Pancreatic deletion of insulin receptor substrate 2 reduces beta and alpha cell mass and impairs glucose homeostasis in mice

Autor: Agharul I. Choudhury, Steven J. Lingard, Shanta J. Persaud, Helen Heffron, Pedro Luis Herrera, Henry Asare-Anane, James Cantley, Dominic J. Withers, Colin Selman
Rok vydání: 2007
Předmět:
medicine.medical_specialty
DNA/genetics/isolation & purification
Genotype
Endocrinology
Diabetes and Metabolism
medicine.medical_treatment
Cre recombinase
Mice/genetics
Biology
Islets of Langerhans
Mice
Insulin resistance
Receptor
Insulin/ deficiency
Internal medicine
Insulin Secretion
Internal Medicine
medicine
Insulin
Animals
Homeostasis
Glucose homeostasis
Calcium Signaling
Pancreas
ddc:616
Insulin/secretion
Mice
Knockout
Microscopy
Confocal
Intracellular Signaling Peptides and Proteins/ deficiency
Intracellular Signaling Peptides and Proteins
DNA
Glucose/ metabolism
Phosphoproteins
medicine.disease
Receptor
Insulin
IRS2
Cell biology
Pancreas/ physiology
Glucose
Endocrinology
medicine.anatomical_structure
Phosphoproteins/ deficiency
Insulin Receptor Substrate Proteins
PDX1
Beta cell
Islets of Langerhans/ physiology
Gene Deletion
Zdroj: Diabetologia, Vol. 50, No 6 (2007) pp. 1248-1256
ISSN: 1432-0428
0012-186X
DOI: 10.1007/s00125-007-0637-9
Popis: AIMS/HYPOTHESIS: Insulin signalling pathways regulate pancreatic beta cell function. Conditional gene targeting using the Cre/loxP system has demonstrated that mice lacking insulin receptor substrate 2 (IRS2) in the beta cell have reduced beta cell mass. However, these studies have been complicated by hypothalamic deletion when the RIPCre (B6.Cg-tg(Ins2-cre)25Mgn/J) transgenic mouse (expressing Cre recombinase under the control of the rat insulin II promoter) is used to delete floxed alleles in insulin-expressing cells. These features have led to marked insulin resistance making the beta cell-autonomous role of IRS2 difficult to determine. To establish the effect of deleting Irs2 only in the pancreas, we generated PIrs2KO mice in which Cre recombinase expression was driven by the promoter of the pancreatic and duodenal homeobox factor 1 (Pdx1, also known as Ipf1) gene. MATERIALS AND METHODS: In vivo glucose homeostasis was examined in PIrs2KO mice using glucose tolerance and glucose-stimulated insulin secretion tests. Endocrine cell mass was determined by morphometric analysis. Islet function was examined in static cultures and by performing calcium imaging in Fluo3am-loaded beta cells. Islet gene expression was determined by RT-PCR. RESULTS: The PIrs2KO mice displayed glucose intolerance and impaired glucose-stimulated insulin secretion in vivo. Pancreatic insulin and glucagon content and beta and alpha cell mass were reduced. Glucose-stimulated insulin secretion and calcium mobilisation were attenuated in PIrs2KO islets. Expression of the Glut2 gene (also known as Slc2a2) was also reduced in PIrs2KO mice. CONCLUSIONS/INTERPRETATION: These studies suggest that IRS2-dependent signalling in pancreatic islets is required not only for the maintenance of normal beta and alpha cell mass but is also involved in the regulation of insulin secretion.
Databáze: OpenAIRE
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