bluuebunny/crossref_metadata_2025 huggingface dataset:
Carvedilol Prevents Counterregulatory Failure in Recurrently Hypoglycemic Rats
Authors: FARHAT RAWAD , SU GONG , CHAN OWEN
Published: June 2018

We showed previously that recurring activation of β2-adrenergic receptors in the ventromedial hypothalamus (VMH) leads to the development of counterregulatory failure, in part by increasing local lactate levels. The current study evaluates whether the non-selective β-blocker, carvedilol, can be used to prevent the development of counterregulatory failure and improve hypoglycemia awareness (HA) in recurrently hypoglycemic (RH) rats. Sprague-Dawley rats (n=6-10 per group) underwent surgery for the implantation of vascular catheters and intracranial guide cannulas that targeted the VMH. These animals then received either 3 bouts of insulin-induced hypoglycemia (RH) over the course of 3 days or they received 3 injections of saline (Controls). A subgroup of RH rats was treated with carvedilol (3mg/kg QID; IP) beginning one day prior to the start of RH and continuing through to the last episode of hypoglycemia. Following the last bout of hypoglycemia, the animals underwent a hypoglycemic clamp with microdialysis to evaluate changes in central lactate and hormone levels. Compared to controls, RH increased VMH lactate by 1.7-fold (P<0.03) and this was associated with an impaired counterregulatory response to hypoglycemia (glucagon and epinephrine responses were reduced by ∼45% and ∼73%, respectively, P<0.04), as expected. Treatment of RH animals with carvedilol restored VMH lactate levels and improved the counterregulatory responses to hypoglycemia. To assess whether carvedilol improved HA, we treated rats that were made “hypoglycemia unaware” with repeated 2-deoxyglucose (2DG; 200mg/kg, SQ) injections with carvedilol and measured food intake in response to insulin-induced hypoglycemia as a surrogate marker for HA. Compared to Controls, 2DG reduced food intake in response to hypoglycemia and treatment with carvedilol increased food intake in 2DG rats (P<0.01). We conclude that carvedilol may be a useful therapeutic strategy to prevent counterregulatory failure and improve HA in RH rats.

Disclosure

R. Farhat: None. G. Su: None. O. Chan: None.
Diet-Dependent Sex Differences in the Response to Bariatric Surgery
Authors: HUTCH CHELSEA , STELMAK DARIA , SINGER KANAKADURGA , SANDOVAL DARLEEN A.
Published: June 2018

Despite the well-known efficacy of bariatric surgery in reducing body mass and improving metabolic outcomes, the mechanisms underlying these dramatic effects are not fully understood. Nearly 80% of patients that receive bariatric surgery are women, yet mechanistic pre-clinical studies have focused exclusively on males. Premenopausal women have a reduced risk for obesity-associated co-morbidities and enhanced lipid metabolism. Although both sexes lose weight and benefit metabolically after bariatric surgery, clear physiological sex differences in metabolism suggest the mechanistic pathway to those outcomes are dependent upon sex and hormone status. The goal of this study was to determine the impact of diet- and surgery-induced weight loss on sex differences in glucose regulation and hepatic lipid metabolism. Male and female mice were fed a 60% high-fat (HF) diet 12 weeks before undergoing either vertical sleeve gastrectomy (VSG) or sham surgery. After surgery, mice either remained on a HF diet or were switched to a standard chow diet. Both males and females decreased fat-mass after VSG, yet males showed further body mass loss on a chow diet. Both sexes improved fasting glucose and oral glucose tolerance on a HF diet after VSG, while only males showed further benefit from surgery and chow diet. Despite continued HF diet feeding, male but not female mice show significant improvements in hepatic triglyceride levels after VSG relative to their sham surgery counterparts. However, when mice were switched to a low-calorie chow diet both males and females reduced hepatic triglycerides after VSG. Furthermore, removing female gonadal hormones, via ovariectomy, did not impact hepatic triglyceride levels after VSG. Overall, these data suggest that the impact of surgery on hepatic triglycerides is diet-dependent in females and support the hypothesis that males and females achieve similar metabolic outcome, at least within the liver, via distinct mechanisms.

Disclosure

C. Hutch: None. D. Stelmak: None. K. Singer: None. D.A. Sandoval: Research Support; Self; Novo Nordisk A/S, Zafgen, Ethicon US, LLC..
Combination Linagliptin and Empagliflozin Therapy Improves Diastolic Function in Female Diabetic db/db Mice
Authors: HABIBI JAVAD , AROOR ANNAYYA R. , KLEIN THOMAS , MAYOUX ERIC , DEMARCO VINCENT
Published: June 2018

We recently reported that linagliptin (LINA) and empagliflozin (EMPA) monotherapies exhibit favorable effects in the heart, vasculature and kidneys in murine models of prediabetes and diabetes. Herein, we extend those studies by testing whether these two drugs used in combination improve diastolic function in diabetic female db/db mice. Eleven week old db/db mice were fed a diet containing LINA (2mg/kg/day) or EMPA (10mg/kg/day) monotherapy for 10 weeks (dbE10, dbL10). Additional groups received add-on therapy after 5 weeks on monotherapy (LINA added to EMPA (dbE10/L5) or EMPA added to LINA (dbL10/E5)). One group received LINA and EMPA combination therapy for the entire 10 week test period (dbL10/E10). One group was untreated (DbC). Glycemia, cardiac function, fibrosis and hypertrophy were examined by HbA1c, tissue Doppler ultrasound and histology. With the exception of LINA monotherapy, HbA1c was reduced in all other treated groups (p<0.05). Compared to lean mice on background strain (CkC), myocardial wall motion during diastole was impaired in untreated db/db mice, indicated by increased E/E’ ratio (LV filling pressure), and this was improved with mono- and add-on therapies. Myocardial fibrosis and hypertrophy were improved with mono- and add-on therapies.

In summary, the combination of LINA and EMPA appeared to be as cardioprotective as monotherapies of each drug.# weeks on E or LType of therapyDiastolic FunctionGlycemiaCardiac RemodelingE, EMPA L, LINAE/E’ RatioHbA1c %Intersititial Fibrosis (AGSI)Cardiomyocyte cross sectional area (μm2)CkCuntreated18 ± 34.3 ± 0.2---368 ± 33DbCuntreated56 ± 3*11.0 ±0.6*4.9 ± 0.6533 ± 34†db E10mono38 ± 3*†5.9±0.2*†2.8 ± 0.2†433 ± 15†dbL10mono36 ± 2*†10.8±0.5*2.8 ± 0.2†411 ± 11†dbE10/L5L added to E35 ± 4*†6.5±0.2*†3.2 ± 0.2†421 ± 26†dbL10/E5E added to L34 ± 2*†6.9±0.3*†2.8 ± 0.1†358 ±12†dbL10/E10combo44 ± 6*†6.1±0.2*†3.2 ± 0.1†430 ± 21†*p<0.vs CkC †p<0.vs DbC

Disclosure

J. Habibi: None. A.R. Aroor: None. T. Klein: Employee; Self; Boehringer Ingelheim GmbH. E. Mayoux: None. V. DeMarco: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc..
Global Prevalence of Type 2 Diabetes over the Next Ten Years (2018-2028)
Authors: KAISER AMY BRADSHAW , ZHANG NICOLE , DER PLUIJM WOUTER VAN
Published: June 2018

Objective: We aimed to estimate the global prevalence of type 2 diabetes over the next ten years, taking into account trends in obesity. Our analysis includes estimates for 45 countries representing almost 90% of the world population. We defined a prevalent case as anyone living with type 2 diabetes, irrespective of whether it has been formally diagnosed or not and excluded type 1 diabetes cases.

Methods: We performed a global systematic search of published studies and other data sources that reported the prevalence of type 2 diabetes, as well as any factors that may change its risk or prognosis over time or between countries. Our analysis is based on critically-appraised literature and database evidence that reports the total prevalence of type 2 diabetes. From the results of this search, we appraised and selected country-specific estimates to project up to national totals. These estimates were adjusted to account for historical or future trends in risk, as well as relevant differences between countries when extrapolations were made. Our model includes country-specific obesity prevalence to incorporate the impact of obesity on diabetes trends.

Results: We estimate that in 2018 there are more than 500 million prevalent cases of type 2 diabetes worldwide and the prevalence is comparable between high- and low-income countries. The prevalence will increase in all countries covered over the projection period, but the greatest growth will be experienced in lower-income countries.

Disclosure

A. Bradshaw Kaiser: None. N. Zhang: None.
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<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<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<0.002), prevented the rise in VMH lactate levels (1.5±0.3 vs. 3.6±0.2 mM; P<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<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<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<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 <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<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<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<0.0001), whereas time in hyperglycemia (>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<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<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<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<0.01) and VAT (p<0.05) than CON. In SSAT, T2D featured 20%, 50%, 70%, 49% reductions in oxidative capacity, SCD, ATGL and HSL mRNA (all p<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<0.01) and HSL mRNA 70% higher (both p<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.
The Relationships between Serum Levels of Adipokines, Body Fat Distribution, and Subcutaneous Microvasculature in Type 2 Diabetic Subjects
Authors: KLIMONTOV VADIM , BULUMBAEVA DINARA , BGATOVA NATALIYA P. , TASKAEVA IULIIA , FAZULLINA OLGA , ORLOV NIKOLAI , KORBUT ANTON I. , SAVCHENKO SERGEY , KONENKOV VLADIMIR
Published: June 2018

The aim of the study: to determine the relationships between serum levels of adipokines, body fat distribution, density and ultrastructure of blood and lymphatic microvessels in subcutaneous adipose tissue (AT) in type 2 diabetic subjects. We observed 125 patients with type 2 diabetes, including 82 subjects with obesity, and 30 lean nondiabetic individuals matched by sex and age. The concentrations of leptin, resistin, visfatin, adipsin, and adiponectin in the fasting serum were determined by Multiplex analysis. The fat mass and AT distribution was assessed by DEXA. The samples of subcutaneous abdominal AT were obtained with the knife biopsy in 25 patients and in 15 healthy subjects. Immunohistochemistry for biomarkers CD-34, podoplanin (D2-40) and LYVE-1 was applied to identify the blood and lymphatic microvessels. The volume density, numeral density and ultrastructure of blood and lymphatic microvessels were assessed. Patients with diabetes, as compared to control, had significantly higher levels of leptin (p=0.004), resistin (p<0.0001), adipsin (p<0.0001) and visfatin (p=0.0003). The concentrations of leptin and adipsin were associated with total, truncal, android and gynoid fat mass. The levels of resistin and adiponectin demonstrated relationships with gynoid fat mass only. In obese diabetic subjects an increase in the volume and numeral density of podoplanin-expressing lymphatic vessels was observed. The swelling of cytoplasm, mitochondria, rough endoplasmic reticulum and reduced content of micropinocytic vesicles was revealed in lymphatic capillaries. The levels of leptin and adipsin, but not resistin and visfatin levels, correlated negatively with the numeral density of microvessels in subcutaneous AT (r=-0.53 and r=-0.32 respectively).

In conclusion, the levels of circulating adipokines in patients with type 2 diabetes are related in varying degrees with body fat distribution and AT microvessel density.

Disclosure

V. Klimontov: None. D. Bulumbaeva: None. N.P. Bgatova: None. I. Taskaeva: None. O. Fazullina: None. N. Orlov: None. A.I. Korbut: None. S. Savchenko: None. V. Konenkov: None.
Overnight Insulin Delivery and Glucose in Children Using the MiniMed™ 670G System
Authors: ROY ANIRBAN , GROSMAN BENYAMIN , PARIKH NEHA , WU DI , LEE SCOTT W. , KAUFMAN FRANCINE R.
Published: June 2018

The Medtronic MiniMed™ 670G hybrid closed-loop system was designed to automatically adjust basal insulin delivery every 5 minutes based on sensor glucose (SG) values. Its safety and effectiveness have been recently investigated in a multi-center pivotal trial conducted in 1T1D children aged 7-13 years.

During the 2 week run-in phase, participants used the system in Manual Mode. This was followed by a 3-month at-home study phase in which the Auto Mode feature was enabled. The SG data and the amount of insulin delivered were analyzed during the overnight period (11:00 p.m.-7:00 a.m.).

Figure-1 (top panel) shows overnight SG tracings from the run-in phase and study phase, and that the median [IQR] reduced significantly from run-in (142 [71]mg/dL) to study phase (126 [34]mg/dL), by 7:00 a.m. This was mainly achieved by the system transferring variability from SG to insulin infusion rate (bottom panel). During the nighttime period, the system suspended insulin for an average 1.3 hours and delivered insulin at the maximum allowable limit for an average 3.6 hours. The remainder of the time, it delivered insulin between 1-99% of the maximum allowable limit.

These data suggest that greater variability of basal insulin delivery, such as that achieved with MiniMed™ 670G system automation, compared to fixed pre-set basal rates, improves nighttime glucose control in children.

Disclosure

A. Roy: Employee; Self; Medtronic MiniMed, Inc. B. Grosman: Employee; Self; Medtronic. N. Parikh: Employee; Self; Medtronic. D. Wu: None. S.W. Lee: Employee; Self; Medtronic. F.R. Kaufman: Employee; Self; Medtronic.
Thyroid Function Improved after Laparoscopic Sleeve Gastrectomy in Severe Obesity and Related to Inflammatory Changes
Authors: ZHU CUILING , MEI FANGYUN , GAO JINGYANG , WANG XINGCHUN , LI LIANG , LU LIESHENG , ZHOU DONGLEI , QU SHEN
Published: June 2018

Objective: Obesity, a state of chronic low grade inflammation, has been reported to be associated with significant alterations of thyroid function. The purpose of this study is to evaluate the effect of laparoscopic sleeve gastrectomy (LSG) on thyroid function and its relation with inflammatory changes in severely obese patients.

Methods: We performed a retrospective observational study of 128 severely obese patients (61.7% female; age 31.8 ± 10.0 years, BMI 39.4 ± 5.8 kg/m2) submitted to LSG. Patients were subdivided in two groups: euthyroid group and subclinical hypothyroidism (SCH) group. TSH, FT4, anthropometric data, and inflammatory markers were collected pre- and 1, 3, 6, and 12 months post-LSG.

Results: The mean percent weight loss at 12 months was 37.2% ± 11.8%. The mean BMI decreased from 39.4 ± 5.8 kg/m2 to 27.1 ± 3.9 kg/m2. Patients with SCH (37.5% of patients) and higher TSH showed higher BMI, HOMA-IR, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) than those in euthyroid group (all P < 0.05). After surgery, TSH levels significantly decreased at 1, 3, 6, and 12 months regardless of thyroid function, which presented more apparent in SCH group. Additionally, we observed marked reduction of IL-6, IL-8, TNF-α, and CRP levels in SCH group, as well as IL-8, TNF-α, and CRP in euthyroid group from baseline by 12 months postoperatively. Moreover, decreased TSH levels correlated significantly with decreased BMI, HOMA-IR, IL-6, and TNF-α at 12 months after LSG.

Conclusion: SCH in severely obesity subjects appears to be associated with excess weight, insulin resistance, and elevated inflammatory markers. LSG promotes a decrease of TSH that is significantly greater in patients with SCH, and associated with alleviation of inflammatory status in addition to substantial weight loss and improved insulin resistance after surgery.

Disclosure

C. Zhu: None. F. Mei: None. J. Gao: None. X. Wang: None. L. Li: None. L. Lu: None. D. Zhou: None. S. Qu: None.
Alteration of Bone Mineral Density Differs between Genders in Obese Subjects after Laparoscopic Sleeve Gastrectomy—Bone Morphogenetic Protein 4 May Count
Authors: WANG XINGCHUN , LI LIANG , ZHU CUILING , GAO JINGYANG , QU SHEN
Published: June 2018

Laparoscopic sleeve gastrectomy (LSG) has been proven successfully in weight reduction but with potential loss of bone mass. Previous studies indicate that bone morphogenetic protein 4 (BMP4) plays an important role both in bone formation and glucose-lipid metabolism. This study aimed to investigate the alteration of bone mineral density (BMD), bone metabolic parameters and serum BMP4 levels in Chinese obese subjects after LSG. Seventy-one obese patients (34 males, age 31.70±9.61 years and 37 females, age 32.80±11.45 years) were enrolled. BMD (at right hip, femoral neck and lumbar spine 1-4 (L1-L4) by dual-energy X-ray absorptiometry), bone metabolic markers and routine anthropometric/laboratory biochemical parameters at baseline, 3, 6 and 12 months after LSG (abbreviated as 3M/6M/12M Post-LSG) were recorded. Serum BMP4 levels were measured by enzyme-link immunosorbent assay. In females, BMD was significantly decreased at right hip at 3M/6M/12M Post-LSG, femoral neck at 6M/12M Post-LSG and L1-L4 at 6M Post-LSG (all P<0.05). In males, BMD was not significantly changed (all P>0.05). Intriguingly, serum BMP4 levels were reduced slightly at 3M Post-LSG (P=0.463), and significantly at 6M Post-LSG (from 75.51±16.54pg/ml to 65.40±10.51pg/ml, P=0.048) in females, while unchanged in males (all P>0.05). In all subjects, free calcium but not total calcium was increased at 12M Post-LSG (P=0.028). Vitamin D and 25(OH)VD were increased in males at 12M Post-LSG (all P<0.05). Osteocalcin was increased in males at 3M/6M/12M Post-LSG and in females at 3M/6M Post-LSG (all P<0.05). Type I collagen was increased in males at 3M/6M Post-LSG and in females at 3M/6M/12M Post-LSG (all P<0.05).

In conclusion, the change of BMD differs between genders after LSG, significantly decreased in females while unchanged in males. Moreover, the decreased BMP4 levels may partly account for the diminished BMD in Chinese female obese subjects after LSG.

Disclosure

X. Wang: None. L. Li: None. C. Zhu: None. J. Gao: None. S. Qu: None.
Collaborative Intensive Lifestyle Weight (Wt) Loss Intervention in Underserved Predominantly African-American (AA) Patients in Chicago
Authors: POKU CAROLINE , TAHSIN BETTINA , FOGELFELD LEON
Published: June 2018

Minorities are disproportionately affected by obesity. Intensive lifestyle interventions (ILI) have been shown to result in a moderate amount of clinically significant weight loss (5% BW), less so in minorities. Few ILI are culturally adapted for minorities. A collaborative multidisciplinary team implemented a culturally-tailored ILI using current guidelines in a predominantly AA obese population in a primary care setting. Program consisted of individual and group sessions led by MD, RD, PT, and psychologist meeting for 6 months. After the initial ILI, a 6 month maintenance period of monthly meetings with an intensification every 3rd month of 3 visits/month aimed to prevent weight regain. Program goals were to attain a 5% weight loss in 6 months and prevent weight regain after the intensive phase. 40 English-speaking patients enrolled: median age 52.0 years (41.5, 60.0), 77.5% female, 72% AA, 15% Hispanic with median weight 279.9 lbs (236.0, 324.1) and median BMI 44.7 kg/m2 (37.7, 50.1). 60% completed the program with 25% of those achieving at least 5% weightt loss in 6 months. Results correlated with attendance (Figure). Of the 25% attaining the initial 5% weight loss, 60% showed continued weight loss in maintenance, notably after intensification periods. In this study, attendance and maintenance intensification appeared to be key to continued loss success.

Disclosure

C. Poku: None. B. Tahsin: None. L. Fogelfeld: None.
Improved Insulin Sensitivity and Irisin after a Dietary Weight-Lowering Program in Obese, Otherwise Healthy Subjects
Authors: PENESOVA ADELA , RADIKOVA ZOFIA , BAJER BORIS , VLCEK MIROSLAV
Published: June 2018

Recent studies suggest that serum irisin might be a predictor of insulin resistance in obese subjects. The aim of the study was to analyze the effect of life style intervention on insulin sensitivity, irisin, and visfatin concentrations.

Methods: A group of 43 obese patients (13M/30F; 43.0 ±12.4 years; BMI 31.2 ± 6.3 kg/m2) participated in a weight loss interventional program (NCT02325804) following an 8-week program consisting of hypocaloric diet (-30% energy intake) and physical activity 150 minutes/week. Insulin sensitivity was evaluated according to the homeostasis model assessment of insulin resistance (HOMA-IR) and insulin sensitivity indices according Matsuda and Cederholm were calculated (ISIMat and ISICed). Plasma ALT, AST, irisin, visfatin, and physical fitness were measured.

Results: The average reduction of body weight was 6.8±4.9 kg (0-15 kg; p=0.0006), accompanied with significant reduction of body fat mass (p=0.03), and waist circumference (p=0.02). Insulin sensitivity improved (IR HOMA 2.71±3.90 vs. 1.24 ±0.83; p=0.01; ISIMat 6.64±4.38 vs. 8.93±5.36 p ≤ 0.001; ISICed 59.1±21.4 vs. 64.7±22.2 p=0.03). Total and LDL cholesterol, as well as triglycerides decreased (p=0.02, p=0.02, p=0.resp.), Physical fitness significantly improved after intervention (as measured by VO2 max: 25.1±5.9 vs. 28.0±6.0 ml.kg-1.min-1, p ≤ 0.001). Plasma irisin significantly decreased after intervention (233 ± 66 vs. 167 ± 88 ng/mL; P ≤ 0.001), while visfatin levels did not changed.

Conclusion: Eight weeks of diet and physical activity intervention program in obese otherwise healthy subjects leaded to improvement of insulin sensitivity, as well as physical fitness and lowering of plasma irirsin levels. Irisin strongly reflects body fat mass, suggesting that the irisin circulating levels are conditioned by adiposity level.

Disclosure

A. Penesova: None. Z. Radikova: None. B. Bajer: None. M. Vlcek: None.
Role of Free Fatty Acids in the Alteration of Cardiovascular Autonomic Activity and Its Postprandial Changes in Obese Patients with Glucose Intolerance
Authors: REZKI AMEL , FYSEKIDIS MARINOS , SABRINA CHIHEB , BANU ISABELA , COSSON EMMANUEL , VALENSI PAUL
Published: June 2018

Rationale: Depressed cardiac vagal activity and elevated sympathetic activity have been reported in prediabetic obese patients. In healthy individuals, insulin was shown to acutely induce such changes, and free fatty acids (FFA) to enhance sympathetic activity. This study aimed to examine the relations between glycemia, insulinemia and plasma FFA with cardio-vascular autonomic activity in obese patients with glucose intolerance.

Patients and Methods: We included 24 obese patients (BMI 36.6±5.0 kg/m²) with glucose intolerance, normal blood pressure, and no cardio-vascular events. Cardiac vagal (HFnu-HR) and sympathetic (LFnu-HR) activity, and sympatho-vagal balance (LF/HF-HR) were measured by spectral analysis of heart rate variations during 6 minutes of controlled breathing rate (12 cycles/minute) (Task Force Monitor®). These measurements were performed at fasting and after a standardised breakfast including 75g of carbohydrates. The changes (∆) between fasting and 2 hours after breakfast were calculated.

Results: At fasting, age correlated positively with LFnu-HR (p=0.02) and negatively with HFnu-HR (p=0.02). There was no significant correlation between autonomic indexes and glycemia and insulinemia. At fasting, FFA correlated positively with LFnu-HR and LF/HF-HR and negatively with HFnu-HR (p<0.04 and <0.02, respectively); and positively with nitrotyrosine (p=0.02). The correlations of FFA with spectral indexes were not altered after age adjustment, but were no more significant after adjustment for nitrotyrosine. Post-prandially, ∆FFA correlated positively with ∆LFnu-HR and ∆LF/HFnu-HR and negatively with ∆HFnu-HR (p<0.04 to <0.02).

Conclusion: In prediabetic obese patients, FFA (lipotoxicity) play an important role both at fasting and post-prandially in sympathetic activation and vagal depression, probably by increasing oxidative stress. These effects could increase the arrhythmogenic risk.

Disclosure

A. Rezki: None. M. Fysekidis: None. C. Sabrina: None. I. Banu: None. E. Cosson: Consultant; Self; Lilly France. Board Member; Self; Novartis France. Consultant; Self; Roche Diagnostics France. Board Member; Self; Ascensia Diabetes Care. Consultant; Self; Bezins France. Board Member; Self; MSD France. P. Valensi: None.