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...

. Development of ␤-cell mass in fetuses of rats deprived of protein and/or energy in last trimester of pregnancy. Am J Physiol Regul Integr Comp Physiol 283: R623-R630, 2002. First published May 16, 2002 10.1152 10. / ajpregu.00037.2002 malnutrition is now proposed as a risk factor of later obesity and type II diabetes. We previously analyzed the long-term impact of reduced protein and/or energy intake strictly limited to the last week of pregnancy in Wistar rats. Three protocols of gestational malnutrition were used: 1) low-protein isocaloric diet (5 instead of 15%) with pair feeding to the mothers receiving the control diet, 2) restricted diet (50% of control diet), and 3) low protein-restricted diet (50% of low-protein diet). Only isolated protein restriction induced a long-term ␤-cell mass decrease. In the present study, we used the same protocols of food restriction to analyze their short-term impact (on day 21.5 of pregnancy) on ␤-cell mass development. A 50% ␤-cell mass decrease was present in the three restricted groups, but low-protein diet, either associated or not to energy restriction, increased fetal ␤-cell insulin content. Among all the parameters analyzed to further explain our results, we found that the fetal plasma level of taurine was lowered by lowprotein diet and was the main predictor of the fetal plasma insulin level (r ϭ 0.63, P Ͻ 0.01). In conclusion, rat fetuses exposed to protein and/or energy restriction during the third part of pregnancy have a similar dramatic decrease in ␤-cell mass, and their ability to recover ␤-cell mass development retardation depends on the type of malnutrition used. Moreover, our results support the hypothesis that taurine might play an important role in fetal ␤-cell mass function. endocrine pancreas EPIDEMIOLOGICAL DATA IN VARIOUS human populations show that low birth weight and especially thinness at birth are associated with susceptibility to the development of impaired glucose tolerance/type II diabetes in adult life (16,23,26,28,31,32). This association has been interpreted as reflecting long-term effects of nutritional factors that reduce fetal growth and impair the development of tissues regulating glucose metabolism (14,29,36).Among these tissues, the endocrine pancreas, and especially ␤-cells, could suffer from fetal malnutrition. Babies with intrauterine growth retardation have a marked reduction in the size of their endocrine pancreas (41). Animal studies also report that fetal malnutrition is associated with persistently impaired pancreatic ␤-cell function and development (11,13). With the use of a low-protein diet during whole rat pregnancy, reduced proliferation rate, size, and insulin content of pancreas islets were observed in fetuses at the end of pregnancy (11,38).However, human data did not highlight a clear relationship between body weight or ponderal index (weight/height 3 ) at birth and ␤-cell function in adult age (8), and human fetal malnutrition was reported to be more strongly related to insulin resistance (5,9,10,23,26,31,40). Some...

An association between low birth weight and later impaired glucose tolerance was recently demonstrated in several human populations. Although fetal malnutrition is probably involved, the biological bases of such a relationship are not yet clear, and animal studies on the matter are scarce. The present study was aimed to identify, in adult (8-wk) female offspring, the effects of reduced protein and/or energy intake strictly limited to the last week of pregnancy. Thus we have tested three protocols of gestational malnutrition: a low-protein isocaloric diet (5 instead of 15%), with pair feeding to the mothers receiving the control diet; a restricted diet (50% of the control diet); and a low-protein restricted diet (50% of low-protein diet). Only the low-protein diet protocols, independent of total energy intake, led to a lower birth weight. The adult offspring female rats in the three deprived groups exhibited no decrease in body weight and no major impairment in glucose tolerance, glucose utilization, or glucose production (basal state and hyperinsulinemic clamp studies). However, pancreatic insulin content and β-cell mass were significantly decreased in the low-protein isocaloric diet group compared with the two energy-restricted groups. Such impairment of β-cell mass development induced by protein deficiency limited to the last part of intrauterine life could represent a situation predisposing to impaired glucose tolerance.

B. Follow-up of GK rats during prediabetes highlights increased insulin action and fat deposition despite low insulin secretion. Am J Physiol Endocrinol Metab 294: E168-E175, 2008. First published November 6, 2007 doi:10.1152/ajpendo.00501.2007.-The adult Goto-Kakizaki (GK) rat is characterized by impaired glucoseinduced insulin secretion in vivo and in vitro, decreased ␤-cell mass, decreased insulin sensitivity in the liver, and moderate insulin resistance in muscles and adipose tissue. GK rats do not exhibit basal hyperglycemia during the first 3 wk after birth and therefore could be considered prediabetic during this period. Our aim was to identify the initial pathophysiological changes occurring during the prediabetes period in this model of type 2 diabetes (T2DM). To address this, we investigated ␤-cell function, insulin sensitivity, and body composition in normoglycemic prediabetic GK rats. Our results revealed that the in vivo secretory response of GK ␤-cells to glucose is markedly reduced and the whole body insulin sensitivity is increased in the prediabetic GK rats in vivo. Moreover, the body composition of suckling GK rats is altered compared with age-matched Wistar rats, with an increase of the number of adipocytes before weaning despite a decreased body weight and lean mass in the GK rats. None of these changes appeared to be due to the postnatal nutritional environment of GK pups as demonstrated by cross-fostering GK pups with nondiabetic Wistar dams. In conclusion, in the GK model of T2DM, ␤-cell dysfunction associated with increased insulin sensitivity and the alteration of body composition are proximal events that might contribute to the establishment of overt diabetes in adult GK rats.Goto-Kakizaki rat; body composition; insulin sensitivity; glucose tolerance ESTABLISHED TYPE 2 DIABETES MELLITUS (T2DM) is associated with profound insulin-secretory alterations and insulin resistance, but the primacy of each of these events over the other remains controversial. According to a widely accepted hypothesis, insulin resistance is the primary defect responsible for the progression toward T2DM (8,30,34,48). However, other data support the concept that ␤-cell dysfunction could be, in fact, a proximal event rather than a secondary phenomenon due to the exhaustion of ␤-cells caused by prolonged insulin resistance (16). This controversy may partly result from the genetic heterogeneity of the population included in the study protocols in humans with high risk of developing the disease, and the presence of confounding parameters such as age, sex, and environmental factors (16). Therefore, animal models of T2DM with a period of prediabetes could help with the understanding of the chronology of events leading to the appearance of clinical symptoms. The Goto-Kakizaki (GK) rat is a spontaneous nonoverweight model of T2DM produced by selective breeding (with glucose intolerance as selection criterion) repeated over many generations, starting from a nondiabetic Wistar colony. In the colony maintained in our laborat...

We assessed the impact of chronic insulin deficiency on basal and insulin-stimulated glucose utilization by the whole-body mass in vivo in female albino Wistar rats. This assessment was based on a comparison of results in rats given streptozocin (STZ) on day of birth (n0-STZ), when 2 days old (n2-STZ), or when 5 days old (n5-STZ). At 10 wk of age, the n2-STZ rats exhibited characteristics similar to those obtained in the n0-STZ rats: normal growth, modest elevation of basal plasma glucose (8.23 +/- 0.24 mM), glucose intolerance, depleted pancreatic insulin stores (approximately 50% of normal value), and lack of insulin release in response to glucose in vivo. In contrast, the n5-STZ rats exhibited frank basal hyperglycemia (glucose 11.9 +/- 1.1 mM) and glucose intolerance, increased glycosylated hemoglobins, strong reduction of the pancreatic insulin stores (10% of normal value), decreased basal plasma insulin levels (50% of normal value), and lack of insulin release in response to glucose in vivo. Changes in the sensitivity of the neonatal beta-cell to STZ and the regeneration capacity of the beta-cells during the 1st postnatal wk were liable factors for the contrast. In vivo insulin action was assessed with the euglycemic-hyperinsulinemic clamp technique in 10-wk-old anesthetized animals. In the n2-STZ rats compared with controls 1) endogenous glucose production was significantly higher despite a normal plasma insulin level in the basal state, 2) endogenous glucose production rate was similarly suppressed by hyperinsulinemia, and 3) glucose utilization by the whole-body mass was similarly increased by hyperglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

We examined to what extent the abnormal glucosedependent insulin secretion observed in NIDDM (noninsulin-dependent diabetes mellitus) is related to alterations in the handling of cytosolic ] i observed in response to high glucose and induced fast [Ca 2+ ] i oscillations with high amplitude in Wistar islets. The latter effect was not seen in GK and nSTZ islets. In these two NIDDM models, several common alterations in glucoseinduced Ca 2+ handling were revealed which may contribute to their poor glucose-induced insulin secretion.

The effects of glucagon-like peptide-1(7-36)-amide (GLP-1) on cAMP content and insulin release were studied in islets isolated from diabetic rats (n0-STZ model) which exhibited impaired glucose-induced insulin release. We first examined the possibility of re-activating the insulin response to glucose in the beta-cells of the diabetic rats using GLP-1 in vitro. In static incubation experiments, GLP-1 amplified cAMP accumulation (by 170%) and glucose-induced insulin release (by 140%) in the diabetic islets to the same extent as in control islets. Using a perifusion procedure, GLP-1 amplified the insulin response to 16.7 mM glucose by diabetic islets and generated a clear biphasic pattern of insulin release. The incremental insulin response to glucose in the presence of GLP-1, although lower than corresponding control values (1.56 +/- 0.37 and 4.53 +/- 0.60 pg/min per ng islet DNA in diabetic and control islets respectively), became similar to that of control islets exposed to 16.7 mM glucose alone (1.09 +/- 0.15 pg/min per ng islet DNA). Since in vitro GLP-1 was found to exert positive effects on the glucose competence of the residual beta-cells in the n0-STZ model. we investigated the therapeutic effect of in vivo GLP-1 administration on glucose tolerance and glucose-induced insulin release by n0-STZ rats. An infusion of GLP-1 (10 ng/min per kg; i.v.) in n0-STZ rats enhanced significantly (P < 0.01) basal plasma insulin levels, and, when combined with an i.v. glucose tolerance and insulin secretion test, it was found to improve (P < 0.05) glucose tolerance and the insulinogenic index, as compared with the respective values of these parameters before GLP-1 treatment.