**Obesity in the Natural History of Type 1 Diabetes Mellitus: Causes and Consequences**

Fernando Valente1, Marília Brito Gomes2 and Sérgio Atala Dib1 *1São Paulo Federal University, São Paulo 2State University of Rio de Janeiro, Rio de Janeiro Brazil* 

### **1. Introduction**

180 Type 1 Diabetes – Complications, Pathogenesis, and Alternative Treatments

Zheng, C., Zhou, Z., Yang, L., Huang, G., Li, X., Zhou, W., Wang, X. & Liu, Z. (2011).

*Research and Reviews* Vol. 27 (No. 1): 70-78. ISSN 1520-7552

Fulminant type 1 diabetes mellitus exhibits distinct clinical and autoimmunity features from classical type 1 diabetes mellitus in Chinese. *Diabetes Metabolism* 

> There has been a worldwide epidemic increasing in the prevalence of sedentary, overweight and obesity that comes with modernity and urbanization (Wang et al., 2002). The consequence is the development of insulin resistance (IR) and type 2 diabetes (T2D). This is classically defined as a metabolic disease that occurs due to a higher IR that leads to a slow setting of lower insulin production (more relative than absolute), in general in adult age. T2D is associated also with a genetic predisposition. The majority of T2D individuals are overweight or obese and the ones who do not, at least present increased abdominal adipose mass (ADA, 1997). The rising prevalence of overweight and obesity is happening also in children and adolescents (Pinhas-Hamiel et al., 1996; Willi & Egede, 2000; Rosenbloom et al., 1999). The metabolic syndrome (MS), which physiopathology is based on IR, shows the same trend in children and adolescents (Jago et al., 2008), as well as isolated pre-diabetes (Li et al., 2009).

> In parallel, it has been seen an elevation in the number of type 1 diabetes (T1D) cases and its establishment at a younger age (EURODIAB ACE Study Group, 2000). T1D is characterized primarily by a pancreatic beta cell destruction, which may lead to ketosis. It can be classified as autoimmune (with positive anti-islet, anti-insulin, anti-GAD, anti-IA2 and/or anti-IA2 beta antibodies) or idiopathic, in which no autoantibodies can be detected, and occurs more frequently in individuals of African-American or Asian origin. Multiple genetic predisposition and environmental factors are involved with T1D (ADA, 1997). At least one of those autoantibodies is present in 85-90% of T1D on diagnosis. The treatment for T1D consists of multiple insulin injections, known as intensive treatment, to obtain adequate glycemic control and therefore prevent micro (The DCCT Research Group, 1993) and macrovascular (Nathan et al., 2005 and 2003) chronic complications. However, it can be followed by weight gain most of the times (Arai et al., 2008), which can amplify the risk of cardiovascular disease (CVD) in spite of good glycemic control. This weight gain can start on puberty and persist along adulthood (Särnblad et al., 2007). Therefore, some of these patients present clinical features of both T1D and T2D, confounding its classification. This phenotype was initially called double diabetes (DD) (Libman & Becker, 2003; Becker et al.,

Obesity in the Natural History of Type 1 Diabetes Mellitus: Causes and Consequences 183

Studies with streptozotocin-induced diabetic baboons showed that to have an abnormal glucose tolerance it is necessary an isolated huge loss of beta-cell mass or a moderate loss of these cells associated to an IR (McCulloch et al., 1991), that could be in humans the physiologically IR of adolescence (Acerini et al., 2000) or gestation (Buschard et al., 1987), periods with higher incidence of T1D, or pathological situations like infection (usually one

Others studies suggest that the increase in the body mass index (BMI) and the consequent IR may accelerate the β cell destruction process in individuals predisposed to T1D, due to the release of obesity-related cytokines that show inflammatory and/or immunomodulatory properties (Aldhahi & Hamdy, 2003), triggering diabetes. This hypothesis may be reinforced by one study that correlated high anti-GAD levels with high BMI (Rolandsson et al., 1999). Two interesting data from studies with non-obese diabetic (NOD) mice are that hyperinsulinemia, an IR marker, precede clinical T1D (Armani et al., 1998) and that T1D incidence falls after treatment with rosiglitazone, an insulin sensitizer drug (Beales &

The IR, autoimmunity and apoptosis of the β cells constitutes the three factors of the called "accelerator hypothesis", proposed by Wilkin (Wilkin, 2001), that contemplate the factors presented in both more common types of diabetes, that is, T2D and T1D. There is a constitucional (intrinsic) high speed of apoptosis of β cells that is necessary to the development of diabetes, but rarely enough. The other two factors, extrinsic, that can speed the apoptosis of beta-cells are IR (result of weight gain and/or physical inactivity) and

It is known that obese individuals have elevated serum levels of leptin, a cytokine secreted by adipocytes in proportion to adipose tissue mass and that is responsible, among other functions, for regulating food intake and thus BMI. Moreover, leptin controls the cellular immune response and is involved in the pathogenesis of autoimmune diseases (Lord, 2002). Studies have shown that administration of leptin in NOD mice promoted an early inflammatory infiltrate in the pancreatic islets, increased production of interferon gamma (IFN-gamma) by T lymphocytes, which accelerated the establishment of a T1D (Matarese,

On the other hand, adiponectin, another important cytokine produced by adipose tissue, inversely proportional to its fat mass, can decrease the systemic and pancreatic islets inflammatory process, acting as a protective factor in the development of T1D, in addition to

However, development report (OECD, 2009) from 16 countries does not show any obvious relationship between national estimates of childhood obesity prevalence and incidence rates of T1D (Table 2). Therefore, obesity does not account for the wide between-country differences in T1D incidence, which range from 0.57 per 100 000 person-years in China to more than 48 per 100 000 person-years in Sardinia and Finland in the 0- to 14-year age group

On the other hand, in a meta-analysis of nine studies (eight case–control studies and one cohort study) comprising a total of 2658 cases (Verbeeten et al., 2011), seven reported a significant association between childhood obesity, BMI or %weight-for-height and increased risk for T1D. Four of these studies reported childhood obesity as a categorical exposure and

reducing IR (Kadowaki et al., 2006; Wellen & Hotamisligil, 2005).

**2. Obesity as a accelerate factor to type 1 diabetes mellitus development** 

of the triggering factors of T1D) or weight gain.

Pozzili, 2002).

2002 e 2005).

(Daneman, 2006).

autoimmunity against beta-cells.

2001), and is characterized by positive pancreatic autoantibodies in patients with clinical features of T2D, as IR and overweight and/or obesity (Pozzilli & Buzzetti, 2007; Gilliam et al., 2005; Reinehr et al., 2006), as shown in Table 1 (Pozzilli & Buzzetti, 2007) and in Figure 1.


Table 1. Clinical and pathogenic features of DD compared to T1D and T2D (Pozzilli & Buzzetti, 2007).

Fig. 1. Schematic representation showing where DD lies in respect to age and the two types of diabetes, as illustrated by two 'rainbows' (Pozzilli & Buzzetti, 2007).

2001), and is characterized by positive pancreatic autoantibodies in patients with clinical features of T2D, as IR and overweight and/or obesity (Pozzilli & Buzzetti, 2007; Gilliam et al., 2005; Reinehr et al., 2006), as shown in Table 1 (Pozzilli & Buzzetti, 2007) and in Figure 1.

T1D DD T2D

secretion - + +++ IR -/+ ++ +++

complications + ++ +++

Table 1. Clinical and pathogenic features of DD compared to T1D and T2D (Pozzilli &

Fig. 1. Schematic representation showing where DD lies in respect to age and the two types

of diabetes, as illustrated by two 'rainbows' (Pozzilli & Buzzetti, 2007).

Childhood ++ Adolescence ++ Adult (LADA) +

?

Life style (diet, sedentary life)

+++ + -

+++ ++ -

+ ++ +++

Childhood + Adolescence ++ Adult +++

*APM1*, *PPARγ 2*, *PtdCho-1*, *TCF7L2* 

Life style (diet, sedentary life)

Childhood +++ Adolescence +++ Adult +

MHC class I and II, *InsVNTR*, *CTLA-4*, *PTPN22* 

Diet, viruses Cow´s milk in infancy

Age at disease onset

Major genetics predisposition

Environmental factors

Circulating antibodies to β cells

T cell-mediated immunity to β cells

C-peptide

Inflammatory markers (cytokines, adipokines)

Macrovascular

Buzzetti, 2007).
