I- Regulation and maintenance of beta-cell mass
Jorge Ferrer (Barcelona, Spain), a research group leader at the August Pi i Sunyer Institute for Biomedical research, explained the role of gene transcription factors in the regulation of beta-cell turnover. This is of considerable clinical interest because the action of major transcription factors such as the Hepatocyte Nuclear Factor (HNF) family is central to understanding abnormalities of insulin secretion during the development of diabetes mellitus. For example, genetic mutations in transcription factors underlie certain variants of maturity onset diabetes of the young (MODY) which are due to severe abnormalities of insulin secretion.
After reviewing beta-cell adaptations during insulin resistance and moderate or severe hyperglycaemia, Rohit Kulkarni (Boston, USA) discussed the role of humoral factors in beta-cell growth and turnover. The principal humoral factors involved in these processes are insulin and glucose. Studies using gene knockout mice have gained further insights into the relationship between the insulin and glucose cellular cellular signalling pathways and the pathophysiology of diabetes. Liver-specific insulin receptor knockout (LIRKO) mice demonstrate insulin resistance with an associated increase in beta-cell size and insulin production. These mice do not develop diabetes implying that the increased beta-cell mass and insulin production are sufficient to overcome insulin resistance.
However, knockout mice with inactivation of insulin receptors in both the liver and beta-cell (LIRKO/betaIRKO), or beta-cell only (betaIRKO), develop diabetes and die prematurely.
It has also been shown that beta-cell growth and survival depends on activation of the insulin receptor (IR), and insulin receptor substrate (IRS). Taken together, these findings suggest that the insulin signalling pathway in itself is critical for normal beta-cell function.
Fred Levine (La Jolla, USA) discussed beta-cell replication and beta-cell neogenesis as pathways to beta-cell regeneration (Figure 1). Both of these have the potential to be developed as a means of beta-cell replacement in the treatment of diabetes, though adult human beta-cells appear to have limited proliferative potential. As well as being an important means of increasing beta-cell mass during fetal and neonatal development, neogenesis also occurs during periods of increased insulin demand such as in obesity and pregnancy. Insight into the factors that influence stem/progenitor cell neogenesis into beta-cells has been gained from in vitro studies using human pancreatic tissue from which islets have been removed for grafts. Progenitor cells with the potential to differentiate into cells that produce insulin have been identified in the pancreatic islets, pancreatic ducts, and pancreatic acinar cells. Of these, in vivo and in vitro studies have provided the most data for neogenesis of beta-cells from the duct epithelium. beta-cell differentiation of non-endocrine epithelial cells from the human pancreas has also been investigated in a recent study by Hao et al.3 Following cotransplantation with fetal pancreatic cells into immunodefficient mice, non-endocrine epithelial cells differentiated into cells capable of producing insulin. Although these findings are promising in terms of developing effective therapeutic beta-cell transplantation, the requirements of sufficient numbers of beta cells and the maintenance of a functional mass of beta cells still need to be fulfilled.
FOCUS: The dual role of mTOR
The mammalian target of rapamycin (mTOR), a conserved serine/threonine kinase, is an important nutrient sensor.
Under conditions of glucolipotoxicity, overactivation of rapamycin-sensitive complex 1 (mTORC1) leads to beta-cell endoplasmic reticulum (ER) stress, dysfunction and apoptosis. Treatment with rapamycin reverses this ER stress phenotype. 1 However, prolonged treatment of diabetic animals with mTORC1 inhibitors leads to increased beta-cell apoptosis and progressive hyperglycemia, implying that inhibition of mTORC1 is unlikely to become a therapeutic approach in type 2 diabetes. In addition, inhibition of mTOR in Psammomys obesus, a rat model of diet-induced type 2 diabetes, dramatically worsened the metabolic syndrome through impairment of beta-cell function and increased beta-cell apoptosis.
This suggests that mTOR activation is necessary for beta-cell adaptation to glucolipotoxicity through regulation of beta-cell mass.2 Thus, mTOR has differing effects on the pancreatic beta cell according to metabolic stress. On the one hand, it is required for the adaptive increase in beta-cell function and proliferation through stimulating protein synthesis, while on the other, it may increase ER stress and apoptosis in beta-cells, e.g. in response to fatty acids. Rapamycin (sirolimus) is commonly used as an immunosuppressant in solid-organ transplantation, including islets, and also as an anti-proliferative agent in the treatment of cancer. Recent studies have shown that rapamycin impaired islet engraftment and beta-cell function following islet transplantation (Cerasi lecture).
I- Regulation and maintenance of beta-cell mass
II – Regulation and production of insulin
III- Factors underlying beta-cell dysfunction in type 2 diabetes
IV- New tools in research and their clinical interest