Comorbidity

Project objectives

The overall objective of the project is to characterize the new comorbidities associated with youth obesity, such as double diabetes (DD), alterations in seminal fluid quality and sperm structure, and macrovascular disease. This will lead to the development of a mathematical model based on instrumental, humoral, and genetic parameters aimed at predicting the onset and progression of new morbidities associated with youth obesity. This mathematical model uses traditional statistical tests and innovative methods such as Multifactor Dimensionality Reduction (MDR) and neural networks, and is developed from data (clinical, humoral, instrumental, and genetic) obtained from the work of the individual Research Units.

Specific objectives:

1. To characterize DD among pediatric and adolescent patients with diabetes mellitus and/or obesity. To this end, subjects are characterized immunologically (evaluation of anti-beta-cell autoantibodies), metabolically (beta-cell reserve, indices of insulin resistance, presence of non-alcoholic steatopathy [NASH] and, in adolescents, polycystic ovary syndrome [PCOS]), and instrumentally (evaluation of complications, bone mineralization, and body fat distribution).

2. To evaluate certain gene polymorphisms and proteins with pleiotropic function in DD involved in low-grade inflammation, which appears to underlie obesity-related complications and of which DD represents one of the most recently identified models. The possible association of DD with candidate genes that play a role in low-grade inflammation, beta-cell destruction, insulin response, and insulin resistance is being assessed, including genes selected based on their association with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Additionally:

   1. To evaluate in DD those gene polymorphisms associated with T1DM (see experimental design) by comparing them to T1DM and T2DM

   2. evaluate in DD those gene polymorphisms associated with T2DM (see experimental design) comparing them to T1DM and T2DM

   3. evaluate the various types of diabetes and in obese control subjects the blood levels of specific proteins (see experimental design) under examination and the polymorphisms of the genes that encode them

   4. evaluate the effect of each single SNP and each single plasma protein dosage on quantitative serum variables (C-peptide, BMI, glycemia, insulinemia, proinsulinemia, lipid profile)

   5. identify metabolic and anthropometric markers of insulin resistance

3. In an obese population aged 18-30 years, the following are evaluated:

   1. hormonal status (Inhibin B, FSH, LH, SHBG, Cortisol, 17-OH-P, TSH, fT3, fT4, E2)

   2. Ejaculate volume, total sperm concentration and count, progressive motility and percentage of atypical forms and autoimmune reactions against spermatozoa (by direct and indirect immunobead test and by Gelatin Agglutination Test)

   3. DNA fragmentation by TUNEL test (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling)

   4. androgen receptor polymorphisms

   5. sperm mitochondrial function (by analysis of mitochondrial membrane potential).

4. To characterize parameters associated with cardiovascular disease and bone metabolism in obese young adults. To this end, the study population will analyze:

   1. instrumental parameters of endothelial function (FMD), vascular morphology (IMT) and bone density

   2. humoral indices of endothelial function/dysfunction (ADMA, selectins and integrins), lipoprotein oxidation (LDL-ox) and bone turnover.

The selected vascular parameters represent indices of the different phases of the atherogenic process, and their combined assessment helps describe this process in our population. Instrumental methods are particularly useful and can more accurately identify obese subjects at particularly high risk of atherosclerotic lesions. Osteometabolic studies in obese young people contribute to the advancement of knowledge in this field, aiming to clarify the role of early fat mass accumulation on bone metabolism during a phase of life that is particularly crucial for defining future bone mass in adults.

Start and end date

22/03/2010 - 22/09/2012

Project Manager

Prof. Paolo Pozzilli, Diabetology and Endocrinology Research Unit - Scientific Coordinator of the Research Program

Coordinating institution of the project

Università Campus Bio-Medico di Roma

Other Institutions involved

• University of Rome "La Sapienza"

• University of the Studies in Genova

Funding source(s).

Italian Ministry of Education, University and Research