bluuebunny/crossref_metadata_2025 huggingface dataset:
Using MetS Severity to Track Risk for T2D during Intervention with Lifestyle and Metformin
Authors: DEBOER MARK D. , FILIPP STEPHANIE L. , GURKA MATTHEW J.
Published: June 2018

While a metabolic syndrome severity Z-score (MetS-Z) predicts incident type 2 diabetes (T2D) in observational cohorts, it is unclear whether MetS-Z can track response to medical intervention and whether changes in MetS-Z during treatment reflect altered risk for T2D. We evaluated data from the Diabetes Prevention Program, which randomized individuals with glucose intolerance (age 51±11 years) to receive: placebo (n=882), metformin 850 mg bid (n=867), or an intensive lifestyle modification program (n=827). We assessed levels of MetS-Z and the individual MetS components during 3 years of intervention (Figure), revealing 1-year decreases in MetS-Z among those treated with lifestyle (effect size -0.6), metformin (-0.3) and placebo (-0.1), driven by improvements in the individual MetS components. We assessed how change in MetS-Z affected T2D risk, finding that each 1-point increase in a participant’s effect size of MetS Z between 0 and 1 year (difference per participant/baseline SD) increased odds of incident T2D by year 3 by 70% (adjusting for intervention group; Figure). This positive association was found in individual models and in a joint model that included changes in MetS-Z and in each MetS component—suggesting independent associations of changes in MetS-Z with future T2D risk. These data support MetS-Z as an important outcome to follow for response to medical treatment in research studies and clinical care.

Disclosure

M.D. DeBoer: None. S.L. Filipp: None. M.J. Gurka: None.
Cardiometabolic Risk Disparities Associated with Health Insurance Status in a Latino Community in California
Authors: AXELROD CEARA , CHAVEZ ELOISA , BEVIER WENDY C. , CREASON JAMIE , CASTORINO KRISTIN , KERR DAVID
Published: June 2018

In the U.S., rates of type 2 diabetes (T2D) are higher in Latinos than in non-Latino whites. In 2015, we began a free community outreach program (Mobile Health Screenings, MHS) for the local Latino community to assess diabetes prevalence, cardiovascular risk and their relationships to insurance status. From July 2015 to November 2017, we measured HBA1c (A1c Now+®, PTS Diagnostics, Indianapolis, IN), body mass index (BMI), and blood pressure (BP) in 593 people at 24 MHS events. Health insurance status and current medications for diabetes and hypertension (HTN) were also recorded. More than half of those screened (55%) had HBA1c values between 5.7-6.4% or ≥6.5%. Of the 589 participants who provided insurance information, 262 (44%) reported either having no insurance (n=212, 36%) or not knowing if they had insurance (n=50, 8%). Individuals with private insurance (n=101) had significantly lower HBA1c levels than those with either government insurance (MediCal, Medicare, etc., (n=113), [5.7±0.7% vs. 6.0±1.0%, p=0.017] and no insurance (n=201), [5.7±0.7% vs. 6.0±1.2%, p=0.002]. The highest rates of prediabetes and diabetes (45% and 17%) were in the uninsured group and the lowest rates (30% and 12%) were in the privately insured group. Those without insurance also took fewer medications for HTN vs. those with insurance (11.3% vs. 20.0%, p=0.005). BMI was also significantly lower for insured participants [28.8±5.4 kg/m2 (n=344) vs. uninsured participants 30.0±5.5 kg/m2 (n=206, p=0.016].

In conclusion, there is an excess burden of cardio-metabolic disease on uninsured adult Latinos in Santa Barbara.

Disclosure

C. Axelrod: None. E. Chavez: None. W.C. Bevier: None. J. Creason: None. K. Castorino: None. D. Kerr: Advisory Panel; Self; Glooko, Inc.. Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Sanofi-Aventis. Stock/Shareholder; Self; Cellnovo. Advisory Panel; Self; Novo Nordisk Inc..
Performance of Clinical/Proteomic Biomarker Panels to Predict Coronary Artery Disease Presence or Cardiovascular Prognosis in Patients With and Without Diabetes Mellitus
Authors: SHRESTHA SHREYA , MCCARTHY CIAN P. , IBRAHIM NASRIEN E. , KIMMENADE ROLAND VAN , GAGGIN HANNA , MUKAI RENATA , MAGARET CRAIG A. , BARNES GRADY , RHYNE RHONDA F. , JANUZZI JAMES
Published: June 2018

Background: Patients with diabetes mellitus (DM) are at increased risk for prevalent coronary artery disease (CAD) and incident major adverse cardiac events (MACE) such as cardiovascular death, myocardial infarction, and stroke. Prediction of risk in those with DM may be challenging. Using unbiased proteomics we recently described biomarker panels to predict prevalent CAD (HART-CAD) and incident MACE (HART-CVE; both Prevencio, Kirkland, WA) in unselected patients undergoing diagnostic coronary angiography. In this study, we sought to compare accuracy of these panels in patients with and without DM.

Methods: The HART-CAD panel includes 2 clinical variables (male sex and prior PCI) and 4 biomarkers: adiponectin, apolipoprotein CI, kidney injury molecule 1 (KIM 1), and midkine. The HART-CVE panel includes 4 biomarkers (amino-terminal pro-B type natriuretic peptide, KIM 1, osteopontin, and tissue inhibitor of matrix metalloproteinase-1). These panels were derived in 167 DM and 482 non-DM patients; performance of each was validated in a second cohort of patients (N=278) with and without DM.

Results: In patients with DM, the HART-CAD panel had excellent performance for prediction of coronary stenosis ≥ 70%, with area under the curve (AUC) of 0.81 (p<0.001), sensitivity 85%, specificity 69%, positive predictive value (PPV) 90%, and negative predictive value (NPV) 58% for detection of CAD, results comparable to those without DM. HART-CVE was highly predictive of incident 1 year MACE in those with DM: AUC of 0.80 (p=0.002), sensitivity 78%, specificity 69%, PPV 47%, and NPV of 90%, again, comparable to those without DM. In Kaplan-Meier analyses, an elevated HART-CVE score predicted shorter time to first MACE (p<0.001).

Conclusion: Previously described multivariate proteomic biomarker panels effectively predict prevalent CAD and risk for incident MACE in at-risk patients with DM.

Disclosure

S. Shrestha: None. C.P. McCarthy: None. N.E. Ibrahim: None. R. van Kimmenade: None. H. Gaggin: Research Support; Self; Roche Diagnostics Corporation, Portola. Consultant; Self; Roche Diagnostics Corporation, Amgen Inc., Ortho clinical. Other Relationship; Self; EchoSense, Radiometer. R. Mukai: None. C.A. Magaret: Consultant; Self; Prevencio. G. Barnes: Employee; Self; Prevencio. R.F. Rhyne: None. J. Januzzi: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc.. Board Member; Self; Jana Care Inc.. Research Support; Self; Prevencio.
A Novel Ceruloplasmin Mutation Causing Aceruloplasminemia with Diabetes in China
Authors: XIAO YUANYUAN
Published: June 2018

Background: Hereditary aceruloplasminemia is a rare adult-onset autosomal recessive disease characterized by a ceruloplasmin(CP) gene mutation and defective or absent ceruloplasmin function. The absence of ceruloplasmin leads to pathological iron overload in the liver, pancreas, retina, and central nervous system. It is clinically characterized by diabetes mellitus, anaemia, retinal degeneration and neurological abnormalities.

Material and Methods: A 34-year-old Chinese woman who had had diabetes mellitus characterized by fast plasma glucose increasing for more than 3 years. She had tried all kinds of hypoglycemic medicines,the postprandial blood glucose could be well controlled, but still had a fast hyperglycemia. Here, we reported the identification, clinical characterization, and analysis of a novel mutation in the ceruloplasmin gene of this patient and her family members.

Results: Laboratory findings revealed a complete undetectable serum Cp. Increased serum ferritin levels, elevated iron saturation, as well as results of iron quantification in the liver and CT scan also suggested iron overload in the liver. Imaging examination showed a pronounced hyperintensity in the bilateral putamina, caudate, thalamus and dentate nuclei suggesting the presence of iron overload. By sequencing the ceruloplasmin gene, A novel homozygous ceruloplasmin gene mutation, c.146+1G>T, was identified as the cause of aceruloplasminemia in this patient. Another healthy family members were heterozygous as well.

Conclusion: So far, less than 60 families cases of aceruloplasminemia have been reported world-wide and mainly missense and nonsense mutations in the ceruloplasmin gene were detected. There was only one case about aceruloplasminemia has been reported in China before. We report herein a case of aceruloplasminemia accompanied by diabetes with a novel mucutation of CP gene, which suggests that increased awareness should be paid to this disorder as diabetes is an important typical symptoms of it.

Disclosure

Y. Xiao: None.
Caloric Restriction Increases the Resistance of Aged Heart to Myocardial Ischemia/Reperfusion Injury
Authors: GUO ZHIJIA , ROUSSELLE THOMAS , LI JI
Published: June 2018

Ischemic tolerance of heart decreases with age. Caloric restriction (CR) is the most reliable intervention to extend lifespan and prevent age-related disorders. We have revealed that both AMPK and SIRT1 signaling pathways are involved in the impairments occurred in aged hearts. We hypothesize that cardiac AMPK-SIRT1 signaling cascade mediates the increased tolerance of aged heart to ischemic insults by caloric restriction. Aged (18-20 months) mice were divided into 2 groups: al libitum (AL) food intake group and caloric restriction (diet 70% of standard food intake for 6 weeks) (CR) group. Each group was divided into sham operations and ischemia/reperfusion (I/R) semi-groups. I/R groups were subjected to ligation of left anterior descending coronary artery for 30 min of ischemia and 24 hours of reperfusion. The body fat composition was significantly decreased in CR group vs. AL group, moreover, the maximum of oxygen consumption was significantly improved in CR group vs. AL group. Importantly, there is a significantly smaller myocardial infarction size induced by ischemia (30 min) and reperfusion (24 hours) in CR group than that in AL group. The immunoblotting results demonstrated that the impaired ischemic AMPK activation in AL group was augmented in CR group, and the AMPK downstream acetyl CoA carboxylase (ACC) phosphorylation and PGC-1alpha phosphorylation were also augmented in CR vs. AL group in response to ischemic insults. Intriguingly, the expression levels of a longevity protein, SIRT1, were upregulated in the heart of CR group vs. the corresponding AL group. Furthermore, the inducible cardiomyocyte SIRT1 deficiency mice (icSIRT1 KO) did not show any recused impaired ischemic AMPK activation in the CR group vs. icSIRT1 KO AL group. Thus, caloric restriction is a non-pharmacological approach to increase the tolerance of aged heart to ischemic insults. The AMPK-SIRT1 signaling cascade plays a critical role in the cardiac CR benefits in the elderly.

Disclosure

Z. Guo: None. T. Rousselle: None. J. Li: None.
Circulating Netrin-1 as a Novel Biomarker for Impaired Fasting Glucose and Newly Diagnosed Type 2 Diabetes Mellitus
Authors: JUNG HYE-IN , BAE JAEHYUN , HAN EUGENE , KIM GYURI , LEE JI-YEON , KIM SO RA , LEE BYUNG-WAN , KANG EUN SEOK , AHN CHUL WOO , CHA BONG-SOO , LEE YONG-HO
Published: June 2018

Aims/Hypothesis: Netrin-1 has been introduced as a neuronal guidance cue, acting as a chemoattractant and chemorepulsive force during axonal migration. In recent studies, netrin-1 was shown to play various roles including tissue regeneration and modulation of inflammatory action. Inflammation is one of the major contributing factors in the development of insulin resistance and type 2 diabetes (T2DM). However, little is known about the possible relationship between serum netrin-1 and the risk of T2DM. Therefore, we investigated the association between levels of netrin-1 and glycometabolic parameters.

Methods: Serum samples were collected from a total of 218 individuals (41 normal controls, 85 subjects with impaired fasting glucose (IFG) and 92 subjects with newly diagnosed T2DM). Clinical and biochemical parameters were assessed after receiving consent. Netrin-1 levels were determined by commercial enzyme-linked immunosorbent assay. Spearman correlation analyses and multivariable-adjusted linear regression analyses were conducted to examine the relationship between serum netrin-1 levels and glycometabolic parameters.

Results: Serum netrin-1 level in subjects with IFG or T2DM was significantly higher than in normal control subjects (mean netrin-1 level; normal, IFG and T2DM; 275.9, 436.6 and 441.0 pg/mL, respectively; p for trend <0.001). Serum netrin-1 levels had a significant positive correlation with fasting glucose, HbA1c, HOMA-IR, AST and ALT. Meanwhile, statistically inverse correlation was found between netrin-1 and HDL cholesterol and eGFR levels. In addition, Serum netrin-1 was independently associated with the presence of IFG or T2DM after adjusting covariates and potential confounders. In terms of the AUC, serum netrin-1 levels presented an AUC of 0.784 for the prediction of IFG or T2DM.

Conclusions/Interpretation: Our results suggest that netrin-1 may be a new biomarker for early detection for IFG or T2DM (Clinical trial no. NCT02650830).

Disclosure

H. Jung: None. J. Bae: None. E. Han: None. G. Kim: None. J. Lee: None. S. Kim: None. B. Lee: None. E. Kang: None. C. Ahn: None. B. Cha: None. Y. Lee: None.
Effects of Hormone-Sensitive Lipase Overexpression on Lipotoxic Cardiomyopathy in Mice Lacking Adipose Triglyceride Lipase
Authors: YAMADA MIKA , SUZUKI JINYA , HIROSE MASAMICHI , NAKAYA TAKAHIRO , ICHIKAWA MAI , SATO SATSUKI , IMAGAWA MICHIKO , ZENIMARU YASUO , KRAEMER FREDRIC B. , KONOSHITA TADASHI , ISHIZUKA TAMOTSU
Published: June 2018

Lipotoxic cardiomyopathy, which is associated with obesity and diabetes, is characterized by intracellular triacylglycerol (TAG) droplet accumulation (steatosis). The first step of TAG hydrolysis is catalyzed by adipose triglyceride lipase (ATGL), and its deficiency results in extreme cardiac steatosis in mice and humans. Although hormone-sensitive lipase (HSL) functions as a diacylglycerol (DAG) lipase in the heart, we hypothesized that activated HSL might catalyze cardiac TAG hydrolysis. To test this hypothesis we generated transgenic mice with cardiac-specific HSL-overexpression (cHSL) and crossed them with ATGL-knockout (KO) mice. By crossing ATGL-KO and cHSL lines, we generated homozygous ATGL-KO (AKO) mice, AKO mice with cardiac HSL-overexpression (AKO/cHSL), and wild type (Wt) mice. Cardiac lipid content was measured and its function was assessed by ultrasonography. Histological investigation was performed by transmission electron microscopy. Cardiac TAG content of AKO mice was 160-fold greater than that of Wt mice, whereas that of AKO/cHSL mice was as low as that of Wt hearts. Cardiac systolic function (fractional shortening; FS) was markedly reduced in AKO mice compared to that of Wt mice (28% vs. 49%), while AKO/cHSL mice showed comparable FS to that of Wt mice (48% vs. 49%). Electron microscopy showed accumulation of huge lipid droplets, damaged mitochondria with destroyed cristae and vacuole degeneration, and disrupted intercalated discs (where gap junctions and desmosomes are localized) in the cardiomyocytes of AKO mice. In contrast, the cardiomyocytes of AKO/cHSL mice showed no such morphological characteristics. These results indicate that cardiac overexpression of HSL normalizes lipotoxic cardiomyopathy in AKO mice and suggest that activation of cardiac HSL could be a potent strategy to regulate the lipotoxic cardiomyopathies that occur in metabolic disorders.

Disclosure

M. Yamada: None. J. Suzuki: None. M. Hirose: None. T. Nakaya: None. M. Ichikawa: None. S. Sato: None. M. Imagawa: None. Y. Zenimaru: None. F.B. Kraemer: None. T. Konoshita: None. T. Ishizuka: None.
Large Relative Skeletal Muscle Mass May Protect against Diabetes Irrespective of Glycometabolic Parameters
Authors: KIM GYURI , CHOI MIN SUN , JIN SANG-MAN , LEE MOON-KYU , KIM JAE HYEON
Published: June 2018

Background: Skeletal muscle mass was negatively associated with the prevalence of diabetes in previous cross-sectional studies. The aim of the study was to investigate the impact of baseline relative skeletal muscle mass on the development of diabetes in a large population-based 7-year longitudinal study.

Methods: A total of 18,269 individuals who underwent medical health check-up examination in a university-affiliated tertiary hospital without diabetes were included. Skeletal muscle mass was estimated by bioelectrical impedance analysis and presented as appendicular skeletal muscle mass (ASM) / body mass index (BMI). We analyzed hazard ratio for developing diabetes associated with ASM/BMI using Cox regression models and evaluated the effects of preexisting impaired fasting glucose (IFG).

Results: Compared to subjects in the lowest baseline sex-specific ASM/BMI tertile, those in the highest ASM/BMI tertile were significantly associated with a decreased adjusted HR (AHR=0.69, 95% CI=0.59-0.81, P <0.001) for incident diabetes after adjusting for age, family history of diabetes, smoking status, regular exercise, metabolic syndrome, and CRP. The reduction in the risk of developing diabetes was also significant in the highest tertile of sex-specific ASM/BMI tertile in the presence (AHR=0.81, 95% CI=0.68-0.97, P<0.001) and in the absence of IFG (AHR=0.51, 95% CI=0.39-0.67, P<0.001) compared to the lowest tertile.

Conclusion: The large relative skeletal muscle mass has a potential preventive effect on developing diabetes, independently of glycometabolic parameters. In particular, in subjects with IFG who are at high risk for diabetes, larger relative skeletal muscle mass may provide a substantial benefit to prevent diabetes.

Disclosure

G. Kim: None. M. Choi: None. S. Jin: None. M. Lee: None. J. Kim: None.
Falsely Decreased HbA1c in Diabetic Patient due to Dapsone
Authors: ALJENAEE KHALED , ALI SULAIMAN HAJI , PAZDERSKA AGNIESZKA
Published: June 2018

HbA1c and fructosamine are glycated proteins used to monitor glucose control over time in patients with diabetes. Many factors can affect HbA1c values leading to spuriously low or elevated results. We report a case of a 67 year old woman with type 1 diabetes with good glycaemic control based on HbA1c values ranging from 44-52 mmol/mol over 7 year follow-up. She was commenced on dapsone for treatment of granuloma anulare; four months into this treatment her HbA1c was 25 mmol/mol. The record of self-monitoring blood glucose showed that most of her glucose values were within the recommended target. She had normal hypoglycaemia awareness and reported only 3 episodes of symptomatic hypoglycaemia in the preceding four months. Given the history of dapsone therapy and the discordant result of self-monitoring blood glucose and HbA1c concentrations, we suspected methemoglobinemia as a cause.

Dapsone treatment has been recognised to cause falsely low HbA1c results by two mechanisms: haemolysis by reducing the erythrocyte life span and the formation of methemoglobin which interferes with HPLC used to measure HbA1c.

In conclusion, dapsone is commonly used in diabetic patients who have other autoimmune diseases. HbA1c monitoring in patients treated with dapsone is unreliable and other markers such as capillary blood glucose records, and other glycated proteins such as fructosamine should be used as an alternative for monitoring of glucose control is such patients.

Table 1 Laboratory resultPrior to dapsone4 months after dapsoneHb level (g/dl)13.211.7MCV (fl/cell)92105Absolute reticulocyte counts (109/L)53303Total bilirubin level (micromol/L)1312Methehaemoglobin fraction(%)4.7HbA1c (mmol/mol)X25

Disclosure

K. Aljenaee: None. S. Haji Ali: None. A. Pazderska: None.
The Flexible Lifestyles Empowering Change (FLEX) Intervention Trial for Adolescents with Type 1 Diabetes—Primary and Secondary Outcomes
Authors: MAYER-DAVIS ELIZABETH J. , BISHOP FRANZISKA K. , DRISCOLL KIMBERLY A. , HUNTER CHRISTINE M. , MAAHS DAVID M. , SEID MICHAEL , STANDIFORD DEBRA , THOMAS JOAN ,   FLEX STUDY GROUP
Published: June 2018

Youth with T1D often have poor glycemic control and compromised health and well-being. Our aim was to test the efficacy of the FLEX adaptive behavioral intervention on the primary (HbA1c) and secondary (psychosocial and metabolic) outcomes at 18 months.

Youth (n=258) aged 13-16 years, diagnosed >1 year with T1D with HbA1c from 8.0-13.0%, were randomized at two sites to FLEX or usual care control. Mean (sd) duration of diabetes was 6.4 (3.8) years, 50% were girls, 78% non-Hispanic white, mean HbA1c was 9.6% (1.2) and 71% used insulin pump therapy. FLEX used motivational interviewing and problem-solving skills training to enhance self-management. Intervention fidelity was assessed via random selection of audiotaped sessions for counseling strategy and session content. Intent-to-treat analyses used mixed effects models, with fixed effects of site, timepoint, intervention group, intervention by timepoint and baseline level of primary or secondary outcomes, with a random intercept (alpha=0.05).

Retention was 97%, with intervention fidelity 4.6 out of 5 for counseling strategy and 97.4% complete for session content. HbA1c was not statistically significantly different between intervention and control at 18 months. Among secondary outcomes at 18 months, the intervention was associated with improved scores for symptoms of depression (p=0.04), quality of life (p=0.01), motivation (p=0.009), problem-solving (p=0.04), and diabetes self-management profile (p=0.01), as well as better total cholesterol (p=0.04), and better diastolic blood pressure (p=0.01).

The FLEX intervention did not change the primary outcome, but did positively effect psychosocial outcomes over the 18 months of the trial. Further analyses will reveal information regarding drivers of positive response to the intervention and will point to directions for improvement in the approach, perhaps incorporating more specific direction towards achievement of glycemic targets.

Disclosure

E.J. Mayer-Davis: None. F.K. Bishop: None. K.A. Driscoll: None. C.M. Hunter: None. D.M. Maahs: Advisory Panel; Self; Insulet Corporation. Consultant; Self; Abbott. Research Support; Self; Medtronic, Bigfoot Biomedical, Dexcom, Inc., Insulet Corporation, Roche Diabetes Care Health and Digital Solutions. M. Seid: None. D. Standiford: None. J. Thomas: None.
Effects of Dulaglutide and Insulin Glargine on Estimated Glomerular Filtration Rate in a Real-World Setting
Authors: BOYE KRISTINA , MODY REEMA , WU JIANMIN , LAGE MAUREEN J. , BOTROS FADY T. , WOODWARD BRAD
Published: June 2018

Dulaglutide (Trulicity) treatment of patients with type 2 diabetes (T2D) and moderate to severe chronic kidney disease was associated with lesser estimated glomerular filtration rate (eGFR) decline compared to insulin glargine (glargine) in a clinical trial. This study examined the relationship between dulaglutide or glargine use and eGFR for adults with T2D using real-world data from a U.S. electronic health records from 10/25/2013 to 6/18/2017.

There were 13,869 glargine and 1,222 dulaglutide patients included in the descriptive analyses. Patients with initial eGFR < 60 or < 30 mL/min/1.73m2 were more likely to be treated with glargine than dulaglutide (31.3% v 17.1%, p<0.01; 5.3% v 1.0%, p<0.01, respectively). Multivariable analyses on a matched cohort (N=2,366) found dulaglutide use, compared to glargine use, was associated with a significantly smaller decline in eGFR and a smaller proportion of patients with ≥30% decline in eGFR in the 1-year post-period (Figure 1). With the caveat of limited numbers of patients with severe renal impairment, dulaglutide treatment, compared to glargine, was associated with a smaller decline in renal function in a real-world setting.

Disclosure

K. Boye: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. R. Mody: Employee; Self; Eli Lilly and Company. J. Wu: None. M.J. Lage: Consultant; Self; Eli Lilly and Company. Consultant; Spouse/Partner; Eli Lilly and Company. F.T. Botros: Employee; Self; Eli Lilly and Company. B. Woodward: Employee; Self; Eli Lilly and Company.
Trends of Nontraumatic Lower Extremity Amputation in End-Stage Renal Disease and Diabetes, U.S. 2000-2014
Authors: HARDING JESSICA L. , PAVKOV MEDA E. , BURROWS NILKA , GREGG EDWARD W. , HORA ISRAEL A.
Published: June 2018

Non-traumatic lower extremity amputation (NLEA) is a complication of end-stage renal disease (ESRD) and diabetes mellitus (DM). Global data suggest hospitalization rates for NLEA among people with DM are declining. Contemporary data from the U.S. and among those with ESRD is lacking. We estimated NLEA hospitalizations during 2000-2014 in adults aged ≥18 years with ESRD and DM (ESRD-DM) and in the broader DM population. We determined NLEA hospitalisations rates (ICD-9 CM procedure codes: 8411-8419, excluding diagnosis codes 895-897) for ESRD-DM using the U.S. Renal Data System and for DM using the U.S. National Health Interview Survey and the National Inpatient Sample. We assessed trends over time using Joinpoint regression. In the ESRD-DM population, age-standardised NLEA rates per 1,000 persons decreased from 61.5 (95% CI: 59.8-63.2) in 2000 to 39.7 (38.4-41.0) in 2014 (Figure). In the DM population, NLEA rates decreased from 10.8 (9.2-12.4) in 2000 to 6.1 (5.1-7.0) in 2009, and then increased to 8.7 (7.7-9.6) by 2014. NLEA rates remained 4.6 times (95% CI: 4.5-4.7) higher in ESRD-DM compared with DM only. Rates of NLEA hospitalisations declined during 2000-2014 in ESRD-DM, while they declined then increased in the population with DM. Increased attention to preventive care among ESRD-DM and DM populations is needed.

Disclosure

J.L. Harding: None. M.E. Pavkov: None. N. Burrows: None. E.W. Gregg: None. I.A. Hora: None.
Effect of Metformin on Mitochondrial Pathways in Human Skeletal Muscle Cells
Authors: SACKS JESSICA , MULYA ANNY , FEALY CIARAN E. , FITZGERALD KELLY M. , HUANG EMILY , KIRWAN JOHN P.
Published: June 2018

Metformin (Met) is the most commonly prescribed antidiabetic agent worldwide. Although it has been marketed in the U.S. for over two decades, the exact molecular mechanisms of Met remain controversial. In addition to suppression of hepatic gluconeogenesis, increasing evidence suggests Met induces extrahepatic tissue-specific effects, such as in skeletal muscle (SKM), where the mitochondrion is believed to be the primary cellular target. We investigated the effects of Met on mitochondrial pathways in human SKM cells isolated by percutaneous needle biopsy from lean control, obese nondiabetic, and type 2 diabetic (T2D) volunteers. Mitochondrial function was assessed by Seahorse XF24 analyzer in SKM cells treated with or without Met for 24 hours. Glycolytic rate increased in Met-treated SKM cells from lean (P<0.01), obese (P<0.0001), and T2D subjects (P<0.01) compared to untreated cells. In contrast, basal respiration and ATP production were dramatically reduced in SKM cells treated with Met (P<0.0001 for all phenotypes). Evaluation of the insulin signaling pathway revealed increased Akt phosphorylation at Ser473 (P<0.05) and Thr308 (P<0.01) in cells pre-treated with Met compared to insulin stimulation alone, indicating an additive effect of Met on insulin action. As expected, muscle cells incubated with Met showed enhanced AMPK phosphorylation at Thr172 (P<0.001). Recent studies have identified a direct link between AMPK activation and mitochondrial dynamics pathways. We therefore assessed changes in markers of mitochondrial fission and fusion and found that Met treatment significantly induced phosphorylation of mitochondrial fission factor (MFF; P<0.01) in human SKM cells. Our data suggest Met may mediate improvements in glycemic control by activating AMPK to directly regulate the mitochondrial fission machinery and alter cellular bioenergetics. Functional morphometric and biochemical studies are ongoing to validate mechanisms by which Met exerts its antihyperglycemic effects in SKM.

Disclosure

J. Sacks: None. A. Mulya: None. C.E. Fealy: None. K.M. Fitzgerald: None. E. Huang: None. J.P. Kirwan: None.
Microvascular Disease Burden and All-Cause Mortality in Type 1 Diabetes-A 10-Year Follow-Up Study
Authors: GAROFOLO MONIA , GIANNARELLI ROSA , ARAGONA MICHELE , LUCCHESI DANIELA , GIUSTI LAURA , SANCHO-BORNEZ VERONICA , DANIELE GIUSEPPE , MICCOLI ROBERTO , PENNO GIUSEPPE , PRATO STEFANO DEL
Published: June 2018

Type 1 diabetes (T1D) is associated with a sustantially increased risk of cardiovascular (CV) events and premature death. The effect of the microvascular disease (MD) burden, i.e., the cumulative burden of retinopathy, nephropathy and peripheral neuropathy on all-cause mortality was evaluated in 774 T1D (age 40.2±11.7; DD 19.4±12.2 years; HbA1c 7.8±1.2%) in a mean follow-up of 10.6±2.5 years. Distribution of MD was: no-MD: n. 425 (54.9%); MD1: 250 (32.3%); MD2: 75 (9.7%); MD3: 24 (3.1%). Distribution was unchanged after esclusion of 41 T1D (5.3%) with previous CV events (CV+; 57.0%, 32.2%, 8.5% and 2.3%, respectively). Compared to no-MD, MD1-3 groups showed an adverse CV risk profile with steeply increase in age, DD, BMI, WHR, BP, HbA1c, uric acid and EURODIAB PCS risk score for major vascular outcomes (p<0.0001); total and LDL cholesterol, and triglycerides (p<0.05). eGFR (CKD-EPI) decreased, albuminuria progressively increased (p<0.0001). Rate of CV events and that of EURODIAB score ≥20 increased with MD: 1.6%, 5.6%, 17.3%, and 29.2%; 4.0%, 14.4%, 41.3% and 79.2%, respectively (p<0.0001). Consistently, rate of subjects on BP-lowering agents, RAS-blockers, statins e anti-platelet drugs increased (p<0.0001). A total of 52 deaths occurred during the 8,184 person-years of follow-up (6.7%; 6.36 x1000 person-years). Death rate increased with MD: no-MD 1.9%; MD1 6.8% (HR: 3.75, 95% CI 1.62-8.69); MD2 14.7% (7.10, 2.85-17.67); MD3 66.7% (45.64, 19.50-106.79; K-M, p<0.0001). Death rate was unchanged after esclusion of 41 CV+: 1.9%, 6.4%, 12.9% and 64.7% (p<0.0001). After adjustment for age and sex, HRs were: MD1 2.61 (95% CI 1.11-6.14); MD2 3.42 (1.29-9.06); MD3 16.21 (6.20-42.35; p<0.0001). In fully adjusted model, HRs were: MD1 2.51 (95% CI 1.01-6.23); MD2 2.97 (1.07-8.25); MD3 9.68 (3.19-29.36; p=0.001), with independent effects for age (HR 1.06), uric acid (HR 1.37) and smoking history (HR 2.45). Thus, the cumulative burden of MD independently affects the risk of all-cause death in T1D.

Disclosure

M. Garofolo: None. R. Giannarelli: None. M. Aragona: None. D. Lucchesi: None. L. Giusti: None. V. Sancho-Bornez: None. G. Daniele: None. R. Miccoli: None. G. Penno: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Intarcia Therapeutics, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Servier, Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Takeda Pharmaceuticals U.S.A., Inc.. Advisory Panel; Self; Janssen Biotech, Inc., Abbott.
FreeStyle Libre™ Use for Self-Management of Diabetes in Teenagers and Young Adults
Authors: CAMPBELL FIONA , BOLINDER JAN
Published: June 2018

The challenges of caring for diabetes in teenagers and young adults are well known. We analyzed two research studies (IMPACT and SELFY) that evaluated FreeStyle LibreTM Flash Glucose Monitoring System as a replacement for self-monitoring of blood glucose (SMBG), looking specifically at outcomes in patients aged 13-24 years. IMPACT enrolled 241 patients with well controlled type 1 diabetes (T1DM), HbA1c 6.74±0.56% (50.1±6.1 mmol/mol), age 43.7±13.9 years (mean±SD) into a 6 month European RCT (23 sites). The control group (n=121) used SMBG and the intervention group used FreeStyle Libre for self-management. Of the 241 patients, 19 were aged 18-24 years. SELFY enrolled 76 young people aged 10.3±4.0 years (mean±SD), baseline HbA1c 7.9±1.0% (62.9±11.1 mmol/mol) into a 10 week single arm European study (10 sites). The study consisted of 2 weeks baseline masked (blinded) wear, followed by 8 weeks open use. Of the 76 patients, 25 were aged 13-17 years. IMPACT study results at 6 months showed no significant interaction of age with treatment group for the primary endpoint of time in hypoglycemia <70 mg/dL. For the younger adults, time in range (TIR) (70-180 mg/dL) significantly increased by 2.9±0.89 hours/day (mean±SE); p=0.0055. Time in hyperglycemia (>180 mg/dL) also significantly improved with a reduction of 2.40±0.834 hours/day (mean±SE); p=0.0113. Intervention group patients scanned the sensor on average 11.3 times daily. Teenagers in the SELFY study significantly improved the primary endpoint of TIR (70-180 mg/dL) by 1.2±2.5 hours/day (mean±SD), p=0.0254. HbA1c also significantly improved, -0.7±0.6%, p<0.0001. Time in hyperglycemia (>180 mg/dL) significantly reduced by -1.7±2.9 hours/day, p=0.0093, no statistically significant changes were observed in hypoglycemia (time<55 mg/dL, baseline 0.7±1.0 hours/day). Scan frequency of FreeStyle Libre was on average 9.7 times daily. The IMPACT and SELFY studies both demonstrated improvements in glycemic control in the teenager and young adult age groups.

Disclosure

F. Campbell: Research Support; Self; Abbott. Consultant; Self; Eli Lilly and Company, Novo Nordisk A/S, Johnson & Johnson Diabetes Institute, LLC., Sanofi, Medtronic, Roche Diabetes Care Health and Digital Solutions. J. Bolinder: Advisory Panel; Self; Abbott. Speaker's Bureau; Self; Abbott. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S, Eli Lilly and Company.
Sex Differences in Insulin Sensitivity Are Related to Muscle Tissue Acylcarnitines and Serum Lysophosphatidylcholines but Not Subcellular Lipid Distribution in Humans
Authors: BROUSSARD JOSIANE L. , PERREAULT LEIGH , NEWSOM SEAN A. , KAHN DARCY E. , KEREGE ANNA , HARRISON KATHLEEN A. , BERGMAN BRYAN
Published: June 2018

Sex differences in insulin sensitivity are present throughout the lifespan, though mechanisms that account for these differences are unclear. Accumulation of diacylglycerol (DAG) and sphingolipids in skeletal muscle are thought to promote insulin resistance, and localization plays an important role. Other lipids and lipid intermediates found in muscle and plasma such as acylcarnitines also relate to insulin sensitivity. However, it is not known whether there are sex differences in accumulation of these lipids that may affect insulin sensitivity. We evaluated insulin sensitivity and sub-cellular localization of skeletal muscle DAG and sphingolipids, as well as muscle acylcarnitines and serum lipidomics, in 25 obese, nondiabetic men and women (13F). Insulin sensitivity was assessed with a hyperinsulinemic-euglycemic clamp. Muscle biopsies were taken during basal and insulin stimulated conditions and fractionated into sub-cellular compartments. Lipids were measured using LC/MS/MS. Insulin sensitivity was significantly lower in men (p=0.05), however we found no sex-differences in localization of DAG or sphingolipids in skeletal muscle. Men had higher total acylcarnitines in muscle tissue (p<0.05) and higher serum lysophosphatidylcholines (LPCs; p<0.01), and both were correlated with insulin sensitivity (r=-0.42 and -0.43, respectively; p<0.05). After correcting for multiple comparisons, the linoleoylcarnitine species (18:2AC) was significantly elevated in men during insulin stimulation (p=0.001), and was negatively associated with insulin sensitivity (r=-0.43; p<0.05). Combined, these data suggest differences in content of acylcarnitines between sexes consistent with differences in fatty acid processing and oxidation that may impact insulin sensitivity. Further, greater serum LPC species may play an important role in the decreased insulin sensitivity associated with male sex.

Disclosure

J.L. Broussard: None. L. Perreault: Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Advisory Panel; Self; Merck & Co., Inc.. Speaker's Bureau; Self; Merck & Co., Inc., AstraZeneca, Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Sanofi. S.A. Newsom: None. D.E. Kahn: None. A. Kerege: None. K.A. Harrison: None. B. Bergman: Research Support; Self; Eli Lilly and Company. Advisory Panel; Spouse/Partner; Novo Nordisk Inc., Merck & Co., Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company.
Glycemic Control and Infections among U.S. Hemodialysis Patients with Diabetes Mellitus
Authors: RHEE JINNIE J. , ZHENG YUANCHAO , MONTEZ-RATH MARIA , WINKELMAYER WOLFGANG
Published: June 2018

Patients with diabetes mellitus (DM) and those who are on hemodialysis (HD) may be particularly vulnerable to infections, but there is a dearth of clinical data on the relationship between glycemic control and infections in patients with DM on HD. We used data from the U.S. Renal Data System and the electronic health records from a large U.S. dialysis provider (DaVita, Inc.) merged at the patient level. We included adult Medicare-insured patients with DM aged ≥18 years who initiated in-center maintenance HD treatment from 20to 2011 and survived >90 days. The exposure was time-averaged HbA1c and quarterly mean HbA1c values were categorized as follows: <5.5%, 5.5-<6.5% (reference), 6.5-<7.5%, 7.5-<8.5%, and ≥8.5%. We used Medicare claims to ascertain infection-related hospitalizations and the ESRD Death Notification (CMS-2746) to identify death from infections. The primary outcome was the composite of infection-related death or hospitalization with all-cause death and transplant treated as competing risks using the Kaplan-Meier multiple imputation (MI) method. Missing data were handled through MI. We used extended-Cox models to estimate multivariable-adjusted hazard ratios (HR) and 95% CI for the associations between time-averaged HbA1c and the outcome, adjusting for baseline demographics and quarterly updated comorbidities from claims, central venous catheter use, and time-averaged vital signs and laboratory results. Among 33,753 eligible patients, 9415 infection-related hospitalizations occurred and 6deaths were linked to infection. Compared with patients with HbA1c 5.5-<6.5%, the adjusted HRs for infection-related death or hospitalization were 1.03 (CI, 0.96, 1.10), 1.03 (CI, 0.97, 1.09), 1.02 (0.95, 1.09), and 1.02 (CI, 0.95, 1.09) for patients with HbA1c <5.5%, 6.5-<7.5%, 7.5-<8.5%, and ≥8.5%, respectively (P-trend=0.97).

In summary, time-averaged HbA1c was not associated with the risk of a composite outcome of infection-related mortality or hospitalization.

Disclosure

J.J. Rhee: None. Y. Zheng: None. M. Montez-Rath: None. W. Winkelmayer: Advisory Panel; Self; Akebia Therapeutics, Amgen Inc., Bayer AG, FibroGen, Inc., AMAG Pharmaceuticals, Vifor Fresenius Medical Care Renal Phama, Relypsa Inc..
The Impact of Sarcopenia and Diabetes on Postoperative Complications in Abdominal Surgery Patients
Authors: DAVIS GEORGIA , FAYFMAN MAYA , SINGER ADAM , UMPIERREZ MONICA , KAKARALA APARNA , PENG LIMIN , NAIR SHAILESH , PASQUEL FRANCISCO J. , UMPIERREZ GUILLERMO E.
Published: June 2018

Sarcopenia and diabetes (DM) are independent predictors of poor postoperative outcomes. Limited data exists on the prevalence and impact of both conditions on perioperative outcomes in abdominal surgery patients. We performed a retrospective analysis of patients undergoing abdominal surgery who had abdominal CT imaging within 30 days prior to surgery. Measurements of psoas muscle surface area and attenuation values (in Hounsfield units) were recorded at the most anterior convex part of the lumbar spine corresponding to the level of the L3/L4 vertebrae. Sarcopenia was defined as the lowest sex-specific quartile of psoas muscle density. Composite of complications was determined using ICD-9 coding and included: acute MI, stroke, wound infection, pneumonia, UTI, bacteremia and respiratory failure. Among 343 patients, 85 (24%) met criteria for sarcopenia. Patients with sarcopenia were older, more likely to be Caucasian, had a longer length of hospital stay and had more postoperative complications. In fully adjusted analyses, patients with both DM and sarcopenia had four-fold higher rates of complications compared to those without DM or sarcopenia (Table).

In summary, sarcopenia is associated with higher rates of complications in patients with and without DM; the combination of sarcopenia and DM confers an additional risk of perioperative complications in patients undergoing abdominal surgery. No Sarcopenia (n=258)Sarcopenia (n=85)P-valueAge, years56.7 ± 15.2763.5 ± 14.290.001BMI, kg/m227.3 ± 6.6827.2 ± 7.030.64Male gender, n (%)119 (46)39 (46)0.97Race, n (%)  0.005Caucasian154 (60)66 (78) African American82 (32)18 (21) Other20 (8)1 (1) Diabetes status, n (%)  0.06No diabetes202 (78)58 (68) Diabetes56 (22)27 (32)LOS, median, days (interquartile range)9 (6, 17)15 (10, 29)<0.01No diabetes, composite complications Odds ratio* (95% CI)1.0 (Ref)2.47 (1.31-4.66)Diabetes, composite complications Odds ratio* (95% CI)0.61 (0.3-1.25)3.68 (1.48-9.19)*Odds ratio of composite of complication adjusted for age, gender, BMI and race

Disclosure

G. Davis: None. M. Fayfman: None. A. Singer: None. M. Umpierrez: None. A. Kakarala: None. L. Peng: None. S. Nair: None. F.J. Pasquel: Consultant; Self; Merck Sharp & Dohme Corp., Sanofi, Boehringer Ingelheim Pharmaceuticals, Inc. G.E. Umpierrez: Research Support; Self; Sanofi US, Merck & Co., Inc., Novo Nordisk Inc., AstraZeneca. Advisory Panel; Self; Sanofi, Intarcia Therapeutics, Inc..
Impact of Glycaemic Control on Bone Metabolism in Adult Patients with Type 1 Diabetes Mellitus
Authors: BARMPA ELEFTHERIA , VLYCHOU MARIANNA , TIGAS STELIOS , KOUKOULIS GEORGE N. , BARGIOTA ALEXANDRA
Published: June 2018

Introduction: Type 1 diabetes mellitus (T1DM) is associated with reduced bone mineral density (BMD), increased bone turnover and impaired bone microarchitecture. However, data regarding the influence of glycaemic control on bone metabolism are limited. The aim of this study was to evaluate BMD and bone remodeling markers in patients with T1DM in relation to changes in glycaemic control.

Methods/Design: We studied 118 patients with T1DM and age 20-50 years (mean 34.6±7.9years, M/F:53/65), diabetes duration >5 years and no diabetic complications and 95 healthy controls matched for age, sex and body mass index (BMI). All T1DM participants were re-examined after one-year (FU). In both groups, measurements of glycated hemoglobin (HbA1c) and BMD at lumbar spine (LS) and femoral neck (FN) by dual energy X-ray absorptiometry (DXA) were performed. Bone resorption and formation was assessed by measurements of β-crosslaps and of type 1 procollagen total N-terminal propeptide (TP1NP) in serum. Currently, seventy T1DM patients completed the FU and had repeat biochemical and BMD measurements. Based on current literature, BMD changes of ≥3% at the LS and of ≥6% at the FN were considered significant.

Results: In the T1DM group, mean duration of the disease was 15.9±7.6 years and mean HbA1c was 8.1±1.4%. Subject in the T1DM group had lower BMD and Z-score at LS and FN compared to those in the control group (LS:p=0.039,p=0.02) (FN:p=0.041,p=0.038). At baseline, no significant differences in β-crosslaps and TP1NP were observed between the two groups. Out of the 70 T1DM patient who have completed FU so far, 42/70 patients had ≥0.5% reduction in HbA1c, 12/70 had about the same HbA1c (±0.4%) and 16/70 had ≥0.5% increase in HbA1c. In the 42 patients with improved HbA1c, BMD increased by 3.4% at the LS and by 5.7% at the FN, and TP1NP was significantly higher compared to baseline (p=0.043).

Conclusion: T1DM is associated with reduced BMD but improvement of glycaemic control appears to ameliorate BMD and bone turnover.

Disclosure

E. Barmpa: None. M. Vlychou: None. S. Tigas: None. G.N. Koukoulis: None. A. Bargiota: None.
Depressive Symptoms and Glycemic Control among Puerto Rican Adults with Diabetes
Authors: MATTEI JOSIEMER , FALCON LUIS M. , TUCKER KATHERINE L.
Published: June 2018

A bidirectional relationship between depression and diabetes risk has been suggested. Less is known about the dynamics between depressive symptomatology and glycemic control among individuals already at risk of both conditions. We aimed to examine the prospective bidirectional associations between depressive symptomatology and glycemic control. We used data from 488 participants of the Boston Puerto Rican Health Study (mean (SD) age= 58.9 (7.2) y) with type 2 diabetes (fasting plasma glucose ≥ 126 mg/dL or use of medication). At baseline, participants were categorized as having uncontrolled hemoglobin A1c (≥7%) vs. controlled, and as having depressive symptomatology (Center for Epidemiological Studies-Depression (CES-D) score ≥16) vs. not. Categories for 2-year changes in glycemic control were set as (>-0.5%=improved; -0.5% to 0.5%=stable; ≥0.5%=worsened); 2-year changes in CES-D score as (>-3=improved; -3 to 3=stable; ≥3=worsened). In logistic regressions adjusted for sociodemographic and lifestyle variables and number of medical conditions, having baseline depressive symptomatology was associated with 1.96 (95% CI: (1.10, 3.50; p=0.022) higher odds of having worsened hemoglobin A1c at 2-year compared to keeping it stable. Baseline uncontrolled hemoglobin A1c was not associated with change in depression score. When modeling 2-year change categories as predictors, improved depression score (vs. stable) was associated with lower odds (0.42 (0.21, 0.81); p=0.01) of worsened hemoglobin A1c, while worsened glycemic control (vs. stable) was associated with lower odds (0.40 (0.21, 0.78); p=0.007) of improved depression score.

In conclusion, a bidirectional association between changes in depressive symptomatology and glycemic control over 2 years among individuals with diabetes suggests that timely attention to both conditions should be given simultaneously. Interconnected diabetes and depression management practices should be recommended for adults with diabetes.

Disclosure

J. Mattei: None. L.M. Falcon: None. K.L. Tucker: None.