bluuebunny/crossref_metadata_2025 huggingface dataset:
2461-PUB: Increased Apolipoprotein A1 Can Suggest the Presence of Latent Autoimmune Diabetes and a Lower Cardiovascular Risk Compared with Type 2 Diabetes
Authors: LJUBIC SPOMENKA , JAZBEC ANAMARIJA , ANTAL IVANA , CUDINA IVONA , TOMIC MARTINA , VUCIC LOVRENCIC MARIJANA
Published: June 2019

Latent autoimmune diabetes (LADA) could be misdiagnosed as type 2 diabetes (DM2). Lipids, apolipoproteins, adiponectin (APN), interleukin-6 (IL-6), homocysteine (HCY), other markers of DM, including antibodies, were tested in 276 patients with DM1, DM2 and LADA. Quartiles of lipid accumulation product (LAP) (Q1:≤21.23, Q2:(21.23, 40.69], Q3:(40.69, 92.02], Q4:>92.02) were calculated as: [waist (cm) - 65 for men/58 for women] x triglycerides (mmol/L)]. In all statistical tests: ANOVA and Tukey post hoc test, and stepwise multivariate regression, α=0.05 was considered statistically significant. ANOVA revealed significant differences in HCY, APN, IL-6 and apolipoprotein A1 (Apo A1) among DM types. Patients with DM1 (1.73±0.33) and LADA (1.66±0.38) had significantly higher values of HDL compared to DM2 (1.33±0.31). IL-6 was statistically increased in DM2 compared to DM1; Apo A1 was statistically increased in LADA (1.7±0.36) compared to DM2 (1.4±0.22), whereas HCY was decreased (LADA: 10.9±2.74 vs. DM2 18.2±9.44). APN was decreased in DM2 compared to the control group. Logistic regression for DM2 pointed to APN (OR=0.826; p=0.02), HCY (OR=1.202; p=0.08) and HDL (OR=0.142; p=0.08) as statistically significant predictors, whereas uric acid (OR=0.991; p=0.08) was a predictor of LADA. After stepwise procedure the best model for APN included HDL (R2=0.46), for HCY glomerular filtration (parR2=0.26) and Apo A1 (parR2=0.08), and for Apo A1 HDL (parR2=0.79) and fasting glucose (parR2=0.03). 60% of DM2 patients, but 10.5% of LADA were in the 4th LAP quartile. Patients in the 4th quartile had significantly lower values of APN and Apo A1 compared to 1th and 2nd quartiles; HCY was increased in 4th compared to the 1th quartile. Significantly increased HDL and Apo A1 and decreased HCY in LADA compared to DM2 uncover LADA prior to determination of antibodies. Only 10.5% of LADA patients in the 4th quartile pointed to a lower cardiovascular risk than in DM2.

Disclosure

S. Ljubic: None. A. Jazbec: None. I. Antal: None. I. Cudina: None. M. Tomic: None. M. Vucic Lovrencic: None.
2482-PUB: Circadian Clock Regulates Fuel Metabolism in Skeletal Muscles
Authors: LIU JIDONG , SUN ZHENG
Published: June 2019

The nuclear receptors Rev-erbα and Rev-erbβ are transcription factors that function both as a core repressive component of the cell-autonomous circadian clock machinery. We conditionally depleted Rev-erbα and Rev-erbβ in skeletal muscles in mice to explore their function into energy metabolism. The conditionally knockout (KO) mice displayed glucose intolerance and reduced grip strength. The KO mice also had lower oxygen consumption and impaired glucose uptake during exercise, without alteration in the muscle fiber type composition, mitochondrial protein content, or home-cage locomotor activity. Transcriptional analysis in muscle revealed that Rev-erbs regulate many genes involved in fatty acid oxidation, glucose transportation, tricarboxylic acid (TCA) cycle, and BCAAs catabolism. These results demonstrate that muscle clock plays an important role in regulating the energy homeostasis for in skeletal muscles.

Disclosure

J. Liu: None. Z. Sun: None.

Funding

National Institutes of Health
2494-PUB: Betatrophin Inhibits Browning through AMPK Signaling in 3T3-L1 Cells
Authors: QI XIAOYAN , LIAO ZHEZHEN , WANG YADI , LI JIAOYANG , LIU JIANGHUA , XIAO XINHUA
Published: June 2019

Browning of white adipocytes (beiging) is an attractive therapeutic strategy against obesity attributed to the enhanced capacity of heat production. Betatrophin as a novel cold-derived adipokines, is necessary for adipogenesis. Recent data suggest that Betatrophin deficient mice displayed increased thermogenesis and reduced body weight. But its role in the browning of white adipocytes remains unknown. Here, we report that deletion of Betatrophin in 3T3-L1 adipocytes enhanced expression of brown fat-specific markers (UCP-1, PRDM16 and CIDEA), mitochondrial biogenesis genes (PGC-1α) and the key lipid metabolism lipases (ATGL), Additionally, those effects were dramatically abolished by compound C, revealing silencing Betatrophin-induced browning depend on activation of AMPK signaling pathways. Overall, our findings suggest that Betatrophin is a candidate target gene treating obesity due to its function of inhibiting white adipocyte browning conversion.

Disclosure

X. Qi: None. Z. Liao: None. Y. Wang: None. J. Li: None. J. Liu: None. X. Xiao: None.
256-OR: Costarting Sitagliptin with Metformin Is Associated with a Lower Likelihood of Disease Progression in Newly Treated Patients with Type 2 Diabetes
Authors: CAMPBELL SCOTT A. , LIGHT PETER E. , SIMPSON SCOT H.
Published: June 2019

Aim: Sitagliptin can potentially preserve beta cell function by promoting local action of GLP-1 in the pancreas. This study examined if early addition of sitagliptin to metformin is associated with a delay in the progression of type 2 diabetes.

Methods: Administrative health records from Alberta, Canada between April 1, 2008 and March 31, 2015 were used to conduct a retrospective cohort study. New metformin users were identified and included if they added sitagliptin during follow-up. Patients costarting therapy with sitagliptin and metformin were compared to those who added sitagliptin after initial metformin therapy. Potential confounding variables included age, sex, comorbidities, and cardiovascular medications at baseline. A multivariable logistic regression model was used to evaluate the association between sitagliptin addition (costart versus delayed) and insulin initiation. Change in A1c 1 year after adding sitagliptin was evaluated using a multivariable linear regression model.

Results: Mean (SD) age of the 8,746 included patients was 52.1 (11.1) years, 5,655 (64.7%) were men, and 1,149 (13.1%) costarted treatment with metformin and sitagliptin. Insulin was added to the therapy of 192 (16.7%) costarters and 1,640 (21.6%) of delayed sitagliptin users (adjusted odds ratio 0.73; 95% CI: 0.62 to 0.86). The A1c change 1 year after starting sitagliptin was greater in the costarters (-2.1%; SD 2.8%) compared to delayed sitagliptin users (-1.0%; SD 1.9%). After adjusting for baseline A1c and other covariables, costarters had a greater reduction in A1c -0.56% (95% CI: -0.74% to -0.38%).

Conclusions: Costarting sitagliptin with metformin is associated with a lower likelihood of disease progression in newly treated patients with type 2 diabetes compared with adding sitagliptin later in therapy.

Disclosure

S.A. Campbell: None. P.E. Light: None. S.H. Simpson: None.

Funding

Canadian Institutes of Health Research
258-OR: Use of High Sensitivity Cardiac Troponin T and I for Risk Classification in Type 2 Diabetes
Authors: TANG OLIVE , MATSUSHITA KUNIHIRO , CORESH JOSEF , MCEVOY BILL , SHARRETT A. RICHEY , BALLANTYNE CHRISTIE M. , HOOGEVEEN RON C. , SELVIN ELIZABETH
Published: June 2019

Introduction: ADA guidelines recommend costly cardioprotective medications as second-line therapy for patients with diabetes and prevalent cardiovascular disease (CVD). High sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI) may identify those at high risk in the absence of CVD and inform prioritization for treatment with newer classes of medications.

Methods: We conducted a prospective cohort analysis of middle-age adults (mean age 63, 52% female, 30% black) in the Atherosclerosis Risk in Communities (ARIC) Study with diabetes (1996-1998, n=1,415). Participants were followed >20 years for heart failure (HF), coronary heart disease, and death. We used Cox models to evaluate the risk associated with independent and joint elevations (>90th percentiles) in hs-cTnT and hs-cTnI.

Results: Elevations in hs-cTnT (26%) or I (19%) were common, with 10% of those without CVD having elevations in both. Elevated hs-cTnT and hs-cTnI were independently associated with all three outcomes (and jointly improved C-statistics). For HF and death, those with elevations in both troponins in the absence of CVD showed similar risk as those with prevalent CVD (Table).

Conclusions: Hs-cTnT and I are independently prognostic of cardiovascular risk and mortality among adults with diabetes. These biomarkers may help identify patients for novel cardioprotective anti-hyperglycemics, even in the absence of pre-existing CVD.

Disclosure

O. Tang: None. K. Matsushita: Consultant; Self; Akebia, Kyowa Hakko Kirin Co., Ltd. Research Support; Self; Fukuda Denshi, Kyowa Hakko Kirin Co., Ltd. J. Coresh: None. B. Mcevoy: None. A. Sharrett: None. C.M. Ballantyne: Consultant; Self; Abbott, Akcea Therapeutics, Amarin Corporation, Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Esperion, Gilead Sciences, Inc., Matinas BioPharma, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Roche Diagnostic USA, Sanofi. Research Support; Self; Abbott, Akcea Therapeutics, Amarin Corporation, Amgen Inc., Esperion, Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals, Roche Diagnostic USA, Sanofi. Other Relationship; Self; Roche Diagnostic USA. R.C. Hoogeveen: Consultant; Self; Denka Seiken. Research Support; Self; Abbott, American Heart Association, National Heart, Lung, and Blood Institute, SomaLogic, Inc. E. Selvin: None.

Funding

National Institutes of Health
263-LB: Functional Inactivation of Mast Cell Enhances Subcutaneous Adipose Tissue Browning through Decreasing Serotonin Release in Mice
Authors: ZHANG XIAN
Published: June 2019

Introduction: Therapeutic targeting of brown adipocyte-mediated thermogenesis to increase energy expenditure may offer a viable alternative approach to combat obesity and metabolic disease. Several immune signaling regulated beige fat thermogenic circuits were established in adipose tissues. Genetic deficiency and pharmacological stabilization of Mast Cells (MCs) increased metabolic rate and UCP1 expression in BAT in western diet-fed mice in concert with their obesity and insulin resistance improvement. Serotonin is an important regulator of energy balance. Yet, it remains unknown whether MCs play a direct role in energy homeostasis or the above-mentioned changes in energy expenditure are merely a consequence of mouse body weight reduction.

Methods and Results: We compared metabolic rate differences between WT and MC-deficient Kitw-sh/w-sh mice. In the context of mice on a chew diet, norepinephrine (NE)-stimulated metabolic rate is increased in MC-deficient Kitw-sh/w-sh mice and MC-stabilized wide-type (WT) mice. Histological staining, qPCR and western blot showed UCP1 and other thermogenic genes also increased in these mice. Such functional inactivation of MCs enhances thermogenesis and browning in subcutaneous adipose tissues (SAT), but not in brown (BAT) and epididymal adipose tissues (EAT). MC reconstitution to SAT blocks the aforesaid changes in Kitw-sh/w-sh mice. Mechanistic studies demonstrate that functional inactivation of MCs not only elevates the numbers and proliferation of PDGFRα+ bipotential adipocyte precursors but also accelerates beige adipocyte differentiation in SAT. Using tryptophan hydroxylase 1 inhibitor and Tph1-/- mast cells, we show that MC-derived serotonin inhibits SAT beige adipocyte biogenesis and systemic energy expenditure.

Conclusions: Together, functional inactivation of MCs or inhibition of MC serotonin synthesis in SAT promotes adipocyte browning and systemic energy metabolism in mice.

Disclosure

X. Zhang: None.

Funding

American Heart Association
271-LB: Intranasal Insulin Treatment Causes Sex-Specific Differences in Metabolism and Behavior in Mice
Authors: CHUDOBA CHANTAL , KLEINRIDDERS ANDRE
Published: June 2019

Brain insulin action regulates metabolism and behavior. Conversely in diabetes, brain insulin resistance associates with obesity and behavioral abnormalities. Intranasal insulin (INI) treatment activates brain insulin signaling in rodents and humans with a more prominent effect on metabolism in males. Recently, we have shown that INI treatment reduces diet-induced high fat diet (HFD) weight gain in males. Here, we investigated whether INI treatment reduces metabolic and behavioral abnormalities in males and females fed a HFD.

We investigated the effect of 1h 1.75U INI treatment on metabolism and behavior in 12 weeks old C57BL/6N male and female mice fed a normal chow diet (NCD) and HFD for two weeks. We analyzed brain insulin signaling using ELISA, qPCR and western blot technique and assessed metabolic parameters as well as behavior using a dark-light box and novelty-suppressed feeding test.

We show that acute INI treatment activates the insulin cascade in a region-dependent manner with highest activation in olfactory bulbus, caudate putamen and hypothalamus in males. INI treatment caused a two-fold increase in insulin levels in the cerebrospinal fluid (CSF) without altering blood glucose and insulin levels. INI reduced anxiety in males fed a NCD using a dark-light box test and novelty-suppressed feeding test. Yet, INI treatment did not alter insulin signaling and behavior in mice fed a HFD. Though male and female mice exhibited equal amounts of insulin receptor signaling proteins in the brain, INI treatment did not alter food intake, body weight gain or behavior in females fed a NCD or a HFD. In females, basal insulin levels in the CSF were comparable to insulin levels of INI-treated males and did not drastically increase further after INI treatment indicating optimal insulin action under basal conditions. Overall, we show that INI treatment activates the insulin signaling throughout the brain and improves in a sex-dependent manner metabolism and behavior only in healthy conditions.

Disclosure

C. Chudoba: None. A. Kleinridders: None.

Funding

German Federal Ministry of Education and Research; State of Brandenburg (82DZD00302)
274-LB: The Anti-inflammatory Effects of Insulin and Hydrocortisone Combination in Obese Subjects
Authors: DANDONA PARESH , GHANIM HUSAM , BATRA MANAV , GREEN KELLY , ABUAYSHEH SANAA , KATKAR RUJUTA
Published: June 2019

Glucocorticoids have been used as the major class of anti-inflammatory agents for over 60 years. However, they have well known side effects including weight gain, adiposity, muscle loss, osteoporosis and diabetogenicity. We have recently described the induction of specific pro-inflammatory genes by a single large dose of hydrocortisone (HC) in normal weight subjects. Since our group discovered the anti-inflammatory actions of insulin, we have now hypothesized that a combination of insulin with a high dose of a HC may neutralize the proinflammatory effects of HC and offer a safe anti-inflammatory combination. Eight obese subjects (BMI:31-46 kg/m2, age: 29-63 years, 3 females) were randomized into a cross over study to be injected in two separate visits (a week apart) with 300 mg of HC (?60 mg prednisolone) intravenously with or without an infusion of 2U/h of insulin with 5% dextrose for 8 hours. HC injection alone induced a significant anti-inflammatory effect including suppression of CCR-2 (by 54±8%), IL-4 (by 68±14%) and TNF-α (by 35±10%) expression in mononuclear cells (MNC). However, the HC injection also induced an increase in the expression of HMG-B1, TLR2, TLR4, TLR9, JNK-1 and RANK-L (by 43±12%, 57±9%, 62±17%, 69±15%, 89±19% and 61±11% over the baseline, respectively, P<0.05 for all). Plasma glucose and FFA concentrations also increased significantly following the HC injection alone. Insulin infusion along with the HC injection further suppressed the expression of CCR-2, TNF-α and IL-4 in MNC and completely inhibited the HC induced increases in FFA concentrations and in HMG-B1, TLR-2, TLR-9 and RANK-L expression (p<0.05 vs. HC alone). In addition, insulin infusion not only inhibited the HC induced increases in JNK-1 and TLR4 expression but also suppressed levels below baseline (by 27±14% and 22±10%, p<0.001 vs. HC alone). Thus, the infusion of insulin at a low dose with a high dose of HC or other corticosteroids may constitute an ideal anti-inflammatory cocktail in the in- patient setting.

Disclosure

P. Dandona: Advisory Panel; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. H. Ghanim: None. M. Batra: None. K. Green: None. S. Abuaysheh: None. R. Katkar: None.
285-OR: Conversations and Reactions around Severe Hypoglycemia (CRASH): U.S. Results from a Global Survey of People with T1DM or Insulin-Treated T2DM and Caregivers
Authors: SNOEK FRANK J. , JILETCOVICI ALINA , BUSHNELL DONALD M. , CHILD CHRISTOPHER J. , BAJPAI SANJAY K. , SPAEPEN ERIK , THOMAS JOSH , BALANTAC ZANETA , PEYROT MARK , MITCHELL BETH
Published: June 2019

The CRASH study examines the experience and treatment of a severe hypoglycemia event (SHE) among people with T1DM (ppl w/T1DM) or insulin-treated ppl w/T2DM and caregivers. The online survey was conducted in 8 countries. To be eligible in the global study, ppl had experienced or cared for a person who had ≥1 SHE in the last 3 years. SHE was defined as low blood glucose requiring assistance for recovery. Here, we report U.S. data for 220 ppl with diabetes (n=110 T1DM; n=110 T2DM). Sixty-five (59.1%) ppl w/T2DM used insulin for >5 years, while mean (SD) duration of diabetes was 30.6 (16.6) years for ppl w/T1DM and 16.0 (8.7) years for ppl w/T2DM. Forty (36.4%) ppl w/T1DM and 22 (20.0%) ppl w/T2DM reported impaired awareness (Gold score ≥4). During the last SHE, glucagon use was low (T1DM [8.2%]; T2DM [3.6%]); reasons for not using glucagon were not having a prescription (T1DM [40.0%]; T2DM [59%]) or it was unavailable (T1DM [20.0%]; T2DM [17.1%]). Also, ppl w/T1DM (75.5%) and ppl w/T2DM (83.6%) reported using oral glucose only for treatment; use of healthcare provider assistance was low. The main causes reported for a SHE were eating less than planned (T1DM [27.3%]; T2DM [47.3%]) or exercising more than planned (T1DM [21.8%]; T2DM [20.0%]). Results indicate that treatment of a SHE mainly occurred outside the healthcare system with fewer ppl having glucagon as an option for recovery.

Disclosure

F.J. Snoek: Advisory Panel; Self; AstraZeneca, Lilly Diabetes, Novo Nordisk A/S, Roche Diabetes Care. Research Support; Self; Sanofi. Speaker's Bureau; Self; Lilly Diabetes. A. Jiletcovici: Employee; Self; Eli Lilly and Company. D.M. Bushnell: None. C.J. Child: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. S.K. Bajpai: Employee; Self; Eli Lilly and Company. E. Spaepen: Consultant; Self; Eli Lilly and Company. J. Thomas: Employee; Self; Eli Lilly and Company. Z. Balantac: Other Relationship; Self; Eli Lilly and Company. M. Peyrot: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Calibra Medical. Research Support; Spouse/Partner; Eli Lilly and Company. B. Mitchell: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.
296-OR: Diminished Sensor Performance of the Abbott Freestyle Libre Intermittently-Viewed Continuous Glucose Monitoring System (ICGMS) during Hypoglycemia and Acute Exercise in People with Type 1 Diabetes
Authors: MOSER OTHMAR , ECKSTEIN MAX L. , MCCARTHY OLIVIA , DEERE RACHEL , PITT JASON , WILLIAMS DAVID M. , HAYES JENNIFER , BAIN STEPHEN C. , BRACKEN RICHARD M.
Published: June 2019

Aim: To determine the sensor performance of the Abbott Freestyle® Libre iCGMS during glycemic challenges and acute exercise during multiple 23-hours inpatient phases.

Methods: 17 people with T1D (4 women, age 34.9 ± 15.5 years, BMI 25.9 ± 3.0 kg/m2, HbA1c 7.3 ± 1.4% (56 ± 15 mmol/mol)) on multiple daily injections were included in the study, consisting of four 23-hours inpatient phases with meal-induced glycemic disturbances and 45-minutes moderate-intensity cycle ergometer exercises. iCGMS was compared to reference blood glucose by median absolute relative difference (MARD), Clarke Error Grid (CEG) and Bland-Altman (intention-to-treat).

Results: The overall MARD (IQR) during the inpatient phases (excluding exercise) was 12.9% (6.1-21.5%), during hypoglycemia 31.6% (14.0-46.8%), euglycemia 14.5% (7.0-22.5%) and hyperglycemia 8.7% (4.6-14.6%). The overall Bland-Altman analysis showed a bias (95% LoA) of 19.8 mg/dL (-78.37-118 mg/dL) and CEG is illustrated in the Figure. The overall MARD during exercise was 29.8% (17.5-39.8%), during hypoglycemia 45.1% (35.2-51.1%), euglycemia 30.7% (18.7-39.2%) and hyperglycemia 16.3% (10.0-22.8%).

Conclusion: iCGMS interstitial glucose readings should be used cautiously during hypoglycemia and exercise and need confirmatory blood glucose measurements.

Disclosure

O. Moser: Research Support; Self; Abbott, Dexcom, Inc., Novo Nordisk A/S. M.L. Eckstein: Research Support; Self; Novo Nordisk A/S. O. McCarthy: None. R. Deere: None. J. Pitt: None. D.M. Williams: None. J. Hayes: None. S.C. Bain: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Mylan, NAPP Pharmaceuticals Limited, Novo Nordisk A/S, Sanofi. R.M. Bracken: None.

Funding

Novo Nordisk A/S
297-LB: Dietary Fructose Increases Plasma Angiopoietin-Like Protein-3 Concentrations in Rhesus Macaques: Prevention with Fish Oil Supplementation
Authors: BUTLER ANDREW , GRAHAM JAMES L. , STANHOPE KIMBER L. , HAVEL PETER J.
Published: June 2019

Homozygous loss-of-function ANGPTL3variants are associated with familial combined hypolipidemia, suggesting the dual LPL/EL inhibitor is a promising target for treating atherogenic dyslipidemia. However, nothing is known regarding the dietary regulation of ANGPTL3, including effects of dietary sugar or n-3 fatty acids. We investigated plasma ANGPTL3 concentrations in a rhesus macaque model of high sugar diet-induced dyslipidemia. Animals provided fructose beverages (300 kcal/d) rapidly gain weight (∼10%) and develop insulin resistance and fasting hypertriglyceridemia within 1 month. Fasting plasma ANGPTL3 concentrations increased by 30-40% with fructose consumption after 1 and 3 months (mean±SD in ng/ml; baseline, 60.6±17.4; 1 month, 83.1±25.3; 3 months, 76.9±23.2; both p<0.001 vs. baseline, n=59). Fish oil supplementation (4 g/d) prevents fructose-induced dyslipidemia and completely prevented the increases of ANGPTL3 (-3% vs. +33% over 6 months, p<0.05). Regression modeling to identify lipid/lipoprotein parameters (TG, TC, HDL-C, LDL-C, VLDL-C, APOA1, APOB, APOC3, APOE) explaining variation in ANGPTL3 levels indicated strong correlations with APOC3 at baseline (p=0.002), and APOC3 and APOE after 3 months of fructose (both p<0.05). Regression modeling also examined whether changes (?) of APOC3, APOE, and ANGPTL3 predict ?TG, explaining 41% of variation after 1 month. (R2=0.41, p<0.001). ?APOC3 (B=0.588, p<0.001) and ?ANGPTL3 (B=0.292, p<0.05) were significant predictors in the model. After 3 months, modeling explained 36% of ∆TG (R2=0.36, p<0.001), with all variables contributing significantly (?APOC3, B=0.616, p<0.001; ?ANGPTL3, B=0.245, p<0.05; ?APOE, B= -0.281, p<0.05). Modeling predicted variation of ∆TG before and during fructose consumption (R2=0.294, p=0.033 at baseline; R2=0.438, p<0.001 at 3 months).

In summary, these are the first findings reporting effects of diet composition (sugar and n-3 FAs) on circulating ANGPTL3.

Disclosure

A. Butler: None. J.L. Graham: Research Support; Self; Arrowhead Research, Bristol-Myers Squibb Company, Magnamosis Inc. K.L. Stanhope: None. P.J. Havel: Research Support; Self; Arrowhead Research, Bristol-Myers Squibb Company, Magnamosis Inc.

Funding

National Institutes of Health
300-LB: FGF21 and a ß3-Adrenergic Agonist Synergistically Lower Blood Glucose in Obese Mice at Thermoneutrality
Authors: ZOUHAR PETR , SPILAKOVA BLANKA , ANDERSEN BIRGITTE , NEDERGAARD JAN , KOPECKY JAN
Published: June 2019

Fibroblast growth factor 21 (FGF-21) treatment is known to lower body weight and to increase insulin sensitivity in rodent models of obesity, probably via increased energy expenditure. Stimulation of non-shivering thermogenesis by FGF-21 was hypothesized to be the crucial antiobesogenic action. Thermogenesis is normally driven by stimulation of β3-adrenergic receptors. FGF-21 has been shown to inhibit lipolysis, while β3-adrenergic agonists are pro-lipolytic. In lean mice, acute β3-adrenergic stimulation results in drop in blood glucose, which is believed to be caused by a rise in non-esterified fatty acid (NEFA) and (subsequently) increase in plasma insulin. Thus, the effects of FGF-21 and β3-adrenergic agonists on thermogenesis could be synergistic, while their effects on NEFA seem opposite. Here we investigate the effect of combination of FGF-21 and the β3-adrenergic agonist CL316.243 on blood glucose level in mice. Dietary obese C57Bl/6 mice were housed at thermoneutral temperature (i.e., at 30 °C) in order to minimize basal adrenergic tone. Animals were treated twice daily with 65 µg FGF-21 or its vehicle for 8 days. This treatment was not sufficient to significantly decrease body weight and non-fasted blood glucose, but it lowered insulin (indicating increase in insulin sensitivity). Subsequently, the mice were injected with 35 µg of the β3-adrenergic agonist CL316.243. CL316.243 increased NEFA and insulin in control mice, but surprisingly (in contrast to earlier observations in lean mice) it acutely increased blood glucose as well. In FGF-21-treated mice, CL316.243 altered neither NEFA nor insulin levels, but it dramatically decreased blood glucose. In contrast to earlier works, our result demonstrates a complex nature of the glucose-lowering effects of β3-adrenergic agonists which does not simply correlate to changes in insulin and NEFA levels. We also show that FGF-21 has a potential to restore the glucose-lowering action of β3-adrenergic stimulation in obese mice.

Disclosure

P. Zouhar: None. B. Spilakova: None. B. Andersen: Employee; Self; Novo Nordisk A/S. J. Nedergaard: None. J. Kopecky: None.

Funding

Czech Science Foundation (19-05356Y)
320-OR: Axonal Swellings in Diabetic Patients With and Without Neuropathy
Authors: KARLSSON PALL , GYLFADOTTIR SANDRA SIF , TESFAYE SOLOMON , RICE ANDREW S. , NYENGAARD JENS RANDEL , JENSEN TROELS S. , BENNETT DAVID , THEMISTOCLEOUS ANDREAS
Published: June 2019

Background: Up to 50% of patients with diabetes develop peripheral neuropathy (DPN). DPN is associated with low intraepidermal nerve fiber density (IENFD), and morphometric degenerative changes such as axonal swellings are also observed. The relationship of swellings to DPN status has not yet been delineated.

Methods: In total 207 patients with type 2 diabetes and 24 age- and gender-matched healthy controls were included in the study. Included in the analysis were participants whose IENFD was >0.5 fiber/mm, thus allowing swelling ratio calculation (n=156). The patients underwent a rigorous DPN assessment, including a neurological examination, nerve conduction studies, skin biopsy and quantitative sensory testing. Patients were divided into three groups: without DPN (n=35), with painless DPN (n=72), and with painful DPN (n=100). Axonal swellings were defined as enlargements on nerve fibers exceeding 1.5 μm in diameter. Swelling ratio was obtained by dividing the number of swellings with IENFD.

Results: Median (IQR) IENFD was significantly different between the groups: without DPN: 6.15 (4.9;8.08) fibers/mm; painless DPN: 1.65 (1.07;2.73); painful DPN: 1.4 (0.80;2.12); controls: 5.8 (4.95;8.0), P<0.01. Median swelling ratios were also significantly different between groups: without DPN: 0.34 (0.16;0.55); painless DPN: 0.14 (0;0.55); painful DPN: 0 (0;0.31); and controls: 0 (0;0.6), p<0.01. This difference disappeared when only including patients with somewhat preserved IENFD (IENFD >2) (P=0.4). Patients with diabetes and IENFD >2 had higher swelling ratio compared with healthy controls, regardless of neuropathy status (P<0.01). Swelling ratio did not correlate with BMI, diabetes duration, pain or Toronto Clinical Neuropathy score (P>0.1), but did correlate negatively with HbA1c levels when only including all patients with IENFD >0.5 (P=0.04).

Conclusions: Axonal swellings are present in most diabetic patients with preserved IENFD and may indicate morphological changes of nerve fibers.

Disclosure

P. Karlsson: Advisory Panel; Self; Grünenthal. S. Gylfadottir: None. S. Tesfaye: Advisory Panel; Self; Mitsubishi Tanabe Pharma Corporation, WÖRWAG Pharma. Speaker's Bureau; Self; AstraZeneca, Merck & Co., Inc., NAPP Pharmaceuticals Limited, Neurometrix, Novo Nordisk Inc., Pfizer Inc. Other Relationship; Self; Impeto Medical. A.S. Rice: Research Support; Self; Orion. Other Relationship; Self; Imperial College Consultants, Spinifex/Novartis. J.R. Nyengaard: None. T.S. Jensen: None. D. Bennett: Consultant; Self; Lilly Diabetes, Orion, Theranexus. A. Themistocleous: None.

Funding

Novo Nordisk Foundation (NNF14OC0011633); Danish Diabetes Academy (to P.K.)
33-LB: Nuclear Factor Erythroid 2 Related Factor 2 (Nrf2) Increases with Hyperbaric Oxygen Therapy and Promotes Wound Healing in Diabetic Foot Ulcers
Authors: UMAPATHY DHAMODHARAN , VIKRAMAN POOJA , ALLADI VAISHNAVI , ARUMUGAM SOMASUNDAR , DORNADULA SIREESH , AMIN KARAN , KESAVAN RAJESH , MOHANRAN RAMKUMAR KUNKA
Published: June 2019

Hyperbaric oxygen (HBO) therapy is proven to be very successful for diabetic foot ulcer (DFU) treatment and has been demonstrated to have antimicrobial effect, increased angiogenesis and enhanced collagen synthesis. In the present study, we investigated the molecular mechanism underlying HBO therapy particularly the role of Nrf2 in wound healing process. In addition, we have studied the levels of angiogenic markers in ulcer tissues and their correlation with Nrf2 during HBO therapy compared with a standard therapy (Non-HBO) for DFU. A total of 32 patients (16 males and 16 females) were recruited and randomized to standard wound care alone (n=17) or HBO therapy in combination with standard wound care (n=15). Our results showed that the tissue levels of Nrf2 along with the downstream targets showed significant increase in patients who underwent HBO therapy. It induces angiogenesis with significantly increasing the levels of angiogenesis markers such as EGF, VEGF, PDGF, FGF-2 and CXCL10 in the tissue samples. The HIF-1α expression showed a 4.9-fold and eNOS with a 4.5-fold among HBO therapy when compared to Day 0 subjects. HBO therapy sensitize macrophages to release FGF-2 and EGF thereby promotes angiogenesis. Further it increased the levels of CXCL-8, which is a potent neutrophil attractant thereby promote the release chemokine CCL2, a well-known mediator of neovascularization. The Spearman’s correlation showed that Nrf2 have a positive correlation with EGF, VEGF, PDGF and HIF-1α.

In conclusion, the findings of the present study suggest that HBO therapy promote wound healing by increasing oxygen dispersion to damaged tissues, stimulating angiogenesis, alleviating inflammation, and increasing the levels of NO. It is evidenced that elevated Nrf2 transiently regulates angiogenic gene expression in wound biopsies, which may enhance chronic wound healing.

Disclosure

D. Umapathy: None. P. Vikraman: None. V. Alladi: None. S. Arumugam: None. S. Dornadula: None. K. Amin: None. R. Kesavan: None. R. Kunka Mohanran: None.
341-LB: Chronic ER Calcium Depletion Resulting from Sarcoendoplasmic Reticulum Ca2+ Atpase 2b (SERCA2b) Deficiency Leads to Impaired Proinsulin Processing in the Pancreatic ß Cell
Authors: IIDA HITOSHI , KONO TATSUYOSHI , TONG XIN , LINDBERG IRIS , EVANS-MOLINA CARMELLA
Published: June 2019

Reductions in pancreatic β cell endoplasmic reticulum (ER) Ca2+ levels are associated with the development of ER stress and impaired proinsulin processing in both type 1 and type 2 diabetes. The SERCA pump transports Ca2+ into the ER lumen in order to maintain a steep Ca2+ gradient between the ER and cytosol. SERCA2 activity and expression are reduced in diabetes, however, the relationship between SERCA2 and proinsulin processing remains incompletely understood. To this end, we developed mice with β cell specific deletion of SERCA2 (βS2KO mice) and S2KO INS1 cells. βS2KO mice exhibited glucose intolerance and reduced insulin secretion in response to glucose without evidence of impaired insulin sensitivity. Islets from βS2KO mice had significantly reduced ER Ca2+ levels and impaired glucose-induced Ca2+ oscillations, while serum proinsulin/insulin (PI/I) ratios and whole pancreas PI/I content were elevated. Immunoblot analysis of βS2KO islets and S2KO INS-1 cells revealed reduced total levels of the proinsulin processing enzymes, PC1/3, PC2 and CPE, and increased levels of proPC2. Restoration of SERCA2b via adenoviral transduction in S2KO INS1 cells was sufficient to restore PC1/3 and PC2 maturation and enzyme activity. Brefeldin A treatment in INS1 cells recapitulated the impairments in PC1/3 and PC2 maturation observed in S2KO INS1 cells, suggesting a disturbance in protein trafficking between the ER and Golgi. Trafficking assays were next performed using a vesicular stomatitis virus G (VSVG) protein construct and revealed a significantly slower rate of VSVG movement from the ER to the Golgi in S2KO INS1 cells. Taken together, these data indicate that loss of SERCA2 activity and impairments in ER Ca2+ lead to reduced proinsulin processing via altered protein trafficking through the β cell secretory pathway.

Disclosure

H. Iida: None. T. Kono: None. X. Tong: None. I. Lindberg: None. C. Evans-Molina: None.
343-LB: The Type 2 Diabetes-Associated Lipid Binding Protein STARD10 Controls Insulin Secretory Granule Biogenesis
Authors: CARRAT GAELLE , HAYTHORNE ELIZABETH , HAATAJA LEENA , ARVAN PETER , TOMAS ALEJANDRA , PIUNTI ALEXANDRA , PULLEN TIMOTHY J. , GEORGIADOU ELENI , STYLIANIDES THEODOROS , SALEM VICTORIA , DISTASO WALTER , CAKEBREAD ANDREW , HODSON DAVID , FUNG ANNIE C. , SESSIONS RICHARD B. , ALPY FABIEN , KONG ALICE P. , LECLERC ISABELLE , RUTTER GUY A.
Published: June 2019

Aim: Risk alleles for type 2 diabetes (T2D) in the STARD10 locus, impair insulin secretion and are associated with decreased proinsulin:insulin ratios. We have shown that the T2D risk associated with variation at this locus is likely to be mediated through lowered STARD10 expression in the β cell. Here, we investigate the mechanisms by which STARD10 may regulate insulin secretion.

Materials and Methods: A 3-dimensional model of STARD10 was constructed from the structure of STARD2, using the modelling tools Chimera and Modeller. Islets were isolated from StarD10fl/fl-Ins1Cre male mice (βStarD10KO). Electron Microscopy (EM) images were obtained from isolated islets after chemical fixation. Total zinc content was measured by inductively coupled plasma mass spectrometry. Pulse-chase analysis of proinsulin processing was performed using 35S-labelled amino acids. RNA-Seq was done on polyadenylated transcripts selected during the preparation of paired-end, directional RNAseq libraries, sequenced on an Illumina HiSeq 4000 machine.

Results: Molecular modelling indicated that STARD10 binds either phosphatidylcholine or phosphatidylethanolamine. EM analysis of islets from βStarD10KO mice revealed a markedly altered dense core granule appearance, with a dramatic increase (Fold change = 4.3; p<0.001) in "rod like" dense cores, and a ∼2-fold increase in total islet zinc content. Unexpectedly, pulse-chase studies revealed enhanced basal secretion of newly-synthesised proinsulin from βStarD10KO islets. Whilst RNA sequencing identified several dysregulated genes in βStarD10KO islets, STARD10 deletion did not affect prohormone convertase (Pcsk1, Pcsk2), or ZnT8 (Slc30a8) expression.

Conclusion: We identify STARD10 as a critical regulator of insulin granule biogenesis and β cell zinc homeostasis. Our data also suggest that increased β cell Zn2+ secretion in risk allele carriers may decrease the clearance of mature insulin to lower plasma proinsulin:insulin ratio.

Disclosure

G. Carrat: None. E. Haythorne: None. L. Haataja: None. P. Arvan: None. A. Tomas: None. A. Piunti: None. T.J. Pullen: None. E. Georgiadou: None. T. Stylianides: None. V. Salem: None. W. Distaso: None. A. Cakebread: None. D. Hodson: None. A.C. Fung: None. R.B. Sessions: None. F. Alpy: None. A.P. Kong: Advisory Panel; Self; Lilly Diabetes. Research Support; Self; AstraZeneca, Lilly Diabetes. Speaker's Bureau; Self; Abbott. Other Relationship; Self; AstraZeneca, Novartis Pharmaceuticals Corporation, Sanofi. I. Leclerc: None. G.A. Rutter: Consultant; Self; Sun Pharma.

Funding

Medical Research Council UK; UK Wellcome Trust; Royal Society; Societe Francophone du Diabete
379-P: Changes in Diabetes Management after a Hospital Visit for Severe Hypoglycemia
Authors: VIJAYAKUMAR PAVITHRA , LIU SHULING , KAHN PETER A. , MCCOY ROZALINA G. , KARTER ANDREW J. , LIPSKA KASIA J.
Published: June 2019

Clinical guidelines recommend reevaluation of glucose-lowering medications and relaxation of HbA1c targets in patients with diabetes after a severe hypoglycemic event. We compared diabetes management before and after hypoglycemia requiring emergency department (ED) visit or hospital admission.

Using data from OptumLabs® Data Warehouse, we identified privately insured and Medicare Advantage enrollees 18+ years with pharmacologically-treated type 2 diabetes and an ED visit or hospitalization for hypoglycemia between July 1, 2013 and June 30, 2014. We assessed the differences in the number of physician office visits, glucometer test strips filled, continuous glucose monitor (CGM) use, diabetes medication fills, and HbA1c levels (available for 1582 [27.7%]), within 6 months prior to and 6 months after hypoglycemia.

Among 5721 patients with type 2 diabetes and severe hypoglycemia, mean age was 67.8 (SD 12.3), 51% women, 63% white, and 68% used insulin. Changes in management are summarized in Table 1. After an event, the proportion of patients filling insulin increased, but the proportion filling sulfonylureas declined. Less than one third of patients with a baseline HbA1c <7% had a substantially higher post-event HbA1c.

Few of the recommended changes in diabetes management occur after a severe hypoglycemic event. These findings suggest the need for better post-event care to improve the safety of glucose-lowering therapy.

Disclosure

P. Vijayakumar: None. S. Liu: None. P.A. Kahn: None. R.G. McCoy: None. A.J. Karter: None. K.J. Lipska: Consultant; Self; Health Services Advisory Group (HSAG). Research Support; Self; National Institute on Aging. Other Relationship; Self; Centers for Medicare and Medicaid Services.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (T35DK104689); National Institute on Aging; American Federation for Aging Research; National Institutes of Health (K23AG048359)
384-P: An Integrated Summary of Safety and Efficacy of a Ready-to-Use Liquid Glucagon Rescue Pen for the Treatment of Severe Hypoglycemia in Adults
Authors: CHRISTIANSEN MARK P. , CUMMINS MARTIN J. , PRESTRELSKI STEVEN J. , JUNAIDI MOHAMMED K.
Published: June 2019

Objective: To prevent medical complications of severe hypoglycemic emergencies, prompt and reliable rescue intervention is critically important. A ready-to-use stable liquid Glucagon Rescue Pen (GRP; Xeris Pharmaceuticals) auto-injector was evaluated for the rescue treatment of severe hypoglycemia.

Method: Two Phase 3 randomized, controlled, blinded, crossover studies were conducted in 161 adults with T1D to compare 1 mg doses of GRP versus Glucagon Emergency Kit (GEK; Eli Lilly) for the treatment of insulin-induced severe hypoglycemia. Efficacy was evaluated as either a return of plasma glucose (PG) to >70 mg/dL or increase in PG ≥20 mg/dL from a baseline PG <50 mg/dL, within 30 min of dosing.

Result: Subjects treated with GRP (98.7%) achieved successful PG recovery within 30 minutes, and (99.4%) had a PG > 70 mg/dL or neuroglycopenic symptom relief within 30 minutes, both comparable to GEK. From glucagon dosing, the mean time to achieve PG >70 mg/dL or increase in PG ≥20 mg/dL was 13.8±5.6 min for GRP and 10.0±3.6 min for GEK. This mean time does not account for the significantly shorter (p<0.0001) drug preparation and administration time for GRP (27.3±19.7 seconds) vs. GEK (97.2±45.1 seconds). The GRP was similar to GEK in terms of glucose Cmax, Tmax, and AUC(0-90min). The overall incidence of treatment emergent adverse events (TEAEs) was comparable in both groups; the most commonly reported TEAEs were nausea (GRP 29.9%, GEK 22.9%) and vomiting (GRP 16.1%, GEK 9.6%). One SAE was reported in these studies (GEK).

Conclusion: A ready-to-use, easy two-step administration GRP achieved plasma glucose recovery reliably, was therapeutically equivalent to GEK, and had an incidence of nausea and vomiting comparable to GEK. There was a significant difference in drug preparation time in favor of the GRP. These results demonstrate that GRP is an effective, safe, and well tolerated rescue treatment for severe hypoglycemia and is a viable alternative to GEK.

Disclosure

M.P. Christiansen: Research Support; Self; Abbott, Biolinq, Dexcom, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Medtronic MiniMed, Inc., Novo Nordisk A/S, Sanofi-Aventis, Xeris Pharmaceuticals, Inc. M.J. Cummins: Employee; Self; Xeris Pharmaceuticals, Inc. S.J. Prestrelski: Employee; Self; Xeris Pharmaceuticals, Inc. M.K. Junaidi: None.
39-LB: Individualised Screening for Diabetic Retinopathy: The ISDR Study—A Randomised Controlled Trial of Safety, Efficacy, and Cost-Effectiveness
Authors: BROADBENT DEBORAH MARY , WANG AMU , CHEYNE CHRISTOPHER P. , LATHE JAMES G. , STRATTON IRENE M. , VORA JITEN , GARCIA-FINANA MARTA , JAMES MARILYN , HARDING SIMON P.
Published: June 2019

Background: Varying the intervals in retinopathy screening informed by personal risk offers reallocation of resources to better target high risk groups and address the increasing prevalence of diabetes. However, safety data especially on extended intervals is minimal.

Aim: To evaluate the safety, efficacy and cost effectiveness (CE) of individualized variable-interval risk-based screening in a population setting compared to usual care.

Methods: Masked 2 arm, parallel assignment, equivalence RCT (largest to date in screening) with independent trials unit monitoring in people with diabetes aged ≥12 years attending screening in a single English program. Randomization was 1:1 to individualized screening (active group; 6, 12 or 24 months for high, medium and low risk) determined by a risk calculation engine using real-time local demographic, retinal and clinical data, compared with annual screening (control). CE analysis measuring NHS and societal costs took a 2-year time horizon.

Findings: 4534 participants entered the study - after withdrawals/loss to follow-up: active 2097; control 2224. Attendance rates at first follow-up visit (primary outcome, safety) were equivalent (per protocol analysis, 5% margin): active 83.6% control 84.7% (difference 1.0, 90% CI -0.8, 2.9). STDR detection rates were non-inferior (1.5% margin): active 1.43% control 1.71% (difference -0.28, CI -0.93, 0.36). Quality of life (EQ5D5L, HUI3) was not significantly different between the groups. Incremental cost saving per person was £18.75 (NHS cost) rising to £49.96 with societal costs. A 39.3% reduction in number of appointments was seen.

Conclusions: All parties involved in diabetes care can be reassured that extended and personalized screening intervals can safely be introduced in established screening program. Scale-up with further validation outside a research setting is recommended. Views expressed are solely those of the authors.

Disclosure

D.M. Broadbent: None. A. Wang: None. C.P. Cheyne: None. J.G. Lathe: None. I.M. Stratton: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Bayer AG, Boehringer Ingelheim International GmbH. J. Vora: None. M. Garcia-Finana: None. M. James: None. S.P. Harding: None.

Funding

UK National Institute for Health Research
395-P: Hypoglycemia and Cardiovascular Outcomes among Older Adults: The Atherosclerosis Risk in Communities Study
Authors: ECHOUFFO TCHEUGUI JUSTIN B. , DAYA NATALIE R. , LEE ALEXANDRA K. , TANG OLIVE , WINDHAM B. GWEN , SHAH AMIL , SELVIN ELIZABETH
Published: June 2019

Background: There is limited community-based data on the association of hypoglycemia with cardiovascular events among older individuals, who are particularly susceptible to hypoglycemia.

Methods: We conducted a prospective cohort analysis of adults with diabetes aged ≥70 years from the Atherosclerosis Risk in Communities (ARIC) Study (baseline visit 5, 2011-2013). History of severe hypoglycemia was defined using first position ICD-9 codes from prior hospitalizations, emergency department visits, and ambulance calls through June 1, 2011. We evaluated the rate of cardiovascular events (myocardial infarction, fatal coronary heart disease, stroke or heart failure) and mortality (follow-up through December 31, 2017), using negative binomial and Cox proportional hazards regression models.

Results: Among 2,194 participants with diabetes (mean age: 75 years [SD: 5], 57% female, 32% blacks), 79 had a history of severe hypoglycemia. During a median follow-up of 5.4 years, a history of severe hypoglycemia was strongly associated with cardiovascular disease (incident and recurrent) and death (Table).

Conclusions: Our findings suggest potential cardiovascular benefits of severe hypoglycemia prevention among older individuals and provide strong evidence for relaxing the targets of blood glucose control among older individuals.

Disclosure

J.B. Echouffo Tcheugui: None. N.R. Daya: None. O. Tang: None. B. Windham: None. A. Shah: Advisory Panel; Self; Philips Ultrasound. Consultant; Self; Bellerophon. Other Relationship; Self; Novartis Pharmaceuticals Corporation. E. Selvin: None.
398-P: Prediction of Five-Year Severe Hypoglycemia Risk in Adult Patients with Type 2 Diabetes
Authors: KO SEUNG-HYUN , YUN JAE-SEUNG , HAN KYUNGDO , KWON HYUK-SANG , SONG KI-HO , AHN YU-BAE
Published: June 2019

Objective: There is a scarcity of long-term prediction models for severe hypoglycemia (SH) in subjects with type 2 diabetes. A model was developed and validated to predict the risk of SH in adult patients with type 2 diabetes (T2DM).

Research Design and Methods: Baseline and follow-up data from patients with T2DM who received health evaluations from January 1, 2009, to December 31, 2010 (n = 1,676,885), were analyzed as development (n = 1,173,820) and validation (n = 503,065) cohorts using the National Health Insurance Database (DB) in Korea. New SH episodes were identified using ICD-10 codes until December 31, 2015. A Cox proportional hazards regression model and Cox model coefficients were used to derive a risk scoring system, and 14 predictive variables were selected. A risk score nomogram based on the risk prediction model was created to estimate the five-year risk of SH.

Results: In the development cohort, a total of 34,955 (2.98%) patients experienced SH episodes during the follow-up period of 5.7 years (5.22/1,000 person-years). After multivariable adjustment, older age, being female sex, being a current smoker, drinking, having a low body mass index, lack of exercise, previous SH events, insulin or multiple oral hypoglycemic agent use, presence of hypertension or chronic kidney disease, longer duration of diabetes, low or high glucose level, and high Charlson Comorbidity Index score were found to be significant risk factors for the development of SH and were incorporated into the risk model. The concordance indices were 0.822 (95% confidence interval, 0.81-0.83). In patients in the top decile, the incidence rate of SH was estimated to be 25.6/1,000 person-years. The calibration plot showed a nearly 45° line, which indicates that this model is a good predictor of an absolute SH event.

Conclusion: This 14-variable prediction model for SH events may be a useful tool to identify high-risk patients and guide prevention of SH in adult patients with T2DM.

Disclosure

S. Ko: None. J. Yun: None. K. Han: None. H. Kwon: None. K. Song: None. Y. Ahn: None.