Abstract:
AIMS/HYPOTHESIS:Microvascular complications in the heart and kidney are strongly associated with an overall rise in inflammation. Annexin A1 (ANXA1) is an endogenous anti-inflammatory molecule that limits and resolves inflammation. In this study, we have used a bedside to bench approach to investigate: (1) ANXA1 levels in individuals with type 1 diabetes; (2) the role of endogenous ANXA1 in nephropathy and cardiomyopathy in experimental type 1 diabetes; and (3) whether treatment with human recombinant ANXA1 attenuates nephropathy and cardiomyopathy in a murine model of type 1 diabetes. METHODS:ANXA1 was measured in plasma from individuals with type 1 diabetes with or without nephropathy and healthy donors. Experimental type 1 diabetes was induced in mice by injection of streptozotocin (STZ; 45 mg/kg i.v. per day for 5 consecutive days) in C57BL/6 or Anxa1 -/- mice. Diabetic mice were treated with human recombinant (hr)ANXA1 (1 μg, 100 μl, 50 mmol/l HEPES; 140 mmol/l NaCl; pH 7.4, i.p.) or vehicle (100 μl, 50 mmol/l HEPES; 140 mmol/l NaCl; pH 7.4, i.p.). RESULTS:Plasma levels of ANXA1 were elevated in individuals with type 1 diabetes with/without nephropathy compared with healthy individuals (66.0 ± 4.2/64.0 ± 4 ng/ml vs 35.9 ± 2.3 ng/ml; p < 0.05). Compared with diabetic wild-type (WT) mice, diabetic Anxa1 -/- mice exhibited a worse diabetic phenotype and developed more severe cardiac (ejection fraction; 76.1 ± 1.6% vs 49.9 ± 0.9%) and renal dysfunction (proteinuria; 89.3 ± 5.0 μg/mg vs 113.3 ± 5.5 μg/mg). Mechanistically, compared with non-diabetic WT mice, the degree of the phosphorylation of mitogen-activated protein kinases (MAPKs) p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) was significantly higher in non-diabetic Anxa1 -/- mice in both the heart and kidney, and was further enhanced after STZ-induced type 1 diabetes. Prophylactic treatment with hrANXA1 (weeks 1-13) attenuated both cardiac (ejection fraction; 54.0 ± 1.6% vs 72.4 ± 1.0%) and renal (proteinuria; 89.3 ± 5.0 μg/mg vs 53.1 ± 3.4 μg/mg) dysfunction associated with STZ-induced diabetes, while therapeutic administration of hrANXA1 (weeks 8-13), after significant cardiac and renal dysfunction had already developed, halted the further functional decline in cardiac and renal function seen in diabetic mice administered vehicle. In addition, administration of hrANXA1 attenuated the increase in phosphorylation of p38, JNK and ERK, and restored phosphorylation of Akt in diabetic mice. CONCLUSIONS/INTERPRETATION:Overall, these results demonstrate that ANXA1 plasma levels are elevated in individuals with type 1 diabetes independent of a significant impairment in renal function. Furthermore, in mouse models with STZ-induced type 1 diabetes, ANXA1 protects against cardiac and renal dysfunction by returning MAPK signalling to baseline and activating pro-survival pathways (Akt). We propose ANXA1 to be a potential therapeutic option for the control of comorbidities in type 1 diabetes.
journal_name
Diabetologiajournal_title
Diabetologiaauthors
Purvis GSD,Chiazza F,Chen J,Azevedo-Loiola R,Martin L,Kusters DHM,Reutelingsperger C,Fountoulakis N,Gnudi L,Yaqoob MM,Collino M,Thiemermann C,Solito Edoi
10.1007/s00125-017-4469-ysubject
Has Abstractpub_date
2018-02-01 00:00:00pages
482-495issue
2eissn
0012-186Xissn
1432-0428pii
10.1007/s00125-017-4469-yjournal_volume
61pub_type
杂志文章相关文献
DIABETOLOGIA文献大全abstract::We have investigated whether the previously demonstrated stimulatory actions of growth hormone on DNA synthesis and (pro)insulin biosynthesis and release of isolated adult rat islets of Langerhans are mediated by an autocrine release of somatomedin-C/insulin-like growth factor I (SM-C/IGF I). In medium containing 1% f...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00265093
更新日期:1989-03-01 00:00:00
abstract:AIMS/HYPOTHESIS:The role of infections in the aetiology of Type I diabetes is controversial. Certain enteroviral infections might be involved in triggering the beta-cell destruction but insufficient exposure to early infections might increase the risk. We studied how the number of infections experienced during several ...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s001250051517
更新日期:2000-10-01 00:00:00
abstract:AIMS/HYPOTHESIS:It has been recently shown that glycated human haemoglobin induces endothelial dysfunction in rat vessels by generating superoxide anions that interfere with nitric oxide mediated responses. Our study analysed the effect of glycated human haemoglobin on the endothelium-dependent relaxations of human ves...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s001250050011
更新日期:2000-01-01 00:00:00
abstract::The 497 members of the London Cohort of the WHO Multinational Study of Vascular Disease in Diabetics have been followed for mortality from 1975 to 1987. During this period 92 patients died. The most common cause of death was myocardial infarction: 36 (39.1%) deaths, heart disease was responsible for 51.1% of deaths an...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00404141
更新日期:1990-09-01 00:00:00
abstract::Lack of insulin receptors in mice is associated with near-normal intrauterine growth, unlike patients with leprechaunism, in whom growth deficiency is a prominent clinical feature. Genetic crosses of insulin receptor- and insulin-like growth-factor-1 (IGF-1) receptor-deficient mice indicate, however, that insulin rece...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s001250050886
更新日期:1998-02-01 00:00:00
abstract::The Schwabing Insulin Prophylaxis Trial is a randomised, controlled pilot study designed to examine whether insulin therapy can delay or prevent the clinical onset of Type I diabetes in high risk first degree relatives of people with the disease. First degree relatives of patients with Type I diabetes, who were aged 4...
journal_title:Diabetologia
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1007/s001250050943
更新日期:1998-05-01 00:00:00
abstract:AIMS/HYPOTHESIS:The initial stages of type 1 diabetes are characterised by an aberrant islet inflammation that is in part regulated by the interaction between type 1 diabetes susceptibility genes and environmental factors. Chromosome 16p13 is associated with type 1 diabetes and CLEC16A is thought to be the aetiological...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-018-4782-0
更新日期:2019-03-01 00:00:00
abstract::There is evidence that the immune system may play a role in the pathogenesis of autonomic neuropathy in Type 1 (insulin-dependent) diabetes mellitus. In the present study, we investigated the presence of autoantibodies to sympathetic and parasympathetic nervous structures and their correlation with other conventional ...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF02743275
更新日期:1993-06-01 00:00:00
abstract::In 1971, 107 newly diagnosed black diabetics admitted to Harare Central Hospital, Rhodesia, were studied. Nine died before discharge. In 1977, 93 of the 98 patients discharged alive were traced but of these 38 (41%) had since died. Of 18 autopsies performed the cause of death was hypoglycaemia in 8 patients and hyperg...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00290487
更新日期:1980-01-01 00:00:00
abstract:AIMS/HYPOTHESIS:MicroRNAs are key regulators of gene expression involved in health and disease. The goal of our study was to investigate the global changes in beta cell microRNA expression occurring in two models of obesity-associated type 2 diabetes and to assess their potential contribution to the development of the ...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-013-2993-y
更新日期:2013-10-01 00:00:00
abstract:AIMS/HYPOTHESIS:White cell count has been shown to predict incident type 2 diabetes, but differential white cell count has received scant attention. We examined the risk of developing diabetes associated with differential white cell count and neutrophil:lymphocyte ratio and the effect of insulin sensitivity and subclin...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-013-3080-0
更新日期:2014-01-01 00:00:00
abstract::Endothelium-derived nitric oxide plays a major role in the regulation of vascular tone and in the maintenance of vascular homeostasis. Endothelial dysfunction with impaired nitric oxide biosynthesis and decreased bioavailability has been implicated in insulin resistance syndrome and Type II (non-insulin-dependent) dia...
journal_title:Diabetologia
pub_type: 杂志文章,评审
doi:10.1007/s00125-002-0975-6
更新日期:2002-12-01 00:00:00
abstract:AIMS/HYPOTHESIS:Low birthweight (LBW) is associated with dysfunctions of adipose tissue and metabolic disease in adult life. We hypothesised that altered epigenetic and transcriptional regulation of adipose-derived stem cells (ADSCs) could play a role in programming adipose tissue dysfunction in LBW individuals. METHO...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-016-4099-9
更新日期:2016-12-01 00:00:00
abstract:AIMS/HYPOTHESIS:Insulin control of glucose output is a major mechanism by which appropriate amounts of glucose are produced to supply energy to the central nervous system, without causing long-term increases of the plasma glucose concentration. It is hypothesised that the primary route by which insulin maintains contro...
journal_title:Diabetologia
pub_type: 杂志文章,评审
doi:10.1007/s001250051474
更新日期:2000-07-01 00:00:00
abstract::Microencapsulation has been proposed to protect islets of Langerhans against immune rejection in xenogenic transplantation. However, to achieve glucose homeostasis in human diabetic patients, insulin release by microencapsulated islets must increase in response to a glucose load. We microencapsulated isolated rat isle...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00279134
更新日期:1988-01-01 00:00:00
abstract:AIMS/HYPOTHESIS:Insulin enhances coronary vasodilation in healthy subjects. We tested whether insulin is able to induce coronary vasodilation in Type I (insulin-dependent) diabetic mellitus patients. Additionally, the effect of short-term hyperglycaemia on myocardial perfusion was studied. METHODS:Myocardial blood flo...
journal_title:Diabetologia
pub_type: 临床试验,杂志文章
doi:10.1007/s00125-002-0819-4
更新日期:2002-06-01 00:00:00
abstract::In order to examine the permeability of microvessels in diabetic children, the glomerular filtration rate, urinary excretion rates of albumin and beta 2-microglobulin, intravascular mass of albumin, and transcapillary escape rate of albumin were studied in 26 diabetic children without clinical signs of microangiopathy...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF01223619
更新日期:1979-05-01 00:00:00
abstract:AIMS/HYPOTHESIS:Dysfunction of lipid metabolism in white adipose tissue can substantially interfere with health and quality of life, for example in obesity and associated metabolic diseases. Therefore, it is important to characterise pathways that regulate lipid handling in adipocytes and determine how they affect meta...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-016-4152-8
更新日期:2017-02-01 00:00:00
abstract::For many, the extent to which blood glucose control can be lowered is limited by risk of hypoglycaemia. Hypoglycaemia is feared and carries fiscal, social and medical costs, with risk of death being associated with severe hypoglycaemia in patients with type 2 diabetes at high cardiovascular risk. In this issue of Diab...
journal_title:Diabetologia
pub_type: 评论,杂志文章
doi:10.1007/s00125-015-3550-7
更新日期:2015-06-01 00:00:00
abstract:AIMS/HYPOTHESIS:Obesity is a major risk factor for type 2 diabetes, but little is known about the contribution of BMI-associated loci to type 2 diabetes risk in East Asian populations. METHODS:In this study, 30 known BMI-associated variants and a genetic risk score (GRS) calculated by summing the BMI-increasing allele...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-014-3308-7
更新日期:2014-09-01 00:00:00
abstract:AIMS/HYPOTHESIS:Apart from transcription factors, little is known about the molecules that modulate the proliferation and differentiation of pancreatic endocrine cells. The early expression of tyrosine hydroxylase (TH) in a subset of glucagon(+) cells led us to investigate whether catecholamines have a role in beta cel...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-014-3341-6
更新日期:2014-11-01 00:00:00
abstract:AIMS/HYPOTHESIS:Reduced oxidative capacity of the mitochondria in skeletal muscle has been suggested to contribute to insulin resistance and type 2 diabetes. Moreover, a set of genes influencing oxidative phosphorylation (OXPHOS) is downregulated in diabetic muscle. Here we studied whether genetic, epigenetic and non-g...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-008-1018-8
更新日期:2008-07-01 00:00:00
abstract::There is ample evidence that environmental factors are involved in the aetiology of type 1 diabetes, but the nature and timing of the interactions are poorly understood. The intrauterine environment is known to play a role in the later development of type 2 diabetes, and this review considers a possible role in type 1...
journal_title:Diabetologia
pub_type: 杂志文章,评审
doi:10.1007/s00125-013-2929-6
更新日期:2013-09-01 00:00:00
abstract::A radioreceptor-assay for glucagon was developed employing pig liver plasma membranes isolated by means of an aqueous two-phase polymer system. The assay is simple, precise, and has a detection limit of 40 pg/ml. Acid-ethanol extracts of porcine intestinal mucosa and entero-glucagon purified by affinity chromatography...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00422324
更新日期:1975-06-01 00:00:00
abstract::Ciglitazone is orally active in preventing and reversing the hyperglycaemic syndrome in C57BL/6J-ob/ob mice and it is only mildly and transiently hypoglycaemic in lean littermates (C57BL/6J-+/?). Its effect on glucose disposal in vivo was estimated by injecting glucose-6-3H/14C and following the specific activity of r...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00284462
更新日期:1983-12-01 00:00:00
abstract::A nationwide mumps-measles-rubella vaccination was introduced in 1982 in Finland to children aged 1.5 to 6 years and since then mumps has virtually disappeared in the country. We investigated whether this rapid epidemiological change had any impact on antibody activity against mumps virus in Type 1 (insulin-dependent)...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00400810
更新日期:1993-12-01 00:00:00
abstract::The presence of HLA-DR 3 was analysed in 745 patients with Type 1 (insulin-dependent) diabetes with age at diagnosis between 1-19 years. HLA-DR 3 and/or 4 was found in 678/745 (91%) of the patients. Presence of DR2 with neither DR 3 nor 4 was demonstrated in 15 patients. Patients with HLA-DR 3 without DR 4 presented w...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00454876
更新日期:1986-04-01 00:00:00
abstract:AIMS/HYPOTHESIS:The intestine is the main site for glucose absorption and it has been suggested that it exhibits insulin resistance. Bariatric surgery has been shown to reverse insulin resistance and type 2 diabetes, but its effects on human intestinal metabolism are unknown. Our aim was to evaluate the effects of insu...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-015-3501-3
更新日期:2015-05-01 00:00:00
abstract:AIMS:This prospective case-control study aimed at evaluating the time course of serum concentrations of soluble adhesion molecules; intercellular adhesion molecule-1 and L-selectin in siblings with signs of pre-clinical Type 1 diabetes in order to relate these concentrations to autoantibody status and to assess whether...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-003-1072-1
更新日期:2003-04-01 00:00:00
abstract:AIMS/HYPOTHESIS:Although the variable number tandem repeat (VNTR) minisatellite 5' to the insulin gene is among the most studied polymorphisms in diabetes, the relationships between VNTR variation, diabetes-related traits and predisposition to type 2 diabetes remain unclear. Since inadequate sample size is likely to ha...
journal_title:Diabetologia
pub_type: 杂志文章,多中心研究
doi:10.1007/s00125-005-1737-z
更新日期:2005-05-01 00:00:00