beta-cell function and viability in the spontaneously diabetic GK rat: information from the GK/Par colony.

Abstract

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...

Chronic Hyperglycemia, Independent of Plasma Lipid Levels, Is Sufficient for the Loss of β-Cell Differentiation and Secretory Function in the db/db Mouse Model of Diabetes

“…Phlorizin treatment normalized blood glucose without affecting plasma NEFA or triglyceride levels, strongly suggesting that hyperglycemia, independent of hyperlipidemia, plays a causal role in the progressive loss of ␤-cell differentiation and secretion in db/db mice. Taken with other studies (4,32,55,56), it is apparent that there are similarities in the abnormal patterns of gene expression that accompany ␤-cell dysfunction in several rodent models of diabetes, suggestive of common mechanisms. Similar mechanisms may be responsible for ␤-cell dysfunction in human type 2 diabetes (44).…”

Increased Number of Islet-Associated Macrophages in Type 2 Diabetes

“…The GK rat is a rodent model of spontaneous type 2 diabetes established by inbreeding Wistar rats selected from the upper limit of a normal distribution for glucose tolerance (18). We analyzed the presence of islet-associated macrophages in 1-month-old (weaning; normogylcemic) and 2-month-old male Wistar and GK rats (1 month after chronic mild hyperglycemia; fasting glycemia: 6.3 Ϯ 0.2 vs. 11.3 Ϯ 0.6 mmol/l, n ϭ 10, respectively; P Ͻ 0.05) using two different antibodies, ED-1 (CD68) and anti-MHC class 2.…”

“…Characteristics of the GK rat maintained in the colony at the Paris 7 University have been described previously (18). This animal model was developed by inbreeding Wistar rats with mild hyperglycemia.…”

Restitution of Defective Glucose-Stimulated Insulin Secretion in Diabetic GK Rat by Acetylcholine Uncovers Paradoxical Stimulatory Effect of β-Cell Muscarinic Receptor Activation on cAMP Production

“…The characteristics of the GK rats maintained in our colony at Paris University 7 have been described previously (9). Plasma glucose levels for Wistar and GK/Par rats at time of death were 6.6 Ϯ 0.2 mmol/l (n ϭ 30) and 9.6 Ϯ 0.5 mmol/l (n ϭ 30), respectively (P Ͻ 0.001).…”