Gerald Charnogursky, ... Norma Lopez, in Handbook of Clinical Neurology, 2014
Diabetic neuropathy occurs when there is an imbalance between nerve fiber damage and repair. The nerve damaging process preferentially affects autonomic and distal sensory fibers, leading to the progressive loss of sensation. Besides metabolic factors listed above, ischemic factors and inflammation also contribute to the development of diabetic neuropathies. Metabolic factors seem to prevail in length-dependent diabetic polyneuropathy, whereas inflammation superimposed on ischemic nerve lesions is found in severe forms of focal neuropathies. The thickening and hyalinization of the walls of small blood vessels due to the reduplication of the basal lamina around endothelial cells suggests a role for nerve ischemia in diabetic neuropathy. There is also a reduction in endoneurial oxygen tension in the sural nerves of diabetic patients with advanced polyneuropathy (Newrick, 1986).
Possible mechanisms for neuropathy development include oxidative stress, nonenzymatic glycation, the polyol pathway, the hexosamine pathway, protein kinase C pathway, poly (ADP-ribose) polymerase and the reduction of neurotrophic factors (Table 51.1). These various pathogenetic factors may act synergistically to cause DPN
Table 51.1. Pathogenetic mechanisms of neuropathy
|Oxidative stress with nitric oxide depletion|
|Advanced glycosylated end products|
|Activation of the polyol pathway|
|Activation of the hexosamine pathway|
|Excessive protein kinase C activity|
|Activation of poly(ADP-ribose) polymerase|
|Diminished neurotrophic peptide factors|
Elevated glucoses can increase oxidative stress by glucose auto-oxidation and production of advanced glycosylation end products and activation of the polyol pathway. Oxidative stress can also lead to activation of cytokoines, vascular adhesion molecules, endothelium-1 and procoagulant tissue factor . Oxidative stress also reduces endothelial production of nitric oxide which leads to impairment of endothelial function and reduced capillary vasodilation. This ultimately contributes to nerve hypoxia.
The AGE pathway
Advanced glycosylation end products (AGEs) from chronic hyperglycemia play an important role in diabetic neuropathy and microvascular complications (Thornalley, 2002; Sugimoto et al., 2008). Excess glucose combines with amino acids on circulating or tissue proteins to form AGEs. AGEs do not resolve when hyperglycemia is corrected. These AGE peptides cross-link strongly with collagen in vitro, damaging nerve fibers. AGEs also bind to and activate the cell surface receptor called RAGE(Receptor for Advanced Glycation Endproducts). RAGE proteins are proinflammatory and expressed on endothelial cells, fibroblasts, mesangial cells, and macrophages. Endothelial cells with RAGE internalize AGEs into subepithelium enhancing permeability and endothelium-dependent coagulant activity which can contribute to vascular injury and endoneural hypoxia (Singh et al., 2001).
The polyol pathway
Excess glucose is shunted into the polyol pathway and converted to sorbitol by aldose reductase and then to fructose by sorbitol dehydrogenase. Increased activity of this metabolic pathway depletes the nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) needed to regenerate the antioxidant glutathione. Without adequate glutathione, nerves are less able to scavenge reactive oxygen species, thus promoting oxidative stress in the nerve. The excess fructose and sorbitol also decrease expression of the sodium/myoinositol cotransporter, leading to a reduction in cellular uptake of myoinositol. Decreased levels of intracellular myoinositol subsequently lower the levels of its metabolite phosphoinositide. Consequently, the phosphoinositide signaling pathway is impaired, interfering with activation of the transmembrane sodium pump and decreasing nerve sodium/potassium ATPase activity. This results in slowed nerve conduction and with chronic exposure neuronal membrane breakdown ensues.
The hexosamine pathway
The glycolytic intermediates of excess glucose are also shunted into the hexosamine pathway. Fructose-6-phosphate is converted to N-acetylglucosamine-6-phosphate by glutamine: fructose-6-phosphate amidotransferase (GFAT). N-Acetylglucosamine-6-phosphate is then converted to N-acetylglucosamine-1,6-phosphate and to uridine diphosphate-N-acetyl glucosamine (UD-PGlcNAc). UD-PGlcNAc modifies gene expression and protein production essential for normal cell function. Many of the proteins produced in this pathway are inflammatory intermediates that promote neuropathy and include plasminogen-activator inhibitor, which inhibits normal blood clotting and increases vascular complications (Brownlee, 2001).
Protein kinase C (PKC) pathway and poly (ADP-ribose) polymerase (PARP)
Protein kinase C (PKC) is involved in controlling the function of proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC is responsible for the activation of essential proteins and lipids in cells that are needed for cell survival (Vincent et al., 2004). Nevertheless, excessive PKC can be harmful to the nervous system. Its contribution to diabetic neuropathy is likely through effects on vascular blood flow and microvascular disease rather than directly on neuronal cells. Glucose is converted to diacylglycerol which activates PKC. PKC then activates the mitogen-activated protein kinases (MAPK) which phosphorylate transcription of stress genes such as heat shock proteins and c-Jun kinases that can lead to cell apoptosis or vascular atherosclerosis ( the 1 last update 05 Jul 2020 Tomlinson, 1999Tomlinson, 1999). The inhibition of PKC reduces oxidative stress and normalizes blood flow and nerve conduction deficits in diabetic rats (Ishii et al., 1998; Cameron and cotter, 2002). Poly (ADP-ribose) polymerase (PARP) is activated in response to hyperglycemia. Overactivation of PARP results in increased free radical formation, enhanced protein kinase C activity, and AGE formation (diabetes and dizziness vomiting korean (🔥 juvenile) | diabetes and dizziness vomiting zero carbhow to diabetes and dizziness vomiting for Pacher et al., 2005). Each promotes nerve damage through the metabolic pathways described above.
diabetes and dizziness vomiting treatment home remedies (☑ epidemiology) | diabetes and dizziness vomiting and exercisehow to diabetes and dizziness vomiting for Neurotrophic factors and nerve repair
The neurotrophic factors comprise a group of endogenous proteins essential to the health and survival of certain populations of neurons. These neurotrophic peptides include nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, the insulin-like growth factors (IGF), and vascular endothelial growth factors. They are important for the maintenance of nerve structure and function as well as repair following injury. Impaired peripheral nerve repair in diabetes may be due to diabetes-induced loss of these peptides (Kennedy, 2000, 2005). Insulin also functions as a neurotrophic factor to peripheral neurons, and thus loss of insulin in diabetics may compromise nerve viability and repair. Intrathecal delivery of low-dose insulin has reversed the slowing of motor and sensory nerve conduction velocity. Insulin and IGF-1 have also been shown to reverse atrophy in myelinated sensory axons in the sural nerve (diabetes and dizziness vomiting urine test (🔴 symptoms in children) | diabetes and dizziness vomiting virushow to diabetes and dizziness vomiting for Brussee et al., 2004).