Abstract:
AIMS/HYPOTHESIS:Sphingolipids play important roles in beta cell physiology, by regulating proinsulin folding and insulin secretion and in controlling apoptosis, as studied in animal models and cell cultures. Here we investigate whether sphingolipid metabolism may contribute to the pathogenesis of human type 1 diabetes and whether increasing the levels of the sphingolipid sulfatide would prevent models of diabetes in NOD mice. METHODS:We examined the amount and distribution of sulfatide in human pancreatic islets by immunohistochemistry, immunofluorescence and electron microscopy. Transcriptional analysis was used to evaluate expression of sphingolipid-related genes in isolated human islets. Genome-wide association studies (GWAS) and a T cell proliferation assay were used to identify type 1 diabetes related polymorphisms and test how these affect cellular islet autoimmunity. Finally, we treated NOD mice with fenofibrate, a known activator of sulfatide biosynthesis, to evaluate the effect on experimental autoimmune diabetes development. RESULTS:We found reduced amounts of sulfatide, 23% of the levels in control participants, in pancreatic islets of individuals with newly diagnosed type 1 diabetes, which were associated with reduced expression of enzymes involved in sphingolipid metabolism. Next, we discovered eight gene polymorphisms (ORMDL3, SPHK2, B4GALNT1, SLC1A5, GALC, PPARD, PPARG and B4GALT1) involved in sphingolipid metabolism that contribute to the genetic predisposition to type 1 diabetes. These gene polymorphisms correlated with the degree of cellular islet autoimmunity in a cohort of individuals with type 1 diabetes. Finally, using fenofibrate, which activates sulfatide biosynthesis, we completely prevented diabetes in NOD mice and even reversed the disease in half of otherwise diabetic animals. CONCLUSIONS/INTERPRETATION:These results indicate that islet sphingolipid metabolism is abnormal in type 1 diabetes and suggest that modulation may represent a novel therapeutic approach. DATA AVAILABILITY:The RNA expression data is available online at https://www.dropbox.com/s/93mk5tzl5fdyo6b/Abnormal%20islet%20sphingolipid%20metabolism%20in%20type%201%20diabetes%2C%20RNA%20expression.xlsx?dl=0 . A list of SNPs identified is available at https://www.dropbox.com/s/yfojma9xanpp2ju/Abnormal%20islet%20sphingolipid%20metabolism%20in%20type%201%20diabetes%20SNP.xlsx?dl=0 .
journal_name
Diabetologiajournal_title
Diabetologiaauthors
Holm LJ,Krogvold L,Hasselby JP,Kaur S,Claessens LA,Russell MA,Mathews CE,Hanssen KF,Morgan NG,Koeleman BPC,Roep BO,Gerling IC,Pociot F,Dahl-Jørgensen K,Buschard Kdoi
10.1007/s00125-018-4614-2subject
Has Abstractpub_date
2018-07-01 00:00:00pages
1650-1661issue
7eissn
0012-186Xissn
1432-0428pii
10.1007/s00125-018-4614-2journal_volume
61pub_type
杂志文章相关文献
DIABETOLOGIA文献大全abstract:AIMS/HYPOTHESIS:We describe a novel model of insulin-deficient diabetes with a single copy of the gene encoding insulin 1 (Ins1) and no gene encoding insulin 2 (Ins2). MATERIALS AND METHODS:We constructed five lines of mice: mice with two copies of Ins1 (NOD( Ins1+/+,Ins2-/-)), mice with a single copy of Ins1 (NOD( In...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-006-0241-4
更新日期:2006-06-01 00:00:00
abstract:AIMS/HYPOTHESIS:White adipose tissue (WAT) consists of various depots with different adipocyte functionality and immune cell composition. Knowledge of WAT-depot-specific differences in expandability and immune cell influx during the development of obesity is limited, therefore we aimed to characterise different WAT dep...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-015-3594-8
更新日期:2015-07-01 00:00:00
abstract:AIMS/HYPOTHESIS:This study compared the incidence rate of type 1 diabetes in children diagnosed with enterovirus (EV) infections with that in age- and sex-matched children without EV infection in a population-based cohort. In addition, we examined whether the direction or magnitude of the association between EV infecti...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-014-3400-z
更新日期:2015-01-01 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:Glucagon-like peptide-1 (GLP-1) lowers glucose levels by potentiating glucose-induced insulin secretion and inhibiting glucagon release. The question of whether GLP-1 exerts direct effects on the liver, independently of the hormonal changes, is controversial. We tested whether an exogenous GLP-1 infusio...
journal_title:Diabetologia
pub_type: 临床试验,杂志文章
doi:10.1007/s00125-012-2738-3
更新日期:2013-01-01 00:00:00
abstract:AIMS/HYPOTHESIS:We had previously reported that stromal cell-derived factor 1 (SDF-1) mediates chemorepulsion of diabetogenic T cell adhesion to islet microvascular endothelium through unknown mechanisms in NOD mice. Here we report that SDF-1-mediated chemorepulsion occurs through slit homologue (SLIT)2-roundabout, axo...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-013-2978-x
更新日期:2013-10-01 00:00:00
abstract:AIMS/HYPOTHESIS:The transcription factor upstream stimulatory factor 1 (USF1) regulates the expression of genes involved in glucose and lipid metabolism and has been associated with familial combined hyperlipidaemia. USF1 is located on chromosome 1q22-23, a region with evidence for linkage to type 2 diabetes and variou...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-005-1914-0
更新日期:2005-10-01 00:00:00
abstract::For the normalisation of blood glucose levels in diabetic patients by feedback controlled insulin delivery, a self-manageable and reliable method for continuous glucose estimation is still not available. By combining a commercially available needle type dialysis probe (molecular cutoff 20,000 Da) with a sensitive gluc...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF02221686
更新日期:1992-11-01 00:00:00
abstract:AIMS/HYPOTHESIS:The aim was to conduct a systematic review and meta-analysis of randomised controlled clinical trials assessing the effect of probiotic, prebiotic or synbiotic supplementation on gut microbiota and glucose control and lipid levels in individuals with diabetes. METHODS:MEDLINE, EMBASE and the Cochrane L...
journal_title:Diabetologia
pub_type: 杂志文章,评审
doi:10.1007/s00125-020-05295-1
更新日期:2021-01-01 00:00:00
abstract::Forearm perfusion studies were carried out to determine the responsiveness to insulin of the superficial forearm tissues in non-obese Type 2 (non-insulin-dependent) diabetics, and the interrelationships among plasma concentrations of glucose, insulin and non-esterified fatty acids (NEFA), tissue uptake of glucose and ...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00281298
更新日期:1982-04-01 00:00:00
abstract::The mechanisms which underlie the development of Charcot joints and foot ulceration are poorly understood. The present study using non-invasive Doppler techniques demonstrates that in the neuropathic leg, the arteries are rigid, peripheral blood flow is increased and associated with arteriovenous shunting. We studied ...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00253862
更新日期:1982-01-01 00:00:00
abstract::498 diabetics were discovered in a survey of ischaemic heart disease in 10,059 men aged 40 years and over in Israel. -The diabetics were divided into previously known and newly diagnosed. -During a 5 year follow-up period, the incidence rates of fatal and non-fatal myocardial infarction and the incidence of intermitte...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF01219704
更新日期:1977-05-01 00:00:00
abstract::An inconsistency has come to light between the conclusion of Lucassen et al. that IDDM2 (11p15.5) must lie within a 4.1 kilobase (kb) segment at the insulin (INS) locus and their own data showing statistically significant associations between insulin-dependent diabetes mellitus (IDDM) and markers beyond the boundaries...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00403307
更新日期:1996-05-01 00:00:00
abstract:AIMS/HYPOTHESIS:An increased risk of type 2 diabetes mellitus is associated with low birthweight after full-term gestation, including amplification of this risk by weight gain during infancy and adult body composition. Premature birth is also associated with insulin resistance, but studies conducted so far have not pro...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-005-0118-y
更新日期:2006-03-01 00:00:00
abstract::To learn more about the preclinical phase of IDDM we observed for a median period of 46.5 months (range 0.5-69 months) a group of 57 siblings positive for ICA and/or IAA when first screened within 6 months of the diagnosis of the proband. Sequential blood samples and IVGTTs were obtained at intervals of 6-12 months. S...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s001250050122
更新日期:1994-04-01 00:00:00
abstract:AIMS/HYPOTHESIS:The main objective of this work was to discover new drugs that can activate the differentiation of multipotent pancreatic progenitors into endocrine cells. METHODS:In vitro experiments were performed using fetal pancreatic explants from rats and mice. In this assay, we examined the actions on pancreati...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-012-2778-8
更新日期:2013-02-01 00:00:00
abstract::The characteristics, progressivity and reversibility of the changes in glucose homeostasis brought about by chronic protein-calorie malnutrition were studied in the rat. Four-week-old male rats received a control diet (15% protein) or a low-protein diet (5% protein) until the age of 28 weeks. Other rats received the l...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00295879
更新日期:1987-12-01 00:00:00
abstract:AIMS/HYPOTHESIS:Fasting plasma levels of branched-chain amino acids (BCAAs) are associated with insulin resistance, but it remains unclear whether there is a causal relation between the two. We aimed to disentangle the causal relations by performing a Mendelian randomisation study using genetic variants associated with...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-017-4222-6
更新日期:2017-05-01 00:00:00
abstract:AIMS/HYPOTHESIS:A high prevalence of diabetes contributes to excess CHD in Indian Asians, but the underlying mechanisms are unclear. Heart rate, heart rate variability (HRV) and baroreflex sensitivity (BRS) are measures of cardiac autonomic function that are disturbed by hyperglycaemia and predict CHD. We compared thes...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-010-1818-5
更新日期:2010-10-01 00:00:00
abstract::Several thrombogenic abnormalities are associated with diabetes. To investigate the underlying molecular mechanisms, we examined the effects of advanced glycation endproducts (AGE), non-enzymatically glycated protein derivatives, on the production of prostacyclin (PGI2), an anti-thrombogenic prostanoid, and of plasmin...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s001250051089
更新日期:1998-12-01 00:00:00
abstract::Loss of neurogenic inflammation in response to tissue injury may be an important complication of diabetes mellitus. We studied local neurogenic inflammation in the peripheral nerve trunk of Sprague-Dawley rats 4 months following the induction of diabetes by streptozotocin injection. To assess neurogenic inflammation, ...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF02743263
更新日期:1993-06-01 00:00:00
abstract::Treatment of diabetic rats with octreotide can inhibit early diabetic renal hypertrophy. Octreotide administration for 6 months from the day of diabetes induction inhibits renal hypertrophy and diminishes increase in urinary albumin excretion. To investigate the effect of octreotide on manifest diabetic renal changes,...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00400087
更新日期:1995-02-01 00:00:00
abstract::Progressive capillary occlusion often leads to severe retinopathy within 15-20 years of the onset of Type 1 (insulin-dependent) diabetes mellitus. Lipoprotein(a), a complex formed by apolipoprotein(a), apo B-100 and lipids, is considered an independent, genetically determined, predictor of cardiovascular disease. It m...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00399100
更新日期:1993-01-01 00:00:00
abstract::N-acetylcysteine (NAC) is a precursor of glutathione (GSH) synthesis, a free radical scavenger and an inhibitor of tumour necrosis factor alpha (TNF). Because these functions might be beneficial in diabetic complications, in this study we examined whether NAC inhibits peripheral neuropathy. Motor nerve conduction velo...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00418340
更新日期:1996-03-01 00:00:00
abstract::We compared the effects of infusing a chemically defined chiro-inositol glycan putative insulin mediator with an equivalent dose of insulin in low-dose (45 mg/kg) streptozotocin diabetic rats. Insulin decreased plasma glucose levels from 17.32 +/- 0.17 to 3.96 +/- 0.064 mmol/l (p < 0.0002) in 120 min, a decrease of 77...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00418546
更新日期:1996-06-01 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::We have studied the presence of GAD65 autoantibodies in women with insulin-dependent diabetes mellitus (IDDM) (n = 28) or gestational diabetes (GDM) (n = 139) diagnosed during pregnancy and investigated the temporal relationship between these autoantibodies and the subsequent recurrence or development of IDDM. Among t...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s001250050578
更新日期:1996-11-01 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:Advances in type 2 diabetes genetics have raised hopes that genetic testing will improve disease prediction, prevention and treatment. Little is known about current physician and patient views regarding type 2 diabetes genetic testing. We hypothesised that physician and patient views would differ regard...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-009-1512-7
更新日期:2009-11-01 00:00:00
abstract::Non-obese diabetic mice aged 30 to 60 days were treated orally with Cyclosporin at doses of 25, 15 and 2.5 mg/kg every 2 days until 160 days of age. Diabetes developed in 12 out of 18 oil-treated mice (67%), with partial to complete Langerhans' islet destruction associated with lymphocytic infiltration. The non-obese ...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00454884
更新日期:1986-04-01 00:00:00