confirmed by q-PCR analysis. Meanwhile, an observably lower nucleus abundance of SREBP1c, the important transcriptional regulator of ACC and FAS, was detected following the treatment, using immunohistochemical approach. These results demonstrate the striking effects of the nanomaterial on the glucose and lipid metabolism. Taken together, our data implies the significance of this novel type of nanomaterial as the next-generation therapy for diabetes and fatty liver, yet the relevant mechanisms are to be further examined.

Disclosure

J. Wu: None. Y. Chen: None. L. Liu: None. Q. Yao: None. X. Liu: None. Y. Wu: None.
Serum Uric Acid (SUA), Urinary Albumin Excretion (UAE), and Hypertension (HTN) in Adolescents with Type 2 Diabetes (T2D) in the TODAY Study
Authors: BJORNSTAD PETTER , LAFFEL LORI M. , LYNCH JANE L. , GHORMLI LAURE EL , WEINSTOCK RUTH S. , TOLLEFSEN SHERIDA E. , NADEAU KRISTEN J.
Published: June 2018

Elevated SUA is increasingly recognized as a risk factor for kidney disease in adults with diabetes, yet there are limited data in youth. We hypothesized that elevated SUA would predict development of elevated UAE and HTN over time in teens with T2D. Serum creatinine, cystatin C, SUA, and urine albumin to creatinine ratio (ACR) were assessed in 539 youth, ages 12-17 with T2D duration <2 years at baseline in the TODAY study. Estimated GFR (eGFR) was calculated using creatinine and cystatin C. HTN was defined as systolic (SBP) or diastolic blood pressure (DBP) ≥130/80 mm Hg and elevated albumin excretion (UAE) as ACR ≥30mg/g. Mean arterial pressure (MAP) was calculated ([SBP + 2 (DBP)]/3). Generalized estimating equations and Cox proportional hazard models evaluated the relationship between SUA and outcome variables longitudinally over 7 years, adjusting for age, sex, race/ethnicity, BMI, A1c, eGFR, ACEi/ARB use, and TODAY treatment group assignment. Hyperuricemia (≥6.8 mg/dL) was present in 25.6%, HTN in 18.7%, and elevated UAE in 6.1% at baseline, and boys had higher baseline SUA than girls (6.7±1.4 vs. 5.4±1.2 mg/dl, p<0.0001). Over 7 years, 37.4% developed HTN and 18.0% elevated UAE. Baseline SUA correlated with increase in SBP (β±SE: 0.66±0.16, p<.0001), DBP (0.37±0.15, p=0.01), MAP (0.47±0.14, p=0.001), and log UAE (0.05±0.02, p=0.01) over time in multivariable models. Higher baseline SUA increased risk of incident HTN (HR: 1.20, 95% CI 1.05-1.36, p=0.007, per 1 mg/dL increase in SUA) and incident elevated UAE (HR: 1.23, 95% CI 1.03-1.47, p=0.02, per 1 mg/dL increase in SUA) in fully adjusted models. Hyperuricemia was common in youth with T2D; higher baseline SUA independently increased risk for onset of HTN and elevated UAE over 7 years. Therapies lowering SUA may hold promise to impede development of diabetic kidney disease and HTN in T2D youth.

Disclosure

P. Bjornstad: Consultant; Self; Boehringer Ingelheim GmbH. L.M. Laffel: Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc., Sanofi US, MannKind Corporation, Roche Diagnostics Corporation, Dexcom, Inc., Insulet Corporation, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Johnson & Johnson Diabetes Institute, LLC. J.L. Lynch: Other Relationship; Self; Novo Nordisk Inc.. Research Support; Self; Daiichi Sankyo Company, Limited. L. El Ghormli: None. R.S. Weinstock: Research Support; Self; Medtronic MiniMed, Inc., Mylan, Kowa Pharmaceuticals America, Inc., Diasome Pharmaceuticals, Inc., Calibra Medical, Dexcom, Inc., Ultradian Diagnostics LLC., JAEB Center For Health Research, JDRF, National Institute of Diabetes and Digestive and Kidney Diseases. S.E. Tollefsen: None. K.J. Nadeau: None.
The TCF7L2 Variant rs7903146 Affects the Risk of Youth-Onset Type 2 Diabetes by Reducing the Incretin Effect on Insulin Secretion
Authors: GALDERISI ALFONSO , PIERPONT BRIDGET , D'ALESSIO DAVID , SANTORO NICOLA , CAPRIO SONIA
Published: June 2018

Background: Common variants of the transcription factor-7-like-2 gene (TCF7L2) have been implicated in the progression of prediabetes to T2D. We explored the effect of the rs7903146 variant on the incretin effect in youths with dysglycemia.

Methods: 5 carriers with the risk-genotype of TCF7L2 (TT at the rs7903146, 14.4±2.3y, BMI 34.7±6.4kg/m2) and 5 with the wild type genotype CC (16.2±1.9y, BMI 36.8±6.0kg/m2) underwent a 3-hour OGTT followed, a week later, by an isoglycemic intravenous glucose infusion (IVGTT), designed to match the plasma glucose concentrations during the OGTT. The incretin effect was measured as 100*(SROGTT-SRIVGTT)/SROGTT where SR was the secretion rate of c-peptide.

Results: As shown in the Figure, the plasma glucose profile in the OGTT and IVGTT were well matched in both groups. The increase in SR during the OGTT compared to IVGTT was significantly lower in the carriers of the TT compared to CC genotype (ΔiAUCc-peptide 1281±688.6 vs. 5632±1604 pmol/L*min, p < 0.025). Thus, relative to the control group, carriers of the TT-risk genotype had a significant reduction of the incretin effect (TT 0% [-11.74, 16.84], CC: +35% [12.05, 55.71]; p <0.018).

Conclusion: The TCF7L2 variant rs7903146 impairs the incretin effect in obese youths carrying the risk-genotype (TT), suggesting a causative mechanism for the association of this variant with progression to T2D.

Disclosure

A. Galderisi: None. B. Pierpont: None. D. D'Alessio: Consultant; Self; Intarcia Therapeutics, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S. N. Santoro: None. S. Caprio: None.
Risk Factors of Youth Type 2 Diabetes (Y-T2DM) and Prevalence of Dysglycemia (DG)
Authors: SALEH MOHAMED , KIM JOON YOUNG , MARCH CHRISTINE , YOUSUF SHAHWAR , ARSLANIAN SILVA A.
Published: June 2018

The incidence of Y-T2DM is increasing parallel with the childhood obesity epidemic. The ADA consensus recommends screening for Y-T2DM or prediabetes in asymptomatic overweight youth who have any two additional risk factors (RFs): family history of T2DM in 1st or 2nd degree relatives, minority race/ethnicity, insulin resistance [acanthosis nigricans, polycystic ovary syndrome, hypertension, dyslipidemia, and small for gestational age], and maternal GDM during the child’s gestation. However, the evidence for these recommendations is minimal, if not nonexistent. In an established pediatric obesity registry, OGTT data of 618 youth ˃10 years old, BMI ≥ 85th%, were analyzed to evaluate the prevalence of DG based on the frequency of RFs. Participants were divided into 4 groups according to the number of RFs. Participants were 70% females, 70% Caucasians, 31% with prediabetes, and 5.1% with Y-T2DM. With increasing RFs, the prevalence of normal glucose tolerance (NGT) declined, DG increased, fasting glucose concentration did not change, but fasting insulin concentration increased significantly (Table: mean ± SE). Participants with 1 RF had ∼25% prevalence of DG. The odds for DG with 2, 3 and ≥ 4RFs were 1.6, 1.7, and 2.5 respectively compared to 1 RF (P=0.01).

In conclusion, the prevalence of prediabetes and T2DM in overweight/obese youth is high ∼25% in the presence of only 1 RF, and escalates with increasing number of RFs.

Obesity + 1 RF (n=45)Obesity + 2 RF (n=165)Obesity + 3 RF (n=223)Obesity + ≥4RF (n=185)P-ANOVAAge (years)13.7 ± 0.314.0 ± 0.214.3 ± 0.114.4 ± 0.2NSGlycemic status (NGT/Dysglycemia), n (%)34 (75.6 %) / 11 (24.4 %)1(65.5 %) / 57 (34.5 %)143 (64.1 %) / 80 (35.9 %)103 (55.7 %) / 82 (44.3 %)0.009BMI percentile97.6 ± 0.498.0 ± 0.398.4 ± 0.298.6 ± 0.2NSFasting glucose (mg/dl)92.4 ± 1.293.9 ± 0.994.0 ± 0.994.9 ± 1.2NSFasting insulin (μu/ml)25.6 ± 2.331.0 ± 1.934.7 ± 1.642.5 ± 2.7< 0.0001OGTT 2-hr. Glucose (mg/dl)117.6 ± 4.7125.9 ± 3.0129.4 ± 2.7138.4 ± 3.30.001OGTT 2-hr. Insulin (μU/ml)121.5 ± 17.6160.7 ± 11.2169.9 ± 10.8217.0 ± 14.3< 0.0001

Disclosure

M. Saleh: None. J. Kim: None. C. March: None. S. Yousuf: None. S.A. Arslanian: None.
Deep Phenotyping of a Spontaneous Nonhuman Primate Model of Diabetic Macular Edema
Authors: CHIA SER MIEN , GONG LI , TIU SARAH , ANNAMALAI SARAYU PARIMAL , LI NINA X. , PAN LINGZHEN , HONG LEWIS , BAKAR ALI ASAD ABU , CHIN CHIH-LIANG , ZENG WEN
Published: June 2018

Diabetic retinopathy (DR) is a diabetic complication involving damages to blood vessels in the retina that, if left untreated, can lead to blindness. It is estimated that over 93 million people suffer from DR worldwide and in fact the disease accounts for 12% of all new cases of blindness each year in the United States. Diabetic macular edema (DME) is one of the manifestations of DR, in which fluids leak from the blood vessels into the centre of the macula, causing pain, swelling, and blurred vision. However, the underlying pathogenesis of DR/DME is complex and not well understood, thus impeding the development of effective treatment. Consequently, the use of animal models of DR is of critical importance for better understanding of the underlying pathogenesis of DME, as well as developing new drugs. Non-human primate (NHP) models of diabetes are known to be the most clinically translatable animal models, where the animals develop major clinical phenotypes along the disease progression, including DR. As such, in this study we phenotyped a cohort of type 2 prediabetes/diabetes NHPs (n=123, weight: 11.5±2.0kg, age: 15.5±2.9years) using clinically relevant circulating and imaging biomarkers. Specifically, spectral domain optical coherence tomography (OCT) was first used to identify a subgroup of the animals with significantly thickened retina (329 ± 6.77µm) with an accumulation of hard exudates and inter-retinal cysts (n= 59). Fundus fluorescein angiography (FA) imaging further confirmed the presence of retinal vascular leakage into the cystoid spaces during the late-phase FA. Levels of vascular endothelial growth factor (VEGF) in both plasma and vitreous fluid were also measured and the results appear to correlate with retina thickness (vs. aged-matched controls). Taken together, our findings demonstrate a clinically translatable NHP model for DR/DME that allows characterization of disease progression in vivo, investigation of co-morbidities, and evaluation of novel therapeutics.

Disclosure

S. Chia: Employee; Self; Merck Sharp & Dohme Corp.. L. Gong: None. S. Tiu: Employee; Self; Merck & Co., Inc. S. Annamalai: Employee; Self; Merck Sharp & Dohme Corp. N.X. Li: Employee; Self; Merck & Co., Inc.. L. Pan: None. L. Hong: Employee; Self; Merck Sharp & Dohme Corp.. Employee; Spouse/Partner; Illumina, Inc. A. Abu Bakar Ali: Employee; Self; Merck & Co., Inc. C. Chin: Employee; Self; Merck & Co., Inc.. W. Zeng: None.
FoxK1/K2 Are New, Important Components of IR and IGF1R Signaling and Control of Cell Proliferation and Metabolism
Authors: SAKAGUCHI MASAJI , CAI WEIKANG , WANG CHIH-HAO , BATISTA THIAGO M. , ARAKI EIICHI , KAHN C. RONALD
Published: June 2018

Insulin and IGF-1 are regulators of cell growth and metabolism. Despite considerable progress in understanding the molecular mechanisms underlying these effects, except for members of the FoxO family, many regulators of the transcriptional effects of these hormones remain poorly understood. To identify new components of IR/IGF1R signaling, we created brown preadipocyte lines in which both endogenous IR and IGF1R genes had been deleted and then reconstituted these cells with normal IR, IGF1R or chimeric receptors containing the extracellular domain of IR fused to intracellular domain of IGF1R and vice versa. Mass spectroscopic proteomic analysis revealed a number of proteins co-precipitated with each receptor construct, in both ligand stimulation-dependent and -independent manners. Among the proteins that associated with both receptors and chimeric receptors in a ligand-dependent manner was FoxK1. In contrast to FoxO1, the transcription factor FoxK1 was translocated from the cytoplasm to the nucleus after insulin stimulation, a pattern that is reciprocal to that of FoxO1 after insulin stimulation. We show that FoxK1 and FoxK2 are phosphorylated in two major domains and that translocation to the nucleus is dependent on the Akt-mTOR mediated phosphorylation, while their localization to the cytoplasm in the basal state is dependent on GSK3 phosphorylation. Knockdown of FoxK1 and FoxK2 in a mouse hepatocyte cell line causes marked alteration of the transcription of genes associated with apoptotic pathway and down-regulation of genes involved in control of cell cycle and metabolism. This resulted in decreased cell proliferation and altered mitochondrial fatty acid metabolism in these cells. Thus, insulin stimulates the reciprocal translocation of FoxKs and FoxO1 between the cytoplasm and nucleus turning off FoxO1-regulated genes and turning on FoxK-regulated genes resulting in an elaborate balance in insulin regulation of metabolism, growth and cell survival.

Disclosure

M. Sakaguchi: None. W. Cai: None. C. Wang: None. T.M. Batista: None. E. Araki: Speaker's Bureau; Self; Astellas Pharma US, Inc., MSD K.K., Kowa Pharmaceuticals America, Inc., Sanofi, Novo Nordisk Inc.. Research Support; Self; Astellas Pharma US, Inc., MSD K.K., Ono Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Takeda Pharmaceuticals U.S.A., Inc., Daiichi Sankyo Company, Limited, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Sanofi, Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co. C. Kahn: Advisory Panel; Self; CohBar, ERX Therapeutics, AntriaBio, Inc.. Board Member; Self; Kaleio Biosciences.
Hyperinsulinemia Invokes Greater Brain Perfusion in Reward and Motivation Regions in Obesity
Authors: GROSKREUTZ DEREK , SINHA RAJITA , LACADIE CHERYL , LAM WAI , HAMZA MUHAMMAD , SCHMIDT CHRISTIAN P. , SEO DONGJU , HWANG JANICE , BELFORT-DEAGUIAR RENATA , LEVENTHAL JESSICA , ROSENBERG SAMUEL , PARIKH LISA , CONSTABLE TODD , SHERWIN ROBERT , JASTREBOFF ANIA M.
Published: June 2018

Elevated insulin levels are often observed in obesity, but the effects of hyperinsulinemia on cerebral blood flow (CBF) are not known. While insulin acts as a satiety factor in lean humans, it is unclear if this CNS effect is maintained in the setting of hyperinsulinemia in obesity. This study aimed to isolate the effects of elevated insulin levels during euglycemia in lean (LN: n=6, BMI 21.1 kg/m2, age 32 years) and obese (OB: n=8, BMI 32, age 30) humans. Participants underwent a 2 hour oral glucose tolerance test [mean 120-min insulin LN 41 mU/ml vs. OB 113 mU/mL (p=.49) and glucose LN 101 mg/dL vs. OB 112 mg/dL (p=.72)] and on 2 separate days received either a saline infusion (control) or underwent a euglycemic-hyperinsulinemic clamp (insulin 2 mU/kg/min, glucose 90 mg/dL) during functional magnetic resonance imaging (fMRI). Whole-brain analyses comparing neural responses on hyperinsulinemic vs. saline control days demonstrated increased CBF in the putamen, insula, anterior cingulate cortex, and middle temporal gyrus in the OB group, but not in the LN group (p=.01, whole-brain corrected; Figure). We conclude that obesity invokes different CBF responses to hyperinsulinemia, specifically in regions implicated in impulsivity, reward processing, and interoceptive signaling. Thus, while in lean humans increased insulin levels signal satiety and reduce food-seeking behavior, this may not be the case in obese humans.

Disclosure

D. Groskreutz: None. R. Sinha: None. C. Lacadie: None. W. Lam: None. M. Hamza: None. C.P. Schmidt: None. D. Seo: None. J. Hwang: None. R. Belfort-DeAguiar: Research Support; Self; GlaxoSmithKline plc.. J. Leventhal: None. S. Rosenberg: None. L. Parikh: None. T. Constable: None. R. Sherwin: Other Relationship; Self; QuintilesIMS, MannKind Corporation. Research Support; Self; Regeneron Pharmaceuticals, Inc.. Other Relationship; Self; ICON plc. A.M. Jastreboff: Consultant; Self; Novo Nordisk Inc., Rhythm Pharmaceuticals Inc., Medtronic.
Regulation of Lipocalin 2 by Estrogen in Human Adipose Tissue—A Link between Erß Pathway and Insulin Resistance
Authors: KAMBLE PRASAD G. , PEREIRA MARIA J. , BOERSMA GRETHA J. , ALMBY KRISTINA E. , ERIKSSON JAN W.
Published: June 2018

We recently showed that the adipokine lipocalin 2 (LCN2) causes insulin resistance in human adipose tissue (AT). Its expression is induced by dexamethasone (Dex) in AT from pre-menopausal women, but not from post-menopausal women or men. We also found that males had higher levels of LCN2 mRNA than females. Together, this proposes a regulation of LCN2 by glucocorticoids and sex steroids. Subcutaneous (SC) AT from post-menopausal women (n=29, 67±7 Y, BMI 28±5 kg/m2) was incubated ± 17 β-hydroxy estradiol (E2, 0.01-100 nM) and ± Dex (0.3 µM) for 24 h and LCN2 mRNA levels were measured. AT was co-treated with E2 (1 nM) and 100 nM and either estrogen receptor (ER) α or β antagonist, MPP or PHTPP, respectively, or with an ERβ agonist (DPN, 100 nM) for 24 h. E2 (1nM) increased LCN2 mRNA (p<0.01) and protein (p<0.05) levels by∼3 fold in AT, which was reversed by ERβ antagonist. Notably, E2 in presence of MPP induced LCN2 mRNA by 6 fold (p<0.05) compared to control. Likewise, ERβ agonist also induced LCN2 mRNA by 3.5 fold (p<0.05). Next, E2 induced ERβ mRNA by 1.8 fold (p<0.05), but not ERα mRNA or protein levels. Dex alone did not change LCN2 mRNA levels in AT from post-menopausal females. Dex reduced ERα mRNA and protein levels by 20% (p<0.001) and 35% (p<0.01), respectively, but increased ERβ mRNA by 220% (p<0.001). Dex-induced reduction in ERα mRNA levels was associated with BMI (r=0.569, p<0.01), waist circumference (r=0.565, p<0.01), fasting insulin (r=0.531, p<0.05) and c-peptide (r=0.560, p<0.01). In multivariate analysis BMI (std β coefficient = 0.626, p < 0.01; model: r 2 = 0.392) remained as significantly associated variable.

In summary, E2 induced LCN2 expression in SCAT of postmenopausal women and this may be mediated via ERβ. Dex stimulation and inhibition of ERα and ERβ respectively implies a selective glucocorticoid mechanism to promote ERβ mediated transcriptional pathways. Overall, our data suggest that ERβ pathway may promote LCN2 expression and hence insulin resistance in AT.

Disclosure

P.G. Kamble: None. M.J. Pereira: None. G.J. Boersma: None. K.E. Almby: None. J.W. Eriksson: Employee; Spouse/Partner; Amgen Inc.. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Consultant; Self; Novo Nordisk A/S, Merck Sharp & Dohme Corp.. Research Support; Self; Bristol-Myers Squibb Company.
Real-World Risk Indicators of Severe Hypoglycemia in T2D—Results of the InHypo-DM Study
Authors: RATZKI-LEEWING ALEXANDRIA , HARRIS STEWART , MEQUANINT SELAM , AU NATALIE H. , BLACK JASON E. , REICHERT SONJA M. , BROWN JUDITH B. , RYAN BRIDGET L.
Published: June 2018

Insight into the self-reported frequency of third-party assisted severe hypoglycemia (SH) is critical for the therapeutic optimization of type 2 diabetes (T2D). This study presents real-world epidemiological evidence on the self-reported incidence and related risk indicators of SH.

A validated questionnaire (InHypo-DMPQ) was administered to a population-based panel of adult Canadians with T2D treated with insulin and/or secretagogues. Questions pertained to respondents’ past hypoglycemia events as well as socio-demographic and clinical characteristics, including hypoglycemia unawareness. Univariable analyses (p≤0.20) followed by a multivariable zero-inflated negative binomial (ZINB) analysis were performed to explore the influence of potential risk indicators on the occurrence of any and repeated SH events.

The current evaluation is based on a cohort of 436 respondents (mean age: 53 years; male: 54%). Among these individuals, 37.8% (95% CI: 33.3%-42.4%) self-reported at least one SH event in the past year; the incidence rate was 2.4 events (95% CI: 2.26-2.55) per person-year. Based on the ZINB analysis, only non-severe (NH) hypoglycemia was independently associated with SH, holding other indicators constant. Among respondents who reported ≥1 (vs. zero) NH events, the odds of never experiencing an SH event decreased by 82% (95% CI: 39.3%-94.7%, p=0.006). Likewise, a history of NH, among those who had a chance of experiencing SH, increased the expected rate of SH by a factor of 4.29 (95% CI: 2.25-8.17, p<0.001).

Real-world estimates of SH in T2D are often limited by sub-optimal reporting and gaps in clinical practice. To help clarify the true frequency of SH, this large, population-based study leveraged the value and clinical relevance of self-reported hypoglycemia data. The results of this study suggest that the burden of third-party assisted SH is substantial in people with T2D. Clinical strategies to prevent NH may reduce the risk of any/repeated SH events and resulting sequelae.

Disclosure

A. Ratzki-Leewing: None. S. Harris: Advisory Panel; Self; Novo Nordisk A/S, Sanofi, Merck, AstraZeneca, Amgen Inc., Lilly/Boehringer Ingelheim, Abbott, Janssen. Consultant; Self; Novo Nordisk A/S, Sanofi, Merck, AstraZeneca, Lilly/Boehringer Ingelheim, Abbott, Janssen. Research Support; Self; Novo Nordisk A/S, Sanofi, Merck, Abbott, AstraZeneca, Janssen. Other Relationship; Self; CIHR, CDA, The Lawson Foundation. S. Mequanint: None. N.H. Au: None. J.E. Black: None. S.M. Reichert: Other Relationship; Self; Novo Nordisk Inc., Sanofi, Abbott, AstraZeneca. Advisory Panel; Self; Servier. Speaker's Bureau; Self; Eli Lilly and Company. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Merck & Co., Inc., Janssen Pharmaceuticals, Inc.. J.B. Brown: None. B.L. Ryan: None.
Does Hypoglycemia Awareness Status on Gold and Clark Questionnaires Predict Hormonal and Symptomatic Responses to Hypoglycemia (HG) in Type 1 Diabetes (T1D)?
Authors: RUBIN NATHAN , MOHEET AMIR , EBERLY LYNN E. , KUMAR ANJALI , MANGIA SILVIA , SEAQUIST ELIZABETH R.
Published: June 2018

Impaired awareness of hypoglycemia (IAH) is characterized by the diminished ability to perceive symptoms of HG. Gold and Clark questionnaires are commonly used in research to identify patients with IAH. However, the relationship between IAH status on questionnaires and the symptom and counterregulatory (CR) hormone responses to HG are not well understood. In this study, we examined data from 51 research subjects with T1D who completed both questionnaires and underwent a hyperinsulinemic hypoglycemic clamp (target glucose 50 mg/dL) on the same day. Clarke and Gold scores were highly correlated with one another (r = 0.78) and each had a similar relationship with epinephrine (EPI) response during HG (Clarke: r = -0.46, Gold: r = -0.53) and symptom response (Clarke: r = -0.60, Gold: r = -0.52). However, Clarke and Gold disagreed on classification of HG awareness status (misclassification=37%, Cohen’s κ=0.54). Clarke classifications were: 26 Aware (A), 13 Indeterminate (I), 12 Unaware (U), whereas Gold classifications were 16 A, 15 I, and 20 U. A mixture model based clustering identified 3 patterns in joint EPI and symptom responses. Cluster 1 subjects (n=10) had low symptom (<5) and EPI responses (<140) to HG and 8/10 were classified as U by one or both questionnaires. Cluster 3 subjects (n=9) had high symptom (20+) and EPI responses (450+) to HG and 8 of 9 were classified as A by one or both questionnaires. Cluster 2 subjects (n=22) had intermediate symptom and EPI responses to HG but concordance of classification by Clarke and Gold was true for only 11 of the 24. Clarke classified cluster 2 subjects as 12 A, 7 I, and 3 U whereas Gold classified the same subjects into 6 A, 7 I, and 9 U. IAH classification may be discordant between Clark and Gold questionnaires and may not always correlate with the CR responses during experimental HG. To ensure reproducibility, researchers must be rigorous and consistent in defining the awareness status of study subjects.

Disclosure

N. Rubin: None. A. Moheet: None. L.E. Eberly: None. A. Kumar: None. S. Mangia: None. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company, Sanofi, Zucera, InfoMed, 360 consulting. Other Relationship; Self; Novo Nordisk Inc..
A Prospective, Multicentric Study to Evaluate the Effects of Saroglitazar on Non-HDL Cholesterol and Small Dense LDL Particles in Patients with Diabetic Dyslipidemia
Authors: KAUL UPENDRA , JAIN PEEYUSH , KACHRU RANJAN , BHATIA VINEET , ARAMBAM PRIYADARSHINI , SHEKHAWAT SUDHIR , DIANA YUMNAM , RAWAT KAVITA , SINGH SHILPI , JAISWAL ASHOK
Published: June 2018

Saroglitazar, a dual PPAR α/γ agonist, is approved in India for the treatment of diabetic dyslipidemia (DD) not controlled with statins. DD is highly atherogenic as it is associated with high triglycerides (TG), high small dense LDL (sdLDL) and low HDL-C. In this, prospective multi-centric study conducted in patients with type 2 diabetes and triglycerides (TG) ≥200 mg/dL after lifestyle and stable statin therapy for at least 3 months, efficacy and safety of saroglitazar has been evaluated. Total 104 patients (78% male) with mean age of 59.1 ± 11.4 years were enrolled. All subjects were given saroglitazar 4mg once daily for 24 weeks. The effects of saroglitazar were evaluated at 24 weeks by using paired t-test. Six months follow-up data is available from 73 patients. At 24 weeks the primary end point showed a significant reduction in non-HDL-C (from 138 ± 51 mg/dL to 113 ± 44 mg/dL; p<0.001) and sdLDL (from 31.7 ± 11.8 mg/dL to 26.0 ± 11.9 mg/dL; p<0.001). Of the secondary end points the values of TG, HDL-C, total cholesterol and HbA1c were also significantly improved at 24 weeks (Table). No major adverse event reported during the study period. This is the first study evaluating the effect of saroglitazar on sdLDL in patients with DD. The results indicate that saroglitazar is safe and well tolerated and effectively reduces sdLDL particles along with non-HDL-C.Change in laboratory parameters at 24 weeks follow-up (All values are Mean±SD)Laboratory parametersBaseline24 weeks follow-upP-valueNon HDL-C (mg/dL)138±51113±44<0.001TG (mg/dL)351±360247±445<0.001LDL-C (mg/dL)90±3882±240.074sdLDL (mg/dL)31.7±11.826.0±11.9<0.001HDL-C (mg/dL)35.6±7.540.6±8.0<0.001Total cholesterol (mg/dL)172±52154±43<0.001HbA1c (%)7.98±1.666.95±0.71<0.001

Disclosure

U. Kaul: None. P. Jain: None. R. Kachru: None. V. Bhatia: None. P. Arambam: None. S. Shekhawat: None. Y. Diana: None. K. Rawat: None. S. Singh: None. A. Jaiswal: Employee; Self; Zydus Cadila.
Insulin Sensitizing Effects of Vitamin D Mediated through Reduced Adipose Tissue Inflammation and Fibrosis
Authors: LONTCHI-YIMAGOU ERIC , KANG SONA , ZHANG KEHAO , GOYAL AKANKASHA , YOU JEE YOUNG , KISHORE PREETI , ROSEN EVAN , HAWKINS MEREDITH
Published: June 2018

Adipose tissue inflammation and fibrosis appear to be mediated by adipocytes and contribute to insulin resistance. Since vitamin D (25(OH)D) has anti-inflammatory and anti-fibrotic effects, expression of its receptor in adipocytes and macrophages suggests that 25(OH)D signaling could mediate paracrine effects within adipose tissue and improve insulin resistance. We performed a randomized, double-blinded placebo-controlled trial to examine the effects of repleting vitamin D in 25(OH)D-deficient (<20 ng/ml), insulin resistant, overweight-to-obese humans (n=19). 25(OH)D repletion to >30 ng/ml was associated with reductions in adipose tissue expression of inflammatory (0.6-0.7-fold decreased expression of TNF-α, IL-6, iNOS and PAI-1) and pro-fibrotic (0.4-0.8-fold decreased expression of TGF-β1, HiF1α, Collagen I, V, VI and MMP7) genes, decreased collagen VI immunofluorescence (19% reduction, p=0.02) and improved hepatic insulin sensitivity, assessed as suppression of endogenous glucose production (EGP) during hyperinsulinemic clamp studies (1.28 ± 0.20 vs. 0.88 ± 0.18 mg/kg/min, p=0.03).

To determine whether vitamin D’s effects are mediated through adipocytes, we studied an adipocyte-specific vitamin D receptor knockout mouse model (Adiponectin-Cre+VDR+/ fl) after 12 weeks on high fat diet. Despite no differences in body weight or adiposity, VDR KO mice exhibited increased adipose tissue expression of several pro-inflammatory (Tnf-α, iNos, Pai-1, Mcp-1 and F4/80; 4-10 fold) and pro-fibrotic genes (Tgf-β1, Collagen VI, and Tsp1; 2-4 fold), in concert with hepatic insulin resistance during 2h hyperinsulinemic (4 mU/kg/min)-euglycemic clamps (EGP 10 ± 3 vs. 3 ± 2 mg/kg/min in WT, p = 0.021).

These human and rodent studies establish a beneficial role of vitamin D in restraining adipose tissue inflammation and fibrosis as well as hepatic insulin resistance, and suggest that normalizing 25(OH)D levels could have metabolic benefits in targeted individuals.

Disclosure

E. Lontchi-Yimagou: None. S. Kang: None. K. Zhang: None. A. Goyal: None. J. You: None. P. Kishore: None. E. Rosen: None. M. Hawkins: None.
Hypoglycemia in Patients with Diabetes in an Australian Public Hospital Setting
Authors: PIYA MILAN K. , ZARORA REETU , FLETCHER THERESE , SIMMONS DAVID
Published: June 2018

Background: Diabetes is a common co-morbidity among hospital inpatients, particularly in medical wards. Diabetes is linked to increased length of stay and mortality in hospital inpatients, and hypoglycemia (hypo) is considered a contributory factor. We sought to determine the prevalence of diabetes in medical wards and the prevalence and patterns of hypo during their hospital stay.

Methods: A daily census on three medical wards (79 beds) was conducted over a 4 month period from June 2017 in a 3bed tertiary Sydney hospital. Charts and medications for inpatients with diabetes were audited each Friday using a questionnaire based on the UK National Diabetes Inpatient Audit. Patients admitted under the care of the diabetes team were excluded. Readmissions were counted as separate episodes.

Results: The mean prevalence of diabetes was 27%, of which 2.4% had T1DM, with 212 patient episodes audited in 196 patients (16 readmissions). Mean age (SD) was 71 years (11.2), 54% male. Only 5.6% had a diabetes related admission. Insulin use was 34% on admission but 52% during hospital stay. There were 74 events of hypo (<72 mg/dL) in 38 patients (18%), with 10 episodes of severe hypo (<54 mg/dL) in 9 patients (4.3%). Within the first week of admission, 50 of these hypo events occurred (8 severe) in 29 patients. Insulin was prescribed in 82% of the patients who had hypo (31/38), and 89% of those who had severe hypo (8/9), with only 50% of them admitted on insulin. A smaller number of hypo events occurred 8am-5pm compared to 5pm-8am (29 vs. 45), with no significant difference between days of the week.

Conclusion: Hypoglycemia is a major burden in patients with diabetes in hospital, particularly in the first week of admission, even when patients are not admitted due to diabetes related problems. Insulin use was the major risk factor and many patients had multiple hypo events. We recommend early involvement of the diabetes inpatient team as well as centralized point of care testing of glucose to allow early identification of patients at risk.

Disclosure

M.K. Piya: None. R. Zarora: None. T. Fletcher: None. D. Simmons: Speaker's Bureau; Self; Roche Diabetes Care Health and Digital Solutions, AstraZeneca, Novo Nordisk Inc., Medtronic.
The Clinical and Economic Effects of Switching Medicare Beneficiaries with Type 2 Diabetes from Analog to Human Insulin
Authors: LUO JING , KHAN NAZLEEN F. , MANETTI THOMAS , ROSE JAMES J. , KALOGHLIAN ANI , GADHE BALU , JAIN SACHIN H. , GAGNE JOSHUA , KESSELHEIM AARON
Published: June 2018

Objective: To evaluate the clinical and economic effects of a managed care organization’s conversion program switching Medicare beneficiaries with type 2 diabetes mellitus from analog to human insulin.

Methods: A consecutive sample of 14,635 participants who filled insulin prescriptions between January 2014 and December 2016 were identified from a Medicare Advantage and prescription drug plan operating in 4 U.S. states (CA, AZ, NV, VA). Outcomes were mean hemoglobin A1c (%), rates of severe hypoglycemia or hyperglycemia events and risk of reaching the Part D coverage gap. Data were analyzed using interrupted time series and segmented regression with cut points at the beginning and end of 2015.

Results: 14,635 members (mean age=72.5) filled 221,866 insulin prescriptions. Insulin conversion decreased the proportion of scripts filled by analog insulins from 90% to 30%. The baseline mean hemoglobin A1c was 8.46% and decreased at a rate of -0.02% per month during 2014. The beginning of the conversion program in 2015 was associated with a level change of +0.14% (p<0.01) and a slope change of 0.02% (p<0.01). The baseline rate of severe hypoglycemia was 4.21 per 1000-person years (py) and increased at a rate of 0.36/1000py during 2014. The baseline rate of severe hyperglycemia was 22.33/1000py and increased at a rate of 0.30/1000py. For both hypoglycemia and hyperglycemia, the level and slope changes in the 12-month intervention and post-intervention segments were not statistically significant. The intervention reduced the risk of reaching the coverage gap by 55% (HR 0.45, nominal 95% CI: 0.43-0.48, p<0.001).

Conclusions: Switching Medicare beneficiaries with diabetes from analog to human insulin did not change the rates of hospitalization for hypoglycemia or hyperglycemia, slightly increased mean A1c, and reduced the risk of reaching the Part D coverage gap.

Disclosure

J. Luo: Consultant; Self; Alosa Health, Inc.. N.F. Khan: None. T. Manetti: None. J.J. Rose: None. A. Kaloghlian: None. B. Gadhe: None. S.H. Jain: Employee; Self; CareMore Health. J. Gagne: Research Support; Self; Eli Lilly and Company, Novartis Pharmaceuticals Corporation. A. Kesselheim: None.
Comparison of Peak Plantar Pressure and Peak Pressure Gradient among Patients with Prediabetes and Diabetes
Authors: IZUORA KENNETH , TRABIA MOHAMED , DEBERARDINIS JESSICA , LIDSTONE DANIEL E. , VARRE MATHEW SUNIL , TROTTER ASHLEY L. , DUFEK JANET S.
Published: June 2018

Background: Foot ulcers are a serious complication associated with diabetes peripheral neuropathy (DPN). Diabetes foot complications associated with increased ulcer risk include: 1) decreases in plantar soft-tissue thickness, 2) increases in plantar tissue stiffness, and 3) increases in forefoot (FF) to rearfoot (RF) loading.

Aim: The purpose of this study was to determine whether patients with DPN demonstrate higher forefoot to rearfoot pressures during barefoot walking compared to diabetes patients without peripheral neuropathy (DWPN) and prediabetes patients without peripheral neuropathy (PWPN).

Methods: Eight PWPN, twenty-six DWPN and fourteen DPN patients participated in the study. Barefoot walking trials were performed while wearing Medilogic® pressure-measuring insoles. Peak plantar pressure (PPP) and peak pressure gradient (PPG) were measured on the right foot for the FF and RF regions. FF to RF PPP and PPG ratios were then calculated and normalized to body mass. Walking velocity was used as a co-variate for ANCOVAs. A priori statistical significance was set at α=0.05.

Results: No significant interactions were observed for Group*Region for PPP (F(2, 89)=1.454, p=0.239) and PPG (F(2, 89)=0.579, p=0.563). Main effects of region revealed significantly higher FF to RF loading in both PPP (F(1, 89)=6.67, p=0.011) and PPG (F(1, 89)=4.02, p=0.048) measures driven by DWPN and DPN patients. No significant differences were observed between groups for FF to RF PPP (F(2, 44)=2.624, p=0.084) or PPG (F(2, 44)=1.331, p=0.275) ratios.

Conclusion: Our findings suggest DWPN and DPN patients demonstrate a pattern of loading related to elevated foot ulcer risk. However, no significant difference was observed between groups for FF to RF PPP and PPG ratios. Inclusion of a more robust sample size will allow better testing of our hypothesis.

Disclosure

K. Izuora: None. M. Trabia: None. J. DeBerardinis: None. D.E. Lidstone: None. M. Varre: None. A.L. Trotter: None. J.S. Dufek: None.
Pathophysiology of Remission in Type 2 Diabetes—The Diabetes Remission Clinical Trial (DiRECT)
Authors: TAYLOR ROY , AL-MRABEH AHMAD , ZHYZHNEUSKAYA SVIATLANA V. , PETERS CARL , BARNES ALISON C. , ARIBISALA BENJAMIN , HOLLINGSWORTH KIEREN G. , SATTAR NAVEED , LEAN MICHAEL E.
Published: June 2018

DiRECT is a prospective, randomised study of type 2 diabetes of <6 years duration. In the intervention group, weight loss was induced using a liquid diet replacement (825-853 kcal/day) for 3-5 months with withdrawal of all antidiabetic drugs on day 1. A subgroup underwent 3-point Dixon MRI of liver and pancreas fat and measurement of hepatic very low density lipoprotein triglyceride (VLDL1-TG) metabolism and first phase insulin secretion, before and after 3-5 months. Those with HbA1c <48mmol/mol (<6.5%) after weight loss (n=37; responders) were compared with those remaining >48mmol/mol (n=16; non-responders). At baseline, the two groups were similar (age 53.3±1.2 vs. 53.6±2.2 years, weight 100.3±2.8 vs. 98.2 ±3.9kg, BMI 34.9±0.7 vs. 34.9±1.2kg/m2) but not duration of diabetes (2.7±0.3 vs. 3.8±0.4 years, p=0.04) nor HbA1c 57.1±1.8 vs. 62.5±2.3 mmol/mol; p<0.07). Weight decreased similarly in responders (100.3±2.8 vs. 84.2±2.3kg; p<0.0001) and in non-responders (98.2 ±3.2 vs. 84.3 ±3.6kg (p<0.0001). HbA1c changed only in responders (57.1±1.8 to 41.2±0.6 mmol/mol, p<0.0001; 62.5±2.3 to 63.8±4.7 mmol/mol, p=0.77, respectively). Decreases occurred in liver fat in responders and non-responders (16.7±1.6 to 3.4±0.7%, p<0.0001 and 15.0±2.7 to 2.4±0.5%, p<0.0001), plasma VLDL1-TG concentration (0.69±0.07 to 0.44±0.mmol/l, p=0.001 and 0.64±0.10 to 0.46±0.11 mmol/l, p=0.15), and intra-pancreatic fat (8.7±0.4 to 7.8±0.4%, p<0.0001 and from 7.6±0.5 to 6.7±0.4%, p=0.001). In contrast, first phase insulin secretion increased in responders only (0.05±0.01 to 0.12±0.02, p<0.0001 vs. 0.02± 0.01 to 0.02±0.01, p=0.98, respectively). Failure of first phase insulin secretion response but not differential lipid or hepatic responses characterises non-responders. De-differentiation of beta cells in early type 2 diabetes is not reversible in all, despite removal of the metabolic stress. Such individuals are characterised by longer duration of diabetes even in early type 2 diabetes.

Disclosure

R. Taylor: None. A. Al-Mrabeh: None. S.V. Zhyzhneuskaya: None. C. Peters: None. A.C. Barnes: None. B. Aribisala: None. K.G. Hollingsworth: None. N. Sattar: Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S, Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Mitsubishi Tanabe Pharma Corporation, Medscape, Sanofi-Aventis Deutschland GmbH. M.E. Lean: Advisory Panel; Self; Novo Nordisk Inc., Orexigen Therapeutics, Inc.. Research Support; Self; Cambridge Weight Plan. Consultant; Self; Counterweight Ltd. Stock/Shareholder; Self; Eat Balanced.