bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of VmnCckbr Neurons as Crucial Mediators of the Counterregulatory Response to Hypoglycemia
Authors: FLAK JONATHAN N. , ANSARI AHSAN , SABATINI PAUL , GOFORTH PAULETTE B. , LI CHIEN , SANDOVAL DARLEEN A. , OLSON DAVID , MYERS MARTIN G. 
Published: June 2018

While the goal of diabetes treatment is normoglycemia, most therapeutics (especially insulin and insulin secretagogues) carry with them a significant risk of potentially life-threatening hypoglycemia; this risk increases with the intensity of therapy. While neurons of the ventromedial hypothalamic nucleus (VMN) play an essential role in the CRR, the VMN contains several populations of neurons that have distinct or even opposing effects, and the neurons that mediate the CRR have not previously been molecularly defined. Since we previously showed that cholecystokinin (CCK) neurotransmission plays an important role in the VMN-mediated CRR, we generated CCK receptor b (Cckbr)-cre mice to study the potential role of VMNCckbr neurons in the CRR. In addition to other expected brain areas that contain Cckbr neurons, CckbrCre reporter mice identified a substantial population of VMNCckbr neurons in the dorsomedial VMN. Consistent with a potential role in the CRR, VMNCckbr neurons project to regions that control sympathetic outflow, including the BST, PAG, and preoptic area. Furthermore, expression of tetanus toxin in VMNCckbr neurons to prevent their downstream neurotransmission reduces blood glucose at baseline and impairs the CRR to insulin-induced hypoglycemia and glucoprivation in both male and female mice. This effect is unique to silencing this discrete population of VMN cells; silencing all VMN neurons (SF1cre) does not alter the CRR, but instead results in obesity and hyperglycemia. Thus, VMNCckbr neurons play a crucial role in the CRR, and their dysfunction may underlie hypoglycemia associated autonomic failure.

Disclosure
J.N. Flak: None. A. Ansari: None. P. Sabatini: None. P.B. Goforth: None. C. Li: Employee; Self; Novo Nordisk Inc. D.A. Sandoval: Research Support; Self; Novo Nordisk A/S, Zafgen, Ethicon US, LLC. D. Olson: Research Support; Self; MedImmune, Novo Nordisk A/S. M.G. Myers: Research Support; Self; MedImmune, Novo Nordisk Inc.. Advisory Panel; Self; Merck & Co., Inc..
Adipocyte Lipolysis Triggers CD11c-ATM Inflammation in Lean Females and Obese Males and Females
Authors: VARGHESE MITA , ABRISHAMI SIMIN , SINGER KANAKADURGA 
Published: June 2018

Men and post-menopausal women are at greater risk for cardiovascular diseases and diabetes than younger women. In obese rodent models, males exhibit profound adipose tissue macrophage (ATM) accumulation in gonadal white adipose tissue (GWAT) linked to insulin resistance, while females are protected even with enhanced adiposity. We hypothesize that these inflammatory differences may be a result of altered lipolysis responses and that females would have enhanced ATM accumulation when lipolysis is induced. Lipolysis was stimulated with a beta3 adrenergic receptor (ADRB3) agonist CL-316, 243 in C57Bl6/j male and female mice fed 16 weeks of 60% high fat diet (HFD). GWAT leukocytes were isolated after 18 h and evaluated by flow cytometry. Lipogenic, lipolytic, oxidative and inflammatory gene expression along with immunofluorescence were performed. ADRB3 activation did not alter adipose tissue weights, but significantly reduced liver weights in obese females. Obese CL treated female mice showed elevated serum free fatty acid (FFA) and triglyceride (TG) levels compared to levels induced in males. Lipid overload impaired TG storage and utilization genes- Lpl, Fasn, Acsl1, Hsl, and Glut4 expression in obese females. Lipolysis promoted appearance of crown like structures (CLS) in males and females but only induced Il6 proinflammatory cytokine and Mcp1 chemokine expression in obese female GWAT. Activated lipolysis triggered CD11c- ATM accumulation in lean females but in both obese male and female GWAT. Obese males showed a marked reduction in GWAT dendritic cells (DC) but a significant reduction in both GWAT and inguinal WAT DCs of obese females. While obese females are resistant to inflammation, this study shows that induced lipolysis elevates FFA levels, alters lipid metabolism and increased CD11c- ATMs and CLSs in obese females. Elucidating the link between lipolysis and inflammation can better explain sex differences in overall metabolic health leading to targeted treatment strategies.

Disclosure
M. Varghese: None. S. Abrishami: None. K. Singer: None.
High Iron Feeding Modulates Glucose Metabolism in Duodenal-Jejunal Bypass Surgery but Not in Vertical Sleeve Gastrectomy in Mice
Authors: NIU JINGJING , DOUROS JONATHAN D. , CAMPBELL JONATHAN , CAPOZZI MEGAN , GRAY SARAH M. , LORENZO FELIPE , D'ALESSIO DAVID , MCCLAIN DON , TONG JENNY 
Published: June 2018

High dietary iron intake is associated with impaired islet-cell function and increased risk of type 2 diabetes mellitus (T2DM) while iron chelation leads to improved glucose tolerance. Bariatric surgery has multiple metabolic benefits but iron-deficiency anemia is a common occurrence following surgery, presumably because of preferential iron absorption in the upper intestine. We hypothesized that a duodenal-jejunal bypass (DJB) procedure that bypasses the proximal small bowel and vertical sleeve gastrectomy (VSG) that eliminate 80% of the stomach without altering the intestine would have differential effects on iron metabolism and glucose homeostasis. C57BL6J mice were fed either high- (2000 ppm) or low-iron diet (4 ppm) for 16 weeks before DJB (n=6 per diet group), VSG (n=6/7 per diet group) or sham surgery (n = 11 per diet group). Intraperitoneal glucose, and insulin, tolerance tests were performed at Day 0, 10 and 20 after surgery. Compared to animals given a low-iron diet, 4 months of high-iron diet significantly impaired glucose tolerance (p&lt;0.05) and decreased insulin and glucagon secretion, but had no effect on body weight or insulin sensitivity prior to surgery. Compared to sham controls neither VSG nor DJB affected glucose or insulin tolerance at day 10 after surgery. However, 20 days after surgery, VSG significantly improved glucose tolerance in both the high- and low-iron diet groups, with increased secretion of islet hormones in in vivo test. In contrast, DJB surgery only improved glucose tolerance in the low-iron-fed mice, this response was not present in the high-iron-fed animals. In sum, these findings indicate that high-iron intake modulates the benefits of DJB, but not VSG on glucose metabolism. This is consistent with an important contribution of GI tract handling of dietary iron to the metabolic effect of surgery to improve glucose tolerance.

Disclosure
J. Niu: None. J.D. Douros: None. J. Campbell: None. M. Capozzi: None. S.M. Gray: None. F. Lorenzo: None. D. D'Alessio: Consultant; Self; Intarcia Therapeutics, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S. D. McClain: None. J. Tong: None.
Glycogen Is the Major Source of Lactate in the Ventromedial Hypothalamus of Recurrently Hypoglycemic Rats
Authors: SU GONG , CHAN OWEN , FARHAT RAWAD , CHAPMAN KIMBERLY 
Published: June 2018

Lactate is an important metabolic substrate for sustaining brain energy demands when glucose supplies are limited. Recurrent hypoglycemia (RH) leads to increased lactate levels in the ventromedial hypothalamus (VMH) which contributes to counterregulatory failure, but the source of this lactate remains unclear. It has been shown that astrocytic glycogen can be broken down into lactate in the brain. Therefore, the present study investigates whether glycogen serves as the major source of lactate in the VMH of RH rats. To address this question, Sprague-Dawley rats were implanted with mini-osmotic pumps and bilateral intracranial guide cannulas that targeted the VMH to deliver either artificial extracellular fluid (aECF) or the glycogen phosphorylase (GP) inhibitor, 1,4-dideoxy-1,4-imino-d-arabinitol (DAB). Subsequently, the rats underwent 3 bouts of hypoglycemia before undergoing a hyperinsulinemic-hypoglycemic clamp on day 4 (n=6/group). A separate group of rats receiving aECF into the VMH were given 3 saline injections as controls before undergoing a hypoglycemic clamp on day 4 (n=6). During the clamps, microdialysis was used to measure VMH lactate levels and VMH glycogen content was determined at the end of the clamp from liquid nitrogen fixed brain samples. VMH lactate levels were elevated in RH rats compared to hypoglycemia-naïve controls (3.6±0.2 vs. 2.3±0.4 mM; P=0.03) and this was associated with impairments in the counterregulatory responses (37% and 45% reduction in glucagon and epinephrine, respectively; P&lt;0.05). Compared to the RH rats, inhibition of GP with DAB prevented the breakdown of VMH glycogen in RH rats (5.3±0.5 vs. 2.4±0.5 μmol/g tissue; P&lt;0.002), prevented the rise in VMH lactate levels (1.5±0.3 vs. 3.6±0.2 mM; P&lt;0.001) and prevented the onset of counterregulatory failure (glucagon and epinephrine responses were similar to controls, P=NS). Our data suggests that astrocytic glycogen likely serves as the primary source of lactate in the VMH of RH rats.

Disclosure
G. Su: None. O. Chan: None. R. Farhat: None. K. Chapman: None.
The Metabolic Effect of Chronic Elevated Erythropoietin in Tg6 Mice
Authors: ROGERS HEATHER , GAVRILOVA OKSANA , NOGUCHI CONSTANCE T. 
Published: June 2018

Erythropoietin (EPO) is the cytokine required for erythrocyte production. However, EPO receptor (EpoR) expression is not restricted to erythroid tissue and non-hematopoietic EPO action has been associated with the regulation of glucose homeostasis and fat mass accumulation in animal models. The hemizygous transgenic tg6 mouse (PDGF- promoter/human EPO cDNA) overexpresses EPO, allowing for the study of chronic elevated levels of EPO. Tg6 mice exhibit a hematocrit of 80-90%, almost twice that of their wild type (wt) littermates. The elevated EPO also alters their glucose metabolism. In both males and females, tg6 mice exhibit significantly lower fasting glucose and improved glucose tolerance with significantly reduced blood glucose levels during a 2-hour glucose tolerance test (GTT). EPO treatment in male wt mice reduces fat mass and body weight compared to saline treatment. Similarly, tg6 mice with chronic elevated EPO have been reported to exhibit reduced body mass compared with control mice. We find that male tg6 mice tend to have reduced body weight, becoming significant with age and due to an associated decrease in fat mass, and a trend toward reduced food intake. In contrast, while female tg6 mice show significant decreases in fat mass, their total body weight is similar to control mice due in part to an increase in lean body mass. These data suggest that metabolically, tg6 mice show improved glucose metabolism compared to control mice associated with a decrease fat store in both male and female mice, and with a sex-specific reduction in body weight in male mice. In addition, the increase in lean body mass in female mice counters the weight loss associated with decrease fat mass resulting in no apparent change in body weight.

Disclosure
H. Rogers: None. O. Gavrilova: None. C.T. Noguchi: None.
SRC-2 in POMC Neurons Mediates Energy Reserving Effects of Foxo1
Authors: YANG YONGJIE , XU YONG 
Published: June 2018

The nuclear receptor coactivator, steroid receptor coactivator-2 (SRC-2) is an essential for body weight control. However, the molecular mechanisms by which SRC-2 regulates energy homeostasis are not fully understood. Here we showed that SRC-2 is highly expressed by hypothalamic pro-opiomelanocortin (POMC) neurons. We then generated mice lacking SRC-2 selectively in POMC neurons. These mutant mice were more resistance to high fat-diet-induced obesity compared to wild type littermates. In addition, we observed that the mutant mice failed to properly suppress energy expenditure during food deprivation, refeeding response after fasting was impaired in these mutant mice, which was accompanied with increased POMC gene expression in the hypothalamus, increased firing rate, and decreased mIPSE amplitude of POMC neurons. Further anxiety-like behavior tests showed the mutant mice exhibited decreased motivational state and incentive salience of the food reward, and enhanced Dopamine signaling to POMC neurons. Interestingly, SRC-2 interacts with FoxO1 in mouse hypothalamus, and this interaction was enhanced by fasting. Finally, using luciferase assay, we showed that over-expression of SRC-2 significantly suppressed POMC expression. Collectively, our results indicate that SRC-2 in POMC neurons, as a nuclear receptor coactivator, interacts with FoxO1 to amplify its transcription suppressing effects on the POMC gene, and therefore mediates the energy reserving effects of FoxO1 during food deprivation.

Disclosure
Y. Yang: None. Y. Xu: None.
Bariatric Surgery in Patients with Type 1 Diabetes and Obesity—A Three-Year Observational Matched Cohort Study
Authors: MOTTALIB ADHAM , ALSIBAI KHALED , TOMAH SHAHEEN , ELSEAIDY TAHA , HOLLEY-CUTHRELL JENAN R. , MIDDELBEEK ROELAND , MAHMOUD NOOR , ASHRAFZADEH SAHAR , BROWN FLORENCE M. , HAMDY OSAMA 
Published: June 2018

Recent data show that ∼50% of patients with type 1 diabetes (T1D) are overweight or obese. Few patients with T1D and obesity resort to bariatric surgery (BS) for weight reduction and possible improvement in glycemic control. However, previous studies reported conflicting long-term effects of BS on glycemic control and other cardiovascular risk factors in this population. Meanwhile, no previous study compared BS outcomes in patients with T1D to a matched cohort receiving standard care.
In our electronic health records, we identified 20 patients with T1D and obesity who underwent BS and received diabetes care at our center (baseline mean age 41±10 years, T1D duration 24±12 years, all female, HbA1c 8.4±1.3%, BMI 43.6±6.3 kg/m2, weight 119.2±18.0 kg, systolic BP 128±11 mmHg, diastolic BP 75±8 mmHg, LDL-C 104±34 mg/dL, HDL-C 59±18 mg/dL, triglycerides 121±61mg/dL). We matched them in a 1:1 ratio with a similar cohort of patients who received standard diabetes care at the same center (baseline mean age 43±12 years, T1D duration 22±11 years, HbA1c 8.4±1.0%, BMI 43.9±6.3 kg/m2, weight 116.1±19.3 kg, systolic BP 123±17 mmHg, diastolic BP 71±9 mmHg, LDL-C 81±22 mg/dL, HDL-C 57±20 mg/dL, triglycerides 103±62mg/dL). T1D was confirmed based on the presence of antibodies, history of DKA and clinical criteria. There were no differences between cohorts at baseline, except that more patients used insulin pump therapy in the BS cohort (55% vs. 35%, p&lt;0.05).
At 3 years, body weight changed by -33.5±2.6 kg (-28.1±2.2%) in the BS cohort and by +2.6±2.8 kg (+2.2±2.4%) in the matched cohort (p&lt;0.0001). However, HbA1c, BP and LDL-C did not change from baseline in both cohorts. HDL-C increased and triglycerides decreased in the BS cohort in comparison to the matched cohort (p&lt;0.for both).
These results show that despite significant reduction in body weight and improvements in HDL-C and triglyceride levels, bariatric surgery has no long-term impact on glycemic control, BP and LDL-C in patients with T1D and obesity.

Disclosure
A. Mottalib: None. K. Alsibai: None. S. Tomah: None. T. Elseaidy: None. J.R. Holley-Cuthrell: None. R. Middelbeek: None. N. Mahmoud: None. S. Ashrafzadeh: None. F.M. Brown: None. O. Hamdy: Research Support; Self; Abbott. Advisory Panel; Self; AstraZeneca. Consultant; Self; Merck & Co., Inc.. Research Support; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Healthimation, LLC.. Consultant; Self; Sanofi-Aventis.
Acarbose and Pasireotide Reduce Hypoglycemia in Roux-en-Y Gastric Bypass Operated Subjects
Authors: ØHRSTRÔM CAROLINE , KIELGAST URD , HOLST JENS J. , WORM DORTE , HANSEN DORTE L. 
Published: June 2018

Introduction: Hypoglycemia is a severe complication after Roux-en-Y gastric bypass (RYGB), with no effective treatment options. We investigated the glucose stabilizing effects of five therapeutic agents in RYGB operated subjects with hypoglycemia.
Methods: In a randomized crossovers study, 11 RYGB operated subjects with documented hypoglycemia (blood glucose &lt;70.2 mg/dL) underwent six separate meal tolerance tests (Fresubin Energy Drink) preceded by either: no treatment (NT), acarbose 50 mg (A), sitagliptin 100 mg for 1 week (S), verapamil 120 mg for 1 week (V), liraglutide 1.2 mg for 3 weeks (L) or pasireotide 300 µg (P). Blood samples were drawn at fixed time intervals from -20 to 180 minutes. Hormonal responses were calculated as the incremental area under the curve (iAUC), and the glucose response was further specified as the area above (+iAUC) and below (-iAUC) baseline values. Data were analyzed by use of linear mixed models.
Results: Treatment with A and P significantly reduced -iAUCglucose (NT: 106±14 mmolxL-1xmin (mean±SEM) A: 63±14 mmolxL-1xmin, p=0.02; P: 0±0 mmolxL-1xmin, p&lt;0.0001). Additionally A reduced +iAUCglucose, whereas P increased this area (NT: 182±18 mmolxL-1xmin; A: 78±18 mmolxL-1xmin, p=0.0008; P: 1,144±62 mmolxL-1xmin, p&lt;0.0001). Time spent in hypoglycemia decreased with both A and P (NT: 48±12 min; A: 5±3 min, p=0.02; P: 0±0 min, p&lt;0.0001), whereas time in hyperglycemia (&gt;140.4 mg/dL) decreased with A but increased with P (NT: 29±4 min; A: 5±5 min, p=0.0017; P: 159±6 min, p&lt;0.0001). Treatment with A and P both reduced iAUCinsulin (NT: 534±8 nmolxL-1xmin; A: 22±3 nmolxL-1xmin, p=0.0009; P: 14±2 nmolxL-1xmin, p&lt;0.0001). Treatment with S, V and L did not have a significant impact on any of the measurements.
Conclusion: Acarbose reduced both hypoglycemia and hyperglycemia, whereas pasireotide resolved hypoglycemia, but at the cost of increased hyperglycemia. Both acarbose and pasireotide can be considered in the treatment of hypoglycemia after RYGB.

Disclosure
C. øhrstrôm: None. U. Kielgast: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. D. Worm: None. D.L. Hansen: None.
The Existence of Superficial Dorsocervical Brown Adipose Tissue in Women
Authors: FLETCHER LAURA , LEITNER BROOKS , KIM KATHERINE I. , MCGEHEE SUZANNE , BRYCHTA ROBERT , CYPESS AARON , CHEN KONG Y. 
Published: June 2018

Background: Cold stimulation of human brown adipose tissue (BAT) can increase its glucose uptake and energy expenditure, making it a potential target for treating obesity and metabolic disease. BAT is commonly found in deeper fascial layers of specific depots. We observed a distinct sexual dimorphism in the dorsal side of the cervical BAT depot.
Methods: Twenty-one healthy, lean, young subjects (12 men, mean BMI 23 ± 2.1 kg/m2), were exposed to five hours of tolerable cold exposure. BAT was measured via by 18F-FDG PET/CT.
Results: Men and women had similar total BAT metabolic activity. We classified the cervical BAT depot into two distinct anatomically continuous areas: a deeper, intermuscular region, and a superficial, dorsocervical region (sdBAT, Figure A-B), sdBAT was present in 6 women, but only in one man (Figure C). Women had less lean mass than men (p&lt;0.001). In women, individual sdBAT metabolic activity was negatively correlated with lean body mass (p=0.05) and positively correlated with total and cervical BAT (p≤0.04).
Conclusions: We believe that sdBAT in women is likely part of the same fascial layer as the classical cervical depot. But based on its location, the sdBAT depot could be a remnant of interscapular BAT seen in rodents and human newborns. These findings are consistent with a model in which the dominant source of thermogenesis is lean tissue, which is lower in women, and when insufficient leads to BAT activation.

Disclosure
L. Fletcher: None. B. Leitner: None. K.I. Kim: None. S. McGehee: None. R. Brychta: None. A. Cypess: None. K.Y. Chen: None.
Lower Stearoyl-CoA Desaturase and Hormone Sensitive Lipase Gene Expression in Superficial Subcutaneous Adipose Tissue of Male, but Not Female, Patients with Type 2 Diabetes
Authors: BÓDIS KÁLMÁN , LUNDBOM JESPER , JELENIK TOMAS , MARKGRAF DANIEL F. , STROM ALEXANDER , ZAHARIA OANA P. , KARUSHEVA YANISLAVA , BURKART VOLKER , MÜSSIG KARSTEN , KUPRIYANOVA YULIYA , OUNI MERIEM , HWANG JONG-HEE , ZIEGLER DAN , SCHUERMANN ANNETTE , RODEN MICHAEL , SZENDROEDI JULIA 
Published: June 2018

Mitochondrial gene expression in visceral (VAT) and lipogenesis in abdominal subcutaneous adipose tissue (SAT) are lower in insulin resistance (IR). Humans with hormone sensitive lipase (HSL) gene mutations are prone to type 2 diabetes (T2D). SAT is divided into deep (DSAT) and superficial SAT (SSAT). SSAT was speculated to be protective in T2D, but gender specificity is unknown. We hypothesized lower mitochondrial efficiency as well as lower markers of lipogenesis and lipolysis in SSAT only in male T2D patients vs. glucose-tolerant humans (CON), which may characterize dysfunctional SSAT. In 20 T2D and 20 CON matched for sex, BMI and age (female/male: 6/14 per group; 32±1 vs. 31±1 kg/m2, 52±2 vs. 54±2 years), we assessed M-values by euglycemic-hyperinsulinemic clamps, liver fat content (HCL) and VAT by MRS. In biopsies of SSAT, mitochondrial oxidative capacity was measured by respirometry, lipogenesis assessed from stearoyl-CoA desaturase (SCD) mRNA, lipolysis from adipocyte triglyceride lipase (ATGL) and HSL mRNA by RTqPCR. The insulin resistant T2D had 63% and 22% higher HCL (p&lt;0.01) and VAT (p&lt;0.05) than CON. In SSAT, T2D featured 20%, 50%, 70%, 49% reductions in oxidative capacity, SCD, ATGL and HSL mRNA (all p&lt;0.05). Gender segregated analyzes showed higher oxidative capacity only in females, whereas only ATGL was also lower in female T2D vs. CON. In T2D, VAT was 22% lower (p&lt;0.01) and HSL mRNA 70% higher (both p&lt;0.001) in female than in male participants.
In conclusion, lower lipogenesis and lipolysis in SSAT of male T2D patients may lead to inadequate lipid storage in SSAT, thereby promoting ectopic fat storage as HCL and VAT.

Disclosure
K. Bódis: None. J. Lundbom: None. T. Jelenik: None. D.F. Markgraf: None. A. Strom: None. O.P. Zaharia: None. Y. Karusheva: None. V. Burkart: None. K. Müssig: None. Y. Kupriyanova: None. M. Ouni: None. J. Hwang: None. D. Ziegler: None. A. Schuermann: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. J. Szendroedi: None.