Extreme Phenotypes to Identify Susceptibility of Patients Living With Type 2 to Diabetes Related Complications

The incidence of diabetes related complications (DRC) in individuals living with type 2 diabetes (T2D) is known to depend on exposure to disease and risk factor control, but it displays a large interindividual variability. In this observational trial we will explore the feasibility to develop a method to estimate the degree of susceptibility to DRC in any single patient living with T2D, based on a standardized clinical assessment.

The study will consist in a systematic review of the clinical records of patients with T2D, referring 4 different diabetes clinics in Italy and Greece, who undergo a regular follow up and a complete assessment for DRC pertaining to 3 major macrovascular (coronary, cerebrovascular and peripheral) and 3 major microvascular (retina, kidney and peripheral nerves) districts. The diseases will be classified as a overt or subclinical in relation to their clinical significance. The clinical criteria for the classification will be standardized across the centers.

The final population (target= 1000 patients) will be then used to test the ability of a score (DRC score) to categorize each individual in a specific subgroup for DRC burden, that reflects the DRC susceptibility.

The DRC score has been designed by a consensus of expert, and calculated as the sum of each overt (3 points) and subclinical (1 point) micro- and macrovascular complication.

By applying the DRC score to the general T2D population referring to the study centers, we expect to select 120 subject with high susceptibility to complications (HS-DRC) and 120 subject with low susceptibility to complications (LS-DRC). These subject will undergo a blood drawn and full characterization of risk factors to test the ability of these biomarkers in predicting complications occurrence, when compared with a control population of T2D patients with moderate susceptibility to complications.

The potential biomarkers identified after a systematic review of the literature will be:

Environmental and lifestyle modulators: Smoke load; Fluctuations of body mass index (BMI), HbA1C, Blood pressure, lipid profile, kidney function; physical activity; diet quality; sleep quality.

Biological modulators of damage: IGF1, insulin, testosterone, leptin, glucagon; circulating non-coding microRNA related to diabetes complications.

Biological transducers of damage: hsCRP (high sensitivity C reactive proteine), interleukin-6, -1beta and -18, tumor necrosis factor alfa, tumor growth factor beta; carboxyl methyl-lysine, pentosidine; total antioxidant capacity, 3-nitrotyrosines, malondialdehyde.

Will be selected as biomarkers with predictive potential for DRC susceptibility all biomarkers showing a clear and unidirectional gradient between the two extreme phenotypes selected by using the proposed DRC score.

Inclusion criteria

• Type 2 Diabetes
• Age 40-80 years old
• Comprehensive screening for DRC within 24 months from the inclusion in the survey.

Exclusion criteria

Diagnosis of forms of diabetes other than T2D

• Any chronic inflammatory diseases or active cancer
• Significant liver disfunction (cirrhosis, AST/ALT > 3-fold normality range, total bilirubin > 1,5-fold normal range w/o Gilbert syndrome)
• Any other life expectancy-changing systemic disease.