Diabetic peripheral neuropathy (DPN) is a highly prevalent microvascular complication of both type 1 and type 2 diabetes. As many as 30% of individuals with type 1 diabetes and 50% of patients with type 2 diabetes develop DPN after 25 and 10 years of disease, respectively. Type 1 diabetes often develops in younger ages of life. This means that when DPN occurs, the individuals with type 1 diabetes are still at a relatively young age. On the contrary, type 2 diabetes, with an even higher prevalence of DPN, mainly affects older people already having other risk factors and an age-related decline in nerve functions.
Despite advancements in glucose control, the treatment with new insulin analogues, the introduction of insulin pumps, or the extended use of glucose sensors, the risk of this diabetes complication is not significantly declining. DPN is still a leading cause of non-traumatic limb amputation and significantly increases cardiovascular and all-cause mortality. Based on previous studies, it is suggested that there is a cluster of factors, including long-term metabolic control, obesity, hypertension, dyslipidemia, and especially high triglyceride levels, which impact the onset and progression of neuropathy. Moreover, recent studies have highlighted that low-grade inflammation plays an important role in the pathogenesis of DPN by leading to a cascade of events, including altered function of chemokines and imbalances in atherosclerotic plaque stability and platelet function. Overall, there is a great need to better understand the pathogenesis of DPN and the underlying risk factors for manifest disease to develop new preventive and curative strategies for patients with diabetes.
This thesis aimed to examine the cumulative incidence and prevalence of diabetic neuropathy, the natural course of neurophysiological changes, and novel biomarkers associated with DPN among patients with childhood-onset type 1 diabetes longitudinally followed for 30 years. This study was an observational, longitudinal follow-up study, and the primary data were collected prospectively.
More specifically, we investigated the role of circulating inflammatory factors, chemokines, and metalloproteinases in the risk of developing DPN. We also examined the impact of longterm metabolic control on the prevalence of DPN over a 30-year follow-up period in this cohort.
In Paper I, we explored the occurrence of biomarkers of ongoing inflammatory processes, particularly chemokines, in DPN through a cross-sectional analysis. Chemokines are a subgroup of cytokines that regulate various immune system reactions. They contribute to increased inflammatory systematic response, leading to increased co-morbidity. Our main hypothesis was that patients with type 1 diabetes and concomitant DPN would exhibit increased circulating chemokines levels compared to control subjects and patients without DPN. The main result of this analysis was the detection of higher levels of the CXCL9 chemokine in patients with type 1 diabetes and DPN in comparison to healthy control subjects. Furthermore, CXCL8 and CXCL10 chemokines were correlated with impaired nerve function in all patients with diabetes.
In Paper II, we examined the association between markers for atherosclerotic plaque stability, inflammation, and platelet function and the prevalence of diabetic neuropathy and nephropathy. The main biomarkers analyzed were Matrix Metalloproteinase-9 (MMP-9) and its tissue inhibitor TIMP-1, soluble P-selectin (sP-selectin), and Neutrophil Gelatinaseassociated Lipocalin-2 (NGAL).
Our findings revealed that TIMP-1 and high-sensitive CRP levels were increased in patients with DPN compared to controls and patients without DPN. sP-selectin levels were elevated in the patients with DPN compared with healthy controls. TIMP-1, NGAL, and MMP-9 were associated with diabetic nephropathy and albuminuria. Our findings indicate that circulating biomarkers might be involved in microvascular complications.
In Paper III, we comprehensively examined the importance of long-term metabolic control for the progression of DPN in patients with type 1 diabetes followed for 30 years. In a longitudinal cohort study, 49 patients with type 1 diabetes diagnosed in childhood were investigated with nerve conduction tests. Weighted HbA1c (wHbA1c) and HbA1c variability were calculated after a diabetes duration of up to 30.6 (±5.2) years.
A high DPN prevalence of 51% was found using nerve conduction tests after a median diabetes duration of 30 years. Deterioration in the amplitudes of both sural and peroneal nerves was found. Moreover, in the repeated nerve conduction tests (NCS), amplitudes showed a gradual deterioration more consistently than velocities, suggesting that measurements of amplitudes are particularly useful in evaluating nerve conduction changes in DPN.
No patient developed neuropathy while preserving a weighted mean HbA1c of less than 62 mmol/mol (7.8%). Corresponding wHbA1c for avoiding nephropathy were wHbA1c < 68 mmol/mol (8.4 %) and for severe retinopathy < 56 mmol/mol (7.3%).
Risk factors in our study associated with DPN included long diabetes duration and impaired glycemic control with higher wHbA1c and significant variability of HbA1c over time, high triglyceride levels, and low HDL-cholesterol levels.
In summary, the findings of this thesis highlight the importance of maintaining stable glycemic control and treating traditional cardiovascular covariates such as dyslipidemia in order to reduce DPN. The results also indicate that patients with type 1 diabetes and concomitant diabetes neuropathy display higher levels of chemokines and metalloproteinases, supporting the hypothesis that atherosclerosis and low-grade inflammation may contribute to the pathogenesis of diabetic neuropathy.