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Elisa Fabbri, Chee W Chia, Richard G Spencer, Kenneth W Fishbein, David A Reiter, Donnie Cameron, Ariel C Zane, Zenobia A Moore, Marta Gonzalez-Freire, Marco Zoli, Stephanie A Studenski, Rita R Kalyani, Josephine M Egan, Luigi Ferrucci
Whether individuals with insulin resistance but without criteria for diabetes exhibit reduced mitochondrial oxidative capacity is unclear; addressing this question could guide research for new therapeutics. We investigated 248 non-diabetic participants from the Baltimore Longitudinal Study of Aging (BLSA) to determine whether impaired mitochondrial capacity is associated with prediabetes, insulin resistance, duration and severity of hyperglycemia exposure. Mitochondrial capacity was assessed as post-exercise phosphocreatine recovery time constant (τPCr) by (31)P-magnetic resonance spectroscopy, with higher τPCr reflecting reduced capacity...
October 13, 2016: Diabetes
Fabio Arturo Grieco, Guido Sebastiani, Jonas Juan-Mateu, Olatz Villate, Laura Marroqui, Laurence Ladrière, Ksenya Tugay, Romano Regazzi, Marco Bugliani, Piero Marchetti, Francesco Dotta, Décio L Eizirik
Type 1 Diabetes is an autoimmune disease leading to beta cell destruction. MicroRNAs (miRNAs) are small non-coding RNAs that control gene expression and organ formation. They participate in the pathogenesis of several autoimmune diseases, but the nature of miRNAs contributing to beta cell death in T1D and their target genes remain to be clarified.We performed a miRNA expression profile on human islet preparations exposed to the cytokines IL-1β+IFN-γ. Confirmation of miRNAs and target genes modification in human beta cells was performed by real-time qPCR...
October 13, 2016: Diabetes
Qilong Wang, Miao Zhang, Gloria Torres, Shengnan Wu, Changhan Ouyang, Zhonglin Xie, Ming-Hui Zou
Metformin is a widely used anti-diabetic drug that exerts cardiovascular protective effects in patients with diabetes. How metformin protects diabetes-related cardiovascular diseases remains poorly understood. Here, we show that metformin abated the progression of diabetes-accelerated atherosclerosis by inhibiting mitochondrial fission in endothelial cells.Metformin treatments markedly reduced mitochondrial fragmentation, mitigated mitochondrial-derived superoxide release, improved endothelial-dependent vasodilation, inhibited vascular inflammation, and suppressed atherosclerotic lesions in streptozotocin (STZ)-induced diabetic ApoE(-/-) mice...
October 13, 2016: Diabetes
Rachael C Aikens, Wei Zhao, Danish Saleheen, Muredach P Reilly, Stephen E Epstein, Emmi Tikkanen, Veikko Salomaa, Benjamin F Voight
Observational studies have shown that elevated systolic blood pressure (SBP) is associated with future onset of type 2 diabetes, but whether this association is causal is not known. We applied the Mendelian Randomization framework to evaluate the causal hypothesis that elevated SBP increases risk to type 2 diabetes. We utilized 28 genetic variants associated with SBP and evaluated their impact on type 2 diabetes using a European-centric meta-analysis comprising 37,293 cases and 125,686 controls. We found that elevation of SBP levels by 1 mmHg due to our genetic score was associated with a 2% increase in risk of type 2 diabetes (OR=1...
October 4, 2016: Diabetes
Manish Saggar, Eva Tsalikian, Nelly Mauras, Paul Mazaika, Neil H White, Stuart Weinzimer, Bruce Buckingham, Tamara Hershey, Allan L Reiss
Sustained dysregulation of blood glucose (hyper or hypoglycemia) associated with type 1 diabetes (T1D) has been linked to cognitive deficits and altered brain anatomy and connectivity. However, a significant gap remains with respect to how T1D affects spontaneous at-rest connectivity in young developing brains. Here, using a large multi-site study, resting state functional Magnetic Resonance Imaging (rsfMRI) data were examined in young children with T1D (N=57, mean age=7.88 years; 27F) as compared to age-matched non-diabetic controls (N=26, mean age=7...
October 4, 2016: Diabetes
Blake J Cochran, Liming Hou, Anil Paul Chirackal Manavalan, Benjamin M Moore, Fatiha Tabet, Afroza Sultana, Luisa Cuesta Torres, Shudi Tang, Sudichhya Shrestha, Praween Senanayake, Mili Patel, William J Ryder, Andre Bongers, Marie Maraninchi, Valerie C Wasinger, Marit Westerterp, Alan R Tall, Philip J Barter, Kerry-Anne Rye
Elevated pancreatic β-cell cholesterol levels impair insulin secretion and reduce plasma insulin levels. This study establishes that low plasma insulin levels have a detrimental effect on two major insulin target tissues: adipose tissue and skeletal muscle. Mice with increased β-cell cholesterol levels were generated by conditional deletion of the ATP binding cassette transporters, ABCA1 and ABCG1, in β-cells (β-DKO mice). Insulin secretion was impaired in these mice under basal and high glucose conditions and glucose disposal was shifted from skeletal muscle to adipose tissue...
October 4, 2016: Diabetes
Zhongbo Liu, Jose Cordoba-Chacon, Rhonda D Kineman, Bruce N Cronstein, Radhika Muzumdar, Zhenwei Gong, Haim Werner, Shoshana Yakar
In humans low levels of growth hormone (GH) and its mediator, insulin-like growth factor-1 (IGF-1), associate with hepatic lipid accumulation. In mice, congenital liver-specific ablation of the GH receptor (GHR) results in reductions in circulating IGF-1 and hepatic steatosis, associated with systemic insulin-resistance. Due to the intricate relationship between GH and IGF-1, the relative contribution of each hormone to the development of hepatic steatosis is unclear. Our goal was to dissect the mechanisms by which hepatic GH resistance leads to steatosis and overall insulin resistance, independent of IGF-1...
September 27, 2016: Diabetes
Jami M Gurley, Olga Ilkayeva, Robert M Jackson, Beth A Griesel, Phillip White, Satochi Matsuzaki, Rizwan Qaisar, Holly Van Remmen, Kenneth M Humphries, Christopher B Newgard, Ann Louise Olson
Impaired GLUT4-dependent glucose uptake is a contributing factor in the development of whole body insulin resistance in obese patients and obese animal models. Previously, we demonstrated that transgenic mice engineered to express the human GLUT4 gene under the control of the human GLUT4 promoter (TG), are resistant to obesity-induced insulin resistance. A likely mechanism underlying increased insulin sensitivity is increased glucose uptake in skeletal muscle. The purpose of this study was to investigate the broader metabolic consequences of enhanced glucose uptake into muscle...
September 27, 2016: Diabetes
Michael J Haller, Stephen E Gitelman, Peter A Gottlieb, Aaron W Michels, Daniel J Perry, Andrew R Schultz, Maigan A Hulme, Jonathan J Shuster, Baiming Zou, Clive H Wasserfall, Amanda Posgai, Clayton E Mathews, Todd M Brusko, Mark A Atkinson, Desmond A Schatz
Low-dose anti-thymocyte globulin (ATG) + pegylated granulocyte-colony stimulating factor (G-CSF) preserves beta cell function for at least 12-months in type 1 diabetes (T1D). Herein, we describe metabolic and immunologic parameters 24-months following treatment. Patients with established T1D (duration 4-24 months) were randomized to ATG and peg-G-CSF (N=17) or placebo (N=8). Primary outcomes included AUC C-peptide following mixed-meal tolerance test (MMTT) and flow cytometry. "Responders" (12-month C-peptide ≥ baseline), "Super-responders" (24-month C-peptide ≥ baseline), and "Non-responders" (12-month C-peptide < baseline) were evaluated for biomarkers of outcome...
September 26, 2016: Diabetes
Mainak Ghosh, Sougata Niyogi, Madhumita Bhattacharyya, Moumita Adak, Dipak K Nayak, Saikat Chakrabarti, Partha Chakrabarti
Optimal control of hepatic lipid metabolism is critical for organismal metabolic fitness. In liver, adipose triglyceride lipase (ATGL) serves as a major triacylglycerol (TAG) lipase and controls bulk of intracellular lipid turnover. However, regulation of ATGL expression and its functional implications in hepatic lipid metabolism particularly in the context of fatty liver disease is unclear. We show that E3 ubiquitin ligase COP1 (also known as RFWD2) binds to the consensus VP-motif of ATGL and targets it for proteasomal degradation by K-48 linked polyubiquitination, predominantly at lysine 100 residue...
September 22, 2016: Diabetes
Theodora Szasz, Camilla F Wenceslau, Beth Burgess, Kenia P Nunes, R Clinton Webb
Diabetic bladder dysfunction (DBD) is a common urological complication of diabetes. Innate immune system activation via Toll-like receptor 4 (TLR4) leads to inflammation and oxidative stress and was implicated in diabetes pathophysiology. We hypothesized that bladder hypertrophy and hypercontractility in DBD is mediated by TLR4 activation. Wild type (WT) and TLR4 knock-out (TLR4KO) mice were made diabetic by streptozotocin (STZ) treatment and bladder contractile function and TLR4 pathway expression were evaluated...
September 20, 2016: Diabetes
Vibe Nylander, Lars R Ingerslev, Emil Andersen, Odile Fabre, Christian Garde, Morten Rasmussen, Kiymet Citirikkaya, Josephine Bæk, Gitte L Christensen, Marianne Aznar, Lena Specht, David Simar, Romain Barrès
Exposure to ionizing radiation increases the risk of chronic metabolic disorders such as insulin resistance and type 2 diabetes later in life. We hypothesized that irradiation reprograms the epigenome of metabolic progenitor cells, which could account for impaired metabolism after cancer treatment. C57Bl/6 mice were treated with a single dose of irradiation and subjected to high fat diet (HFD). RNA Sequencing and Reduced Representation Bisulfite Sequencing were used to create transcriptomic and epigenomic profiles of preadipocytes and skeletal muscle satellite cells collected from irradiated mice...
September 20, 2016: Diabetes
Wensheng Zhang, Vijay S Gorantla, Phil G Campbell, Yang Li, Yang Yang, Chiaki Komatsu, Lee E Weiss, Xin Xiao Zheng, Mario G Solari
Pancreatic islet transplantation (PIT) represents a potential therapy to circumvent the need for exogenous insulin in type 1 diabetes. However, PIT remains limited by lack of donor islets and need for long-term multi-drug immunosuppression to prevent alloimmune islet rejection. Our goal was to evaluate a local immunoregulatory strategy that sustains islet allograft survival and restores glucose homeostasis in the absence of systemic immunosuppression. Nanogram quantities of murine CTLA4/Fc fusion protein were controllably delivered within human acellular dermal matrix scaffolds using an inkjet-based biopatterning technology and co-transplanted with allogeneic islets under the renal capsule to create an immunoregulatory microenvironment around the islet allograft...
September 20, 2016: Diabetes
Kristina M Mueller, Kerstin Hartmann, Doris Kaltenecker, Sabine Vettorazzi, Mandy Bauer, Lea Mauser, Sabine Amann, Sigrid Jall, Katrin Fischer, Harald Esterbauer, Timo D Müller, Matthias H Tschöp, Christoph Magnes, Johannes Haybaeck, Thomas Scherer, Natalie Bordag, Jan P Tuckermann, Richard Moriggl
Glucocorticoids (GCs) are important regulators of systemic energy metabolism, while aberrant GC action is linked to metabolic dysfunctions. Yet, the extent to which normal and pathophysiologic energy metabolism depend on the glucocorticoid receptor (GR) in adipocytes remains unclear. Here, we demonstrate that adipocyte GR-deficiency in mice significantly impacts systemic metabolism in different energetic states. Plasma metabolomics and biochemical analyses revealed a marked global effect of GR-deficiency on systemic metabolite abundance and thus, substrate partitioning in fed and fasted states...
September 20, 2016: Diabetes
Cristina Contreras, Ismael González-García, Patricia Seoane-Collazo, Noelia Martínez-Sánchez, Laura Liñares-Pose, Eva Rial-Pensado, Johan Fernø, Manuel Tena-Sempere, Núria Casals, Carlos Diéguez, Rubén Nogueiras, Miguel López
The chaperone GRP78/BiP (glucose regulated protein 78 kDa/binding immunoglobulin protein) modulates protein folding in reply to cellular insults that lead to ER stress. The aim of this study was to investigate the role of hypothalamic GRP78 on energy balance, with particular interest on thermogenesis and browning of white adipose tissue (WAT). For this purpose, we used diet-induced obese rats and thapsigargin-treated rats and by combining metabolic, histologic, physiologic, pharmacologic, thermographic and molecular techniques, we studied the effect of genetic manipulation of hypothalamic GRP78...
September 15, 2016: Diabetes
Jie-Mei Wang, Yining Qiu, Zeng-Quan Yang, Li Li, Kezhong Zhang
Diabetic skin ulcers represent a challenging clinical problem with mechanisms not fully understood. In this study, we investigated the role and mechanism for the primary Unfolded Protein Response (UPR) transducer inositol requiring enzyme 1 (IRE1α) in diabetic wound healing. Bone marrow-derived progenitor cells (BMPCs) were isolated from adult male type-2 diabetic and their littermate control mice. In diabetic BMPCs, IRE1α protein expression and phosphorylation were repressed. The impaired diabetic BMPC angiogenic function was rescued by adenovirus-mediated expression of IRE1α, but not by the RNase-inactive IRE1á or the activated X-box binding protein 1 (XBP1), the canonical IRE1á target...
September 15, 2016: Diabetes
Piero Ruggenenti, Manuela Abbate, Barbara Ruggiero, Stefano Rota, Matias Trillini, Carolina Aparicio, Aneliya Parvanova, Ilian Petrov Iliev, Giovanna Pisanu, Annalisa Perna, Angela Russo StatSciD, Olimpia Diadei, Davide Martinetti, Antonio Cannata Chemist, Fabiola Carrara Chemist, Silvia Ferrari Chemist, Nadia Stucchi Chemist, Giuseppe Remuzzi, Luigi Fontana
In type-2 diabetics with abdominal obesity, hyperfiltration is a risk factor for accelerated GFR decline and nephropathy. In this academic, single-center, parallel-group, Prospective, Randomized, Open-label, Blinded Endpoint (PROBE) trial ( number: NCT01213212), consenting >18-year-old, type-2 diabetics with waist circumference >94 (males) or >80 (females) cm, serum creatinine <1.2 mg/dl, and normoalbuminuria were randomized (1:1) with permuted blocks to 6-month 25% CR or standard diet (SD)...
September 15, 2016: Diabetes
Victoria Catalán, Javier Gómez-Ambrosi, Amaia Rodríguez, Beatriz Ramírez, Víctor Valentí, Rafael Moncada, Manuel F Landecho, Camilo Silva, Javier Salvador, Gema Frühbeck
Interleukin (IL)-32 is a recently described cytokine involved in the regulation of inflammation. We aimed to explore whether IL-32 could function as an inflammatory and angiogenic factor in human obesity and obesity-associated type 2 diabetes. Samples obtained from 90 subjects were used in the study. We show, for the first time that increased circulating levels of IL-32 in obese patients decreased after weight loss achieved by Roux-en-Y gastric bypass but not following a conventional hypocaloric diet. Obese patients exhibited higher expression levels of IL-32 in visceral adipose tissue (AT) as well as in subcutaneous AT and peripheral mononuclear blood cells...
September 14, 2016: Diabetes
Akiko Takikawa, Arshad Mahmood, Allah Nawaz, Tomonobu Kado, Keisuke Okabe, Seiji Yamamoto, Aminuddin Arif, Satoko Senda, Koichi Tsuneyama, Masashi Ikutani, Yasuharu Watanabe, Yoshiko Igarashi, Yoshinori Nagai, Kiyoshi Takatsu, Keiichi Koizumi, Johji Imura, Nobuhito Goda, Masakiyo Sasahara, Michihiro Matsumoto, Kumiko Saeki, Takashi Nakagawa, Shiho Fujisaka, Isao Usui, Kazuyuki Tobe
Adipose tissue hypoxia is an important feature of pathological adipose tissue expansion. Hypoxia-inducible factor-1α (HIF-1α) in adipocytes reportedly induces oxidative stress and fibrosis, rather than neoangiogenesis via VEGF-A. We previously reported that macrophages in crown-like structures (CLSs) are both hypoxic and inflammatory. In the present study, we examined how macrophage HIF-1α is involved in high-fat diet (HFD)-induced inflammation, neovascularization, hypoxia, and insulin resistance using mice with myeloid cell-specific HIF-1α deletion fed an HFD...
September 13, 2016: Diabetes
Brian H Chen, Marie-France Hivert, Marjolein J Peters, Luke C Pilling, John D Hogan, Lisa M Pham, Lorna W Harries, Caroline S Fox, Stefania Bandinelli, Abbas Dehghan, Dena G Hernandez, Albert Hofman, Jaeyoung Hong, Roby Joehanes, Andrew D Johnson, Peter J Munson, Denis V Rybin, Andrew B Singleton, André G Uitterlinden, Saixia Ying, Magic Investigators, David Melzer, Daniel Levy, Joyce B J van Meurs, Luigi Ferrucci, Jose C Florez, Josée Dupuis, James B Meigs, Eric D Kolaczyk
Genome-wide association studies (GWAS) have successfully identified genetic loci associated with glycemic traits. However, characterizing the functional significance of these loci has proven challenging. We sought to gain insights into the regulation of fasting insulin and fasting glucose through the use of gene expression microarray data from peripheral blood samples of non-diabetic participants in the Framingham Heart Study (n=5,056), the Rotterdam Study (n=723), and the InCHIANTI Study (n=595). Using a false discovery rate q<0...
September 13, 2016: Diabetes
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