Pathophysiology and treatment of defective insulin secretion in diabetes
Summary, in English
In a specifically designed congenic animal model of defective insulin secretion, we were able to identify two genetic loci on rat chromosome 1 that confer impaired beta-cell glucose metabolism and perturbed exocytosis of insulin-containing granules, respectively. The exocytotic defect was scrutinized in further detail and demonstrated to result from genetically encoded overexpression of the alpha2a-adrenoreceptor (adra2a). Adra2a mediates adrenergic inhibition of insulin secretion, and both pharmacological receptor antagonism and adra2a gene silencing accomplished full normalization of insulin release. This illuminates a novel disease mechanism for beta-cell dysfunction and introduces adra2a as a candidate gene for defective insulin secretion.
Impaired insulin release can be enhanced by the insulinotropic hormones PACAP and GLP-1. Both peptides were demonstrated to enhance insulin release by almost 200 %. This was attributed to a 50 % increase in depolarization-evoked Ca influx as well as a direct potentiation of exocytosis. The hormones acted mainly by activation of protein kinase A, which is suggested to increase the recruitment of insulin granules for release.
High hopes are attached to the use of stem cell therapy to correct decreased beta-cell mass in diabetes. In our study, transplanted adult bone marrow stem cells readily engrafted the pancreas. A reduction in blood glucose levels was observed, and this was paralleled by a two-fold increase in beta-cell replication. As there was no evidence for transdifferentiation of bone marrow cells into beta-cells, we suggest that the engrafted cells have an adjuvant function in the regulation of beta-cell mass.
In conclusion, defective insulin secretion in diabetes involves distinct functional defects in beta-cell exocytosis and glucose metabolism, conferred by two different genetic subloci. The exocytotic defect results from genetically encoded overexpression of the alpha2a-adrenoreceptor. Insulin exocytosis can be potentiated by the peptide hormones PACAP and GLP-1, through activation of protein kinase A. Moreover, transplanted bone marrow cells stimulate replication of endogenous beta-cells and have beneficial effects on blood glucose.
- Endocrinology and Diabetes
- pancreatic beta-cells
- stem cells
- secreting systems
- insulin secretion
- Diabetes mellitus
- Diabetes - Islet Patophysiology
- ISBN: 978-91-85559-94-7
15 June 2007
Clinical Research Center (CRC) Lecture Hall, Malmö University Hospital, Malmö, Sweden
- Claes Wollheim (Professor)