We investigated the specific and associated effects of insulin and glucose on beta-cell growth and function in adult rats. By combining simultaneous infusion either of glucose and/or insulin or glucose and diazoxide, three groups of rats were constituted: hyperglycemic-hyperinsulinemic rats (high glucose-high insulin), hyperglycemic-euinsulinemic rats (high glucose), and euglycemic-hyperinsulinemic rats (high insulin). All the infusions lasted 48 h. Control rats were infused with 0.9% NaCl (saline controls). In all groups, beta-cell mass was significantly increased, compared with controls (by 70% in high glucose-high insulin rats, 65% in high glucose rats, and 50% in high insulin rats). The stimulation of neogenesis was suggested by the high number of islets budding from pancreatic ducts in high glucose-high insulin and high glucose rats and by the presence of numerous clusters of few beta-cells within the exocrine pancreas in high insulin rats. beta-Cell hypertrophy was observed only in high glucose-high insulin rats. The rate of beta-cell proliferation was similar to that of controls in high glucose-high insulin rats after a 48-h glucose infusion, dropped dramatically in high insulin rats, and dropped to a lesser extent in high glucose rats. In high glucose-high insulin and high glucose rats, beta-cell mass increase was related to a higher beta-cell responsiveness to glucose in vitro as measured by islet perifusion studies, whereas in high insulin rats, no significant enhancement of glucose induced insulin secretion could be noticed. The data show that glucose and insulin may have specific stimulating effects on beta-cell growth and function in vivo in adult rats independently of the influence they exert each other on their respective plasma concentration.

Endocrine pancreas plasticity may be defined as the ability of the organ to adapt the ␤-cell mass to the variations in insulin demand. For example, during late pregnancy and obesity, the increase of the ␤-cell mass, in association with ␤-cell hyperactivity, contributes to insulin oversecretion in response to insulin resistance. There is increasing evidence that the ability of the ␤-cell mass to expand in adult mammals is much higher than previously thought. During pregnancy, placental hormones, especially placental lactogens, are mainly responsible for the changes in ␤-cell mass. The factors involved in ␤-cell growth in obesity are far from clear, although increased free fatty acids seem to be the main candidate. Many data suggest that the impairment of insulin secretion in type 2 diabetes is partly related to reduction of ␤-cell mass, at least relative to prevailing insulin demand. This defect may originate from genetic predisposition, but the situation is likely worsened by environmental factors such as hyperglycemia (glucotoxicity) and hyperlipidemia (lipotoxicity). Better understanding of ␤-cell growth and regeneration mechanisms may allow new strategies in the treatment of type 2 diabetes based on early limitation of ␤-cell damage and/or restoration of a functional ␤-cell mass. Diabetes 50 (Suppl. 1):S30-S35, 2001 E ndocrine pancreas plasticity may be defined as the ability of the organ to adapt the ␤-cell mass to the variations in insulin demand to warrant optimal control of glucose homeostasis. Our current knowledge is that in adult mammals, the ␤-cell mass is governed by a permanent balance between ␤-cell growth (␤-cell replication and neogenesis) and ␤-cell death (mainly apoptosis). Disruption of this balance may lead to rapid and marked changes in islet cell mass. For example, during late pregnancy and obesity, the increase of the ␤-cell mass contributes to insulin oversecretion in response to insulin resistance. There is now growing evidence that impaired insulin secretion in type 2 diabetes is in part related to the reduction of ␤-cell mass in relation to prevailing insulin demand; i.e., the ability of the ␤-cell mass to expand in response to insulin resistance is altered.We review here the main factors involved in islet plasticity in adults and the possible causes of its deterioration in type 2 diabetes. FACTORS INVOLVED IN ␤-CELL MASS CHANGES IN THE ADULTDuring development, endocrine cells arise from undifferentiated stem cells located in pancreatic ducts, which migrate into the exocrine pancreas to form the islets of Langerhans (neogenesis). Then, differentiated ␤-cells proliferate within the islets (replication). These processes are essential during development of the endocrine pancreas, but they are also necessary for the further islet cell mass homeostasis.In vitro and in vivo studies have shown that ␤-cells from fetuses and adults respond to the same stimuli: nutrients, hormones, or growth factors. In this review, we will focus only on the role of glucose and insulin.Glucose appears to be a po...

To clarify the relationship between variations in ␤-cell mass and pancreatic function, we investigated the possibility to analyze, quantify, and sort ␤-cell subpopulations with different functional maturity. To this aim, we tested the reliability of the sialylated form of neural cell adhesion molecule (NCAM) (PSA-NCAM) as a marker of ␤-cell functional activity. Islet cells isolated from adult rats were analyzed for their PSA-NCAM abundance using an anti-PSA-NCAM antibody. We found that PSA-NCAM is expressed only in ␤-cells. The PSA-NCAM labeling was also studied with a fluorescenceactivated cell sorter. We showed that the ␤-cell population is heterogeneous for PSA-NCAM labeling. To directly determine the relationship between PSA-NCAM labeling and ␤-cell activity, in vitro insulin secretion studies were performed on sorted ␤-cell subpopulations using a perifusion technique. Two ␤-cell subpopulations were analyzed: one that was highly labeled for PSA-NCAM and another that was poorly labeled. Insulin secretion from high PSA-NCAMlabeled ␤-cells was significantly higher than that in low PSA-NCAM-labeled ␤-cells. This differential expression in the ␤-cell population was well correlated with differences in glucose responsiveness. PSA-NCAM seems thus suitable for use as a tool to identify ␤-cell subpopulations according to their glucose responsiveness. Diabetes 50 (Suppl. 1):S125-S130, 2001

We investigated the possible interplay between insulin and glucose signaling pathways in rat pancreatic β-cell with a special focus on the role of glucose in IRS signaling in vivo. Three groups of rats were constituted by combining simultaneous infusion during 48 h either of glucose and/or insulin, or glucose+diazoxide: HyperglycemicHyperinsulinemic (HGHI), euglycemic-Hyperinsulinemic (eGHI), Hyperglycemic-euinsulinemic (HGeI). Control rats were infused with 0,9% NaCl. In HGHI and HGeI rats plasma glucose levels were maintained at 20-22 mmol/l. In eGHI rats, plasma glucose was not different from that of controls, whereas plasma insulin was much higher than in controls. In HGHI rats, IRS-2 mRNA expression, total protein and phosphorylated protein amounts were increased compared to controls. In HGeI rats, only IRS-2 mRNA expression was increased. No change was observed in eGHI rats whatever the parameter considered. In all groups, mRNA concentration of IRS-1 was similar to that of controls. The quantity of total and phosphorylated IRS-1 protein was dramatically increased in HGHI rats and to a lesser extent in eGHI rats. Neither mRNA nor IRS-1 protein expression were modified in HGeI rats. The data suggest that glucose and insulin play at once a specific and a complementary role in islet IRSs signaling. Especially, glucose stimulates IRS-2 mRNA expression whatever the insulin status and independently of the secretory process. The differential regulation of IRS-1 and IRS-2 expressions is in agreement with their supposed