bluuebunny/crossref_metadata_2025_split huggingface dataset:
1766-P: Androgen Action in Hypothalamic Arcuate Nucleus Neurons Increases Hepatic Glucose Production in Female Mice
Authors: MORFORD JAMIE , MAUVAIS-JARVIS FRANCK 
Published: June 2020

Androgen excess predisposes females to type 2 diabetes. Using mouse models, we reported that androgen excess causes insulin resistance via activation of the androgen receptor (AR) in the brain. Neurons of the arcuate nucleus of the hypothalamus (ARC) regulate hepatic glucose production (HGP). Thus, we hypothesized that in female mice, androgen excess in neurons of the ARC causes peripheral insulin resistance by increasing HGP. To test this, we injected AaV-Cre-GFP or AaV-GFP into the ARC of ARlox/lox female mice to generate ARC-specific AR knockout (ARC-ARKO) and control mice, respectively. When exposed to a Western diet, control female mice chronically treated with dihydrotestosterone (DHT) developed insulin resistance and fasting hyperglycemia compared to vehicle-treated control mice. In contrast, DHT-treated ARC-ARKO mice remained insulin sensitive and normoglycemic compared to vehicle-treated ARC-ARKO mice. During a hyperinsulinemic-euglycemic clamp, insulin’s ability to suppress HGP was blunted in DHT-treated control mice. In contrast, insulin was still able to suppress HGP in DHT-treated ARC-ARKO females. Additionally, during the clamp, DHT-treated control mice showed no alteration in hepatic activation of AKT, a marker of hepatocyte insulin sensitivity, but exhibited reduced activation of hepatic STAT3, a marker of hypothalamic insulin sensitivity. In contrast, in DHT-treated ARC-ARKO mice activation of hepatic STAT3 was increased. Together these results suggest that in female mice exposed to a Western diet, androgen excess causes insulin resistance in ARC neurons via action at the AR leading to impairments in the brain-IL6-STAT3 pathway which results in unsuppressed HGP.

Disclosure
J. Morford: None. F. Mauvais-Jarvis: None.

Funding
National Institutes of Health (R01DK074970, R01107444); U.S. Department of Veterans Affairs (BX003725)
1768-P: The Role of Hypothalamic Growth Hormone Receptor–Expressing Neurons in Glucose Metabolism and Energy Homeostasis
Authors: LIMA JULIANA , DEBARBA LUCAS K. , AYYAR IVEN T. , UBAH CHIDERA , KHAN MANAL , ALROMDHAN HAWRAA , ALYSOFI MOHAMMED , SADAGURSKI MARIANNA 
Published: June 2020

GH and the GH receptor (GHR) are present in regions known to participate in the regulation of feeding, energy balance and glucose metabolism, including the hypothalamus. We have previously demonstrated that GHR signals in nutrient-sensing neurons is critical for hepatic glucose production and lipid metabolism. Given the high expression pattern of GHR in the arcuate nucleus (ARC) of the hypothalamus, we aimed to define the specific role of the ARC GHR-expressing neurons in energy homeostasis and glucose metabolism. For this purpose, we have developed a novel GHR cell-specific molecular tool (GHRcre) using CRISPR/Cas9 gene editing technology. We show that GHR+ neurons in the ARC are mostly co-localized with AgRP, GHRH, and SST neurons and rapidly respond to fasting. Specific chemogenetic activation of GHR+ neurons in the ARC (ARCGHR+) by the DREADDs technique impaired glucose metabolism, suggesting the role of these neurons in metabolic homeostasis. Additionally, while activation of ARCGHR+ neurons increased energy homeostasis (RER, VO2) under metabolic resting phase, the responses to fasting were significantly attenuated, demonstrating the inhibitory role of GHR+ neurons in the ARC for fasting responses. Sirtuin 1 (SIRT1) is highly expressed in the ARC and had been associated with hypothalamic responses to fasting. The majority of ARCGHR+ neurons express SIRT1 and respond to fasting by upregulating the SIRT1 expression. Importantly, hypothalamic upregulation of SIRT1 in response to fasting is blunted in mice lacking GHR in AgRP neurons (AgRPEYFP∆GHR mice), suggesting a novel role of SIRT1 within the hypothalamic GH axis and providing evidence for a link between the somatotropic system and SIRT1 function in responses to fasting.

Disclosure
J. Lima: None. L.K. Debarba: None. I.T. Ayyar: None. C. Ubah: None. M. Khan: None. H. AlRomdhan: None. M. Alysofi: None. M. Sadagurski: None.

Funding
American Diabetes Association (1-18-JDF-063 to M.S.); Wayne State University
178-OR: The Causal Effect of BMI on Health-Related Quality of Life: A Mendelian Randomization Study
Authors: LAXY MICHAEL 
Published: June 2020

Background: Previous studies showed that obesity is negatively associated with health related quality of life (HRQoL), however, this association might be biased by reversed causation and omitted variables. To overcome these limitations, this study aims to estimate the causal effect of body mass index (BMI) on HRQoL using genetic variants as instrumental variables - a method that is often called Mendelian Randomization (MR).
Methods: We use a) individual-level data on BMI, 77 identified single nucleotide polymorphism (SNPs), HRQoL measured by the physical (PCS) and mental component score (MCS) of the SF-12 of 3080 participants from a population-based German study, and b) meta-data on the SNP-BMI association of 77 identified SNPs from a meta-analysis with &gt;300,000 individuals. We apply a) an ordinal least square (OLS) regression model, b) a one sample MR approach in which we fit a two stage least square (2SLS) regression model with a genetic SNP-score as instrument, and c) a two sample MR approach in which we estimate Wald estimates using the techniques of inverse variance weighting, simple and weighted medians, and MR Egger regression.
Results: The OLS model shows a 0.32 point decrease in PCS (p&lt;0.001) and a 0.04 point decrease in MCS (p=0.54) per BMI unit. The 2SLS regression of the one sample MR approach indicates endogeneity (Durbin-Wu-Hausman-Test; p&lt;0.05) and shows a nonsignificant 0.92 point decrease in PCS and a nonsignificant 0.32 point decrease in MCS per BMI unit. The two sample MR models also show consistently larger, but non-significant PCS and MCS decreases per BMI unit than the linear model.
Conclusion: The negative effect of BMI on HRQoL might be higher than previous studies suggested. This highlights the potential value resulting from obesity prevention. MR studies with larger sample sizes are needed to obtain more precise causal effect estimates.

Disclosure
M. Laxy: None.
1801-P: Novel De Novo INS P.T97P Variant Presenting with Severe Neonatal DKA
Authors: LAL RAYHAN , MOELLER HANNAH P. , FREEMAN RAQUEL , PRAHALAD PRIYA , ANNES JUSTIN P. 
Published: June 2020

Objective: A 5 month old, premature male infant with history of hydrops fetalis and hernia repair presented unresponsive in respiratory distress requiring intubation and was found to have pH 6.93, bicarbonate 6 mmol/L, anion gap 23 mmol/L, glucose 669 mg/dL and HbA1c 14.2%. His condition improved with insulin drip, fluid and electrolyte management. Work-up revealed negative autoantibodies and the University of Chicago Neonatal Diabetes Sequencing Panel was performed. Testing revealed a heterozygous sequence variant of unknown significance in the INS gene (c.289A&gt;C), resulting in the amino acid change p.T97P. In silico pathogenicity prediction tools provided contradictory results. Neither parent carried the variant. INS gene mutations have been associated with Mutant INS-gene-induced Diabetes of Youth (MIDY) that includes permanent neonatal diabetes and MODY 10. Expression of mutant proinsulin is thought to lead to misfolded complexes in the endoplasmic reticulum (ER), leading to ER stress and β-cell death.
Methods: To determine the effects of this variant on insulin processing and release, we utilized a validated luminescent insulin secretion assay where Gaussia luciferase is inserted into the C-peptide portion of proinsulin. We compared luciferase secretion for wild type and variant INS sequences.
Results: The mutation decreased luciferase release ∼10-fold versus wild type. Proteasome inhibition led to partial rescue. However, overall expression of proinsulin-luciferase peptide was unchanged between the wild type and mutant. Therefore, it is likely that the mutation causes disruptions in processes downstream of transcription and translation, such as folding, proteolytic processing and transport.
Conclusions: The novel INS p.T97P is the first identified A-chain mutation resulting in MIDY not involving the creation or deletion of cysteine residues. The substitution of the polar threonine with nonpolar proline may be sufficient to disrupt nearby disulfide bonding in the proinsulin folding pathway.

Disclosure
R. Lal: Consultant; Self; Abbott, Biolinq. H.P. Moeller: None. R. Freeman: None. P. Prahalad: None. J.P. Annes: None.

Funding
National Institutes of Health (1K12DK122550, T32DK007217, R01DK101530, T32GM113854, P30DK116074)
1809-P: Liver Pyruvate Carboxylase Knockout Mice Suggest Noncanonical Sources of Acetyl-CoA for Hepatic Lipid Synthesis
Authors: INIGO MELISSA MAE R. , DEJA STANISLAW , KUCEJOVA BLANKA , FLETCHER JUSTIN A. , FU XIAORONG , BURGESS SHAWN C. 
Published: June 2020

Elevated hepatic de novo lipogenesis (DNL) is a key characteristic of patients with Nonalcoholic Fatty Liver Disease (NAFLD). Liver pyruvate carboxylase (PC) may be critical for DNL since PC replenishes oxaloacetate that is converted to citrate as source for acetyl-CoA during DNL. PC may also play a role in triglyceride (TG) synthesis by replenishing oxaloacetate that is used for glyceroneogenesis. Thus, PC is considered a lipogenic enzyme, though most evidence has been derived from non-liver cell culture models and indirect measures in livers of animal models. Liver-specific PC knockout mice (LPCKO) have lower circulating TG on a high fat diet, but fasting liver TG was not improved. To determine whether liver-specific PC is required for DNL and glyceroneogenesis, we examined LPCKO mice using a 1H/2H NMR approach to directly measure flux through DNL and TG-glycerol synthesis. PCf/f and LPCKO mice were exposed to either standard chow or a high sucrose diet (HSD) for 10 days. Ad libitum fed PCf/f and LPCKO mice were then administered D2O overnight. Liver lipids were extracted, and positional isotopomer analysis by 1H/2H NMR was used to determine DNL and TG-glycerol synthesis fluxes. DNL flux was not significantly different between PCf/f and LPCKO mice under standard chow conditions and only tended to be moderately lower in LPCKO mice after a short-term HSD treatment. TG-glycerol synthesis was also similar between PCf/f and LPCKO, regardless of diet. Surprisingly, liver triglyceride levels were modestly higher in standard chow fed LPCKO than PCf/f mice, and no significant differences were found between HSD-fed PCf/f and LPCKO mice. Our initial findings suggest that PC is not required for DNL and TG-glycerol synthesis during the fed state and therefore indicate that alternative pathways may exist to supply of cytosolic acetyl-CoA for lipid synthesis.

Disclosure
M.R. Inigo: None. S. Deja: None. B. Kucejova: None. J.A. Fletcher: None. X. Fu: None. S.C. Burgess: None.

Funding
Robert A. Welch Foundation (I-1804)
1873-P: Glycemic Impact of Pancreatic Enzyme Replacement in Patients with Diabetes and Exocrine Pancreatic Insufficiency: A Case Series
Authors: UWAIFO GABRIEL I. 
Published: June 2020

Some patients with type 2 diabetes (T2DM) and/or pancreatogenous diabetes have exocrine pancreatic insufficiency (EPI). The impact of pancreatic enzyme replacement (PER) on diabetes (DM) control is largely undocumented and unknown. We present 4 cases suggesting PER may positively impact DM glycemic and lipids. Case 1 is a 46 yr Caucasian (C) man with T2DM and recurrent gall stone pancreatitis. Prior to onset his HBA1c was between 6.3-7.4 but with recurrent episodes reached peak of 10.8. He was diagnosed with chronic pancreatitis with EPI and commenced PER. After 3 mths on PER his HBA1c was 6.7 with resolution of hypertriglyceridemia (HTG) and improved total cholesterol (TC). Case 2 is a 57 yr old C man with T2DM and episodic HTG related pancreatitis. He had erratic medication access due to insurance limitations. He was recently diagnosed with EPI but initially could not afford PER. HBA1c at diagnosis of EPI was 9.7 with elevated TC and HTG. When he secured PER, within 8 wks of use HBA1c reduced to 7.6 with improved HTG and TC. Case 3 is a 24 yr old C man with known cystic fibrosis and cystic fibrosis related DM. Initial HBA1c was 8.6 and he had been of PER voluntarily for yrs. He had features of EPI and was urged to resume PER which he did. At 4 mth follow up after restarting PER his HBA1c was 6.4 with improvement in HTG. Case 4 is a 36 yr old C man with prior well controlled T2DM and known MEN-1. His prior mean HBA1c was 6.7. Due to recurrent bouts of severe hypoglycemia in the prior 2 yrs work up revealed multiple pancreatic insulinomas for which he had partial pancreatectomy. His DM control declined with peak HBA1c of 11.3. He developed symptoms of EPI and was commenced on PER. 3mths after starting PER his HBA1c was 7.1 with resolution of HTG and improved TC. Early recognition of EPI in patients with DM is important. Commencement of PER in such patients may positively impact glycemia and dyslipidemia especially HTG. Further study of the relationship of PER to DM metabolic control is warranted.

Disclosure
G.I. Uwaifo: None.
190-OR: Impact of Prenatal Exposure to Maternal Obesity and Child Physical Activity Levels on Neurocognition
Authors: ALVES JASMIN , ANGELO BRENDAN C. , LUO SHAN H. , CHOW TING , YUNKER ALEXANDRA G. , XIANG ANNY , PAGE KATHLEEN A. , ZINK JENNIFER , BELCHER BRITNI R. , CLARK KRISTI 
Published: June 2020

Prenatal exposure to maternal obesity is linked to neurocognitive deficits in offspring. In contrast, engaging in physical activity (PA) is beneficial for cognition and brain development. We aimed to determine if greater PA is associated with higher intelligence quotient (IQ) scores and greater brain white matter integrity in children born to mothers with a range of pre-pregnancy BMI. Ninety-nine children (59 girls) ages 7-13 years completed the study. Maternal pre-pregnancy BMI was obtained from electronic medical records. Wechsler Abbreviated Scale of Intelligence was used to measure IQ. Diffusion tensor imaging was used to measure mean global fractional anisotropy (FA), a marker of white matter integrity. Time spent in moderate-to-vigorous PA (MVPA) and vigorous PA (VPA) was assessed using 3-day PA recalls. Linear regressions were used to assess whether maternal pre-pregnancy BMI or child MVPA and VPA were associated with child IQ scores and global FA. Maternal pre-pregnancy BMI ranged from 19.0-54.0 kg/m2 (43% obese). Mean±SD child IQ was 106.4±14.0, MVPA was 132.8±95.4 min/day, and VPA was 19.0±27.1 min/day. Maternal pre-pregnancy BMI was negatively associated with child IQ scores (β=-0.31; p=0.10); this marginal association remained after adjusting for child age, sex, puberty, BMI z-score, and socioeconomic status (β=-0.42; p=0.095). MVPA was not associated with child IQ (β=2.63; p=0.16). However, children who spent more time in VPA had higher IQ scores before (β=7.05; p=0.003) and after adjusting for the same co-variates (β=5.65; p=0.024) and further adjusting for maternal pre-pregnancy BMI (β=5.01; p=0.049). Children who spent more time in VPA also had greater mean global FA (unadjusted: β=0.01; p=0.017; adjusted: β=0.01; p=0.005). These findings suggest that engaging in VPA is beneficial for cognition and white matter microstructure in children, independent of maternal pre-pregnancy BMI.

Disclosure
J. Alves: None. B.C. Angelo: None. S.H. Luo: None. T. Chow: None. A.G. Yunker: None. A. Xiang: None. K.A. Page: None. J. Zink: None. B.R. Belcher: None. K. Clark: None.

Funding
American Diabetes Association (1-14-ACE-36 to K.A.P.); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK116858); National Institute of Mental Health (F31MH115640)
1906-P: Glucose-Dependent Insulinotropic Polypeptide (GIP) Reduces Bone Resorption in Patients with Type 2 Diabetes
Authors: CHRISTENSEN MIKKEL B. , LUND ASGER , JØRGENSEN NIKLAS R. , HOLST JENS J. , VILSBØLL TINA , KNOP FILIP K. 
Published: June 2020

In healthy individuals, GIP enhances insulin secretion and reduces bone resorption As GIP has impaired insulinotropic effects in patients with type 2 diabetes (T2D), we investigated the effect of glucose and GIP on bone resorption in these patients.
In a randomized, double-blinded, cross-over study, 12 male patients with T2D underwent six study days with 90-minute GIP or matching placebo (saline) infusions on paired days with plasma glucose (PG) clamped at three levels: Fasting hyperglycemia (mean PG ∼8 mmol/l), aggravated hyperglycemia (mean PG ∼12 mmol/l), or insulin-induced hypoglycemia (mean PG 3-8 mmol/l). Primary outcome measure was CTX (a marker of bone resorption expressed as %-change from baseline ± SD).
On days with fasting hyperglycemia, CTX was suppressed by 36±15% during GIP compared to 0±9% during saline infusion (p&lt;0.0001). On days with aggravated hyperglycemia, CTX was suppressed by 47±23% during GIP compared to 10±9% during saline infusion (p=0.0005). On days with insulin-induced hypoglycemia, CTX was suppressed by 40±15% during GIP compared to 12±11% during saline infusion (p&lt;0.0001).
In conclusion, Short-term GIP infusions during hyperglycemia reduce bone resorption by more than a third suggesting that GIP has preserved effects on bone in patients with T2D.

Disclosure
M.B. Christensen: None. A. Lund: Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. N.R. Jørgensen: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Norgine B.V., Novo Nordisk A/S.
1945-P: Pioglitazone Promotes the Function of White and Brown Adipose Tissue in Diet-Induced Obese Mice
Authors: XU FEN , WANG WEI , ZHENG XIAOBIN , GUO WANRONG , SHEN YUNFENG 
Published: June 2020

PPARγ agonist pioglitazone is an insulin sensitizer in the treatment of type 2 diabetes. Here, we investigate the effects of pioglitazone on white and brown fat in diet-induced obese mice. After 16-week diet intervention, C57BL/6 mice were divided randomly into three groups: normal chow diet group (NC group), high-fat diet group (HFD group) and high-fat diet + pioglitazone group (HFDP group). Pioglitazone (30-40mg/kg/day) was administered in drinking water for 6 weeks. After 6-week pioglitazone treatment, there was no significant difference in both body weight and fat mass between the HFDP group and the HFD group. However, fasting blood glucose, glucose tolerance and insulin sensitivity were significantly improved in HFDP group. What’s more, the weight of liver and epididymal adipose tissue (eWAT) were not reduced by pioglitazone treatment. However, the weight of brown adipose tissue (BAT) in the HFDP group was significantly higher than HFD group. Histological staining showed that the hepatic steatosis was ameliorated by pioglitazone. Quantitative real-time PCR revealed that mRNA levels of heat-producing genes (PRDM16, FGF-21, UCP1) and mitochondrial biosynthesis and functional genes (Tfam, cidea, cox7a1, Fabp4) were upregulated in eWAT by pioglitazone. Western blotting results also showed that the protein expression of UCP1 and PGC1α was upregulated by pioglitazone both in eWAT and in BAT when compared with the HFD group. To sum up, our study revealed that pioglitazone could promote the browning of WAT and activate the function of BAT with improved hepatic steatosis in diet-induced obese mice.

Disclosure
F. Xu: None. W. Wang: None. X. Zheng: None. W. Guo: None. Y. Shen: None.
1946-P: Dapagliflozin Suppresses Adipose Fatty Acid Accumulation in Rats Fed on High-Fat Diet but Not on Normal Chow
Authors: SATO DAISUKE , AMARUME JOTA , YANO MIZUNA , UMEHARA YUTA , KUSUNOKI MASATAKA , FENG ZHONGGANG , NAKAMURA TAKAO 
Published: June 2020

SGLT2 inhibitor (SGLT2i) exerts not only on enhancement of glucose excretion but also on improvement of serum lipid profile via increase in lipid utilization as an energy source instead of glucose. That is, SGLT2i might affect the lipid storage. In the present study, we evaluated the effects of dapagliflozin (DAPA) on weight and fatty acid contents of adipose tissues.
At 8 weeks of age, male rats were divided into four groups: (a) NC (n=6) fed on a standard laboratory chow (LC); (b) NC+DAPA (n=6) on the LC with 1 mg/kg/day DAPA administration; (c) HFD (n=6) on a high-fat diet (HF); (d) HFD+DAPA (n=6) on the HF with 1 mg/kg/day DAPA administration. After 7 weeks, we weighed epididymal (EPI), mesenteric (MES), retroperitoneal (RET), and inguinal subcutaneous (SUB) adipose tissues, and measured 21 adipose fatty-acid contents (μmol/g BW).
As a result, adipose tissue weight in the examined four sites in HFD rats were significantly higher (P&lt;0.01) than those, respectively, in NC rats. No significant differences were observed in weights of any adipose tissues or in their contents of fatty acids between the NC and NC+DAPA rats. In contrast, MES weight in HFD+DAPA rats was significantly lower (P&lt;0.05) than that in the HFD rats. Contents of 1, 3, 2 and 1 saturated fatty acids (SFAs) in EPI, MES, RET and SUB, respectively, in the HFD+DAPA rats were significantly lower (P&lt;0.05) than those, respectively, in the HFD rats. Contents of 3 and 2 monounsaturated fatty acids in MES and SUB, respectively, and contents of 2 and 1 polyunsaturated fatty acids in MES and RET, respectively, in the HFD+DAPA rats were significantly lower (P&lt;0.05) than those, respectively, in the HFD rats.
These results suggest that DAPA could reduce some SFAs in any adipose tissues in HF-fed rats, but not in LC-fed rats. The reduction might sometimes arise without concomitant decrease in tissue weight. In addition, DAPA might suppress accumulation of a wide range of fatty acids in MES of HF-fed rats in particular, probably due to their consumption.

Disclosure
D. Sato: None. J. Amarume: None. M. Yano: None. Y. Umehara: None. M. Kusunoki: Other Relationship; Self; Kaken Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd. Z. Feng: None. T. Nakamura: Research Support; Self; AstraZeneca K.K., Ono Pharmaceutical Co., Ltd.

Funding
Ono Pharmaceutical Co., Ltd.; AstraZeneca K.K.