Tacrolimus-Induced BMP/SMAD Signaling Associates With Metabolic Stress-Activated FOXO1 to Trigger β-Cell Failure.

Abstract:

:Active maintenance of β-cell identity through fine-tuned regulation of key transcription factors ensures β-cell function. Tacrolimus, a widely used immunosuppressant, accelerates onset of diabetes after organ transplantation, but underlying molecular mechanisms are unclear. Here we show that tacrolimus induces loss of human β-cell maturity and β-cell failure through activation of the BMP/SMAD signaling pathway when administered under mild metabolic stress conditions. Tacrolimus-induced phosphorylated SMAD1/5 acts in synergy with metabolic stress-activated FOXO1 through formation of a complex. This interaction is associated with reduced expression of the key β-cell transcription factor MAFA and abolished insulin secretion, both in vitro in primary human islets and in vivo in human islets transplanted into high-fat diet-fed mice. Pharmacological inhibition of BMP signaling protects human β-cells from tacrolimus-induced β-cell dysfunction in vitro. Furthermore, we confirm that BMP/SMAD signaling is activated in protocol pancreas allograft biopsies from recipients on tacrolimus. To conclude, we propose a novel mechanism underlying the diabetogenicity of tacrolimus in primary human β-cells. This insight could lead to new treatment strategies for new-onset diabetes and may have implications for other forms of diabetes.

journal_name

Diabetes

journal_title

Diabetes

authors

Triñanes J,Ten Dijke P,Groen N,Hanegraaf M,Porrini E,Rodriguez-Rodriguez AE,Drachenberg C,Rabelink TJ,de Koning E,Carlotti F,de Vries APJ

doi

10.2337/db19-0828

subject

Has Abstract

pub_date

2020-02-01 00:00:00

pages

193-204

issue

2

eissn

0012-1797

issn

1939-327X

pii

db19-0828

journal_volume

69

pub_type

杂志文章

相关文献

DIABETES文献大全
  • C(2)-ceramide influences the expression and insulin-mediated regulation of cyclic nucleotide phosphodiesterase 3B and lipolysis in 3T3-L1 adipocytes.

    abstract::Cyclic nucleotide phosphodiesterase (PDE) 3B plays an important role in the antilipolytic action of insulin and, thereby, the release of fatty acids from adipocytes. Increased concentrations of circulating fatty acids as a result of elevated or unrestrained lipolysis cause insulin resistance. The lipolytic action of t...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.51.3.631

    authors: Mei J,Holst LS,Landström TR,Holm C,Brindley D,Manganiello V,Degerman E

    更新日期:2002-03-01 00:00:00

  • Diurnal pattern to insulin secretion and insulin action in healthy individuals.

    abstract::Evaluation of the existence of a diurnal pattern of glucose tolerance after mixed meals is important to inform a closed-loop system of treatment for insulin requiring diabetes. We studied 20 healthy volunteers with normal fasting glucose (4.8 ± 0.1 mmol/L) and HbA(1c) (5.2 ± 0.0%) to determine such a pattern in nondia...

    journal_title:Diabetes

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.2337/db11-1478

    authors: Saad A,Dalla Man C,Nandy DK,Levine JA,Bharucha AE,Rizza RA,Basu R,Carter RE,Cobelli C,Kudva YC,Basu A

    更新日期:2012-11-01 00:00:00

  • Progression to type 2 diabetes characterized by moderate then rapid glucose increases.

    abstract:OBJECTIVE:The transition of an individual from normoglycemia to diabetes has generally been thought to involve either moderate or rapid changes in glucose over time, although few studies have analyzed these changes. We sought to determine whether a general pattern of glucose change exists in most individuals who become...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db07-0053

    authors: Mason CC,Hanson RL,Knowler WC

    更新日期:2007-08-01 00:00:00

  • Genetic analysis of HNF4A polymorphisms in Caucasian-American type 2 diabetes.

    abstract::Hepatocyte nuclear factor 4alpha (HNF4A), the gene for the maturity-onset diabetes of the young type 1 monogenic form of type 2 diabetes, is within the type 2 diabetes-linked region on chromosome 20q12-q13.1 and, consequently, is a positional candidate gene for type 2 diabetes in the general population. Previous studi...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.54.4.1185

    authors: Bagwell AM,Bento JL,Mychaleckyj JC,Freedman BI,Langefeld CD,Bowden DW

    更新日期:2005-04-01 00:00:00

  • Increased dietary fat promotes islet amyloid formation and beta-cell secretory dysfunction in a transgenic mouse model of islet amyloid.

    abstract::Transgenic mice expressing the amyloidogenic human islet amyloid polypeptide (hIAPP) in their islet beta-cells are a model of islet amyloid formation as it occurs in type 2 diabetes. Our hIAPP transgenic mice developed islet amyloid when fed a breeder chow but not regular chow. Because the breeder chow contained incre...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.52.2.372

    authors: Hull RL,Andrikopoulos S,Verchere CB,Vidal J,Wang F,Cnop M,Prigeon RL,Kahn SE

    更新日期:2003-02-01 00:00:00

  • Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants.

    abstract:OBJECTIVE:Zinc ions are essential for the formation of hexameric insulin and hormone crystallization. A nonsynonymous single nucleotide polymorphism rs13266634 in the SLC30A8 gene, encoding the secretory granule zinc transporter ZnT8, is associated with type 2 diabetes. We describe the effects of deleting the ZnT8 gene...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db09-0551

    authors: Nicolson TJ,Bellomo EA,Wijesekara N,Loder MK,Baldwin JM,Gyulkhandanyan AV,Koshkin V,Tarasov AI,Carzaniga R,Kronenberger K,Taneja TK,da Silva Xavier G,Libert S,Froguel P,Scharfmann R,Stetsyuk V,Ravassard P,Parker H,Gri

    更新日期:2009-09-01 00:00:00

  • Fat-Specific Knockout of Mecp2 Upregulates Slpi to Reduce Obesity by Enhancing Browning.

    abstract::Abnormalities of methyl-CpG binding protein 2 (Mecp2) cause neurological disorders with metabolic dysfunction; however, its role in adipose tissues remains unclear. Here, we report upregulated Mecp2 in white adipose tissues (WAT) of obese humans, as well as in obese mice and during in vitro adipogenesis. Normal chow-f...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db19-0502

    authors: Liu C,Wang J,Wei Y,Zhang W,Geng M,Yuan Y,Chen Y,Sun Y,Chen H,Zhang Y,Xiong M,Li Y,Zheng L,Huang K

    更新日期:2020-01-01 00:00:00

  • Inhibition of net HepG2 cell apolipoprotein B secretion by the citrus flavonoid naringenin involves activation of phosphatidylinositol 3-kinase, independent of insulin receptor substrate-1 phosphorylation.

    abstract::The flavonoid naringenin improves hyperlipidemia and hyperglycemia in streptozotocin-treated rats. In HepG2 human hepatoma cells, naringenin inhibits apolipoprotein B (apoB) secretion primarily by inhibiting microsomal triglyceride transfer protein and enhances LDL receptor (LDLr)-mediated apoB-containing lipoprotein ...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.52.10.2554

    authors: Borradaile NM,de Dreu LE,Huff MW

    更新日期:2003-10-01 00:00:00

  • Effect of physical exercise on secretion of growth hormone, glucagon, and cortisol in obese and diabetic children.

    abstract::The effect of muscular exertion of moderate intensity on blood sugar (BS), plasma levels of growth hormone (GH), glucagon, and cortisol (F) has been studied in endocrinologically normal children with short stature and compared with children with clinical diabetes mellitus and obese children with normal and diminished ...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.24.8.758

    authors: Garlaschi C,di Natale B,del Guercio MJ,Caccamo A,Gargantini L,Chiumello G

    更新日期:1975-08-01 00:00:00

  • Leucine deprivation decreases fat mass by stimulation of lipolysis in white adipose tissue and upregulation of uncoupling protein 1 (UCP1) in brown adipose tissue.

    abstract:OBJECTIVE:White adipose tissue (WAT) and brown adipose tissue (BAT) play distinct roles in adaptation to changes in nutrient availability, with WAT serving as an energy store and BAT regulating thermogenesis. We previously showed that mice maintained on a leucine-deficient diet unexpectedly experienced a dramatic reduc...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db09-0929

    authors: Cheng Y,Meng Q,Wang C,Li H,Huang Z,Chen S,Xiao F,Guo F

    更新日期:2010-01-01 00:00:00

  • Differential effect of the antidiabetic thiazolidinediones troglitazone and pioglitazone on human platelet aggregation mechanism.

    abstract::Troglitazone and pioglitazone, antidiabetic thiazolidinediones, are known to improve insulin resistance. However, the effect of these drugs on platelet aggregation remains unclear. The chemical structure of troglitazone contains vitamin E. Accordingly, we studied the effect of troglitazone, pioglitazone, and vitamin E...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.47.9.1494

    authors: Ishizuka T,Itaya S,Wada H,Ishizawa M,Kimura M,Kajita K,Kanoh Y,Miura A,Muto N,Yasuda K

    更新日期:1998-09-01 00:00:00

  • Demonstration of a dawn phenomenon in normal human volunteers.

    abstract::To ascertain whether the dawn phenomenon occurs in nondiabetic individuals and, if so, whether it is due to an increase in glucose production or a decrease in glucose utilization, we determined plasma concentrations of glucose, insulin, C-peptide, and counterregulatory hormones, as well as rates of glucose production,...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.33.12.1150

    authors: Bolli GB,De Feo P,De Cosmo S,Perriello G,Ventura MM,Calcinaro F,Lolli C,Campbell P,Brunetti P,Gerich JE

    更新日期:1984-12-01 00:00:00

  • Estimation of the secretion rate of insulin from the urinary excretion rate of C-peptide. Study in obese and diabetic subjects.

    abstract::Direct methods for measuring the secretion rate of insulin are too cumbersome for clinical application. Since C-peptide is secreted in an equimolar ratio with insulin and is excreted into the urine, measuring the urinary excretion rate of C-peptide (U-C) could serve as an indicator of its secretion rate (SR-C) if its ...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.31.5.449

    authors: Meistas MT,Rendell M,Margolis S,Kowarski AA

    更新日期:1982-05-01 00:00:00

  • Comparison of alpha- and beta-cell secretory responses in islets isolated with collagenase and in the isolated perfused pancreas of rats.

    abstract::The inhibitory actions of somatostatin (100 ng./ml.) on insulin release, stimulated by high glucose (20 mM), and on glucagon release, stimulated by arginine (15 mM), were studied with two in vitro systems: the isolated perifused rat islets prepared by the collagenase procedure and the isolated perfused rat pancreas. S...

    journal_title:Diabetes

    pub_type: 历史文章,杂志文章

    doi:10.2337/diab.24.11.961

    authors: Norfleet WT,Pagliara AS,Haymond MW,Matschinsky F

    更新日期:1975-11-01 00:00:00

  • The frequency and immunodominance of islet-specific CD8+ T-cell responses change after type 1 diabetes diagnosis and treatment.

    abstract:OBJECTIVE:Islet-reactive CD8(+) T-cells play a key role in the pathogenesis of type 1 diabetes in the NOD mouse. The predominant T-cell specificities change over time, but whether similar shifts also occur after clinical diagnosis and insulin treatment in type 1 diabetic patients is unknown. RESEARCH DESIGN AND METHOD...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db07-1594

    authors: Martinuzzi E,Novelli G,Scotto M,Blancou P,Bach JM,Chaillous L,Bruno G,Chatenoud L,van Endert P,Mallone R

    更新日期:2008-05-01 00:00:00

  • Helper-inducer T-lymphocytes mediate diabetes in EMC-infected BALB/c ByJ mice.

    abstract::Diabetes mellitus developing in BALB/c ByJ mice infected with the M variant of encephalomyocarditis (EMC) virus is dependent on thymic immune mechanisms. We treated mice with the anti-T-lymphocyte monoclonal anti-L3T4 and anti-Lyt2.2 antibodies before virus inoculation and monitored the infection and occurrence of dia...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.36.7.877

    authors: Haynes MK,Huber SA,Craighead JE

    更新日期:1987-07-01 00:00:00

  • Time-Resolved Autoantibody Profiling Facilitates Stratification of Preclinical Type 1 Diabetes in Children.

    abstract::Progression to clinical type 1 diabetes varies among children who develop β-cell autoantibodies. Differences in autoantibody patterns could relate to disease progression and etiology. Here we modeled complex longitudinal autoantibody profiles by using a novel wavelet-based algorithm. We identified clusters of similar ...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db18-0594

    authors: Endesfelder D,Zu Castell W,Bonifacio E,Rewers M,Hagopian WA,She JX,Lernmark Å,Toppari J,Vehik K,Williams AJK,Yu L,Akolkar B,Krischer JP,Ziegler AG,Achenbach P,TEDDY Study Group.

    更新日期:2019-01-01 00:00:00

  • Molecular detection of circulating beta-cells after islet transplantation.

    abstract::Islet transplantation is a promising treatment for type 1 diabetes. However, islet grafts are submitted to multiple injuries, including immunosuppressive drug toxicity, hyperglycemia, hypoxia, unspecific inflammatory reactions, as well as allo- and autoimmune destruction. Therapeutic approaches to these damage mechani...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.51.3.557

    authors: Ritz-Laser B,Oberholzer J,Toso C,Brulhart MC,Zakrzewska K,Ris F,Bucher P,Morel P,Philippe J

    更新日期:2002-03-01 00:00:00

  • Developmental-stage-dependent teratogenic effects of maternal spontaneous diabetes in the chinese hamster.

    abstract::The effect of maternal diabetes on teratogenesis was examined utilizing female Chinese hamsters with typical diabetic symptoms from our closed colony (CHA) and F13-F19 of the brother-sister mating generations of a diabetic strain (CHAD). Both groups were mated with nondiabetic males from CHA. Embryologic studies on da...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.32.7.637

    authors: Funaki K,Mikamo K

    更新日期:1983-07-01 00:00:00

  • Effect of coxsackievirus B4 infection in mice on expression of 64,000-Mr autoantigen and glucose sensitivity of islets before development of hyperglycemia.

    abstract::Diabetogenic strains of Coxsackievirus B4 (CB4) produce a diabetes syndrome in susceptible mice that resembles insulin-dependent diabetes mellitus. To assess the possible role of autoimmunity, the expression of a 64,000-Mr islet antigen in SJL/J and CD1 mice infected with a diabetogenic strain of CB4 was monitored in ...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.37.10.1419

    authors: Gerling I,Nejman C,Chatterjee NK

    更新日期:1988-10-01 00:00:00

  • Changing metabolic signatures of amino acids and lipids during the prediabetic period in a pig model with impaired incretin function and reduced β-cell mass.

    abstract::Diabetes is generally diagnosed too late. Therefore, biomarkers indicating early stages of β-cell dysfunction and mass reduction would facilitate timely counteraction. Transgenic pigs expressing a dominant-negative glucose-dependent insulinotropic polypeptide receptor (GIPR(dn)) reveal progressive deterioration of glu...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db11-1133

    authors: Renner S,Römisch-Margl W,Prehn C,Krebs S,Adamski J,Göke B,Blum H,Suhre K,Roscher AA,Wolf E

    更新日期:2012-08-01 00:00:00

  • Newly identified pancreatic protein islet amyloid polypeptide. What is its relationship to diabetes?

    abstract::Islet amyloid polypeptide (IAPP) or amylin is a newly identified 37-amino acid COOH-terminal-amidated polypeptide that is the major protein constituent of amyloid deposits in insulinomas and amyloid deposits in pancreatic islets of non-insulin-dependent (type II) diabetic humans and adult diabetic cats. IAPP is stored...

    journal_title:Diabetes

    pub_type: 杂志文章,评审

    doi:10.2337/diab.40.3.310

    authors: Johnson KH,O'Brien TD,Westermark P

    更新日期:1991-03-01 00:00:00

  • GLP-1 receptor antagonist exendin-(9-39) elevates fasting blood glucose levels in congenital hyperinsulinism owing to inactivating mutations in the ATP-sensitive K+ channel.

    abstract::Infants with congenital hyperinsulinism owing to inactivating mutations in the K(ATP) channel (K(ATP)HI) who are unresponsive to medical therapy will require pancreatectomy to control the hypoglycemia. In preclinical studies, we showed that the GLP-1 receptor antagonist exendin-(9-39) suppresses insulin secretion and ...

    journal_title:Diabetes

    pub_type: 杂志文章,随机对照试验

    doi:10.2337/db12-0166

    authors: Calabria AC,Li C,Gallagher PR,Stanley CA,De León DD

    更新日期:2012-10-01 00:00:00

  • Influence of hyperinsulinemia and insulin resistance on in vivo β-cell function: their role in human β-cell dysfunction.

    abstract:OBJECTIVE:Recent work has shown that insulin stimulates its own secretion in insulin-sensitive humans, suggesting that insulin resistance in the β-cell could cause β-cell dysfunction. We have tested whether insulin exposure and insulin sensitivity modulate β-cell function in subjects with normal glucose tolerance (NGT)...

    journal_title:Diabetes

    pub_type: 临床试验,杂志文章

    doi:10.2337/db11-0827

    authors: Mari A,Tura A,Natali A,Anderwald C,Balkau B,Lalic N,Walker M,Ferrannini E,RISC Investigators.

    更新日期:2011-12-01 00:00:00

  • Combinations of nondiabetic parental genomes elicit impaired glucose tolerance in mouse SMXA recombinant inbred strains.

    abstract::Type 2 diabetes in humans is not a single gene disorder but a multifactorial disease caused by the interaction of multiple genes and environmental factors. Recombinant inbred (RI) strains are a powerful tool for analyzing not only single genetic traits but also multifactorial genetic traits. By using the SMXA RI mice,...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.52.1.180

    authors: Kobayashi M,Ohno T,Tsuji A,Nishimura M,Horio F

    更新日期:2003-01-01 00:00:00

  • Gene transfer to human pancreatic endocrine cells using viral vectors.

    abstract::We have studied the factors that influence the efficiency of infection of human fetal and adult pancreatic endocrine cells with adenovirus, murine retrovirus, and lentivirus vectors all expressing the green fluorescent protein (Ad-GFP, MLV-GFP, and Lenti-GFP, respectively). Adenoviral but not retroviral vectors effici...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.48.4.745

    authors: Leibowitz G,Beattie GM,Kafri T,Cirulli V,Lopez AD,Hayek A,Levine F

    更新日期:1999-04-01 00:00:00

  • Increased urea synthesis in insulin-dependent diabetic dogs maintained normoglycemic: effect of portal insulin administration and food protein content.

    abstract::In IDDM, the gluconeogenic turnover of amino acids is increased even if glycemia is well controlled and may be restored to normal by means of prehepatic insulin substitution. Therefore, the present study was designed 1) to investigate the influence of route of insulin administration (portal versus peripheral) on the u...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.45.5.667

    authors: Freyse EJ,Rebrin K,Schneider T,Petrzika M,Fischer U

    更新日期:1996-05-01 00:00:00

  • Report of the American Diabetes Association's Task Force on standardization of the insulin assay.

    abstract::Recent large-scale epidemiological studies demonstrate that blood concentrations of immunoreactive insulin predict the development of NIDDM and IDDM and are associated with the risk of several degenerative diseases, such as coronary and peripheral vessel atherosclerosis, hypertension, and dyslipidemia. The reliability...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.45.2.242

    authors: Robbins DC,Andersen L,Bowsher R,Chance R,Dinesen B,Frank B,Gingerich R,Goldstein D,Widemeyer HM,Haffner S,Hales CN,Jarett L,Polonsky K,Porte D,Skyler J,Webb G,Gallagher K

    更新日期:1996-02-01 00:00:00

  • Effects of insulin and IGF-I on vascular smooth muscle glucose and cation metabolism.

    abstract::Data is accumulating indicating that impaired insulin action predisposes to increased vascular smooth muscle (VSM) tone, the hallmark of hypertension associated with diabetes. During the last several years, it has been established that VSM is an insulin-sensitive tissue like skeletal muscle and adipocytes. Investigato...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.45.3.s47

    authors: Sowers JR

    更新日期:1996-07-01 00:00:00

  • Membrane-Initiated Estrogen Receptor Signaling Mediates Metabolic Homeostasis via Central Activation of Protein Phosphatase 2A.

    abstract::Women gain weight and their diabetes risk increases as they transition through menopause; these changes can be partly reversed by hormone therapy. However, the underlying molecular mechanisms mediating these effects are unknown. A novel knock-in mouse line with the selective blockade of the membrane-initiated estrogen...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db17-1342

    authors: Ueda K,Takimoto E,Lu Q,Liu P,Fukuma N,Adachi Y,Suzuki R,Chou S,Baur W,Aronovitz MJ,Greenberg AS,Komuro I,Karas RH

    更新日期:2018-08-01 00:00:00