Abstract:
OBJECTIVE:To evaluate whether healthy or diabetic adult mice can tolerate an extreme loss of pancreatic α-cells and how this sudden massive depletion affects β-cell function and blood glucose homeostasis. RESEARCH DESIGN AND METHODS:We generated a new transgenic model allowing near-total α-cell removal specifically in adult mice. Massive α-cell ablation was triggered in normally grown and healthy adult animals upon diphtheria toxin (DT) administration. The metabolic status of these mice was assessed in 1) physiologic conditions, 2) a situation requiring glucagon action, and 3) after β-cell loss. RESULTS:Adult transgenic mice enduring extreme (98%) α-cell removal remained healthy and did not display major defects in insulin counter-regulatory response. We observed that 2% of the normal α-cell mass produced enough glucagon to ensure near-normal glucagonemia. β-Cell function and blood glucose homeostasis remained unaltered after α-cell loss, indicating that direct local intraislet signaling between α- and β-cells is dispensable. Escaping α-cells increased their glucagon content during subsequent months, but there was no significant α-cell regeneration. Near-total α-cell ablation did not prevent hyperglycemia in mice having also undergone massive β-cell loss, indicating that a minimal amount of α-cells can still guarantee normal glucagon signaling in diabetic conditions. CONCLUSIONS:An extremely low amount of α-cells is sufficient to prevent a major counter-regulatory deregulation, both under physiologic and diabetic conditions. We previously reported that α-cells reprogram to insulin production after extreme β-cell loss and now conjecture that the low α-cell requirement could be exploited in future diabetic therapies aimed at regenerating β-cells by reprogramming adult α-cells.
journal_name
Diabetesjournal_title
Diabetesauthors
Thorel F,Damond N,Chera S,Wiederkehr A,Thorens B,Meda P,Wollheim CB,Herrera PLdoi
10.2337/db11-0876subject
Has Abstractpub_date
2011-11-01 00:00:00pages
2872-82issue
11eissn
0012-1797issn
1939-327Xpii
db11-0876journal_volume
60pub_type
杂志文章相关文献
DIABETES文献大全abstract:OBJECTIVE:Emerging data demonstrate that maternal diabetes has long-term health consequences for offspring, including the development of hypertension. In adults, circulating endothelial progenitor cells (EPCs) participate in vascular repair, and EPC numbers and function inversely correlate with the risk of developing v...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db07-1507
更新日期:2008-03-01 00:00:00
abstract::Zucker (fa/fa) rats with defective leptin receptors are obese, hyperphagic, and hyperinsulinemic. For testing whether chronic activation of the central melanocortin pathway can bypass the defective leptin signaling and normalize altered energy homeostasis in these rats, recombinant adeno-associated virus encoding pro-...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.52.8.1951
更新日期:2003-08-01 00:00:00
abstract::The antihyperglycemic drug dimethylbiguanide (DMB, also known as metformin) reduces the risk of cardiovascular complications in type 2 diabetes, although the mechanism(s) involved are unclear. DMB reduces glycosylation-related protein cross-linking, a process similar to fibrin cross-linking catalyzed by activated fact...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.51.1.189
更新日期:2002-01-01 00:00:00
abstract::Current evidence suggests that reactive oxygen species (ROS) may participate in the destruction of pancreatic beta-cells leading to type 1 diabetes. Genetic factors pre-disposing individual susceptibility to type 1 diabetes might therefore include those affecting the efficacy of ROS metabolism. In a direct in vivo tes...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.46.10.1563
更新日期:1997-10-01 00:00:00
abstract::Expansion of pancreatic β-cells is a key goal of diabetes research, yet induction of adult human β-cell replication has proven frustratingly difficult. In part, this reflects a lack of understanding of cell cycle control in the human β-cell. Here, we provide a comprehensive immunocytochemical "atlas" of G1/S control m...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db12-0777
更新日期:2013-07-01 00:00:00
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
更新日期:2007-08-01 00:00:00
abstract::AS160 is a newly described substrate for the protein kinase Akt that links insulin signaling and GLUT4 trafficking. In this study, we determined the expression of and in vivo insulin action on AS160 in human skeletal muscle. In addition, we compared the effect of physiological hyperinsulinemia on AS160 phosphorylation...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.54.6.1692
更新日期:2005-06-01 00:00:00
abstract::Streptozocin-induced diabetic (STZ-D) mice have reduced brain concentrations of tryptophan, a precursor substance for 5-hydroxytryptamine, and show lengthened immobility in Porsolt's swim test, a putative animal model of depression. This study investigated whether tryptophan affects behavior in Porsolt's swim test in ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.40.12.1598
更新日期:1991-12-01 00:00:00
abstract::Hyperglycemia-triggered vascular abnormalities are the most serious complications of diabetes mellitus (DM). The major cause of vascular dysfunction in DM is endothelial injury and dysfunction associated with the reduced number and dysfunction of endothelial progenitor cells (EPCs). A major challenge is to identify ke...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db18-1178
更新日期:2019-08-01 00:00:00
abstract::Cytoplasmic islet cell antibody-negative (ICA-; less than 20 Juvenile Diabetes Foundation units, n = 1670) and ICA+ (n = 42) first-degree relatives of type I (insulin-dependent) diabetic individuals were studied for competitive insulin autoantibodies (CIAAs) with a radioassay. Overall, 3.7% of first-degree relatives (...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.38.10.1320
更新日期:1989-10-01 00:00:00
abstract::Type 1 diabetes appears to progress not as an uncontrolled autoimmune attack on the pancreatic islet beta-cells, but rather in a highly regulated manner. Leukocytic infiltration of the pancreatic islets by autoimmune cells, or insulitis, can persist for long periods of time before the terminal destruction of beta-cell...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.53.9.2310
更新日期:2004-09-01 00:00:00
abstract:OBJECTIVE:Atherosclerotic cardiovascular disease is the leading cause of death among people with diabetes. Generation of oxidized LDLs and reduced nitric oxide (NO) availability because of endothelial NO synthase (eNOS) dysfunction are critical events in atherosclerotic plaque formation. Biochemical mechanism leading f...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db09-0167
更新日期:2009-10-01 00:00:00
abstract::Chronic high-fat feeding in rats induces profound whole-body insulin resistance, mainly due to effects in oxidative skeletal muscle. The mechanisms of this reaction remain unclear, but local lipid availability has been implicated. The aim of this study was to examine the influence of three short-term physiological man...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.46.12.2022
更新日期:1997-12-01 00:00:00
abstract:OBJECTIVE:The presence of autoantibodies to islet antigens GAD and/or tyrosine phosphatase 2 (IA-2) in type 2 diabetic patients (latent autoimmune diabetes in adults [LADA]) identifies subjects at high risk to develop insulin dependency. The aim of this study was to dissect humoral anti-IA-2 immune response in Caucasia...
journal_title:Diabetes
pub_type: 杂志文章,多中心研究
doi:10.2337/db07-0874
更新日期:2008-05-01 00:00:00
abstract::Recently, a missense mutation replacing tryptophan with arginine at codon 64 of the beta 3-adrenergic receptor gene was shown to be associated with insulin resistance in nondiabetic subjects and to an earlier onset of NIDDM in Pima Indians. We studied whether the codon 64 amino acid polymorphism of the beta 3-adrenerg...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.45.8.1115
更新日期:1996-08-01 00:00:00
abstract::Numerous reports have confirmed the presence of islet cell antibodies in diabetic patients. These are found mostly in newly diagnosed insulin-dependent diabetic patients and in patients who have autoimmune polyendocrine disorders. Antibodies to beta cells, somatostatin, and glucagon-producing cells have been described...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.28.2.102
更新日期:1979-02-01 00:00:00
abstract::High glucose concentrations such as are seen in diabetes mellitus are known to have deleterious effects on cells, but the pathways by which glucose induces these effects are unknown. One hypothesis is that metabolism of glucose to glucosamine might be involved. For example, it has been shown that glucosamine is more p...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.42.9.1289
更新日期:1993-09-01 00:00:00
abstract::Insulin replacement therapy in type 1 diabetes is imperfect because proper glycemic control is not always achieved. Most patients develop microvascular, macrovascular, and neurological complications, which increase with the degree of hyperglycemia. Engineered muscle cells continuously secreting basal levels of insulin...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.51.3.704
更新日期:2002-03-01 00:00:00
abstract::We report a genomewide linkage analysis of a large consanguineous family segregating autosomal recessively inherited neonatal diabetes and the identification of a novel neonatal diabetes locus. Neonatal diabetes was characterized by low levels of circulating C-peptide with very low to undetectable levels of insulin in...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.52.10.2636
更新日期:2003-10-01 00:00:00
abstract::In humans, low levels of growth hormone (GH) and its mediator, IGF-1, associate with hepatic lipid accumulation. In mice, congenital liver-specific ablation of the GH receptor (GHR) results in reductions in circulating IGF-1 and hepatic steatosis, associated with systemic insulin resistance. Due to the intricate relat...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db16-0649
更新日期:2016-12-01 00:00:00
abstract::The large Maf family of basic leucine-zipper-containing transcription factors are known regulators of key developmental and functional processes in various cell types, including pancreatic islets. Here, we demonstrate that within the adult pancreas, MafB is only expressed in islet alpha-cells and contributes to cell t...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.55.02.06.db05-0946
更新日期:2006-02-01 00:00:00
abstract::We studied the effects of short-term (5 days) and long-term (2 wk) high carbohydrate (75%) feedings on insulin binding to isolated adipocytes and insulin sensitivity in vivo in normal subjects. Ingestion of the high carbohydrate diet led to daylong hyperinsulinemia in both short- and long-term groups. Insulin binding ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.28.8.731
更新日期:1979-08-01 00:00:00
abstract::The relationships between diabetes and pancreatic ductal adenocarcinoma (PDAC) are complex. Longstanding type 2 diabetes (T2DM) is a risk factor for pancreatic cancer, but increasing epidemiological data point to PDAC as also a cause of diabetes due to unknown mechanisms. New-onset diabetes is of particular interest t...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db16-1477
更新日期:2017-05-01 00:00:00
abstract::p21(cip1), a regulatory molecule upstream of the G(1/0) checkpoint, is increased in beta-cells in response to mitogenic stimulation. Whereas p21(cip1) can variably stimulate or inhibit cell cycle progression, in vitro studies suggest that p21(cip1) acts as an inhibitor in the pancreatic beta-cell. To determine the fun...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db06-0627
更新日期:2006-12-01 00:00:00
abstract::We used mouse genetics to model how polygenic thresholds for the transition from impaired glucose tolerance (IGT) to NIDDM are reached. NON/Lt and NZO/Hl are inbred mouse strains selected for IGT and polygenic obesity, respectively. Their F1 male progeny consistently developed NIDDM. Genetic analysis of F2 males from ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.47.8.1287
更新日期:1998-08-01 00:00:00
abstract::Exogenous ghrelin reduces glucose-stimulated insulin secretion and endogenous ghrelin protects against hypoglycemia during starvation. Islet ε-cells produce ghrelin and δ-cells express growth hormone secretagogue receptor (GHSR), suggesting the possibility of a paracrine mechanism for islet ghrelin to reach high local...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db19-0079
更新日期:2019-09-01 00:00:00
abstract::The aim of the present study was to evaluate and cor-relate islet to brown and white adipose tissue (WAT) blood perfusion in one obese rat and one nonobese rat with type 2 diabetes (obese Zucker [OZ] and GK rats, respectively). We measured blood perfusion with a microsphere technique in anesthetized animals and subseq...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.54.9.2620
更新日期:2005-09-01 00:00:00
abstract::Impaired wound healing is one of the main causes of diabetic foot ulcerations. However, the exact mechanism of delayed wound healing in diabetes is not fully understood. Long noncoding RNAs (lncRNAs) are widely involved in a variety of biological processes and diseases, including diabetes and its associated complicati...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db20-0147
更新日期:2020-10-01 00:00:00
abstract::Insulin is a short-lived species in the circulatory system. After binding to its receptor sites and transmission of its biological signals, bound insulin undergoes receptor-mediated endocytosis and consequent degradation. An inactive insulin derivative that is not recognized by the receptor has a longer circulation li...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.48.7.1437
更新日期:1999-07-01 00:00:00
abstract::To investigate the effects of insulin on platelets in obesity and in non-insulin-dependent diabetes mellitus (NIDDM)--classic insulin-resistant states--we determined ADP-induced platelet aggregation and platelet cGMP (guanosine 3',5'-cyclic monophosphate) content in platelet-rich plasma obtained from nine obese subjec...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.44.11.1318
更新日期:1995-11-01 00:00:00