Analysis of Apoptotic, Clinical, and Laboratory Parameters in Type 1 Diabetes and Early Diabetic Nephropathy: Clustering and Potential Groups Evaluation for Additional Therapeutic Interventions

Abstract

Objective: Type 1 diabetes (T1D) is one of the most prevalent chronic illnesses diagnosed in childhood. Diabetic nephropathy (DN) is one of the commonest complication of T1D. Therefore the development of specific treatment that arrests progression of DN based on an individual approach would be beneficial. Analysis of criteria of apoptosis, and clinical, and laboratory characteristics in T1D and early DN in the framework of clustering may be helpful in the identification of potential groups for additional therapeutic interventions. Methods: A survey of 104 children (62 males, 42 females) with T1D and DN aged 2 to 17 years in the Endocrinology unit of Clinical Pediatric Hospital No 6 (Kyiv, Ukraine) was performed. Clinical data (age, gender, disease duration, blood pressure), conventional laboratory markers including complete blood count, serum cholesterol, hemoglobin A1c (Hb1Ac), glomerular filtration rate (GFR), and microalbuminurea (MAU), and markers of apoptosis (BcL-xL, caspase-3) and transcriptional factor HIF-1alfa were analyzed. Results: A cluster group in T1D children was characterized by somewhat higher number of platelets (PLT) - 344.9±7.88·10 9 /L, increased GFR up to hyperfiltration level 124.5±8.86 mL/min/1.73 m 2 and decreased anti-apoptotic defense - BcL-xL 144.9±2.35 a.u. was identified. Children with DN may be divided into three groups based on age, body mass index, systolic blood pressure, PLT count, erthyrocyte sedimentation rate, albumin/globulin ratio, serum cholesterol, Hb1Ac, number of diabetic ketoacidosis (DKA) episodes, GFR, MAU, HIF-1alfa, Bcl-xL, caspase-3 levels. Among children with early DN a cluster characterized by the following parameters was found: PLT count - 311.±12.05·10 9 /L, frequency of DKA episodes - 4.82±0.26 episodes/year, MAU - 112.0±10.12 mm/24 h, HIF - 200.5±3.49 a.u., BcL-xL - 128.8±3.1 a.u., and caspase-3 - 159.6±5.5 a.u. Conclusion: Thus, we hypothesize that T1D pediatric patients with increased PLT count, hyperfiltration and reduced anti-apoptotic defense may represent a group for additional therapeutic interventions, such as antioxidants along with stndard therapies to achieve optimal glycemic control. Within the DN group there was a sub-group with somewhat increased PLT count, high frequency of DKA episodes/year, high MAU, prominent increase in HIF level, prominent disturbances in apoptosis controlling factors BcL-xL and caspase-3 tht may require additional therapeutic interventions, again including antioxidants, but may additionally benefit from anti-apoptotic effectors along with optimal glycemic control, and management of hypertension and albuminuria.

Apoptosis-Controlling, Clinical, Laboratory, Anamnestic Factors in Prediction of the Early Stage of Diabetic Nephropathy in Children

“…Higher mean HbA1c, higher mean triglycerides, older age, and higher systolic blood pressure were the most important risk factors for incident decreased GFR. 7, 21 Yet not enough research has been done on the variables that predict the early stage of DN linked with microalbuminuria, particularly in juvenile patients.…”

“…6 Numerous clinical variables, such as the length of diabetes, puberty, age at onset, family history of insulin resistance, type 1 and type 2 diabetes, genetic factors, race/ethnicity, modifiable, glycemic (metabolic) control, smoking, hyperlipidemia, intrauterine exposure, obesity, pregnancy, and social status, have been discussed in terms of factors predicting the development of DN. 7 In tubular cells, hyperglycemia causes the production of free radicals and oxidative stress. Reactive oxygen species are thought to be crucial mediators of a number of biological processes, such as apoptosis, extracellular matrix deposition, and proliferation.…”

“…Numerous clinical variables, such as the length of diabetes, puberty, age at onset, family history of insulin resistance, type 1 and type 2 diabetes, genetic factors, race/ethnicity, modifiable, glycemic (metabolic) control, smoking, hyperlipidemia, intrauterine exposure, obesity, pregnancy, and social status, have been discussed in terms of factors predicting the development of DN. 7…”

Approach to correction of apoptotic disorders in children with early diabetic nephropathy ‎

“…Children with early DN have disturbances in the apoptosis controlling system, i.e. down-regulation of anti-apoptotic agent BcL-xL and up-regulation of apoptosis factor caspase-3 were previously shown [17]. This research aim at evaluating whether Vitamin D administration together with conventional treatment of DN may treat apoptosis disorders in children with DN.…”