Fulminant Type 1 Diabetes Mellitus in IRS-2 Deficient Mice

Abstract

Type 1 diabetes mellitus (T1DM), one of two major forms of diabetes, results from nearly complete destruction of pancreatic beta (┚) cells. According to the classification of diabetes made by the American Diabetes Association, T1DM is divided into two subtypes: immunemediated (type 1A) and idiopathic (type 1B) (American Diabetes Association, 2008). Fulminant type 1 diabetes mellitus (FT1DM), which was first reported by Imagawa et al. in 2000, is thought to be a unique subtype of type 1B diabetes. The initial reports of FT1DM were exclusively in Japanese population and accounted for about 20% of their T1DM (Imagawa et al., 2000; 2003). Outside Japan, Cho et al. (2007) reported prevalence for FT1DM of 7.1% in the newly diagnosed Korean T1DM patients. However, epidemiological study of FT1DM is lacking in other Asian populations and its incidence and pathogenesis remain to be elucidated. While a search for FT1DM was reported to be negative in the Caucasian population, case reports on FT1DM had surfaced in different ethnic groups, predominantly from Asian origins (Jung et al., 2004; Taniyama et al., 2004; Moreau et al., 2008). However, the causative mechanism of FT1DM is currently unknown. On the other hand, insulin receptor substrate (IRS) disorders are associated with onset of insulin resistance and diabetes mellitus (Withers et al., 1998; Kido et al., 2000). A small population of male IRS-2 deficient mice showed hyperglycemia associated with markedly diminished pancreatic islet size, and these extremely hyperglycemic IRS-2 deficient mice exhibited 1) abrupt onset of diabetes and 2) very short duration of diabetic symptoms, such as polyuria, thirst, and body weight loss. These symptoms resembled the features of human nonautoimmune FT1DM (Hashimoto et al., 2006). Characteristics of abrupt onset of hyperglycemia associated with marked diminished islet mass in IRS-2 deficient mice were investigated to analyze the onset mechanism of FT1DM.