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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the detailed pathogenesis of diabetic polyneuropathy is not known, several mechanisms appear to be involved and may occur sequentially. Hence, the early and much researched activation of the polyol-pathway appears to secondarily affect nonenzymatic glycation, perturbation of vasoactive substances, the immune system and neurotrophism. These metabolic abnormalities may be differentially expressed in the neuropathy occurring in insulin dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM) diabetes. This notion is supported by differences in the structural abnormalities of the neuropathies in the two types of diabetes. Distinct and characteristic nodal changes occur in IDDM but not in NIDDM neuropathy, which also shows a milder axonal atrophy. On the other hand, nerve fiber loss which characterizes diabetic neuropathy tends to be focal in the older NIDDM patients, suggesting a more prominent vascular genesis. A further characteristic feature of diabetic neuropathy is blunted fiber regeneration, which probably is consequent to impairments of the necessary immune response and local synthesis of neurotrophic factors. Nerve biopsies from diabetic patients, although not necessary for diagnosis, provide valuable tissue for biochemical and molecular analysis of underlying mechanisms, the detailed elucidation of which will facilitate the design of targeted therapies.
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PMID:Neuropathology of diabetic neuropathy and its correlations with neurophysiology. 935 80

The most common microvascular diabetic complication, diabetic peripheral polyneuropathy (DPN), affects type 1 diabetic patients more often and more severely. In recent decades, it has become increasingly clear that perpetuating pathogenetic mechanisms, molecular, functional, and structural changes and ultimately the clinical expression of DPN differ between the two major types of diabetes. Impaired insulin/C-peptide action has emerged as a crucial factor to account for the disproportionate burden affecting type 1 patients. C-peptide was long believed to be biologically inactive. However, it has now been shown to have a number of insulin-like glucose-independent effects. Preclinical studies have demonstrated dose-dependent effects on Na+,K(+)-ATPase activity, endothelial nitric oxide synthase (eNOS), and endoneurial blood flow. Furthermore, it has regulatory effects on neurotrophic factors and molecules pivotal to the integrity of the nodal and paranodal apparatus and modulatory effects on apoptotic phenomena affecting the diabetic nervous system. In animal studies, C-peptide improves nerve conduction abnormalities, prevents nodal degenerative changes, characteristic of type 1 DPN, promotes nerve fiber regeneration, and prevents apoptosis of central and peripheral nerve cell constituents. Limited clinical trials have confirmed the beneficial effects of C-peptide on autonomic and somatic nerve function in patients with type 1 DPN. Therefore, evidence accumulates that replacement of C-peptide in type 1 diabetes prevents and even improves DPN. Large-scale food and drug administration (FDA)-approved clinical trials are necessary to make this natural substance available to the globally increasing type 1 diabetic population.
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PMID:Type 1 diabetic neuropathy and C-peptide. 1519 72

Despite documented superiority of positron emission tomography over other investigative modalities in the preoperative staging of non-small cell lung cancer, a proportion of patients will have an inaccurate staging of their mediastinal nodes. The aim of this retrospective review is to analyse the clinicopathological factors responsible for inaccurate nodal staging by integrated PET-CT. A total of 100 consecutive patients with histologically proven non-small cell lung cancer underwent staging with PET-CT prior to lung resection. Thirty-three patients, inaccurately staged by PET-CT, were analysed. Univariate analysis identified the following as significant in causing inaccurate nodal staging: history of tuberculosis (P=0.039) and non-insulin dependant diabetes (P=0.014). In multivariate analysis, we have identified the following as independent factors in causing inaccurate staging of mediastinal lymph nodes: rheumatoid arthritis, non-insulin dependent diabetes, history of tuberculosis, presence of atypical adenomatous hyperplasia and pneumonia (P<0.05). The highest rate of inaccuracy in mediastinal nodal staging was in nodal station 4 (11%, P=0.01) followed by station 7 (10%, P=0.02) and station 9 (3.5%, P=0.01). Interpretation of PET-CT staging of the mediastinum in patients with a history of the above should be with caution, as the incidence of false upstaging and down staging in these subgroups is high. Vigilance of such factors may improve the accuracy of PET-CT in staging mediastinal lymph nodes. Histological confirmation should always be sought.
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PMID:Factors causing inaccurate staging of mediastinal nodal involvement in non-small cell lung cancer patients staged by positron emission tomography. 1766 63

Diabetic polyneuropathy (DPN) is the most common late complication of diabetes mellitus. The underlying pathogenesis is multifaceted, with partly interrelated mechanisms that display a dynamic course. The mechanisms underlying DPN in type 1 and type 2 diabetes mellitus show overlaps or may differ. The differences are mainly due to insulin deficiency in type 1 diabetes which exacerbates the abnormalities caused by hyperglycaemia. Experimental DPN in rat models have identified early metabolic abnormalities with consequences for nerve conduction velocities and endoneurial blood flow. When corrected, the early functional deficits are usually normalised. On the other hand, if not corrected, they lead to abnormalities in lipid peroxidation and expression of neurotrophic factors which in turn result in axonal, nodal and paranodal degenerative changes with worsening of nerve function. As the structural changes progress, they become increasingly less amendable to metabolic interventions. In the past several years, experimental drugs--such as aldose reductase inhibitors, antioxidants and protein kinase C inhibitors--have undergone clinical trials, with disappointing outcomes. These drugs, targeting a single underlying pathogenetic factor, have in most cases been initiated at the advanced stage of DPN. In contrast, substitution of acetyl-L-carnitine (ALC) or C-peptide in type 1 DPN target a multitude of underlying mechanisms and are therefore more likely to be effective on a broader spectrum of the underlying pathogenesis. Clinical trials utilising ALC have shown beneficial effects on nerve conduction slowing, neuropathic pain, axonal degenerative changes and nerve fibre regeneration, despite relatively late initiation in the natural history of DPN. Owing to the good safety profile of ALC, early initiation of ALC therapy would be justified, with potentially greater benefits.
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PMID:Acetyl-L-carnitine in diabetic polyneuropathy: experimental and clinical data. 1769 89

Diabetic polyneuropathy (DPN) occurs more frequently in type 1 diabetes resulting in a more severe DPN. The differences in DPN between the two types of diabetes are due to differences in the availability of insulin and C-peptide. Insulin and C-peptide provide gene regulatory effects on neurotrophic factors with effects on axonal cytoskeletal proteins and nerve fiber integrity. A significant abnormality in type 1 DPN is nodal degeneration. In the type 1 BB/Wor-rat, C-peptide replacement corrects metabolic abnormalities ameliorating the acute nerve conduction defect. It corrects abnormalities of neurotrophic factors and the expression of neuroskeletal proteins with improvements of axonal size and function. C-peptide corrects the expression of nodal adhesive molecules with prevention and repair of the functionally significant nodal degeneration. Cognitive dysfunction is a recognized complication of type 1 diabetes, and is associated with impaired neurotrophic support and apoptotic neuronal loss. C-peptide prevents hippocampal apoptosis and cognitive deficits. It is therefore clear that substitution of C-peptide in type 1 diabetes has a multitude of effects on DPN and cognitive dysfunction. Here the effects of C-peptide replenishment will be extensively described as they pertain to DPN and diabetic encephalopathy, underpinning its beneficial effects on neurological complications in type 1 diabetes.
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PMID:The effects of C-peptide on type 1 diabetic polyneuropathies and encephalopathy in the BB/Wor-rat. 1843 23

The present study was conducted to evaluate whether experimentally induced type 1 diabetes results in alterations to atrioventricular nodal (AVN) electrophysiology at the cellular level. Spontaneous action potentials (APs) and ionic currents were recorded from AVN myocytes isolated from the hearts of control rats and from those with streptozotocin-induced diabetes. Perforated patch-clamp recordings were used to assess changes in cellular AP parameters and in ionic currents. Type 1 diabetes significantly increased AP duration, whilst reducing AP firing rate, upstroke velocity and rate of diastolic depolarization. The diabetes-induced changes in AP parameters were accompanied by a significant leftward shift in the zero current potential under voltage clamp, a reduction in peak L-type Ca(2+) current density and reduced amplitude of delayed rectifier and hyperpolarization-activated currents. These findings demonstrate that experimentally induced type 1 diabetes can lead to remodelling of AVN cellular electrophysiology.
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PMID:Streptozotocin-induced diabetes modulates action potentials and ion channel currents from the rat atrioventricular node. 1994 31

Diabetic polyneuropathy (DPN) is a common complication in diabetes. At present, there is no adequate treatment, and DPN is often debilitating for patients. It is a heterogeneous disorder and differs in type 1 and type 2 diabetes. An important underlying factor in type 1 DPN is insulin deficiency. Proinsulin C-peptide is a critical element in the cascade of events. In this review, we describe the physiological role of C-peptide and how it provides an insulin-like signaling function. Such effects translate into beneficial outcomes in early metabolic perturbations of neural Na+/K+-ATPase and nitric oxide (NO) with subsequent preventive effects on early nerve dysfunction. Further corrective consequences resulting from this signaling cascade have beneficial effects on gene regulation of early gene responses, neurotrophic factors, their receptors, and the insulin receptor itself. This may lead to preventive and corrective results to nerve fiber degeneration and loss, as well as, promotion of nerve fiber regeneration with respect to sensory somatic fibers and small nociceptive nerve fibers. A characteristic abnormality of type 1 DPN is nodal and paranodal degeneration with severe consequences for myelinated fiber function. This review deals in detail with the underlying insulin-deficiency-related molecular changes and their correction by C-peptide. Based on these observations, it is evident that continuous maintenance of insulin-like actions by C-peptide is needed in peripheral nerve to minimize the sequences of metabolic and molecular abnormalities, thereby ameliorating neuropathic complications. There is now ample evidence demonstrating that C-peptide replacement in type 1 diabetes promotes insulin action and signaling activities in a more enhanced, prolonged, and continuous fashion than does insulin alone. It is therefore necessary to replace C-peptide to physiological levels in diabetic patients. This will have substantial beneficial effects on type 1 DPN.
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PMID:The beneficial effects of C-Peptide on diabetic polyneuropathy. 2003 8

Type 1 diabetes mellitus (T1DM) is the most common type of diabetes in children and adolescents. Diabetic subjects are more likely to experience a myocardial infarction compared to nondiabetic subjects. In recent years, induced pluripotent stem cells (iPSCs) have received increasing attention from basic scientists and clinicians and hold promise for myocardial regeneration due to their unlimited proliferation potential and differentiation capacity. However, cardiomyogenesis of type 1 diabetic donor-derived iPSCs (T1DM-iPSCs) has not been investigated yet. The aim of the study was to comparatively analyze cardiomyocyte (CM) differentiation capacity of nondiabetic donor-derived iPSCs (N-iPSCs) and T1DM-iPSCs. The differentiated CMs were confirmed by both expression of cardiac-specific markers and presence of cardiac action potential. Since mitochondrial bioenergetics is vital to every aspect of CM function, extracellular acidification rates and oxygen consumption rates were measured using Seahorse extracellular flux analyzer. The results showed that N-iPSCs and T1DM-iPSCs demonstrated similar capacity of differentiation into spontaneously contracting CMs exhibiting nodal-, atrial-, or ventricular-like action potentials. Differentiation efficiency was up to 90%. In addition, the CMs differentiated from N-iPSCs and T1DM-iPSCs (N-iPSC-CMs and T1DM-iPSC-CMs, respectively) showed 1) well-regulated glucose utilization at the level of glycolysis and mitochondrial oxidative phosphorylation and 2) the ability to switch metabolic pathways independent of extracellular glucose concentration. Collectively, we demonstrate for the first time that T1DM-iPSCs can differentiate into functional CMs with well-regulated glucose utilization as shown in N-iPSCs, suggesting that T1DM-iPSC-CMs might be a promising autologous cell source for myocardial regeneration in type 1 diabetes patients.
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PMID:Comparison of Cardiomyocyte Differentiation Potential Between Type 1 Diabetic Donor- and Nondiabetic Donor-Derived Induced Pluripotent Stem Cells. 2556 86

Cardiovascular complications are common in type 1 diabetes mellitus (TIDM) and there is an increased risk of arrhythmias as a result of dysfunction of the cardiac conduction system (CCS). We have previously shown that, in vivo, there is a decrease in the heart rate and prolongation of the QRS complex in streptozotocin-induced type 1 diabetic rats indicating dysfunction of the CCS. The aim of this study was to investigate the function of the ex vivo CCS and key proteins that are involved in pacemaker mechanisms in TIDM. RR interval, PR interval and QRS complex duration were significantly increased in diabetic rats. The beating rate of the isolated sinoatrial node (SAN) preparation was significantly decreased in diabetic rats. The funny current density and cell capacitance were significantly decreased in diabetic nodal cells. Western blot showed that proteins involved in the function of the CCS were significantly decreased in diabetic rats, namely: HCN4, Cav1.3, Cav3.1, Cx45, and NCX1 in the SAN; RyR2 and NCX1 in the atrioventricular junction and Cx40, Cx43, Cx45, and RyR2 in the Purkinje network. We conclude that there are complex functional and cellular changes in the CCS in TIDM. The changes in the proteins involved in the function of this electrical system are expected to adversely affect action potential generation and propagation, and these changes are likely to be arrhythmogenic.
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PMID:Electrical Conduction System Remodeling in Streptozotocin-Induced Diabetes Mellitus Rat Heart. 3133 36

Our study objective was testing for anti-neuronal autoantibodies within commercially available intravenous immunoglobulin (IVIg) preparations. Sixteen samples from 5 different commercially available IVIg preparations were tested with cell-based assays (CBA) and enzyme-linked immunosorbent assay (ELISA) to detect and characterize common neuronal autoantibodies, and with immunohistochemistry on teased fibers from mouse sciatic nerve and on mouse brain sections to screen for nodal and not yet identified neuronal antigens. In 15/16 IVIg preparations, anti-GAD antibodies were detected in titers ranging from 40 to 1507 IU/mL, as typically seen in type 1 diabetes, but not in the range (> 2000 IU/mL) seen in GAD-positive neurological patients. None of the preparations was however positive with anti-GAD CBA. Antibodies to AQP4 were also detected by ELISA in 15/16 IVIg preparations with titers comparable to those seen in AQP4-seropositive NMO patients; with CBA, however, all IVIg samples were AQP4-negative. IVIg preparations contained IgG-anti-MAG antibodies by ELISA at statistically significant higher titers compared to controls. Two of the 16 IVIg samples were positive for human 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies. All IVIg preparations were negative for antibodies to MOG, NMDAR, anti-nodal, and other neuronal-specific proteins. IVIg preparations contain antibodies against GAD and AQP4 in titers comparable to those seen in autoimmune patients when tested by ELISA, but not by CBA or tissue immunohistochemistry, suggesting that the autoantibodies within the IVIg are against linear rather than structural epitopes, as part of the natural antibody immune repertoire. The information is clinically important for diagnosis when testing patients' sera after they have received therapy with IVIg to avoid false interpretation.
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PMID:Anti-Neuronal Antibodies Within the IVIg Preparations: Importance in Clinical Practice. 3167 65


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