Background Mortality rate of diabetic patients is about twice as much that of non-diabetic individuals of similar age; this makes diabetes a leading risk factor for mortality, especially of cardiovascular origin, which accounts for 2.9 million global events yearly. Such scenario is expected to further deteriorate, given that the prevalence of type 2 diabetes mellitus (T2DM), by far the most common form of diabetes comprising more than 90% of all diabetic individuals, is increasing worldwide. Predicting such devastating event is, therefore, urgently needed in order to target aggressive prevention strategies in high risk T2DM patients.~Aims This observational study is aimed at identifying new molecular promoters of all-cause mortality in patients with T2DM.~Secondary endpoints are to identify in these individuals molecular markers of~cardiovascular mortality;~myocardial infarction;~stroke;~dialysis.~Other pre-specified endpoints are to assess in these subjects:~LADA;~severe hypoglycemic episodes;~revascularization procedures;~hospitalization for heart failure;~other co-morbidities (cancer - at follow-up only, liver disease, chronic obstructive pulmonary disease, autoimmune and endocrine disorders, other - non-diabetic - renal diseases, fractures, cognitive impairment).~Patients A total of 5,000 patients with T2DM of both sexes will be recruited. Measures The following parameters will be recorded as exposure variables at baseline.~Age, BMI, waist circumference, systolic and diastolic pressure;~Lifestyle habits, including diet, physical activity (both by validated questionnaires) and smoking.~Menopausal state (for women).~Family history of diabetes (3 consecutive generations).~Family history of cardiovascular disease (first degree relatives).~Diabetes duration.~Severe (requiring assistance) hypoglycemic episodes (per year).~Myocardial infarction, stroke, ulcer/gangrene/amputation, coronary and peripheral revascularization, hospitalization for heart failure, dialysis (at follow-up only).~Glucose, HbA1c, creatinine, uric acid, total and HDL cholesterol, triglycerides, high sensitive C reactive protein, testosterone, Vitamin D, uric acid levels, white blood cells counting, urinary albumin creatinine ratio (ACR)~Current glucose-, lipid-, blood pressure-lowering and anti-platelet or anti-coagulant treatment.~Other relevant treatments (steroids, NSAIDs, immunomodulators, androgens, estrogens, anti-fracturative therapy).~Main co-morbidities (cancer, chronic liver disease, chronic obstructive pulmonary disease, autoimmune and endocrine disorders, other - non-diabetic - renal diseases, fractures, cognitive impairment).~The following parameters will be assessed at baseline only:~GADAs (by a radiobinding assay using in vitro translated [35S] methionine-labelled GAD65) and IA-2 antibodies (by radioimmunoprecipitation assays) to identify subjects with LADA.~Genomic (common and rare variants in genes of interest according to a pathway-centric approach by means of Affymetrix platforms), transcriptomic (differential levels of mRNA by GeneChip Human Gene 1.0 ST Array from Affymetrix) and metabolomic by a combination of ultra-pressure liquid chromatography and gas chromatography coupled to mass spectrometry) analysis.~Measurements of testosterone, Vitamin D, GADAs and IA-2 antibodies as well as gnomic, transcriptomic and metabolomic analysis will be centralized.~Time schedule Recruitment of patients will last approximately 3 years. The enrolled patients will be followed for at least 5 years with yearly visits and telephone calls or consultation of death records in case of drop-out for unknown reasons.
This observational study is aimed at identifying new molecular promoters of mortality (and morbidity) in patients with type 2 diabetes mellitus (T2DM).