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D Accili, S C Talchai, J Y Kim-Muller, F Cinti, E Ishida, A M Ordelheide, T Kuo, J Fan, J Son
Diabetes is caused by a combination of impaired responsiveness to insulin and reduced production of insulin by the pancreas. Until recently, the decline of insulin production had been ascribed to β-cell death. But recent research has shown that β-cells do not die in diabetes, but undergo a silencing process, termed "dedifferentiation." The main implication of this discovery is that β-cells can be revived by appropriate treatments. We have shown that mitochondrial abnormalities are a key step in the progression of β-cell dysfunction towards dedifferentiation...
September 2016: Diabetes, Obesity & Metabolism
Ja Young Kim-Muller, Jason Fan, Young Jung R Kim, Seung-Ah Lee, Emi Ishida, William S Blaner, Domenico Accili
Insulin-producing β cells become dedifferentiated during diabetes progression. An impaired ability to select substrates for oxidative phosphorylation, or metabolic inflexibility, initiates progression from β-cell dysfunction to β-cell dedifferentiation. The identification of pathways involved in dedifferentiation may provide clues to its reversal. Here we isolate and functionally characterize failing β cells from various experimental models of diabetes and report a striking enrichment in the expression of aldehyde dehydrogenase 1 isoform A3 (ALDH(+)) as β cells become dedifferentiated...
August 30, 2016: Nature Communications
Leo C T Ng, Igor Putrenko, Victoria Baronas, Filip Van Petegem, Eric A Accili
Cyclic AMP is thought to facilitate the opening of the HCN2 channel by binding to a C-terminal domain and promoting or inhibiting interactions between subunits. Here, we correlated the ability of cyclic nucleotides to promote interactions of isolated HCN2 C-terminal domains in solution with their ability to facilitate channel opening. Cyclic IMP, a cyclic purine nucleotide, and cCMP, a cyclic pyrimidine nucleotide, bind to a C-terminal domain containing the cyclic nucleotide-binding domain but, in contrast to other cyclic nucleotides examined, fail to promote its oligomerization, and produce only modest facilitation of opening of the full-length channel...
October 4, 2016: Structure
Brian T O'Neill, Kevin Y Lee, Katherine Klaus, Samir Softic, Megan T Krumpoch, Joachim Fentz, Kristin I Stanford, Matthew M Robinson, Weikang Cai, Andre Kleinridders, Renata O Pereira, Michael F Hirshman, E Dale Abel, Domenico Accili, Laurie J Goodyear, K Sreekumaran Nair, C Ronald Kahn
Diabetes strongly impacts protein metabolism, particularly in skeletal muscle. Insulin and IGF-1 enhance muscle protein synthesis through their receptors, but the relative roles of each in muscle proteostasis have not been fully elucidated. Using mice with muscle-specific deletion of the insulin receptor (M-IR-/- mice), the IGF-1 receptor (M-IGF1R-/- mice), or both (MIGIRKO mice), we assessed the relative contributions of IR and IGF1R signaling to muscle proteostasis. In differentiated muscle, IR expression predominated over IGF1R expression, and correspondingly, M-IR-/- mice displayed a moderate reduction in muscle mass whereas M-IGF1R-/- mice did not...
September 1, 2016: Journal of Clinical Investigation
Reema P Vazirani, Akanksha Verma, L Amanda Sadacca, Melanie S Buckman, Belen Picatoste, Muheeb Beg, Christopher Torsitano, Joanne H Bruno, Rajesh T Patel, Kotryna Simonyte, Joao P Camporez, Gabriela Moreira, Domenick J Falcone, Domenico Accili, Olivier Elemento, Gerald I Shulman, Barbara B Kahn, Timothy E McGraw
Insulin controls glucose uptake into adipose and muscle cells by regulating the amount of GLUT4 in the plasma membrane. The effect of insulin is to promote the translocation of intracellular GLUT4 to the plasma membrane. The small Rab GTPase, Rab10, is required for insulin-stimulated GLUT4 translocation in cultured 3T3-L1 adipocytes. Here we demonstrate that both insulin-stimulated glucose uptake and GLUT4 translocation to the plasma membrane are reduced by about half in adipocytes from adipose-specific Rab10 knockout (KO) mice...
June 2016: Diabetes
Marit Westerterp, Kyoichiro Tsuchiya, Ian W Tattersall, Panagiotis Fotakis, Andrea E Bochem, Matthew M Molusky, Vusisizwe Ntonga, Sandra Abramowicz, John S Parks, Carrie L Welch, Jan Kitajewski, Domenico Accili, Alan R Tall
OBJECTIVE: Plasma high-density lipoproteins have several putative antiatherogenic effects, including preservation of endothelial functions. This is thought to be mediated, in part, by the ability of high-density lipoproteins to promote cholesterol efflux from endothelial cells (ECs). The ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1) interact with high-density lipoproteins to promote cholesterol efflux from ECs. To determine the impact of endothelial cholesterol efflux pathways on atherogenesis, we prepared mice with endothelium-specific knockout of Abca1 and Abcg1...
July 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
Ja Young Kim-Muller, Young Jung R Kim, Jason Fan, Shangang Zhao, Alexander S Banks, Marc Prentki, Domenico Accili
Pancreatic β-cell dysfunction contributes to onset and progression of type 2 diabetes. In this state β-cells become metabolically inflexible, losing the ability to select between carbohydrates and lipids as substrates for mitochondrial oxidation. These changes lead to β-cell dedifferentiation. We have proposed that FoxO proteins are activated through deacetylation-dependent nuclear translocation to forestall the progression of these abnormalities. However, how deacetylated FoxO exert their actions remains unclear...
May 6, 2016: Journal of Biological Chemistry
Taiyi Kuo, Ja Young Kim-Muller, Timothy E McGraw, Domenico Accili
Insulin resistance and β cell dysfunction contribute to the pathogenesis of type 2 diabetes. Unlike insulin resistance, β cell dysfunction remains difficult to predict and monitor, because of the inaccessibility of the endocrine pancreas, the integrated relationship with insulin sensitivity, and the paracrine effects of incretins. The goal of our study was to survey the plasma response to a metabolic challenge in order to identify factors predictive of β cell dysfunction. To this end, we combined (i) the power of unbiased iTRAQ (isobaric tag for relative and absolute quantification) mass spectrometry with (ii) direct sampling of the portal vein following an intravenous glucose/arginine challenge (IVGATT) in (iii) mice with a genetic β cell defect...
April 29, 2016: Journal of Biological Chemistry
Francesca Cinti, Ryotaro Bouchi, Ja Young Kim-Muller, Yoshiaki Ohmura, P R Sandoval, Matilde Masini, Lorella Marselli, Mara Suleiman, Lloyd E Ratner, Piero Marchetti, Domenico Accili
CONTEXT: Diabetes is associated with a deficit of insulin-producing β-cells. Animal studies show that β-cells become dedifferentiated in diabetes, reverting to a progenitor-like stage, and partly converting to other endocrine cell types. OBJECTIVE: To determine whether similar processes occur in human type 2 diabetes, we surveyed pancreatic islets from 15 diabetic and 15 nondiabetic organ donors. DESIGN: We scored dedifferentiation using markers of endocrine lineage, β-cell-specific transcription factors, and a newly identified endocrine progenitor cell marker, aldehyde dehydrogenase 1A3...
March 2016: Journal of Clinical Endocrinology and Metabolism
Alice Abraham, Mishaela Rubin, Domenico Accili, John P Bilezikian, Utpal B Pajvani
Insulin, proinsulin, and C-peptide levels increase with sulfonylurea exposure but the acuity of increase has not been described in dialysis patients. We present a case of a dialysis patient who presented with hypoglycemia and was found to have accidental sulfonylurea ingestion. This is a 73-year-old man with ESRD on peritoneal dialysis, without history of diabetes, who presented with hypoglycemia. Past medical history includes multiple myeloma, congestive heart failure, and hypertension. At initial presentation, his blood glucose was 47 mg/dL, with concomitant elevations in the following: C-peptide 30...
2015: Case Reports in Endocrinology
Utpal B Pajvani, Domenico Accili
No abstract text is available yet for this article.
November 2015: Diabetologia
B Thorens, D Accili, B Ahrén, E Cerasi, S Seino, C Boitard
No abstract text is available yet for this article.
September 2015: Diabetes, Obesity & Metabolism
Utpal B Pajvani, Domenico Accili
Until recently, type 2 diabetes was seen as a disease caused by an impaired ability of insulin to promote the uptake and utilisation of glucose. Work on forkhead box protein O (FOXO) transcription factors revealed new aspects of insulin action that have led us to articulate a liver- and beta cell-centric narrative of diabetes pathophysiology and treatment. FOXO integrate a surprisingly diverse subset of biological functions to promote metabolic flexibility. In the liver, they controls the glucokinase/glucose-6-phosphatase switch and bile acid pool composition, directing carbons to glucose or lipid utilisation, thus providing a unifying mechanism for the two abnormalities of the diabetic liver: excessive glucose production and increased lipid synthesis and secretion...
November 2015: Diabetologia
Hongxia Ren, Joshua R Cook, Ning Kon, Domenico Accili
Hypothalamic neurons expressing agouti-related peptide (AgRP) regulate eating and glucose metabolism. Ablation of FOXO1 in AgRP neurons of mice results in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to insulin and leptin. We tentatively identified G-protein-coupled receptor Gpr17 as an effector of FOXO1 orexigenic signals in AgRP neurons. In this study, we generated and characterized AgRP neuron-specific Gpr17 knockout mice (Agrp-Gpr17(-/-)) to test the hypothesis that Gpr17 regulates appetite, energy expenditure, and metabolism...
November 2015: Diabetes
Li Qiang, Ning Kon, Wenhui Zhao, Le Jiang, Colette M Knight, Carrie Welch, Utpal Pajvani, Wei Gu, Domenico Accili
Obesity is associated with higher incidence of cancer, but the predisposing mechanisms remain poorly understood. The NAD(+)-dependent deacetylase SirT1 orchestrates metabolism, cellular survival, and growth. However, there is no unifying mechanism to explain the metabolic and tumor-related effects of SirT1. In this work, we demonstrate that genetic ablation of the endogenous inhibitor of SirT1, Deleted-in-Breast-Cancer-1 (Dbc1), unexpectedly results in obesity and insulin resistance. Dbc1 deficiency promoted SirT1-dependent gain of function of stearoyl-coenzyme A desaturase 1 (Scd1), increasing plasma and tissue levels of unsaturated fatty acids...
June 23, 2015: Cell Reports
Rafael Mayoral, Olivia Osborn, Joanne McNelis, Andrew M Johnson, Da Young Oh, Cristina Llorente Izquierdo, Heekyung Chung, Pingping Li, Paqui G Traves, Gautam Bandyopadhyay, Ariane R Pessentheiner, Jachelle M Ofrecio, Joshua R Cook, Li Qiang, Domenico Accili, Jerrold M Olefsky
OBJECTIVE: Adipose tissue is the primary site for lipid deposition that protects the organisms in cases of nutrient excess during obesogenic diets. The histone deacetylase Sirtuin 1 (SIRT1) inhibits adipocyte differentiation by targeting the transcription factor peroxisome proliferator activated-receptor gamma (PPARγ). METHODS: To assess the specific role of SIRT1 in adipocytes, we generated Sirt1 adipocyte-specific knockout mice (ATKO) driven by aP2 promoter onto C57BL/6 background...
May 2015: Molecular Metabolism
Joshua R Cook, Fanny Langlet, Yoshiaki Kido, Domenico Accili
The development of insulin resistance (IR) in the liver is a key pathophysiologic event in the development of type 2 diabetes. Although insulin loses its ability to suppress glucose production, it largely retains its capacity to drive lipogenesis. This selective IR results in the characteristic hyperglycemia and dyslipidemia of type 2 diabetes. The delineation of two branched pathways of insulin receptor (InsR) signaling to glucose versus triglyceride production, one through FoxO and the other through SREBP-1c, provides a mechanism to account for this pathophysiological abnormality...
May 29, 2015: Journal of Biological Chemistry
Domenico Accili
Biomedical research is not immune to economic imperatives. But as the realities of profit encroach ever closer on what was once regarded as an idealistic and selfless endeavor, the author reflects on four trends that are hollowing out the research enterprise.
April 7, 2015: Cell Metabolism
Shivatra Chutima Talchai, Domenico Accili
β-Cell dysfunction in diabetes results from abnormalities of insulin production, secretion, and cell number. These abnormalities may partly arise from altered developmental programming of β-cells. Foxo1 is important to maintain adult β-cells, but little is known about its role in pancreatic progenitor cells as determinants of future β-cell function. We addressed this question by generating an allelic series of somatic Foxo1 knockouts at different stages of pancreatic development in mice. Surprisingly, ablation of Foxo1 in pancreatic progenitors resulted in delayed appearance of Neurogenin3(+) progenitors and their persistence into adulthood as a self-replicating pool, causing a fourfold increase of β-cell mass...
August 2015: Diabetes
Joshua R Cook, Michihiro Matsumoto, Alexander S Banks, Tadahiro Kitamura, Kyoichiro Tsuchiya, Domenico Accili
Insulin signaling in the liver blunts glucose production and stimulates triglyceride biosynthesis. FoxO1 is required for cAMP induction of hepatic glucose production and is permissive for the effect of insulin to suppress this process. Moreover, FoxO1 ablation increases lipogenesis. In this study, we investigated the pleiotropic actions of FoxO1 on glucose and lipid metabolism. To this end, we reconstituted FoxO1 function in mice with a liver-specific deletion of Foxo1 using targeted knock-in of an allele encoding a DNA binding-deficient FoxO1 mutant (L-DBD)...
June 2015: Diabetes
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