bluuebunny/crossref_metadata_2025 huggingface dataset:
1765-P: PACAP from the Ventromedial Hypothalamic Nucleus Controls Energy Expenditure
Authors: JOHNSON DAVID Q. , FLAK JONATHAN
Published: June 2020

Body energy homeostatic mechanisms dynamically balance energy expenditure with energy intake, and the brain plays a critical role in this process. However, the specific circuits responsible for controlling energy expenditure are only superficially understood. Because Ventromedial Hypothalamic (VMN)-specific expression of pituitary adenylate cyclase-activating polypeptide (PACAP) decreases with both under-nutrition and loss of leptin action, we tested the hypothesis that VMN PACAP controls energy expenditure. Since PACAP is expressed in the periphery, we administered a VMN-targeted injection of AAVcre in PACAPflox mice to remove VMN PACAP (PACAPVMNKO), which resulted in a near complete bilateral ablation of PACAP mRNA in the VMN without interfering with PACAP mRNA in nearby sites (e.g., preoptic area (POA) and medial amygdala). In both male and female mice, PACAPVMNKO induced massive obesity and more than a two-fold increase in adipose mass. This induced obesity, similar to other VMN loss of function studies, is due to chronically suppressed energy expenditure because VO2, but not activity, was decreased in these mice. PACAPVMNKO mice were also hyperinsulinemic, hyperglycemic, and exhibited impaired glucose clearance in the hyperinsulinemic/hyperglycemic clamp. However, PACAPVMNKO mice were normoglycemic 4 weeks post-injection (prior to obesity), indicating that glycemic effects were secondary to obesity. Because the VMN does not contain directly pre-autonomic neurons, PACAP must activate a circuit via a downstream site to stimulate energy expenditure. PAC1r cells primarily overlay with VMN projections in the POA and to a lesser extent in the periaqueductal grey and bed nucleus of the stria terminalis. VMN PACAP, as well as associated signaling targets, are critical components to the control of energy balance by activating energy expenditure.

Disclosure

D.Q. Johnson: None. J. Flak: None.

Funding

American Diabetes Association/Pathway to Stop Diabetes (1-17-INI-15 to J.F.); National Institutes of Health (DK020572)
1770-P: Role of Prolactin Rhythm in the Development of Nonalcoholic Fatty Liver Disease
Authors: YAN BI , ZHANG PENGZI , ZHU DALONG
Published: June 2020

Circadian disorder such as light exposure at night are risk factors for NAFLD Prolactin (PRL), a pituitary derived hormone, is recently shown to improve fatty liver. Noteworthy, PRL is secreted in an oscillating pattern. We aimed to explore the role of PRL rhythm in hepatic lipid metabolism. Serum PRL levels in 8:00, 16:00, and 24:00 of subjects without or with NAFLD were evaluated. A cosine model was fitted to the curve of dynamic PRL levels. Luciferase report assay, ChIP and EMSA were used to examine the mechanism of PRL rhythm. Hight fat diet (HFD) C57BL/6 mice were categorized into HFD, HFD+jet-lag group for 16 weeks and serum PRL levels at ZT0, ZT4, ZT8, ZT12, ZT16, ZT20 were determined. Then mice in HFD+jet-lag group were randomly assigned to HFD+ jet lag and HFD+jet-lag+PRL for 14 days. Hepatic lipid content, clock genes and lipid metabolic genes in liver were detected. PRL in 8:00, 16:00 and 24:00 were all significantly lower in NAFLD group than in controls. Cosine curve analysis showed that NAFLD patients had reduced amplitude and delayed phase shift of PRL levels. After adjusted for confounders, light exposure at night is a risk factor for NAFLD, yet this association was dampened after adjusted for PRL rhythm. Luciferase report assay in 293T cell and EMSA assay in human pituitary tissue showed that Prl can be transactivated by core clock gene Rorα via RORα response element RORE. In mice, dynamic PRL attained highest levels at ZT12 in HFD mice but remained low in HFD+jet-lag mice. ChIP analysis showed that binding of Rorα and Prl promoter in HFD mouse pituitary at ZT12 was inhibited under HFD+jet-lag. Furthermore, hepatic lipid content was significantly higher in HFD+jet-lag group than that in HFD, and can be mitigated after 14 days PRL intervention at ZT12. We also found that PRL injection reversed changes of clock and lipid metabolic gene rhythm caused by jet-lag. PRL can serve as an endocrine sensor that transmits rhythmic signals from central nervous system to liver and thus regulating hepatic lipid metabolism.

Disclosure

B. Yan: None. P. Zhang: None. D. Zhu: None.

Funding

National Natural Science Foundation of China (81900787, 81770819)
1772-P: Reversibility of Altered Brain Glucose Kinetics in T2DM
Authors: RANGEL ELIZABETH SANCHEZ , GUNAWAN FELONA , JIANG LIHONG , SAVOYE MARY , DAI FENG , ROTHMAN DOUGLAS L. , MASON GRAEME F. , HWANG JANICE J.
Published: June 2020

Poor glycemic control is associated with central nervous system complications. We have previously shown that compared to healthy controls, individuals with uncontrolled T2DM have a blunted rise in brain glucose levels measured by 1H magnetic resonance spectroscopy (MRS). In this study, we investigate whether reduction in HbA1C improves intracerebral glucose levels. Six T2DM subjects with poor glycemic control were recruited (4F, age 46.0 ± 8.8 yrs, BMI 34.2 ± 4.1 kg/m2, HgbA1c 9.6 ± 1.1%) to participate in 1HMRS scanning at 4 Tesla during a hyperglycemic clamp (∼220 mg/dl) before and after a 12-week intervention to improve glycemic control through use of continuous glucose monitoring, intensification of diabetes regimen, and frequent visits with an endocrinologist and nutritionist. Following the intervention, HbA1c decreased by 2.1%±1.5 (P=0.02) with minimal BMI changes (P=0.10). Using a hierarchical linear regression model to compare glucose time courses during the clamp pre and post intervention, brain glucose levels were modestly and significantly higher during the clamp after the intervention (P=0.02) despite no differences in plasma glucose levels during the clamp (P=0.45). These findings suggest that brain glucose levels increase after improvement of glycemic control and provide evidence that reducing HbA1C may improve brain glucose transport and/or metabolism.

Disclosure

E. Sanchez Rangel: None. F. Gunawan: None. L. Jiang: None. M. Savoye: None. F. Dai: None. D.L. Rothman: None. G.F. Mason: None. J.J. Hwang: Research Support; Self; General Electric.

Funding

National Institutes of Health (DK109284)
1785-P: Drug-Induced Blockade of the Herg-Voltage-Gated Potassium Channel Decreases Glucose-Stimulated Insulin and GLP-1 Secretion in Healthy Participants: A Crossover Study
Authors: JUHL CHRISTIAN R. , BURGDORF JOSEPHINE , KNUDSEN CECILIE , VEEDFALD SIMON , HOLST JENS J. , KANTERS JØRGEN , TOREKOV SIGNE S.
Published: June 2020

Background: Patients with Long-QT syndrome (LQTS) due to a loss-of-function mutation in hERG, encoding the hERG-voltage-gated potassium channel (Kv11.1), exhibit increased glucose-stimulated insulin secretion, defective glucagon secretion, and postprandial hypoglycemia. Recently, LQTS has been reported to be associated with an increased risk of type 2 diabetes. We aimed to investigate the effect of drug-induced (moxifloxacin) blockade of the hERG-channel on glucose homeostasis.

Methods: Using a double-blinded, randomized, placebo-controlled, crossover design, 40 healthy young participants underwent two 6-hours oral glucose tolerance tests (OGTT). The intervention was a 4-day treatment period with a selective hERG-blocker (the antibiotic moxifloxacin 800 mg/day) or placebo, final dose two hours before the OGTT, separated by a 3-week washout period.

Results: Moxifloxacin prolonged the QTc interval by 25 ms. Figure 1 shows the means and 95% CI from the moxifloxacin/placebo 6-hour OGTTs. Insulin and GLP-1 levels were reduced the first 90 min and glucose was reduced the first 15 min with moxifloxacin blockade, thereby increasing the Matsuda-index by 1.16 (95% CI -1.9;-0.4).

Conclusion: Moxifloxacin-induced hERG blockade reduced peak postprandial glucose excursions and decreased the secretion of insulin and GLP-1.

Disclosure

C.R. Juhl: None. J. Burgdorf: None. C. Knudsen: None. S. Veedfald: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. J. Kanters: None. S.S. Torekov: Research Support; Self; Novo Nordisk Inc.

Funding

Independent Research Fund Denmark; Danish Heart Association; Lundbeck Foundation
1790-P: ACE2-Ang1-7-Mas Axis Protects Islets from Endoplasmic Reticulum Stress
Authors: SHI TING-TING , LU JING
Published: June 2020

The derangement of endoplasmic reticulum (ER) homeostasis triggers β-cell dysfunction and apoptosis, leading to diabetes. The angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) [Ang-(1-7)]/Mas axis has been evidenced to protect islet function, but its role in ER stress remains undefined. Here we confirmed that upon treatment with the ER stress inducers thapsigargin (TG) or palmitic acid (PA), the protein levels of ACE2 rapidly increased in mouse islets. ACE2 overexpression and Ang-(1-7) treatment in islets reduced EIF2α-ATF4-mediated ER stress induced by TG or PA. On the contrary, islets from aged Ace2−/y mice (20-month old) were substantially more sensitive to ER stress and cell loss compared with Ace2+/y mice. ACE2 overexpression improved glucose-stimulated insulin secretion (GSIS) and ACE2 ablation resulted in impaired GSIS in mice islets. In vitro, the defective GSIS and ER stress in Ace2−/y islets were rescued by replenishment of ACE2. Furthermore, PI3K-Akt signaling was activated by ACE2 and participated in ER stress in islets. The present study is the first to clarify the possible mechanisms of ACE2/Ang-(1-7)/Mas axis regulate ER stress in islets.

Disclosure

T. Shi: None. J. Lu: None.

Funding

National Natural Science Foundation of China (81561128015, 81370946, 81400824)
1792-P: Measures of ß-Cell Function from Two-Step Hyperglycemic Clamps: Relation to Glycemia
Authors: XIANG ANNY , HANNON TAMARA S. , MATHER KIEREN J. , BARENGOLTS ELENA , CREE-GREEN MELANIE , NADEAU KRISTEN J. , SAM SUSAN , KAHN STEVEN E. , BUCHANAN THOMAS A. ,   THE RISE CONSORTIUM
Published: June 2020

We derived β-cell measures compensating for insulin resistance (disposition indices [DI]) from two-step hyperglycemic clamps with arginine stimulation, and examined their associations with glycemia cross-sectionally and longitudinally after treatment. Data included 355 adults (age 23-66 y; 51% female) and 89 youth (age 10-19 y; 71% female) from the RISE Consortium studies. Clamps were done at baseline and after 12 mo treatment with medications or gastric banding. Insulin sensitivity was quanitfied as M/I. β-cell responses included acute insulin (AIRg) and C-peptide (ACPRg) responses to glucose; steady-state C-peptide (SSCP) at glucose ∼11.1 mmol/L; and maximum insulin (AIRmax) or C-peptide (ACPRmax) responses to arginine at glucose >25 mmol/L. DIs were calculated from M/I and β-cell responses as [responses x (M/I)-b ]. The Table shows the correlations between each DI and glucose at baseline, and changes after treatment. The correlations were higher in youth than adults, except for changes in AIRmax or ACPRmax and 2-hour glucose. The correlations for ACPRg and AIRg were generally higher, followed by SSCP and then maximal responses. Thus, in the RISE cohorts, measures of early β-cell response were more strongly associated with glycemia than were late responses, with stronger correlations in youth. This underscores different contributions of early and late insulin secretion in the regulation of glycemia.

Disclosure

A. Xiang: None. T.S. Hannon: None. K.J. Mather: Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. E. Barengolts: None. M. Cree-Green: Advisory Panel; Self; Novo Nordisk Inc. K.J. Nadeau: None. S. Sam: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc. T.A. Buchanan: None. T. Consortium: None.

Funding

American Diabetes Association (1-14-RISE-01 to S.E.K.); National Institute of Diabetes and Digestive and Kidney Diseases
1822-P: Regulation of Trafficking of Lipids from Liver to Fat by ApoA4 in a Mouse Model of Nonalcoholic Steatohepatitis
Authors: LI XIAOMING , LIU XIAO-HUAN , CHENG CHENG , ZHOU JING-TING , FAN JING-NA , LI SHENGBIN
Published: June 2020

Lipogenesis and lipolysis largely determining adipose tissues and liver lipid content, and the imbalance between them contributes to fatty liver disease and metabolic syndromes. Lipogenesis and lipolysis are regulated by nutritional signals and metabolic hormones such as insulin through multiple mechanisms. Apolipoprotein A-IV (ApoA4), secreted largely by intestine, is existed as the composition of HDL and as the free form mostly in blood. ApoA4 plays the important roles in anti-atherosclerosis and lowering blood glucose. After we found its suppressing hepatic gluconeogenesis via NR1D1/NR4A1, and promoting glucose uptake in adipose tissues through PI3K-Akt-GLUT4, we have studied the action of ApoA4 on lipid metabolism with ApoA4 knock-out mice (A4KO). We found that ApoA4 deficiency resulted in worse fatty liver in diet induced obesity (DIO) mice. ApoA4 deficiency lowered the expression of hepatic ATGL, the rate-limiting enzyme for lipolysis, but enhanced the expression of key lipogenic enzymes such as ACC and SCD1. However, the expression of ATGL was increased and the expression of ACC, SCD1, FAS as well as their transcriptional activator SREBP1 were decreased from both BAT and WAT in A4KO mice. Furthermore, ApoA4 deletion also resulted in the inhibited expression of key proteins in thermogenesis pathway SIRT1, PGC1 and UCP1. Moreover, either overexpression of ApoA4 by delivery of AAV-ApoA4 or one time injection of ApoA4 protein resulted in reversed expression of key enzymes for lipogenesis and lipolysis both in liver and adipose tissues from A4KO DIO mice. These data suggest that ApoA4 may promote lipolysis in liver, but inhibited lipolysis and enhance lipogenesis and energy metabolism in adipose tissues, implying ApoA4’s action of regulating the trafficking of lipids from liver to fat and then turn fat into energy for burning.

Disclosure

X. Li: None. X. Liu: None. C. Cheng: None. J. Zhou: None. J. Fan: None. S. Li: None.

Funding

National Natural Science Foundation of China (81770798, 81700691)
1827-P: Pioglitazone Improves Nonalcoholic Steatohepatitis (NASH) in a Diet-Induced Cynomolgus Monkey Model
Authors: CAMACHO RAUL , POLIDORI DAVID , CHEN TAO , GAO BIN , WONG PEGGY , GABRIEL JOSEPH A. , ZHU EDWARD , WANG TONY , NAWROCKI ANDREA R.
Published: June 2020

Nonalcoholic fatty liver disease (NAFLD) ranges in severity from steatosis to NASH. NASH, which is characterized by steatosis, ballooning, inflammation (NAFLD Activity Score [NAS]), and frequently fibrosis, can progress to cirrhosis and hepatocellular carcinoma. Despite the unmet medical needs of NASH leading to end stage liver disease and increased risk for cardiovascular death, there are no approved treatments to date. In clinical trials, pioglitazone treatment (6-24 months) has led to NASH resolution and/or reduction in fibrosis. We developed a cynomolgus monkey (cyno) model of NASH by feeding a high fat/cholesterol diet for 2+ years and demonstrated accelerated disease progression by adding fructose to this diet. A total of 31 obese (mean±SD, 10.4±1.8 kg), insulin resistant (HOMA-IR: 29±32) cynos with NASH were used. Histological assessments of liver biopsies were used to characterize disease progression and response to therapy and compared to human studies. Baseline NAS of 5.6±0.9 was similar to those in NASH patients, whereas baseline fibrosis scores of 1.2±0.5 were slightly lower than values of ∼2 typically enrolled in Phase 2 trials. Cynos were treated daily with vehicle (n=10) or pioglitazone (3 mg/kg; n=21) for 6 months. Drug exposures 24 hours post-dose averaged 233±145 ng/mL, similar to that seen in humans (∼200 ng/mL) dosed with 45 mg. Adiponectin, a biomarker for PPARγ activation, increased ∼2-fold in treated cynos. NAS improvement (a decrease in NAS of ≥2 with changes in 2 or more components of NAS) was seen in 30% of treated cynos (p=0.08). No vehicle animals showed NAS improvement. Treated cynos showed significant decreases in ballooning, trends in decreases (p=0.07) in steatosis and inflammation, but no change in fibrosis whereas vehicle animals showed no changes or worsening. We have validated and benchmarked a novel cyno model for NASH that has characteristics similar to human pathology and responds to a treatment known to improve NASH in clinical trials.

Disclosure

R. Camacho: Employee; Self; Janssen Pharmaceuticals, Inc. D. Polidori: Employee; Self; Janssen Research and Development. Stock/Shareholder; Self; Janssen Research and Development. T. Chen: Employee; Self; Janssen Pharmaceuticals, Inc. B. Gao: Employee; Self; Janssen Pharmaceuticals, Inc. P. Wong: Employee; Self; Johnson & Johnson. Stock/Shareholder; Self; Merck & Co., Inc. J.A. Gabriel: Employee; Self; Kunming Biomed International (KBI). E. Zhu: None. T. Wang: None. A.R. Nawrocki: Employee; Self; Janssen Pharmaceuticals, Inc.
1870-P: Glucose Metabolism after Overnight and Prolonged Fasting in Participants with Different Glucose Tolerances
Authors: TRIPOLT NORBERT J. , PFERSCHY PETER N. , OBERMAYER ANNA , ECKSTEIN MAX L. , KOJZAR HARALD , SOURIJ CAREN , MOSER OTHMAR , OBERMAYER-PIETSCH BARBARA M. , RIEDL REGINA , SOURIJ HARALD
Published: June 2020

Background: Metabolic regulation of glucose can be altered by fasting periods. The aim of our study was to examine the glucose metabolism after an overnight fast (12 hours) as well as after prolonged fasting (36 hours of fasting) in non-obese people, people with obesity and people with type 2 diabetes (T2DM).

Material and Methods: Glucose metabolism was assessed by a 75 g oral glucose tolerance test after 12 and 36 hours fasting, respectively. Area under the curve (AUC) was calculated according to the trapezoidal rule. Insulin sensitivity was estimated by using QUICKI and HOMA-IR.

Results: In total 60 participants (age 43±16 years, 62% women) were included. Fasting levels of glucose, insulin and c-peptide were significantly lower in all cohorts after 36 hours vs. 12 hours of fasting (p<0.05). However, in non-obese people mean 2h-glucose level was significant higher after prolonged fasting [108.7±31.1 mg/dL vs. 79.4±18.4mg/dL after 12h fasting; p<0.05] with significantly lower 30 minutes insulin levels following prolonged fasting, while within the two other cohorts no change in this 2h-glucose was observed. Indices of insulin sensitivity improved in all groups after prolonged fasting.

Conclusion: Our data demonstrate higher glucose excursions and a reduced early insulin response after 36 hours of fasting compared to an overnight fasting period in participants with various glucose tolerance levels.

Disclosure

N.J. Tripolt: None. P.N. Pferschy: None. A. Obermayer: None. M.L. Eckstein: Research Support; Self; Dexcom, Inc., Novo Nordisk A/S, Sanofi-Aventis. H. Kojzar: None. C. Sourij: None. O. Moser: Other Relationship; Self; Dexcom, Inc., Novo Nordisk A/S, Sanofi. B.M. Obermayer-Pietsch: None. R. Riedl: None. H. Sourij: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi.
1871-P: Dietary Iron and Hypoxia Interact to Alter Glucose Homeostasis and ß-Cell Activity in a Fast Food Diet Mouse Model
Authors: HARRISON ALEXANDRIA V. , SINK SANDY T. , LORENZO FELIPE , JAIN SHALINI , MCCLAIN DONALD A.
Published: June 2020

Dietary iron overload is linked to increase risk of type 2 diabetes (T2D), with iron significantly affecting insulin sensitivity/secretion, hepatic glucose production, as well as other physiological responses altered in T2D. These effects are in part mediated through the iron-dependent hypoxia sensing pathway. The interactions between iron and hypoxia in T2D have yet to be elucidated. We therefore fed mice a fast food (FF) diet with varying iron concentrations, from a low 4 mg/kg to a high 2000 mg/kg, under normoxic and hypoxic conditions. There was a reduction in weight for hypoxic mice (by 30% for 4mg-Fe diet, 20% for 35mg-Fe diet, and 15% for 2000mg-Fe diet; p<0.05) as compared to normoxic mice, independent of food consumption. ECHO-MRI measurements revealed higher fat mass with increased iron in normoxic mice. Hypoxic mice had significantly lower fat mass and increased leaner muscle mass. Both fasting glucose (FG) and glucose tolerance were significantly improved under hypoxia (improvement of 15-45% for FG, p<0.05 and 25-40% for glucose tolerance, p<0.01). High iron decreased the homeostasis model assessment of insulin resistance (HOMA-IR) in normoxic mice, and hypoxic mice were less insulin resistant than those in normoxia (p<0.05). Higher iron also decreased the homeostasis model assessment of beta-cell function (HOMA-B) for both normoxic and hypoxic mice. Consistent with the HOMA-B results, islet perifusion shows that glucose-stimulated insulin secretion (GSIS) is comparatively lower under the combination of high iron and hypoxia. We conclude that while iron is able to independently affect glucose tolerance in mice on a FF diet, the effects of dietary iron still depend on oxygen level. Our perifusion data suggests that iron and hypoxia work in synergy to alter β-cell activity. The synergistic effects of iron and hypoxia may be mediated by the two HIF regulatory arms, iron-dependent dioxygenases prolyl-hydroxylase (PHD) and factor inhibiting HIF (FIH).

Disclosure

A.V. Harrison: None. S.T. Sink: None. F. Lorenzo: None. S. Jain: None. D.A. McClain: None.
1875-P: The Impact of Carbohydrate/Fat Intake Balance on Beta-Cell Dedifferentiation and Fatty Liver in Obese Mouse Model
Authors: ISHIDA EMI , LEI XIAO , YAMADA EIJIRO , OKADA SHUICHI , YAMADA MASANOBU
Published: June 2020

In clinical, the ’fatigue’ of the pancreatic beta cells is a famous phenomenon in type 2 diabetes. Nowadays, researchers describe the several mechanisms of beta cell dysfunction, such as glucolipotoxicity, endoplasmic reticulum stress and oxidative stress. In 2012, Talchai et al. revealed that the beta cells were dedifferentiated in diabetes, and previously we showed that food restriction had the most manifold good effects to restore beta cell gene expression, among the known diabetic treatments that we tested. In the current study, we aimed to unveil which nutrients should be cut down to protect beta cell differentiation, sugar or fat. First, we performed the pair-feeding with db/+ and db/db to reduce food intake of db/db mice. We utilized the high-fat/low carbohydrate diet (HF) or low-fat/high carbohydrate (HC) diet which were adjusted to the same total calorie intake. Pair fed-db/db mice had better body weight and glucose tolerance control than ad libitum db/db group, as previously we reported, and there was no significant difference between HF and HC diet. Albeit the same metabolic profile, HC diet group had more enlarged islets and more dedifferentiated beta cell features, which indicated the compensatory beta cell response in HC diet group. Moreover, HC diet group showed more severe fatty liver than HF diet group, along with the elevated synthesis and accumulation of triglycerides and cholesterol in liver. We are now investigating the relationship between sugar load, insulin resistance in liver and beta cell dedifferentiation.

Disclosure

E. Ishida: None. X. Lei: None. E. Yamada: None. S. Okada: None. M. Yamada: None.

Funding

Japan Society for the Promotion of Science (18K16222)
1881-P: Separate Free Fatty Acid (FFA) Pools Are Involved in Muscle Lipid Utilization
Authors: CHOW LISA S. , MASHEK DOUGLAS G. , JENSEN MICHAEL D.
Published: June 2020

Despite discrepant phenotypes, the insulin resistant (IR) and trained states have high levels of intramyocellular lipid. We hypothesize that higher muscle lipid turnover in the trained state may explain this discrepancy.

Obese, IR subjects and trained subjects were fasted overnight (Table1). To characterize muscle lipid turnover, we conducted a pulse-chase experiment using sequential [U-13C]palmitate and [9-2H]palmitate infusions (6 h each) with a 1 hour overlap to label endogenous and exogenous FFA pools. Biopsy#1 (Bx#1 -s/p 14 hr fast) was performed at the time of the overlap (last hour of the 6 h [U-13C]palmitate infusion, after 1 h of starting the [9-2H]palmitate). Bx#2 was performed at the study conclusion (last hour of the [9-2H]palmitate infusion-s/p 20 hr fast). Plasma and muscle samples were analyzed for palmitate enrichment and concentration.

Regardless of phenotype, muscle triglyceride (IMTG) synthesis at Bx#1 was not different as assessed by either [U-13C]palmitate or [9-2H]palmitate; IMTG synthesis assessed by [9-2H]palmitate was 9-fold higher than [U-13C]palmitate. At Bx#2, IMTG breakdown as assessed by [U-13C]palmitate was similar between groups, whereas [9-2H]palmitate showed IMTG synthesis in the obese, IR group and IMTG breakdown in the trained group.

IMTG synthesis was higher with recent (1 hour) FFA exposure than more prolonged (6 hour) FFA exposure supporting separate FFA pools in lipid utilization.

Disclosure

L.S. Chow: None. D.G. Mashek: None. M.D. Jensen: None.

Funding

National Institutes of Health (R01DK098203, UL1TR000114)
189-LB: Household Food Insecurity and Associations with Glycemic Control and Acute Diabetes-Related Complications in Youth and Young Adults with Type 1 Diabetes: The SEARCH for Diabetes in Youth Study
Authors: MALIK FAISAL , LIESE ANGELA D. , ELLYSON ALICE M. , REID LAUREN A. , SAUDER KATHERINE A. , FRONGILLO EDWARD A. , PIHOKER CATHERINE , DABELEA DANA , LAWRENCE JEAN M. , JENSEN ELIZABETH T. , SAYDAH SHARON , MARCOVINA SANTICA M. , BOWLBY DEBORAH , MENDOZA JASON A.
Published: June 2020

Objectives: To examine, among youth and young adults (YYAs) with type 1 diabetes (T1D), the independent association of household food insecurity (HFI) with: 1) glycemic control and 2) episodes of diabetic ketoacidosis (DKA) and severe hypoglycemia.

Methods: This cross-sectional study included SEARCH for Diabetes in Youth participants with T1D examined between 2016-2019. HFI was assessed using the U.S. Household Food Security Survey Module. HbA1c was measured from blood drawn at a research visit; episodes of DKA and severe hypoglycemia were collected by survey. Linear and logistic regression models adjusted for age, sex, race, income, health insurance, diabetes duration, and SEARCH site.

Results: Of 1834 participants (mean age 20.8±5.0 years, 69.9% non-Hispanic white, diabetes duration 11.1±3.2 years), HbA1c was collected for 1029 individuals (mean HbA1c 9.2%±2.0%). The prevalence of HFI was 16.4%. In this sample, 18.7% and 9.9% reported an episode of DKA or severe hypoglycemia in the past 12 months, respectively. Compared to participants who were food secure, HFI was associated with a 0.43% [CI: 0.02%-0.68%] higher HbA1c. In two separate adjusted models, those with HFI had 1.86 [CI: 1.03, 2.34] times the odds of an episode of DKA and 1.64 [CI: 1.03, 2.34] times the odds of an episode of severe hypoglycemia as those without HFI.

Conclusions: HFI is independently associated with poor glycemic control and increased odds of diabetes-related complications in YYAs with T1D. Interventions to reduce HFI and studies to longitudinally examine its impact on glycemic control and complications are warranted.

Disclosure

F. Malik: None. A.D. Liese: None. A.M. Ellyson: None. L.A. Reid: None. K.A. Sauder: None. E.A. Frongillo: None. C. Pihoker: None. D. Dabelea: None. J.M. Lawrence: None. E.T. Jensen: None. S. Saydah: None. S.M. Marcovina: None. D. Bowlby: None. J.A. Mendoza: None.

Funding

Centers for Disease Control and Prevention (00097, DP-05-069, DP-10-001); National Institute of Diabetes and Digestive and Kidney Diseases (1UC4DK108173)
189-OR: Prepregnancy Plant-Based Diet and the Risk of Gestational Diabetes Mellitus: A Prospective Cohort Study of 15,999 Women
Authors: CHEN ZHANGLING , QIAN FRANK , LIU GANG , LI MENGYING , VOORTMAN TRUDY , LEY SYLVIA H. , CHAVARRO JORGE E. , BHUPATHIRAJU SHILPA , SUN QI , HU FRANK , ZHANG CUILIN
Published: June 2020

Objective: To identify novel modifiable factors that may help prevent gestational diabetes mellitus (GDM) by examining associations of plant-based diet indices with GDM risk.

Methods: We included 15,999 women (22,524 singleton pregnancies) in the Nurses’ Health Study II (1991-2001), who reported at least one singleton pregnancy between 1991 and 2001. Pre-pregnancy plant-based diets (i.e., overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI)) were assessed every 4 years using a food frequency questionnaire. Incident first time GDM was ascertained from a self-reported physician diagnosis of GDM, which was previously validated to have high concordance with medical records. We used log-binomial models with generalized estimating equations to estimate relative risks (RR) and 95% confidence intervals (CI) for quartiles of PDI, hPDI, and uPDI and GDM with adjustment for demographic, lifestyle, and other factors.

Results: We documented 891 GDM cases over the 10 years of follow-up. Both PDI and hPDI were significantly and inversely associated with GDM (PDI: adjusted RR for extreme quartiles (highest vs. lowest) 0.75, (95% CI: 0.62, 0.92), p trend = 0.01; hPDI: RR for extreme quartiles 0.76, (0.61, 0.94), p trend = 0.01). Further adjustment for pre-pregnancy BMI attenuated the associations (RR for extreme quartiles for PDI: 0.87 (0.71, 1.06); for hPDI: 0.81 (0.65, 1.00)). We estimated that pre-pregnancy BMI mediated 61.3% (95% CI: 21.7%, 90.1%) of the association between PDI and GDM, and 44.4% (18.1%, 74.3%) of the association between hPDI and GDM. uPDI was not significantly associated with GDM.

Conclusions: Our study suggests that pre-pregnancy adherence to overall and healthful plant-based diets may be associated with a lower risk of GDM. These associations were substantially mediated through pre-pregnancy BMI.

Disclosure

Z. Chen: None. F. Qian: None. G. Liu: None. M. Li: None. T. Voortman: None. S.H. Ley: None. J.E. Chavarro: None. S. Bhupathiraju: None. Q. Sun: None. F. Hu: None. C. Zhang: None.
1892-P: Meal- and Glucose-Induced Suppression of Ghrelin Release Is Mediated Primarily by Ghrelin Cell-Expressed Insulin Receptors
Authors: SHANKAR KRIPA , TAKEMI SHOTA , GUPTA DEEPALI , MANI BHARATH K. , OSBORNE-LAWRENCE SHERRI , METZGER NATHAN , BERGLUND ERIC , ZIGMAN JEFFREY M.
Published: June 2020

Objective: The hormone ghrelin both regulates and is regulated by food intake and blood glucose. Yet, the mechanisms restricting ghrelin release after meals or upon glucose delivery have remained elusive. Here, we tested whether meal and glucose-associated rises in plasma insulin act via ghrelin cell-expressed insulin receptors to suppress ghrelin release.

Methods: We generated ghrelin cell-selective insulin receptor-knock out (GIRKO) mice by crossing ghrelin-Cre mice with floxed-insulin receptor mice. We examined ghrelin release using hyperinsulinemic-hypoglycemic clamps, glucose tolerance tests (GTTs), a fast-refeed protocol, and gastric mucosal cell primary cultures.

Results: During clamps, plasma ghrelin fell in WT control groups (by 85%) but not in GIRKO mice, leading to a 29% lower glucose infusion rate in GIRKO mice. During GTTs, plasma ghrelin was suppressed in controls (by 42%) but not in GIRKO mice. During the refeed phase of a fast-refeed protocol, plasma ghrelin fell in controls (by 49%) but not in GIRKO mice. Also, insulin suppressed ghrelin release in isolated ghrelin cells of controls (by 19%) but not of GIRKO mice.

Conclusions: These data suggest that insulin, acting via ghrelin cell-expressed insulin receptors, is a key mediator of ghrelin release in response to meals, glucose administration, and insulin infusion. Further, suppressed ghrelin release resulting from direct insulin action on ghrelin cells restricts ghrelin’s capacity to protect against hypoglycemia during over-insulinization.

Disclosure

K. Shankar: None. S. Takemi: None. D. Gupta: None. B.K. Mani: None. S. Osborne-Lawrence: None. N. Metzger: None. E. Berglund: None. J.M. Zigman: Stock/Shareholder; Self; Medtronic.

Funding

National Institutes of Health (R01DK119341-01A1, R01DK103884 to J.M.Z.), (R01DK109408 to E.B.), (R01DK119341 to J.M.Z., E.B.); David and Teresa Disiere Foundation (to J.M.Z.); Diana and Richard C. Strauss Professorship in Biomedical Research; Mr. and Mrs. Bruce G. Brookshire Professorship in Medicine; Kent and Jodi Foster Distinguished Chair in Endocrinology (to J.M.Z.); Uehara Memorial Foundation (to S.T.)
1926-P: Potent Weight Loss Mechanism of a Novel Long-Acting Glucagon Analog, HM15136, in Animal Models of Obesity
Authors: LEE JONG SUK , LEE SEON MYEONG , KIM JUNG KUK , LEE JONGSOO , LEE SANG DON , BAE SUNGMIN , KIM DAEJIN , CHOI IN YOUNG
Published: June 2020

Several studies have demonstrated that glucagon plays an essential role in the regulation of body weight via both increase of energy expenditure and suppression of appetite, suggesting its potential application for obesity management. Consistent with this, we previously observed that chronic treatment of the novel long-acting glucagon analog, HM15136, led to efficient body weight loss (BWL) in diet-induced obesity (DIO) mice. To further investigate the therapeutic benefits of HM15136 in obesity, the present study compared the BWL effect with available GLP-1 agonists and investigated the underlying mechanism for efficient BWL by HM15136. In DIO mice, chronic treatment of HM15136 showed greater BWL (-38.5% vs. vehicle) than GLP-1 agonists such as liraglutide, dulaglutide, and semaglutide (-16.8, -2.5, and -11.0% vs. vehicle). Of note, unlike liraglutide, more BWL was observed even under pair-feeding conditions, indicating the appetite regulation-independent BWL by HM15136. As to the responsible mechanism, HM15136 increased the expression of PGC-1α and UCP-1 in white adipose tissue (WAT), leading to enhanced energy expenditure. Together with the reduced respiratory exchange ratio, these results suggest that HM15136 induce WAT browning through which fat utilization and energy expenditure increases. To explore an additional mechanism for BWL by HM15136, oral lipid tolerance test (oLTT) was performed. Interestingly, blood TG level during oLTT was significantly decreased by HM15136 treatment, which coincided with decreased blood bile acid and ApoB48. These results suggest that the inhibition of lipid absorption is involved, at least in part, in efficient BWL by HM15136. Therefore, HM15136 could be a potential option for the management of obesity via favorable regulation of energy expenditure and lipid absorption in addition to appetite inhibition. Efficacy study in obese patients is ongoing to assess the clinical relevance of these findings.

Disclosure

J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. J. Kim: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Spouse/Partner; Hanmi Pharmaceutical. S. Bae: Employee; Self; Hanmi Pharmaceutical. D. Kim: Board Member; Self; Hanmi Pharmaceutical. I. Choi: Board Member; Self; Hanmi Pharmaceutical.
1932-P: A Novel Antiobesity Peptide Secreted from Brown Adipocytes
Authors: ZHANG ZHUO , ZHANG XIAOXIAO , ZHONG HONG , CHI XIA , CUI XIANWEI , JI CHENBO
Published: June 2020

Obesity, the most common metabolic disorder worldwide, is characterized by excess adipose tissue accumulation and causes to serious complications. Many studies have suggested that brown adipocytes contribute to weight loss with increased energy expenditure. Since white adipocytes could be convertible to a “brown-like” state, and induction of browning of white fat also become a promising strategy in the treatment of obesity. Notably, brown fat is not only a heat-producing but also a secretory organ communicating with other metabolic organs. In this study, we focused on peptides secreted by brown adipose tissue to discover new treatment against obesity and metabolic disorder. We successfully obtained a novel polypeptide from the secretory components of brown adipocytes named as BATSP1 (Brown Adipose Tissue Secreted Peptide), which played crucial role in stimulating browning of white adipocytes. The function and mechanism of BATSP1 were comprehensively evaluated in animal models, and we found that administration of BATSP1 stimulated browning of white adipose tissue and elevated mitochondria number dramatically consisting with the activation of energy metabolism. Moreover, to evaluate the feasibility of BATSP1 as a treatment for obesity, we treated DIO mice with BATSP1 and caused significant weight loss as well as decreased glucose and triglyceride content via browning. Taken together, we described an anti-obesity peptide secreted from brown adipocytes, and the underlying mechanism require further study to develop its clinic application.

Disclosure

Z. Zhang: None. X. Zhang: None. H. Zhong: None. X. Chi: None. X. Cui: None. C. Ji: None.

Funding

National Natural Science Foundation of China (81770866, 81770837, 81900783)
1936-P: The Role of Adipose Tissue in Intestinal Functions
Authors: LONG KEKAO
Published: June 2020

Introduction: Adipokines regulate whole-body energy homeostasis, insulin sensitivity and immunity by mediating the crosstalk between adipose tissues and multiple tissues, including liver, skeletal muscle, brain, pancreas and intestines. Recent studies revealed that intestines also exhibit insulin resistance and dysregulated immune homeostasis in obese condition. On the other hand, several adipokines including adiponectin and adipocyte fatty acid binding protein have been shown to regulate intestinal function. Here, we aim to investigate the relationship between the adipose tissue and gut homeostasis using lipodystrophy animal models.

Methods: We employed our recently developed lipodystrophic mouse model, in which adipocyte MDM2 is genetically deleted (so-called Adipo-MDM2-KO mice). In fat transplantation experiment, subcutaneous fat form their wild type (WT) littermates was transplanted to the Adipo-MDM2-KO mice for 8 weeks. To assess gut permeability, Adipo-MDM2-KO mice and their wild type (WT) littermates were orally gavaged with DX-4000-FITC for 1 hour. Circulating LPS level were measured using the endotoxin assays, which reflects gut permeability and endotoxemia. For assessment of gut morphology, ileum isolated from Adipo-MDM2-KO mice and their WT littermates were subjected to Haemotoxylin and Eosin (H and E) staining.

Results and Conclusion: Adipo-MDM2-KO mice exhibited impaired gut barrier function and altered gut microbiota composition when compared with the WT littermates. A higher level of DX-4000-FITC in the serum of Adipo-MDM2-KO mice were detected. In addition, circulating level of LPS was significantly increased in Adipo-MDM2-KO mice. H and E staining showed a change in gut morphology and an increased number of inflammatory cells in the ileum of Adipo-MDM2-KO mice. These results demonstrated that fat loss leads to intestinal dysfunction, therefore, the adipose tissue is required for gut homeostasis.

Disclosure

K. Long: None.

Funding

National Natural Science Foundation of China (91857119)
195-LB: Metabolomic Characterization of Laron and Guevara-Rosenbloom Syndromes Using UHPLC-HRMS
Authors: RUBIO VANESSA , CHAMBERLAIN CASEY A. , WASSERFALL CLIVE , GUEVARA-AGUIRRE JAIME , GUEVARA ALEXANDRA , ROSENBLOOM ARLAN L. , ATKINSON MARK A. , YOST RICHARD A. , GARRETT TIMOTHY J.
Published: June 2020

Laron syndrome (LS) is a rare autosomal recessive growth hormone (GH) insensitivity condition due to GH receptor mutation, and with phenotypic features likened to GH deficiency. The incidence of LS in Ecuador is very high and has gained worldwide attention due to its low incidence of cancer and diabetes mellitus. A more recently described population is affected with “Guevara-Rosenbloom syndrome” (GRS). While both groups exhibit severe short stature (-4 to -12 SDS), GRS subjects have normal GH signaling and responses and, unlike LS, have intrauterine growth retardation and early onset type 2 diabetes (T2DM). Since both groups have diminished insulin secretion, there is a unique opportunity to investigate their metabolome under each specific disease. Levels of certain amino acids in insulin-resistant (IR) states such as T2DM are distinct and special attention has been given to the predicting power of branched chain and aromatic amino acids, carnitines, and free fatty acids for IR and T2DM risk assessment. Our aim was to understand the metabolic differences between LS and GRS, which both have diminished insulin secretion but different GH counter-regulation as well as to compare these groups to normal controls. The metabolome of these 3 cohorts was assessed at the following instances: a) At the fasting state, and b) After an oral challenge of 1.5 mg/kg of glucose per kilogram of body weight, administered immediately after the fasting sample was drawn (samples were taken every 30 minutes for 5 hours [5h]). Preliminary results (by ANOVA) show a strong correlation, in the fasting state, between the control and the LS groups with clear discrimination from the GRS cohort, as determined by a heatmap of the top 100 features. Furthermore, the analysis of the 5h profile after the glucose challenge in the 3 groups revealed significant correlations in the levels of amino-acids that have been related to the genesis of IR and T2DM. This work represents the first deep-metabolome analysis in this unique study group.

Disclosure

V. Rubio: None. C.A. Chamberlain: None. C. Wasserfall: None. J. Guevara-Aguirre: None. A. Guevara: None. A.L. Rosenbloom: None. M.A. Atkinson: None. R.A. Yost: None. T.J. Garrett: None.

Funding

National Institutes of Health (U24DK097209)
195-OR: Safety and Performance of the Tandem T:slim X2 with Control-IQ Automated Insulin Delivery System in Preschoolers, Age 2-6 Years Old
Authors: EKHLASPOUR LAYA , FORLENZA GREGORY P. , SCHOELWER MELISSA , DEBOER MARK D. , HSU LIANA , KINGMAN RYAN S. , BORANIAN EMILY , EMORY EMMA , WADWA R. PAUL , BUCKINGHAM BRUCE A. , BRETON MARC D.
Published: June 2020

Glycemic control is particularly challenging for young children with T1DM. We studied the Tandem Control-IQ AP system (CIQ) in children ages 2-5.9 years old during 48hr of supervised outpatient hotel/Airbnb use (SH) followed by 3 days of at home use (H). A minimum of 48hr Tandem standard pump therapy at home (B) preceded the SH phase. Meals and snacks were chosen by parents, without restrictions, and boluses were estimated per parents’ routine. While on closed-loop, all participants were remotely monitored by study staff. There were at least 30 minutes of exercise each day of SH phase. Twelve participants with >3 months of T1D, mean age 4.7±1y, A1C 7.3±0.8%, weight 19.3±3.1kg were enrolled at 3 sites. All were using sensor augmented pumps before entry, with or without automation. All participants completed the study with no adverse events. Outcomes are reported below. CIQ improved mean glucose and TIR without an increase in hypoglycemia during the SH phase; at home CIQ improved all hypoglycemia outcomes as well as TIR, with a tendency towards a better mean glucose. All overnight outcomes were further improved. The Tandem Control IQ system was safe and significantly improved glycemic control in these young children in both the supervised hotel/Airbnb and the home setting.

Disclosure

L. Ekhlaspour: None. G.P. Forlenza: Advisory Panel; Self; Medtronic. Consultant; Self; Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care. Research Support; Self; Abbott, Dexcom, Inc., Insulet Corporation, Medtronic, Tandem Diabetes Care. M. Schoelwer: Research Support; Self; Tandem Diabetes Care. M.D. DeBoer: Research Support; Self; Tandem Diabetes Care. L. Hsu: Stock/Shareholder; Self; Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care. R.S. Kingman: None. E. Boranian: Other Relationship; Self; American Diabetes Association. E. Emory: None. R. Wadwa: Advisory Panel; Self; Eli Lilly and Company, Medtronic. Research Support; Self; Dexcom, Inc., Eli Lilly and Company, MannKind Corporation, Medtronic, Novo Nordisk Inc., Tandem Diabetes Care. B.A. Buckingham: Advisory Panel; Self; ConvaTec Inc., Medtronic. Research Support; Self; Beta Bionics, Inc., Dexcom, Inc., Insulet Corporation, Medtronic, Tandem Diabetes Care. M.D. Breton: Research Support; Self; Dexcom, Inc., Novo Nordisk A/S, Sanofi, Tandem Diabetes Care. Speaker’s Bureau; Self; Dexcom, Inc., Tandem Diabetes Care.

Funding

Tandem Diabetes Care
1960-P: A Novel Nitric Oxide Releasing Nanomatrix Gel Prevents High-Fat Diet-Induced Obesity and Insulin Resistance
Authors: REN GUANG , SHAW AUBREY L. , HWANG PATRICK , MILLICAN REID C. , JUN HO-WOOK , KIM JEONGA
Published: June 2020

Endothelial dysfunction is characterized by reduction of the bioavailability of nitric oxide (NO), and is associated with metabolic syndrome including, obesity, insulin resistance, hypertension, coronary heart disease, and aging. Because NO plays important roles in mitochondrial biogenesis, we hypothesize that exogenous application of NO may prevent high fat diet (HFD)-induced obesity and insulin resistance by promotion of adipose tissue browning. In the current study, we developed a novel NO releasing nanomatrix gel with natural peptide amphiphiles (PANO). 8 week old male C57BL/6 mice were randomly divided into 2 groups, and then either vehicle (PA) or PANO was subcutaneously injected into brown adipose tissue area every 2 weeks for 11 weeks while the mice were fed HFD. The mice injected with PANO gained less body weight compared to the mice injected with vehicle. PANO injected mice demonstrated improved glucose tolerance and insulin tolerance. Fasting glucose, insulin and leptin levels were lower in the PANO injected mice compared to the vehicle injected mice. Furthermore, the expression of pro-inflammatory genes in epididymal fat tissue was lower, and the expression of uncoupled protein (UCP1) in brown adipose tissue and inguinal adipose tissue was higher in the PANO-injected mice compared to the vehicle injected mice. Thus, the novel nitric oxide releasing nanomatrix gel ameliorated HFD-induced obesity and insulin resistance by promotion of adipose tissue browning. The results suggest that injection of PANO can be a novel therapeutic for obesity and insulin resistance.

Disclosure

G. Ren: None. A.L. Shaw: None. P. Hwang: None. R.C. Millican: None. H. Jun: None. J. Kim: None.

Funding

National Institutes of Health (1R01HL125391-01)