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β-Cell Replication by Loosening the Brakes of Glucagon-Like Peptide-1 Receptor Signaling

¹ Gene Expression Unit, Department of Molecular Cell Biology Katholieke Universiteit Leuven, Belgium
² Banting and Best Diabetes Centre, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, University of Toronto, Canada

Address correspondence and reprint requests to Frans C. Schuit, frans.schuit@med.kuleuven.be, or to Daniel J. Drucker, d.drucker@utoronto.ca

Abbreviations: GLP-1, glucagon-like peptide-1; GLP-1R, GLP-1 receptor

The first 300 words of the full text of this article appear below.

A decrease in β-cell mass is a well-known key pathogenic event in diabetes, not only in human subjects with type 1 patients, where β-cells are destroyed by the immune system, but also in type 2 diabetes where reduced β-cell function results in hyperglycemia and associated metabolic abnormalities (1,2). These concepts have made the search for the set of rules that control pancreatic β-cell mass an important area of islet research. An interesting emerging topic with clinical relevance is the notion that the actions of glucagon-like peptide-1 (GLP-1) on islet β-cells could be harnessed to improve and preserve β-cell function and potentially reverse defects in β-cell mass (3). GLP-1 is a proglucagon-derived peptide secreted from gut endocrine cells that acts on β-cells at multiple levels, acutely stimulating insulin secretion while chronically promoting proinsulin biosynthesis and growth and survival of β-cells. During meals, GLP-1 is secreted and acts immediately as an incretin, acutely potentiating glucose-dependent insulin release. However, GLP-1 also enhances glucose competence of β-cells and restores glucose sensitivity to diabetic β-cells in vivo. These findings, taken together with the clinical development of GLP-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 inhibitors, have focused on attention to the extent to which incretin-based agents may exert long-term beneficial effects on preservation of β-cell function in subjects with type 2 diabetes (4).

In an exciting study published in this issue of Diabetes (5), two mechanisms by which GLP-1 causes β-cell replication have been explored. As the authors state, "the overall effect of GLP-1 on increasing β-cell mass in both in vivo and in vitro conditions is relatively small, and augmenting this effect would be beneficial for the treatment or prevention of both type 1 and type 2 diabetes." The goal of the study by Klinger . . . [Full Text of this Article]

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Increasing GLP-1–Induced β-Cell Proliferation by Silencing the Negative Regulators of Signaling cAMP Response Element Modulator- and DUSP14

Sonia Klinger, Carine Poussin, Marie-Bernard Debril, Wanda Dolci, Philippe A. Halban, and Bernard Thorens
Diabetes 2008 57: 584-593. [Abstract] [Full Text] [PDF]