The molecular pathways leading to islet fibrosis in diabetes are unknown. Therefore, we studied gene expression in islets of 4-month-old Goto-Kakizaki (GK) and Wistar control rats. Of 71 genes found to be overexpressed in GK islets, 24% belong to extracellular matrix (ECM)/cell adhesion and 34% to inflammatory/immune response families. Based on gene data, we selected several antibodies to study fibrosis development during progression of hyperglycemia by immunohistochemistry. One-month-old GK and Wistar islets appeared to be similar. Two-month-old GK islets were strongly heterogenous in terms of ECM accumulation compared with Wistar islets. GK islet vascularization, labeled by von Willebrand factor, was altered after 1 month of mild hyperglycemia. Numerous macrophages (major histocompatibility complex class II ؉ and CD68 ؉ ) and granulocytes were found in/around GK islets. These data demonstrate that marked inflammatory reaction accompanies GK islet fibrosis and suggest that islet alterations in this nonobese model of type 2 diabetes develop in a way reminiscent of microangiopathy. Diabetes 55: [1625][1626][1627][1628][1629][1630][1631][1632][1633] 2006
Increasing evidence indicates that decreased functional beta-cell mass is the hallmark of type 2 diabetes (T2D) mellitus. Nowadays, the debate focuses on the possible mechanisms responsible for abnormal islet microenvironment, decreased beta-cell number, impaired beta-cell function, and their multifactorial aetiologies. This review is aimed to illustrate to what extend the Goto-Kakizaki rat, one of the best characterized animal models of spontaneous T2D, has proved be a valuable tool offering sufficient commonalities to study these aspects. We propose that the defective beta-cell mass and function in the GK model reflect the complex interactions of multiple pathogenic players: (i) several independent loci containing genes responsible for some diabetic traits (but not decreased beta-cell mass); (ii) gestational metabolic impairment inducing an epigenetic programming of the pancreas (decreased beta-cell neogenesis and/or proliferation) which is transmitted to the next generation; and (iii) loss of beta-cell differentiation due to chronic exposure to hyperglycemia/hyperlipidemia, inflammatory mediators, oxidative stress and to perturbed islet microarchitecture.
The GK rat model of type 2 diabetes is especially convenient to dissect the pathogenic mechanism necessary for the emergence of overt diabetes because all adult rats obtained in our department (GK/Par colony) to date have stable basal mild hyperglycemia and because overt diabetes is preceded by a period of normoglycemia, ranging from birth to weaning. The purpose of this article is to sum up the information so far available related to the biology of the -cell in the GK/Par rat. In terms of -cell function, there is no major intrinsic secretory defect in the prediabetic GK/Par -cell, and the lack of -cell reactivity to glucose (which reflects multiple intracellular abnormalities), as seen during the adult period when the GK/Par rats are overtly diabetic, represents an acquired defect (perhaps glucotoxicity). In terms of -cell population, the earliest alteration so far detected in the GK/Par rat targets the size of the -cell population. Several convergent data suggest that the permanently reduced -cell mass in the GK/Par rat reflects a limitation of -cell neogenesis during early fetal life, and it is conceivable that some genes among the set involved in GK diabetes belong to the subset of genes controlling early -cell development. Diabetes 50 (Suppl. 1):S89-S93, 2001T ype 2 diabetes develops as a consequence of interplay among -cell dysfunction, peripheral insulin resistance, and elevated hepatic glucose production. However, it is not known which is the primary abnormality and which are abnormalities secondary to elevated plasma glucose, so-called glucose toxicity. To delineate the primary abnormalities, it is desirable to analyze individuals destined to become diabetic before the development of the disease. The advantage of using an animal model is that the development of diabetes can be predicted and thus it is possible to dissect the pathogenic mechanism necessary for the emergence of overt diabetes. The Goto-Kakizaki Wistar rat (GK rat) is especially useful because all adult animals of both sexes exhibit type 2 diabetes. This spontaneous diabetes model was produced by selective breeding (with glucose intolerance as a selection index) repeated over many generations, starting from a nondiabetic Wistar rat colony. The characteristics of GK animals bred in our colony in Paris (GK/Par) for more than 10 years (1) are very stable and remain close to those of the animals in the original Japanese colony (2): all of the rats have a basal mild hyperglycemia and impaired glucose tolerance. Males and females are similarly affected, and their diabetic state is stable over 72 weeks of follow-up (3). In adult GK rats, plasma insulin release in vivo in response to intravenous glucose is abolished (1,3). In vitro studies of insulin release with the isolated perfused pancreas (1) or with perifused islets (4) indicate that both early and late phases of glucoseinduced insulin release are markedly affected in the adult GK rat. Concerning insulin action in adult GK rats, we have reported decreased insulin sensitivity in the...
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