bluuebunny/crossref_metadata_2025 huggingface dataset:
IDegAsp Improves Glycemic Control with Minimal Hypoglycemia—An Indian Real-World Study in T2D Subjects
Authors: KESAVADEV JOTHYDEV , SABOO BANSHI D. , SHANKAR ARUN , DAVID ASHWIN , WARRIER ROHIT , KRISHNAN GOPIKA , RAMACHANDRAN LAKSHMY , JOTHYDEV SUNITHA
Published: June 2018

Background: IDegAsp is the first insulin co-formulation constituting 70% insulin degludec and 30% insulin aspart. In contrast to conventional premix analogues, degludec component of IDegAsp lowers variability, fasting glucose with comparable glycemic control and fewer hypoglycemic events. Re-suspension errors inherent to premix analogues also does not occur with IDegAsp. In routine diabetes practice, patients have customised A1c goals depending on the associated comorbidities and risk factors.

Aim: To assess the safety and efficacy of IDegAsp in Indian T2D subjects in a real-world setting.

Methods: T2D initiated on IDegAsp and on regular follow-up were de-identified from EMR. Clinical outcomes and hypoglycemic events were captured. n= 152, age= 52.9±11.9y, diabetes duration= 11.5±13.8y, 78.57% males, treatment duration= 10.3±6.5mths.

Results: 92% of the patients achieved customised A1c targets.Reduction from baseline: 0.91% in A1c(p=0.0004), 41.4 mg/dL in FBS(p<0.0001), 0.80 kg in body weight(p=0.0083).Five hypoglycemic episodes were reported (none severe). There were no reported episodes of nocturnal hypos.

Conclusion: In this real-world study involving T2D subjects in India, IDegAsp improved HbA1c and FBS significantly,with less hypoglycemia and no weight gain. Some of these outcomes are contrary to those reported in clinical trials and could have resulted from the new combination oral therapies.

Disclosure

J. Kesavadev: Advisory Panel; Self; Novo Nordisk India Private Limited. Speaker's Bureau; Self; Novo Nordisk India Private Limited. Advisory Panel; Self; Medtronic. Speaker's Bureau; Self; Medtronic. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; MSD. Speaker's Bureau; Self; MSD. Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. B.D. Saboo: None. A. Shankar: None. A. David: None. R. Warrier: None. G. Krishnan: None. L. Ramachandran: None. S. Jothydev: None.
Target Fasting Plasma Glucose (FPG) without Nocturnal Hypoglycemia in Patients with Type 1 Diabetes or Type 2 Diabetes—Results from SWITCH Trials
Authors: WYSHAM CAROL H. , LANE WENDY , LADELUND STEEN , TUTKUNKARDAS DENIZ , HELLER SIMON
Published: June 2018

Insulin degludec (degludec) is a basal insulin that results in a lower FPG than insulin glargine 100 units/mL (glargine U100), which may increase the risk of nocturnal hypoglycemia in patients with type 1 diabetes (T1D) or type 2 diabetes (T2D). This post-hoc analysis investigated the proportion of patients with T1D or T2D treated with degludec or glargine U100 meeting the ADA recommended upper limit of the pre-meal plasma glucose goal of <130 mg/dL (<7.2 mmol/L) at each visit (start and end of 16 week maintenance) without nocturnal hypoglycemia. Patients with T1D or T2D and with FPG measurements during the 16-week maintenance period of the SWITCH 1 (n=501) and SWITCH 2 (n=720) trials (randomized, double-blind, crossover, treat-to-target trials of patients treated with degludec or glargine U100) were included. Nocturnal hypoglycaemia was defined as any blood glucose-confirmed (<56 mg/dL [<3.1 mmol/L]) symptomatic event occurring from 00:01-05:59. In the SWITCH trials, significantly more patients with T1D or T2D treated with degludec achieved FPG target during the maintenance period, and did so without nocturnal hypoglycemia, compared with glargine U100 (Figure).

In conclusion, compared with glargine U100, treatment with degludec was associated with greater opportunity to reach target FPG without an increased risk of nocturnal hypoglycemia.

Disclosure

C.H. Wysham: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi. Consultant; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Insulet Corporation, Novo Nordisk Inc., Sanofi. W. Lane: Advisory Panel; Self; Novo Nordisk A/S, Insulet Corporation, Intarcia Therapeutics, Inc., Sanofi. Research Support; Self; Novo Nordisk A/S, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Sanofi, Dexcom, Inc.. Speaker's Bureau; Self; Novo Nordisk A/S, Insulet Corporation. S. Ladelund: Employee; Self; Novo Nordisk A/S, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Technical University of Denmark. Research Support; Self; Metropolitan University College, Denmark. D. Tutkunkardas: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. S. Heller: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S, Takeda, Sanofi-Aventis, Boehringer Ingelheim GmbH. Consultant; Self; Eli Lilly and Company, Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S, Eli Lilly and Company, Merck Sharp & Dohme Corp., Takeda, AstraZeneca, Boehringer Ingelheim GmbH.
Somatostatin Receptor II Antagonism Improves Glucagon Counterregulatory Responses to Recurrent Hypoglycemia in Male Sprague-Dawley Rats
Authors: RIDDELL MICHAEL , JAHANGIRIESMAILI MAHSA , MANDEL ERIN R. , GREENBERG CAYLEE A. , PASIEKA AOIBHE M. , TEICH TREVOR , CHAN OWEN , LIGGINS RICHARD T.
Published: June 2018

Glucagon (GCN) helps prevent hypoglycemia when blood glucose levels drop; however, recurrent hypoglycemia attenuates GCN counterregulation to subsequent bouts of hypoglycemia. As somatostatin normally inhibits GCN secretion, we tested the hypothesis that a somatostatin receptor type 2 antagonist (SSTR2a), PRL-2903, improves GCN responses attenuated by recurrent hypoglycemia in healthy rats. Healthy male Sprague-Dawley rats (n=22) were made hypoglycemic on three consecutive days (days 1-3, blood glucose 1.7-2.2 mmol/L for ∼2 h) via exogenous insulin administration (10-, 8- and 5- U/kg of Humulin-R on days 1-3, respectively). GCN levels during hypoglycemia on day 3 were significantly lower than on day 1 (117±47 pg/mL vs. 184±77 [mean±SD] pg/mL; P=0.001), highlighting the role of recurrent hypoglycemia in counterregulatory failure. On day 4, rats were treated with either PRL-2903 (10 mg/kg IP; n=13) or vehicle (n=9) 1 h prior to the induction of hypoglycemia with 5 U/kg of R-insulin. GCN levels during hypoglycemia (i.e., glucose ≤3.5 mmol/L) were 2.5-fold higher (109±55 vs. 44±26 pg/mL; P=0.004) compared to vehicle, and time to reach hypoglycemia was 3.2-fold longer (64±45 vs. 20±10 min; P =0.001), with PRL-2903 pre-treatment. Interestingly, C-peptide levels were also lower (P=0.001) with PRL-2903 (0.35±0.22 ng/mL), compared to vehicle (0.63±0.21 ng/mL), inferring a lower insulin secretion during hypoglycemia with PRL-2903 treatment.

In conclusion, our data suggests that SSTR2a improves GCN responses following recurrent hypoglycemia, and that this improvement may be associated with a reduction in insulin secretion in healthy rats. Therefore, SSTR2a treatment may be a useful therapeutic approach to improve GCN counterregulatory responses to hypoglycemia.

Disclosure

M. Riddell: Speaker's Bureau; Self; Medtronic. Consultant; Self; Eli Lilly and Company, JAEB Center For Health Research, Xeris Pharmaceuticals, Inc.. Research Support; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Ascensia Diabetes Care. Stock/Shareholder; Self; Zucara Theraputics. Other Relationship; Self; JDRF. M. Jahangiriesmaili: None. E.R. Mandel: None. C.A. Greenberg: None. A.M. Pasieka: None. T. Teich: None. O. Chan: None. R.T. Liggins: Employee; Self; Zucara Therapeuytics, Inc..
Severe Hypoglycemia Rates Are Highest among those with Suboptimal Reporting Behaviour—Results from the InHypo-DM Study
Authors: RATZKI-LEEWING ALEXANDRIA , BLACK JASON E. , MEQUANINT SELAM , AU NATALIE H. , RYAN BRIDGET L. , REICHERT SONJA M. , BROWN JUDITH B. , HARRIS STEWART
Published: June 2018

Many patients fail to report severe hypoglycemia (SH) events to their healthcare provider (HCP). This limits the ability of HCPs to adjust treatment regimens and optimize glycemia. This study aimed to explore the independent association between patients’ disclosure of SH events to their HCP and self-reported rates of SH. Data were obtained from the InHypo-DM population-based study, Canada’s largest hypoglycemia-specific survey. To indicate SH disclosure, patients at risk for hypoglycemia rated how often they reported their SH events (using ADA definitions) to their HCP on a scale from Never to Always. Univariable analyses identified significant clinical or demographic confounders (p≤0.2). Based on the distribution of SH events, zero-inflated negative binomial (ZINB) regression was used to test the relationship between hypoglycemia disclosure and the retrospective incidence of SH events. A total of 552 people with T1DM (17%) or T2DM (83%) completed the InHypo-DM survey. Forty percent of respondents reported at least one or more SH events. The overall incidence rate of SH was 2.45 events/person-year. Thirty-four percent of respondents indicated that they always report SH events. Results of the ZINB model showed that the odds of experiencing any event was not significantly associated with disclosure behaviour (p=0.86). However, the rate of repeated events was almost double (IRR=1.9, 95% CI: 1.2 to 3.0, p=0.004) among individuals who under-reported their SH as compared to those who did not. These results persisted after adjusting for age, medication type, income, most recent HbA1c, and presence of comorbidities. This population-based study revealed a nearly two-fold higher rate of SH among those who under-report to their HCP. Thus, HCPs should be aware that patient reporting may not be a true reflection of SH events and make efforts to elicit accurate information regarding SH events from their patients, especially for those at risk for repeated SH.

Disclosure

A. Ratzki-Leewing: None. J.E. Black: None. S. Mequanint: None. N.H. Au: None. B.L. Ryan: None. S.M. Reichert: Other Relationship; Self; Novo Nordisk Inc., Sanofi, Abbott, AstraZeneca. Advisory Panel; Self; Servier. Speaker's Bureau; Self; Eli Lilly and Company. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Merck & Co., Inc., Janssen Pharmaceuticals, Inc.. J.B. Brown: None. S. Harris: Advisory Panel; Self; Novo Nordisk A/S, Sanofi, Merck, AstraZeneca, Amgen Inc., Lilly/Boehringer Ingelheim, Abbott, Janssen. Consultant; Self; Novo Nordisk A/S, Sanofi, Merck, AstraZeneca, Lilly/Boehringer Ingelheim, Abbott, Janssen. Research Support; Self; Novo Nordisk A/S, Sanofi, Merck, Abbott, AstraZeneca, Janssen. Other Relationship; Self; CIHR, CDA, The Lawson Foundation.
Decreasing Incidence of Postinsulin Hypoglycemia for Hyperkalemia Treatment
Authors: MACMASTER HEIDEMARIE W. , TRAN ALLEN , MONASH BRADLEY , MURRAY SARA G. , PRASAD PRIYA A. , RUSHAKOFF ROBERT J.
Published: June 2018

Acute hyperkalemia (K = 5.1 mEq/L) treatment may include a 10 unit bolus of IV insulin regular. Nationally, this treatment results in a 20% rate of hypoglycemia and a 7% rate of severe hypoglycemia. At UCSF, after introduction of a updated hyperkalemia orderset (Revision a) that standardized blood glucose (BG) POCT pre-insulin administration and post-insulin administration (1, 2, 4, and 6 hours post-insulin), we found 21% of treatments resulted in hypoglycemia (<70 mg/dl) with 92% of these occurring <3 hours of insulin administration. After analysis for independent hypoglycemia risk factors, we further revised the hyperkalemia order set(Revision b) to: 1) weight-based insulin dosing 2) If pre-insulin BG < 50 mg/dL, then add an additional dextrose 50% (50 mL) IV once one-hour post-insulin administration 3) If pre-insulin BG >300 mg/dL, then remove dextrose 50% (50 mL) with insulin administration. There was a significant reduction in both hypoglycemia and severe hypoglycemia following implementation of the Revision b hyperkalemia orderset (Table).

Post-Insulin Hypoglycemia for Hyperkalemia TreatmentGlycemic Control - Post-Insulin for Hyperkalemia TreatmentHyperkalemia Orderset - Revision a (n=225) 01/01/16-03/19/17Hyperkalemia Orderset -Revision b (n=146) 03/30/17-09/30/17Hypoglycemia (<70mg/dL)21%10%Severe Hypoglyemia (<40 mg/dL)5%2%

In conclusion, we believe that an EMR hyperkalemia order set can help significantly reduce hypoglycemia events with predefined times for glucose monitoring, weight-based insulin dosing, standard glucose administration guidelines and prompts to warn providers of risks for hypoglycemia. This data supports optimization of glycemic control into the AHA hyperkalemia guidelines.

Disclosure

H.W. Macmaster: None. A. Tran: None. B. Monash: None. S.G. Murray: None. P.A. Prasad: None. R.J. Rushakoff: None.
Diabetes Mellitus and High Triglycerides Are Significant Predictors of Major Cardiovascular Events and Increased Health Care Costs and Resource Utilization—A Real-World Analysis of High-Risk Statin-Treated Patients
Authors: TOTH PETER P. , GRANOWITZ CRAIG B. , HULL MICHAEL , PHILIP SEPHY
Published: June 2018

Background: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality in patients with diabetes. We investigated real-world impact of high triglycerides (TG) and diabetes on cardiovascular (CV) outcomes and costs.

Methods: This retrospective administrative claims multivariate analysis (controlled for patient characteristics and comorbidities) of the Optum Research Database included patients aged ≥45 years with diabetes and/or ASCVD who had a statin prescription filled in 2010, had continuous medical/pharmacy coverage, and were followed for ≥6 months up to March 2016. Patients with TG 200-499 mg/dL (n=13,411) and a comparator cohort with TG <150 mg/dL and high-density lipoprotein cholesterol (HDL-C) >40 mg/dL (n=32,506) were included.

Results: Multivariate analyses showed a 35% higher rate of occurrence of composite major CV events per unit time in the high-TG vs. comparator cohort (hazard ratio [HR] 1.349, 95% CI 1.225-1.485, P<0.001). Diabetes was found to be a significant predictor of CV events, costs, and risk of inpatient hospital stay (Table).

Conclusions: In statin-treated patients with high CV risk, high TG and diabetes were found to be significant predictors of worse CV and health economic outcomes in a real-world setting.

Disclosure

P.P. Toth: Speaker's Bureau; Self; Amarin Corporation. Consultant; Self; Amarin Corporation. Speaker's Bureau; Self; Amgen Inc.. Consultant; Self; Amgen Inc.. Speaker's Bureau; Self; Kowa Pharmaceuticals America, Inc.. Consultant; Self; Kowa Pharmaceuticals America, Inc.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Consultant; Self; Merck Sharp & Dohme Corp.. Speaker's Bureau; Self; Regeneron Pharmaceuticals, Inc.. Consultant; Self; Regeneron Pharmaceuticals, Inc.. Speaker's Bureau; Self; Sanofi US, Novo Nordisk Inc. C.B. Granowitz: Employee; Self; Amarin Corporation. M. Hull: None. S. Philip: Stock/Shareholder; Self; Amarin Corporation. Employee; Self; Amarin Corporation.
Total Oxidative Index Is Associated with Glycated Hemoglobin, Low-Grade Inflammation, and Non-HDL Cholesterol in Type 2 Diabetes
Authors: DALAN RINKOO , GOH LIUH LING , TANG XIN , CHEW DANIEL E.K. , BOEHM BERNHARD
Published: June 2018

Objectives: To study associations of established cardiovascular risk factors, inflammation and carotid artery intima-media thickness (CIMT) with oxidative stress in type 2 diabetes mellitus (T2DM).

Methods: We recruited 343 T2DM subjects from the three main ethnic groups in Singapore (Chinese: 196, Indians: 106, Malays: 41; Age: 54.7±10.4 years; Males: 46%). Measurements: Demographics, BMI, blood pressure, HbA1c, glucose and lipids; CIMT and C-reactive protein (hsCRP). Derivatives of reactive oxygen metabolites (dROMS) and total anti-oxidant status (TAC) was estimated by the automated clinical chemistry analyser (Diacron, Italy). The total oxidative index (OXY) was calculated as the difference between standardised dROMS and TAC values. The relationship between OXY, dROMS and TAC as dependent variable and age, gender, ethnicity, BMI, blood pressure, HbA1c, fasting lipids, log CRP and CIMT as co-variates was assessed using multiple regression analysis. Associations with gender and ethnicity were assessed by student’s t test and Kruskal Wallis test respectively.

Results: The mean OXY was higher in the females (0.2±1.3) compared to the males (0.2±1.0); p<0.001 and highest in the Indians (0.3±1.2) when compared to Chinese (-0.1±1.2) and Malays (-0.1±1.0); p=0.01. OXY exhibited a linear relationship with HbA1c (β=0.09, p=0.01), Non-HDL cholesterol ((β=0.28, p<0.001) and CRP (β=0.21, p<0.001). dROMS associated with HbA1c (β=5.3, p=0.04) and CRP (β=14.80, p<0.001) and TAC associated inversely with non-HDL-cholesterol (β= -121.4, p<0.001). No association with CIMT was seen.

Conclusions: In T2DM, total oxidative stress is a function of HbA1c, non-HDL-Cholesterol and low-grade inflammation. HbA1c and inflammation increase reactive oxygen metabolites, whereas non-HDL cholesterol decreases the anti-oxidant potential. The mechanisms of oxidative stress generation, in particular in various ethnic groups, needs to be studied further.

Disclosure

R. Dalan: None. L. Goh: None. X. Tang: None. D.E.K. Chew: None. B. Boehm: None.
Amino Acid Metabolism Is Regulated by Glucagon Receptor Signaling in Mice
Authors: WINTHER-SOERENSEN MARIE , GALSGAARD KATRINE D. , KUHRE RUNE E. , PEDERSEN JENS , ALBRECHTSEN NICOLAI J. WEWER , HOLST JENS J.
Published: June 2018

The pancreatic hormone glucagon contributes to diabetic hyperglycemia and glucagon receptor antagonists lower blood glucose in patients with type 2 diabetes. A liver-alpha cell axis has recently been identified which when disrupted leads to hypersecretion of glucagon and may contribute to the development of diabetes. Here, we investigated the hepatic effects of glucagon receptor signaling in rodents and hypothesized that intact glucagon receptor signaling is necessary for amino acid metabolism via non-transcriptional changes leading to increased ureagenesis. Female C57BL/6JRj mice (n=64) were given a glucagon receptor antagonist (GRA) or vehicle orally three hours prior to an intraperitoneal injection with amino acids (Vamin, 3.6 µmol/g body weight), glucagon (200 ng/g body weight), or both, and blood samples were obtained at 0, 4, 12, and 20 minutes after injection. GRA treated animals had a significant decrease in plasma urea (8.6±0.3 vs. 11.1±0.4 mmol/L, p<0.0001) and blood glucose (8.1±0.2 vs. 9.0±0.2, p<0.001 mmol/L) and a concomitant increase in plasma amino acids (3.5±0.1 vs. 2.7±0.1 mmol/L, p<0.0001) and glucagon (32.5±3.5 vs. 12.5±1.7 pmol/L, p<0.0001). In addition, amino acid-stimulated ureagenesis, reflected by increased plasma urea, was inhibited in GRA treated mice compared to controls (incremental area under the curve: 27.6±3.3 vs. 41.2±5.3 min × mmol/L, p<0.05). Production of urea in perfused rat livers (n=6) increased rapidly upon administration of amino acids (1 mM) compared to baseline (683±254 vs. 518±198 pmol/min/100 g body weight, p<0.05) and was further increased in response to amino acids + glucagon (10 nM) stimulation (846±229 vs. 518±198 pmol/min/100 g body weight, p<0.001). Glucagon therefore acutely regulates hepatic amino acid metabolism through increased ureagenesis via non-transcriptional mechanism(s), and disruption of this, due to e.g., nonalcoholic liver disease, may therefore contribute to the diabetogenic effect of hyperglucagonemia.

Disclosure

M. Winther-Soerensen: None. K.D. Galsgaard: None. R.E. Kuhre: None. J. Pedersen: None. N.J. Wewer Albrechtsen: Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Other Relationship; Self; Mercodia, Alpco. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics.
Serum Uromodulin (SUMOD) Inversely Correlates with Aortic Stiffness in Type 1 Diabetes (T1D) Youth
Authors: WIROMRAT PATTARA , BJORNSTAD PETTER , RONCAL-JIMENEZ CARLOS ALBERTO , SCHÄFER MICHAL , BAUMGARTNER AMY , PYLE LAURA , CREE-GREEN MELANIE , REYES YESENIA GARCIA , BROWNE LORNA , JOHNSON RICHARD , NADEAU KRISTEN J.
Published: June 2018

Lower SUMOD correlates with decreasing kidney function and atherosclerosis in adults with T1D, but its relationship with markers of arterial stiffness in youth with T1D is unknown. We sought to evaluate the relationship between SUMOD and central arterial stiffness in youth with T1D. Participants (n=49, 12-21 years old, 51% female, BMI 25.2±4.6 kg/m2, mean HbA1c8.6±1.4) were enrolled in EMERALD, a randomized controlled trial of metformin in youth with T1D. Post-hoc SUMOD was measured using Euroimmun ELISA kits from serum from the baseline visit. Ascending (AA) and descending aortic (DA) stiffness (pulse wave velocity [PWV] and strain) were determined by MRI at baseline and 3 months of follow-up. SUMOD positively correlated with AA strain (r: 0.37, p=0.04) and negatively with AA PWV (r: -0.41, p=0.03). According to SUMOD tertiles, participants in the lower tertile had higher AA PWV vs. the middle and high tertiles (Figure).

Lower baseline SUMOD also predicted worsening in AA PWV over 3 months (β±SE: -0.04±0.01, p=0.03) adjusting for age, sex, baseline AA PWV, treatment group (metformin vs. placebo) and estimated glomerular filtration rate. In T1D youth, decreased SUMOD is associated with increased aortic stiffness. Further research is needed in T1D youth to understand the pathogenesis of SUMOD in cardiovascular disease.

Disclosure

P. Wiromrat: None. P. Bjornstad: Consultant; Self; Boehringer Ingelheim GmbH. C. Roncal-Jimenez: None. M. Schäfer: None. A. Baumgartner: None. L. Pyle: None. M. Cree-Green: None. Y. Garcia Reyes: None. L. Browne: None. R. Johnson: Board Member; Self; XORT Therapeutics. Stock/Shareholder; Self; Colorado Research Partners LLC. Consultant; Self; Danone Research Foundation. K.J. Nadeau: None.
Do Greenlandic Carriers of the TBC1D4 p.Arg684Ter Variant Have Increased Risk of Cardiovascular Disease?
Authors: JØRGENSEN MARIT E. , TVERMOSEGAARD MARIA , RØNN PERNILLE F. , BJERREGAARD PETER , DAHL-PETERSEN INGER K. , LARSEN CHRISTINA V. , PEDERSEN MICHAEL L. , ALBRECHTSEN ANDERS , MOLTKE IDA , GRARUP NIELS , HANSEN TORBEN
Published: June 2018

Background: The nonsense polymorphism p.Arg684Ter in the TBC1D4 gene is associated with severe skeletal muscle insulin resistance and postprandial hyperglycemia in the Greenlandic population. Homozygous carriers have an increased risk for type 2 diabetes (odds ratio of 10.3) and the variant has an allele frequency of 17% with 4% homozygous carriers in the population. However, we do not know, if p.Arg684Ter carrier status also confers a greater risk of cardiovascular disease (CVD). Thus the aim is to investigate if carriers of the variant are more at risk of CVD than non-carriers.

Materials and Methods: The study included adult participants in the Inuit Health in Transition study completed in the years 2005-2010 with sampling from 12 regions in Greenland (n= 3115) and the B99 study conducted from 1999-2001 (n=1401). Outcome was a first time CVD event from the Greenlandic Patien Register or the Causes of Death Register. Incidence rates of CVD were estimated by Poisson regression for wild type, heterozygous and homozygous carriers followed until the end of 2013, adjusted for European admixture proportion, age, sex, smoking, lipids, blood pressure, lipid- and blood pressure lowering drugs, blood glucose and known diabetes.

Results: During a median follow-up time of 7 years [IQR: 5.0, 10.0], 273 had an incident CVD event, 13 events among homozygous (HO), and 78 events among heterozygous (HE) carriers. Both in crude and adjusted analyses, there was a higher risk of incident CVD with p.Arg684Ter carrier status, although not statistically significant, with unadjusted incidence rate ratios (IRR) of 2.2 [CI 0.3- 15.5] for HO vs. WT; multivariable adjusted IRR 1.6 [0.12-19.5] for HO vs. WT. The same pattern was seen for HE vs. WT.

Conclusions: Overall, there was a trend towards increased risk of incident CVD with the TBC1D4 p.Arg684Ter variant although not statistically significant. Lack of statistical power may partly explain this, and replication in a larger sample or longer follow-up is needed.

Disclosure

M.E. Jørgensen: Stock/Shareholder; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca, Amgen Inc.. M. Tvermosegaard: None. P.F. Rønn: Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. P. Bjerregaard: None. I.K. Dahl-Petersen: None. C.V. Larsen: None. M.L. Pedersen: None. A. Albrechtsen: None. I. Moltke: None. N. Grarup: None. T. Hansen: None.
Asymptomatic Coronary Artery Disease (CAD) in a Norwegian Cohort with Type 2 Diabetes (T2D)—A Prospective Invasive Coronary Angiographic (ICA) Study
Authors: OFSTAD ANNE P. , ARORA SATISH , ULIMOEN GEIR R. , BIRKELAND KARE I. , ENDRESEN KNUT , GULLESTAD LARS L. , JOHANSEN ODD ERIK
Published: June 2018

Effective treatment strategies to reduce the CAD burden in T2D are needed. We investigated whether progression of CAD, evaluated by ICA, could be modulated with a hospital-based multi-intervention (MULTI) to reduce cardiovascular (CV) risk. Patients with T2D and ≥ 1 CV risk factor (n=56, 21% women, age/T2D duration 57.9±7.9/5.8±5.6 years, HbA1c 7.4±1.6%, systolic BP 139±19 mmHg, LDL-cholesterol 2.8±0.9 mmol/L) were randomized to 2 years of MULTI (n=30), or standard care (STAND) by general physicians (n=26), with a pre-planned follow-up at year 7. ICA was performed at baseline (BL) and year 7. At BL 21 (36%) had no CAD, 17 (29%) wall changes, 4 (7%) 25-50% stenosis and 14 (24%) >50% stenosis. Angiograms were scored as: grade 0:<25% stenosis (st), 1:<50% st, 2: <75% st, 3: >75% st, 4: occlusion. CAD burden was described by the extent score (sc) (number of segments graded ≥1, adjusted to 16 segments) and severity sc (average gr of the diseased segments graded ≥1). After 2 years of intervention, CV risk factors in MULTI (HbA1c, systolic BP, LDL-cholesterol) were reduced, without between-group differences in CAD progression at year 7 (Table). Our data indicate that asymptomatic T2D patients have extensive CAD that increases over time and is not modulated by a 2-year multi-intervention. This suggests a need for more durable CV risk management using alternative approaches.Progression of CAD from baseline to 7 years in the two treatment groupsT2D populationBaseline7 yearspMULTI (n=30)STAND (n=26)MULTI (n=30)STAND (n=26)CAD progressionExtent Score0.038±0.0670.078±0.120.050±0.0810.10±0.110.30*Severity Score0.47±0.840.83±1.110.67±0.981.18±1.060.20**p for between-group difference in change from baseline to 7 years by ANCOVA Abbreviations: CAD: coronary artery disease, T2D: type 2 diabetes, MULTI: multi-intervention, STAND: standard care. Data given as mean±standard deviation.

Disclosure

A.P. Ofstad: Employee; Self; Boehringer Ingelheim GmbH. S. Arora: None. G.R. Ulimoen: None. K.I. Birkeland: Research Support; Self; AstraZeneca, Novo Nordisk A/S, Eli Lilly and Company, Sanofi, Boehringer Ingelheim GmbH, Merck Sharp & Dohme Corp.. K. Endresen: None. L.L. Gullestad: None. O. Johansen: Employee; Self; Boehringer Ingelheim GmbH.
A Machine-Learning Model Accurately Predicts Projected Blood Glucose
Authors: GOLDNER DANIEL R. , OSBORN CHANDRA Y. , SEARS LINDSAY E. , HUDDLESTON BRIAN , DACHIS JEFF
Published: June 2018

Background: Clinical guidelines do not specify the frequency of self-monitoring of blood glucose (SMBG) for the ∼85% of people with type 2 diabetes (T2D) not on intensive insulin therapy. For these individuals, insurance covers a limited amount of testing supplies, and blood glucose (BG) checks are infrequent. With limited BG data, people may not know how foods, activity, and other factors affect their BG levels. Other, non-SMBG-dependent, approaches are needed to illustrate how self-care choices affect BG.

Objectives: 1.) Use a large dataset to train a machine learning model 2.) Use the model and minimal data inputs to predict BG values at variable times 3.) Test the accuracy of the prediction.

Methods: The One Drop | Mobile app collected 1,923,416 BG measurements from 14,706 people with noninsulin treated T2D. Contextual information (CI), when available, included demographics, health metrics (e.g., weight, A1c), and self-care. Inputs to each BG prediction included a prior BG and available CI. The model did not distinguish whether BGs with similar CI were from the same or different users. Forecast horizons were set by the time since prior BG and varied from 10 minutes to several days. Machine learning algorithms to predict BG values were trained and vetted on BGs entered prior to Sept. 2017 (83% of all BGs). BGs (17%) entered from Sept.-Nov. 2017 were held out and predicted.

Results: Users were 59% male, with 80% from North America, 9% from Europe, and 11% from elsewhere; 50% were diagnosed with T2D in the past 3 years. The median and mean absolute error of holdout predictions were 14.2 and 21.3 mg/dL respectively, with 91% of predictions within +/-50 mg/dL.

Discussion: A machine learning model with minimal inputs accurately predicts future BG values in noninsulin treated people with T2D. Whether people modify their behavior (e.g., eating less carbohydrates) after knowing a planned behavior (e.g., a 60 carbohydrate gram meal) produces an undesirable BG (>140 mg/dL postprandial) is an empirical question worth investigating.

Disclosure

D.R. Goldner: Consultant; Self; One Drop. C.Y. Osborn: Employee; Self; One Drop. Research Support; Self; MannKind Corporation. Stock/Shareholder; Self; One Drop. L.E. Sears: Employee; Self; Informed Data Systems Inc.. Research Support; Self; MannKind Corporation. B. Huddleston: Employee; Self; One Drop. J. Dachis: Stock/Shareholder; Self; One Drop. Board Member; Self; One Drop. Employee; Self; One Drop.
Evaluation of Endothelial Function and Sympathetic Nervous Activity along the Glucose Continuum in Individuals with Habitual Low Sodium Intake
Authors: BAQAR SARA , EKINCI ELIF I.
Published: June 2018

Objective: To assess endothelial function and sympathetic nervous activity in individuals with low sodium intake along the glucose continuum.

Research Designs and Methods: In this prospective observational study, participants (n=54) with low sodium intake (single 24hour urine sodium excretion <150mmol/24h) were recruited and categorized based on an oral glucose tolerance test as: controls (n=10), with impaired glucose tolerance (IGT) (n=15) and with untreated (n=12) type 2 diabetes and were then compared to individuals with treated type 2 diabetes (n=17) with established cardio-metabolic risk factors. We assessed pulse amplitude tonometry (PAT) derived measures of endothelial function using the reactive hyperemic index and arterial stiffness using augmentation index; muscle sympathetic nerve activity (MSNA) using microneurography; cardiac baroreflex; heart rate; blood pressure; fasting glucose; glycosylated hemoglobin A1c (HbA1c) and lipid profile.

Results: The mean (SD) sodium excretion was 110.6 (26) mmol/24hour. Compared to individuals from the other groups, the treated type 2 diabetes group had a lower PAT ratio (p=0.04), lower baroreflex (p=0.0002) and higher heart rate (p=0.02) suggestive of sympatho-vascular dysfunction. This occurred despite lower MSNA (p=0.005) and appropriate glycemic (mean +/-SD): HbA1c 7.2 (1.72)% (55mmol/mol), total cholesterol 4.2 (1.0) mmol/L, LDL 2.2 (1.0) mmol/L) and blood pressure (mean +/-SD) 136 (13) systolic and 78 (12) diastolic pressure (mmHg) control.

Conclusion: In individuals with treated type 2 diabetes, despite a low sodium intake and appropriately managed cardio-metabolic risk factors, endothelial and baroreflex function were impaired. Whether sodium restriction may be associated with an attenuated sympatho-vascular response in individuals with diabetes requires further investigations.

Disclosure

S. Baqar: None. E.I. Ekinci: None.
Low Prevalence of Peripheral Arterial Disease in Type 2 Diabetes Patients in North India
Authors: MAKKAR BRIJ M. , SHARMA JUGAL K. , JAGGI SHALINI , SOOTA KIRTI , GUPTA VIPUL , KHURANA GIRISH
Published: June 2018

Introduction: Peripheral Arterial Disease (PAD) is a major macrovascular complication of type 2 diabetes (T2D). Though data is limited, studies have indicated a lower prevalence of PAD in Indian diabetes patients as compared to western population. Present study assessed prevalence of PAD in T2D patients in Delhi, North India. Methodology: This study is a retrospective analysis of patient records of T2D patients. A total of 1000 patient were screened, 195 patients were excluded due to incomplete data and 8patients were included in the study. Diagnosis of PAD was based on ankle brachial index (ABI) measurement. An ABI value of <0.9 indicated diagnosis of PAD, 0.9 to 1.3 was taken as normal, and ABI>1.3 as indicator of non-compressible arteries.

Results: Study population consisted of 470 male and 335 female T2D patients (n=805), group 22 to 83 years. PAD (ABI <0.9) was present in 12 patients (1.49%), 9males (75% of PAD) and 3 females (25% of PAD). Diabetes patients with PAD had a higher mean age (57.±10.96 vs. 50.97 ±10.03years) a longer duration of diabetes (12.67 ±7.9 vs. 8.±8.06years, p=0.02) and significantly lower BMI (24.92kg/m2±2.42 vs. 29.55±5.87 kg/m2, p=0.0066) as compared to nondiabetic patients. More patients with PAD had hypertension (58.33% vs. 47.79%, p=0.96) and coronary artery disease (16.67% vs. 7.44%, p=0.908) which, however, were not statistically significant. PAD patients had significantly higher levels of total cholesterol (198.75±66.39 vs. 162.23±44.71mg/dl, p=0.0055) and LDL cholesterol (120.66±40.48mg/dl, p=0.039). No difference was seen in triglyceride levels (165.67±70.92mg/dl vs. 165.4±110.14,p=0.99) and A1c levels (8.97±3.vs. 9.08±2.54%, p=0.87) in two groups.

Conclusion: Our study shows that prevalence of PAD in T2D patients in Delhi, North India, is much lower than that reported in western population (∼20%) and from south India (6.3%). Prevalence of PAD was higher in patients with higher age, longer duration of diabetes, lower BMI, and higher total and LDL cholesterol.

Disclosure

B.M. Makkar: None. J.K. Sharma: None. S. Jaggi: None. K. Soota: None. V. Gupta: None. G. Khurana: None.
CXCR7 Agonist TC14012 Improves Angiogenic Function of Endothelial Progenitor Cells in Diabetic Limb Ischemia
Authors: WANG KAI , DAI XIAOZHEN , CHEN JING , EPSTEIN PAUL N. , CAI LU , WINTERGERST KUPPER A. , QIAN YAN , TAN YI
Published: June 2018

Stromal cell-derived factor 1 (SDF-1)-chemokine receptors CXCR4/7 axis plays a vital role in diabetic limb ischemia. Our previous studies demonstrated that elevated CXCR7 improves therapeutic efficacy of endothelial progenitor cells (EPCs) in diabetic limb ischemia. The effects of a specific CXCR7 agonist TC14012 on diabetic hind limb ischemia remains untested. We hypothesize that CXCR7 expression is reduced in diabetic EPCs and TC14012 improve angiogenic function of EPCs in diabetic limb ischemia. Early WT-EPCs were transfected with siRNA against CXCR7, and early db/db-EPCs were infected with CXCR7 lentivirus. Tube formation and capillary density of ischemic gastrocnemius muscle (GS) and soleus muscle (SS) at 4 weeks post-ischemic surgery were adopt for indication of angiogenesis. Diabetic hind limb ischemia (HLI) models were established by femoral artery ligation, followed by administration of TC14012 subcutaneously. Total and cell surface expression of CXCR7 were significantly decreased in EPCs from db/db mice compared with those from WT mice, whereas no significant differences of CXCR4 expression were observed. Tube formation by EPCs from db/db mice was also impaired compared with WT-EPCs. siRNA knockdown of CXCR7 was accompanied by impaired tube formation. Conversely, increasing CXCR7 levels in db/db EPCs completely reversed impaired tube formation function. High glucose (HG) dose dependently decreased the expression of CXCR7 in vitro but not that of CXCR4. HG also impaired tube formation of EPC from WT mice. Tube formation function of HUVEC was impaired after treated with HG (25mM) for 24 hours, which could be prevented by TC14012. Most importantly, TC14012 significantly improved blood flow restoration of ischemic hind limb starting from 2 weeks after ligation and promoted angiogenesis of ischemic GS and SS. Diabetes attenuates CXCR7 expression and impairs angiogenesis of EPCs. TC14012 improves blood reperfusion of diabetic hind limb ischemia.

Disclosure

K. Wang: None. X. Dai: None. J. Chen: None. P.N. Epstein: None. L. Cai: None. K.A. Wintergerst: None. Y. Qian: None. Y. Tan: None.
Mechanistic Role of Mitochondrial AKT1 in Kidney Injury and Diabetic Nephropathy
Authors: LIN HUGO YOU-HSIEN , CHEN YUMAY , CHEN YU-HAN , TA ALBERT , LEE HSIAOCHEN , WANG PING H.
Published: June 2018

Diabetes increases the risks of ischemia/reperfusion kidney injury, but the etiology is not known. Mitochondrial dysfunction, which can be modulated by AKT1, may play a critical role in nephropathy and subsequent kidney failure. We hypothesized that impaired mitochondrial AKT1 signaling plays a mechanistic role in the pathogenesis of kidney injury. Insulin acutely stimulated AKT1 translocation from the cytosol to mitochondria in renal proximal tubules, however, the translocation was impaired in diet-induced diabetes. In our murine kidney ischemia-reperfusion injury (IRI) model (30 min ischemia followed by reperfusion), serum BUN increased by 2-fold (p=0.001) and creatinine by 5-fold (p=0.038). The Jablonski score of renal tubular injury was significantly elevated after reperfusion (24 hours, p=0.0004; 1 week, p=0.027). Renal fibrosis (% area) in the IRI mice was significantly higher than the sham control mice (p<0.001). Rapid accumulation of phyosphorylated AKT1 in the mitochondria at proximal tubules were found 30 minutes (p=0.0303) and 60 minutes (p=0.0173) after IRI. AKT1 translocation to IRI renal tubule mitochondria was confirmed with confocal microscope and western blots of mitochondria proteins. To further dissect the role of mitochondrial AKT1 signaling during IRI in the renal tubules, we have generated novel renal tubule-specific transgenic mice harboring an inducible mitochondria-targeting dominant negative AKT1 (KiDAKT) with cre-lox strategy. After tamoxifen induction, markers for renal tubule injuries (KIM-1, and CD44) were significantly increased in the KiDAKT mice. Histology analysis confirmed renal injury with increased Jablonski score. Therefore, inhibition of mitochondrial AKT1 signaling led to development kidney injury. These findings shed new light into the mechanistic role of mitochondrial AKT1 in nephropathy, and mitochondria signaling may become a novel target to develop new strategies for the prevention and treatment of kidney diseases.

Disclosure

H. Lin: None. Y. Chen: None. Y. Chen: None. A. Ta: None. H. Lee: None. P.H. Wang: None.
A Low-Protein Calorie-Restricted Diet Attenuates Renal Injury and Facilitates Podocyte Autophagy in Type 2 Diabetic Rats
Authors: CHEN GUOFANG , GENG YAN , LIU CHAO
Published: June 2018

Purpose: Caloric restrictionhas been shown to exert a renoprotective effect in diabetic rats. Dietary protein restriction slows the progression of nephropathy in diabetic patients.We explored whether a low-protein calorie-restricted (LPCR) diet reduces renal injury and whether the renoprotective effect of LPCR diet isrelated to the activation of podocyte autophagy.

Methods: The type 2 diabeticrat model was induced by a combination of high fat diet and low dose streptozotocin injection. The diabetic rats were randomly divided into 3 groups, normal protein (NP, 20% protein) group, low protein(LP, 8% protein) group and LPCR (8% protein, 30% restriction)group. Nondiabetic rats were used as normal control (NC). After 4 weeks of dietary intervention, urine albumin-to-creatinine ratio,creatinine clearance, serum creatinine, and kidney-to-body weight ratio, renal histologies, podocyte density, autophagy activity in glomeruli as well as glomerular basement membrane thickness and autophagic vacuoles in podocytesunder electron microscopy were estimated.

Results: TheLPCR-diettreated diabetic ratsexhibited reduced body weight, serum triglycerides, and fasting blood glucose levels, as well as improved insulin resistance comparedwith NP-diettreated diabetic rats. LPCR diet attenuated renal injury, includingpodocyte injury, in type 2 diabetic rats. The reduced number of autophagic vacuolesin podocytesand insufficient podocyte autophagyin type 2 diabetic rats were reversed by LPCR diet.

Conclusions: The findings suggest that a LPCR diet can ameliorate renal injury in type 2 diabetic rats, which maybe linked to the activation of podocyte autophagy.

Disclosure

G. Chen: None. Y. Geng: None. C. Liu: None.
Glycemic Index and Glycemic Load of the Diet in a Sample of Pregnant Women with Type 2 Diabetes Mellitus in Northwest Brazil
Authors: FACANHA CRISTINA , PASSOS TATIANA U. , MARANHÃO LIVIANE C. , COPPOLA FRANCIELLE C. , MARTINS JULIANA D. , MELO ANA E.F. , NOGUEIRA GERLIANO , SANTOS MILIANA D. , PONTES PEDRO A.C. , MORAIS LUCIANA M. , COSTA DOUGLAS D.
Published: June 2018

During pregnancy, women with type 2 diabetes mellitus (DM2) needs specific dietary care to improve glycemic control and improve pregnancy outcomes. The recent updated researches points to dietary assessment and prescription based on glycemic index (GI) and glycemic load (GL) as possible strategies for achieving these goals. This study evaluated the GI and GL of the diet consumed by pregnant women with DM2. It is a quantitative-descriptive study, carried out in a diabetes treatment and care reference center in Brazil, with 20 DM2 pregnant women, randomly selected and interviewed during the outpatient routine visits follow-up. Dietary data were obtained in two 24-hour food recall (one weekday and one on weekend), one of that was collected by phone. These data were taken at home measurements and converted into grams/milliliters for subsequent determination of the GI and GL of the diets (protocol: FAO/WHO,1998) and classified according to Brand-Miller; Foster-Powell and Colagiuri (2003) and Burani (2006). Statistical analysis used the program S.P.S.S version 17, with the chi-square statistical test (p <0.05). The diet of the pregnant women had a low GI (46.27 ± 7.18) and a low GL (64.15 ± 22.79). There was a positive relationship between schooling and GI, and the pregnant DM2 with a lower level of education consumed a moderate GI diet. Few studies have evaluated GI and GL in pregnancy and there are no studies with DM2 pregnant women. Similar studies point to the benefits of low GI and GL diets for glycemic control during gestation to decreased maternal-fetal comorbidities. The study population’s diet had adequate GI and CG, which promotes glycemic control and reduce adverse outcomes. However, it is suggested that larger dietary assessments be performed to further deepen the relationship between diet, metabolic control and pregnancy outcomes of woman with DM2.

Disclosure

C. Facanha: None. T.U. Passos: None. L.C. Maranhão: None. F.C. Coppola: None. J.D. Martins: None. A.E.F. Melo: None. G. Nogueira: None. M.D. Santos: None. P.A.C. Pontes: None. L.M. Morais: None. D.D. Costa: None.
CKD Prevalence and Risk Are Higher in Adults with Type 2 vs. Type 1 Diabetes-An Assessment of 1.5 Million Patients Recently Evaluated in U.S. Clinical Practices
Authors: CRESSMAN MICHAEL , ENNIS JENNIFER L. , GOLDSTEIN BARRY J. , GOURGIOTIS LOUKAS , LUO DAJIE , PURI MALA , GILLESPIE BARBARA
Published: June 2018

Background: NHANES data (2009-2014) suggests that 25% of U.S. adults with diabetes have CKD (eGFR < 60 ml/min/1.73m2 or ACR ≥ 30 mg/g). However, prevalence may be different among patients evaluated in clinical practice or in adults with T1D compared to T2D.

Methods: We utilized a clinical laboratory database maintained by LabCorp® to assess CKD prevalence and classified risk (low, moderate, high or very high) based on KDIGO criteria. The population included 48,036 adults with T1D and 1,461,915 with T2D who had both an ACR and a CKD-EPI eGFR between August 2014 and August 2017. Rates of eGFR decline were calculated for patients with ≥ 3 eGFR results over at least a 1 year period.

Results: CKD prevalence was 40% higher in T2D than T1D (44.3% vs. 31.6%, p<0.001). The proportion classified as high or very high risk was also higher in T2D (17.8% vs. 12.0%, p<0.001). Macroalbuminuria (MA), defined as an ACR > 300, was uncommon (T1D: 7.8%, T2D: 8.3%); the majority with MA had an eGFR ≥ 60 (T1D: 60%, T2D: 53%). Median eGFR decline (ml/min/year) was low in the entire population (T1D: -0.6, T2D: -0.8), and in patients with ACR < 30 (T1D: -0.34, T2D: -0.47) or ACR 30-300 (T1D: -0.97, T2D: - 1.06). However, median annual rates of decline in patients with MA were -3.80 in T1D and -3.58 in T2D.

Conclusions: These findings suggest that CKD prevalence and risk are higher in T2D than T1D among adult patients recently evaluated in U.S. clinical practices. Although MA is uncommon and most frequently observed in patients with normal or only mildly reduced eGFR, it was a potent predictor of eGFR decline in both T1D and T2D. Availability of a large clinical laboratory database may add value when eligibility criteria, enrichment strategies, study endpoints or feasibility are assessed in clinical trials of patients with diabetes and CKD.

Disclosure

M. Cressman: Employee; Self; Covance Inc. J.L. Ennis: Employee; Self; LabCorp. Stock/Shareholder; Self; LabCorp. B.J. Goldstein: Employee; Self; Covance Inc.. L. Gourgiotis: None. D. Luo: None. M. Puri: Employee; Self; Covance Inc.. B. Gillespie: None.