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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The concentration and distribution of labile elements in nerve cells is tightly regulated by multiple membrane transport processes and by binding to lipids and proteins. The multifaceted nature of elemental regulation provides numerous sites at which toxicants or disease processes might act to disrupt this regulation. Such disruption can affect cytoskeletal integrity, macromolecular synthesis, energy production, osmoregulation and other cellular processes. The possible role of perturbed elemental homeostasis in the mechanism of nerve injury caused by certain chemicals (e.g., acrylamide, 2,5-hexanedione) and neuropathic diseases (e.g., diabetes) has not been determined. To investigate this possibility, we have used electron probe x-ray micro-analysis (EPMA) to measure the distribution of elements and water in cellular compartments of myelinated axons (axoplasm, mitochondria) and glial cells (cytoplasm, myelin) in normal rat central and peripheral nervous systems. Results indicate that each compartment exhibits a characteristic composition of elements and water which might reflect function of that anatomical region or organelle. Injury-induced changes in elemental content of PNS axons and Schwann cells have been identified using several neurotoxic models (i.e., acrylamide, axotomy, diabetic neuropathy). Each type of injury initiated early alterations in element and water composition of both axons and glial cells. Compositional changes were specific and developed sequentially instead of simultaneously. Results of these studies suggest that, rather than being an epiphenomenon, altered elemental regulation might represent a primary component of many neurotoxic mechanisms.
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PMID:Perturbation of axonal elemental composition and water content: implication for neurotoxic mechanisms. 150 12

A unifying metabolic hypothesis completely accounting for the development of one or more of the chronic complications of diabetes on the basis of a single aspect of disturbed glucose metabolism resulting from insulin deficiency and/or hyperglycemia has been sought by clinical and basic scientists for decades. A growing body of loosely related but internally consistent scientific data obtained from cultured cells, incubated tissue preparations, animal models, and man implicate sorbitol- and glucose-induced myo-inositol depletion and altered phosphoinositide metabolism in a series of secondary biochemical, functional, and architectural abnormalities in the PNS in diabetes. These early metabolically based functional and structural changes simulate those that characterize human diabetic neuropathy. Can abnormal phosphoinositide metabolism in diabetic nerve thereby by itself explain the development of chronic diabetic neuropathy with all of its clinical complexity and heterogeneity? Almost certainly not. Even if the entire contribution of hyperglycemia to the development of diabetic neuropathy were mediated by secondary abnormalities in phosphoinositide metabolism, other factors must also play a role. Witness the differences in the histopathological picture of neuropathy in patients with IDDM and NIDDM despite similar durations and severity of diabetes, the apparent influence of age and gender on the appearance of early neuropathy in patients with IDDM, and the association of alcohol consumption with diabetic neuropathy. While early metabolic and functional disturbances in diabetic nerve such as impaired (Na,K)-ATPase function and paranodal swelling are empirically attributable to abnormal myo-inositol and phosphoinositide metabolism, more advanced abnormalities such as axo-glial dysjunction may reflect superimposed independent biochemical and/or hormonal defects (although, as mentioned previously, aldose reductase inhibition decreases axo-glial dysjunction in diabetic humans). The PNS has only a limited repertoire of responses to a variety of insults, so that Wallerian degeneration, axonal atrophy, impaired axonal transport, and dystrophic changes in diabetic neuropathy may represent multiple factors. On the other hand, the increasingly recognized importance of the phosphoinositide cascade in neuromodulation may attribute a progressively wider range of disturbances in the diabetic PNS to myo-inositol depletion and associated defects in phosphoinositide metabolism. Thus, while all effects of aldose reductase inhibitors in the PNS of diabetic rats have been reproduced by myo-inositol supplementation when this alternative intervention has been tested, the exact role of phosphoinositide metabolism in most of these responses is not well understood.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pathogenesis of diabetic neuropathy: role of altered phosphoinositide metabolism. 256 4

Because onset of autonomic neural dysfunction in the diabetic syndrome has not been well established, sensitive and quantitative measures of autonomic nervous system (ANS) function were made in 19 non-insulin-dependent (NIDD) and 14 insulin-dependent (IDD) recent-onset diabetic subjects. The known duration of diabetes mellitus in the NIDD subjects was less than or equal to 12 mo. The duration in the IDD subjects was less than or equal to 24 mo. RR-variation during beta adrenergic blockade (an index of an ANS reflex involving the cardiac parasympathetic nervous system [PNS] pathway) was smaller than that of control subjects in both NIDD (P less than 0.001) and IDD subjects (P less than 0.01). This PNS abnormality was not likely to be due to volume depletion since acute volume depletion induced by furosemide in six normal subjects (1608 +/- 105 ml, mean +/- SEM) did not change RR-variation. Dark-adapted pupil size after topical PNS blockade (an index of iris sympathetic nervous system [SNS] activity) was also smaller in both groups of diabetic subjects (NIDD, P less than 0.01; IDD, P less than 0.05). Pupillary latency time (an index of an ANS reflex involving iris PNS pathway) was prolonged in the NIDD subjects (P less than 0.005) but was not significantly altered in the IDD subjects. Thus, it would appear that the ANS is impaired soon after the diagnosis of diabetes mellitus. We hypothesize that early impairment of the ANS is common in IDD and NIDD subjects. This finding is consistent with the hypothesis that abnormal carbohydrate metabolism is an important factor in the etiology of diabetic autonomic neuropathy.
Diabetes Care
PMID:Autonomic neural dysfunction in recently diagnosed diabetic subjects. 649 37

The amount of nonenzymatic glycosylation present in normal and diabetic rat peripheral nerve myelin, whole brain, brain myelin, and individual myelin protein components was determined using NaB3H4 reduction followed by either boronic acid affinity chromatography or SDS-polyacrylamide gel electrophoresis (SDS-PAGE). Diabetic peripheral nerve myelin (PNS-M) showed a 5.2-fold increase over normal, indicating that myelin is the major peripheral nerve component undergoing excessive glycosylation in diabetes. SDS-PAGE of diabetic and normal PNS-M showed no differences in the pattern of protein bands or in the distribution of glycosylated adducts. However, in the diabetic, the amount of incorporated radioactivity was 3.74 times greater in the P0 protein and 2.8 times greater in the high-molecular-weight material that did not enter the gel. In whole brain, a 2.4-fold increase in the amount of nonenzymatic glycosylation was observed when diabetic was compared with normal, while diabetic brain myelin (CNS-M) was 3.8 times more glycosylated than normal brain myelin. SDS-PAGE of diabetic and normal CNS-M, like that of PNS-M, showed no differences in the pattern of protein bands or in the distribution of glycosylated adducts. The amount of incorporated radioactivity, however, was 3.18 times greater in the proteolipid region, 2.37 times greater for basic myelin protein, and 2.9 times greater for the high-molecular-weight proteins that did not enter the gel. This excessive nonenzymatic glycosylation of the main peripheral and central nervous system myelin components may contribute to the functional abnormalities of myelinated neurons associated with diabetes.
Diabetes 1983 Jul
PMID:Excessive nonenzymatic glycosylation of peripheral and central nervous system myelin components in diabetic rats. 686 12

The use of quantitative measurements of pupil size as an index of autonomic nervous system (ANS) activity in normal and diabetic subjects is described. The dual innervation of the iris by the parasympathetic (PNS) and sympathetic (SNS) nervous system was demonstrated by measurement of steady-state pupil size before and after changes in ANS activity by pharmacologic agents. In the presence of total PNS blockade, dark-adapted pupil size was a reliable index of SNS activity to the iris. Latency time (time from light stimulation to initial pupil response) appeared to be a good index of PNS activity. However, increased SNS activity may also prolong the latency time. Thus, consideration of SNS activity is necessary when evaluating the latency time. In 25 diabetic subjects, there was evidence of impaired SNS activity (smaller dark-adapted pupil size during total PNS blockade) and PNS activity (prolonged latency time). In a subgroup of diabetic subjects without clinical manifestations of autonomic neuropathy and normal subjects, both dark-adapted pupil size during PNS blockade (SNS index) and latency time (PNS index) were abnormal. The coefficient of variation for these two indices was less than 5% in glycemic stable diabetic subjects. Thus, these two indices are reliable and sensitive measures of the SNS and PNS activity to the iris in normal and diabetic subjects.
Diabetes Care
PMID:Quantitative evaluation of sympathetic and parasympathetic control of iris function. 718 36

Insulin-like growth factor-I (IGF-I) is a pleiotropic protein that acts on many tissues and organs. As it is one of the major trophic factors in the circulation, its actions in peripheral tissues are well established. It has been used for the treatment of several diseases, including growth deficiency, osteoporosis, catabolic disorders and diabetes. Recent evidence supports the significance of IGF-I in the maintenance of the integrity and homeostasis of the nervous system. The widespread distribution of its receptor allows IGF-I to affect the survival of numerous populations of neurones and glial cells in both the CNS and the PNS. Most recently, a clinical trial has revealed the beneficial effects of IGF-I in amyotrophic lateral-sclerosis (ALS), a degenerative disease of the motoneurones. We review briefly here experimental and clinical information that suggests the potential usefulness of IGF-I in the treatment of certain neurodegenerative diseases, including ALS, Alzheimer's disease, various neuropathies and brain trauma. The rather unique propensity of IGF-I to act on a variety of neuronal cells might provide a general means of reducing or slowing down neuronal losses that occur following various brain insults.
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PMID:Rediscovering an old friend, IGF-I: potential use in the treatment of neurodegenerative diseases. 924 19

Despite continuously improving diagnostic facilities, respiratory chain disorders (RCDs) are easily overlooked or misdiagnosed. We thus studied phenotype variability and the diagnostic potential of clinical and laboratory investigations in patients with RCD. We retrospectively evaluated clinical and laboratory investigations in 130 patients with RCD: 63 women and 67 men, aged 17-87 years, diagnosed between January 1992 and December 1999. mtDNA mutations were found in 20 patients; a respiratory chain defect but no mutation in 4; an abnormal lactate stress test but no mutation or biochemical defect in 66; and ragged-red fibres or reduced oxidative enzyme staining but no mutation, biochemical defect or abnormal lactate stress test in 40 patients. The most frequent initial manifestation of RCD were limb weakness, muscle pain and sensory disturbances. The most frequent clinical findings at diagnosis were muscle pain, fatiguability, limb weakness, reduced tendon reflexes and muscle wasting, irrespective of the diagnostic evidence. Mean age at onset, disease duration and time until diagnosis were 39, 14 and 13 years, respectively, without sex differences. The family history was positive in 29% of the patients. Hyperlipidaemia was found in 45%, hyper-CK-aemia in 42%, short stature in 33%, thyroid dysfunction in 17%, diabetes in 12%, and epilepsy in 8% of the patients. Laboratory investigations that prove useful to support the diagnosis of RCD are muscle biopsy, electromyography, lactate stress testing, echocardiography and mtDNA analysis. Systems most often involved in RCDs were the PNS, CNS, endocrine system and heart. The diagnosis of RCD requires awareness of the great phenotypic heterogeneity and an individualized, integral, multidisciplinary approach.
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PMID:Phenotype variability in 130 adult patients with respiratory chain disorders. 1175 84

Cholecystokinin-8 (CCK-8), the small peptide initially described as a gastric factor involved in the regulation of feeding behavior, is today recognized as one of the most abundant neurotransmitters/ neuropeptides in brain and is an important signal factor for the peripheral and central nervous systems. In the past twenty years, many studies have focused on possible clinical applications of this peptide and its receptor ligands in psychiatric diseases and gastrointestinal pathologies. Recently it has been suggested that CCK-8 may also have a neuroprotective role, thus opening a new field of interest around the physiology and the pharmacology of this neuropeptide and its receptors. It has been demonstrated that CCK-8 counteracts neuronal deficit following chemical or surgical lesions in both the central and peripheral nervous systems and that Nerve Growth factor (NGF) is involved in the CCK-induced recovery process. By using selective CCK receptor antagonists it has been demonstrated that CCK-8, when injected intraperitoneally, has the ability to stimulate NGF synthesis in brain and peripheral organs by a mechanism that involves the activation of CCK receptors. As has been widely reported, NGF is an essential survival and differentiative factor for selective neuronal populations of the PNS and CNS and plays a role in the events of degeneration and repair of the nervous system in diseases with different etiologies, e.g. neurodegenerative and autoimmune diseases as well as diabetes-associated pathologies. The possibility of using NGF in therapy has been evaluated and systemic and intracerebral NGF treatment have been tested in patients and animal models. Although the results of these studies are encouraging, the difficulty to predict and/or eliminate the side effects of NGF/NGF antibody treatment has made it difficult to fully evaluate the potential of the beneficial effects. In this context recent results obtained in our laboratories may offer a new prospective for the pharmacological approaches to the diseases associated with altered NGF production and functions. The data of our recent observations on NGF and CCK-8 is covered in this review.
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PMID:Cholecystokinin-8 and nerve growth factor: two endogenous molecules working for the upkeep and repair of the nervous system. 1276 2

The World Health Organization (WHO) predicts there will be 300 million people world-wide with diabetes mellitus by 2025. Currently it is estimated that there are 20 and 60 million people suffering from diabetes mellitus in North America and Europe, respectively. Within this huge population of diabetic persons approximately 50% will develop some form of sensory polyneuropathy, which involves the dying back of distal axons and a failure of axons to regenerate. This leads to incapacitating pain, sensory loss and poor wound healing. The end result is lower extremity amputation with approximately 90,000 diabetes-related amputations occurring each year in North America and the expectation of a 5-fold increase over the next 10 years due to increased incidence of type 2 diabetes. Abnormal neuronal Ca(2+) homeostasis and impaired mitochondrial function have been implicated in numerous CNS and PNS diseases including diabetic sensory neuropathy. The endoplasmic reticulum (ER), in part, regulates cellular Ca(2+) homeostasis and this process is linked to regulation of mitochondrial function and activity of anti-apoptotic signal transduction pathways. Here we review the current state of research regarding role of Ca(2+) dyshomeostasis and mitochondrial physiology in neuronal dysfunction in diabetes. The central impact of diabetes-induced alteration of Ca(2+) handling on sensory neurone function is discussed and related to abnormal ER performance. New results are presented showing suboptimal Ca(2+) concentration in the ER lumen in association with reduced SERCA2 expression in sensory neurones from type 1 diabetic rats. We hypothesize that deficits in neurotrophic factor support, specifically linked to diabetes-induced lowered expression of insulin and neurotrophin-3, triggers alterations of sensory neurone phenotype that are critical for the development of abnormal Ca(2+) homeostasis and associated mitochondrial dysfunction. The role of hyperglycaemia in diabetes is also discussed and we propose that high glucose concentration may impact at other sites to contribute to the heterogeneous aetiology of nerve damage in diabetes.
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PMID:Mitochondrial malfunction and Ca2+ dyshomeostasis drive neuronal pathology in diabetes. 1819 Nov 98

l-Glutamate is one of the major excitatory neurotransmitters in the mammalian central nervous system, but recently it has been shown to have a role also in the transduction of sensory input at the periphery, and in particular in the nociceptive pathway. An excess of glutamate is implicated in cases of peripheral neuropathies as well. Conventional therapeutic approaches for treating these diseases have focused on blocking glutamate receptors with small molecules or on reducing its synthesis of the receptors through the inhibition of glutamate carboxypeptidase II (GCPII), the enzyme that generates glutamate. In vivo studies have demonstrated that the pharmacological inhibition of GCPII can either prevent or treat the peripheral nerve changes in both BB/Wor and chemically induced diabetes in rats. In this study, we characterized the expression and distribution of glutamate transporters GLT1, GLAST, EAAC1 and of the enzyme GCPII in the peripheral nervous system of female Wistar rats. Immunoblotting results demonstrated that all glutamate transporters and GCPII are present in dorsal root ganglia (DRG) and the sciatic nerve. Immunofluorescence localization studies revealed that both DRG and sciatic nerves were immunopositive for all glutamate transporters and for GCPII. In DRG, satellite cells were positive for GLT1 and GCPII, whereas sensory neurons were positive for EAAC1. GLAST was localized in both neurons and satellite cells. In the sciatic nerve, GLT1 and GCPII were expressed in the cytoplasm of Schwann cells, whereas GLAST and EAAC1 stained the myelin layer. Our results give for the first time a complete characterization of the glutamate transporter system in the peripheral nervous system. Therefore, they are important both for understanding glutamatergic signalling in the PNS and for establishing new strategies to treat peripheral neuropathies.
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PMID:Expression and distribution of 'high affinity' glutamate transporters GLT1, GLAST, EAAC1 and of GCPII in the rat peripheral nervous system. 1901 61


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