bluuebunny/crossref_metadata_2025_split huggingface dataset:
1760-P: Brain Sh2b1 Protects against Obesity and Insulin Resistance through Multiple Hypothalamic Neural Circuits
Authors: LI YUAN , KIM MIN-HYUN , JIANG LIN , MYERS MARTIN G. , RUI LIANGYOU 
Published: June 2020

Sh2b1 is a SH2 and PH domain-containing adaptor protein and enhances signal transduction in response to leptin, insulin, brain-derived neurotrophic factor (BDNF), and other ligands. Leptin, insulin and BDNF are known to activate the hypothalamic neural circuitry that controls energy balance, body weight, and metabolism. Genome-wide studies have identified numerous SH2B1 single nucleotide polymorphisms linked to human obesity and diabetes. SH2B1 nonsense and missense mutations have also been reported to be associated with obesity and type 2 diabetes in humans. We previously reported that global deletion of Sh2b1 results in hyperphagia, obesity, and type 2 diabetes in mice. Here, we attempted to identify Sh2b1 target cells, using conditional Sh2b1 knockout mice. We ablated Sh2b1 in the ventromedial hypothalamus (VMH) of Sh2b1flox/flox mice (Sh2b1ΔVMH) either by transducing the VMH with AAV-Cre vectors or using Sf1-Cre drivers. Both Sh2b1ΔVMH males and females, like global Sh2b1 knockout mice, developed obesity, insulin resistance, and liver steatosis. To further map Sh2b1 neurons, we generated leptin receptor (LepR) neuron-specific Sh2b1 knockout (Sh2b1ΔLepR) mice using LepR-Cre drivers. Sh2b1ΔLepR males and females also developed obesity, insulin resistance, glucose intolerance, and liver steatosis. Brown adipose tissue (BAT) thermogenic programs were severely impaired in Sh2b1ΔLepR mice, leading to decreased core body temperature and cold intolerance. Remarkably, Sh2b1 deficiency completely abrogated the ability of leptin to stimulate sympathetic nerves projecting to BAT in Sh2b1ΔLepR mice, indicating that Sh2b1 mediates leptin actions on sympathetic-controlled energy expenditure and metabolism. Collectively, our data suggest that hypothalamic Sh2b1 influences multiple neural circuits controlling food intake, energy expenditure, and metabolic processes by integrating leptin, insulin, BDNF, and/or other nutritional signals.

Disclosure
Y. Li: None. M. Kim: None. L. Jiang: None. M.G. Myers: Research Support; Self; AstraZeneca, Novo Nordisk Inc. L. Rui: None.
1763-P: Acarbose Protects from Central and Peripheral Metabolic Imbalance Induced by Exposure to Benzene
Authors: DEBARBA LUCAS KNIESS , MULKA ADAM , FAKHOURY PATRICK I. , DIDYUK OLESYA , AWADA ABEAR A. , LIMA JULIANA , KOSHKO LISA , KLUEH ULRIKE , SADAGURSKI MARIANNA 
Published: June 2020

Benzene is a well-known human carcinogen that is one of the major components of air pollution. Few epidemiological studies suggested an association between adverse health effects of benzene at low doses and the development of insulin resistance. Regardless, a detailed analysis of the metabolic effects of benzene exposure and its target tissues has rarely been done. We assessed the effects of chronic and acute exposure to benzene at 50 ppm in inhalation chambers in mice. We show that exposure to benzene for 4 weeks (5h/day), induced hyperglycemia and hyperinsulinemia, associated with impairment in gluconeogenesis and lipid metabolism in males. Females were completely resistant to the negative metabolic consequences of benzene exposure. Moreover, chronic benzene exposure promoted hypothalamic gliosis, ER stress, and elevation of inflammatory genes in male mice. In support, a global proteome profile has identified inflammatory and ER stress pathways in the hypothalamus of the benzene exposed animals suggesting their role in a benzene-induced metabolic imbalance. In support, benzene exposure triggered alterations in neuron-glia interactions by modulating neuronal sensing under hyperglycemic conditions within hypothalamic glucose-sensing VMH neurons. Mechanistically, acute benzene exposure activated hypothalamic ER stress and neuroinflammatory responses, while pharmacological inhibition of IRE1α-XBP1 pathway alleviated glial inflammatory cytokines production suggesting that this may be the primary mechanism by which benzene causes changes in metabolic status. A diabetes drug, Acarbose that extends animals’ life span in a sex-specific manner, and protected against benzene induced metabolic imbalance, ER stress, and neuroinflammatory responses. Acarbose imitates the slowing of dietary carbohydrate digestion, suggesting that choosing a diet with a low glycemic index might be a potential strategy for reducing the effect of benzene exposure even at lower levels.

Disclosure
L. Kniess Debarba: None. A. Mulka: None. P.I. Fakhoury: None. O. Didyuk: None. A.A. Awada: None. J. Lima: None. L. Koshko: None. U. Klueh: Research Support; Self; Abbott. Other Relationship; Self; Cell and Molecular Tissue Engineering, LLC. M. Sadagurski: None.

Funding
American Diabetes Association (1-18-JDF-063 to M.S.)
1769-P: Microglial Activation and Inactivation via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) Alters Peripheral Glucose Homeostasis
Authors: NESS KELLY M. , DOUGLASS JOHN , VALDEARCOS-CONTRERAS MARTIN , DORFMAN MAURICIO D. , NIRAULA ANZELA , KOLIWAD SUNEIL K. , THALER JOSHUA 
Published: June 2020

Obesity, a condition affecting more than one in three American adults, is associated with hypothalamic neuronal injury, inflammation, and gliosis- a process characterized by accumulation of activated microglia. Experimental evidence from our lab suggests that microglial activation and inflammatory signaling play a functional role in obesity pathogenesis and, furthermore, that this inflammation, or the blockade of such, may affect whole-body glucose homeostasis. Microglial-specific NF-kB knock-out mice are protected from diet-induced obesity, but, despite their lean phenotype, develop glucose intolerance similar to wild type controls. We therefore used stimulatory (hM3Dq) and inhibitory (hM4Di) DREADDs to test the hypothesis that microglial activation or inactivation acutely affects systemic glucose homeostasis. We generated novel mouse models that selectively express the hM3Dq- and hM4Di-DREADD transgenes in microglia. Expression was verified via qRT-PCR, flow cytometry, and IHC. Cohorts of mice and littermate controls were maintained on either normal chow diet or high-fat diet (HFD). Glucose tolerance tests were performed on mice following administration of the DREADD receptor agonist clozapine-N-oxide (CNO). Acute microglial activation via CNO administration in hM3Dq-DREADD animals improved glucose tolerance under both chow and HFD conditions. Acute CNO-induced microglial inactivation in hM4Di-DREADD animals increased fasting glucose in chow-fed animals and worsened glucose tolerance in HFD-fed animals. These findings provide the first evidence that peripheral glucose homeostasis is affected by microglial activity and inflammatory signaling and can be manipulated on an acute timescale using DREADD technology.

Disclosure
K.M. Ness: None. J. Douglass: None. M. Valdearcos-Contreras: None. M.D. Dorfman: None. A. Niraula: None. S.K. Koliwad: Consultant; Self; AstraZeneca. Stock/Shareholder; Self; Suggestic, Yes Health. J. Thaler: None.

Funding
National Institutes of Health (T32DK007247, R01DK119754)
1783-P: Effects of DPP-4 Inhibition on the Enteroinsular Axis in Pancreatic Insufficient Cystic Fibrosis
Authors: SHEIKH SABA , KELLY ANDREA , STEFANOVSKI DARKO , PELECKIS AMY J. , NYIRJESY SARAH , EIEL JACK N. , SIDHAYE ANIKET , DE LEON DIVA D. , HADJILIADIS DENIS , RUBENSTEIN RONALD C. , RICKELS MICHAEL R. 
Published: June 2020

Impaired incretin secretion may contribute to insulin secretion defects in pancreatic insufficient cystic fibrosis (PI-CF). We hypothesized that dipeptidyl peptidase-4 (DPP-4) inhibitor therapy would increase glucagon-like peptide-1 (GLP-1) and improve insulin secretion in glucose intolerant CF. We conducted a randomized, double blind, placebo-controlled trial in 24 subjects with PI-CF and abnormal glucose tolerance who received the DPP-4 inhibitor sitagliptin 100 mg (n = 12) or matched-placebo (n = 12) for 6 months. Randomization was stratified by oral glucose tolerance. Mixed-meal tolerance tests (MMTT) and glucose-potentiated arginine (GPA) tests were performed at baseline and after 6 months intervention. Incremental area-under-the-curves were calculated for GLP-1 (AUCGLP-1) post meal. Insulin secretory rates (ISR), derived by parametric deconvolution of C-peptide kinetics, were modeled using linear mixed effects models. Acute insulin and glucagon response to arginine were calculated under fasting, 230, and 340 mg/dL hyperglycemic clamp conditions. Subjects in the sitagliptin vs. placebo groups were similar in age (median 24 [range 18-43] vs. 28 [18-43] years), sex (5 females each), and BMI (24 [19-34] vs. 22 [17-24] kg/m2). HbA1c, similar at baseline (5.6 [4.8-6.1] vs. 5.7 [5.4-5.9] %), improved after 3 months of sitagliptin (-0.2 %, 95% CI -0.4- -0.2, P = 0.02). AUCGLP-1 was higher after sitagliptin vs. placebo (1400 pmol·min/L, 95% CI 750-2050, P &lt; 0.001). ISR after sitagliptin showed a faster rise through 60 min post meal (9.1 µU·mL-1·min-1, 95% CI 4.4-13.9, P &lt; 0.001) and returned to baseline faster vs. placebo (-12.0 µU·mL-1·min-1, 95% CI -16.9- -7.2, P &lt; 0.001). Acute insulin responses did not differ between groups, but acute glucagon responses were lower after sitagliptin vs. placebo (P = 0.03). In glucose intolerant CF, six-month therapy with sitagliptin resulted in modest improvement in glycemic control and islet function.

Disclosure
S. Sheikh: None. A. Kelly: None. D. Stefanovski: None. A.J. Peleckis: None. S. Nyirjesy: None. J.N. Eiel: None. A. Sidhaye: None. D.D. De Leon: Consultant; Self; Crinetics, Novartis Pharmaceuticals Corporation, Soleno Therapeutics, Zealand Pharma A/S. Employee; Spouse/Partner; Merck & Co., Inc. Research Support; Self; Crinetics, Zealand Pharma A/S. Stock/Shareholder; Self; Merck & Co., Inc. D. Hadjiliadis: Other Relationship; Self; AstraZeneca. R.C. Rubenstein: None. M.R. Rickels: Consultant; Self; Semma Therapeutics, Inc. Research Support; Self; Xeris Pharmaceuticals, Inc.

Funding
National Institutes of Health (R01DK97830, K23DK107937, UL1TR001878, P30DK19525, T32 DK007314); Merck & Co., Inc. (MISP50512)
1786-P: The New Insulin Sensitizer MSDC-0602K Synergizes with the GLP-1 Receptor Agonist Liraglutide
Authors: PYLES KELLY D. , KAMM DAKOTA , COLCA JERRY R. , MCCOMMIS KYLE S. 
Published: June 2020

First generation insulin sensitizers improve both hyperglycemia and hyperinsulinemia and can preserve beta cell mass and function. GLP-1 receptor agonists work by augmenting glucose-stimulated insulin secretion. Our objective was to assess potential additive effects of the new insulin sensitizer, MSDC-0602K (0602K) when combined with a GLP-1 receptor agonist in db/db mice. Mice were gavaged daily with 30 mg/kg 0602K or vehicle, injected subcutaneously every other day with 200 μg/kg Liraglutide (Lira) or vehicle, or received both drugs. Lira reduced glycemia and plasma fructosamine levels, while 0602K or 0602K+Lira normalized glycemia and fructosamine to lean db/+ mouse levels. Both drugs alone improved glucose tolerance compared to vehicle db/db, while the combination of 0602K+Lira further improved glucose tolerance even compared to lean db/+ mice. Vehicle treated db/db mice displayed elevated insulin and C-peptide levels, which were both reduced by 0602K treatment. C-peptide levels were lowered to a greater degree than insulin, indicating that 0602K treatment exerted a major effect on insulin secretion. In contrast, Lira increased the insulin and C-peptide levels in db/db mice, while the combination of 0602K+Lira displayed reduced levels of insulin and C-peptide similar to 0602K-alone treatment. Pancreas immunohistochemistry of vehicle treated db/db mice showed little islet insulin content, but islet insulin was significantly increased by 0602K or 0602K+Lira treatment. Isolated islets from lean, naïve mice showed no defect in glucose-stimulated insulin secretion with 0602K treatment, suggesting that the lowered insulinemia in vivo is due to corrected insulin resistance rather than direct inhibition of insulin secretion.
In conclusion, the new insulin sensitizer MSDC-0602K improves insulinemia and helps to restore islet insulin content when used alone or in combination with Liraglutide. Glucose tolerance displayed additive effects with combined 0602K+Lira treatment.

Disclosure
K.D. Pyles: None. D. Kamm: None. J.R. Colca: Stock/Shareholder; Self; Cirius Therapeutics, Metabolic Solutions Development Company. K.S. McCommis: None.

Funding
National Institutes of Health (R01HL136658)
1788-P: Islet Function in Youth with Cystic Fibrosis with and without Liver Disease
Authors: RAYAS MARIA S. , HUGHAN KARA S. , JAVAID RIDA , LEUNG DANIEL , STEFANOVSKI DARKO , KELLY ANDREA , SALEHI MARZIEH 
Published: June 2020

Insulin deficiency largely underlies cystic fibrosis related diabetes (CFRD). CF liver disease (CFLD) is a risk factor for CFRD development, but the mechanisms linking these mortality-increasing comorbidities are unknown. This pilot study sought to characterize prandial glucose metabolism and islet function in youth across glycemia and CFLD spectrums.
Glucose, insulin, c-peptide (CP) and glucagon were obtained during a 3-hr oral glucose tolerance test in youth (9M/11F, ages 12-21y) with pancreatic insufficient CF from two centers. Fasting insulin sensitivity (HOMA-IR) and insulin clearance (CP:insulin), and prandial glucose and glucagon excursion (AUC180), insulin sensitivity (Matsuda index), β-cell sensitivity to glucose, insulin secretory rates (ISR; by parametric deconvolution of CP kinetics) and disposition index (DI, composite of insulin secretion and insulin sensitivity) were calculated. CFLD status was defined using CFLD guidelines: CFLD with portal hypertension (CFLDPH), CFLD without portal hypertension (CFLD) and no liver disease (CFnoLD).
CFLDPH (n=3), CFLD (n=3) CFnoLD (n=14) did not differ in age, BMI-Z, or HbA1c. CFRD was present in 2 CFLDPH, 0 CFLD, 4 CFnoLD. Fasting glucose was greater in CFLDPH vs. CFLD or CFnoLD (p&lt;0.05). HOMA-IR and fasting CP:insulin were reduced in CFLDPH vs. CFLD and CFnoLD, but post-meal glucose-AUC180 and indices of insulin sensitivity and clearance were similar. ISR and DI tended to be lower in CFLDPH vs. CFLD (p=0.008 and p=0.077) and CFnoLD (p=0.071 and p=0.058), respectively. β-cell sensitivity was reduced in CFLDPH vs. CFLD (p&lt;0.05). Fasting and AUC180 glucagon did not differ among groups.
In this limited group of youth, reduced fasting insulin sensitivity and magnified insulin secretory defects are present in CFLDPH, the more severe form of CFLD, and may explain their heightened CFRD risk. Larger studies are warranted to define pathogenesis and inform glycemic treatment targets in individuals with severe CFLD.

Disclosure
M.S. Rayas: None. K.S. Hughan: Research Support; Self; Novo Nordisk Inc. R. Javaid: None. D. leung: None. D. Stefanovski: None. A. Kelly: None. M. Salehi: None.

Funding
Cystic Fibrosis Foundation (RAYAS16GEO, HUGHAN16GE0, MOR16CFF); National Institutes of Health (5T32DK00772923)
1789-P: Inactivation of Acyl-Protein Thioesterase 1, a Major Mediator of Palmitoylation Cycling, Promotes Insulin Secretion and ß-Cell Failure
Authors: DONG GUIFANG , WEI XIAOCHAO , YIN LI , FENG CHU , ADAK SANGEETA , SHYR ZEENAT A. , ZHANG QIANG , MORIKAWA SHUNTARO , ASADA RIE , URANO FUMIHIKO , REMEDI MARIA S. , SEMENKOVICH CLAY F. 
Published: June 2020

Palmitoylation cycling involves successive addition and removal of lipid from proteins to regulate cell structure and membrane interactions. Cycling requires depalmitoylation, mediated mostly by the enzyme acyl-protein thioesterase 1 (APT1). To test the hypothesis that depalmitoylation is critical for normal glucose metabolism, we generated global and islet-specific (using tamoxifen-inducible Pdx1 Cre) APT1 knockout mice. Both models on a chow diet had enhanced glucose tolerance due to increased insulin secretion. Pancreatic insulin content was unaffected by APT1 deficiency. Isolated islets from APT1-deficient models demonstrated increased glucose-stimulated insulin secretion under static and dynamic conditions. Quantitative histomorphometry demonstrated β cell hypertrophy in islets from global APT1 KO mice. Calcium dynamics in isolated islets were unaffected by APT1 deficiency, suggesting that increased insulin secretion is mediated downstream of depolarization-dependent calcium influx. APT1 knockdown in replicates of human islets from two donors showed increased insulin secretion. At 4 weeks of age, global APT1 KO db/db mice had improved glucose tolerance due to increased insulin secretion compared to littermate db/db mice. However, by 16 weeks of age APT1-deficient db/db mice had severe glucose intolerance, hypoinsulinemia, and β cell atrophy compared to littermate db/db mice. Islet palmitoylation proteomics identified putative APT1 substrates including Scamp1, -2 and -3. Scamp1 was validated as a palmitoylated protein, APT1 deficiency would be predicted to impair Scamp1 function, and Scamp1 knockdown in insulinoma cells increased insulin secretion. These results suggest that deficiency of APT1, an enzyme susceptible to post-translational regulation in the setting of insulin resistance, causes hypersecretion of insulin that leads to β cell failure, modeling the clinical evolution of human type 2 diabetes.

Disclosure
G. Dong: None. X. Wei: None. L. Yin: None. C. Feng: None. S. Adak: None. Z.A. Shyr: None. Q. Zhang: None. S. Morikawa: None. R. Asada: None. F. Urano: Stock/Shareholder; Self; CytRx Corporation. Other Relationship; Self; AETAS Pharma, Amylyx Pharmaceuticals, Mitochon, National Center for Advancing Translational Sciences, Novus Biologicals?. M.S. Remedi: None. C.F. Semenkovich: None.
179-OR: Mitochondrially Targeted Tamoxifen Improves Diet-Induced Obesity and Diabetes and Reduces Adipose Tissue Senescence in Experimental Mice
Authors: TRNOVSKA JAROSLAVA , DAVIDOVA ELISKA , SVOBODA PETR , KRATOCHVILOVA HELENA , MRAZ MILOS , HUBACKOVA SONA , NEUZIL JIRI , HALUZIK MARTIN 
Published: June 2020

Diabetes and ageing are mutually linked and senescent cells might be involved in the development of obesity and type 2 diabetes mellitus (T2DM). Recent studies have shown that senolytic agents may improve diabetes-related pathologies. To this end we have tested our novel anti-cancer agent with senolytic properties, mitochondrially targeted tamoxifen (MitoTam), in a mouse model of T2DM. Obesity and diabetic metabolic profile were induced by high fat diet (HFD) feeding in 20 C57BL/6J male mice for 6 months with another group fed a standard diet (SD) serving as controls. Subsequently, both groups were divided into 2 subgroups (n=10 each) treated either with MitoTam (2µg/1g of body weight dissolved in 4% ethanol in corn oil) or the excipient given i.p. twice a week for a period of 4 weeks. In HFD animals, MitoTam decreased body weight already after 2 weeks of treatment, with most pronounced reduction of visceral adipose tissue (VAT, P&lt;0.001), whereas it had no effect on body weight in SD group. MitoTam also reduced fasting glucose (P&lt;0.001) as well as postprandial glucose AUC (P&lt;0.001) of HFD mice to levels comparable with SD group. This glucose-lowering effect was accompanied by a decrease in serum triglycerides (P&lt;0.002), insulin (P&lt;0.002), leptin (P&lt;0.001) and glucose-dependent insulinotropic peptide (GIP, P&lt;0.03) together with reduction of mRNA expression of leptin in epididymal adipose tissue (EAT, P&lt;0.001), EAT adipocyte size and lipid accumulation in the liver (P&lt;0.002). HFD-induced obesity and T2DM phenotype was associated with elevated levels of senescent markers p16 and β-gal in EAT (P&lt;0.001 for p16 and P&lt;0.03 for β-gal vs. SD), both of which were markedly reduced by MitoTam treatment (P&lt;0.001 for p16 and P&lt;0.002 for β-gal vs. HFD).
In conclusion, our results suggest that MitoTam significantly improves HFD-induced obesity and diabetes in mice and that this effect might be in part mediated by alleviated senescence in adipose tissue.

Disclosure
J. Trnovska: None. E. Davidova: None. P. Svoboda: None. H. Kratochvilova: None. M. Mraz: None. S. Hubackova: None. J. Neuzil: None. M. Haluzik: Advisory Panel; Self; Lilly Diabetes, Sanofi. Consultant; Self; Ethicon US, LLC. Speaker’s Bureau; Self; AstraZeneca, Mundipharma International, Novartis AG, Novo Nordisk A/S.

Funding
Institute for Clinical and Experimental Medicine (00023001); Czech Science Foundation (GA 18-02550S)
1791-P: The Threshold for Fasting Insulin Secretion Is Independent of the Beta-Cell Secretory Response to Glucose in Nondiabetic Humans
Authors: KOHLENBERG JACOB D. , LAURENTI MARCELLO C. , EGAN AOIFE M. , MAN CHIARA DALLA , RIZZA ROBERT A. , COBELLI CLAUDIO , VELLA ADRIAN 
Published: June 2020

The transition from normal fasting glucose (NFG) and normal glucose tolerance (NGT) to type 2 diabetes is characterized by impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Graded Glucose Infusion (GGI) has been used to measure β-cell function in response to glucose and to extrapolate the β-cell threshold for insulin secretion. However, this assumes a linear relationship between fasting insulin secretion and the response to a GGI. This may not be the case in e.g., humans with IFG/NGT who have normal β-cell function despite IFG. As part of a series of experiments examining the pathogenesis of prediabetes, we examined the relationship of fasting insulin secretion with the subsequent β-cell response to GGI. To do so, we studied nondiabetic, weight-stable individuals (53 ± 2 yrs, BMI 27.5 ± 1.2 kg/m2). At the time of screening, subjects underwent a 75 g oral glucose tolerance test. On the study day, after an overnight fast, at 0700 (-120 min) a variable insulin infusion was used to maintain glucose at ∼80 mg/dL (until 0845). At 0900, GGI commenced (0-240 min total, starting at 1 mg/kg/min and doubling every 60 min). Insulin Secretion Rate (ISR) was estimated by deconvolution of frequently sampled peripheral C-peptide concentrations. The rate of change of ISR in response to increasing glucose concentrations was used to calculate β-cell responsivity to glucose and the set-point of insulin secretion. As expected, ISR rose throughout the study (0.07 ± 0.01, 0.21 ± 0.05, 0.30 ± 0.07, 0.55 ± 0.13, 0.94 ± 0.15 nmol/min; 0, 60, 120, 180, and 240 min respectively). The individual glucose threshold for insulin secretion (4.8 ± 0.1 mmol/l) was independent of β-cell function during the screening glucose tolerance test (R2 = 0.07, p = 0.67) and during the GGI (R2 = 0.06, p = 0.68). These data imply that the glucose threshold for insulin secretion is independent of β-cell function.

Disclosure
J.D. Kohlenberg: None. M.C. Laurenti: None. A.M. Egan: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. R.A. Rizza: None. C. Cobelli: None. A. Vella: Advisory Panel; Self; vTv Therapeutics, Zealand Pharma A/S. Research Support; Self; Novo Nordisk A/S, Xeris Pharmaceuticals, Inc.

Funding
Endocrine Fellows Foundation; National Institutes of Health (R01DK78646, R01DK116231)