bluuebunny/crossref_metadata_2025 huggingface dataset:
1383-P: Longitudinal Changes in Transition Readiness (TR) in Teens with Type 1 Diabetes (T1D) Are Unrelated to Glycemic Control
Authors: GOETHALS EVELINE R. , VOLKENING LISA K. , COMMISSARIAT PERSIS V. , BUTLER DEBORAH A. , MCGILL DAYNA E. , LAFFEL LORI M.
Published: June 2019

Aim: During adolescence, teens with T1D increase self-care, anticipating future independence. To assess TR skills (i.e., affective, behavioral, and cognitive preparation to transfer from pediatric to adult care), teens with T1D and parents completed the validated Readiness for Independent Self-Care Questionnaire (RIS-Q).

Methods: Teens, ages 13-17, with T1D and parents completed RIS-Q every 6 months over 18 months. Teen and parent reports of teen treatment adherence and self-efficacy were assessed as predictors of TR and A1c with longitudinal mixed models.

Results: At entry, teens (N=178, 52% male, 88% white) had mean±SD age 14.9±1.3 years, T1D duration 7.4±3.7 years, 4.9±2.0 BG checks/day, and A1c 8.5±1.0%; 67% were pump users. Teen and parent reported TR increased over time while teen A1c was unchanged (Figure). In multivariate models, teen age, teen reported adherence, and self-efficacy predicted TR (all p<.001). Teen TR did not predict A1c while teen reported adherence, self-efficacy, and BG checks/day predicted A1c (all p<.008). Longitudinal models using parent reports had similar results.

Conclusion: Teen TR increased with age and over time but was unrelated to A1c, suggesting a disconnect between teen perceptions of self-care readiness and self-care behaviors. While TR may be important, it is insufficient, highlighting need to improve self-care behaviors and A1c in teens with T1D.

Disclosure

E.R. Goethals: None. L.K. Volkening: None. P.V. Commissariat: None. D.A. Butler: None. D.E. McGill: None. L.M. Laffel: Advisory Panel; Self; Lilly Diabetes, Novo Nordisk A/S, Roche Diabetes Care, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Janssen Pharmaceuticals, Inc., UpToDate.

Funding

National Institutes of Health (R01DK095273, P30DK036836, T32DK007260, K12DK094721); JDRF (2-SRA-2014-253-M-B)
1386-P: A Comparison of Ectopic Fat Stores and Insulin Sensitivity among Women With and Without Gestational Diabetes
Authors: VESCO KIMBERLY , LEO MICHAEL C. , FRANCISCO MELANIE , MARSHALL NICOLE E. , ROONEY WILLIAM , BAETSCHER ERIC , VALENT AMY M. , PURNELL JONATHAN Q.
Published: June 2019

Background: We assessed relationships between ectopic lipid stores [intrahepatic (IHL), intramyocellular (IMCL), and extramyocellular (EMCL)] and parameters of insulin sensitivity in women with gestational diabetes (GDM) compared with BMI-matched controls.

Methods: We performed a case-control analysis nested within a prospective cohort study of 54 pregnant women with normal weight, overweight, and obesity without pregestational diabetes. From the prospective cohort, 7 women developed GDM. Three additional women with GDM were recruited in late pregnancy to increase sample size. All women underwent insulin clamps to assess insulin disposal (Rd) and endogenous glucose production (EGP); 1H magnetic resonance spectroscopy to assess IHL, IMCL, and EMCL content; MRI to assess subcutaneous abdominal (SAT) and visceral adipose tissue (VAT) volume, BODPOD to assess % body fat, fat mass, and fat free mass; and measurement of fasting free fatty acid levels. Measures were performed in early and late pregnancy [mean (minute-max), 15.5 (12.4-17.6) and 34.1 (31.6-37.3) weeks gestation, respectively].

Results: Women with GDM were matched on BMI to women in the prospective cohort who did not develop GDM. In early pregnancy, compared to controls, women with GDM had greater % body fat (P=.02), fasting free fatty acids (P<.01), and insulin resistance (lower Rd, P<.01), but did not significantly differ in amounts of VAT, SAT, IHL, EGP, IMCL, or EMCL. In late pregnancy, cases and controls did not significantly differ by body composition or free fatty acid levels, but insulin resistance remained greater among women with GDM (P=.02).

Conclusion: Women who would be later diagnosed with GDM exhibited greater percent body fat, insulin resistance, and fasting free fatty acid levels early in pregnancy, but not visceral or ectopic fat stores. Accumulation of excess lipids in VAT and ectopic fat stores does not appear to play an important role in distinguishing women who develop GDM from those that do not.

Disclosure

K. Vesco: None. M.C. Leo: None. M. Francisco: None. N.E. Marshall: None. W. Rooney: None. E. Baetscher: None. A.M. Valent: None. J.Q. Purnell: Advisory Panel; Self; Novo Nordisk A/S.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK098707)
1391-P: Longitudinal Changes of Plasma Sphingomyelins during Gestation in Women With and Without Type 1 Diabetes and Preeclampsia
Authors: KELLY CLARE B. , HAMMAD SAMAR M. , KLEIN RICHARD L. , LOPES-VIRELLA MARIA F. , LEYVA MISTI J. , YU JEREMY , JENKINS ALICIA J. , NANKERVIS ALISON J. , HANSSEN KRISTIAN F. , GARG SATISH K. , SCARDO JAMES A. , ASTON CHRISTOPHER E. , LYONS TIMOTHY
Published: June 2019

Preeclampsia (PE), a major cause of maternal and fetal morbidity and mortality worldwide, has significantly higher incidence in women with type 1 diabetes mellitus (T1DM) than in nondiabetic populations (∼20% vs. 5%, respectively). Sphingolipids are key signaling molecules, and have many roles in the structure and regulation of cellular functions. Sphingomyelin (SM) is the most abundant sphingolipid in plasma lipoproteins. There is evidence that altered SM metabolism may contribute to cardiovascular and renal complications in diabetes.

We aimed to determine whether plasma concentrations of 12 SM species were associated with PE in T1DM in a prospective study of pregnancy of 23 T1DM women who developed PE and 24 T1DM who remained normotensive. Additionally, 19 normotensive nondiabetic pregnant women were included for reference. All subjects were free of microalbuminuria and hypertension at enrolment, and all visits (12, 22, 32 weeks’ gestation) preceded clinical PE onset.

Results: There were no cross-sectional differences in total SM, or in any individual SM species, between diabetic women with and without PE, or between normotensive women with and without diabetes at any stage of gestation. With advancing gestation in all groups, C18-SM, C18:1-SM, C20-SM, C20:1-SM, C22-SM, C22:1-SM, C24-SM, and C24:1-SM increased (all p<0.001). LDL- and VLDL-cholesterol also increased, while HDL-cholesterol did not change. In contrast, C14-SM, C16-SM, C26-SM and C26:1-SM decreased (all p<0.001). There were no correlations between any SM species and conventional lipid profiles.

Conclusions: With advancing gestation, plasma concentrations of most SM species increased, as did LDL and VLDL; however, two long-chain and two very long-chain SM species decreased. Although there were no differences in SM according to diabetes or PE status at any time point, further studies should address the significance of differential changes of SM species during pregnancy.

Disclosure

C.B. Kelly: None. S.M. Hammad: None. R.L. Klein: None. M.F. Lopes-Virella: None. M.J. Leyva: None. J. Yu: None. A.J. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. A.J. Nankervis: None. K.F. Hanssen: None. S.K. Garg: Advisory Panel; Self; Eli Lilly and Company, Roche Pharma, Sanofi-Aventis, Zealand Pharma A/S. Research Support; Self; Eli Lilly and Company, WebMD. J.A. Scardo: None. C.E. Aston: None. T. Lyons: None.

Funding

JDRF; Novo Nordisk; National Institutes of Health
1405-P: Glycemic Variability among Pregnant Women with Type 1 Diabetes (T1D) Based on Use of CGM Share Technology
Authors: POLSKY SARIT , SNELL-BERGEON JANET K. , JOSHEE PRAKRITI , DEMMITT JAMIE K. , GARCETTI RACHEL , VIGERS TIM B. , PYLE LAURA
Published: June 2019

Pregnancies complicated by T1D have more glycemic variability than pregnancies associated with other kinds of diabetes. We examined whether remote monitoring of Continuous Glucose Monitoring (CGM) data by family/friends affects glycemic variability during pregnancy.

Women with T1D were stratified to groups during preconception or the 1st trimester: (1) CGM Alone (n=13): women without Apple devices, or (2) CGM Share (n=15, DexCom, San Diego, CA): women with iPhone and followers with data viewing devices. Data within 12 hours of acetaminophen use were excluded. Linear mixed models were used to compare indices of glycemic variability over time between groups.

A1C decreased in both groups over time and was lower in CGM Share compared to CGM Alone (p=0.0376, Table). Mean sensor glucose was lower in CGM Share than CGM Alone (p=0.0492). Times spent within targeted pregnancy ranges were not different between groups. CGM Alone had a significantly higher High Blood Glucose Index (HGBI) than CGM Share (p=0.0347).

CGM Share was associated with a lower risk of hyperglycemia (as measured by HBGI) than CGM Alone among pregnant women with T1D, but other measures of glycemic variability were similar between groups.

Disclosure

S. Polsky: Consultant; Self; Jaeb Center for Health Research. Research Support; Self; Barbara Davis Center for Diabetes, Children's Diabetes Foundation, Dexcom, Inc., Eli Lilly and Company, JDRF, Leona & Harry Helmsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases, Sanofi US. J.K. Snell-Bergeon: None. P. Joshee: None. J.K. Demmitt: None. R. Garcetti: None. T.B. Vigers: None. L. Pyle: None.

Funding

Dexcom, Inc.; National Center for Research Resources/Colorado Clinical and Translational Science Institute (UL1RR025780)
141-LB: Engineered Silica Particles Work as a Molecular Sieve and Reduce Metabolic Risk Factors in Obese Male Volunteers
Authors: LINDGREN MARIA E. , WAARA ERIK ROLLMAN , BENZIANE BOUBACAR , VALLHOV HELEN , IQBAL NAEEM , JOHNSTON ERIC V. , BENGTSSON TORE
Published: June 2019

Mesoporous silica particles (MSPs) are thermally and chemically stable porous materials composed exclusively of silicon dioxide. Here we report the results of a First-in-Man clinical trial evaluating engineered MSPs with controlled surface area, pore volume, pore size, particle size and morphology, named SiPore, in obese but otherwise healthy male volunteers (n=20). SiPore is orally ingested and passes through the body without being absorbed and is safely eliminated via the feces. The clinical effects of SiPore were significant reduction in several metabolic and cardiovascular risk factors. HbA1c was reduced by 5% and LDL-C by 15% on average from baseline, both clinically meaningful reductions. Adverse events observed were mild and transient. These promising effects led to further investigations into SiPore’s mode of action.

We hypothesized that SiPore acts as a molecular sieve by sequestration of biomolecules in the gastrointestinal tract, which could explain the observed clinical results. This merited a more detailed analysis of the interaction between SiPore and digestive enzymes. SiPore significantly sequestered amylase and lipase in vitro while MSPs with smaller pore size had no effect. Lipase and amylase were depleted by SiPore from more complex biological matrices, such as porcine pancreatin and mouse intestinal fluid. Moreover, SiPore inhibited the activity of human salivary amylase in human saliva. Further studies of amylase depletion in vitro indicated that the availability of pores of a certain pore size is a critical parameter for enzyme sequestration.

This innovative mode of action, combined with SiPore’s promising safety profile, makes SiPore an exciting candidate for treatment or prevention of metabolic diseases, particularly prediabetes and type 2 diabetes (T2D). SiPore is currently being investigated in an ongoing clinical trial in 40 prediabetic or newly diagnosed T2D subjects (NCT03823027).

Disclosure

M.E. Lindgren: Employee; Self; Sigrid Therapeutics AB. E. Rollman Waara: Employee; Self; Sigrid Therapeutics AB. B. Benziane: Employee; Self; Sigrid Therapeutics. H. Vallhov: Employee; Self; Sigrid Therapeutics. N. Iqbal: None. E.V. Johnston: None. T. Bengtsson: Other Relationship; Self; Atrogi, Sigrid Therapeutics.

Funding

Vinnova (2015-02023)
1414-P: Prolactin as a Potential Modulator for the Adaption to Insulin Resistance in Pregnancy
Authors: FRITSCHE LOUISE , HENI MARTIN , HAERING HANS-ULRICH , FRITSCHE ANDREAS , WAGNER ROBERT
Published: June 2019

Aims: Plasma prolactin levels are associated with insulin sensitivity and diabetes in an age dependent manner. Pregnancy is a state of physiologically high prolactin concentrations and insulin resistance. Only when beta cells fail to compensate by producing sufficient amounts of insulin, gestational diabetes mellitus (GDM) develops. We aimed to elucidate the relationship of prolactin levels, insulin sensitivity, and the incidence of GDM in pregnancy.

Material and Methods: 321 women from the German Gestational Diabetes study were phenotyped with 5-point 75 g oral glucose tolerance tests during gestational weeks 27.1 ± 2.1 and repeatedly 1 to 10 years after delivery. Prolactin was measured in fasting state.

Results: GDM was diagnosed in 29%. During pregnancy, physiologically high prolactin levels associated negatively with insulin sensitivity. By contrast, prolactin was positively associated with insulin sensitivity after delivery (pinteraction < 0.0001). Despite prolactin’s association with impaired insulin sensitivity in pregnancy, higher prolactin levels were neither associated with AUC-glucose0-120 nor GDM incidence (p>0.14). Prolactin interacted with AUC-glucose0-120 on insulin secretion (disposition index, p=0.01) with higher prolactin levels associating with improved insulin secretion in case of AUC-glucose0-120 above median (p=0.04).

Conclusion: Our findings on countercurrent changes in insulin sensitivity and secretion with higher prolactin levels could indicate a role for this hormone in mounting and compensating for physiologic insulin resistance in pregnant women.

Disclosure

L. Fritsche: None. M. Heni: Research Support; Self; Boehringer Ingelheim International GmbH, Sanofi. Speaker's Bureau; Self; Lilly Diabetes, Merck Sharp & Dohme Corp., Sanofi. H. Haering: None. A. Fritsche: None. R. Wagner: Other Relationship; Self; Lilly Diabetes, Novo Nordisk A/S.

Funding

German Federal Ministry of Education and Research (01GI0925)
1417-P: Glycemic Control and Insulin Dosing in Pregnancies Complicated by Type 2 Diabetes Mellitus
Authors: NADEAU HUGH C. , MAXTED MARTA E. , MADHAVAN DEVIKA , PIERCE STEPHANIE , FEGHALI MAISA N. , SCIFRES CHRISTINA M.
Published: June 2019

Type 2 diabetes mellitus (DM) is associated with adverse perinatal outcomes, but insulin requirements and the prevalence of inadequate glycemic control across gestation are not well characterized. We therefore conducted a retrospective cohort study of women with type 2 DM who delivered from 2015 to 2017. Self-monitored blood glucose and insulin doses across gestation were abstracted, and inadequate glycemic control was defined as a mean blood glucose >95 mg/dL fasting or >140 mg/dL 1 hour post-prandial. We compared insulin dosing in early gestation and at delivery by maternal glycemic control. Multivariable logistic regression was used to identify predictors of high insulin requirements at delivery.

Inadequate glycemic control occurred in 96/155 (62%) of women. Maternal BMI, gestational age at first prenatal visit, and duration of diabetes were similar between women with inadequate and adequate control. Baseline HbA1c (8.1 ±2.0 vs. 7.5 ±1.9%, p=0.10) and percent of women receiving medical therapy before initiation of prenatal care (71.3% vs. 69.5%, p=0.81) were also similar between groups. Women with inadequate and adequate control had similar insulin doses in early pregnancy (0.7 ±0.5 vs. 0.7 ±0.5 units/kg, p=0.86), but by delivery women with inadequate control required significantly higher doses (2.3 ±1.2 vs. 1.8 ±1.0 units/kg, p=0.004). The highest quartile of insulin dose at delivery was >2.7 units/kg. Multivariable logistic regression modeling demonstrated that maternal BMI at the first prenatal visit (aOR 1.0, 95% CI 0.99-1.01), non-white race (aOR 0.35, 95% CI 0.16-0.78), and baseline HbA1c (aOR 1.22, 95% CI 1.02-1.46) had poor ability to predict high insulin requirements at delivery (AUC 0.67). Although high insulin requirements may be related to suboptimal glycemic control in women with type 2 DM, it is difficult to identify these women using baseline characteristics. Further studies are urgently needed to optimize insulin dosing in women with Type 2 DM.

Disclosure

H.C. Nadeau: None. M.E. Maxted: None. D. Madhavan: None. S. Pierce: None. M.N. Feghali: None. C.M. Scifres: None.
142-LB: First Non-sulfonylurea Type Inhibitors of SUR1 Showed Superior Efficacy over Sulfonylureas, and Reversed Sulfonylurea Failure
Authors: LIM DONGCHUL , PARK JUNG GYU , KIM DONG WOOK , PARK HEE DONG , KIM YOUNG KWAN
Published: June 2019

Sulfonylureas (SUs) have been used widely for a long time as a diabetic drug since first discovered in 1942. Because of their good glucose lowering effect and low cost it had been drug of choice until recently. However, SUs are lack of the glycemic durability and lose their efficacy mostly within 1-2 years, resulting in a steady HbA1c rise to or above pretreatment levels. This, so called SU failure, has been the main reason for limiting their use in the clinic. Our efforts for overcoming the SU failure led to the discovery of de novo type sulfonylurea receptor 1 (SUR1) antagonists (e.g., Cpd7). To the best of our knowledge, this is the first report of non-SU type SUR1 antagonists with the superior efficacy to known SU drugs. Molecular modeling with a recently published cryogenic electron microscopy structure of KATP channel showed that Cpd7 occupies the SUR1 binding site in a totally different region from known SUs such as glimepiride with a higher docking score. We hoped that such differences in structure classes and binding patterns lead to improved phenotypic effects. In insulinoma Min6 and INS-1 cells, treating with Cpd7 increased calcium influx and triggered a superior insulin secretion to glimepiride. In mouse oral glucose tolerance test, cpd7 showed a highly effective blood glucose lowering effect at a 30 mg/kg dose. It is well known that chronic glibenclamide treatment in Min6 cells induces unresponsiveness to most of SU drugs. So far no other SUR1 antagonists have been found effective in SU resistance. But we found that Cpd7 overcomes the SU resistance induced by chronic treatment of glibenclamide in Min6 and InS-1 cells. Therefore, it becomes clear that our newly discovered non-SU type SUR1 antagonists can be used for solving the resistance problems caused by the existing SU drugs. We expect that our discovery will lead to the development of a new type of SU drug which gives an alternative treatment option to diabetic patients in the near future.

Disclosure

D. Lim: None. J. Park: Employee; Self; LG Chem. D. Kim: Employee; Self; LG Chem. H. Park: None. Y. Kim: None.
1422-P: Human Milk Composition in Type 2 Diabetes Imparts Higher Insulin Exposure
Authors: RODEL RACHEL , CARLI JAYNE MARTIN , HIRSCH NICOLE , HEISS KRISTY P. , HERNANDEZ TERI L. , KREBS NANCY F. , BARBOUR LINDA (LYNN) A , YOUNG BRIDGET
Published: June 2019

Little is known about human milk (HM) composition in T2 diabetes (T2DM) and data support that HM insulin may be absorbed from the immature newborn gut and be metabolically active. We characterized HM composition and measured fasting and 90 min postprandial insulin and glucose (gluc) in HM (mid-feed) and plasma in 12 T2DM mothers (BMI 32± 4) after a 60 g carb meal at 2 weeks postpartum. We compared fasting HM samples with 12 normoglycemic (NGT) and 10 GDM mothers who were matched by BMI and infant sex. The study was powered on our hypothesis that fasting HM insulin would be higher in T2DM (2 insulin requiring). All macronutrients and energy density (Miris) in HM of T2DM were in the expected range (mean fat 4.1; protein 1.6; carbs 7.2 g/100mL; energy 74 kcal/100ml) and did not differ postprandially. Notably, paired fasting HM insulin in T2DM was 30.2 and 16.1 μIU/mL higher in the NGT (p<0.01) and GDM groups (p<0.05), respectively (Figure A). HM gluc did not differ by groups. In T2DM, HM gluc (p<0.001) and insulin (p<0.05) increased after the meal. Strikingly, mean fasting insulin was 4-fold higher in T2DM HM vs. plasma (p<0.005; Figure B). These are the first data to show that while HM macronutrients and calories from mothers with T2DM are reassuringly in expected quantities, HM insulin is higher and concentrated in T2DM milk. Given that the newborn gut may be permeable to insulin, potential effects on the newborn pancreas, growth, and the microbiome deserve further study.

Disclosure

R. Rodel: None. J. Martin Carli: None. N. Hirsch: None. K.P. Heiss: None. T.L. Hernandez: None. N.F. Krebs: None. L.A. Barbour: None. B. Young: None.

Funding

Colorado Clinical and Translational Sciences Institute (UL1TR000154); National Center for Advancing Translational Sciences (UL1TR002535); National Institutes of Health (T32DK007658-28), (R01DK101659 to T.L.H.), (F32-HD0978068), (T32-DK007658-21); Thrasher Research Fund; University of Colorado Center for Women’s Health Research
1426-P: Type 1 Diabetes Pregnancies Complicated by Hypertensive Disorders
Authors: SNELL-BERGEON JANET K , PYLE LAURA , SIPPL RACHEL M. , POLSKY SARIT
Published: June 2019

Women with type 1 diabetes (T1D) are at higher risk for Gestational Hypertensive Disorders (GHD) and cardiovascular disease (CVD) compared to women without diabetes. However, the long-term consequences of GHD complicated by T1D on CVD are unknown. We compared CVD risk factors pre-pregnancy (median follow-up 3 years, IQR 2-4 years) to post-pregnancy (median 2 years, IQR 1-3 years) excluding six weeks post-partum in women with T1D with a first pregnancy complicated by GHD (n=27) vs. those with an uncomplicated pregnancy (n=49), frequency matched for age (mean age 25 years) and diabetes duration (mean duration 12 years). Linear mixed models adjusted for age, diabetes duration, and weeks gestation were used to examine CVD risk factors. Pre-pregnancy, the groups did not differ in age, diabetes duration, body mass index (BMI), lipids, systolic or diastolic blood pressure (BP) (Table). A1c was higher pre-pregnancy in the complicated vs. uncomplicated group (p=0.004); post-pregnancy there was no change in the complicated group but an increase in A1c in the uncomplicated group (p=0.003). Complicated pregnancies resulted in increased systolic (p=0.001) and diastolic BP (p=0.01) post-pregnancy; uncomplicated pregnancies were not associated with significant changes in BP. Women with T1D and a pregnancy complicated by GHD had similar BP but higher A1c pre-pregnancy, and persistently higher BP post-pregnancy, suggesting a need to intervene to prevent CVD.

Disclosure

J.K. Snell-Bergeon: None. L. Pyle: None. R.M. Sippl: None. S. Polsky: Consultant; Self; Jaeb Center for Health Research. Research Support; Self; Barbara Davis Center for Diabetes, Children's Diabetes Foundation, Dexcom, Inc., Eli Lilly and Company, JDRF, Leona & Harry Helmsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases, Sanofi US.

Funding

American Diabetes Association (7-13-CD-10 to J.K.S-B.)
143-LB: Calorie Restriction in Combination with GABA Ameliorates Type 2 Diabetes
Authors: RATHWA NIRALI NANDUBHAI , PATEL ROMA , PRAMANIK SAYANTANI , PARMAR NISHANT R. , A.V. RAMACHANDRAN , BEGUM RASHEEDUNNISA
Published: June 2019

Dysfunction of adipocytes and β-cells are crucial in the progression of obesity-related insulin resistance and type 2 diabetes (T2D). γ-Aminobutyric Acid (GABA) is a key neurotransmitter and is secreted by β-cells. It exerts protective and regenerative effects on β-cells. At the metabolic level, Calorie Restriction (CR) has been shown to improve insulin sensitivity, reduces Fasting Blood Glucose (FBG) and increases insulin levels. GABA and CR are speculated to show an additive effect on insulin secretion and β-cell regeneration via GABA signaling and enhance insulin sensitivity ameliorating T2D manifestations. We have evaluated the effect of GABA and CR combination on β-cell regeneration and insulin sensitivity in High Fat Diet (HFD) and streptozotocin (STZ) induced late stage T2D mouse model. Our results show favorable changes in the measured parameters. GABA+CR group showed reduced FBG levels and improved whole-body insulin responsiveness indicated by increased insulin levels, insulin sensitivity, and glucose tolerance. The combination therapy improved the lipid profile by significantly reducing triglycerides, total cholesterol, and LDL levels and increased HDL levels. The transcript expression profile of metabolic enzymes in the liver indicates a significant decrease in gluconeogenesis and glycogenolysis. The transcript levels indicate decreased lipolysis and increased fatty acid synthesis in the adipose tissue. The transcript levels of mitochondrial biogenesis in the skeletal muscle indicate increased effect of combination therapy, thereby promoting insulin sensitivity. Also, combination therapy promoted β-cell proliferation.

In conclusion, calorie restriction in combination with GABA ameliorates T2D in the mouse model by inducing β-cell regeneration mediated by GABA and increased insulin sensitivity by CR diet.

Disclosure

N.N. Rathwa: None. R. Patel: None. S. Pramanik: None. N.R. Parmar: None. R. A.v.: None. R. Begum: None.

Funding

Department of Biotechnology, New Delhi, India (BT/PR21242/MED/30/1750/2016)
1439-P: Risk of Dementia and Cognitive Dysfunction in Individuals with Diabetes or Elevated Blood Glucose in Four Large Cohorts
Authors: WIUM-ANDERSEN IDA , JØRGEN RUNGBY , BALSLEV MARTIN , RGENSEN JØ , OSLER MERETE , WIUM-ANDERSEN MARIE
Published: June 2019

Objective: To determine risk of dementia in both patients with type 1 or type 2 diabetes and in individuals without a diagnosis of dementia but with glycosylated hemoglobin, type A1C (HbA1c) of ≥ 6,5% (48 mmol/mol).

Method: In this register- and cohort-based study, we included all incident diabetes cases registered in the National Diabetes Registry in Denmark from January 2000 through December 2012 (n=151,413) and a reference population, adult participants from the Glostrup cohort (n=16,801), the ADDITION Study (n=26,586) and Copenhagen Aging and Midlife Biobank (n=5,408). Using these cohorts, we analyzed if a diagnosis of type 1 or type 2 diabetes in the National Diabetes Registry or HbA1c level of ≥ 6,5% in the cohorts increased risk of dementia in the Danish National Patient Registry or cognitive performance assessed by the Intelligenz-Struktur-Test 2000R.

Results: Both type 1 and type 2 diabetes were associated with increased risk of dementia with the highest risk estimates for dementia diagnosed before age 65. Self-reported diabetes or high HbA1c levels were associated with lower cognitive performance (p=0.004), while high HbA1c was associated with increased risk of dementia in the Glostrup cohort but not in the ADDITION study.

Conclusions: Both type 1 and type 2 diabetes are associated with increased risk of dementia, however results for screening detected high HbA1c were equivocal.

Disclosure

I. Wium-Andersen: None. J. Rungby: None. M. Jørgensen: None. M. Osler: None. M. Wium-Andersen: None.

Funding

Jaschafonden; Lundbeck Foundation; Danish Medical Association; Danish Diabetes Association; M.D. Gerhard Linds Grant; Lundbeck Foundation/Novo Nordisk Foundation; Family Hede Nielsen Foundation; Holger Rabitz and Wife Doris Mary, born Phillip’s Memorial Foundation
1454-P: Cerebral Glutathione Is Associated with Insulin Resistance in Older Individuals
Authors: PACH JOLANTA J. , GROSKREUTZ DEREK , LEVENTHAL JESSICA , KNIGHT MARI-LYNET , JAIN KANIKA , HWA JOHN , JIANG LIHONG , GRAAF ROBIN DE , HWANG JANICE
Published: June 2019

Glutathione (GSH) is the primary defense against oxidative stress through its role in reducing reactive oxygen species (ROS) in the body, and its levels have been shown to be lower in both metabolic disease and aging. In this study, we sought to determine whether GSH levels in the human brain are lower in older individuals and whether these levels are associated with metabolic changes that come with age, such as increasing insulin resistance. 14 young (age 30.1 ±3.2 years, BMI 26.1 ±0.8 kg/m2, A1c 5.3% ±0.1, HOMA-IR 1.6 mg(μU)/dL(mL) ±0.2) and 9 old (age 73.7 ±1.8, BMI 28.1 ±1.6, A1c 5.6 ±0.1, HOMA-IR 2.9 ±0.7) individuals underwent an oral glucose tolerance test as well as magnetic resonance spectroscopy (MRS) scanning at 4T for measurement of intracerebral GSH levels in the prefrontal cortex and striatum. Older individuals had higher levels of plasma ROS compared to younger individuals (P<0.001); however, there were no differences in plasma GSH levels (P=0.15). Intracerebral GSH levels (normalized to creatine(cr)) were not different between groups (P=0.76 prefrontal cortex, P=0.53 striatum). Amongst the older individuals, cerebral GSH/cr levels correlated inversely with HOMA-IR in both the striatum (r = -0.74, P=0.04) as well as prefrontal cortex (r= -0.95, P<0.001). Moreover, amongst older individuals, intracerebral GSH levels correlated inversely with performance on several measures of visual-spatial memory including the spatial working memory task (ρ= -0.9, P=0.003). There were no relationships between HOMA-IR and cerebral GSH levels amongst the younger individuals. Our findings indicate that amongst older individuals, increased insulin resistance is associated with diminished intracerebral GSH levels as well as visual-spatial cognitive deficits. These findings suggest that intracerebral GSH levels may be a useful marker for assessing the impact of metabolic dysfunction on neurocognitive function.

Disclosure

J.J. Pach: None. D. Groskreutz: None. J. Leventhal: None. M. Knight: None. K. Jain: None. J. Hwa: None. L. Jiang: None. R. de Graaf: None. J. Hwang: None.

Funding

National Institutes of Health (P30AG021342)
1456-P: Cardiovascular Outcomes in Subjects with Acute Myocardial Infarction (AMI) and Newly Discovered Abnormal Glucose Tolerance (AGT): A Meta-analysis
Authors: LAICHUTHAI NITCHAKARN , DEFRONZO RALPH A.
Published: June 2019

Aims: To study: (1) the prevalence of newly discovered AGT in subjects presented with AMI and (2) the risk of recurrent major adverse cardiovascular events (MACE and mortality) in this population.

Methods: Electronic databases were searched. Studies were included for analysis if: (1) they were prospective or retrospective studies in AMI subjects without known history of diabetes; (2) diagnosis of AGT was made with FPG, 2-hour PG (OGTT) or A1c, (3) provided incidence of MACE and/or all-cause mortality in newly discovered AGT subjects compared with NGT subjects. AGT was further divided into prediabetes and diabetes. Pooled prevalence and hazard ratios (HR) were calculated using random-effect model.

Results: Total of41,677 subjects from 20 studies were included in the analysis. Median follow-up time was 3.7 ±2.8 years. The pooled prevalence of newly discovered AGT in AMI subjects was 49.3%. Compared to NGT, subjects with AGT had higher risk of mortality (HR = 1.66, 95% CI 1.34-2.05, p<0.001) and MACE (HR = 1.80, 95% CI 1.40-2.31, p<0.001). Compared to NGT, prediabetes group had higher risk for mortality (HR = 1.82, 95% CI 1.30-2.54, p<0.001) and MACE (HR = 1.67, 95% CI 1.24-2.26, p<0.001). Of note, prediabetes subjects had a higher risk of MACE compared to subjects with newly diagnosed diabetes (HR = 1.76, 95% CI 1.35-2.29, p<0.001), whereas there was no difference in all-cause mortality between prediabetes and diabetes subjects (HR = 0.97 95% CI 0.60-1.55, p=NS).

Conclusion: This meta-analysis showed a high prevalence of newly discovered AGT in patients with AMI. The increased risk in MACE and mortality was observed before the onset of diabetes, i.e., in prediabetes. The discovery of AGT in patients who present with an AMI is a strong predictor for mortality and MACE. Since prediabetes and diabetes subjects are at the same high CV risk, factors other than hyperglycemia must explain the markedly increased incidence of MACE and all-cause mortality.

Disclosure

N. Laichuthai: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.
1465-P: Cardiovascular Risk Factors among Young Adults with Diabetes in the U.S.
Authors: SAYDAH SHARON , MERCADO CARLA , SIEGEL KAREN R. , GREGG EDWARD W. , IMPERATORE GIUSEPPINA
Published: June 2019

Although the prevalence of diabetes (DM) among young adults age 18 to 44 years in the United States (U.S.) has increased in the past two decades, little is known about how cardiovascular disease (CVD) risk factors for DM complications in this age group compare to older adults with DM. We used data from the National Health and Nutrition Examination Survey from 2007-2016 to characterize young adults with and without DM by CVD risk factors and compared the differences to middle- aged and older adults (aged ≥45 years). DM was defined by self-report or by A1c levels ≥ 6.5% among those without self-reported diabetes. Measures included demographics, health insurance, and CVD risk factors. Absolute difference in difference was calculated as the difference in prevalence by DM status among young adults minus the difference by DM status among middle-aged and older adults. Among young adults in the U.S., DM prevalence was 3.5%, corresponding to 3.6 million people with DM. As expected, participants of both age groups with DM had higher levels of adiposity, hypertension, high cholesterol, and chronic kidney disease (CKD), and lower levels of physical activity, compared to those without (Table). However, the difference in adiposity and high cholesterol by DM status was greater among young adults compared to middle-aged and older adults. Young adults with DM have a high burden of CVD risk factors that could lead to future increases in morbidity and mortality.

Disclosure

S. Saydah: None. C. Mercado: None. K.R. Siegel: None. E.W. Gregg: None. G. Imperatore: None.
1466-P: Estimating Cardiovascular Risk in People with Type 2 Diabetes and Cardiovascular Disease: UKPDS Outcomes Model
Authors: COLEMAN RUTH L. , GRAY ALASTAIR M. , MCGUIRE DARREN K. , HOLMAN RURY R.
Published: June 2019

Background and Aims: Type 2 diabetes (T2D) cardiovascular (CV) risk calculators focus mainly on those without CVD. We evaluated a T2D clinical outcomes simulation model (UKPDS Outcomes Model v2 [OM2]) estimates of CV risk in TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin) participants with T2D and CVD.

Materials and Methods: We compared estimated 3-year CV event and all-cause mortality (ACM) rates with observed rates. Covariates included: sex, ethnicity, age, diabetes duration, atrial fibrillation, albuminuria; baseline plus annual measures of smoking, HDL and LDL-cholesterol, weight, systolic blood pressure, HbA1c, heart rate, white cell count, haemoglobin, estimated glomerular filtration rate; and prior history of ischaemic heart disease, heart failure, amputation, blindness, kidney failure, stroke, myocardial infarction (MI) or diabetic foot ulcer.

Results: 1491/14671 (10.2%) participants experienced ≥1 major CV event over median 3.0 years follow-up. Predicted compared with observed rates were 6.4% vs. 5.1% for CV death, 7.7% vs. 4.2% ≥1 MI event and 3.5% vs. 2.5% for ≥1 stroke event (Table). Discrimination was fair (aROC>0.6) for stroke, CV death and ACM, but poor for MI. Simulated relative risks matched those observed.

Conclusion: OM2 overestimates absolute CV and ACM risk in TECOS participants, but correctly simulates the lack of sitagliptin impact.

Disclosure

R.L. Coleman: None. A.M. Gray: Advisory Panel; Self; Sanofi-Aventis. D.K. McGuire: Consultant; Self; Eisai Co., Ltd., Eli Lilly and Company, Pfizer Inc. Research Support; Self; Janssen Pharmaceuticals, Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. R.R. Holman: Advisory Panel; Self; Bayer AG, Novartis AG, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Bayer AG, Merck Sharp & Dohme Corp. Other Relationship; Self; AstraZeneca, Bayer AG, GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc.
1467-P: National Trends in the Use of Lipid-Lowering Drugs among Type 2 Diabetes Patients in Denmark from 1997 to 2017
Authors: RØNN PERNILLE F , CARSTENSEN BENDIX , KNUDSEN JAKOB S. , PERSSON FREDERIK , JØRGENSEN MARIT E
Published: June 2019

Background: Lipid-lowering drug (LLD) treatment is important for cardiovascular risk reduction in type 2 diabetes. Statins are first choice of treatment but increasing public concern of side effects may have changed the prescription patterns of LLDs. We mapped trends in LLD usage among type 2 diabetes patients in Denmark from 1997 to 2017.

Methods: The study population was defined as all persons registered with type 2 diabetes in the national registers in the period 1997 through 2017. All redeemed LLDs (ATC-codes: C10) were extracted from the Register of Medicinal Product Statistics. Medication coverage at any given day was calculated based on amount purchased and doses prescribed if recorded; otherwise on Defined Daily Dose.

Results: A total of 420,751 persons living in Denmark with type 2 diabetes was included. Out of these, 266,385 (63%) individuals redeemed at least two LLD prescriptions in the period. The proportion covered by LLDs increased from 24% in 1997 to 58% in 2013, where after it declined (Figure 1). By 2017, 35% of the population was on simvastatin, 15% on atorvastatin, 4% on rosuvastatin, 2% on ezetemibe and 1% on other drugs.

Conclusion: Changing guidelines has had a clear impact on the actual use of LLDs among type 2 diabetes patients, but the declining tendency emphasize that there is still room for improvement. There was, however, not a noteworthy shift from statins to other drugs.

Figure 1.

Disclosure

P.F. Rønn: Research Support; Self; Amgen AB. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. B. Carstensen: Consultant; Self; Leo Pharma. Speaker's Bureau; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk Inc. J.S. Knudsen: None. F. Persson: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. M.E. Jørgensen: Research Support; Self; Amgen Inc., AstraZeneca, Danish Diabetes Association, Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S.

Funding

Amgen AB
1493-P: Sickle Cell Trait, Hemoglobin C Trait, and Glucose-6-Phosphate Dehydrogenase Deficiency Contribute to Decreased Detection of Hyperglycemia by A1C
Authors: BRIKER SARA M. , HORLYCK-ROMANOVSKY MARGRETHE F. , ADUWO JESSICA Y. , MUGENI REGINE , DUBOSE CHRISTOPHER , MABUNDO LILIAN , CHUNG STEPHANIE T. , HA JOON , SHERMAN ARTHUR , SUMNER ANNE E.
Published: June 2019

A1C is easier to perform than an OGTT, but A1C has a lower rate of detection of diabetes (DM) and prediabetes (preDM). Underperformance of A1C in the detection of hyperglycemia may be magnified in Africans. Three single gene mutations common in Africa, specifically sickle cell trait (SCT), hemoglobin C (HbC) trait and glucose-6-phosphate dehydrogenase (G6PD) deficiency may lead to artefactually low A1C levels. Our goals were: (1) compare DM and preDM prevalence diagnosed by either A1C or OGTT; (2) evaluate whether SCT, HbC trait or G6PD deficiency impact A1C levels. Participants were 421 African-born blacks living in America (male: 66% (276/421), age: 38±10y (mean±SD)). A1C and OGTT were done with repeat studies done in 105 participants 11±7 days later. Diagnosis of DM and preDM required meeting either A1C criteria or glucose guidelines for the OGTT. G6PD activity was assayed in 50 consecutively enrolled participants. DM prevalence was 8% (32/421). Detection of DM by A1C-alone, A1C and OGTT and OGTT-alone were: 16% (5/32), 16% (5/32), and 68% (22/32), respectively. PreDM prevalence was 42% (177/421) with detection rates by A1C-alone, A1C and OGTT and OGTT-alone: 28% (49/177), 30% (53/177) and 42% (75/177), respectively. Repeat testing gave similar results. Among people with DM, 40% (13/32) had either SCT or HbC trait. A1C failed in 77% (10/13) of people with both DM and either SCT or HbC trait. Overall, A1C was 3 times more likely to fail in the detection of DM if either SCT or HbC trait was present (Odds Ratio 3.5 (95% CI: 1.7, 7.5), P<0.01). Prevalence of G6PD deficiency was 16% (8/50). At similar levels of glycemia, A1C levels were lower with G6PD deficiency (4.3±0.1 vs. 5.5±1.0%, P<0.01). Working with African-born blacks living in America, we found that if only A1C was performed, 68% with DM and 42% with preDM would be undiagnosed. SCT, HbC trait and G6PD deficiency contribute to inappropriately low A1C levels and missed opportunity to detect hyperglycemia.

Disclosure

S.M. Briker: None. M.F. Horlyck-Romanovsky: None. J.Y. Aduwo: None. R. Mugeni: None. C. DuBose: None. L. Mabundo: None. S.T. Chung: None. J. Ha: None. A. Sherman: None. A.E. Sumner: None.
15-LB: Diabetes Duration Did Not Moderate the Reduction in Severe Hypoglycemia Seen with Degludec vs. Glargine U100 in DEVOTE
Authors: ALEXOPOULOS ANASTASIA-STEFANIA , KVIST KAJSA , HACHMANN-NIELSEN ELISE , BUSE JOHN B.
Published: June 2019

Hypoglycemia is associated with significant morbidity in type 2 diabetes (T2D). Progression of T2D leads to declining counterregulatory responses and heightened hypoglycemia risk. In this secondary analysis of data from DEVOTE, a CVOT with 7637 patients with T2D at high risk of cardiovascular events, we investigated diabetes duration as a moderator of severe hypoglycemia (SH) with use of glargine U100 (IGlar U100) versus insulin degludec. Patients in DEVOTE were categorized by diabetes duration in years: <10, 10-15, 15-20 and ≥20. Prevalence of SH was examined by treatment arm (Table) using a negative binomial model with log-observation time as an offset term, and diabetes duration categories as moderators. Both proportion of patients with SH events and rate of SH increased with progression of disease in both arms. Degludec preserved its relative benefit over IGlar U100 for SH across diabetes duration groups, even in less progressed disease groups, i.e., an observed 52% relative risk reduction for degludec vs. IGlar U100 for patients within 10 years of disease onset (95% CI: 0.29; 0.81). There was no significant difference in treatment ratios across categories (p-value for interaction=0.50). Similar findings were confirmed in the SWITCH 2 trial (data not shown). Thus, diabetes duration did not moderate the relative reduction in rate of SH for degludec vs. IGlar U100 in DEVOTE.

Disclosure

A. Alexopoulos: None. K. Kvist: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. E. Hachmann-Nielsen: Employee; Self; Novo Nordisk A/S. J.B. Buse: Consultant; Self; Neurimmune AG. Research Support; Self; AstraZeneca, National Center for Advancing Translational Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk A/S, Sanofi, vTv Therapeutics. Stock/Shareholder; Self; Mellitus Health, PhaseBio Pharmaceuticals, Inc., Stability Health. Other Relationship; Self; ADOCIA, AstraZeneca, Dance Biopharm Holdings Inc., Eli Lilly and Company, MannKind Corporation, NovaTarg, Novo Nordisk A/S, Senseonics, vTv Therapeutics, Zafgen, Inc.

Funding

Novo Nordisk A/S
1510-P: A1C-Modified Atherosclerosis Risk in Communities Prediction Equation for Diabetes Can Be Replaced in Africans by Fasting Glucose
Authors: HORLYCK-ROMANOVSKY MARGRETHE F. , MUGENI REGINE , ADUWO JESSICA Y. , BRIKER SARA M. , DUBOSE CHRISTOPHER , MABUNDO LILIAN , CHUNG STEPHANIE T. , HA JOON , SHERMAN ARTHUR , SUMNER ANNE E.
Published: June 2019

In Africa 70% of people living with diabetes (DM) are undiagnosed. To address this challenge, prediction equations must be tested in Africans. As the A1C-modified Atherosclerosis Risk in Communities (ARIC) DM prediction equation was optimized in African Americans, our goal was to test in Africans: 1) ability of the equation to detect undiagnosed DM; 2) contribution of each biochemical variable to the equation; 3) independent value of each biochemical variable. The equation has 5 clinical and 4 biochemical variables: HDL, TG, A1C and fasting plasma glucose (FPG). Participants were 421 African-born blacks living in the U.S. (66% male; age 38±10y (mean ±SD); BMI 27.5±4.4 kg/m2). OGTT was performed. DM diagnosis required 2h glucose ≥200 mg/dL. Area under the receiver operating characteristic curve (AROC) predicted DM. Youden Index estimated optimal cut points. DM occurred in 6% (27/421). AROC for the full equation was 0.84. Only with FPG excluded from the equation did the AROC decline (P<0.01) (Table 1A). Single predictor variables HDL, TG, A1C had low AROC. However, FPG as a single predictor had AROC 0.89 and was equivalent to the full equation (Table 1B). Thus, DM was identified by the full equation in 78% (21/27) and by FPG alone in 81% (22/27). Optimal cut point for FPG was 100 mg/dL. For the detection of DM, FPG ≥100 mg/dL performed as well as the A1C-modified ARIC equation.

Disclosure

M.F. Horlyck-Romanovsky: None. R. Mugeni: None. J.Y. Aduwo: None. S.M. Briker: None. C. DuBose: None. L. Mabundo: None. S.T. Chung: None. J. Ha: None. A. Sherman: None. A.E. Sumner: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Minority Health and Health Disparities