Diabetic neuropathy: a heterogeneous, dynamic, and progressive disorder.
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Acute Disease↗
Biomedical subjects
A A Sima
Publications and source records attributed to A A Sima.
C-peptide attenuates protein tyrosine phosphatase activity and enhances glycogen synthesis in L6 myoblasts.
Recent studies suggest that C-peptide might play a role in a broad range of biological activities. We have provided evidence that C-peptide stimulates glycogen synthesis in insulin-responsive rat skeletal muscle cells in a dose-related manner. To explore the mechanism by which C-peptide exerts this insulinomimetic effect, here we report the effect of C-peptide on protein tyrosine phosphatase (PTP) activity and phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1). C-peptide inhibited PTP activity in a dose-dependent manner. A reverse bell-shaped dose-response curve was shown with the maximum inhibition of PTP activity at a concentration of 3 nM of C-peptide, which is the same concentration achieving the maximum stimulatory effect on glycogen synthesis. In association with the PTP inhibition by C-peptide, autophosphorylation of the insulin receptor and activation of IRS-1 were enhanced. These results suggest that C-peptide signal transduction may crosstalk with the insulin signaling pathway at the level of the insulin receptor.
Animals↗
Alzheimer's disease versus dementia with Lewy bodies: cerebral metabolic distinction with autopsy confirmation.
Seeking antemortem markers to distinguish Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), we examined brain glucose metabolism of DLB and AD. Eleven DLB patients (7 Lewy body variant of AD [LBVAD] and 4 pure diffuse Lewy body disease [DLBD]) who had antemortem position emission tomography imaging and autopsy confirmation were compared to 10 autopsy-confirmed pure AD patients. In addition, 53 patients with clinically-diagnosed probable AD, 13 of whom later fulfilled clinical diagnoses of DLB, were examined. Autopsy-confirmed AD and DLB patients showed significant metabolic reductions involving parietotemporal association, posterior cingulate, and frontal association cortices. Only DLB patients showed significant metabolic reductions in the occipital cortex, particularly in the primary visual cortex (LBVAD -23% and DLBD -29% vs AD -8%), which distinguished DLB versus AD with 90% sensitivity and 80% specificity. Multivariate analysis revealed that occipital metabolic changes in DLB were independent from those in the adjacent parietotemporal cortices. Analysis of clinically diagnosed probable AD patients showed a significantly higher frequency of primary visual metabolic reduction among patients who fulfilled later dinical criteria for DLB. In these patients, occipital hypometabolism preceded some clinical features of DLB. Occipital hypometabolism is a potential antemortem marker to distinguish DLB versus AD.
Aged↗
C-peptide prevents and improves chronic Type I diabetic polyneuropathy in the BB/Wor rat.
AIMS/HYPOTHESIS: Insulin and C-peptide exert neuroprotective effects and are deficient in Type I (insulin-dependent) diabetes mellitus but not in Type II (non-insulin-dependent) diabetes mellitus. These studies were designed to test the preventive and interventional effects of C-peptide replacement on diabetic polyneuropathy in the Type I diabetic BB/Wor rat. METHODS: Diabetic BB/Wor rats were replaced with rat C-peptide from onset of diabetes and between 5 and 8 months of diabetes. They were examined at 2 and 8 months and compared to non-C-peptide replaced BB/Wor rats, Type II diabetic (non-C-peptide deficient) BB/Z rats and non-diabetic control rats. Animals were monitored as to hyperglycaemia and nerve conduction velocity (NCV). Acute changes such as neural Na+/K+-ATPase and paranodal swelling were examined at 2 months, morphometric and teased fiber analyses were done at 8 months. RESULTS: C-peptide replacement for 2 months in Type I diabetic rats prevented the acute NCV defect by 59% (p < 0.005), the neural Na+/K+-ATPase defect by 55% (p < 0.001) and acute paranodal swelling by 61% (p < 0.001). Eight months of C-peptide replacement prevented the chronic nerve conduction defect by 71% (p < 0.001) and totally prevented axoglial dysjunction (p < 0.001) and paranodal demyelination (p < 0.001). C-peptide treatment from 5 to 8 months showed a 13% (p < 0.05) improvement in NCV, a 33% (p < 0.05) improvement in axoglial dysjunction, normalization (p < 0.001) of paranodal demyelination, repair of axonal degeneration (p < 0.01), and a fourfold (p < 0.001) increase in nerve fibre regeneration. CONCLUSION/INTERPRETATION: C-peptide replacement of Type I BB/Wor-rats partially prevents acute and chronic metabolic, functional and structural changes that separate Type I diabetic polyneuropathy from its Type II counterpart suggesting that C-peptide deficiency plays a pathogenetic role in Type I diabetic polyneuropathy.
Animals↗
Molecular basis for the insulinomimetic effects of C-peptide.
AIMS/HYPOTHESIS: C-peptide, released by the beta-cells of pancreatic islets, elicits salutary responses in Type I (insulin-dependent) diabetes mellitus but the molecular mechanisms behind these effects are not known. We assessed whether synthetic rat C-peptide stimulates insulin-like cellular effects in a classic insulin target tissue. METHODS: To clarify the molecular mechanisms involved in several insulinomimetic actions, we investigated the effect of C-peptide on the insulin signalling pathway in rat skeletal muscle cells. We used L6 myoblasts and myocytes to measure the effects of C-peptide or insulin or both on glycogen synthesis and amino acid uptake. We also studied the effects of C-peptide on insulin receptor autophosphorylation, its tyrosine kinase activity, phosphorylation of IRS-1, PI 3-kinase, Akt, p90Rsk, MAPK, and GSK3 in these cells. RESULTS: In L6 cells, physiological concentrations of C-peptide (0.3-3 nmol/l) significantly activated insulin receptor tyrosine kinase, IRS-1 tyrosine phosphorylation, PI 3-kinase activity, MAPK phosphorylation, p90Rsk, and GSK3 phosphorylation. A scrambled C-peptide sequence - the control - showed no effects. Wortmannin blocked C-peptide-induced glycogen synthesis while pertussis toxin had no effect. Only submaximal insulin concentrations (up to 10 nmol/l) combined with submaximal C-peptide concentrations led to additive effects. CONCLUSION/INTERPRETATION: C-peptide added to the maximal insulin dose (100 nmol/l) did not increase the effect of insulin alone. We thus conclude that the same signalling elements are used by both ligands. However, the lack of Akt activation by C-peptide and the bell-shaped dose response induced by C-peptide indicate that C-peptide has some effects by another distinct mechanism. We speculate that C-peptide could modulate the metabolic effects of insulin by enhancing them at low hormone concentrations and dampening them at high hormone concentrations.
3T3 Cells↗
Ceruloplasmin immunoreactivity in neurodegenerative disorders.
Ceruloplasmin (CP) is a 132 kd cuproprotein which, together with transferrin, provides the majority of anti-oxidant capacity in serum. Increased iron deposition and lipid peroxidation in the basal ganglia of subjects with hereditary CP deficiency suggest that CP may serve as an anti-oxidant in the brain as well. The present study compared CP immunoreactivity in brain specimens from normal controls and subjects with neurodegenerative disorders (Alzheimer's disease [AD], Parkinson's disease [PD], progressive supranuclear palsy [PSP], and Huntington's disease [HD]) (n = 5 per group). The relative intensity of neuronal CP staining and the numbers of CP-stained neurons per 25x microscope field were determined in hippocampus (CA1, subiculum, and parahippocampal gyrus), parietal cortex, frontal cortex, substantia nigra, and caudate. CP was detected in both neurons and astrocytes in all specimens, and in senile plaques and occasional neurofibrillary tangles in AD brain. Neuronal CP staining intensity tended to increase in most AD brain regions, but was statistically significant vs controls only in the CA1 region of hippocampus (p = .016). Neuronal CP staining in brain specimens from other neurodegenerative disorders showed a slight but nonsignificant increase vs controls. The numbers of CP-stained neurons per field did not differ between the various neurodegenerative disorders and controls. These results suggest that a modest increase in neuronal CP content is present in the AD brain, and lesser elevations in neuronal CP occur in the other neurodegenerative disorders in this study. Though CP functions as both an acute phase protein and an anti-oxidant in peripheral tissues, whether it does so in the brain remains to be determined.
Aged↗
Altered immediate early gene expression in injured diabetic nerve: implications in regeneration.
To study the role that immediate early gene responses may play in impaired nerve fiber regeneration in diabetes, diabetic male BB/Wor rats were subjected to sciatic nerve crush at 6 wk of diabetes. Sciatic nerve mRNA expression of IGF-I, IGF-1-receptor, NGF, and p75 (low affinity NGF receptor), as well as protein expression of C-FOS, were examined at various time points following crush injury and compared with age- and sex-matched nondiabetic BB/Wor rats. Diabetic rats showed a delay in the early peak expression of IGF-1, C-FOS, NGF, and p75. The earliest immediate gene responses were those of IGF-I and IGF-1-receptor, which peaked at 0.5 h post-crush in control rats. In diabetic rats, IGF-1 peaked at 24 h whereas IGF-1-receptor mRNA revealed no early peak. The early NGF mRNA expression showed a maximum response at 6 h and of p75 at 4 days post-crush in control rats, whereas in diabetic rats they occurred at 2 days and 6 days, respectively. C-FOS protein expression showed a maximum at 6 h in control rats and in diabetic animals an attenuated peak was present at 2 days. These data provide the first evidence that immediate early gene responses are delayed in diabetes following sciatic nerve crush injury. The delayed IGF-1 expression may affect C-FOS induction and may be responsible for the delay in the NGF response in diabetic rats. The delayed immediate early gene responses precede the previously described perturbed macrophage recruitment and delayed Wallerian degeneration in this type I model and provide a possible explanation for impaired nerve regeneration in diabetes.
Animals↗
Impaired inhibitory G-protein function contributes to increased calcium currents in rats with diabetic neuropathy.
There is a growing body of evidence that sensory neuropathy in diabetes is associated with abnormal calcium signaling in dorsal root ganglion (DRG) neurons. Enhanced influx of calcium via multiple high-threshold calcium currents is present in sensory neurons of several models of diabetes mellitus, including the spontaneously diabetic BioBred/Worchester (BB/W) rat and the chemical streptozotocin (STZ)-induced rat. We believe that abnormal calcium signaling in diabetes has pathologic significance as elevation of calcium influx and cytosolic calcium release has been implicated in other neurodegenerative conditions characterized by neuronal dysfunction and death. Using electrophysiologic and pharmacologic techniques, the present study provides evidence that significant impairment of G-protein-coupled modulation of calcium channel function may underlie the enhanced calcium entry in diabetes. N- and P-type voltage-activated, high-threshold calcium channels in DRGs are coupled to mu opiate receptors via inhibitory G(o)-type G proteins. The responsiveness of this receptor coupled model was tested in dorsal root ganglion (DRG) neurons from spontaneously-diabetic BB/W rats, and streptozotocin-induced (STZ) diabetic rats. Intracellular dialysis with GTPgammaS decreased calcium current amplitude in diabetic BB/W DRG neurons compared with those of age-matched, nondiabetic controls, suggesting that inhibitory G-protein activity was diminished in diabetes, resulting in larger calcium currents. Facilitation of calcium current density (I(DCa)) by large-amplitude depolarizing prepulses (proposed to transiently inactivate G proteins), was significantly less effective in neurons from BB/W and STZ-induced diabetic DRGs. Facilitation was enhanced by intracellular dialysis with GTPgammaS, decreased by pertussis toxin, and abolished by GDPbetaS within 5 min. Direct measurement of GTPase activity using opiate-mediated GTPgamma[(35)S] binding, confirmed that G-protein activity was significantly diminished in STZ-induced diabetic neurons compared with age-matched nondiabetic controls. Diabetes did not alter the level of expression of mu opiate receptors and G-protein alpha subunits. These studies indicate that impaired regulation of calcium channels by G proteins is an important mechanism contributing to enhanced calcium influx in diabetes.
Analgesics, Opioid↗
Proinsulin C-peptide--a consensus statement.
In recent years the physiological role of the proinsulin C-peptide has received increasing attention, focusing on the potential therapeutic value of C-peptide replacement in preventing and ameliorating type 1 diabetic complications. In order to consolidate these new data and to identify the immediate directions of C-peptide research and its clinical usefulness, an International Symposium was held in Detroit, Michigan, on October 20-21, 2000, under the auspices of the Wayne State University/Morris Hood Jr. Comprehensive Diabetes Center. In this communication, we review the cellular, physiological and clinical effects of C-peptide replacement in animal models and in patients with type 1 diabetes. Finally, recommendations are presented as to the most urgent studies that should be pursued to further establish the biological action of C-peptide and its therapeutic value.
Apoptosis↗
Human C-peptide dose dependently prevents early neuropathy in the BB/Wor-rat.
In order to explore the neuroprotective and cross-species activities of C-peptide on type 1 diabetic neuropathy, spontaneously diabetic BB/W-rats were given increasing doses of human recombinant C-peptide (hrC-peptide). Diabetic rats received 10, 100, 500, or 1000 microg of hrC-peptide/kg body weight/day from onset of diabetes. After 2 months of hrC-peptide administration, 100 microg and greater doses completely prevented the nerve conduction defect, which was associated with a significant but incomplete prevention of neural Na+/K+-ATPase activity in diabetic rats with 500 microg or greater C-peptide replacement. Increasing doses of hrC-peptide showed increasing prevention of early structural abnormalities such as paranodal swelling and axonal degeneration and an increasing frequency of regenerating sural nerve fibers. We conclude that hrC-peptide exerts a dose dependent protection on type 1 diabetic neuropathy in rats and that this effect is probably mediated by the partially conserved sequence of the active C-terminal pentapeptide.
Animals↗
Has C-peptide come of age?
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Blood Glucose↗
Clinical characteristics of a family with chromosome 17-linked disinhibition-dementia-parkinsonism-amyotrophy complex. 1994.
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Chromosome Disorders↗
Adult-onset MLD: a gene mutation with isolated polyneuropathy.
A 22-year-old man presented with recurrent ulnar mononeuropathies and diffusely slow nerve conduction velocities. Arylsulfatase A (ASA) activity from leukocytes and fibroblasts was reduced, and urinary sulfatides were increased. Sural nerve biopsy revealed a reduction in myelinated fibers and Schwann cell inclusions. Results of studies of CNS integrity, including cranial MRI, evoked potentials, and neuropsychologic tests, were normal. Molecular genetic analyses revealed a novel homozygous missense mutation (Thr286Pro) in the ASA gene.
Adult↗
A comparison of diabetic polyneuropathy in type II diabetic BBZDR/Wor rats and in type I diabetic BB/Wor rats.
AIMS/HYPOTHESIS: To examine the functional, metabolic and structural abnormalities in peripheral nerve in the spontaneously Type II (non-insulin-dependent) diabetic BBZDR/Wor rat and compare these data with those in the Type I (insulin-dependent) diabetic BB/Wor rat. METHODS: Animals were examined at 6 and 14 months of diabetes. Nerve conduction velocity was measured longitudinally. Nerve polyols were analysed using gas liquid chromatography and Na/K(+)-ATPase activity was measured enzymatically. Light and electron microscopic techniques were used for nerve morphometry. RESULTS: Diabetic BBZDR/Wor rats showed a slowly progressive nerve conduction defect that reached 17% (p < 0.01) at 14 months. There was a decrease in Na+/K(+)-ATPase of 35% (p < 0.05). Structurally, there were mild myelinated fibre atrophy (p < 0.05), mild or absent changes of the node of Ranvier, but significant (p < 0.001) segmental demyelination and Wallerian degeneration. These findings point to a more severe nerve conduction defect, severe myelinated fibre atrophy and profound nodal changes in Type I spontaneously diabetic BB/Wor rats maintained at the same hyperglycaemic concentrations. CONCLUSION/INTERPRETATION: We conclude that other factors, beside hyperglycaemia, are involved in the pathogenesis of the more severe Type I diabetic neuropathy which possibly involve insulin and C-peptide deficiencies.
Animals↗
Sorbitol and myo-inositol levels and morphology of sural nerve in relation to peripheral nerve function and clinical neuropathy in men with diabetic, impaired, and normal glucose tolerance.
AIMS: Sorbitol and myo-inositol levels and morphology of sural nerve were compared with nerve function and clinical neuropathy in men with diabetic, impaired (IGT), and normal glucose tolerance. METHODS: After neurography of sural nerve and determinations of sensory thresholds for vibration, warm and cold on the foot, whole nerve sural nerve biopsy was performed in 10 men with Type 1 diabetes mellitus, 10 with IGT, and 10 with normal glucose tolerance. Polyol levels were assessed by gas-liquid chromatography/mass spectrometry. RESULTS: Sural nerve amplitudes were significantly lower and sorbitol levels significantly higher in diabetic patients (median (interquartile range)) (3.7 (3.5) microV and 643 (412) pmol/mg protein, respectively) both compared with IGT (11.3 (10.6)microV; P = 0.04 and 286 (83) pmol/mg protein; P = 0.0032, respectively) and normally glucose tolerant (10.0 (11.6); P = 0.0142 and 296 (250) pmol/mg protein; P = 0.0191, respectively) subjects. There were no differences in nerve morphology between the three groups. Nerve myo-inositol levels correlated, however, positively with cluster density (rs = 0.56; P = 0.0054). In diabetic and IGT subjects, sural nerve amplitudes (2.6 (3.8) vs. 12.1 (10.6) microV; P = 0.0246) and myelinated nerve fibre density (MNFD; 4,076 (1091) vs. 5,219 (668) nerve fibres/mm2; P = 0.0021) were significantly lower in nine subjects with clinical neuropathy than in 10 without. CONCLUSIONS: Nerve degeneration (i.e. MNFD) correlated with clinical neuropathy but not with glucose tolerance status whereas nerve myo-inositol levels positively correlated with signs of nerve regeneration (i.e. increased cluster density).
Diabetes Mellitus, Type 1↗
Does insulin play a role in cardiovascular autonomic regulation?
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Animals↗
Experimental diabetic neuropathy: an update.
Diabetic neuropathy consists of several clinical syndromes affecting motor, sensory and autonomic nerves. Of these the most common is distal symmetric sensory polyneuropathy usually referred to as diabetic neuropathy. Animal studies, mainly in diabetic rodents, have contributed tremendously to our understanding of this disease. From these it is clear that the pathogenesis of diabetic neuropathy is multifactorial involving sequentially occurring and often closely interrelated metabolic aberrations. Major pathogenetic mechanisms include increased activity of the polyol pathway, abnormalities in vasoactive substances, non-enzymatic glycation, increased presence of free radicals, and perturbed neurotrophism. Traditionally the neuropathies accompanying Type I (insulin-dependent) and Type II (non-insulin-dependent) diabetes mellitus have been regarded as identical. Recent investigations have, however, clearly delineated distinct differences in the functional and structural expressions of the neuropathies in the two types of diabetes. Major future challenges are the identification of the differences in underlying pathogenetic mechanisms in the two types of neuropathy and in gaining a better understanding of the hierarchy of the multifactorial mechanisms underlying the disease. This will be important for designing meaningful therapies which to date have failed miserably in diabetic neuropathy.
Animals↗
Neuropathology of chromosome-17-linked dementia.
We describe the characteristic neuropathologic changes in chromosome-17-linked dementia. Identified cases to date demonstrate a uniform pathology consisting of neuronal loss, gliosis and vacuolization of frontal, anterior cingulate and temporal cortex and occipital association areas. Similar changes are present in substantia nigra, ventral striatum and amygdala. Hippocampus itself is spared, whereas the afferent perforant tract is consistently affected. Characteristic neuronal inclusions consisting of lattice-like neurofilaments are present in subcortical nuclei and glial cytoplasmic tau-positive inclusions are present throughout the white matter. These pathologic changes appear to be unique for chromosome-17-linked dementia.
Chromosomes, Human, Pair 17↗