bluuebunny/crossref_metadata_2025_split huggingface dataset:
DAG Accumulation due to Type 1 DGK Inhibition Has Contradictory Dual Effect on Ca2+ Signaling in Pancreatic ß Cells
Authors: SAWATANI TOSHIAKI , KANEKO YUKIKO K. , ISHIKAWA TOMOHISA 
Published: June 2018

Pathophysiologically, excessive accumulation of diacylglycerol (DAG), a lipid signal messenger, in pancreatic β-cells has been shown to lead to the insufficiency of insulin secretion. Thus, the regulation of intracellular DAG levels is expected to be an important factor in maintaining β-cell function. The intracellular DAG levels are strictly controlled by DAG kinases (DGKs). We have previously shown that DGKα and γ, type I DGK isoforms, are highly expressed in mouse β-cells, and that DAG accumulation resulting from dysfunction of these DGKs reduces insulin secretion. In the present study, we investigated the effect of type I DGK dysfunction on the regulation of intracellular Ca2+ concentration ([Ca2+]i), which is correlated with insulin secretion, in the β-cell line MIN6B. We also analyzed changes in expression levels of DGKα and γ in β-cells of type 2 diabetes model NSY mice. The amplitude of glucose-induced [Ca2+]i oscillations was increased by 1 μM R59949, a type I DGK inhibitor, and by 10 μM DiC8, a DAG analog. These effects were abolished by Ro31-8220, a protein kinase C (PKC) inhibitor. In contrast, 10 μM R59949 and 100 μM DiC8 suppressed the glucose-induced [Ca2+]i elevation, which was insensitive to Ro31-8220, and furthermore reduced voltage-dependent Ca2+ channel (VDCC) currents, which were measured by patch-clamp recording, implying that DAG accumulation due to type I DGK dysfunction suppresses VDCC, thereby reducing [Ca2+]i in β-cells. Real-time qPCR showed that the expression level of DGKα and γ was lower in islets from NSY mice compared with control mice. Taken together, the results obtained here suggest that DAG accumulation due to type I DGK dysfunction has contradictory dual effect in β-cells depending on the degree of accumulation; mild accumulation PKC-dependently induces a stimulatory effect on insulin secretion, whereas excessive accumulation suppresses it independently of PKC. DGK is likely a key molecule for the progression of type 2 diabetes.

Disclosure
T. Sawatani: None. Y.K. Kaneko: None. T. Ishikawa: None.
Nonalcoholic Fatty Liver Disease (NAFLD) Outcome Post–Bariatric Surgery in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) Consortium
Authors: BACHA FIDA , GUPTA RESMI , JENKINS TODD M. , BRANDT MARY , INGE THOMAS H. , KLEINER DAVID , XANTHAKOS STAVRA , CONSORTIUM TEEN-LABS 
Published: June 2018

Teen-LABS is a multicenter, prospective observational study of adolescents undergoing bariatric surgery. Predictors of resolution of NAFLD post-surgery are unclear. We evaluated changes in serum ALT levels, an acceptable surrogate when liver biopsy is not feasible, in 219 Teen-LABS subjects 3 years post gastric bypass or vertical sleeve gastrectomy. Three years post-surgery, median BMI declined to 38.4 from 52.6 kg/m2 at baseline (p&lt;0.01). Median ALT (IU/L) decreased between baseline (36.5 ± 2.6 [95% CI: 31.4, 41.7]) and 6 months after surgery (28.9 ± 2.5 [95% CI: 24.4, 33.9]), and remained stable at 1, 2 and 3 years, all p&lt;0.01 vs. baseline. 58% had abnormal ALT at baseline, which decreased to 10% at 3 years. After adjustment by logistic regression, 6 month improvement in BMI, fasting glucose, HOMA-IR, triglycerides, TG/HDL, and HDL were independently associated with reduced ALT. Improvement in metabolic indices remained significantly associated with decline in ALT, after adjusting for BMI (Table).
In conclusion, while weight loss was associated with decreased ALT by 6 months post-surgery, improved fasting glycemia, insulin resistance and dyslipidemia indices were also independently associated with ALT decline.
Association between change in predictor variables and decline in ALT from baseline to 6 months.Change in predictor variables over 6 monthsEstimate (SE) adjusted for age, race, sexp-valueEstimate (SE) adjusted for age, race, sex, change in BMIp-valueDecline in BMI0.64 (0.13)&lt;0.01Decline in fasting glucose0.40 (0.07)&lt;0.010.28 (0.08)0.01Decline in HbA1C4.59 (2.28)0.041.57 (2.32)0.50Decline in HOMA-IR1.11 (0.22)&lt;0.010.82 (0.27)&lt;0.01Decline in Triglycerides0.17 (0.02)&lt;0.010.15 (0.02)&lt;0.01Increase in HDL-0.75 (0.15)&lt;0.01-0.52 (0.16)&lt;0.01Decline in TG/HDL ratio5.11 (0.56)&lt;0.014.85 (0.66)&lt;0.01

Disclosure
F. Bacha: Research Support; Self; AstraZeneca, JAEB Center For Health Research, National Institutes of Health, Pediatric Diabetes Consortium. R. Gupta: None. T.M. Jenkins: None. M. Brandt: None. T.H. Inge: Consultant; Self; Standard Bariatrics, Independent Medical Expert Consulting Services, UpToDate. D. Kleiner: None. S. Xanthakos: None.
DNA Methylation at Birth Is Associated with Adiposity and Infant Growth during the First Six Months of Life in the Healthy Start Study
Authors: BORENGASSER SARAH J. , STARLING ANNE P. , ZHANG WEIMING , FRIEDMAN JACOB , HAMMAN RICHARD F. , YANG IVANA , KECHRIS KATERINA , DABELEA DANA 
Published: June 2018

In utero exposures have been shown to impart increased risk for obesity in the offspring and are associated with epigenetic changes. DNA methylation was measured in 351 umbilical cord blood (UCB) samples within the Healthy Start Study, a well-characterized prebirth cohort that is following mother-infant pairs from pregnancy-early childhood. The primary objective was to test if DNA methylation at birth was associated with fat mass (FM) gains and infant growth (weight-for-age Z-score, WAZ) during the first 6 months (mos) of life to identify potential biomarkers of future obesity risk. DNA methylation was assessed in UCB via the Illumina 450K array. Adiposity was measured at birth and 4-6 mos of age via PeaPod. Infant weight was obtained from medical records. After adjusting for cellular heterogeneity, sex, and race we found 742 methylation sites (CpGs) through a univariable analysis that were associated with the rate of FM (g/day) in the first 6 mos of life (p &lt; 0.001). Then, partial least squares (PLS) fitting using a multivariable analysis selected a subset of 235 predictor CpGs in this list for KEGG pathway analysis. Similarly, 1314 CpGs were associated with WAZ (p &lt; 0.001); PLS selected a subset of 198 CpGs for KEGG analysis. Using a FDR &lt; 0.001 for KEGG analysis, 3 pathways were associated with FM gain (Metabolic pathways, Glyoxylate and dicarboxylate metabolism, Neurotrophin signaling) and 8 pathways for WAZ gain (Gastric acid secretion, Oocyte meiosis, Metabolic pathways, Endocytosis, Tight Junction, Oxytocin signaling, GnRH signaling, and Inflammatory mediator regulation of TRP channels). The KEGG: Metabolic pathways was identified for both FM and WAZ gain, and 3 gene targets enriched in this pathway, ATP5C1, CYP26A1, and IDH3A are known to be involved in fat metabolism. Our studies have identified potential candidate methylation biomarkers, present at birth, which can be used for early risk detection in order to mitigate development of childhood obesity.

Disclosure
S.J. Borengasser: None. A.P. Starling: None. W. Zhang: None. J. Friedman: Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. R.F. Hamman: None. I. Yang: None. K. Kechris: None. D. Dabelea: None.
BioChaperone Technology Enables the Development of Pramlintide-Prandial Insulin Combinations
Authors: MEIFFREN GRÉGORY , GEISSLER ALEXANDRE , MEYER YVES , RANSON AYMERIC , FORTIER CHARLES , SOULA OLIVIER , SOULA RÉMI , ALLUIS BERTRAND , CHARVET RICHARD 
Published: June 2018

Pramlintide (Symlin®) is currently used on top of mealtime insulin therapy by T1D or T2D patients to achieve a better control of post-prandial glucose excursion. Indeed, pramlintide affects the rate of postprandial glucose appearance by slowing down gastric emptying, reducing postprandial glucagon secretion and modulating satiety, which affects caloric intake. Nevertheless, the use of pramlintide is currently limited as it cannot be combined with prandial insulin due to formulation pH incompatibility and results in a high burden of the number of injections. BioChaperone (BC) technology stabilizes pramlintide in aqueous solution at neutral pH and enables a pramlintide - prandial insulin co-formulation. BC pramlintide-human insulin (BC Pram Ins) formulation is physically and chemically stable for at least 6 weeks at 30°C and 9 weeks at 25°C. Physical stability was evidenced by visual inspection and MFI analysis. Chemical stability (recovery measured by RP-HPLC and high molecular weight species measured by SE-HPLC) was similar to that of commercial Humulin® and Symlin®. Under simulated in-use pump conditions at 37°C, BC Pram Ins formulation shows excellent physical and chemical stability for at least 1 week, with insulin and pramlintide recoveries higher than 95% and a formulation essentially free of particles. The pharmacokinetics of pramlintide was evaluated following single subcutaneous administration (0.1875 U/kg insulin, 1.125 µg/kg pramlintide) of BC Pram Ins formulation and pramlintide co-injected with human insulin (separate injections) to fasted healthy pigs. BC Pram Ins shows a slower absorption of pramlintide (LSM ratio [95% CI] ΔAUCPram0-30min: 0.45 [0.20; 1.05]) while the late exposure to pramlintide is higher (ΔAUCPram60-180min: 2.65 [1.44; 4.90]) compared to the separate injections.
In conclusion, the in-vitro and preclinical PD properties of BC Pram Ins support its clinical development to afford a better mealtime treatment for T1D and T2D patients.

Disclosure
G. Meiffren: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. A. Geissler: None. Y. Meyer: None. A. Ranson: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. C. Fortier: None. O. Soula: Board Member; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. Employee; Spouse/Partner; ADOCIA. R. Soula: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. Board Member; Self; Cellnovo. B. Alluis: None. R. Charvet: None.
Improvements in A1C and Time-in-Range in DIY Closed-Loop (OpenAPS) Users
Authors: LEWIS DANA M. , SWAIN RICHARD S. , DONNER THOMAS W. 
Published: June 2018

Overview: We performed a retrospective study that analyzed outcomes from a subset (n=20) of the Do It Yourself (DIY) closed loop community. This already well-controlled, highly motivated T1D population realized further improvements in A1c and glucose time in range (TIR), and a reduction in time spent high and low during all timeframes after beginning a DIY hybrid closed loop “artificial pancreas” system.
Objective: To compare mean BG, TIR (70-180 mg/dl), and time above and below clinically meaningful thresholds before and after OpenAPS initiation.
Methods: We performed a retrospective cross-over analysis of continuous BG readings recorded during 2-week segments 4-6 weeks before and after initiation of OpenAPS (Johns Hopkins IRB00121066). Mean BG and TIR were analyzed overall, as well as by day (7am-11pm) and night (11pm-7am), and statistical significance was assessed using paired t-tests.
Results: Mean BG and TIR improved in every time category. Overall, mean BG (mg/dl) improved (135.7 to 128.3); as did mean estimated HbA1c (6.4 to 6.1%). TIR increased from 75.8 to 82.2% overall. Overnight, BG time &lt;70 was reduced from 6.4 to 4.2%, and time &lt;50 was reduced from 2.3 to 1.0%. Overall, BG excursions &gt;300 were reduced from 1.7 to 0.35%.
Conclusion: Even with tight initial control, persons with T1D saw meaningful improvements in estimated A1c, TIR, and a reduction in time spent high and low, during the day and at night, after initiating OpenAPS.

Disclosure
D.M. Lewis: Consultant; Self; Tandem Diabetes Care, Inc.. R.S. Swain: None. T.W. Donner: Research Support; Self; Novo Nordisk Inc., Viacyte, Inc..
The Role of GLP-1 Receptor Expressed in Pancreatic a Cells in Regulating Glucagon Secretion
Authors: ZHANG YANQING , PARAJULI KESHAB R. , SMITH GENEVIEVE E. , GUPTA RAJESH , XU WEIWEI , NGUYEN LAUREN U. , ZAKARIA ANADIL F. , MAUVAIS-JARVIS FRANCK , FONSECA VIVIAN , SLOOP KYLE W. , WU HONGJU 
Published: June 2018

Glucagon-like peptide-1 (GLP-1) inhibits glucagon secretion from a cells and stimulates insulin secretion from ß cells in a blood-glucose dependent manner. Whereas the effects of GLP-1 on ß cells are mediated by GLP-1 receptor (GLP-1R) has been described in detail. The action of GLP-1 on a-cells, however, is not clear. To determine whether the inhibition is due to a direct effect that occurs through GLP-1R of a-cells, or indirect effect on a-cells through insulin stimulation from ß-cells, we generated a-cell specific GLP-1R knockout (aGLP-1R KO) mice after GLP-1R expression was verified by glucagon-producing a-cells at protein and mRNA level in both mouse and human pancreas. Compared to control mice, the aGLP-1R KO female mice had impaired glucose tolerance following intraperitoneal glucose administration, and had more impaired glucose tolerance after 1m high fat diet-fed, but their insulin secretion and insulin sensitivity were maintained. Interestingly, non-fasting glucagon level of aGLP-1R KO mice was significantly higher than that of the control mice, whereas insulin and GLP-1 levels were similar between the two groups of mice. More importantly, we found glucagon secretion was stimulated by glucose 15 minutes following glucose administration in the aGLP-1R KO mice, but not in the control mice. Furthermore, we isolated islets from aGLP-1R KO mice and directly examined the effects of aGLP-1R deletion on glucagon secretion. Glucose-stimulated insulin secretion assay showed the aGLP-1R KO islets had no significant differences from the control islets. However, arginine significantly stimulated glucagon secretion in the two group islets and the stimulation was significantly enhanced in aGLP-1R KO islets. Taken together, these data showed that aGLP-1R deletion disturbed glucose-dependent glucagon secretion, whereas insulin secretion was not affected, demonstrating aGLP-1R plays a direct role in regulating glucagon secretion.

Disclosure
Y. Zhang: None. K.R. Parajuli: None. G.E. Smith: None. R. Gupta: None. W. Xu: None. L.U. Nguyen: None. A.F. Zakaria: None. F. Mauvais-Jarvis: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. V. Fonseca: Consultant; Self; Abbott. Board Member; Self; American Association of Clinical Endocrinologists. Consultant; Self; Eli Lilly and Company. Stock/Shareholder; Self; Amgen Inc.. Consultant; Self; Asahi Kasei Corporation, AstraZeneca, Novo Nordisk Inc., ADOCIA, Intarcia Therapeutics, Inc., Sanofi-Aventis. K.W. Sloop: Employee; Self; Eli Lilly and Company. H. Wu: None.
Brain Insulin Sensitivity Predicts Adiposity—Nine-Year Results of the Tulip Study
Authors: SCHMID VERA , TSCHRITTER OTTO , MACHANN JÜRGEN , WAGNER ROBERT , STEFAN NORBERT , PREISSL HUBERT , HAERING HANS-ULRICH , FRITSCHE ANDREAS , HENI MARTIN 
Published: June 2018

Lifestyle intervention reduces body weight and prevents type 2 diabetes. One crucial modulator of food intake and whole body energy metabolism is insulin action in the brain. We now test whether brain insulin sensitivity is a long-term predictor of weight and body fat distribution during and after a lifestyle intervention program. Before, after 9 months, at the end of lifestyle intervention at 24 months, as well as after 8.7 ±1.6 years follow-up, participants of the Tuebingen Lifestyle Intervention Program underwent a 75g OGTT, and whole body MRI. Brain insulin sensitivity was measured at baseline by changes in neuronal signals (theta frequency band) with magnetoencephalography during a hyperinsulinemic-euglycemic clamp in a subgroup of 28 participants of whom long-term follow-up was available in 15 persons. Higher brain insulin sensitivity before lifestyle intervention was associated with a more pronounced reduction in total and visceral fat during the lifestyle intervention (all p&lt;0.01). High brain insulin sensitivity was also associated with less regain of fat mass during the long-term follow-up. In contrast to visceral fat, changes in subcutaneous adipose tissue were independent of the brain insulin responsiveness. Our results extend previous findings on the role of brain insulin for the success of lifestyle intervention to a long-term perspective. Insulin action in the human brain appears to be not only important for weight loss, but seems to determine regain of body weight and especially total and visceral fat mass thereafter. Experimental findings demonstrated that insulin administration to the brain modulates peripheral energy fluxes in humans. In line, our results indicate fat depots specific effects of brain insulin with particular benefits in the visceral compartment. These findings support the role of brain insulin in the regulation of body fat distribution and body weight.

Disclosure
V. Schmid: None. O. Tschritter: None. J. Machann: None. R. Wagner: None. N. Stefan: Consultant; Self; Merck Sharp & Dohme Corp.. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca, OmniaMed Ltd.. H. Preissl: None. H. Haering: None. A. Fritsche: Advisory Panel; Self; Sanofi-Aventis Deutschland GmbH, Novo Nordisk A/S, Eli Lilly and Company, Boehringer Ingelheim GmbH. M. Heni: Research Support; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Merck Sharp & Dohme Corp., Novo Nordisk Inc..
Deciphering a GABAergic Neural Circuit in Critical Control of Leptin-Mediated Feeding, Body Weight, and Glucose Homeostasis
Authors: WU QI , HAN YONG 
Published: June 2018

Leptin plays a major role in control of glucose metabolism and feeding behavior by acting upon the LepR neurons that widely distribute through the brain. Although several LepR-expressing neuronal groups were identified in distinct nuclei, a dominant neural circuit that mediates the physiological roles of leptin remains elusive, largely due to the inadequate phenotypes as a result of developmental and neural compensations. In this report, a novel, non-sense suppression-based, inducible genetic system is implemented to rapidly delete a specific group of LepR signaling from adult mice within 4 days. Acute deletion of LepR from AgRP neurons show a drastic increase of food intake, massive weight gain, and severe glucose intolerance, developing in a rate with tight manifestation of the global leptin deficiency. Furthermore, a neural circuit comprising of LepR-expressing AgRP neurons and downstream GABAergic neurons in the DMH is mapped by genetic and functional tracing approaches. Optogenetic manipulation of AgRPLepR-DMHGABA neural circuit or the post-synaptic DMHMC4R neurons strongly altered food intake and glucose tolerance in a bidirectional controlled manner. Among all GABAA subunits examined, Gabra3 (encoding GABAA α3 subunits) displayed the most robust changes in response to genetic inactivation of LepRAgRP signaling. Using CRISPR/Cas9 gene editing technique, loss of Gabra3 in DMHMC4R neurons reduced food intake and enhanced glucose intolerance. Surprisingly, chronic infusion of bicuculline into the DMH fully reversed the obesity and glucose intolerance as a result of acute deletion of LepRAgRP signaling. Furthermore, genetic ablation of GABADMH neurons blunted leptin-mediated control of glucose metabolism and food intake.
In conclusion, we unveil a novel AgRPLepR-DMHGABA neural circuit and associated GABAA receptor signaling system in fundamental control of leptin-associated obesity and diabetes.

Disclosure
Q. Wu: None. Y. Han: None.
Microglia Activation Regulates Systemic Glucose Tolerance
Authors: DOUGLASS JOHN , VALDEARCOS MARTIN , KOLIWAD SUNEIL K. , THALER JOSH 
Published: June 2018

Obesity and high fat diet (HFD) consumption in rodents is associated with hypothalamic inflammation and activation of microglia, the resident CNS immune cells. Recently, we provided evidence that microglia are critical intermediary cells that transmit the inflammatory signal induced by HFD exposure. Mice with a conditional knockout of IKKb specifically in microglia (CX3CR1CreERT2 x IKKbeta fl/fl, MGKO) have reduced susceptibility to HFD-associated hyperphagia and DIO compared with IKKb fl/fl littermate controls (Ctl). Surprisingly, despite their reduced fat mass, HFD-fed MGKO mice have equal glucose intolerance to Ctls as well as no improvement in white adipose tissue inflammation or hepatic triglyceride content. Together these data suggest dissociation between microglial regulation of energy and glucose homeostasis. To address this possibility, we pair-fed MGKO mice to Ctl mice, resulting in matched body weights during HFD feeding. Pair-fed MGKO mice showed a greater degree of impairment in glucose tolerance and insulin sensitivity with preserved insulin secretion compared to controls. Similarly, chemical inactivation of microglia using centrally-administered minocycline worsens insulin sensitivity in HFD-fed rats. Finally, using several distinct genetic models, we show that microglial activation acutely improves glucose tolerance and insulin sensitivity. Together, these data reveal a novel aspect of CNS regulation of metabolism in which microglial inflammatory activation promotes HFD overconsumption and weight gain but offsets obesity-associated dysregulation of glucose homeostasis. These results indicate the need for pathway-specific targeting to develop glial-based therapeutics for obesity and diabetes.

Disclosure
J. Douglass: None. M. Valdearcos: None. S.K. Koliwad: None. J. Thaler: Research Support; Self; Novo Nordisk A/S.