bluuebunny/crossref_metadata_2025_split huggingface dataset:
264-OR: Treatment with Human Placental Lactogen (hPL-A) Improves Glucose Homeostasis One Year after Pancreatic Islets Transplantation in Mice Anterior Eye Chamber
Authors: DONADEL GIULIA , ARRIGA ROBERTO , MARCHETTI VALENTINA , PASTORE DONATELLA , COPPOLA ANDREA , PACIFICI FRANCESCA , SCIOLI MARIA GIOVANNA , ORLANDI AUGUSTO , DELLA-MORTE DAVID 
Published: June 2019

Type 1 diabetes (T1D) is a chronic disease characterized by destruction of insulin producing beta cells in the pancreas. In addition to conventional insulin treatment, islets transplantation represents an alternative and promising therapeutic approach to treat patients with T1D. Increasing evidences suggest that human placental lactogen (hPL), a polypeptide placental hormone, is able to promote islets survival and proliferation in vitro, however it is unknown its implication in vivo models. Therefore, in the present study, we used hPL isoform A (hPL-A) to evaluate the role of this hormone in murine engrafted islets. T1D was induced in C57BL6/J male mice by a single intraperitoneal high dose (180 mg/kg) of streptozotocin (STZ). Collagenase p and a Histopaque 1110 gradient solution were used to isolate pancreatic islets. The anterior chamber of the eye was used to inject isolated islets. The engraftment was evaluated by confocal microscopy and immunohistochemical staining on section of the right and left eye. Glucose tolerance test (GTT) was used to assess glucose tolerance in mice. First, we evaluated the engraftment of freshly isolated pancreatic islets. Iris dissections showed a positive staining for insulin and glucagon. Second, since 2 months after transplantation, STZ-treated mice injected with islets stimulated with hPL-A, showed an improvement in fed glycaemia compared to STZ-treated mice transplanted with islets alone, and non-transplanted STZ-treated mice, for a follow-up of 1 year. Furthermore, mice treated with hPL-A, showed GTT with a similar pattern to untreated control mice; islets vascularization and angiogenesis was showed using CD31. Taken together, present results provide evidence that hPL-A could have a long-term effect on islet graft function and survival through enhancing glucose homeostasis.

Disclosure
G. Donadel: None. R. Arriga: None. V. Marchetti: Employee; Self; STEMCELL Technologies. D. Pastore: None. A. Coppola: None. F. Pacifici: None. M. Scioli: None. A. Orlandi: None. D. Della-Morte: None.

Funding
Italian Ministry of Instruction University and Research; Fondazione Roma
266-OR: Plasma Membrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance
Authors: LYU KUN , ZHANG YE , ZHANG DONGYAN , KAHN MARIO , NOZAKI YUICHI , BHANOT SANJAY , BOGAN JONATHAN , CLINE GARY , SAMUEL VARMAN , SHULMAN GERALD I. 
Published: June 2019

The identity and subcellular localization of the bioactive lipid species that causes hepatic insulin resistance remain controversial. Though chronic diacylglycerol acyltransferase 2 (DGAT2) knockdown improves hepatic steatosis and insulin action, we hypothesized that acute DGAT2 knockdown would transiently increase hepatic diacylglycerol (DAG) content to specifically assess the role of hepatic DAG on hepatic insulin action. Regular chow-fed rats were treated with a single dose of DGAT2 antisense oligonucleotide and studied 2 days later. The content and subcellular localization of sn-1,2, sn-2,3 and sn-1,3 DAGs were assessed by LC-MS/MS in the endoplasmic reticulum (ER), mitochondrial (MIT), plasma membrane (PM), lipid droplet (LD) and cytosol (CYT) fractions. Acute knockdown of hepatic DGAT2 induced hepatic insulin resistance with impaired suppression of hepatic glucose production during a hyperinsulinemic-euglycemic clamp. Insulin receptor kinase (IRK) activation was impaired, as reflected by reduced insulin-stimulated IRK Y1162 phosphorylation. This was associated with increased PKCε activation, as reflected by increased translocation from CYT to membrane, and increased sn-1,2 DAG content specifically in the PM. In contrast, there were no changes in hepatic ceramide content or sn-2,3 and sn-1,3 DAGs in the five subcellular fractions tested (ER, MIT, PM, LD, CYT). We next infused [13C16] palmitate in 24-hr-fasted rats to track hepatic DAG synthesis in vivo and observed that sn-1,2 DAGs were the major (73%) product of re-esterification from exogenous fatty acids, compared to sn-2,3 (25%) and sn-1,3 (2%) DAGs. We also found that sn-1,2 and sn-2,3 DAGs were primarily synthesized in the ER before translocating to PM, whereas sn-1,3 DAGs were exclusively produced in the LD by lipolysis.
Conclusion: These data demonstrate that sn-1,2 DAGs in the PM, derived from re-esterification of exogenous fatty acids, are sufficient to induce hepatic insulin resistance at the level of IRK.

Disclosure
K. Lyu: None. Y. Zhang: None. D. Zhang: None. M. Kahn: None. Y. Nozaki: None. S. Bhanot: None. J. Bogan: None. G. Cline: None. V. Samuel: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc. Advisory Panel; Spouse/Partner; Merck & Co., Inc. Board Member; Self; Novo Nordisk A/S. Consultant; Self; Aegerion Pharmaceuticals, IMetabolic BioPharma Corporation, Longitude Capital, Nimbus Discovery, Inc., Staten Biotechnology B.V.

Funding
National Institutes of Health (R01DK116774)
268-LB: Investigating the Role of MPO and ANGPTL6 in Obesity and Diabetes and Their Potential Role in Wound Healing
Authors: QADDOUMI MOHAMMAD G. , ABU-FARHA MOHAMED , THOMAS CHERIAN PREETHI , AL KHAIRI IRINA , MOHAMED CHANNANATH ARSHAD , ALANBAEI MUATH , ABUBAKER JEHAD , AL-MULLA FAHD 
Published: June 2019

Purpose: Myeloperoxidase (MPO) is a major neutrophil-derived protein known to play an important role in inflammation, oxidative stress, and atherosclerosis. Like other angiopoietin-like protein (ANGPTL), ANGPTL6 is reported to regulate metabolic processes but is thought to counteract obesity through increased energy expenditure. This study evaluated the plasma level of both MPO and ANGPTL6 in obese and diabetic people to investigate their clinical association.
Methods: A total of 204 people were enrolled in this study (109 nondiabetic and 95 T2D). ANGPTL6, MPO, and other biomarkers plasma levels were measured by ELISA.
Results: MPO plasma level was unchanged between diabetics and nondiabetics, whereas ANGPTL 6 plasma level increased in diabetics (33.73±1.31 pg/mL) compared to nondiabetics (28.74±1.01 pg/mL) (P &lt;0.003). However, MPO plasma level increased in obese diabetics (75.28±3.19 ng/mL) compared to non-obese diabetics (65.71±2.54 ng/mL) (P &lt;0.02). Similarly, ANGPTL6 plasma level was increased in obese diabetics (35.74±1.68 pg/mL) compared to non-obese diabetics (29.05 ± 1.61 pg/mL) (P &lt;0.01). Obese nondiabetics had a higher level of MPO compared to non-obese nondiabetics although it did not reach statistical significance (P = 0.05). In contrast, no changes in the plasma levels of ANGPTL6 were seen in nondiabetics irrespective of weight. Both MPO and ANGPTL plasma levels were higher in obese than non-obese people (P &lt; 0.05). MPO was positively associated with ANGPTL6, TG, BMI, TNF alpha, HsCRP, IL6, and PAI1.
Conclusion: Both MPO and ANGPTL6 seem to regulate obesity, although MPO might do it independently of diabetes status and they might be also involved in wound healing as previously reported. The positive association of MPO with several biomarkers of inflammation and atherosclerosis may underlie its pathogenic mechanism in obesity and diabetes related wound healing and other diabetes related pathways.

Disclosure
M.G. Qaddoumi: None. M. Abu-farha: None. P.T. Cherian: None. I. Al khairi: None. A.M. Channanath: None. M. Alanbaei: None. J. Abubaker: None. F. Al-Mulla: None.
270-OR: Adipocyte Integrin-Linked Kinase Is Necessary for the Development of Diet-Induced Adipose Insulin Resistance
Authors: BUGLER-LAMB AIMEE , HENNAYAKE CHANDANI , HASIB ANNIE , ASHFORD MICHAEL L. , KANG LI 
Published: June 2019

The remodeling of the extracellular matrix (ECM) in tissues including adipose tissue, and the expression of collagen binding integrin α2β1 have been associated with the development of insulin resistance. Integrin-linked Kinase (ILK), an adaptor protein and a key component of the IPP (ILK-Parvin-PINCH) complex mediates integrins linking the ECM with intracellular signalling. This study determines the role of ILK in adipose function and insulin resistance in chow and high fat (HF)-fed mice. HF feeding increased adipose ILK expression in mice (2.7 ±0.62 vs. 1±0.23; p=0.01). Adipocyte-specific deletion of ILK resulted in a decrease in fat mass (21.6±1.6% vs. 27.3±1.4%; p=0.009) and epididymal tissue weight (eWAT) (1.04±0.07g vs. 1.62±0.11g; p&lt;0.001) in HF-fed mice, but not in chow-fed mice. During the hyperinsulinemic-euglycemic clamp, HF-fed ILK deficient mice showed increased glucose uptake (66.22±p=0.028) in the brown adipose tissue (BAT) compared with the wild type littermate controls. Increased glucose uptake in BAT is associated with increased phosphorylation of AKT (1.96±0.16 vs. 1±0.28 fold change; p=0.01), and decreased phosphorylation of p38 and JNK (0.23 ± 0.17 vs. 1±0.48; p=0.024 and 0.41 ±0.12 vs. 1±0.17; p=0.025 respectively). The inhibition of lipolysis by insulin was also improved in HF-fed ILK deficient mice determined by plasma NEFA level during the clamp. This could be attributed to decreased cell size (0.85±0.042 vs. 1±0.06; p=0.0001), decreased collagen deposition (22.8±0.98 vs. 30.28± 2.05; p=0.01) and a trend increase in vascularization (3.47±1.26 vs. 1±0.23; p=0.07) in the eWAT. These data suggest that adipocyte ILK plays an important role in regulating adipocyte morphology, signaling and glucose and lipid homeostasis, therefore representing a potential target for obesity, insulin resistance and diabetes.

Disclosure
A. Bugler-Lamb: None. C. Hennayake: None. A. Hasib: None. M.L. Ashford: None. L. Kang: None.

Funding
Diabetes UK; Diabetes Research & Wellness Foundation
282-LB: Dysregulated FGF21 Links Hepatic Insulin Resistance to Dysfunctional BAT
Authors: STOEHR OLIVER , TAO RONGYA , COPPS KYLE D. , WHITE MORRIS F. 
Published: June 2019

LDKO (hepatic Irs1/Irs2 double knockout) mice show a severe diabetic phenotype owing to the impaired communication of the insulin resistant liver throughout the body by the dysregulated production and secretion of hepatokines. Excess Fst (follistatin) secreted by the liver of LDKO-mice inhibits insulin action in WAT (white adipose tissue) and promotes hepatic glucose production; however, Fst does not dysregulate BAT (brown adipose tissue). Regardless, BAT in LDKO-mice lacked typical BAT characteristics on the anatomical and molecular level. Glucose uptake was severely impaired, which might contribute to the diabetic phenotype of LDKO-mice. Succinate stimulates BAT and protects control mice against obesity and hyperglycemia during HFD feeding; however, succinate has no beneficial effect in LDKO-mice revealing non-responsive/dysfunctional BAT in these mice. Transplantation of healthy BAT from wild type mice into LDKO-mice was unbeneficial, whereas transplantation of healthy BAT into control mice improved their whole-body glucose metabolism and glucose tolerance. Next, we investigated whether dysregulated hepatokines might impair BAT function in LDKO-mice. Among the dysregulated hepatokines in LDKO-mice FGF-21 (fibroblast growth factor 21) was reduced significantly. Re-expression of FGF-21 in the liver via adenoviral infection increased FGF-21 serum levels into the normal range and restored normal glucose uptake into BAT and improved glucose tolerance during chow or HFD feeding. These results suggest that reduced FGF-21 promotes BAT dysfunction during hepatic insulin resistance, whereas re-expression of FGF-21 restored glucose metabolism regardless of the persistent hepatic insulin resistance and uncontrolled gluconeogenesis owing to elevated hepatic Fst.

Disclosure
O. Stoehr: None. R. Tao: None. K.D. Copps: None. M.F. White: Advisory Panel; Self; Housey Pharmaceutical Research Laboratories.
282-OR: Impact of a Hybrid Closed-Loop Insulin Delivery System on Hypoglycemia Awareness in Individuals with Type 1 Diabetes
Authors: BURCKHARDT MARIE-ANNE , DART JULIE , SMITH GRANT J. , ABRAHAM MARY B. , PARAMALINGAM NIRUBASINI , O'DEA JOANNE M. , BOCK MARTIN DE , DAVIS ELIZABETH A. , JONES TIMOTHY 
Published: June 2019

Background: Individuals with impaired awareness of hypoglycemia (IAH) are at risk of severe hypoglycemia. Although it is known that elimination of hypoglycemia can restore hypoglycemia awareness in this high-risk group, this has been challenging in real life. Technological advancements like closed loop system provide an opportunity to minimize hypoglycemia. Hence, the aim of this study was to evaluate whether a hybrid closed loop insulin delivery system can improve hypoglycemia awareness in individuals with IAH.
Methods: Participants with type 1 diabetes and IAH (Gold Score ≥4) were randomized to either a hybrid closed loop system (Medtronic 670G) (intervention) or standard insulin pump therapy (control) for 8 weeks. Gold scores and hyperinsulinemic hypoglycemic clamp studies were undertaken at baseline and at the end of the study with evaluation of the hormonal and symptomatic responses to hypoglycemia.
Results: A total of 17 participants completed the study (mean (SD) age 35.8 years (11.2), diabetes duration 24.2 years (11.3), HbA1c 7.8% (1.2)). 8 participants were randomized to control and 9 participants to intervention. The baseline (Median, IQR) Gold score was 6.0 (5.0; 6.0) in the overall cohort and did not differ between groups. At the study end, Gold score improved in the intervention group: control vs. intervention 6.0 (4.5; 6.0) vs. 3.5 (3.0; 4.5); p = 0.027. Symptom scores (adrenergic and neuroglycopenic) during the clamp were not different between the control and intervention groups.
Conclusions: The use of a hybrid closed loop system over 8 weeks improved self-reported hypoglycemia awareness, however there was no evidence for improvement in the symptomatic responses to experimentally induced hypoglycemia.

Disclosure
M. Burckhardt: None. J. Dart: None. G.J. Smith: None. M.B. Abraham: None. N. Paramalingam: None. J.M. O'Dea: None. M. de Bock: None. E.A. Davis: None. T. Jones: Research Support; Self; Dexcom, Inc., Medtronic MiniMed, Inc. Speaker's Bureau; Self; Eli Lilly and Company, Roche Diabetes Care.
284-OR: How Do Patients and Caregivers Prioritize Outcomes for Type 1 Diabetes (T1D) Treatment?
Authors: MARINAC MARJANA , HUTTON CAMPBELL T. , MANSFIELD CAROL , SUTPHIN JESSIE , GALLAHER KATHLEEN , SULLIVAN SEAN 
Published: June 2019

Background: Currently, HbA1c is the primary measure of treatment effectiveness for type 1 diabetes (T1D). We investigated patient priorities for measures of T1D control in addition to HbA1c.
Method: We developed discrete-choice experiment surveys for adult patients and caregivers of children with T1D that presented choices between hypothetical treatments described by 6 attributes with varying levels: HbA1c, time in range, weekly number and severity of hypoglycemia and hyperglycemia events, additional disease management time, and additional treatment cost. The clinical outcomes were defined based on a 2017 consensus report standardizing the definition of outcomes beyond HbA1c. Respondents answered nine treatment choice questions, and the data were analyzed using random-parameters logit.
Results: Recruited through an online market research panel, 300 adult patients and 400 caregivers completed the survey. Patients and caregivers placed the most importance on reducing low and high events. Additional time in range was as important as a reduction of more than ½ point in HbA1c, but both were less important than avoiding weekly lows and highs. Patients who did not use an insulin pump or CGM placed relatively more weight on reducing lows and highs and on improvements in HbA1c and time in range compared to patients who use technology. For patients, avoiding 1 to 5 lows (54-69 mg/dL) per week was 5 times more important than achieving target HbA1c from ½ point above. Avoiding 1 to 5 highs (181-250 mg/dL) per week was 7 times more important than achieving target HbA1c from ½ point above. Caregivers of children &lt; 12 years placed relatively more weight on avoiding lows and highs than those with older children.
Conclusion: Overall, patients and caregivers prioritized control of hypoglycemia and hyperglycemia events, including mild to moderate events. The research has implications for outcomes used to measure the benefits of treatment in research, development, and reimbursement of therapies for T1D.

Disclosure
M. Marinac: None. C.T. Hutton: None. C. Mansfield: Other Relationship; Self; Multiple companies. J. Sutphin: Other Relationship; Self; Multiple Companies. K. Gallaher: Other Relationship; Self; Multiple companies. S. Sullivan: None.

Funding
The Leona M. and Harry B. Helmsley Charitable Trust; JDRF International
288-LB: Effects of the Hepatic Mitochondrial Calcium Uniporter on Hepatic Gluconeogenesis and Mitochondrial Metabolism in Awake Mice
Authors: LEE JI EUN , GOEDEKE LEIGH , ZHANG YE , PERRY RACHEL J. , GOODMAN RUSSELL , MOOTHA VAMSI , SHULMAN GERALD I. 
Published: June 2019

Increased hepatic glucose production, due to increased rates of gluconeogenesis, is a contributor to both fasting and postprandial hyperglycemia in patients with T2D. Recent evidence implicates a role for hepatic calcium signaling in mediating glucagon's effect to stimulate glucose production and mitochondrial oxidation; however, the cellular and molecular mechanisms by which glucagon promotes these alterations remain poorly understood. We hypothesize that an acute physiological increase in plasma glucagon concentrations will increase cytosolic and mitochondrial calcium concentrations, promoting increases in rates of hepatic mitochondrial oxidation and gluconeogenesis in a transcription-independent manner. To test this hypothesis, we used mice with a liver-specific loss of the mitochondrial calcium uniporter (MCU), which is the main transporter that allows rapid transport of calcium into the mitochondrial matrix. We found that glucagon increased oxygen consumption rate by 80% (p&lt;0.0001) in WT hepatocytes, while this effect was abrogated in MCU KO hepatocytes. We also measured hepatic mitochondrial oxidation (VCS) in vivo using Positional Isotopomer NMR Tracer Analysis (PINTA) and found a 74% decrease in VCS (p=0.05) in MCU KO mice compared to WT mice. This suggests that tightly regulated mitochondrial calcium signaling is necessary for regulating hepatic mitochondrial oxidation. Next, we measured intrahepatic lipolysis and hepatic gluconeogenesis in vitro and in vivo. We found that glucagon increased lipolysis (p=0.05) and glucose production (p=0.024) by ∼1.5 fold in MCU KO compared to WT hepatocytes. Furthermore, in vivo PINTA results showed that glucagon increased pyruvate carboxylase flux (VPC) by 68% (p=0.08) in MCU KO mice. Taken together, these results suggest that mitochondrial calcium signaling through MCU is necessary to regulate the effect of glucagon to modulate hepatic gluconeogenesis and mitochondrial oxidation.

Disclosure
J. Lee: None. L. Goedeke: None. Y. Zhang: None. R.J. Perry: Research Support; Self; AstraZeneca. R. Goodman: None. V. Mootha: Advisory Panel; Self; Janssen Pharmaceuticals, Inc. Consultant; Self; 5AM Ventures. Other Relationship; Self; Raze Therapeutics. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc. Advisory Panel; Spouse/Partner; Merck & Co., Inc. Board Member; Self; Novo Nordisk A/S. Consultant; Self; Aegerion Pharmaceuticals, IMetabolic BioPharma Corporation, Longitude Capital, Nimbus Discovery, Inc., Staten Biotechnology B.V.

Funding
National Institutes of Health
289-LB: Hepatic Gamma-Amino Butyric Acid Release Drives Hyperinsulinemia and Insulin Resistance
Authors: GEISLER CAROLINE , GHIMIRE SUSMA , RENQUIST BENJAMIN J. 
Published: June 2019

The degree of hepatic lipid accumulation in obesity directly correlates with the severity of hyperinsulinemia and systemic insulin resistance. Here, we propose a mechanism that explains this associative link, whereby, hepatic steatosis dysregulates glucose and insulin homeostasis. Obesity-induced lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic vagal afferent nerve (HVAN) firing (22.9 ± 7.6%; P &lt; 0.05). The HVAN plays a key role in regulating whole-body glucose homeostasis. Accordingly, we propose that dysregulated hepatocyte-vagal communication underlies the metabolic dysfunction in obesity. Using an ex vivo explant liver slice model, we showed that diet induced obesity nearly triples hepatic GABA release/mg DNA in mice (P &lt; 0.05). We hypothesize that hepatic GABA release decreases HVAN activity to stimulate insulin release and decrease peripheral insulin sensitivity. To establish that hepatocyte depolarization encourages GABA export in obesity, we virally induced expression of Kir2.1, a hyperpolarizing channel, in hepatocytes. Kir2.1 expression decreased hepatic slice GABA release to half of that observed in control obese mice, while protecting against hyperinsulinemia and insulin resistance on a high fat diet. Hepatic GABA is synthesized by GABA-Transaminase (GABA-T). To determine the role of hepatic GABA production in diet induced metabolic dysfunction, we treated obese mice with the irreversible GABA-T inhibitors, ethanolamine-O-sulphate (EOS) or vigabatrin (8mg/day; IP). Within 5 days, GABA-T inhibition ameliorated the hyperinsulinemia and insulin resistance of obesity (P &lt; 0.05). These improvements in glucose homeostasis are dependent on an intact HVAN, as EOS did not affect serum insulin or insulin sensitivity in obese hepatic vagotomized mice. This work establishes that limiting hepatocyte GABA production or release can mute the glucoregulatory dysfunction common to obesity.

Disclosure
C. Geisler: None. S. Ghimire: None. B.J. Renquist: None.

Funding
Arizona Biomedical Research Commission (ADHS14-082986, ADHS18-201472 to B.J.R.); American Heart Association (15BGIA25090300 to B.J.R.)