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Mechanism of diabetic neuropathy: Where are we now and where to go?

Yagihashi S, Mizukami H, Sugimoto K - J Diabetes Investig (2011)

Bottom Line: As a consequence of longstanding hyperglycemia, a downstream metabolic cascade leads to peripheral nerve injury through an increased flux of the polyol pathway, enhanced advanced glycation end-products formation, excessive release of cytokines, activation of protein kinase C and exaggerated oxidative stress, as well as other confounding factors.Extremely long axons originating in the small neuronal body are vulnerable on the most distal side as a result of malnutritional axonal support or environmental insults.Such dual influences exerted by long-term hyperglycemia are critical for peripheral nerve damage, resulting in distal-predominant nerve fiber degeneration.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pathology and Molecular Medicine.

ABSTRACT
Neuropathy is the most common complication of diabetes. As a consequence of longstanding hyperglycemia, a downstream metabolic cascade leads to peripheral nerve injury through an increased flux of the polyol pathway, enhanced advanced glycation end-products formation, excessive release of cytokines, activation of protein kinase C and exaggerated oxidative stress, as well as other confounding factors. Although these metabolic aberrations are deemed as the main stream for the pathogenesis of diabetic microvascular complications, organ-specific histological and biochemical characteristics constitute distinct mechanistic processes of neuropathy different from retinopathy or nephropathy. Extremely long axons originating in the small neuronal body are vulnerable on the most distal side as a result of malnutritional axonal support or environmental insults. Sparse vascular supply with impaired autoregulation is likely to cause hypoxic damage in the nerve. Such dual influences exerted by long-term hyperglycemia are critical for peripheral nerve damage, resulting in distal-predominant nerve fiber degeneration. More recently, cellular factors derived from the bone marrow also appear to have a strong impact on the development of peripheral nerve pathology. As evident from such complicated processes, inhibition of single metabolic factors might not be sufficient for the treatment of neuropathy, but a combination of several inhibitors might be a promising approach to overcome this serious disorder. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00070.x, 2010).

No MeSH data available.


Related in: MedlinePlus

 Pro‐inflammatory reactions and experimental diabetic neuropathy. In the sciatic nerve of STZ‐induced diabetic rats, there were many macrophages stained positive for ED1 (upper center). Migration of macrophages was inhibited when diabetic rats were treated with pioglitazone (upper right). Pioglitazone treatment also corrected the delay of motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV), and activation of extracellular signal‐regulated kinase (ERK), one of mitogen activated protein kinases (MAPK) (adapted from reference 134).
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f7:  Pro‐inflammatory reactions and experimental diabetic neuropathy. In the sciatic nerve of STZ‐induced diabetic rats, there were many macrophages stained positive for ED1 (upper center). Migration of macrophages was inhibited when diabetic rats were treated with pioglitazone (upper right). Pioglitazone treatment also corrected the delay of motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV), and activation of extracellular signal‐regulated kinase (ERK), one of mitogen activated protein kinases (MAPK) (adapted from reference 134).

Mentions: There is emerging evidence that nerve tissues in diabetes undergo a pro‐inflammatory process that presents symptoms and enhances the development of neuropathy129,130. Indeed, diabetic nerves contain macrophages, occasionally lymphocytes and release increased TNF‐α or interleukins (IL) in humans and animals129,131,132 (Figure 7). Inhibition of cytokine release or macrophage migration was associated with the improvement of NCV delay and structure in STZ‐diabetic rats treated with N‐acetylcysteine133 or pioglitazone134. The arachidonic acid pathway is activated to increase in cyclooxygenase (COX)‐2 concentrations in the peripheral nerves of STZ diabetic rats in which inhibition of COX‐2 corrected nerve blood flow and NCV delay135. To further confirm this data, COX‐2 gene‐deficient mice were protective for NCV delay and neuropathic deficits after STZ‐induced hyperglycemia136. The pro‐inflammatory condition activated the stress‐kinase, mitogen‐activated protein (MAP)‐kinase, in diabetic nerves, which was also suppressed by treatment with pioglitazone134. Thus, MAP‐kinase is considered to be a potential target for a new treatment of diabetic neuropathy137,138. In this process, NF‐κB is activated to lead the cell to cell death or proliferation139,140. Because a pro‐inflammatory reaction is induced by the polyol pathway hyperactivity or increased AGE formation as well, it should be clear to what extent the pro‐inflammatory process is a single initiating or influential factor for the development of neuropathy. Ischemia reperfusion might also accelerate the inflammatory processes to which diabetic nerves are susceptible77,78.


Mechanism of diabetic neuropathy: Where are we now and where to go?

Yagihashi S, Mizukami H, Sugimoto K - J Diabetes Investig (2011)

 Pro‐inflammatory reactions and experimental diabetic neuropathy. In the sciatic nerve of STZ‐induced diabetic rats, there were many macrophages stained positive for ED1 (upper center). Migration of macrophages was inhibited when diabetic rats were treated with pioglitazone (upper right). Pioglitazone treatment also corrected the delay of motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV), and activation of extracellular signal‐regulated kinase (ERK), one of mitogen activated protein kinases (MAPK) (adapted from reference 134).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4008011&req=5

f7:  Pro‐inflammatory reactions and experimental diabetic neuropathy. In the sciatic nerve of STZ‐induced diabetic rats, there were many macrophages stained positive for ED1 (upper center). Migration of macrophages was inhibited when diabetic rats were treated with pioglitazone (upper right). Pioglitazone treatment also corrected the delay of motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV), and activation of extracellular signal‐regulated kinase (ERK), one of mitogen activated protein kinases (MAPK) (adapted from reference 134).
Mentions: There is emerging evidence that nerve tissues in diabetes undergo a pro‐inflammatory process that presents symptoms and enhances the development of neuropathy129,130. Indeed, diabetic nerves contain macrophages, occasionally lymphocytes and release increased TNF‐α or interleukins (IL) in humans and animals129,131,132 (Figure 7). Inhibition of cytokine release or macrophage migration was associated with the improvement of NCV delay and structure in STZ‐diabetic rats treated with N‐acetylcysteine133 or pioglitazone134. The arachidonic acid pathway is activated to increase in cyclooxygenase (COX)‐2 concentrations in the peripheral nerves of STZ diabetic rats in which inhibition of COX‐2 corrected nerve blood flow and NCV delay135. To further confirm this data, COX‐2 gene‐deficient mice were protective for NCV delay and neuropathic deficits after STZ‐induced hyperglycemia136. The pro‐inflammatory condition activated the stress‐kinase, mitogen‐activated protein (MAP)‐kinase, in diabetic nerves, which was also suppressed by treatment with pioglitazone134. Thus, MAP‐kinase is considered to be a potential target for a new treatment of diabetic neuropathy137,138. In this process, NF‐κB is activated to lead the cell to cell death or proliferation139,140. Because a pro‐inflammatory reaction is induced by the polyol pathway hyperactivity or increased AGE formation as well, it should be clear to what extent the pro‐inflammatory process is a single initiating or influential factor for the development of neuropathy. Ischemia reperfusion might also accelerate the inflammatory processes to which diabetic nerves are susceptible77,78.

Bottom Line: As a consequence of longstanding hyperglycemia, a downstream metabolic cascade leads to peripheral nerve injury through an increased flux of the polyol pathway, enhanced advanced glycation end-products formation, excessive release of cytokines, activation of protein kinase C and exaggerated oxidative stress, as well as other confounding factors.Extremely long axons originating in the small neuronal body are vulnerable on the most distal side as a result of malnutritional axonal support or environmental insults.Such dual influences exerted by long-term hyperglycemia are critical for peripheral nerve damage, resulting in distal-predominant nerve fiber degeneration.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pathology and Molecular Medicine.

ABSTRACT
Neuropathy is the most common complication of diabetes. As a consequence of longstanding hyperglycemia, a downstream metabolic cascade leads to peripheral nerve injury through an increased flux of the polyol pathway, enhanced advanced glycation end-products formation, excessive release of cytokines, activation of protein kinase C and exaggerated oxidative stress, as well as other confounding factors. Although these metabolic aberrations are deemed as the main stream for the pathogenesis of diabetic microvascular complications, organ-specific histological and biochemical characteristics constitute distinct mechanistic processes of neuropathy different from retinopathy or nephropathy. Extremely long axons originating in the small neuronal body are vulnerable on the most distal side as a result of malnutritional axonal support or environmental insults. Sparse vascular supply with impaired autoregulation is likely to cause hypoxic damage in the nerve. Such dual influences exerted by long-term hyperglycemia are critical for peripheral nerve damage, resulting in distal-predominant nerve fiber degeneration. More recently, cellular factors derived from the bone marrow also appear to have a strong impact on the development of peripheral nerve pathology. As evident from such complicated processes, inhibition of single metabolic factors might not be sufficient for the treatment of neuropathy, but a combination of several inhibitors might be a promising approach to overcome this serious disorder. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00070.x, 2010).

No MeSH data available.


Related in: MedlinePlus