Mechanisms of axonal dysfunction in diabetes mellitus
|Institution:||University of New South Wales|
|Keywords:||Neuropathy; Nerve Excitability; Diabetes; Type 1 diabetes; Continuous Subcutaneous Insulin Infusion; Quality of Life|
|Full text PDF:||http://handle.unsw.edu.au/1959.4/54290|
This thesis explores the pathophysiology of axonal dysfunction in diabetes, utilizing excitability techniques which provide information on axonal ion channel function in human subjects. The rationale was that excitability studies may be useful to determine the mechanisms underlying axonal dysfunction in diabetic peripheral neuropathy (DPN) and that it may serve as a biomarker of incipient neuropathy and possibly as a means of monitoring treatment efficacy. Excitability studies were initially undertaken in 54 patients with type 2 diabetes (T2DM), and demonstrated a relationship between neuropathy-specific-quality-of-life and excitability markers that reflect activity of persistent Na+ conductances. These changes occurred concurrently with progressive axonal depolarization with increasing neuropathy severity. Further studies were then undertaken to explore these mechanisms in type 1 diabetes (T1DM). Assessment of sensory and motor excitability in 30 patients suggested membrane depolarization in sensory and motor axons. Mathematical modelling demonstrated that these changes were due to reduced nodal Na+ and K+ conductances and abnormal Na+/K+pump activity. Having demonstrated prominent changes in axonal function in T1DM, studies were conducted to explore the basis for these changes. The possibility that different forms of insulin administration may have differing effects on axonal function was considered. Axonal function was assessed in two separate cohorts of T1DM patients: those treated with continuous subcutaneous insulin infusion (CSII) and a second cohort who received multiple daily insulin injections (MDII). The studies demonstrated abnormalities of axonal function in MDII-treated patients. In contrast, CSII-treated patients had normal axonal function. The final series of studies explored the effect of glycaemic variability on axonal function in T1DM. The relationship between glycaemic variability and axonal excitability was assessed in 12 T1DM patients, using a continuous glucose monitoring system. Patients were studied at three different glucose ranges and glycaemic variability was separately measured over a 48-hour period at the time of testing. The studies demonstrated that acute glucose level did not correlate with axonal dysfunction. However, glycaemic variability was strongly correlated with neurophysiological parameters, suggesting that it is an important determinant of axonal dysfunction in T1DM.