**6. Conclusion**

IRS-2 mice tend to become obese accompanying insulin resistance after 8 weeks of age. IRS-2 deficient mice develop diabetes, presumably due to inadequate β cell proliferation combined with insulin resistance compared to IRS-1 deficient mice with the β cell hyperplasia to compensate for the insulin resistance. Heterotopic accumulation of lipid observed frequently in obese IRS-2 mice, and corpulent adipocytes secrete various inflammatory cytokines, such as TNF-α and ILs, whereas production of adiponectin as antidiabetic agent is decreased significantly. About 20% of male IRS-2 deficient mice showed clinical characteristics of (1) remarkably abrupt onset of disease; (2) very short (< 1 week) duration of diabetic symptoms; (3) acidosis at diagnosis; (4) negative status of islet-related antibodies; (5) virtually no C-peptide secretion; and (6) elevated serum pancreatic enzyme level. These symptoms resembled the features of human nonautoimmune FT1DM. In IRS-2 deficient mice with FT1DM, insulitis with macrophage dominated infiltration to islet β cell area was observed frequently as in human FT1DM patients. Inflammatory cytokines appear to have important roles in the process of β cell destruction leading to FT1DM. IRS-2 deficient mice are considered to be useful animal model for studying the mechanism of β cell destruction leading to FT1DM.

#### **7. References**


of type 1 diabetic patients carry these predisposing alleles, but the occurrence of these alleles in the background population is high, approximately 50%. It is believed that the diabetes predisposing DQ antigens have a shape of the antigen presenting groove of the molecule that leads to more efficient presentation of β cell associated autoantigens (Donath et al., 2003). HLA comment should be in the text. In FT1DM patients, the haplotype frequency of HLA DRB1\*0901-DQB1\*0303 was significantly higher than those in controls (Moreau et al., 2008). HLA phenotyping of these Caucasian patients did not find the specific HLA haplotype (DRB1\*0405-DQB1\*0401) found to be linked to FT1D in Japanese patients. More investigation about haplotype frequency of MHC was necessary for IRS-2 mice in the

IRS-2 mice tend to become obese accompanying insulin resistance after 8 weeks of age. IRS-2 deficient mice develop diabetes, presumably due to inadequate β cell proliferation combined with insulin resistance compared to IRS-1 deficient mice with the β cell hyperplasia to compensate for the insulin resistance. Heterotopic accumulation of lipid observed frequently in obese IRS-2 mice, and corpulent adipocytes secrete various inflammatory cytokines, such as TNF-α and ILs, whereas production of adiponectin as antidiabetic agent is decreased significantly. About 20% of male IRS-2 deficient mice showed clinical characteristics of (1) remarkably abrupt onset of disease; (2) very short (< 1 week) duration of diabetic symptoms; (3) acidosis at diagnosis; (4) negative status of islet-related antibodies; (5) virtually no C-peptide secretion; and (6) elevated serum pancreatic enzyme level. These symptoms resembled the features of human nonautoimmune FT1DM. In IRS-2 deficient mice with FT1DM, insulitis with macrophage dominated infiltration to islet β cell area was observed frequently as in human FT1DM patients. Inflammatory cytokines appear to have important roles in the process of β cell destruction leading to FT1DM. IRS-2 deficient mice are considered to be useful animal model for studying the mechanism of β cell

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**10** 

*Brazil* 

**Obesity in the Natural History** 

**of Type 1 Diabetes Mellitus:** 

**Causes and Consequences** 

Fernando Valente1, Marília Brito Gomes2

*2State University of Rio de Janeiro, Rio de Janeiro* 

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

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.,

**1. Introduction** 

et al., 2009).

*1São Paulo Federal University, São Paulo* 

and Sérgio Atala Dib1

Zheng, C., Zhou, Z., Yang, L., Huang, G., Li, X., Zhou, W., Wang, X. & Liu, Z. (2011). Fulminant type 1 diabetes mellitus exhibits distinct clinical and autoimmunity features from classical type 1 diabetes mellitus in Chinese. *Diabetes Metabolism Research and Reviews* Vol. 27 (No. 1): 70-78. ISSN 1520-7552
