bluuebunny/crossref_metadata_2025 huggingface dataset:
2187-P: Gsα Deficiency in Pancreatic a Cells Leads to Enlarged Islets
Authors: TAIRA AKIKO , SUN HUI , LE CHRISTINA , GAVRILOVA OKSANA , CHEN MIN , WEINSTEIN LEE
Published: June 2019

Pancreatic β-cell dysfunction leads to diabetes with reduced β-cell mass and impaired glucose-stimulated insulin secretion. The G protein α subunit Gsα couples receptors to generate cAMP, which mediates the insulinotropic effects of incretin hormones, such as GLP-1. We previously reported that β-cell-specific Gsα deficiency causes insulin-deficient diabetes due to reduced islet size and β-cell mass, and that mice with whole pancreatic Gsα deficiency develop insulin deficient diabetes and reduced β-cell mass, but also showed increased proliferation of α-cells, indicating that Gsα plays divergent roles in pancreatic α-and β-cell growth. In the present study, we generated mice with α-cell-specific Gsα deficiency (αGsKO) by mating Gsα-floxed mice with glucagon-cre mice and studied the metabolic consequences. Deletion of Gsα in α-cells did not affect growth, blood glucose, or serum insulin or glucagon levels. However, αGsKO mice displayed enlarged islet size of normal architecture with significant increases in both α- and β-cell numbers, accompanied with increased β-cell proliferation and reduced apoptosis. This increased β-cell proliferation could be detected as early as at 3 days after birth. Consistent with this, αGsKO mice showed increased insulin response to acute glucose loading (3mg/g i.p.), although they had unaltered glucose tolerance when given a lower dose of glucose (2 mg/g i.p.). The results of RT-PCR on pancreatic islets isolated from aged mice (9-10 months old) showed that expression of Maf B and Pax6, transcription factors required for β-cell development, tended to be increased; whereas cell cycle factors, such as Cyclin D1, D2, and CDK4, tended to be decreased. Taken together, our results show that Gsα/cAMP signaling pathway in pancreatic α-cells is critical for both α- and β-cell growth as well as for maintenance of β-cell mass.

Disclosure

A. Taira: None. H. Sun: None. C. Le: None. O. Gavrilova: None. M. Chen: None. L. Weinstein: None.

Funding

National Institutes of Health
2218-PUB: Increased Platelet Reactivity Is Associated with Inflammation and Arterial Stiffness in Subjects with Prediabetes
Authors: PINO ANTONINO DI , URBANO FRANCESCA , SCICALI ROBERTO , PIRO SALVATORE , RABUAZZO AGATA MARIA , PURRELLO FRANCESCO
Published: June 2019

We investigated markers of platelet reactivity and low-grade inflammation, and their association with early markers of vascular disease in subjects with prediabetes and new onset type 2 diabetes (NODM).

Methods: 121 subjects without history of diabetes were stratified into 3 groups according to glycemic status: controls (n=41), prediabetes (n=42) and NODM (n=39). Platelet reactivity was evaluated as 11-dehydro thromboxane B2 urinary levels (TXB2), mean platelet volume (MPV) and platelet/lymphocytes ratio (PLR); cardiovascular risk was evaluated with arterial stiffness [pulse wave velocity (PWV), Augmentation pressure (AP), Subendocardial viability ratio (SEVR)] and intima media thickness (IMT).

Results: Subjects with prediabetes exhibited: higher TXB2 urinary levels (10.7 ± 4.8 vs. 6.4 ± 1.8 pg/mg creatinine, p<0.05), PLR (143.7 ± 43 vs. 106.1 ± 26.7, p<0.05) and lower MPV (8.7 ± 0.7 vs. 9.5 ± 1.1 fl, p<0.05). Prediabetes showed higher fibrinogen and C creative protein (CRP) serum levels (333.2 ± 63 vs. 310.6 ± 58 mg/dL, p<0.05; 0.34 (0.11-0.47) vs. 0.14 (0.08-0.27) mg/dL, p<0.05, respectively). Subjects with prediabetes exhibited increased PWV, AP and IMT (8.1 ± 0.9 cm/sec vs. 7.5 ± 1.5, p<0.05; 13.2 ± 9.5 mmHg vs. 11.2 ± 4.6, p<0.05 and 710.2 ± 93.4 vs. 659 ± 93.1 μm, p<0.05, respectively) and decreased SEVR (159.4 ± 11 vs. 171.8 ± 32.3, p<0.05) compared with controls. No differences were found between prediabetes and NODM subjects regarding platelet reactivity and cardiovascular risk markers.TXB2 urinary levels were independently associated with hs-CRP, fibrinogen and HbA1c in multiple regression analysis. In simple regression analysis AP, PWV and SEVR showed a significant association with TXB2 urinary levels (r=0.32, p<0.05, r=0.16, p<0.05 and r=0.26 p<0.05 respectively).

Conclusions: Subjects with prediabetes showed increased platelet reactivity and inflammation markers. These alterations were associated with early markers of cardiovascular disease.

Disclosure

A. Di Pino: None. F. Urbano: None. R. Scicali: None. S. Piro: None. A. Rabuazzo: None. F. Purrello: None.

Funding

University of Catania
2228-PUB: Meta-analysis of Recent Data from Several Independent Sources Suggests That Methylgloxal (MGO) Is Trapped by Dietary Flavonoids and Excreted in Urine as MGO-Flavonoid Adducts
Authors: SZWERGOLD BENJAMIN , MILLER CRAIG B.
Published: June 2019

Methylglyoxal (MGO) is a reactive α-dicarbonyl produced as an unavoidable byproduct of glycolysis. Because it reacts readily with amino acids, nucleic acids and ethanolamine in phospholipids, MGO is deleterious to living systems and contributes significantly to diabetic complications. The primary defense against MGO is the glyoxalase system that oxidizes MGO to D-lactate. However, about 1% of MGO evades this mechanism and remains free to react with susceptible biomolecules. Consequently MGO, whose concentrations increase chronically in diabetics and temporarily in all individuals after meals, leads to increasing production of Advanced Glycation Endproducts (AGE) in diabetes and aging. Several recent papers suggest that residual MGO, can be trapped by scavengers with the resulting adduct safely removed via the urinary system One such report is Metformin, a drug that not only reduces blood glucose but is also beneficial for cardiovascular health and lowers mortality. In 2016 Kinsky et al. showed that Metformin reacts with MGO in diabetics and the adduct is eliminated in urine. This MGO-scavenging activity is also seen with some endogenous amine-containing compounds such as carnosine, taurine and creatine. In addition to metformin and other amine-based scavengers, there is solid evidence that phytochemicals, such as flavonoids in fruit and vegetables, are also MGO scavengers. Most recently Schalkwjik et al. have published data showing that modest ingestion of quercetin, reduces MGO in plasma by 10%. Prior to that, Sang et al. have shown that three other polyphenols: genistein, 6-shagaol and epicatechin, react with MGO in mice and are subsequently excreted as covalent adducts in urine. These studies can be interpreted in many ways, however the simplest interpretation may be that scavenging of MGO and its elimination may account, in part, for the widely reported positive effects of flavonoids on human health.

Disclosure

B. Szwergold: None. C.B. Miller: None.
224-LB: Celiac Disease Prevalence and Screening Practices in Adults with Type 1 Diabetes
Authors: SLOANE JASON , PORNEALA BIANCA , WEXLER DEBORAH J.
Published: June 2019

There is a well-established association between type 1 diabetes mellitus (T1D) and celiac disease (CD) with CD conferring an increased risk of lower bone mineral density (BMD), depression, and overall mortality. The prevalence of CD in the general population is estimated at 1%, while the prevalence of CD in the T1D population has been estimated to be 2.4-16.4%. There are no CD screening guidelines for screening adult patients with T1D. We aimed to determine the prevalence and characteristics of T1D patients with and without CD, and screened and unscreened patients. We analyzed data from 1,001 people with T1DM from a large single center T1D population. Chart review confirmed CD status and screening with serum antibody or duodenal biopsy since 2010. The prevalence of CD was 4%. Of adults with T1D, 39% had evidence of serologic screening for CD, and 58% of diagnoses were found through screening since 2010. The average age of people with T1D and prevalent CD was 40.7 years, which was younger than unscreened patients (mean age 47.9 years, P<0.006). Unscreened patients had significantly higher BMI (mean BMI 27.5 kg/m2) than those who screened negative (mean BMI 26.2) (p<0.0001). Unscreened patients and those with CD had similar A1C, LDL, and microalbumin suggesting that it may be challenging to risk stratify by clinical characteristics, and that there may be undiagnosed CD in the unscreened population.

Disclosure

J. Sloane: None. B. Porneala: None. D.J. Wexler: Other Relationship; Spouse/Partner; APOLO1BIO.
224-OR: Diurnal Pattern of Insulin Action and Beta-Cell Function in Health and Type 2 Diabetes
Authors: ROMERES DAVIDE , SCHIAVON MICHELE , COBELLI CLAUDIO , MAN CHIARA DALLA , BASU ANANDA , BASU RITA
Published: June 2019

We have previously reported differences in insulin sensitivity (SI) between T1D and nondiabetic (ND) subjects throughout the day. To explore differences in the diurnal pattern of SI, beta-cell responsivity to glucose (Φ) and disposition index (DI) between type 2 diabetes (T2D) and ND subjects, we present novel preliminary data from 5 ND (BMI 26.6±1.8 kg/m2, age 62.6±4.8 years, Mean±SE) and 5 T2D subjects (BMI 33.6±2.4 kg/m2, age 60.0±6.0 years, HbA1c 55±11 mmol/mol). Studies were conducted in the Clinical Research Unit. Subjects ingested identical mixed meals (75 g carbs, 55% carbohydrate, 15% protein, 30% fat) at either breakfast (B), lunch (L) or dinner (D) in randomized Latin Square order on three consecutive days. Plasma glucose (G), insulin (I) and C-peptide (C) concentrations were frequently sampled. Oral glucose and C-peptide minimal models were applied to estimate SI, Φ and DI. Differences among B, L and D and between ND and T2D were assessed by two-way ANOVA (a p-value <0.05 was considered statistically significant). The emerging patterns suggest that SI, Φ and DI were lower in T2D than ND (Figure 1) subjects throughout the day. While SI steadily decreased in T2D, it was variable in ND subjects as the day progressed. DI was significantly lower in T2D at dinner than at Breakfast. The data to date indicate that the diurnal patterns of insulin action and beta cell function differ between ND and T2D subjects through the day.

Disclosure

D. Romeres: None. M. Schiavon: None. C. Cobelli: None. C. Dalla Man: None. A. Basu: Research Support; Spouse/Partner; AstraZeneca. R. Basu: Other Relationship; Self; AstraZeneca.

Funding

National Institutes of Health (R01029953)
2245-PUB: The Epidemiology and Diagnosis of Diabetic Cardiovascular Autonomic Neuropathy: A Multicenter Clinical Study
Authors: PAN QI , GUO LIXIN , WANG XIAOXIA , ZHANG LINA , XIAN TONGZHANG , MAN FULI , LIU LI
Published: June 2019

Objective: To evaluate the risk factors of cardiovascular autonomic neuropathy(CAN) in Chinese diabetic patients, estimate the optimal CAN diagnostic method to different diabetics, assess CAN prevalence in our dataset.

Methods: 2, 048 subjects randomly sampled from 13 hospitals were available for data analysis, including 73 type 1 diabetes mellitus (T1DM) and 1, 975 type 2 diabetes mellitus (T2DM). The general data of patients were collected and sympathetic and parasympathetic function tests were executed to CAN preliminary diagnosis. The final CAN diagnosis was based on Ewing's test in which heart rate variation (HRV values were evaluated through deep-breathing (DB), lying-to-standing (LS), Valsalva (V) tests and systolic blood pressure (SBP) variation values was evaluated through LS.

Results: 1) In T1DM group, 61.64% patients were diagnosed with CAN; baseline data and clinical data of CAN group had no difference with those of none-CAN group (P>0.05);while in T2DM group, 62.58% patients were diagnosed with CAN; there were significant differences between CAN and none-CAN group in age, course of the disease, use of metformin, course of metformin treatment, retinopathy and hypertension history (P<0.05). 2) Among various symptoms in CAN group, most frequent symptoms were weakness (28.65%), dizziness (23.42%), frequent urination (19.59%), upper body sweating (18.35%) and enuresisnocturna (15.93%). 3) Course of disease and age were independent risk factors for CAN in T1DM and T2DM, respectively. 4) For T1DM, the optimal CAN diagnostic method was Vtest+LStes (sensitivity=97.62% , AUC=0.887); while for T2DM, DBtest had the highest sensitivity (83.62%) and Vtest+DBtest had the maximal AUC (0.856).

Conclusion: The prevalence of diabetes with CAN was up to 63%.The course of disease and age are independent risk factors of CAN in TIDM and T2DM, respectively. Furthermore, Vtest+LStest and Vtest+DBtest were the optimal CAN diagnostic method for T1DM and T2DM, respectively.

Disclosure

Q. Pan: None. L. Guo: None. X. Wang: None. L. Zhang: None. T. Xian: None. F. Man: None. L. Liu: None.
2259-PUB: Improving the Quality of Life of T1DM Patients in a Community: A KT1DP Initiative
Authors: KESAVADEV JOTHYDEV , SABOO BANSHI D. , SHANKAR ARUN , DAVID ASHWIN , WARRIER ROHIT , AJAI NEETHU A. , SANAL GEETHU , THAMPIRAJ KAVITHA , RAMACHANDRAN LAKSHMY , KRISHNAN GOPIKA , JOTHYDEV SUNITHA
Published: June 2019

Overall quality of life including longevity is poor among T1DM except for a very few being treated at specialty centers. A trained team for customized education can help improve outcomes. KT1DP Sweet Stars has been conducting a series of workshops partnering with patient organizations. A situational assessment was made during the first session in a community. Patients/parents were administered with ViDa1 questionnaire. n=58, 50% males, age=13.0±4.3y, duration=4.1±3.0y, HbA1c=10.3±2.3%. ViDa1 measures 4 HRQoL dimensions-interference of diabetes with life, self-care, wellbeing and concern about the disease. Interference scores varied significantly w.r.t. healthcare sector consulted (public vs. private; 33.9±8.8 vs. 29.3±7.3; p=0.024) and disease duration (<5 vs. ≥5y; 34.9±9.0 vs. 30.6±8.7; p= 0.047); higher scores indicating greater interference. No other scores varied significantly w.r.t. disease duration, age, gender, HbA1c and healthcare sector. Many were concerned about future complications, 62.07%; unsatisfied with glucose control, 50%; concerned about and afraid of hypoglycemia, 65.51% and 49.15%; and felt diabetes makes life stressful, 55.17%. 93.75% appreciated the educational initiative in improving their perspectives and T1DM management skills. Customized and continuing training programs targeting key areas of failure are expected to improve outcomes and quality of life in T1DM.

Disclosure

J. Kesavadev: None. B.D. Saboo: None. A. Shankar: None. A. David: None. R. Warrier: None. N.A. Ajai: None. G. Sanal: None. K. Thampiraj: None. L. Ramachandran: None. G. Krishnan: None. S. Jothydev: None.
2269-PUB: Early Attrition from a Randomized Lifestyle Modification Protocol
Authors: REVERE CATHY , SMITH A. GORDON , KLUDING PATRICIA , MARCUS ROBIN L. , DIMACHKIE MAZEN , VIVANCO FELIX , FOSTER-PALMER STORMY C. , HAUER PETER E. , APERGHIS ADRIENNE B. , PASNOOR MAMATHA , STONEBRAKER ANGELA , HAWKS ALEXIS N. , HERBELIN LAURA , SINGLETON J. ROBINSON
Published: June 2019

Assigned exercise and other lifestyle modification can alter the natural history of diabetic neuropathy, but adherence to lifestyle change protocols poses a challenge in a clinical trial setting. In particular, the commitment for participants to begin engagement with the assigned intervention is a critical juncture. The Activity for DiAbetic neuroPaThy (ADAPT) trial is an NIDDK sponsored two-center single blinded protocol that randomizes type 2 diabetic neuropathy patients for 18 months to either brief lifestyle counseling or a combination of monitored exercise, diet counseling and actigraphy driven anti-sedentary behavioral modification. 103 participants have consented, screened, and been found eligible for ADAPT. Of these, 20 dropped from the trial during baseline evaluation (n=3), randomization (n=1), or before the first intervention visit or 3-month follow-up (n=16). Of the 83 who have reached 3-month follow-up, only 7 participants have dropped from the study. The pattern of early attrition has differed at the two sites. At one site, early attrition was essentially equal between assigned groups. The second site 9 of those randomized to intervention and one assigned to control dropped before 3 months. At the second site, protocol changes to improve “hand-off” from the assessment to intervention coordinators, and marked reduction in time from randomization to first intervention visit has improved retention. Structured counseling to set expectations, reduce performance anxiety, and address disappointment with assignment to the less intensive arm has improved initial retention at both sites. Once familiar with the intervention process, most participants will continue with behavioral modification. Clinical trials utilizing patient-motivated lifestyle modification protocols should seek to minimize physical barriers to initial engagement, and focus counseling and motivational effort on the critical early trial period during which participants commit internally to the intervention process.

Disclosure

C. Revere: None. A. Smith: Consultant; Self; Alexion Pharmaceuticals, Inc., Disarm, Regenesis. P. Kluding: None. R.L. Marcus: None. M. Dimachkie: Research Support; Self; Viromed. F. Vivanco: None. S.C. Foster-Palmer: None. P.E. Hauer: None. A.B. Aperghis: None. M. Pasnoor: Advisory Panel; Self; Alexion Pharmaceuticals, Inc., Terumo BCT. Consultant; Self; Momenta Pharmaceuticals. A. Stonebraker: None. A.N. Hawks: None. L. Herbelin: None. J. Singleton: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases; National Center for Advancing Translational Sciences
227-OR: Novel Method of Assessing Hypothalamic KATP Channel Activation in Humans Using Magnetic Resonance Imaging (MRI)
Authors: SHARMA SHIKSHA , ALEKSIC SANDRA , MAGINLEY ROGER , YIMAGOU ERIC LONTCHI , UPADHYAY LAXMI , BHANSALI SHOBHIT , SANDU OANA , BRANCH CRAIG A. , HAWKINS MEREDITH
Published: June 2019

Hypothalamic KATP channels play an important role in regulating metabolism: activation of these channels with diazoxide (DZX) reduces endogenous glucose production (EGP) in rodents. When insulin is maintained at basal levels, oral DZX similarly suppresses EGP in humans (JCI 121:4916, 2011). Given the need to directly examine central regulation of EGP in humans, we developed a novel non-invasive measure of hypothalamic KATP channel activation.

Since cerebral blood flow (CBF) and neuronal activity are coupled, we mapped hypothalamic neuronal activity using pseudo-continuous arterial spin labeling (pCASL) to measure CBF using 3 Tesla MRI with high resolution 3-dimensional (3D) acquisition and published analyses approaches (MRM 73: 102, 2015). The hypothalamus was extracted from each 3D map (3x3x3mm) using a hypothalamus region-of-interest (ROI) mask delineated upon the Johns Hopkins Template. To directly assess hypothalamic KATP channel activity using pCASL, we examined the time dependent effects of DZX (6mg/kg) vs. placebo in a randomized, double blinded fashion. Eight healthy nondiabetic individuals (42±4 yr, BMI 24±1 kg/m2, 7M) underwent a baseline scan, with repeat scans at 2.5 and 5 hours following DZX or placebo. This time course was determined based on previous observations that DZX appearance in rat CSF precedes EGP suppression, which is maximal at ∼6 hours in rats and humans.

DZX induced an ∼11% drop in hypothalamic CBF, from 59.5±2.5 to 53.0±3.1 ml/100g/min at 2.5 hours (p=0.06), returning to baseline at 5 hours (57.7±2.7 ml/100g/min, p=0.3). Following placebo there was no change in CBF (p=0.8 by repeated measures ANOVA). No change in CBF was observed in other brain regions (e.g., cerebral cortex, thalamus, or hippocampus).

In conclusion, pCASL provides a novel image-based measure of hypothalamic response to KATP channel activation in vivo, and can thus be used to examine the metabolic significance of hypothalamic KATP channel activation in humans.

Disclosure

S. Sharma: None. S. Aleksic: None. R. Maginley: None. E. Lontchi Yimagou: None. L. Upadhyay: None. S. Bhansali: None. O. Sandu: None. C.A. Branch: None. M. Hawkins: Other Relationship; Self; Novo Nordisk Inc.

Funding

National Institutes of Health (R01DK069861); Albert Einstein College of Medicine
2276-PUB: A Palatable, Novel Whey Protein Shot Attenuates Postprandial Glycemia in Lean and Centrally Obese Adult Males
Authors: SMITH KIERAN , TAYLOR GUY S. , OKWOSE NDUKA , ALLERTON DEAN M. , BRUNSGAARD LISE HOEJ , STEVENSON EMMA J. , WEST DANIEL J.
Published: June 2019

Background: Consuming large doses of whey protein (WP) ∼30 minutes before high-glycemic load meals reduces postprandial glycemia (PPG). However, it is unclear if this effect is retained at smaller doses of WP, ingested at realistic times before typical meals. Moreover, as central obesity is associated with elevated PPG, WP may offer benefit in improving PPG within such individuals. We examined the PPG responses to breakfast following consumption of a small WP shot in centrally obese and lean males.

Methods: In a randomized-crossover design, 7 lean (BMI 24.3±1.5; waist circumference 79.3±7.1 cm; waist/hip ratio [WHR] 0.83±0.04) and 9 centrally obese (34.6±1.9; 112.8±10.2 cm; 0.97±0.1) age-matched, adult males performed two 240 minutes mixed-meal tests, 7d apart. After an overnight fast, participants consumed either a 100ml ready-to-drink WP shot (15g Protein) or 100ml water (CON) 10 minutes before a typical breakfast meal. Interval blood samples were collected for the measurement of plasma glucose. Data (mean±SD) were analyzed by a mixed-design ANOVA and Pearson’s correlation with significance accepted as p≤0.05.

Results: WP reduced early PPG AUC0-60min by 22±9.3% and 13.1±10% in lean and obese males, respectively, vs. CON (p<0.01). Obese males had greater AUC0-60min following WP vs. lean (p=0.02) with no differences after CON (p=0.62). Total trial glucose AUC0-240min was comparable between conditions in both groups (p>0.05). WP reduced peak PPG vs. CON (lean: -26.5±7% [p<0.001]; obese: -16.4±9.8% [p<0.01]) with a tendency for more marked reductions within lean males (p=0.052). Central obesity (WHR) was associated with greater increases in glucose from fasting values, despite WP consumption (r=0.7; p<0.01).

Conclusion: Consuming a palatable, ready-to-drink WP shot before breakfast attenuates early elevations in PPG and reduces hyperglycemia in lean and centrally obese males. Central obesity predicts the glucose lowering effect of WP and may limit its application in this group.

Disclosure

K. Smith: None. G.S. Taylor: None. N. Okwose: None. D.M. Allerton: None. L.H. Brunsgaard: Employee; Self; Arla Foods Ingredients. E.J. Stevenson: None. D.J. West: Research Support; Self; Arla Foods Ingredients, Dexcom, Inc.

Funding

Arla Foods Ingredients Group P/S
23-OR: The Effect of 14-Day Atorvastatin Treatment on Postprandial Glucose Metabolism in Healthy Males—A Link to Why Statin Therapy Increases the Risk of Type 2 Diabetes?
Authors: THOMASEN MARTIN L. , SONNE DAVID P. , KÅRHUS MARTIN L. , BRØNDEN ANDREAS , STAELS BART , HOLST JENS J. , VILSBØLL TINA , KNOP FILIP K.
Published: June 2019

Background and Aim: Statins are LDL cholesterol-lowering drugs that are highly effective in the prevention of cardiovascular disease and death. Recently, it has become known that statin therapy increases the risk of type 2 diabetes, but the mechanism behind this phenomenon remains obscure. We evaluated the gluco-metabolic effects of statin therapy in healthy male individuals.

Methods: In a placebo-controlled, double-blinded, randomized, cross-over study, we investigated the effect of 14 days of treatment with atorvastatin (40 mg once-daily for one week and 80 mg once-daily the second week) on fasting and postprandial concentrations of glucose, gluco-regulatory hormones and bile acid profiles in 15 healthy male individuals (age 25.6±3.8 years; BMI 24.7±2.8 kg/m2; glycated hemoglobin A1c 4.8±0.2% (mean±SD)). Four-hour mixed meal tests were performed following each of the two 14-day treatment periods with placebo or atorvastatin, respectively.

Results: Treatment with atorvastatin did not affect postprandial plasma glucose or insulin concentrations, but basal as well as postprandial concentrations of glucagon were increased compared to placebo. Postprandial plasma concentrations of the gut-derived incretin hormones glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 were increased after atorvastatin treatment compared to placebo. Also, postprandial concentrations of taurine-conjugated primary bile acids increased, whereas glycine-conjugated secondary bile acids decreased.

Conclusion: In healthy male individuals, 14 days of atorvastatin treatment did not affect postprandial glucose tolerance or insulin concentrations. Fasting and postprandial glucagon concentrations were increased by atorvastatin treatment, which may point to hyperglucagonemia as a possible link between statin treatment and type 2 diabetes.

Disclosure

M.L. Thomasen: None. D.P. Sonne: None. M.L. Kårhus: None. A. Brønden: Other Relationship; Self; AstraZeneca. B. Staels: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. T. Vilsbøll: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S.

Funding

Augustinus Fonden
2347-PUB: Relationship between Aging and Effects of SGLT2 Inhibitors on Glucose and Lipid Metabolisms and Hepatic Function in Japanese Patients with Type 2 Diabetes
Authors: KUSUNOKI MASATAKA , NATSUME YUKIE , OSHIDA YOSHIHARU , MIYATA TETSURO
Published: June 2019

SGLT2 inhibitors (SGLT2is) have been found to improve blood glucose, HbA1c and triglyceride levels and also hepatic dysfunction in patients with type 2 diabetes. However, scarcely any studies have examined whether there are differences in the effects of SGLT2is according to patient age. In this study, we stratified the patients into 3 groups according to the age and investigated whether age influences the effects of SGLT2is on glucose and lipid metabolisms and hepatic function in these patients.

The patients were stratified into the following 3 age groups: <50, 50 to 64, and ≥65 years. Five SGLT2is were administered for 6 months at the following doses: 2.5 mg/day luseogliflozin, 5 mg/day dapagliflozin, 20 mg/day tofogliflozin, 10 mg/day empagliflozin, and 100 mg/day canagliflozin. Blood samples were collected before and after the treatment to measure biochemical parameters.

Significant decreases, compared to the baseline, of HbA1c, serum glucose and insulin, and HOMA-R were observed after the treatment with the SGLT2is in the <64 years age groups, but not the ≥65 years age group. With regard to the effects on lipid metabolism, increase in serum HDL cholesterol and decrease in LDL cholesterol/HDL cholesterol ratio were observed in the ≥65 years age group. In addition, hepatic function parameters improved significantly in the <64 years age groups, but to a lesser degree in the ≥65 years age group. The effects on BMI were not affected.

The results revealed that some effects of SGLT2is were affected by aging. The SGLT2is improved glucose metabolism in the patients aged <64 years, but this effect was weaker in those aged ≥65 years. However, the SGLT2is led to a more anti-atherogenic serum lipid profile in patients aged ≥65 years than in those aged <65 years. In addition, it appears that the hepatic function-improving effect of SGLT2is decreases with age, especially in patients aged ≥65 years. The effects of SGLT2 inhibitors on BMI were not affected.

Disclosure

M. Kusunoki: Other Relationship; Self; Kaken Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd. Y. Natsume: Other Relationship; Self; Kaken Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd. Y. Oshida: None. T. Miyata: Research Support; Self; Bayer AG, Daiichi Sankyo Company, Limited.
238-LB: Prevalence of GCK-MODY in 92,412 Exomes from an Unselected Clinical Population
Authors: MIRSHAHI UYENLINH L. , GOEHRINGER JESSICA M. , HU YING , WARDEH AMR H. , WILLIAMS JANET , MANNEY CATARINA B. , STAPLES JEFFREY C. , LEADER JOSEPH B. , SHULDINER ALAN R. , POLLIN TONI I. , CAREY DAVID J.
Published: June 2019

Maturity onset diabetes of the young (MODY) is a monogenic form of diabetes attributed to a highly penetrant variant in one of several genes, including GCK. GCK-MODY rarely requires pharmacotherapy, however, the clinical management of pregnant mothers depends on whether the fetus inherited the GCK variant. The classic GCK-MODY phenotype is young (diagnosed before 25 years), lean (BMI < 25 mg/kg2), with stable, mild hyperglycemia (Hba1c 5.8-7.6%). We hypothesized that strict application of these guidelines has led to under-reporting of GCK-MODY (prevalence 1.1 per 1000). In a cohort of 92,412 individuals from the DiscovEHR study, we identified 252 heterozygous carriers of 88 rare GCK variants (minor allele frequency < 0.02%). None had an existing diagnosis of monogenic diabetes. The median BMI of GCK carriers was 35 mg/kg2, compared to 31 mg/kg2 for nondiabetic noncarriers and 38 mg/kg2 for noncarriers with type 2 diabetes (T2D). Excluding variants with no evidence of hyperglycemia in 50% of the carriers resulted in 70 variants in 213 individuals. GCK-MODY variant carriers had mean HbA1c, fasting blood glucose (FBG), and random glucose measurements that were greater than nondiabetic non-carriers but less than those with T2D. Kaplan-Meier analysis adjusted for left-truncation bias showed that the age at which 50% of GCK-MODY subjects diagnosed with impaired fasting glucose and diabetes is 35 and 55 years, respectively, compared to 60 and 65 years in non-carriers with T2D (p< 2e-16). Within-individual variability of lifetime FBG measurements of GCK-MODY carriers was less than noncarriers with T2D (GCK-MODY, 7.9 ± 2.0 mg/dL; T2D, 17.6 ± 0.03 mg/dl, p <1e-4). The odds ratios [95% confidence intervals] for diabetes in GCK-MODY carriers was 4.0 [3.1 - 5.2], p<0.0001. We estimate a GCK-MODY prevalence of 1 per 508 individuals and 1 per 59 individuals with gestational diabetes. GCK variant carriers in this study had a broader spectrum of clinical characteristics compared to the classic GCK phenotype.

Disclosure

U.L. Mirshahi: None. J.M. Goehringer: None. Y. Hu: None. A.H. Wardeh: None. J. Williams: None. C.B. Manney: None. J.C. Staples: Employee; Self; Regeneron Pharmaceuticals. J.B. Leader: None. A.R. Shuldiner: Employee; Self; Regeneron Pharmaceuticals. Stock/Shareholder; Self; Rhythm Pharmaceuticals, Inc. T.I. Pollin: Other Relationship; Self; Regeneron Genetics Center. D.J. Carey: None.
2398-PUB: The Interplay of Type 1 Diabetes and Weight: A Qualitative Study of Thematic Progression with Age
Authors: ADDALA ANANTA , IGUDESMAN DARIA , KAHKOSKA ANNA R. , MUNTIS FRANKLIN R. , SOURIS KATHERINE J. , WHITAKER KERI J. , PRATLEY RICHARD E. , MAYER-DAVIS ELIZABETH
Published: June 2019

The impact of weight management in persons with type 1 diabetes (T1D) from childhood into adulthood is not well described. The purpose of the study is to explore qualitative themes presented by young adults on both weight and T1D management.

We analyzed focus group data from 17 young adults with T1D via inductive qualitative analysis. Major themes were compared to published themes presented by youth with T1D to categorize thematic progression from youth to adulthood.

Themes from young adults with T1D, when compared to youth, are categorized as: unchanged, evolving, and newly reported. Hypoglycemia and a sense of futility around exercise was an unchanged theme. Importance of insulin usage and a need for a healthy personal relationship with T1D evolved to gather greater conviction. Newly reported themes are unique to integration of adulthood into T1D, such as family planning and work-diabetes balance. Young adults also newly reported negative experiences with providers in their younger years and desire for more supportive provider relationships.

Issues identified by youth regarding the dual management of T1D and weight rarely resolve, but rather, persist unchanged or integrate other aspects of young adulthood via evolving or newly emerged themes. Individualized and age-appropriate clinical support and practice guidelines are warranted to facilitate the dual management of weight and T1D in persons with T1D

Disclosure

A. Addala: None. D. Igudesman: None. A.R. Kahkoska: None. F.R. Muntis: None. K.J. Souris: None. K.J. Whitaker: None. R.E. Pratley: Consultant; Self; Sanofi US. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Janssen Global Services, LLC., Janssen Research & Development, Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk Inc., Pfizer Inc., Sanofi, Takeda Development Center Americas, Inc. E. Mayer-Davis: None.
2399-PUB: Multidisciplinary Clinic-Based Model for Mild Ketosis and Dehydration Management in Youth with Diabetes
Authors: KIM GRACE K. , MIXON ALVA , MARSHALL MELISSA A. , TAUB MICHELLE E. , JARAMILLO MARIANA , SCROGGINS DIANA , BANSAL NIDHI , KARAVITI LEFKOTHEA , MCKAY SIRIPOOM
Published: June 2019

Background: Diabetic ketoacidosis (DKA) is a major cause of emergencies in youth with type 1 diabetes constituting a health burden. Nonadherence and knowledge gaps are key contributors. Patients with mild ketosis and dehydration are typically managed in the EC without multidisciplinary evaluation.

Objective: We developed a quality improvement initiative to improve access and reduce emergency center (EC) visits for pediatric patients with type I diabetes with mild ketosis not tolerating oral intake, and to deliver family centered multidisciplinary education addressing diabetes knowledge gaps and psychosocial barriers.

Methods: A multidisciplinary focus group of physicians, nurses, certified diabetes educators (CDE), and social workers (SW), determined criteria for patients who could be cared for in Urgent Care Bay (UCB) rather than EC. Eligible patients with type 1 diabetes were >5 years old who could not tolerate oral intake, and had low-to-moderate ketones. SW identified and addressed psychosocial barriers to optimal diabetes management. CDE assessed and provided structured education addressing knowledge gaps.

Results: Of 17 referred patients, 9 were seen in UCB (8 by CDE; 7 by SW). None required transfer to EC. SW referred 4 patients to psychology: 2 seen in UCB, 2 referred to community psychology. Time spent in multidisciplinary UCB visit was not longer than traditional EC-managed visits.

Conclusion: This multidisciplinary approach may help pediatric patients with diabetes with mild ketosis who are not tolerating oral intake. Multidisciplinary teaching and psychosocial interventions provided while patients are only mildly sick may help patients avoid future admissions. It remains to be seen whether this comprehensive model of education and hydration of mildly sick patients with diabetes will provide cost effectiveness in terms of overall EC admissions.

Disclosure

G.K. Kim: None. A. Mixon: None. M.A. Marshall: None. M.E. Taub: None. M. Jaramillo: None. D. Scroggins: None. N. Bansal: None. L. Karaviti: None. S. Mckay: None.
2400-PUB: Assessment of Parental Preparedness for Transition of Their Child’s Diabetes Care from Pediatric to Adult Providers
Authors: SHANK KAITLYN R. , REALL MACY , KRISHNA KANTHI BANGALORE
Published: June 2019

Background: Youth with diabetes and their parents are not prepared for transition to adult care. Several studies suggest that transition planning should start early, however, the role for parental input in this process is not well defined. At our center, we are working on implementing a transition readiness class to better prepare our families for transition care to adult providers. Parents were administered a standardized questionnaire (Gottransition.org) to assess their perspectives on their child’s transition readiness.

Results: Of the parents of 19 youth (13M, 6F; 11 on pumps, 8 on multiple daily injections (MDI)) only 37% felt confident about their child’s transition preparedness while nearly all (84%) felt it was important for their child to prepare for the transition before age 22. Table 1 shows the parental assessment of their child’s healthcare navigation and autonomy.

Discussion: While there is recognized importance for improving transition preparedness amongst diabetic youth, parents have poor confidence in their child’s ability to do so, which was found to be even lower in patients on MDI than on a pump. Parents believe there is need for education particularly on healthcare navigation and autonomy. These findings support the need for implementation of a formal curriculum to educate diabetic youth on specific healthcare navigation elements before transitioning to adult providers.

Disclosure

K.R. Shank: None. M. Reall: None. K. Bangalore Krishna: None.
2421-PUB: Effect of Incidental Postprandial Hypoglycemia on OGTT in Pregnancy on Maternal and Foetal Outcomes
Authors: POTHINA NARAYANA PRASAD , DESHMUKH HARSHAL , PANIKKAR MOHINI , MOHAMMED M. , SATHYAPALAN THOZHUKAT
Published: June 2019

Aim: The implications of incidental hypoglycaemia during 75g oral glucose tolerance test in pregnant women affects the maternal and fetal outcomes is unclear.

Materials and Methods: We conducted a retrospective analysis of the 1663 women who underwent 75g 2 hour OGTT at 24-28 weeks of gestation between January 2015 to December 2017. Post-prandial hypoglycaemia was defined as blood sugar levels less than 4mmol/L. Sub-optimal birth weight was defined as birth weight less than 3000g. Parametric and non-parametric tests were used to compare baseline characteristics of those with and without post-prandial hypoglycaemia. Linear regression analysis was used to identify independent predictors of birth weight.

Results: Of the 1663 patients, 178 (10.7%) had GDM. In patients without GDM 126 (8%) had post-prandial hypoglycaemia. There were no significant differences in baseline anthropometric and clinical characteristics of those with and without post-prandial hypoglycaemia. After adjustments for age (p=0.003), gestational age at delivery (p<0.0001), ethnicity (p-value<00001), fasting glucose (p<0.0001), and smoking (p-value<0.0001), post-prandial hypoglycaemia was associated with lower birth weight (beta=-106.5, p value=0.01). After adjustment for the above covariates post-prandial hypoglycaemia was significantly associated with suboptimal-birth weight (OR=1.99(CI 1.5-2.4)p-value=0.005). There were no significant differences in APGAR score at 1 and 5 minute (9.63 vs. 9.70 p-value=0.28 at 5 minutes), mode of delivery, bleeding complications during delivery (p=0.8) and neonatal admission to critical care (p=0.8) in those with post-prandial hypoglycaemia as compared to those without it.

Conclusion: Incidental post-prandial hypoglycaemia during the OGTT is associated with suboptimal birth weight and these pregnant women need close follow-up to monitor fetal growth.

Disclosure

N. Pothina: Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. H. Deshmukh: None. M. Panikkar: None. M. Mohammed: None. T. Sathyapalan: Speaker's Bureau; Self; Novo Nordisk Foundation. Other Relationship; Self; Bristol-Myers Squibb Company, Eli Lilly and Company, Sanofi-Aventis.
2424-PUB: Progressive Albuminuria as a Key Factor Potentially Determining Cardiovascular Prognosis in the Elderly with Type 2 Diabetes: From a Three-Year Interim Report of a Cohort Study, Nagano Study 2
Authors: YAMAZAKI MASANORI , SHIBATA YUSUKE , KAWAI YUKO , KOMATSU MITSUHISA
Published: June 2019

Objective: The purpose of this study is to explore potential prognostic factors and contribute scientific evidence of treatment for the elderly with type 2 diabetes (T2D).

Methods: Japanese patients with T2D aged ≥20, who had received regular medical examination for at least a year and had no history of malignancy for 5 years before enrollment, were consecutively registered. Information on subjects’ physical findings, laboratory data, and outcome was collected each year. In this study statistical analysis was performed in the participants followed for 3 years.

Results: As of October 2017, 205 patients were identified as analytical objects. The patients were divided into two groups; the elderly: ≥65 years (n=111, age 73.6 years, T2D duration 16.4 years, HbA1c 7.1%) and the non-elderly: <65 years (n=94, age 55.6 years, T2D duration 12.3 years, HbA1c 7.1%). At baseline, as compared with the non-elderly, the elderly had significantly low BMI (24.4 vs. 27.1 kg/m2), diastolic blood pressure (74.1 vs. 78.2 mmHg), fasting plasma glucose levels (107.5 vs. 125.0 mg/dL), eGFR (63.7 vs. 75.5 mL/min/1.73 m2), and fasting triglyceride levels (107.5 vs. 125.0 mg/dL). Over 3 years, a significant difference in those above was continuously observed between the two groups, whereas the elderly had significantly lower postprandial triglyceride levels than the non-elderly (130.0 vs. 155.7 mg/dL). In addition, urinary albumin excretion rate significantly increased from a baseline of 220.7 to 400.5 mg/gCr with eGFR decline (56.9 mL/min/1.73 m2) in the elderly, but not in the non-elderly.

Conclusions: Albuminuria is well known to be associated with development of cardiovascular diseases. In Japanese elderly patients with long T2D duration and well-controlled HbA1c, blood pressure, and blood lipid, progressive albuminuria with eGFR decline may have the potential to determine their cardiovascular prognosis.

Disclosure

M. Yamazaki: None. Y. Shibata: None. Y. Kawai: None. M. Komatsu: None.
2431-PUB: Distance from Glycemic Target at the Time of Intensification in Patients with Type 2 Diabetes (T2D) Failing Metformin Dual Therapy in the United States
Authors: FERNANDES GAIL , SAWHNEY BAANIE , HANNACHI HAKIMA , WANG TONGTONG , MCNEILL ANN MARIE , IGLAY KRISTY , RAJPATHAK SWAPNIL
Published: June 2019

Several studies have previously reported “clinical inertia” in the sequential treatment of T2D patients. The objective of the study was to quantify the distance from HbA1c target at the time of treatment intensification among patients failing dual therapy of metformin and another oral antihyperglycemic agent (OAHA). This retrospective study was conducted using GE Centricity Electronic Medical Record database (2015 data). Patients included those with diagnosed T2D on metformin dual therapy with at least 12 months of continuous enrollment prior to index date (initiation of dual therapy), documented HbA1c ≥7% and intensifying therapy within two years following index date. Treatment intensification was defined as either addition of another OAHA or initiation of insulin/glucagon-like peptide-1 receptor agonists. Distance from glycemic target was calculated as the median difference of HbA1c from target of 7% at the time of therapy intensification. 864 patients met the study criteria; mean age of 57.5 years, 48% were female, 26.3% had microvascular and 18.4% had macrovascular complications. Median difference from HbA1c target of 7% was 1.4%, with 29% (n=253) of patients between 1 to 2%, and 36% (n=315) greater than 2% distance from HbA1c target. When we excluded those for whom higher HbA1c target may be more appropriate (those ≥65 years, with micro- or macrovascular complications or with history of hypoglycemia), the median difference was 1.6%. This study suggests that majority of metformin dual therapy patients (65.7%) were at least 1% away from target of 7% at the time of intensification of therapy. Future studies should explore reasons behind this lack of earlier intensification and factors associated with clinical inertia.

Disclosure

G. Fernandes: None. B. Sawhney: Consultant; Self; Merck & Co., Inc. H. Hannachi: Employee; Self; Merck & Co., Inc. T. Wang: Employee; Spouse/Partner; Johnson & Johnson. Employee; Self; Merck & Co., Inc. A. McNeill: Employee; Self; Merck & Co., Inc. K. Iglay: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. S. Rajpathak: None.
2437-PUB: Prevalence of Liver Fibrosis in Diabetic Nonalcoholic North Indian Patients Attending a Tertiary Care Hospital
Authors: KAKKAR ARPIT
Published: June 2019

Introduction: India, diabetes capital of the world has over 50 million people with type 2 DM. Incidence of DM is increasing, so does the complications, including nonalcoholic fatty liver disease (NAFLD) and consequent liver fibrosis. NAFLD, regarded as hepatic manifestation of metabolic syndrome, affects 40-70% of DM patients and about 7% of these had advanced liver fibrosis on MR Elastography.

Aim: To determine prevalence of liver fibrosis in nonalcoholic diabetics attending our hospital in North India.

Material and Methods: Type 2 DM patients aged between 18-65 years, who attended outdoor clinics were included in this single center prospective observational study. Patients with decompensated chronic liver disease, pregnancy and T1 DM were excluded. All patients underwent ultrasound shear wave elastrography (USG-SWE). Average of serial intercostals space scan values (kilopascals and metavir) was calculated and analyzed.

Results: Of the 64 eligible patients, their mean age was 54 years and male to female ratio was 0.7:1. Normal liver parenchyma was found in 59.37% diabetic patients and 40.6% were found to have different grades of fibrosis.

Conclusion: The prevalence of nonalcoholic liver fibrosis among type 2 DM patients in North Indian population is 40.6%. With this obtained high number, we recommend screening of every diabetic patient with USG-SWE as an early modality to diagnose liver fibrosis.

Disclosure

A. Kakkar: None.
2445-PUB: Impact of Primary Aldosteronism on Renal Function in Type 2 Diabetes Patients
Authors: KATSURAGAWA SHO , TSURUTANI YUYA , TAKIGUCHI TOMOKO , SAITO JUN , NISHIKAWA TETSUO
Published: June 2019

Primary aldosteronism (PA) is associated with higher renal damage than essential hypertension (HT). In particular, the prevalence of chronic kidney disease increases after treatment for PA, as actual renal damage may be underestimated in untreated PA due to glomerular hyperfiltration. Previous studies have indicated the role of the renin-angiotensin-aldosterone system in renal dysfunction in type 2 diabetes (T2DM) patients, but whether PA causes additional renal function damage in T2DM is unclear. The aim of this study was to investigate this issue. A retrospective review of all T2DM outpatients who visited our high-volume center for PA in the FY 2017 was carried out. We segregated patients that underwent PA treatment (PA group) and those without PA (non-PA group). Treatment for PA was defined as adrenalectomy or the use of aldosterone receptor antagonists (MRAs). Untreated PA was excluded, since renal damage might be underestimated in these patients. We compared the renal function between these two groups. There were 83 patients in the PA group and 1580 patients in the non-PA group. In the PA group, 21 patients underwent adrenalectomy, 60 patients underwent MRA treatment, and 2 patients underwent both. Compared to the non-PA group, patients in the PA group were younger (62 [55-69] vs. 66 [55-75] years, p=0.014), and had a higher BMI (25.9 [23.8-27.8] vs. 24.8 [21.7-28.1] kg/m2, p=0.019) and lower HbA1c (6.8 [6.5-7.1] vs. 7.3 [6.7-8.0]%, p<0.001). In the renal function evaluation, the PA group had significantly lower eGFR (66.3 [52.4-78.2] vs. 70.5 [56.0-85.6] ml/min/1.73 m2, p=0.047) than the non-PA group. Multiple regression analysis revealed that PA was a factor for decreased eGFR, independent from age, sex, BMI, HbA1c, and HT (p=0.007). PA induced a 3.3 (95% CI: 0.90-5.7)-ml/min/1.73 m2 decrease in eGFR, equivalent to 3.8 years of aging. Our results show that PA was a risk factor for renal dysfunction independent from HT in T2DM patients. To prevent the progression of renal failure, PA should not be overlooked.

Disclosure

S. Katsuragawa: None. Y. Tsurutani: Research Support; Self; Astellas Pharma Inc. T. Takiguchi: None. J. Saito: None. T. Nishikawa: None.