Functional pancreatic beta-cell mass: involvement in type 2 diabetes and therapeutic intervention.

In the adult, the pancreatic beta-cell mass adapts insulin secretion to meet long-term changes in insulin demand and, in particular, in the presence of insulin resistance that is either physiological, such as pregnancy, or pathophysiological, such as obesity. The failure of beta cells to compensate for insulin resistance is a major component of impaired glucose homeostasis and overt diabetes. This defect is clearly the consequence of a decline of insulin response to glucose due to functional beta-cell deficiency. It is also the consequence of an inability of the endocrine pancreas to adapt the beta-cell mass to insulin demand (pancreas plasticity), which eventually leads to a decrease in functional beta-cell mass. This idea has resulted in considerable attention being paid to the development of new therapeutic strategies aiming to preserve and/or regenerate functional beta-cell mass. The latter is governed by a constant balance between beta-cell growth (replication from pre-existing beta cells and neogenesis from precursor cells) and beta-cell death (mainly apoptosis). Disruption of this balance may lead to rapid and marked changes in beta-cell mass. Glucagon-like peptide-1 (GLP-1), an incretin, enhances beta-cell survival (by activating beta-cell proliferation and differentiation, and inhibiting beta-cell apoptosis), thus contributing to the long-term regulation of insulin secretion by maintaining a functional beta-cell mass. The development of drugs regulating this parameter will be the major challenge of the next few years in the management of type 2 diabetes.

Anatomical versus functional beta-cell mass in experimental diabetes.

The ability of pancreatic beta-cell mass to vary according to insulin requirements is an important component of optimal long-term control of glucose homeostasis. It is generally assumed that alteration of this property largely contributes to the impairment of insulin secretion in type 2 diabetes. However, data in humans are scarce and it is impossible to correlate beta-cell mass and function with the various stages of the disease. Thus, the importance of animal models is obvious. In rodents, increased beta-cell mass associated with an increase in the function of individual beta-cells contributes to the adaptation of the insulin response to insulin resistance in late pregnancy and in obesity. A reduction in beta-cell mass always corresponds to an alteration in insulin secretory capacity of islet tissue (Zucker diabetic fatty and Goto-Kakisaki rats, db/db mice). During regenerative processes following experimental reduction of beta-cell mass [partial pancreatectomy, streptozocin (STZ) injection], beta-cell mass increase is not associated with a corresponding improvement of beta-cell function, thus indicating that regenerative beta-cells did not achieve functional maturity. The main lesson from experimental diabetes is therefore that beta-cell mass cannot always predict functional capacity of the beta-cell tissue and that the functional beta-cell mass rather than the anatomical beta-cell mass must be taken into account at all times.

Sialylated form of the neural cell adhesion molecule (NCAM): a new tool for the identification and sorting of beta-cell subpopulations with different functional activity.

To clarify the relationship between variations in beta-cell mass and pancreatic function, we investigated the possibility to analyze, quantify, and sort beta-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 beta-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 beta-cells. The PSA-NCAM labeling was also studied with a fluorescence-activated cell sorter. We showed that the beta-cell population is heterogeneous for PSA-NCAM labeling. To directly determine the relationship between PSA-NCAM labeling and beta-cell activity, in vitro insulin secretion studies were performed on sorted beta-cell subpopulations using a perifusion technique. Two beta-cell subpopulations were analyzed: one that was highly labeled for PSA-NCAM and another that was poorly labeled. Insulin secretion from high PSA-NCAM-labeled beta-cells was significantly higher than that in low PSA-NCAM-labeled beta-cells. This differential expression in the beta-cell population was well correlated with differences in glucose responsiveness. PSA-NCAM seems thus suitable for use as a tool to identify beta-cell subpopulations according to their glucose responsiveness.

Endocrine pancreas plasticity under physiological and pathological conditions.

Endocrine pancreas plasticity may be defined as the ability of the organ to adapt the beta-cell mass to the variations in insulin demand. For example, during late pregnancy and obesity, the increase of the beta-cell mass, in association with beta-cell hyperactivity, contributes to insulin oversecretion in response to insulin resistance. There is increasing evidence that the ability of the beta-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 beta-cell mass. The factors involved in beta-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 beta-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 beta-cell growth and regeneration mechanisms may allow new strategies in the treatment of type 2 diabetes based on early limitation of beta-cell damage and/or restoration of a functional beta-cell mass.