Mechanisms of diabetic neuropathy: axon dysfunction.

Diabetic neuropathy is the most common complication of diabetes. It shows a progressive development with sensory loss, pain and autonomic dysfunction as common symptoms. Pathologically it is characterized by a series of interrelated metabolic abnormalities with insulin deficiency and hyperglycemia as the initiating culprits.

The identification of gene expression profiles associated with progression of human diabetic neuropathy.

Diabetic neuropathy is a common complication of diabetes. While multiple pathways are implicated in the pathophysiology of diabetic neuropathy, there are no specific treatments and no means to predict diabetic neuropathy onset or progression. Here, we identify gene expression signatures related to diabetic neuropathy and develop computational classification models of diabetic neuropathy progression.

Encephalopathies: the emerging diabetic complications.

Diabetic encephalopathies are now accepted complications of diabetes. They appear to differ in type 1 and type 2 diabetes as to underlying mechanisms and the nature of resulting cognitive deficits. The increased incidence of Alzheimer's disease in type 2 diabetes is associated with insulin resistance, hyperinsulinemia and hyperglycemia, and commonly accompanying attributes such as hypercholesterolemia, hypertension and obesity.

Insulin and IGF-1 receptors, nitrotyrosin and cerebral neuronal deficits in two young patients with diabetic ketoacidosis and fatal brain edema.

Gray and white matter structural deficits may accompany type 1 diabetes. Earlier experimental studies have demonstrated neuronal deficits associated with impaired neurotrophic support, inflammation and oxidative stress. In this study we demonstrate in two patients with histories of poorly controlled type 1 diabetes and fatal brain edema of ketoacidosis neuronal deficits associated with a decreased presence of insulin and IGF-1 receptors and accumulation of nitrotyrosin in neurons of affected areas and the choroid plexus.

A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition.

We have studied a family with severe mental retardation characterized by the virtual absence of speech, autism spectrum disorder, epilepsy, late-onset ataxia, weakness and dystonia. Post-mortem examination of two males revealed widespread neuronal loss, with the most striking finding being neuronal and glial tau deposition in a pattern reminiscent of corticobasal degeneration. Electron microscopic examination of isolated tau filaments demonstrated paired helical filaments and ribbon-like structures.

Sequential abnormalities in type 1 diabetic encephalopathy and the effects of C-Peptide.

Diabetic encephalopathy is a recently recognized complication in type 1 diabetes. In this review, we summarize a series of experimental results obtained longitudinally in the spontaneously type 1 diabetic BB/Wor-rat, and bringing out the beneficial effects of C-peptide replacement. It is increasingly clear that lack of insulin and C-peptide, and perturbations of their signaling cascades in type 1 diabetes are detrimental to the regulation of neurotrophic factors and their receptors.

The beneficial effects of C-Peptide on diabetic polyneuropathy.

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.

Dynamic changes of neuroskeletal proteins in DRGs underlie impaired axonal maturation and progressive axonal degeneration in type 1 diabetes.

We investigated mechanisms underlying progressive axonal dysfunction and structural deficits in type 1 BB/Wor-rats from 1 week to 10 month diabetes duration. Motor and sensory conduction velocities were decreased after 4 and 6 weeks of diabetes and declined further over the remaining 9 months. Myelinated sural nerve fibers showed progressive deficits in fiber numbers and sizes.

Zinc-activated C-peptide resistance to the type 2 diabetic erythrocyte is associated with hyperglycemia-induced phosphatidylserine externalization and reversed by metformin.

Insulin resistance can broadly be defined as the diminished ability of cells to respond to the action of insulin in transporting glucose from the bloodstream into cells and tissues. Here, we report that erythrocytes (ERYs) obtained from type 2 diabetic rats display an apparent resistance to Zn(2+)-activated C-peptide. Thus, the aims of this study were to demonstrate that Zn(2+)-activated C-peptide exerts potentially beneficial effects on healthy ERYs and that these same effects on type 2 diabetic ERYs are enhanced in the presence of metformin.

Neuronal loss in Pelizaeus-Merzbacher disease differs in various mutations of the proteolipid protein 1.

Mutations affecting proteolipid protein 1 (PLP1), the major protein in central nervous system myelin, cause the X-linked leukodystrophy Pelizaeus-Merzbacher disease (PMD). We describe the neuropathologic findings in a series of eight male PMD subjects with confirmed PLP1 mutations, including duplications, complete gene deletion, missense and exon-skipping. While PLP1 mutations have effects on oligodendrocytes that result in mutation-specific degrees of dysmyelination, our findings indicate that there are also unexpected effects in the central nervous system resulting in neuronal loss.

Inflammation in Diabetic Encephalopathy is Prevented by C-Peptide.

Encephalopathy is an increasingly recognized complication of type 1 diabetes. The underlying mechanisms are not well understood, although insulin deficiency has been implicated. The spontaneously diabetic BB/Wor-rat develops neuro-behavioral deficits and neuronal cell death in hippocampus and frontal cortex, which can be prevented by insulinomimetic C-peptide.

Receptor for advanced glycation end products and neuronal deficit in the fatal brain edema of diabetic ketoacidosis.

Radiologic and neuropsychologic studies suggest that diabetes mellitus causes structural changes in the brain and adversely effects cognitive development. Experimental animal models of type 1 diabetes mellitus (T1DM) have advanced these findings by demonstrating duration-related neuronal and cognitive deficits in T1DM BB/Wor rats. We studied the expression of receptor for advanced glycation end products (RAGE) and neuronal densities in the brains of two patients who died as the result of clinical brain edema(BE)that developed during the treatment of severe diabetic ketoacidosis (DKA).

The heterogeneity of diabetic neuropathy.

Diabetic neuropathy and its underlying pathogenesis are reviewed. It has been documented for some time that diabetic neuropathy differs in both human and experimental type 1 versus type 2 diabetes. Such differences are accounted for by impaired insulin action and signal transduction in type 1 diabetes, whereas hyperglycemia per se contributes equally to neuropathy in the two types of diabetes.

The effects of C-peptide on type 1 diabetic polyneuropathies and encephalopathy in the BB/Wor-rat.

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.

Is C-peptide replacement the missing link for successful treatment of neurological complications in type 1 diabetes?

In this review we will describe the interaction between insulin and C-peptide which enhances and attenuates insulin-signaling functions. We will describe how replenishment of C-peptide prevents and reverses the early metabolic abnormalities in type 1 diabetic polyneuropathy, such as Na(+)/K(+)-ATPase activity and endoneurial vascular NO release, resulting in prevention and reversal of early nerve dysfunction. The effects on expression of neurotrophic factors and their receptors, mediated by corrections of early gene responses and transcription factors, have downstream beneficial effects on cytoskeletal protein mRNAs and protein expression.

Acetyl-L-carnitine in diabetic polyneuropathy: experimental and clinical data.

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.

SREBP-1c expression in Schwann cells is affected by diabetes and nutritional status.

Our previous work demonstrated that the sterol response element binding proteins (SREBP)-1 and SREBP-2, which are the key regulators of storage lipid and cholesterol metabolism respectively, are highly expressed in Schwann cells of adult peripheral nerves. In order to evaluate the role of Schwann cell SREBPs in myelination and functioning of peripheral nerves we have determined their expression during development, after fasting and refeeding, and in a rodent model of diabetes. Our results show that SREBP-1c and SREBP-2, unlike SREBP-1a, are the major forms of SREBPs present in peripheral nerves.

Diabetes and Alzheimer's disease - is there a connection?

It has been known for some time that diabetes may be associated with impaired cognitive function. During the last decade, epidemiological data have emerged suggesting a linkage between diabetes, particularly type 2 diabetes, and Alzheimer's disease (AD). There is evidence to suggest that impaired activities of neurotrophic factors such as insulin, IGF-1 and NGF, which occur in both diabetes and AD, may provide a mechanistic link between the two disorders.

Alzheimer-like changes in rat models of spontaneous diabetes.

Objective: To examine whether changes characteristic of Alzheimer's disease occur in two rat models with spontaneous onset of type 1 and type 2 diabetes.

Research Design And Methods: The frontal cortices of 8-month-diabetic rats were examined with respect to neuronal densities, neurite degeneration, expression, and/or immunolocalization of amyloid precursor protein (APP), beta-secretase, beta-amyloid, COOH-terminal fragment (CTF), insulin receptor, IGF-1 receptor, glycogen synthase kinase 3-beta (GSK-3beta), protein kinase B (Akt), phosphorylated tau (phospho-tau), synaptophysin, and phosphorylated neurofilaments (SMI-31).

Results: Neuronal loss occurred in both models, significantly more so in type 2 diabetic BBZDR/Wor rats compared with type 1 diabetic BB/Wor rats and was associated with a ninefold increase of dystrophic neurites.

Diabetic neuropathy differs in type 1 and type 2 diabetes.

In this article we describe differences in early metabolic abnormalities between type 1 and type 2 diabetic polyneuropathy (DPN), and how these differences lead to milder initial functional defects in type 2 diabetes, despite the same hyperglycemic exposures. This early reversible metabolic phase is progressively overshadowed by structural degenerative changes eventually resulting in nerve fiber loss. In comparison, the late structural phase of DPN affects type 1 diabetes more severely.