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Domenico Accili AND Diabetes

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https://www.readbyqxmd.com/read/27572106/aldehyde-dehydrogenase-1a3-defines-a-subset-of-failing-pancreatic-%C3%AE-cells-in-diabetic-mice
#1
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
https://www.readbyqxmd.com/read/27525440/insulin-and-igf-1-receptors-regulate-foxo-mediated-signaling-in-muscle-proteostasis
#2
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
https://www.readbyqxmd.com/read/26984405/foxo1-deacetylation-decreases-fatty-acid-oxidation-in-%C3%AE-cells-and-sustains-insulin-secretion-in-diabetes
#3
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
https://www.readbyqxmd.com/read/26917725/altered-plasma-profile-of-antioxidant-proteins-as-an-early-correlate-of-pancreatic-%C3%AE-cell-dysfunction
#4
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
https://www.readbyqxmd.com/read/26713822/evidence-of-%C3%AE-cell-dedifferentiation-in-human-type-2-diabetes
#5
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
https://www.readbyqxmd.com/read/26664768/hypoglycemia-secondary-to-sulfonylurea-ingestion-in-a-patient-with-end-stage-renal-disease-results-from-a-72-hour-fast
#6
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
https://www.readbyqxmd.com/read/26376798/erratum-to-the-new-biology-of-diabetes
#7
Utpal B Pajvani, Domenico Accili
No abstract text is available yet for this article.
November 2015: Diabetologia
https://www.readbyqxmd.com/read/26248647/the-new-biology-of-diabetes
#8
REVIEW
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
https://www.readbyqxmd.com/read/25873396/pathogenesis-of-selective-insulin-resistance-in-isolated-hepatocytes
#9
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
https://www.readbyqxmd.com/read/25784544/legacy-effect-of-foxo1-in-pancreatic-endocrine-progenitors-on-adult-%C3%AE-cell-mass-and-function
#10
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
https://www.readbyqxmd.com/read/25307742/integrated-control-of-hepatic-lipogenesis-versus-glucose-production-requires-foxo-transcription-factors
#11
Rebecca A Haeusler, Kirsten Hartil, Bhavapriya Vaitheesvaran, Isabel Arrieta-Cruz, Colette M Knight, Joshua R Cook, Helene L Kammoun, Mark A Febbraio, Roger Gutierrez-Juarez, Irwin J Kurland, Domenico Accili
Insulin integrates hepatic glucose and lipid metabolism, directing nutrients to storage as glycogen and triglyceride. In type 2 diabetes, levels of the former are low and the latter are exaggerated, posing a pathophysiologic and therapeutic conundrum. A branching model of insulin signalling, with FoxO1 presiding over glucose production and Srebp-1c regulating lipogenesis, provides a potential explanation. Here we illustrate an alternative mechanism that integrates glucose production and lipogenesis under the unifying control of FoxO...
October 13, 2014: Nature Communications
https://www.readbyqxmd.com/read/25264246/metabolic-inflexibility-impairs-insulin-secretion-and-results-in-mody-like-diabetes-in-triple-foxo-deficient-mice
#12
Ja Young Kim-Muller, Shangang Zhao, Shekhar Srivastava, Yves Mugabo, Hye-Lim Noh, YoungJung R Kim, S R Murthy Madiraju, Anthony W Ferrante, Edward Y Skolnik, Marc Prentki, Domenico Accili
Pancreatic β cell failure in type 2 diabetes is associated with functional abnormalities of insulin secretion and deficits of β cell mass. It's unclear how one begets the other. We have shown that loss of β cell mass can be ascribed to impaired FoxO1 function in different models of diabetes. Here we show that ablation of the three FoxO genes (1, 3a, and 4) in mature β cells results in early-onset, maturity-onset diabetes of the young (MODY)-like diabetes, with abnormalities of the MODY networks Hnf4α, Hnf1α, and Pdx1...
October 7, 2014: Cell Metabolism
https://www.readbyqxmd.com/read/24979718/foxo1-inhibition-yields-functional-insulin-producing-cells-in-human-gut-organoid-cultures
#13
Ryotaro Bouchi, Kylie S Foo, Haiqing Hua, Kyoichiro Tsuchiya, Yoshiaki Ohmura, P Rodrigo Sandoval, Lloyd E Ratner, Dieter Egli, Rudolph L Leibel, Domenico Accili
Generation of surrogate sources of insulin-producing β-cells remains a goal of diabetes therapy. While most efforts have been directed at differentiating embryonic or induced pluripotent stem (iPS) cells into β-like-cells through endodermal progenitors, we have shown that gut endocrine progenitor cells of mice can be differentiated into glucose-responsive, insulin-producing cells by ablation of transcription factor Foxo1. Here we show that FOXO1 is present in human gut endocrine progenitor and serotonin-producing cells...
June 30, 2014: Nature Communications
https://www.readbyqxmd.com/read/24220675/a-differential-dielectric-affinity-glucose-sensor
#14
Xian Huang, Charles Leduc, Yann Ravussin, Siqi Li, Erin Davis, Bing Song, Dachao Li, Kexin Xu, Domenico Accili, Qian Wang, Rudolph Leibel, Qiao Lin
A continuous glucose monitor with a differential dielectric sensor implanted within the subcutaneous tissue that determines the glucose concentration in the interstitial fluid is presented. The device, created using microelectromechanical systems (MEMS) technology, consists of sensing and reference modules that are identical in design and placed in close proximity. Each module contains a microchamber housing a pair of capacitive electrodes residing on the device substrate and embedded in a suspended, perforated polymer diaphragm...
January 21, 2014: Lab on a Chip
https://www.readbyqxmd.com/read/23884887/human-insulin-resistance-is-associated-with-increased-plasma-levels-of-12%C3%AE-hydroxylated-bile-acids
#15
Rebecca A Haeusler, Brenno Astiarraga, Stefania Camastra, Domenico Accili, Ele Ferrannini
Bile acids (BAs) exert pleiotropic metabolic effects, and physicochemical properties of different BAs affect their function. In rodents, insulin regulates BA composition, in part by regulating the BA 12α-hydroxylase CYP8B1. However, it is unclear whether a similar effect occurs in humans. To address this question, we examined the relationship between clamp-measured insulin sensitivity and plasma BA composition in a cohort of 200 healthy subjects and 35 type 2 diabetic (T2D) patients. In healthy subjects, insulin resistance (IR) was associated with increased 12α-hydroxylated BAs (cholic acid, deoxycholic acid, and their conjugated forms)...
December 2013: Diabetes
https://www.readbyqxmd.com/read/23659636/application-of-combined-omics-platforms-to-accelerate-biomedical-discovery-in-diabesity
#16
Irwin J Kurland, Domenico Accili, Charles Burant, Steven M Fischer, Barbara B Kahn, Christopher B Newgard, Suma Ramagiri, Gabriele V Ronnett, John A Ryals, Mark Sanders, Joe Shambaugh, John Shockcor, Steven S Gross
Diabesity has become a popular term to describe the specific form of diabetes that develops late in life and is associated with obesity. While there is a correlation between diabetes and obesity, the association is not universally predictive. Defining the metabolic characteristics of obesity that lead to diabetes, and how obese individuals who develop diabetes different from those who do not, are important goals. The use of large-scale omics analyses (e.g., metabolomic, proteomic, transcriptomic, and lipidomic) of diabetes and obesity may help to identify new targets to treat these conditions...
May 2013: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/23401241/loss-of-timp3-underlies-diabetic-nephropathy-via-foxo1-stat1-interplay
#17
Loredana Fiorentino, Michele Cavalera, Stefano Menini, Valentina Marchetti, Maria Mavilio, Marta Fabrizi, Francesca Conserva, Viviana Casagrande, Rossella Menghini, Paola Pontrelli, Ivan Arisi, Mara D'Onofrio, Davide Lauro, Rama Khokha, Domenico Accili, Giuseppe Pugliese, Loreto Gesualdo, Renato Lauro, Massimo Federici
ADAM17 and its inhibitor TIMP3 are involved in nephropathy, but their role in diabetic kidney disease (DKD) is unclear. Diabetic Timp3(-/-) mice showed increased albuminuria, increased membrane thickness and mesangial expansion. Microarray profiling uncovered a significant reduction of Foxo1 expression in diabetic Timp3(-/-) mice compared to WT, along with FoxO1 target genes involved in autophagy, while STAT1, a repressor of FoxO1 transcription, was increased. Re-expression of Timp3 in Timp3(-/-) mesangial cells rescued the expression of Foxo1 and its targets, and decreased STAT1 expression to control levels; abolishing STAT1 expression led to a rescue of FoxO1, evoking a role of STAT1 in linking Timp3 deficiency to FoxO1...
March 2013: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/22980982/pancreatic-%C3%AE-cell-dedifferentiation-as-a-mechanism-of-diabetic-%C3%AE-cell-failure
#18
Chutima Talchai, Shouhong Xuan, Hua V Lin, Lori Sussel, Domenico Accili
Diabetes is associated with β cell failure. But it remains unclear whether the latter results from reduced β cell number or function. FoxO1 integrates β cell proliferation with adaptive β cell function. We interrogated the contribution of these two processes to β cell dysfunction, using mice lacking FoxO1 in β cells. FoxO1 ablation caused hyperglycemia with reduced β cell mass following physiologic stress, such as multiparity and aging. Surprisingly, lineage-tracing experiments demonstrated that loss of β cell mass was due to β cell dedifferentiation, not death...
September 14, 2012: Cell
https://www.readbyqxmd.com/read/22928578/the-hyperstimulated-%C3%AE-cell-prelude-to-diabetes
#19
EDITORIAL
Christian Boitard, Domenico Accili, Bo Ahrén, Erol Cerasi, Susumu Seino, Bernard Thorens
No abstract text is available yet for this article.
October 2012: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/22426206/regulation-of-hepatic-ldl-receptors-by-mtorc1-and-pcsk9-in-mice
#20
Ding Ai, Chiyuan Chen, Seongah Han, Anjali Ganda, Andrew J Murphy, Rebecca Haeusler, Edward Thorp, Domenico Accili, Jay D Horton, Alan R Tall
Individuals with type 2 diabetes have an increased risk of atherosclerosis. One factor underlying this is dyslipidemia, which in hyperinsulinemic subjects with early type 2 diabetes is typically characterized by increased VLDL secretion but normal LDL cholesterol levels, possibly reflecting enhanced catabolism of LDL via hepatic LDLRs. Recent studies have also suggested that hepatic insulin signaling sustains LDLR levels. We therefore sought to elucidate the mechanisms linking hepatic insulin signaling to regulation of LDLR levels...
April 2012: Journal of Clinical Investigation
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