Evidence for rapamycin toxicity in pancreatic β-cells and a review of the underlying molecular mechanisms.

Abstract:

:Rapamycin is used frequently in both transplantation and oncology. Although historically thought to have little diabetogenic effect, there is growing evidence of β-cell toxicity. This Review draws evidence for rapamycin toxicity from clinical studies of islet and renal transplantation, and of rapamycin as an anticancer agent, as well as from experimental studies. Together, these studies provide evidence that rapamycin has significant detrimental effects on β-cell function and survival and peripheral insulin resistance. The mechanism of action of rapamycin is via inhibition of mammalian target of rapamycin (mTOR). This Review describes the complex mTOR signaling pathways, which control vital cellular functions including mRNA translation, cell proliferation, cell growth, differentiation, angiogenesis, and apoptosis, and examines molecular mechanisms for rapamycin toxicity in β-cells. These mechanisms include reductions in β-cell size, mass, proliferation and insulin secretion alongside increases in apoptosis, autophagy, and peripheral insulin resistance. These data bring into question the use of rapamycin as an immunosuppressant in islet transplantation and as a second-line agent in other transplant recipients developing new-onset diabetes after transplantation with calcineurin inhibitors. It also highlights the importance of close monitoring of blood glucose levels in patients taking rapamycin as an anticancer treatment, particularly those with preexisting glucose intolerance.

journal_name

Diabetes

journal_title

Diabetes

authors

Barlow AD,Nicholson ML,Herbert TP

doi

10.2337/db13-0106

subject

Has Abstract

pub_date

2013-08-01 00:00:00

pages

2674-82

issue

8

eissn

0012-1797

issn

1939-327X

pii

62/8/2674

journal_volume

62

pub_type

杂志文章,评审

相关文献

DIABETES文献大全
  • Diminished specific activity of cytosolic protein kinase C in sciatic nerve of streptozocin-induced diabetic rats and its correction by dietary myo-inositol.

    abstract::The impaired Na(+)-K(+)-ATPase activity in peripheral nerve from diabetic rats is prevented by dietary myo-inositol (MI) supplementation in vivo and corrected by protein kinase C (PKC) agonists in vitro, suggesting that PKC may mediate the effects of nerve MI depletion on Na(+)-K(+)-ATPase activity. However, little is...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.40.11.1545

    authors: Kim J,Rushovich EH,Thomas TP,Ueda T,Agranoff BW,Greene DA

    更新日期:1991-11-01 00:00:00

  • Parathyroid hormone-related protein induces insulin expression through activation of MAP kinase-specific phosphatase-1 that dephosphorylates c-Jun NH2-terminal kinase in pancreatic beta-cells.

    abstract::Parathyroid hormone-related protein (PTHrP) increases the content and mRNA level of insulin in a mouse beta-cell line, MIN6, and primary-cultured mouse islets. We examined the mechanism of PTHrP-induced insulin expression. The PTHrP effect was markedly augmented by SB203580, a mitogen-activated protein (MAP) kinase in...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.52.11.2720

    authors: Zhang B,Hosaka M,Sawada Y,Torii S,Mizutani S,Ogata M,Izumi T,Takeuchi T

    更新日期:2003-11-01 00:00:00

  • Reduced expression of the leptin gene (ob) by catecholamine through a G(S) protein-coupled pathway in 3T3-L1 adipocytes.

    abstract::Leptin, a recently identified hormone, is believed to reduce appetite and maintain body weight. The mRNA of leptin is expressed only in mature adipose cells. To clarify the regulation of leptin gene expression in adipocytes, 3T3-L1 adipocytes were treated for 16 h with various agents known to modulate lipid metabolism...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.45.12.1744

    authors: Kosaki A,Yamada K,Kuzuya H

    更新日期:1996-12-01 00:00:00

  • Analysis of the mouse CD30 gene: a candidate for the NOD mouse type 1 diabetes locus Idd9.2.

    abstract::Members of the tumor necrosis factor receptor superfamily play an important role in the initiation, expansion, and termination of an immune response. It has recently been demonstrated that one member of this family, CD30, plays a central role in maintaining peripheral tolerance by controlling the expansion of autoreac...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.49.9.1612

    authors: Siegmund T,Armitage N,Wicker LS,Peterson LB,Todd JA,Lyons PA

    更新日期:2000-09-01 00:00:00

  • Increased Effector Memory Insulin-Specific CD4+ T Cells Correlate With Insulin Autoantibodies in Patients With Recent-Onset Type 1 Diabetes.

    abstract::Type 1 diabetes (T1D) results from T cell-mediated destruction of insulin-producing β-cells. Insulin represents a key self-antigen in disease pathogenesis, as recent studies identified proinsulin-responding T cells from inflamed pancreatic islets of organ donors with recent-onset T1D. These cells respond to an insulin...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db17-0666

    authors: Spanier JA,Sahli NL,Wilson JC,Martinov T,Dileepan T,Burrack AL,Finger EB,Blazar BR,Michels AW,Moran A,Jenkins MK,Fife BT

    更新日期:2017-12-01 00:00:00

  • Major histocompatibility complex-encoded antigen processing gene polymorphism in IDDM.

    abstract::Susceptibility to insulin-dependent diabetes mellitus (IDDM) is greatly influenced by polymorphisms in the genes of the class II region of the human leukocyte antigen (HLA) complex. The complexity of this genetic association and the lack of a direct proof of involvement of HLA class II genes in human IDDM have continu...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.43.1.110

    authors: van Endert PM,Liblau RS,Patel SD,Fugger L,Lopez T,Pociot F,Nerup J,McDevitt HO

    更新日期:1994-01-01 00:00:00

  • Gene expression profiles of nondiabetic and diabetic obese mice suggest a role of hepatic lipogenic capacity in diabetes susceptibility.

    abstract::Obesity is a strong risk factor for the development of type 2 diabetes. We have previously reported that in adipose tissue of obese (ob/ob) mice, the expression of adipogenic genes is decreased. When made genetically obese, the BTBR mouse strain is diabetes susceptible and the C57BL/6J (B6) strain is diabetes resistan...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.52.3.688

    authors: Lan H,Rabaglia ME,Stoehr JP,Nadler ST,Schueler KL,Zou F,Yandell BS,Attie AD

    更新日期:2003-03-01 00:00:00

  • A novel locus, Mody4, distal to D7Mit189 on chromosome 7 determines early-onset NIDDM in nonobese C57BL/6 (Akita) mutant mice.

    abstract::In this article, we report on a nonobese C57BL/6 (B6) mouse model of NIDDM named Akita mouse, characterized by early age onset and autosomal dominant mode of inheritance. At 7 weeks of age, the mean morning blood glucose levels (mmol/l) under ad libitum feeding conditions were significantly higher (P < 0.01, analysis ...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.46.5.887

    authors: Yoshioka M,Kayo T,Ikeda T,Koizumi A

    更新日期:1997-05-01 00:00:00

  • Insulin receptor-related receptor is expressed in pancreatic beta-cells and stimulates tyrosine phosphorylation of insulin receptor substrate-1 and -2.

    abstract::The receptor-type protein tyrosine kinases in murine pancreatic islets were screened to identify possible growth/differentiation factors in pancreatic beta-cells. The analysis revealed that insulin receptor-related receptor (IRR) is highly expressed in the islets as well as in several highly differentiated beta-cell l...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.48.6.1237

    authors: Hirayama I,Tamemoto H,Yokota H,Kubo SK,Wang J,Kuwano H,Nagamachi Y,Takeuchi T,Izumi T

    更新日期:1999-06-01 00:00:00

  • Insulin Delivery Into the Peripheral Circulation: A Key Contributor to Hypoglycemia in Type 1 Diabetes.

    abstract::Hypoglycemia limits optimal glycemic control in type 1 diabetes mellitus (T1DM), making novel strategies to mitigate it desirable. We hypothesized that portal (Po) vein insulin delivery would lessen hypoglycemia. In the conscious dog, insulin was infused into the hepatic Po vein or a peripheral (Pe) vein at a rate fou...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db15-0071

    authors: Gregory JM,Kraft G,Scott MF,Neal DW,Farmer B,Smith MS,Hastings JR,Allen EJ,Donahue EP,Rivera N,Winnick JJ,Edgerton DS,Nishimura E,Fledelius C,Brand CL,Cherrington AD

    更新日期:2015-10-01 00:00:00

  • Dipeptidyl peptidase IV inhibition reduces the degradation and clearance of GIP and potentiates its insulinotropic and antihyperglycemic effects in anesthetized pigs.

    abstract::Glucose-dependent insulinotropic peptide (GIP) is known to be degraded by dipeptidyl peptidase IV (DPP IV), forming an inactive metabolite, but the extent of the enzyme's role in regulating the biological activity of GIP in vivo is still largely unknown. In nonfasted anesthetized pigs given an intravenous infusion of ...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.50.7.1588

    authors: Deacon CF,Danielsen P,Klarskov L,Olesen M,Holst JJ

    更新日期:2001-07-01 00:00:00

  • The greater contribution of gluconeogenesis to glucose production in obesity is related to increased whole-body protein catabolism.

    abstract::Obesity is associated with an increase in the fractional contribution of gluconeogenesis (GNG) to glucose production. We tested if this was related to the altered protein metabolism in obesity. GNG(PEP) (via phosphoenol pyruvate [PEP]) was measured after a 17-h fast using the deuterated water method and 2H nuclear mag...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.55.03.06.db05-1117

    authors: Chevalier S,Burgess SC,Malloy CR,Gougeon R,Marliss EB,Morais JA

    更新日期:2006-03-01 00:00:00

  • Mechanism by Which Caloric Restriction Improves Insulin Sensitivity in Sedentary Obese Adults.

    abstract::Caloric restriction (CR) improves insulin sensitivity and reduces the incidence of diabetes in obese individuals. The underlying mechanisms whereby CR improves insulin sensitivity are not clear. We evaluated the effect of 16 weeks of CR on whole-body insulin sensitivity by pancreatic clamp before and after CR in 11 ob...

    journal_title:Diabetes

    pub_type: 杂志文章,随机对照试验

    doi:10.2337/db15-0675

    authors: Johnson ML,Distelmaier K,Lanza IR,Irving BA,Robinson MM,Konopka AR,Shulman GI,Nair KS

    更新日期:2016-01-01 00:00:00

  • The natural history of progression from normal glucose tolerance to type 2 diabetes in the Baltimore Longitudinal Study of Aging.

    abstract::The natural history of progression from normal glucose tolerance (NGT) to impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes is not well defined. We studied this progression using biennial oral glucose tolerance tests performed in the Baltimore Longitudinal Study of Aging and surviva...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.52.6.1475

    authors: Meigs JB,Muller DC,Nathan DM,Blake DR,Andres R,Baltimore Longitudinal Study of Aging.

    更新日期:2003-06-01 00:00:00

  • A role for protein phosphatase 2A-like activity, but not atypical protein kinase Czeta, in the inhibition of protein kinase B/Akt and glycogen synthesis by palmitate.

    abstract::We have shown previously that palmitate treatment of C2C12 skeletal muscle myotubes causes inhibition of the protein kinase B (PKB) pathway and hence reduces insulin-stimulated glycogen synthesis through the elevation of intracellular ceramide levels. Ceramide is known to activate both atypical protein kinase C (aPKC)...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.50.10.2210

    authors: Cazzolli R,Carpenter L,Biden TJ,Schmitz-Peiffer C

    更新日期:2001-10-01 00:00:00

  • Intrinsic differences in adipocyte precursor cells from different white fat depots.

    abstract::Obesity and body fat distribution are important risk factors for the development of type 2 diabetes and metabolic syndrome. Evidence has accumulated that this risk is related to intrinsic differences in behavior of adipocytes in different fat depots. In the current study, we demonstrate that adipocyte precursor cells ...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db11-1753

    authors: Macotela Y,Emanuelli B,Mori MA,Gesta S,Schulz TJ,Tseng YH,Kahn CR

    更新日期:2012-07-01 00:00:00

  • Diabetic patients without vascular complications display enhanced basal platelet activation and decreased antioxidant status.

    abstract::Vascular complications are the leading causes of morbidity and mortality in diabetic patients. The contribution of platelets to thromboembolic complications is well documented, but their involvement in the initiation of the atherosclerotic process is of rising interest. Thus, the aim of the present study was to evalua...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.53.4.1046

    authors: Véricel E,Januel C,Carreras M,Moulin P,Lagarde M

    更新日期:2004-04-01 00:00:00

  • Normoglycemia after reflux of islet-containing pancreatic fragments into the splenic vascular bed in dogs.

    abstract::Canine pancreata obtained at total pancreatectomy were cannulated via the ducts and perfused with collagenase to prepare a tissue suspension that was isografted into the spleen (preparation congruent to 2 h, mean graft vol = 10 +/- 1 ml containing 24% of the B-cell mass/pancreas). In 13 dogs the tissue was implanted b...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.32.5.452

    authors: Warnock GL,Rajotte RV,Procyshyn AW

    更新日期:1983-05-01 00:00:00

  • A functional melanocortin system may be required for chronic CNS-mediated antidiabetic and cardiovascular actions of leptin.

    abstract:OBJECTIVE:We recently showed that leptin has powerful central nervous system (CNS)-mediated antidiabetic and cardiovascular actions. This study tested whether the CNS melanocortin system mediates these actions of leptin in diabetic rats. RESEARCH DESIGN AND METHODS:A cannula was placed in the lateral ventricle of Spra...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db08-1221

    authors: da Silva AA,do Carmo JM,Freeman JN,Tallam LS,Hall JE

    更新日期:2009-08-01 00:00:00

  • Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function.

    abstract::To determine the relationship between insulin sensitivity and beta-cell function, we quantified the insulin sensitivity index using the minimal model in 93 relatively young, apparently healthy human subjects of varying degrees of obesity (55 male, 38 female; 18-44 yr of age; body mass index 19.5-52.2 kg/m2) and with f...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.42.11.1663

    authors: Kahn SE,Prigeon RL,McCulloch DK,Boyko EJ,Bergman RN,Schwartz MW,Neifing JL,Ward WK,Beard JC,Palmer JP

    更新日期:1993-11-01 00:00:00

  • Cumulative risk, age at onset, and sex-specific differences for developing end-stage renal disease in young patients with type 1 diabetes: a nationwide population-based cohort study.

    abstract:OBJECTIVE:This study aimed to estimate the current cumulative risk of end-stage renal disease (ESRD) due to diabetic nephropathy in a large, nationwide, population-based prospective type 1 diabetes cohort and specifically study the effects of sex and age at onset. RESEARCH DESIGN AND METHODS:In Sweden, all incident ca...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db09-1744

    authors: Möllsten A,Svensson M,Waernbaum I,Berhan Y,Schön S,Nyström L,Arnqvist HJ,Dahlquist G,Swedish Childhood Diabetes Study Group.,Diabetes Incidence Study in Sweden.,Swedish Renal Registry.

    更新日期:2010-07-01 00:00:00

  • The transcriptional coactivator peroxisome proliferator activated receptor (PPAR)gamma coactivator-1 alpha and the nuclear receptor PPAR alpha control the expression of glycerol kinase and metabolism genes independently of PPAR gamma activation in human w

    abstract:OBJECTIVE:The purpose of this work was to determine the pattern of genes regulated by peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 alpha (PGC-1 alpha) in human adipocytes and the involvement of PPARalpha and PPARgamma in PGC-1 alpha transcriptional action. RESEARCH DESIGN AND METHODS:Primary c...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db06-1465

    authors: Mazzucotelli A,Viguerie N,Tiraby C,Annicotte JS,Mairal A,Klimcakova E,Lepin E,Delmar P,Dejean S,Tavernier G,Lefort C,Hidalgo J,Pineau T,Fajas L,Clément K,Langin D

    更新日期:2007-10-01 00:00:00

  • Brown and Beige Fat: Molecular Parts of a Thermogenic Machine.

    abstract::The epidemic of obesity and type 2 diabetes has increased interest in pathways that affect energy balance in mammalian systems. Brown fat, in all of its dimensions, can increase energy expenditure through the dissipation of chemical energy in the form of heat, using mitochondrial uncoupling and perhaps other pathways....

    journal_title:Diabetes

    pub_type: 杂志文章,评审

    doi:10.2337/db15-0318

    authors: Cohen P,Spiegelman BM

    更新日期:2015-07-01 00:00:00

  • Elevated NF-κB activation is conserved in human myocytes cultured from obese type 2 diabetic patients and attenuated by AMP-activated protein kinase.

    abstract:OBJECTIVE:To examine whether the inflammatory phenotype found in obese and diabetic individuals is preserved in isolated, cultured myocytes and to assess the effectiveness of pharmacological AMP-activated protein kinase (AMPK) activation upon the attenuation of inflammation in these myocytes. RESEARCH DESIGN AND METHO...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db11-0263

    authors: Green CJ,Pedersen M,Pedersen BK,Scheele C

    更新日期:2011-11-01 00:00:00

  • Islet cell DNA is a target of inflammatory attack by nitric oxide.

    abstract::NO has been identified recently as the prime islet-toxic product of inflammatory macrophages. The adverse effects of IL-1 on isolated islets also have been reported to involve NO. We now show that exposure of an islet cell suspension to the NO donor nitroprusside or to activated macrophages leads to DNA strand breaks....

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.42.3.496

    authors: Fehsel K,Jalowy A,Qi S,Burkart V,Hartmann B,Kolb H

    更新日期:1993-03-01 00:00:00

  • Dense core vesicle proteins IA-2 and IA-2beta: metabolic alterations in double knockout mice.

    abstract::IA-2 and IA-2beta are members of the transmembrane protein tyrosine phosphatase family located in dense core vesicles of neuroendocrine cells, including the beta-cells of pancreatic islets. In the present study, by mating C57BL/6Nci IA-2(+/-) with IA-2beta(+/-) mice, we generated double knockout mice (IA-2(-/-)/IA-2be...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.54.suppl_2.s46

    authors: Kubosaki A,Nakamura S,Notkins AL

    更新日期:2005-12-01 00:00:00

  • Overexpression of monocarboxylate transporter-1 (SLC16A1) in mouse pancreatic β-cells leads to relative hyperinsulinism during exercise.

    abstract::Exercise-induced hyperinsulinism (EIHI) is an autosomal dominant disorder characterized by inappropriate insulin secretion in response to vigorous physical exercise or pyruvate injection. Activating mutations in the monocarboxylate transporter-1 (MCT1, SLC16A1) promoter have been linked to EIHI. Expression of this pyr...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db11-1531

    authors: Pullen TJ,Sylow L,Sun G,Halestrap AP,Richter EA,Rutter GA

    更新日期:2012-07-01 00:00:00

  • The composition of dietary fat directly influences glucose-stimulated insulin secretion in rats.

    abstract::Acute elevations of plasma free fatty acid (FFA) levels augment glucose-stimulated insulin secretion (GSIS). Prolonged elevations of FFA levels reportedly impair GSIS, but no one has previously compared GSIS after prolonged exposure to saturated or unsaturated fat. Rats received a low-fat diet (Low-Fat) or one enriche...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.51.6.1825

    authors: Dobbins RL,Szczepaniak LS,Myhill J,Tamura Y,Uchino H,Giacca A,McGarry JD

    更新日期:2002-06-01 00:00:00

  • The endothelium, triglyceride-rich lipoproteins, and atherosclerosis: insights from cell biology and lipid metabolism.

    abstract::Endothelial cells in culture retain many of the functional properties of the endothelium in vivo. At high cell density, they become contact-inhibited. Endothelial cells, like vascular smooth muscle cells and fibroblasts, express binding sites for low density lipoprotein when depleted of sterol. In contact-inhibited en...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.30.2.s19

    authors: Fielding CJ

    更新日期:1981-01-01 00:00:00

  • Increased rate of Cori cycle in obese subjects with NIDDM and effect of weight reduction.

    abstract::To determine the contribution of the rate of glucose recycling via the Cori cycle (glucose----3-carbon compounds----glucose) to the higher rate of endogenous glucose production (EGPR) in subjects with non-insulin-dependent diabetes mellitus (NIDDM), we studied eight obese, weight-stabilized diabetic Pima Indians befor...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.37.2.154

    authors: Zawadzki JK,Wolfe RR,Mott DM,Lillioja S,Howard BV,Bogardus C

    更新日期:1988-02-01 00:00:00