bluuebunny/crossref_metadata_2025 huggingface dataset:
Toll-Like Receptors 2/4 and Diabetic Peripheral Neuropathy
Authors: ELZINGA SARAH , MURDOCK BENJAMIN , HAYES JOHN M. , TABBEY MAEGAN A. , FELDMAN EVA L.
Published: June 2018

Peripheral neuropathy (PN) is a common, morbid complication of diabetes and prediabetes. Dysfunction of toll like receptors (TLR) 2 and 4 has been implicated in PN pathogenesis, and blocking TLR4 is proposed as a treatment for neuropathic pain.

WT and TLR 2/4 global KO (TLR2/4-/-; n=5) mice were placed on a 60% high fat diet (HFD, n=5), with 5 WT controls provided a standard diet (CON, n=5). Mice underwent metabolic, neuropathic, and immunological phenotyping (Table 1) at early and late disease time points.

TLR2/4-/- mice weighed more (P ≤ 0.023) but did not have increased fasting blood glucose levels. They had reduced hind paw withdrawal latencies (HPL) compared to HFD mice (P ≤ 0.01) and were similar to CON in early disease, but worsened in later disease. TLR2/4-/- mice consistently had lower sural nerve conduction velocities than CON and worsened as disease progressed (P ≤ 0.048). Immunophenotyping during late disease showed differences in the number of peripheral blood Ly6C- myeloid cells (P ≤ 0.05) and F4/80+ expression (P ≤ 0.0001). Inflammatory profiles of the sural nerve indicated a lower gene expression of the chemoattractant CCL-12 chemokine in TLR2/4-/- compared to CON mice.

These results suggest that TLR2/4 KO may be initially protective against HFD induced neuropathy, but as PN progresses this effect is lost. Differences in circulating immune cells and CCL-12 gene expression may indicate an anti-inflammatory phenotype in TLR2/4-/- mice.Table 1. Metabolic, neuropathic and immunological phenotyping.Phenotypic MetricCON (n=5)HFD (n=5)TLR2/4-/-(n=5)Late stage weight (g)26 ± 339 ± 351 ± 3Late stage fasting blood glucose (mg/dL)150 ± 22190 ± 22172 ± 22HPL (sec)Early: 3.6 ± 0.3Late: 3.5 ± 0.4Early: 5.7 ± 0.3Late: 5.5 ± 0.4Early: 4.4 ± 0.3Late: 6.1 ± 0.4Sural NCV (m/s)Early: 22.0 ± 0.7Late: 23.9 ± 0.7Early: 18.5 ± 0.7Late: 17.9 ± 0.7Early: 20.0 ± 0.7Late: 17.2 ± 0.9Late stage Ly6C- circulating myeloid cells (104 cells/mL)7.8 ± 2.614.0 ± 2.74.8 ± 2.7Late stage circulating myeloid F4/80 expression (mean florescent intensity)978 ± 9611383 ± 10199967 ± 1019Late stage CCL-12 sural nerve gene expression (relative quantity)1.16 ± 0.240.59 ± 0.280.32 ± 0.24

Disclosure

S. Elzinga: None. B. Murdock: None. J.M. Hayes: None. M.A. Tabbey: None. E.L. Feldman: None.
CD70 Modulates Thymocyte Development and Type 1 Diabetes in NOD Mice
Authors: YE CHENG , DRIVER JOHN , WILES MICHAEL V. , SERREZE DAVE
Published: June 2018

CD70 is a tumor necrosis factor (TNF) superfamily member expressed by activated T cells, B cells, dendritic cells, NK cells and mature macrophages. It interacts with CD27, a TNF receptor family member on T cells that regulates T cell activation, proliferation and survival. Type 1 diabetes (T1D) is caused by T cell mediated beta cell destruction, however, T1D-prone NOD mice developed accelerated disease in the absence of CD70. This was associated with altered proportions of double negative vs. double positive thymocytes in CD70 knockout mice, indicating that CD70 modulates global thymopoiesis. Also affected, but in opposing directions, was the development of regulatory T cells (Treg) and natural killer T (NKT) cells, two immunoregulatory lymphocyte subsets that are functionally and numerically deficient in NOD mice. Tregs frequencies were reduced by 23% and 32% in CD70 heterozygous (CD70-/+) and homozygous (CD70-/-) knockout mice. In contrast, NKT cell frequencies were respectively increased by 48% and 61% in CD70-/+ and CD70-/- mice compared to standard NOD mice. The higher level of NKT cells in CD70 knockout mice was unexpectedly associated with reduced levels of thymic CD1d, a molecule that is required for NKT cell development. Collectively, our results show that CD70 controls the development of several T cell populations that are known to modulate T1D development in NOD mice and that, in the absence of CD70, T1D is exacerbated. These finding may facilitate the development of clinical therapeutics aimed at enhancing the stimulatory function of CD70 as a way to suppress disease.

Disclosure

C. Ye: None. J. Driver: None. M.V. Wiles: None. D. Serreze: None.
Adiponectin Increases Glucose-Dependent Electrical Activity and Insulin Secretion in Mouse Pancreatic ß Cells
Authors: REAL JOANA I. , GARCIA BELEN CHANCLON , ASTERHOLM INGRID WERNSTEDT , RORSMAN PATRIK
Published: June 2018

Decreased plasma adiponectin has been implicated as a cause of diabetes. However, the functional impact of adiponectin on glucose-dependent responses of β-cells remains poorly understood. Here we have investigated whether chronically and acutely increased adiponectin levels affect electrical activity (sharp electrodes) and insulin secretion in β-cells using respectively, adiponectin overexpressing (APNtg) mice and acute application of adiponectin. In the acute exposure experiments, adiponectin (20 µg/ml, 11 mM glucose) increased insulin secretion 42% and β-cell electrical activity (measured as the fraction ‘active phase’) 32%. In islets from APNtg mice insulin secretion increased 44% and active phase increased 25%. The effects on electrical activity in APNtg β-cells correlated with membrane hyperpolarization and the resting membrane potential at 0 mM glucose averaged -60±2 in control and -69±2 in APNtg β-cells. There was a moderate effect on action potential width (<20%) and a more pronounced impact on action potential frequency by exogenous adiponectin (+35%) and in APNtg β-cells (+50%).These results suggest that both acutely and chronically increased adiponectin levels have a positive effect on electrical activity and insulin secretion of pancreatic β-cells.

Disclosure

J.I. Real: None. B. Chanclon Garcia: None. I. Wernstedt Asterholm: None. P. Rorsman: None.
Recombinant Probiotics Expressing Angiotensin-(1-7) Improves Glucose Metabolism and Diabetes-Induced Renal and Retinal Injury
Authors: LI QIUHONG , XU KANG , DU TAO , ZHU PING , VERMA AMRISHA
Published: June 2018

Purpose: Multitude of animal studies substantiate the beneficial effects of Ang-(1-7) in diabetes and associated complications. However, the biggest impediment to translate this into clinical application is large-scale production of high quality Ang-(1-7) with enhanced tissue bioavailability. As emerging evidence also implicates the beneficial effects of probiotics in managing diabetes, this study aimed to test the hypothesis that oral delivery of recombinant probiotics expressing Ang-(1-7) will improve glucose metabolism and diabetes-induced tissue damage in animal models.

Method: Ang-(1-7) was expressed as a secreted fusion protein with a transepithelial carrier in Lactobacillus paracasei (LP) to allow uptake into circulation and target tissues. Adult diabetic eNOS-/- mice were orally gavaged daily with 1x109 CFU of LP secreting Ang-(1-7) (LP-A), or LP alone for eight weeks. Glucose metabolism and tissues were assessed using standard assays and histochemical techniques.

Result: Oral feeding of LP-A significantly lowered fasted-state blood glucose (P=0.042); improved the intraperitoneal glucose tolerance test (P=0.034) than control mice. LP-A-treated mice showed higher plasma insulin level (P=0.028) and insulin expression in islets β cells compared to control mice. LP-A treatment significantly reduced apoptotic cell death in kidney, improved diabetes-induced collagen deposits in the glomerular tuft and the tubular epithelia in diabetic mice. LP-A treatment also significantly reduced retinal gliosis, inflammation, neuronal cell death and loss of retinal vascular capillaries.

Conclusion: Oral administration of recombinant probiotics secreting Ang-(1-7) improved glucose tolerance by enhancing insulin level, and reduced diabetes-induced damage in kidney and retina. Thus, recombinant probiotics-based delivery of Ang-(1-7) may hold promising therapeutic potential for diabetes and associated complications.

Disclosure

Q. Li: None. K. Xu: None. T. Du: None. P. Zhu: None. A. Verma: None.
Angiopoietin-Like Protein 3 Directly Regulates HDL Metabolism and Function
Authors: YANG LONGYAN , WANG YAN , FU YING , LANG JIANAN , ZHAO DONG , FENG YINGMEI
Published: June 2018

Background: Angiopoietin-like protein 3 (ANGPTL3) is produced by hepatocytes. Once secreted, it inhibits endothelial lipase activity and regulates angiogenesis. We previously reported the positive association between serum ANGPTL3 and HDL function in nondiabetic participants. Hereby, we investigated whether ANGPTL3 directly modulates HDL function.

Methods: HDLs were isolated from plasma. ANGPTL3 in HDLs was studied by western blot and ELISA. Cholesterol efflux to HDLs was analyzed in macrophages preloaded with fluorescent cholesterol. Recombinant human ANGPTL3 was subjected to endothelial cells treated with TNF-α and ICAM-1 expression was analyzed by FACS. Similar experiments were repeated in db mice injected with AAV encoding human ANGPTL3 cDNA or shRNA.

Results: ANGPTL3 was present in human HDLs, which were lower in T2DM patients than controls (p=0.04). ANGPLT3 in HDLs was positively associated with cholesterol efflux in nondiabetic controls (r=0.33, p=0.044) but not in T2DM patients (r=0.05, p=0.77). Recombinant ANGPTL3 reduced ICAM-1 expression in endothelial cells exposed to TNF-α (p=0.0001). Similarly, ANGPTL3 levels in HDLs were lower in db mice at 18 weeks old than 8 weeks old, which was accompanied with reduced cholesterol reflux to HDLs and rendered inhibition of ICAM-1 expression in endothelial cells (p<0.for all). Following AAV-mediated ANGPTL3 cDNA transfer, ANGTL3 levels were increased in HDLs of db mice, which increased cholesterol efflux and decreased ICAM-1 expression compared with db mice with vector transfer. Vice versa, decreased ANGPTL3 levels in HDLs by AAV-mediated shRNA transfer abrogated HDL function mentioned above (p<0.for both). When placed on high fat diet for 10 weeks, atherosclerotic plaque was larger in db mice with ANGPTL3 shRNA transfer than other gene transferred groups (p<0.05).

Conclusion: ANGPTL3 is a HDL component and direct regulates HDL function. Decrease of ANGPTL3 expression may reduce HDL function and accelerate atherosclerosis in T2DM.

Disclosure

L. Yang: None. Y. Wang: None. Y. Fu: None. J. Lang: None. D. Zhao: None. Y. Feng: None.
Unaltered Fatty Acid Uptake, Utilization, and Mitochondrial Respiration in Right Atrial Appendage of Type 2 Diabetic Human Heart
Authors: RJ NANDINI , RAJI SR , PILLAI VIVEK V. , K. JAYAKUMAR , GOPALA SRINIVAS
Published: June 2018

Previous studies on diabetic human heart have shown decreased utilization of fatty acid (FA)/carbohydrate substrates. We hypothesized that increased mitochondrial dysfunction with concomitant decrease in fatty acid utilization would be found in diabetic hearts of patients from the Indian subcontinent that would explain their increased propensity of cardiovascular complications. We have compared mitochondrial respiration in atrial appendage tissue from nondiabetic and diabetic human subjects undergoing elective coronary artery bypass graft (CABG) surgery using high-resolution respirometry with FA and carbohydrate substrate combinations. In the presence of FA, diabetic mitochondria showed unimpaired complex I and electron transferring flavoprotein (ETF) mediated respiration while significantly lower oxygen consumption was noted when succinate was added, indicating the possible derangement of complex II respiration. Unlike other human studies, we report no significant reduction in FA- mediated mitochondrial respiration. However, the carbohydrate protocol indicated impairment of complex I mediated respiration. There was no significant change in the expression of OXPHOS proteins. Unchanged levels of FA uptake proteins like CD36 and FABP, FA oxidation enzyme, long chain acyl CoA deydrogenase (LCAD), regulators of FA metabolism like sirtuins and nuclear receptors, PPARα and transcription coactivators, PGC1α/β were observed in diabetic heart. The acetylation status of mitochondrial specific proteins involved in fatty acid oxidation (acetylated LCAD and PGC1α/β) also showed no significant changes. Diabetic patients showed equal expression of the antioxidant enzymes and other markers of oxidative stress. The unimpaired FA uptake, oxidation and mitochondrial respiration indicates absence of overt mitochondrial dysfunction in type 2 diabetic human heart.

Disclosure

N. Rj: None. R. Sr: None. V.V. Pillai: None. J. K.: None. S. Gopala: None.
Adipocyte Insulin Resistance Index in Youth along the Span of Glycemia from Normal Glucose Tolerance (NGT) to Impaired Glucose Tolerance (IGT) to Type 2 Diabetes (T2D)
Authors: YOUNG KIM JOON , BACHA FIDA , TFAYLI HALA , MICHALISZYN SARA , ARSLANIAN SILVA A.
Published: June 2018

One of the pathophysiological components of T2D is adipocyte insulin resistance. We demonstrated diminished insulin suppression of lipolysis, using the hyperinsulinemic-euglycemic clamp combined with [2H5]glycerol tracer, in obese IGT vs. NGT youth (Diabetes 66: 2017). Herein we examined a surrogate index of adipose tissue insulin resistance (AT-IR= fasting insulin x FFA) to test the hypothesis that AT-IR increases from normal weight (NW) to obese NGT to IGT to T2D. A total of 2youth (70 M/135 F; Tanner IV-V) had body composition, visceral adipose tissue (VAT), fasting glucose, insulin and free fatty acids (FFA), and AT-IR evaluated. Despite hyperinsulinemia in obese IGT youth, fasting FFA was higher compared with NW and obese NGT peers (Table). AT-IR was 2.2 fold higher in obese NGT, 4.3 fold higher in IGT and 4.6 fold higher in T2D compared with NW before and after adjusting for sex, Tanner stage, BMI and VAT.

In conclusion, the surrogate index of AT-IR reflects pathophysiological alterations in adipose tissue insulin sensitivity showing progressive increase in AT-IR in youth from normal weight to obese, and from NGT to IGT to T2D. This AT-IR, derived from fasting blood samples, could be used in epidemiological, observational and/or interventional studies investigating changes in adipocyte insulin sensitivity in obese youth with IGT and T2D.

Variables, mean ± SEMNW (n=49)Obese-NGT (n=89)Obese-IGT (n=38)Obese-T2D (n=29)P, ANCOVAAge (years)14.4 ± 0.314.6 ± 0.214.9 ± 0.415.2 ± 0.3NSBMI (kg/m2)20.6 ± 0.333.9 ± 0.736.8 ± 1.036.8 ± 1.0<0.0001Visceral adipose tissue (cm2)24.4 ± 2.260.8 ± 4.185.1 ± 5.183.6 ± 7.7<0.0001Fasting glucose (mg/dL)95.1 ± 0.895.4 ± 0.696.8 ± 1.2121.5 ± 4.8<0.0001Fasting insulin (µU/mL)16.2 ± 0.831.3 ± 1.550.4 ± 4.957.6 ± 9.6<0.0001Fasting FFA (mmol/L)0.25 ± 0.020.28 ± 0.010.35 ± 0.020.32 ± 0.020.001AT-IR (µU/mL x mmol/L)4.± 0.388.98 ± 0.6917.51 ± 1.9918.59 ± 3.00<0.0001

Disclosure

J. Kim: None. F. Bacha: Research Support; Self; AstraZeneca, JAEB Center For Health Research, National Institutes of Health, Pediatric Diabetes Consortium. H. Tfayli: None. S. Michaliszyn: None. S.A. Arslanian: None.
The Role of Exosomes in Improvement of Insulin Sensitivity in Obese Adolescents following Bariatric Surgery
Authors: KIM AHLEE , MURAKAMI KAZUTOSHI , BORRA VISHNUPRIYA J. , DOLAN LAWRENCE M. , SHAH AMY , NAKAMURA TAKAHISA
Published: June 2018

Background: Exosomes, a type of extracellular vesicle, are a novel mode of tissue-to-tissue communication. Recent work suggests a role of exosomes in the development of obesity-related metabolic disease, such as insulin resistance or type 2 diabetes. With bariatric surgery, individuals undergo significant weight reduction and dramatic metabolic improvements. We hypothesize that exosomes mediate the metabolic improvements following bariatric surgery.

Methods: We performed comprehensive exosome analyses, including measuring size and serum concentration of exosomes, and evaluating exosomal microRNAs expression pattern in 30 teenagers who underwent sleeve gastrectomy (age=16.7± 0.4 years; gender=26 females, 4 males; race= 19 Caucasians, 11 African Americans). Individuals who had ever been diagnosed with diabetes were excluded from the study.

Results: We observed a significant reduction in serum exosome concentration (pre-op= 4.47x108± 6.28X107particles/mL; post-op=2.56x108± 2.44X107particles/mL, p=0.01), and a drastic shift of exosomal RNA expression pattern 1 month after bariatric surgery in obese adolescents, in concurrent with a modest initial weight loss (Pre-op weight=138.6± 5.3kg, Post-op weight=123.3± 5.0kg).

Conclusion: Drastic changes in exosome profile were observed 1 month after bariatric surgery in severely obese adolescents. It is interesting that the most significant change happens in the first month after the surgery with a modest initial weight reduction, indicating the presence of molecular processes responsible for the improvements in metabolic condition following bariatric surgery, independent of weight loss. These findings suggest that the exosomes play a key role in the profound metabolic improvements following bariatric surgery, and serve as a novel biomarker or a therapeutic target for metabolic diseases.

Disclosure

A. Kim: None. K. Murakami: None. V.J. Borra: None. L.M. Dolan: None. A. Shah: None. T. Nakamura: None.
Serum Exosomal Proteins—A New Component of Intercellular Communication in Metabolism
Authors: BRANDAO BRUNA B. , ALTINDIS EMRAH , GARCIA MARTIN RUBEN , KAHN C. RONALD
Published: June 2018

Adipose tissue is an important endocrine organ; both excess or deficiency of adipose is associated with metabolic syndrome. MicroRNAs (miRNAs) play a fundamental role in regulating adipocyte function and metabolism. Recently, we showed that a large fraction of circulating miRNAs comes from exosomes released by adipose tissue and that mice with an adipose-specific knockout of the miRNA-processing enzyme Dicer (ADicerKO) exhibit lipodystrophy and metabolic syndrome. This is due, in part, to a loss of multiple circulating exosomal microRNAs and their effects on gene expression in liver and other tissues. In this study, we explored the role of exosomal proteins in metabolism by comparing the serum exosomal proteome of wild type (WT) and AdicerKO mice. To this end, we isolated serum exosomes from WT and KO mice and performed quantitative proteomics by LC-MS. A total of 277 exosomal proteins were identified, of which 12 were significantly downregulated and 16 were upregulated by ≥1.5 in AdicerKO mice. Among these were two important adipokines. Thus, the insulin sensitizer adiponectin was downregulated in exosomes, while the insulin resistance-associated adipokine retinol-binding protein-4 (Rbp4) was upregulated. Transthyretin, which binds to and extends Rbp4 half-life, was also increased in serum exosomes from AdicerKO mice. Additionally, serum amyloids A-1 and A-4, serum amyloid component P, haptoglobin and ceruloplasmin, which are adipose and/or liver-specific in origin and often altered in insulin resistant states, were down-regulated in the exosomes of knockout mice.

In summary, serum exosomes contain multiple proteins which can modulate insulin sensitivity or insulin resistance. Induction of lipodystrophy by KO of Dicer in adipose markedly alters the circulating exosomal proteome due to loss of fat or the secondary hepatosteatosis this produces. These exosomal proteins provide potential new signals in the crosstalk between fat, liver and other tissues in response to metabolic disease.

Disclosure

B.B. Brandao: None. E. Altindis: None. R. Garcia Martin: None. C. Kahn: Advisory Panel; Self; CohBar, ERX Therapeutics, AntriaBio, Inc.. Board Member; Self; Kaleio Biosciences.
NAD-Mediated Metabolic Reprogramming Epigenetically Regulates Gene Expression to Promote Preadipocyte Differentiation
Authors: OKABE KEISUKE , USUI ISAO , NAWAZ ALLAH , FUJISAKA SHIHO , KADO TOMONOBU , IGARASHI YOSHIKO , YAGI KUNIMASA , TOBE KAZUYUKI , NAKAGAWA TAKASHI
Published: June 2018

During cell differentiation, intracellular energetic pathways are drastically reorganized. Although this alteration had been considered as a passive process to adapt to environmental change during differentiation, recent studies suggested that the metabolic alteration rather actively regulates the differentiation process. It is known that the dynamic metabolic reprogramming occurs during differentiation of preadipocytes, however its implication in adipogenesis is unknown. In this study, we employed mass spectrometry-based metabolomics and investigated the metabolic change during differentiation of 3T3-L1 preadipocytes. We found that the level of nicotinamide adenine dinucleotide (NAD), a cofactor mediating redox reaction and protein modification, was significantly increased during the differentiation. Consistently Nampt, a rate-limiting enzyme of NAD synthesis, was also upregulated in the early phase of adipogenesis. Further, we found that pharmacological or genetic inhibition of Nampt reduced NAD synthesis and repressed the metabolic reprogramming during adipogenesis. Notably, inhibition of Nampt blocked the gene expression of Pparg and impeded the preadipocyte differentiation. The effect of Nampt inhibition was cancelled by the supplementation of nicotinamide mononucleotide, a precursor of NAD. Our metabolomic analysis also revealed that TCA cycle intermediate, α-ketoglutarate (αKG) was upregulated during the differentiation and Nampt inhibition disturbed the rise of αKG. Interestingly, αKG is known as a cofactor of the demethylation of histones. The ChIP assay revealed that αKG mediated the demethylation of H3K9me3 on Pparg promoter region and promote the gene expression of Pparg during adipogenesis. This process was inhibited by Nampt inhibitor treatment, and was reversed by the supplementation of αKG. Altogether, our data indicated that Nampt-mediated NAD synthesis is necessary for differentiation of preadipocyte.

Disclosure

K. Okabe: None. I. Usui: None. A. Nawaz: Research Support; Spouse/Partner; Kobayashi Foundation, Kobayashi Foundation, Kobayashi Foundation. S. Fujisaka: Research Support; Self; Mochida Pharmaceutical Co., Ltd., Eli Lilly and Company, MSD K.K., Toyama First Bank. T. Kado: None. Y. Igarashi: None. K. Yagi: None. K. Tobe: Research Support; Self; Bristol-Myers Squibb Company, Takeda Pharmaceutical Company, Teijin Pharma Limited, Japan Diabetes Society, Eli Lilly and Company, MSD K.K., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Astellas Parma Inc, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Tsumura & Co., Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., Sumitomo Dainippon Pharma Co. T. Nakagawa: None.
Effects of High BMI on Synaptic Function and Metabolic Connectivity in the Brain—Evidence of Gender Difference
Authors: SALA ARIANNA , MALPETTI MAURA , FERRULLI ANNA , GIANOLLI LUIGI , LUZI LIVIO , PERANI DANIELA
Published: June 2018

Several studies reported a significant association with obesity and cognitive deficits in aging, especially for executive, attention and memory domains. The neural effects of obesity and the correlated cognitive dysfunction have yet to be elucidated. We retrospectively collected a large cohort of healthy elderlies (N=222; age=74.03±5.88y; M/F=112/105; BMI range=19.21-38.79), from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. All subjects underwent in vivo positron emission tomography with 18F-Fluorodeoxyglucose (FDG), thus we were able to evaluate the correlation between BMI, synaptic function and metabolic connectivity in the whole brain and within the resting-state neural networks, crucially considering the effect of gender. We found a significant positive correlation between BMI levels and brain metabolism in female group only (R=.435; P<0.001), with high BMI associated with increased glucose consumption in the orbitofrontal cortex. Whole brain connectivity analysis revealed an altered pattern in frontal regions in females with high BMI, namely a decreased connectivity between orbitofrontal regions and high-order prefrontal cortex, and an abnormally elevated connectivity with nucleus accumbens. The connectivity analysis of the resting-state brain networks confirmed that in elderly females with high BMI, the core of vulnerability is within the frontal regions, with impaired connectivity in executive and salience networks. In contrast, elderly males with high BMI showed loss of long-distance connections between frontal and parietal cortices, invariantly across attentional, executive and posterior default mode networks. Our findings support a strong detrimental effect of high BMI levels on brain metabolism and neural connectivity in healthy aging, with gender differences. Notably, high BMI in females affects the executive and reward systems. This evidence brings to considerations for medical practice and health policy.

Disclosure

A. Sala: None. M. Malpetti: None. A. Ferrulli: None. L. Gianolli: None. L. Luzi: Speaker's Bureau; Self; A. Menarini Diagnostics, AstraZeneca, Eli Lilly and Company. Research Support; Self; Gelesis. Consultant; Self; McKinsey & Company. Speaker's Bureau; Self; Menarini Group, Merck Sharp & Dohme Corp.. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sunstar Foundation. Speaker's Bureau; Self; Smith & Nephew. D. Perani: None.
GIP Signaling Integrates with Insulin Signaling to Regulate Glucose and Lipid Metabolism in Human Adipocytes
Authors: REGMI AJIT , THOMAS MELISSA K. , MICHAEL M. DODSON , ROELL WILLIAM C.
Published: June 2018

Recent studies suggest that activation of GIP (glucose-dependent insulinotropic peptide) receptor in conjunction with GLP-1 and/or glucagon receptors reduces adiposity and body weight in mice. Incretin actions of GIP on pancreatic beta cells are well characterized, but functions of GIP on adipose tissue are incompletely understood. Using differentiated human adipocytes we investigated GIP regulation of carbohydrate and lipid metabolism in the context of insulin signaling. GIP dose-dependently stimulated lipolysis without affecting ATGL or HSL lipolytic enzyme mRNA expression. Insulin dose-dependently suppressed lipolysis, and addition of GIP attenuated insulin effects on lipolysis without affecting Akt phosphorylation at Thr308or Ser473. Insulin administration increased lipogenesis, but GIP, in the presence or absence of insulin, had little effect on lipogenesis in [14C]glucose incorporation assays. GIP increased glucose utilization in adipocytes, as measured by depletion of glucose in culture media over a 24 hour period. Notably GIP dose-dependently enhanced insulin-stimulated glucose uptake ([14C]-2-deoxyglucose), but GIP alone did not appreciably regulate acute glucose uptake. We propose a new mechanistic model in which GIP signaling integrates with insulin signaling to regulate glucose and lipid metabolism. In the presence of low plasma insulin levels resembling a fasting state, GIP can increase lipolysis to mobilize nutrients from adipocytes. When insulin levels rise in a fed state, GIP can increase insulin-mediated glucose uptake in adipocytes to augment efficiency of energy storage. Further elucidation of the integration of insulin and GIP signaling will be needed to support efforts to counteract dysregulated nutrient metabolism in obesity and diabetes.

Disclosure

A. Regmi: Employee; Self; Eli Lilly and Company. M.K. Thomas: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. M. Michael: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. W.C. Roell: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.
An Action in the Hypothalamic Arcuate Nucleus Is Sufficient to Explain the Sustained Remission of Diabetes Induced by Central Administration of Fibroblast Growth Factor-1 (FGF-1)
Authors: BROWN JENNY M. , SCARLETT JARRAD , MATSEN MILES E. , SECHER ANNA , JORGENSEN RASMUS , MORTON GREGORY J. , SCHWARTZ MICHAEL W.
Published: June 2018

Our recent finding that a single intracerebroventricular (icv) injection of FGF-1 elicits sustained diabetes remission in rodent models of type 2 diabetes supports a growing consensus that the brain is a key target for diabetes drug development. The current work was undertaken to pinpoint the brain area responsible for this action of FGF-1. To this end, we considered the following preliminary findings: 1) both FGF Receptor 1 and integrin receptor αvβ3 (known to be involved in sustained FGF-1 signaling) are concentrated in the hypothalamic arcuate nucleus (ARC), 2) neuronal activation and sustained induction of the MAP Kinase / ERK pathway occurs in this brain area following icv FGF-1 injection, and 3) labeled FGF-1 is concentrated in this area following icv injection. We therefore hypothesized that in rodent models of T2D, an action in the ARC (a brain area known to participate in glucose homeostasis) mediates the sustained diabetes remission elicited by icv FGF-1 injection. To test this hypothesis, we investigated whether a single microinjection of a low dose of FGF-1 into the ARC (0.3 µg bilaterally, for a total of 0.6 µg) can mimic the response elicited by icv injection of a higher dose (3.0 µg). We report that in Zucker Diabetic Fatty rats, a single microinjection of FGF-1 bilaterally into the ARC (via an indwelling dual guide cannula) induced remission of hyperglycemia lasting >3 week, whereas intra-arcuate microinjection of saline vehicle was without effect (P<0.vs. Veh). Since icv injection of the same FGF-1 dose (0.6 µg) had no significant effect on glycemia, sustained diabetes remission induced by intra-ARC microinjection of FGF-1 cannot be explained by leakage into ventricular cerebrospinal fluid. We conclude that an action in the ARC is sufficient to explain the effect of FGF-1 to induce sustained diabetes remission.

Disclosure

J.M. Brown: None. J. Scarlett: None. M.E. Matsen: None. A. Secher: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Spouse/Partner; Gubra. R. Jorgensen: Employee; Self; Novo Nordisk Inc.. G.J. Morton: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S.
Correlates of Hypoglycemia among Youth with Type 1 Diabetes (T1D) and Suboptimal Glycemic Control
Authors: KAHKOSKA ANNA R. , CRANDELL JAMIE , DRISCOLL KIMBERLY A. , KOSOROK MICHAEL R. , MAAHS DAVID M. , MAYER-DAVIS ELIZABETH J.
Published: June 2018

Hypoglycemia is a major challenge of T1D. We examined the prevalence and correlates of hypoglycemia assessed by 7-day blinded continuous glucose monitoring at baseline among 233 youth with hemoglobin A1c (HbA1c) of 8-13% per inclusion criteria in the Flexible Lifestyles Empowering Change trial. The sample was 76.1% non-Hispanic white and 49.8% female with mean age 14.9±1.1 years and mean T1D duration 6.4±3.7 years. Mean HbA1c was 9.6±1.2%. Over 7-days, 85.4% of youth experienced hypoglycemia (i.e., time ≤70 mg/dL and >54 mg/dL; an average of 32.5±37.3 min/day). 62.7% of youth experienced clinically serious hypoglycemia (i.e., time ≤54 mg/dL; an average of 24.5±40.5 min/day). Duration of hypoglycemia was inversely associated with HbA1c (Figure). In logistic regression modeling, sex, race/ethnicity, T1D duration, body mass index z-score (BMIz), fear of hypoglycemia (from the Hypoglycemia Fear Survey) and diabetes adherence (from the Diabetes Self-Management Profile-Self Report) were not associated with hypoglycemia. Youth with higher HbA1c were less likely to experience hypoglycemia (for a 1% higher HbA1c, odds ratio (OR) for clinical hypoglycemia: 0.52, (95% CI 0.39, 0.69); OR for clinically serious hypoglycemia: 0.58 (95% CI 0.43, 0.77)). The data suggest that hypoglycemia is common among youth with elevated HbA1c and and guidance to limit hypoglycemia should be part of care in these patients.

Disclosure

A.R. Kahkoska: None. J. Crandell: None. K.A. Driscoll: None. M.R. Kosorok: None. D.M. Maahs: Advisory Panel; Self; Insulet Corporation. Consultant; Self; Abbott. Research Support; Self; Medtronic, Bigfoot Biomedical, Dexcom, Inc., Insulet Corporation, Roche Diabetes Care Health and Digital Solutions. E.J. Mayer-Davis: None.
Inadequate Use of Glucagon in Patients with T1D
Authors: HAYMOND MOREY W. , LIU JINGWEN , BISPHAM JEOFFREY , HICKEY AILEEN , MCAULIFFE-FOGARTY ALICIA H.
Published: June 2018

Glucagon is an invaluable tool for patients with type 1 diabetes (T1D) who experience severe hypoglycemia, but little is known about the actual use of glucagon in this patient population. This study was undertaken among individuals with T1D or caregivers to assess the perceptions and/or past experiences using the currently available glucagon rescue kits, and factors that might increase its utility in the management of T1D. Survey responses from 264 adults with T1D (mean age 41.2 years [SD 15.5]) and 58 caregivers of a person with T1D (mean age 11.8 years [SD 3.7]) were included in the analyses. Overall the participants were highly educated, predominantly covered by private health insurance, and the majority were on insulin pumps. The survey revealed that the majority of the individuals with T1D had been prescribed glucagon; however, almost a third of the adult patients did not receive any education on its use, and a third of the adult patients did not have a current prescription. Caregivers reported higher percentages of receiving education on glucagon use and also having a current prescription. Of those with severe hypoglycemia who had glucagon available, half did not receive a glucagon injection. The majority of patients who had received glucagon injection reported various problems with the procedure; those who did not receive glucagon injection reported a number of barriers to its use. These data strongly suggest the need for 1) standards of practice that would increase prescribing of glucagon 2) initial and ongoing education on its use and administration 3) development of a glucagon rescue option that would eliminate the complexity relating to current formulations and packaging of rescue glucagon kits.

Disclosure

M.W. Haymond: Advisory Panel; Self; Zealand Pharma A/S. Other Relationship; Self; Xeris Pharmaceuticals, Inc.. J. Liu: None. J. Bispham: None. A. Hickey: None. A.H. McAuliffe-Fogarty: Advisory Panel; Self; Novo Nordisk Inc..
Heart Rate Variability in Patients with Type 1 Diabetes and Hypoglycemia with Different Control of Diabetes Mellitus
Authors: MOSHENETS KATERYNA , PERTSEVA NATALIIA
Published: June 2018

Background and Aims: To study the correlation of heart rate variability (HRV) in patients with type 1 diabetes mellitus (T1DM) depending on glucose control and hypoglycemia.

Materials and Methods: The study involved 87 patients with T1D, including 45 men (52%), women - 42 (48%). The average age of patients - 26,6±1,48 years, disease duration 11,6±1,42 years, BMI 23,2 ± 0,63 kg/m2. All patients used basic-bolus insulin therapy with daily dose of Units 45±2,26. All patients were conducted with Continuous Glucose Monitoring System (CGMS) and 24-Hour Holter Monitoring (HM) in same time. Echocardiography was used to exclude organic pathology of the heart. Patients were divided to groups according to HbA1c. Group 1 had HbA1c?7,5%; group 2 had HbA1c>7,5%, and subgroups: A-without hypoglycemia, B-with hypoglycemia.

Results. Groups did not differ in the frequency of hypoglycemia. Calculation of results depending on the duration T1DM showed an increase LF/HF (r=0,472; p<0,05). Groups differed significantly according to the following frequency characteristics of heart rate such as VLF, LF, HF (p<0,05). The groups did not differ in other factors. In Group 2B as compared to 2A identified decrease such time-domain indicators of HRV: RMSSD 22,8 ms (15,0; 36,0) vs. 32,6 ms (27,0; 43,0); pNN50 daily 3.50% (1.0; 10.0) vs. 8.50% (6,00-13,50) and daily frequency characteristics HRV: HF 380,0 ms2 (149,0; 715,0) to 719.0 ms2 (475.0, 1153.0) and increased LF/HF 4,35 (4,10; 6,50) vs. 3.30 (2.30; 4.30). All findings are significant (p<0,05). A similar pattern was observed in patients in 1st group.

Conclusions: HRV is lower in patients with bed glucose control (HbA1c>7,5%). The most reliable criteria for assessing changes in HRV are in patients with T1DM are RMSSD, LF, HF and LF/HF are. Hypoglycemia is the most significant factor that reduces the HRV.

Disclosure

K. Moshenets: None. N. Pertseva: None.
Lipocalin-Type Prostaglandin D2 Synthase (L-PGDS) Knockout Mice Exhibits Hepatosteatosis Mediated by Enhanced Cd36 Hepatic Expression as a Result of Hyperinsulinemia
Authors: KUMAR SUNIL , PALAIA THOMAS , HALL CHRIS , LEE JENNY , STEVENSON MATTHEW , RAGOLIA LOUIS
Published: June 2018

Hepatosteatosis is strongly associated with hyperinsulinaemia and obesity. Previously, we demonstrated accelerated atherosclerosis and impaired glucose tolerance in L-PGDS knockout (KO) mice. Interestingly, L-PGDS KO mice also exhibit hyperinsulinemia on high fat diet in a time-dependent manner. In this study, we investigated the role of L-PGDS on liver pathophysiology using L-PGDS KO mice compared to control C57BL/6 mice) (n=6/group). Mice were kept on high fat diet (60% fat) for 14 weeks and all parameters were measured initially and at 4-, 8- and 14-weeks post high fat diet. Data were analyzed by unpaired t-test or one-way ANOVA where appropriate with p<0.05 deemed significant. Fasting insulin, blood glucose and calculated HOMA-IR were determined. KO mice showed significantly higher HOMA-RI 19.3± 4.62 and 19.7±4.74 at 8 and 14 weeks, respectively, compared to the C57BL/6 mice, which were 7.73±1.14 and 10.1±1.87 at 8 and 14 weeks, respectively. Hepatic Cd36 protein expression was significantly increased at 14 weeks in KO mice compared to the control. Liver steatosis directly correlated with elevated serum triglyceride levels, which significantly increased to 81.7±3.24 and 82.8±1.63 mg/dl at 8 and 14 week,s respectively, compared to the initial level of 64.1±5.66 mg/dl Control serum triglyceride levels were 61.1±3.49 and 73.6±3.2 mg/dl at 8 and 14 weeks, respectively. Furthermore, immunohistochemistry staining of lipid showed severely more liver steatosis in KO mice at all-time points when compared to control mice. Interestingly, KO mice always weighed less compared to the control mice at all-time points, which suggests that L-PGDS partially or fully contributes towards the development of hepatosteatosis independent of body weight. We conclude that L-PGDS is an essential component of hepatic metabolic substrate utilization and may play a significant role in diabetes-related steatosis.

Disclosure

S. Kumar: None. T. Palaia: None. C. Hall: None. J. Lee: None. M. Stevenson: None. L. Ragolia: None.
A Novel Continuous Glucose Monitoring System Accurately Detects Existing and Impending Hypoglycemia
Authors: CALHOUN PETER , JOHNSON TERRI , BALO ANDREW , PRICE DAVID A.
Published: June 2018

Autonomous real-time continuous glucose monitors (rtCGM), unlike intermittently scanned continuous glucose monitors (isCGM), can proactively warn users of impending hypoglycemia. This study assessed the likelihood of realized hypoglycemia when an alert is triggered in the novel factory-calibrated rtCGM system ("G6 FC" Dexcom). Subjects wearing a G6 rtCGM participated in 1 to 3 in-clinic sessions where venous YSI plasma glucose measurements were sampled every 15 minutes. Three types of hypoglycemic alerts were assessed: “Low” (<70 mg/dL), “Urgent Low” (<55 mg/dL), and the new “Urgent Low Soon” (≤55 mg/dL within 30 minutes). YSI glucose values were linearly interpolated to give estimated glucose values between YSI glucose measurements. The first “Low” and “Urgent Low” alerts were matched with actual and interpolated YSI values within ±15 minutes. The first “Urgent Low Soon” alerts were matched with actual and interpolated YSI values within 30 minutes after the alert. The Table shows 77% of “Low” alerts and 86% of “Urgent Low” alerts correctly warned of a hypoglycemic event (YSI reading below 70 mg/dL) within ±15 minutes. There were 480 “Urgent Low Soon” alerts, 86% of which correctly predicted a hypoglycemic event in the next 30 minutes. The G6 FC CGM System provides accurate alerts to patients which could facilitate actions to prevent or minimize hypoglycemia.

Table.Hypoglycemic rates during a "Low" or "Urgent Low" alertType of alertNumber of alertsNumber (%) of alert events with a nadir YSI<55 mg/dL<70 mg/dL<90 mg/dLLow620185 (29.8%)478 (77.1%)596 (96.1%)Urgent Low410249 (60.7%)353 (86.1%)394 (96.1%)

Disclosure

P. Calhoun: Employee; Self; Dexcom, Inc.. Stock/Shareholder; Self; Dexcom, Inc. T. Johnson: Employee; Self; Dexcom, Inc. A. Balo: Employee; Self; Dexcom, Inc. D.A. Price: Employee; Self; Dexcom, Inc..
Machine Learning Identification of Multiple Predictively Equivalent Risk Models for Severe Hypoglycemia in Patients with Type 2 Diabetes
Authors: MA SISI , SCHREINER PAMELA , ZMORA RACHEL , SEAQUIST ELIZABETH R. , CHOW LISA S.
Published: June 2018

Severe hypoglycemia (SH), hypoglycemia requiring medical assistance and either blood glucose ≤ 50 mg/dL or glucose administration, instills fear in patients treated for diabetes. While risk models for SH may categorize an individual’s risk, incomplete or unavailable (“missing”) data limit clinical application. To circumvent the “missing” data issue, we used machine learning to identify multiple predictively equivalent risk models for SH in patients with type 2 diabetes (T2DM). Data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (n=10,251) were analyzed. Over ACCORD follow-up (mean 4.7± SD 1.4 years), 721 incident SH events were observed. We examined 95 candidate risk factors for model construction. Multiple predictively equivalent risk models (n=194) for SH were induced using the SurvTIE* algorithm (an adaptation of TIE* algorithm to survival outcome) and constructed with Cox regression and time-varying covariates. For each risk model, the number of risk factors ranged from 18-23 (median = 19). Unbiased performance estimations of c-index 0.78±0.03 were obtained from repeated cross-validation. Table 1 shows several unique models with equivalent predictive ability. In patients with T2DM, multiple predictively equivalent risk models for SH can be identified, potentially personalizing model selection when data are “missing.”

Disclosure

S. Ma: None. P. Schreiner: None. R. Zmora: None. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company, Sanofi, Zucera, InfoMed, 360 consulting. Other Relationship; Self; Novo Nordisk Inc. L.S. Chow: Research Support; Self; Eli Lilly and Company, National Institute of Diabetes and Digestive and Kidney Diseases.
Canagliflozin (CANA) vs. Other Antihyperglycemic Agents on the Risk of Below-Knee Amputation (BKA) for Patients with T2DM—A Real-World Analysis of >700,000 U.S. Patients
Authors: RYAN PATRICK , BUSE JOHN B. , SCHUEMIE MARTIJN , DEFALCO FRANK , YUAN ZHONG , STANG PAUL , BERLIN JESSE A. , ROSENTHAL NORM
Published: June 2018

Sodium glucose co-transporter 2 inhibitors (SGLT2i) are indicated for treatment of T2DM; some SGLT2i have reported a CV benefit and some reported a risk of BKA. U.S. claims databases were analyzed using a prespecified protocol to examine CANA-associated effects on BKA and hospitalization for heart failure (HHF) vs. other SGLT2i and non-SGLT2i. Analyses used a propensity score adjusted new user design with numerous sensitivity analyses. The 4 databases included 142K new users of CANA, 110K of other SGLT2i, and 460K of non-SGLT2i AHAs. Meta-analysis results are reported when heterogeneity across databases was not substantial (I2 <0.4). There was no evidence of increased risk of BKA with CANA vs. non-SGLT2i or other SGLT2i in on-treatment or ITT analyses (Table). HHF benefits were demonstrated in these analyses, consistent with clinical trials. Similar BKA and HHF results were seen in a subgroup with established CV disease. In this large comprehensive analysis, neither CANA nor other SGLT2i showed an increased risk of amputation vs. non-SGLT2i. Because on-treatment median exposure was <6 months, future observational studies with longer duration are needed. This study helps to further characterize the potential benefits and harms of SGLT2i as observed in routine clinical practice to complement the evidence from clinical trials and prior observational studies.

Disclosure

P. Ryan: Employee; Self; Janssen Research & Development, LLC. J.B. Buse: Other Relationship; Self; ADOCIA, AstraZeneca, Dexcom, Inc., Elcelyx Therapeutics, Inc., Eli Lilly and Company, Fractyl Laboratories, Inc., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Metavention, NovaTarg, Novo Nordisk A/S, Sanofi, VTV Therapeutics. Research Support; Self; Boehringer Ingelheim GmbH, Johnson & Johnson Services, Inc., Theracos, Inc.. Other Relationship; Self; Shenzhen Hightide Biopharmaceutical, Ltd.. Research Support; Self; National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences. Other Relationship; Self; National Institute of Diabetes and Digestive and Kidney Diseases, American Diabetes Association. Research Support; Self; Patient-Centered Outcomes Research Institute. Other Relationship; Self; National Institute of Environmental Health Sciences. M. Schuemie: Employee; Self; Janssen Research & Development, LLC. F. Defalco: Employee; Self; Janssen Research & Development, LLC. Z. Yuan: Employee; Self; Janssen Research & Development, LLC. P. Stang: Employee; Self; Janssen Research & Development, LLC. J.A. Berlin: Employee; Self; Johnson & Johnson, LLC. N. Rosenthal: Employee; Self; Janssen Research & Development.
Increased Fluctuation of Measured Glucose in Critically Ill Patients Is an Independent Predictor of Mortality
Authors: KANAPARTHY NAGA SASIDHAR , MATHEWS SHERIN ELSA , KALLUR KAMALA RAMYA
Published: June 2018

Background: Extreme glucose values in critically ill patients have been studied and shown to be predictors of mortality. In addition, glucose fluctuation is also proposed to have been a determinant of poor outcome. In our study, we attempt to understand whether there is a relation between the fluctuations of glucose in critically ill patients to their mortality.

Methods: Data was obtained from "Medical Information Mart for Intensive Care III" database between 2001 and 2012. Fluctuation was measured as coefficient of variance of glucose (CVG). Patients were split into four groups based on the CVG of glucose levels during their ICU stay, namely Group 1: <25%, Group 2: 25%-50%, Group 3: 50%-100% and Group 4: >100%. Outcomes were measured at 3-day mortality interval and the relative risk was compared across the four groups. Multinomial logistic regression with length of stay, prednisone administration and Simplified Acute Physiology Score (SAPS) II as variables were run to assess the relative risk ratios (RRR) of increased CVG with mortality.

Results: A total of 45,302 adult ICU admissions were considered, 82.1% (n=37,192) had no diabetes, 17.6% (n=7,952) were type 2 diabetic (T2DM) and 0.04% (n=168) were type 1 diabetic (T1DM). The RRR for 3-day mortality, among the nondiabetics compared to the base outcome (Group 1) was 1.51 (p<0.0001) in Group 2, 3.76 (p<0.0001) in Group 3 and 2.17 (p=0.10) in Group 4. Among T2DM, the RRR for 3-day mortality was 1.04 (p=0.7) in Group 2, 2.97 (p<0.0001) in Group 3, 14.03 (p=0.025) in Group 4. Due to the small number of observations for T1DM, they were excluded.

Conclusion: In nondiabetics there was higher mortality at a lower CVG as compared to the diabetics. In diabetics the increased mortality was observed at slightly higher CVG. In patients admitted to critical care units, increased fluctuation in glucose during their ICU admission is an independent predictor of mortality and additional caution should be taken to avoid wide fluctuations.

Disclosure

N. Kanaparthy: None. S. Elsa Mathews: None. K. Kallur: None.