The GK rat spontaneously develop 1nild hyper­ glycemia from 3 to 4 weeks onwards without obesity. In 4-month-old dia­ betic GK rats, total p-cell mass is decreased by 60% in parallel to pancreatic insulin stores, while 2 populations of islets are observed: 1) large islets with spots of heterogenously insulin-stained cells intermingled with fibrosis and 2) small (normal) islets with heavily stained p cells and normal architecture. Such alterations also exist in other spontaneous rat T2D models (Zucker, OLEFT and Torii). Here, we present a complementary approach using gene expression analysis and immunohistochemistry to identify potential inflammatory reaction that might lead to islet fibrosis and beta­ cell impairment in the GK model of T2D. Affymetrix micrroarrays were used to compare gene expression in islets isolated from 4-month-old GK rats and contrai age-matched Wistar rats, from which the GK strain was originally selected. Immunohistochemistry was performed on 1- and 4-month-old Wistar and GK cryostat pancreas sections for proteins related to extracellular matrix (ECM), different types of macrophages, cytokines, vascularization and a Schwann cell marker (glial fibrillary acidic protein or GFAP). Affymetrix micrroarrays showed overexpression of genes for mol­ ecules that belong to: 1) the extracellular matrix (ECM)-related proteins and cell adhesion molecules, particularly, collagen I and III, fibronectin, osteopontin and TIMP-1 (tissue inhibitor of metalloprotease-1); 2) the inflammatory/immune response, particularly MHC class II and immuno­ globulins; 4) the oxidative stress. The overexpression of some of these genes has been confirmed by quantitative RT-PCR, Immunohistochemi­ cally, compared to 4-month-old contrai Wistar islets, GK islets showed: 1) diffuse intra-islet labeling for collagen I and III, fibronectin, with an almost complete disappearance of intra-islet vascularization, as confirmed by von Willebrand factor (vWF) and laminin labeling; 2) a more marked intra-islet labeling of osteopontin, an adhesion and chemotactic protein linked to inflammation; 3) signs of intra-islet gliosis as demonstrated by the pres­ ence of GFAP+ cells that normally surround the islets; 4) more vWF+ and TIMP-1 + peri-islet vessels; 5) accumulation of various populations of macrophages (MHC dass ri+, EDl + and ED2+) around some islets and/or at their vascular-ductal pole; 6) more intense TNFa (tumor necrosis factor-ex) labeling of endocrine cells. No fibrosis nor vessels anomalies were observed, at diabetes onset, in 1-month-old GK islets. These data shed light on the islet inflammatory process that is associated with the chronic, even mild, hyperglycemia of T2D GK rats. They also suggest that islet inflammation might be a common pathway leading to diabetes (whether of type 2 or 1)-induced beta-cell impairment, probably via cytokine-related events.