Reg protein expression is associated with islet development, β-cell damage, diabetes and pancreatitis. We previously reported that islets of 4-month-old (4-mo) GK rats, a spontaneous model of type 2 diabetes, overexpress Reg1, 3α, 3β and 3γ vs age-matched Wistar control islets. Reg1 and 3β are involved in cell growth/survival control and inflammation, respectively. Diabetic GK islets also exhibit progressive inflammation reaction, consisting of high CCL2 (MCP-1), CCL3 (MIP-1α), CXCL-1 (murine IL-8 analog) and IL-6 expression/release and mostly peri-islet macrophage infiltration. Importantly, Reg1 gene promoters contain IL-6-responsive elements. Here we analyzed in greater detail the pancreatic expression of Reg1 and Reg3β in diabetic GK rats. Isolated pancreatic islets and acinar tissue from male Wistar and GK rats were used for quantitative RT-PCR analysis. Islet IL-6, CCL2, CCL3 and CXCL1 release was measured by LuminexTM technology after a 48h islet culture on collagen. Pancreatic Reg immunohistochemistry (IHC) was performed on paraffin sections with a rabbit anti-human polyclonal antibody (Ab) and a mouse anti-rat monoclonal anti-Reg1 Ab. Macrophage infiltration was detected on cryostat sections using CD68 and MHC class II antibodies. Islet macrophage+ area was quantified and expressed as % of corresponding islet area. Statistical analyses used the Student’s t-test for unpaired data. The exocrine/endocrine ratio of Reg mRNA expression in 4-mo normoglycemic Wistar and diabetic GK rats was: 1) Reg1: 41.3±2.4 and 5.0±1.5, respectively (n=3 different isolations/group, p<0.005); 2) Reg3β: 74.2±17.0 and 7.0±4.9, respectively (n=3, p<0.02). Furthermore, Reg1 and 3β were overexpressed in GK vs Wistar islets (x11.2±1.4, p<0.005 and 77.9±16.3, p<0.01, respectively, n=3 in both cases). Next, the polyclonal Reg Ab stained most islet insulin+ cells in 4-mo Wistar pancreas but much less so in GK pancreas. By contrast, the monoclonal anti-Reg1 Ab stained just a few peri-islet exocrine cells in Wistar pancreas but many more in GK rats, particularly around large islets. Since IL-6 stimulates Reg1 expression, we compared cytokine/chemokine release by small and large 2.5-mo Wistar and GK islets. Large GK islets released significantly more IL-6 and CCL3 than large Wistar islets (x4.7±0.9, p<0.02 and 2.7±0.2, p<0.005, respectively, n=3 in both cases). Concomitantly, CD68+ and MHC II+ peri-islet macrophage infiltration correlated with islet size in 2.5-mo GK rats (r=0.57 and r=0.95, respectively). Reg1 and 3β genes are strongly expressed in the exocrine pancreas of control rats. The two genes are markedly overexpressed in islets of diabetic GK vs control Wistar rats, probably reflecting an adaptive stress response. While the polyclonal Ab mainly stains islet insulin+ cells, Reg1 protein is the hallmark of acinar tissue around large GK islets. Its peri-insular localization might result from increased islet release of IL-6 (a factor stimulating Reg1 expression) and is similar to that of macrophage infiltration.