The effect of autoimmunity on the development time of microvascular complications in patients with type 1 diabetes mellitus

Background

Diabetes mellitus (DM) is a chronic progressive disease characterized by hyperglycemia with disturbances of carbohydrate, protein, and lipid metabolism. DM is the most common endocrine disorder, with an increasing prevalence all over the world [1]. According to data from the U.S. Centers for Disease Control and Prevention, the prevalence of type 1 DM is 0.017% in the United States and about 13 000 Americans are diagnosed with type 1 diabetes mellitus every year [2].

The onset of the disease occurs when the immune system attacks and destroys insulin-producing beta cells found in the pancreas. In this stage, antigen-induced T-lymphocytes and macrophages constantly attack the beta cells [3–6]. From the pathological standpoint, this autoimmune attack on pancreatic beta cells is a process called insulitis. The basic indicators of insulitis are circulating islet cell antibodies (ICA), insulin antibodies (IAA), protein tyrosine phosphatase antibodies (IA-2), and glutamic acid decarboxylase (GAD) antibodies. It is widely accepted that type 1 DM is associated with a genetically determined modification in immunity, which leads to the destruction of pancreatic beta cells.

Today, the number of elderly diabetic patients is increasing, mostly because of increased longevity of the diabetic population. Thus, the incidence of microvascular complications (neuropathy, retinopathy, and nephropathy) increases with the duration of diabetes, which calls for a solution effective in reducing the incidence of diabetic complications.

The purpose of this study was to determine to what extent the presence of autoimmunity can be used in predicting the development time of microvascular complications.

Material and Methods

STATISTICAL ANALYSIS:

Data was classified as sex, autoantibody existence, microvascular complication development, development time of microvascular complications, and HbA1C values. The data obtained during the study were compared by using Student’s t-test analysis, because there was no normal distribution. For all tests, we considered p<0.05 to be statistically significant.

Results

The study included 52 patients with type 1 DM who developed microvascular complications: 30 females (57.7%) and 22 males (42.3%). Comparison of mean values within each sex group revealed no statistically significant differences between males and females (p>0.05). The mean age of the patients was calculated as 33.94±8: 45.

At the diagnosis of diabetes, 20 patients (38.5% of the sample) tested negative for autoantibodies (anti-GAD and anti-ICA), while 32 (61.5%) of patients tested positive for anti-GAD and/or anti-ICA. Thirty-six patients (69.2%) had developed diabetic nephropathy and diabetic retinopathy, 11 patients (21.2%) had diabetic retinopathy, and 5 patients (9.6%) had diabetic neuropathy.

In autoantibody-negative patients, the mean HbA1C level was 7.7%, while antibody-positive patients had slightly higher HbA1c levels (7.9%), but this difference was not considered statistically significant (p>0.05).

Patients were compared in terms of autoantibody positivity and development time of microvascular complications. The mean time to onset of diabetes-related microvascular complications in patients with positive autoimmune markers was 11: 40±6.46 years. The mean time to development of microvascular complications in patients with negative autoimmunity was calculated as 10.91±6.70 years. When the results of both autoimmunity positive and negative groups were analyzed by Student’s t-test, no statistically significant difference between the 2 groups was found with respect to the time to development of microvascular complications (p>0.05) (Table 1).

Discussion

Patients with diabetes mellitus may develop chronic hyperglycemia and capillary membrane changes resulting from other metabolic disorders, as well as accelerated atherosclerosis and microvascular and macrovascular complications during the clinical follow-up period [8–14]. Today, the longer life expectancy of the diabetic population has significantly increased the incidence and prevalence of diabetes-related chronic complications. Therefore, identifying and addressing the risk factors associated with microvascular complications in type 1 DM and eliminating or reducing the known risks in these patients is crucial [13,14]. For this reason, in our study, we focused on the microvascular complications of type 1 DM and examined the role of autoantibodies in patients with type 1 DM on the development time of microvascular complications. We also aimed to determine whether the presence of autoantibodies is a potentially useful prognostic marker. There are only a limited number of studies examining the prognostic significance of positivity for autoantibodies [15–19].

Roll et al. examined the prevalence of GAD-ab and ICAs in 146 insulin-dependent diabetes DM with different disease duration (2–52 years, median 13.2 years), and they detected anti-GAD positivity as 37% (54 of 146) and ICA positivity as 22% (32 of 146), thus concluding that the presence of autoantibodies is not related to the development time of diabetic complications [15]. Zanone et al. reported that autoantibodies to GAD were present in 56% of diabetic patients with neuropathy, 57% of long-standing patients without complications, 69% of the short-duration diabetic patients with no complications, 78% of the recently diagnosed diabetic patients, and 13% of the non-diabetic neuropathic patients [16]. In parallel with these results, they found that there is no correlation between anti-GAD antibody positivity and the presence of diabetic neuropathy [16]. Ko et al. examined the relationship between antibodies to GAD and diabetic microangiopathic complications in diabetic patients, dividing them into 2 separate groups as anti-GAD-positive and anti-GAD-negative patients, and they reported that both groups had similar prevalence of microangiopathic complications [17]. Glastras et al. demonstrated that the presence of diabetes-associated autoantibodies did not predict the development of microvascular complications [18]. In our study, we found similar results to those reported in these studies, suggesting that the presence of autoimmunity has no significant effect on the development of microvascular complications in patients with type 1 DM.

Szepietowska et al. evaluated the presence of late complications in 41 hospitalized subjects with latent autoimmune diabetes (LADA) by measuring anti-GAD, anti-ICA, and anti-IA-2 (protein tyrosine phosphatase antibodies) levels, and found a higher incidence of microangiopathy in the autoantibody-positive patients [19]. Their results differ from our findings and from those reported by several of the studies mentioned above.

Our study has some limitations. We did not record and classify the blood pressure, creatinine, antihypertensive therapy, antidiabetic therapy, or body mass index data of the patients. More accurate results would have been obtained by performing statistical analysis to define more detailed differences between these parameters with positive and negative autoimmunity.

Conclusions

Based on our study findings, we can suggest that positivity for autoantibodies associated with type 1 DM plays no significant role in the development time of microvascular complications. Further studies in this field are needed to confirm these findings before a definitive conclusion can be reached.