Controversy to define the pathophysiology and treatment of human diabetic neuropathy.

Controversy to define the pathophysiology and treatment of human diabetic neuropathy.

Much data has been generated from animal models and cell culture, to provide a conceptual framework for the cause and treatment of diabetic neuropathy. However, limited translational in diabetic patients continues to generate debate and controversy over the cause(s) of human diabetic neuropathy. Changes in metabolic pathways so often demonstrated in animal models have only partially been verified in man.

Hyperglycemia

Epidemiological data lend support to the contention that the duration and severity of exposure to hyperglycemia is related to the severity of neuropathy in man. The development of neuropathy was related to hypoinsulinaemia  although  the  overall  severity  of  neuropathy was  related  to  poorer  glycemic  control.    This  suggests  that hyperglycaemia  may  not  necessarily  be  fundamental  to  the development  of  human  diabetic  neuropathy  but  may  play  a major  role  in  determining  progression  and  hence  severity  of nerve damage.

Vascular factors

There is a large body of data implicating vascular disease in the pathogenesis of diabetic neuropathy.  The most direct evidence that improving tissue blood flow may improve diabetic neuropathy  is  derived  from  large  vessel  revascularization  studies  which have  shown  improved nerve conduction velocity  in  some   but  not  all  studies.

Key messages

• The pathogenesis of human diabetic neuropathy is complex

• Much data exists in animal models and in cell culture

• Limited progress from preclinical to clinical studies

• There is no single effective treatment

In conclusion, our failure to develop an effective treatment for human diabetic neuropathy is based on: Ineffective translation of experimental studies to the diabetic patient.    Failure to take heed of the often-contradictory findings in the patient (lack of sorbitol accumulation in some human nerve biopsy  studies  –  ARI’s,  no  evidence  of  a  deficit  in  neurotrophins  or  expression  of  their  receptors  –  recombinant human  nerve  growth  factor)  before  embarking  on  clinical intervention trials.