**4. Body weight in type 1 diabetes families**

According to epidemiological findings and the accelerator hypothesis, the prevalence of overweight in preadolescent children is increasing, it tracks into adulthood and may increase diabetes and cardiovascular disease risk in adulthood. The risk of childhood obesity seems to increase with exposure to diabetes or cigarette smoke in utero, high birth weight, rapid weight gain in infancy, and shorter breastfeeding duration. The Diabetes Autoimmunity Study in the Young (DAISY) examined longitudinally 1,718 children from birth that were at increased risk for type 1 diabetes (Lamb et al., 2010). Gender, diabetes exposure in utero, size for gestational age, weight gain in the first year of life, and total breastfeeding duration (inverse) showed significant association with higher childhood BMI. Mediation analysis suggested that 1) the protective effect of breastfeeding duration on childhood BMI was largely mediated by slower infant weight gain, and 2) the increased risk of higher childhood BMI associated with exposure to diabetes in utero was partially explained by greater birth size. Maternal obesity before pregnancy and weight gain during pregnancy significantly predicted increased risk of persistent multiple positivity for islet autoantibodies in offspring with high genetic susceptibility for type 1 diabetes (Rasmussen et al., 2009). A systematic review and meta-analysis (12 studies) indicated that high birth

The Enlarging List of Phenotypic Characteristics That

remains throughout life.

(Matteucci et al., 2010).

**5. Familial cardiovascular abnormalities** 

Might Allow the Clinical Identification of Families at Risk for Type 1 Diabetes 311

its vascular complications (Reis et al., 2005). Whatever the case, our data in adult members of type 1 diabetes families highlight that the 'familial' predisposition to overweight

Fig. 1. Body mass index (BMI) in control subjects, type 1 diabetic patients and their siblings

Diabetes and hypertension are strongly associated although the role of glycaemia in promoting hypertension is a matter of debate (Invitti, 2003). HbA1c variability predicts not only incident microalbuminuria and progression of established renal disease but also cardiovascular disease events in patients with type 1 diabetes (Wadén et al., 2009). Moreover, HbA1c concentration predicts cardiovascular disease and all-cause mortality in adults without diabetes (Khaw et al., 2004). In healthy non-diabetic and non-hypertensive men, fasting plasma glucose is independently associated with blood pressure at rest and during exercise and development of elevated blood pressure after 7-years follow-up (Biornholt et al., 2003). Usually, in type 1 diabetes families, parental hypertension has been associated with diabetic nephropathy in adult and young offspring (Viberti et al., 1987; Marcovecchio et al., 2010), but the familial/hereditary factors that have an impact on diabetic nephropathy have not been so far identified. In a large homogeneous population from the Finnish Diabetic Nephropathy study, a cluster of parental hypertension, cardiovascular disease, cardiovascular mortality, and type 1 diabetes was associated with diabetic nephropathy in offspring with type 1 diabetes. It seemed that the more the traits

clustered in family, the higher the risk for diabetes nephropathy (Thorn et al., 2007).

In this regard it is noteworthy that enhanced sodium/lithium countertransport and sodium/hydrogen exchange had been suggested to predict diabetic nephropathy (Walker et al., 1990; Ng et al, 1990). However, we found evidence contradicting this favourite hypothesis. Indeed, our data demonstrated convincingly that sodium/hydrogen exchange activity was significantly higher in type 1 diabetes with no difference among the two groups

weight and increased weight gain during the first year of life were associated with an increased risk of type 1 diabetes in later life (Harder et al., 2009).

Metabolic demand and insulin resistance have been suggested to be involved in the development of type 1 diabetes (Evertsen et al., 2009; Wilkin, 2009), but the evidence is not consistent across the studies. In 1650 prospectively followed children of mothers or fathers with type 1 diabetes (BABYDIAB cohort), islet autoantibodies-positive children were not insulin resistant (based on homeostasis model assessment of insulin resistance, HOMA-IR) and did not have increased BMI around and early after seroconversion (Winkler at al., 2009). In this study, of 777 children with HOMA-IR measurements, 84 developed islet antibodies during the study: analysis of HOMA-IR by age showed no significant difference between islet autoantibody-positive and islet autoantibody-negative children, with a tendency towards a lower HOMA-IR in the antibody-positive children compared with the antibody-negative children.

In a primary school health program in Pisa we screened 869 primary school children (448 M, 421 F, mean age 1185 months): height, weight, four skinfolds, and four circumferences were measured; a family-reported questionnaire was used to determine family composition, history, and lifestyle (Giampietro et al., 2002). The percentages of children who could be considered overweight (BMI 95th percentile of age- and sex-specific National Health and Nutrition Examination Survey I, NHANES I, reference data) were boys, 10.0%, and girls, 9.3%. It emerged that offspring BMI was correlated with birth weight, parental BMI and scholarship level, children blood pressure, and hours per day spent in television viewing. Family history for diabetes was associated with higher BMI, skinfold thickness at the subscapular area (SSF), waist circumference, and upper thigh. Family history for hypertension was associated with higher SSF/skinfold thickness at the triceps area (TCF) ratio. We concluded that anthropometric and anamnestic data on child and family yield more accurate estimates of risk profile: fat distribution seems relevant for metabolic and cardiovascular disorders.

Since our initial investigations on type 1 diabetes families, we found that first degree relatives' BMI tended to be higher when compared with healthy control subjects who had no first-degree relative with type 1 diabetes, although the difference did not always reach statistical significance (Matteucci & Giampietro, 2000a; Matteucci et al. 2004a, 2004b; Matteucci et al. 2006). In recent years, on the contrary, the difference in BMI between unaffected siblings of type 1 diabetic probands and healthy control subjects has reached the statistical significance (Figure 1, Matteucci et al., 2010).

This finding probably reflects the trend toward increasing body weight and obesity in the general population, declining physical activity and unhealthy dietary habits that we have documented (Matteucci et al., 2004b, 2007, 2008). However, the emerging difference in BMI between unaffected relatives and control subjects suggests that additional factors are operative in type 1 diabetes families, which remain unknown. The single nucleotide polymorphism rs9939609 in the fat mass and obesity associated gene (FTO) region on chromosome 16q12, which increases the risk of childhood obesity and type 2 diabetes, did not alter susceptibility to type 1 diabetes (Field et al., 2007). Although increased early growth was associated with disease risk in various European populations, any role of infant feeding in this association remained unclear (EURODIAB Substudy 2 Study Group, 2002). Scientific evidences suggested associations of allelic variations in the Vitamin D receptor gene and phenotypes related to body weight, glucose homeostasis, diabetes and

weight and increased weight gain during the first year of life were associated with an

Metabolic demand and insulin resistance have been suggested to be involved in the development of type 1 diabetes (Evertsen et al., 2009; Wilkin, 2009), but the evidence is not consistent across the studies. In 1650 prospectively followed children of mothers or fathers with type 1 diabetes (BABYDIAB cohort), islet autoantibodies-positive children were not insulin resistant (based on homeostasis model assessment of insulin resistance, HOMA-IR) and did not have increased BMI around and early after seroconversion (Winkler at al., 2009). In this study, of 777 children with HOMA-IR measurements, 84 developed islet antibodies during the study: analysis of HOMA-IR by age showed no significant difference between islet autoantibody-positive and islet autoantibody-negative children, with a tendency towards a lower HOMA-IR in the antibody-positive children

In a primary school health program in Pisa we screened 869 primary school children (448 M, 421 F, mean age 1185 months): height, weight, four skinfolds, and four circumferences were measured; a family-reported questionnaire was used to determine family composition, history, and lifestyle (Giampietro et al., 2002). The percentages of children who could be considered overweight (BMI 95th percentile of age- and sex-specific National Health and Nutrition Examination Survey I, NHANES I, reference data) were boys, 10.0%, and girls, 9.3%. It emerged that offspring BMI was correlated with birth weight, parental BMI and scholarship level, children blood pressure, and hours per day spent in television viewing. Family history for diabetes was associated with higher BMI, skinfold thickness at the subscapular area (SSF), waist circumference, and upper thigh. Family history for hypertension was associated with higher SSF/skinfold thickness at the triceps area (TCF) ratio. We concluded that anthropometric and anamnestic data on child and family yield more accurate estimates of risk profile: fat distribution seems relevant for metabolic and

Since our initial investigations on type 1 diabetes families, we found that first degree relatives' BMI tended to be higher when compared with healthy control subjects who had no first-degree relative with type 1 diabetes, although the difference did not always reach statistical significance (Matteucci & Giampietro, 2000a; Matteucci et al. 2004a, 2004b; Matteucci et al. 2006). In recent years, on the contrary, the difference in BMI between unaffected siblings of type 1 diabetic probands and healthy control subjects has reached the

This finding probably reflects the trend toward increasing body weight and obesity in the general population, declining physical activity and unhealthy dietary habits that we have documented (Matteucci et al., 2004b, 2007, 2008). However, the emerging difference in BMI between unaffected relatives and control subjects suggests that additional factors are operative in type 1 diabetes families, which remain unknown. The single nucleotide polymorphism rs9939609 in the fat mass and obesity associated gene (FTO) region on chromosome 16q12, which increases the risk of childhood obesity and type 2 diabetes, did not alter susceptibility to type 1 diabetes (Field et al., 2007). Although increased early growth was associated with disease risk in various European populations, any role of infant feeding in this association remained unclear (EURODIAB Substudy 2 Study Group, 2002). Scientific evidences suggested associations of allelic variations in the Vitamin D receptor gene and phenotypes related to body weight, glucose homeostasis, diabetes and

increased risk of type 1 diabetes in later life (Harder et al., 2009).

compared with the antibody-negative children.

statistical significance (Figure 1, Matteucci et al., 2010).

cardiovascular disorders.

its vascular complications (Reis et al., 2005). Whatever the case, our data in adult members of type 1 diabetes families highlight that the 'familial' predisposition to overweight remains throughout life.

Fig. 1. Body mass index (BMI) in control subjects, type 1 diabetic patients and their siblings (Matteucci et al., 2010).
