Identification of a major locus for islet inflammation and fibrosis in the spontaneously diabetic Torii rat

Abstract

of inflammation and fibrosis in the pancreatic islets in diabetes is largely unknown. Spontaneously diabetic Torii (SDT) rats exhibit inflammation and fibrosis in and around the islets during the development of the disease. We investigated genetic factors for diabetes, islet inflammation, and fibrosis in the SDT rat. We produced F1 and F2 rats by intercross between SDT and F344 rats, examined the onset of diabetes, glucose tolerance, and histology of the pancreas, and performed genetic analysis of these traits. We then established a congenic strain carrying the SDT allele at the strongest diabetogenic locus on the F344 genetic background and characterized glucose tolerance and histology of the pancreas. F1 rats showed glucose intolerance and inflammatory changes mainly in the islets. Genetic analysis of diabetes identified a major locus on chromosome 3, designated Dmsdt1, at which a dominantly acting SDT allele was involved. Quantitative trait locus (QTL) analysis of glucose tolerance revealed, in addition to Dmsdt1 [logarithm of odds (LOD) 5.3 near D3Mit12], three other loci, designated Dmsdt2 (LOD 4.2 at D8Rat46), Dmsdt3 (LOD 3.8 near D13Arb5), and Dmsdt4 (LOD 5.8 at D14Arb18). Analysis of a congenic strain for Dmsdt1 indicates that the dominantly acting SDT allele induces islet inflammation and fibrosis. Thus we have found a major locus on chromosome 3 for islet inflammation and fibrosis in the SDT rat. Identification of the genes responsible should provide insight into the pathogenesis of diabetes. congenic analysis; diabetes; genetic factor; glucose tolerance; quantitative trait locus DIABETES MELLITUS IS a multifactorial disease involving interaction of genetic and environmental factors. Spontaneous animal models of diabetes are widely used in research and have provided valuable information on the nature of the disease. Inflammation and fibrosis in pancreatic islets have been described in human type 2 diabetes (4) and in spontaneous animal models of type 2 diabetes, including the Goto-Kakizaki (GK) rat (12), the Zucker diabetic fatty rat (33), and the Otsuka Long-Evans Tokushima fatty (OLETF) rat (16). A role of inflammation and fibrosis in the pathogenesis of type 2 diabetes has been suggested (17), but the mechanism and genetic factors remain to be elucidated. Genetic, pathophysiological, and histological analyses using animal models should provide useful information for understanding the molecular mechanism of the inflammatory process in the development of the disease.The spontaneously diabetic Torii (SDT) rat was established from an outbred colony of Sprague-Dawley rats in 1997 as a nonobese diabetic animal model (37,38). Male SDT rats develop diabetes at 15 wk of age or later and show 100% incidence of diabetes by 40 wk of age. Pathological changes including microvascular congestion and hemorrhage in pancreatic islets appear from ϳ8 wk of age and are followed by inflammation and fibrosis in and around the islets. These pathological changes in the pancreas of SDT rats differ from those of typical autoi...

Isolation and characterization of islet stellate cells in rat

“…Islet fibrosis has been observed in the late stage of β-cell failure during the progression to T2DM in diabetic patients as well as in animal models, with increased deposition of many ECM components, including Col-I, Col-III, and FN. [13][14][15][16][17][18] The precise mechanisms underlying islet fibrosis are largely unknown, although the deposition of islet amyloid, activation of RAS and oxidative stress have all been implicated. 16,17,[28][29][30] Our demonstration of a specialized ISC population in rodent islets is consistent with an important role for these cells in islet fibrosis, in an analogous manner to that of classical PSCs in pancreatic fibrosis.…”

“…[5][6][7][8][9][10][11][12] Fibrotic responses to inflammatory insults may also be important in pathological responses in the endocrine portion of the pancreas, the islets of Langerhans. Islet fibrosis has been demonstrated in the pancreas of humans with T2DM, and in a number of animal models of diabetes, [13][14][15][16][17][18] where it is associated with the late stage of β cell failure during the progression to T2DM. 19 However, the mechanisms responsible for the development of islet fibrosis are largely unknown.…”

Genetics of the Spontaneously Diabetic Torii Rat

“…By selective genotyping on N2 rats with marked glucose intolerance (n = 26) and normal glucose tolerance (n = 30), followed by chi-square test, we found significant differences (P < 0.01) in the genotype frequencies at several markers on chromosomes 1,2,6,7,8,11,14,18, and X. These chromosomes were then subjected to QTL analysis using all of the N2 rats.…”

“…To perform genetic analysis of diabetes and glucose intolerance in SDT rats, we produced (F344 SDT) F2 rats, phenotyped for the onset of diabetes up to 60 weeks of age, and performed OGTT at the same age [14]. F2 rats developed diabetes at 25 weeks of age or later, and the cumulative incidence of diabetes reached 19% (31/167) at 60 weeks of age.…”

“…To clarify the genetic basis of diabetes, glucose intolerance, islet inflammation, and fibrosis in SDT rats, we performed genetic analysis of these traits using two different crosses: the (BN SDT) F1 SDT backcross [13] and the (F344 SDT) F2 intercross [14]. Analysis of the former cross identified three QTLs (Gisdt1, Gisdt2, and Gisdt3) for glucose intolerance on rat chromosomes 1, 2, and X, respectively.…”