Altered glucose-stimulated insulin secretion in a mouse line with activated polyamine catabolism

• Published in: Transgenic research 2012-08, Vol.21 (4), p.843-853
• Main Authors: Cerrada-Gimenez, M, Tusa, M, Casellas, A, Pirinen, E, Moya, M, Bosch, F, Alhonen, L
• Format: Article
• Language: English
• Subjects: Acetyltransferases - genetics; adenosine triphosphate; Adenosine Triphosphate - metabolism; AKT protein; AMP-Activated Protein Kinases - metabolism; Animal Genetics and Genomics; Animals; Beta cells; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biotechnology; Energy balance; energy expenditure; Enzymes; Fundamental and applied biological sciences. Psychology; Genetic Engineering; Genetic technics; Glucose - pharmacology; Glucose tolerance; Glucose transporter; Hepatocyte Nuclear Factor 3-beta - metabolism; Hepatocyte nuclear factor 4; High fat diet; Insulin; Insulin - metabolism; insulin resistance; Insulin Secretion; Insulin-Secreting Cells - metabolism; Islets of Langerhans; Islets of Langerhans - metabolism; Life Sciences; Methods. Procedures. Technologies; Mice; Mice, Transgenic - metabolism; Molecular Medicine; Original Paper; Pancreas; Plant Genetics and Genomics; polyamines; Polyamines - metabolism; Protein kinase; protein kinases; Putrescine; Secretion; Spermidine; Spermine; Transcription factors; Transgenic animals and transgenic plants; Transgenic mice; Transgenics
• ISSN: 0962-8819; 1573-9368
• DOI: 10.1007/s11248-011-9579-6

Ubiquitous activation of polyamine catabolism has been demonstrated to have protective effects in mice on fat accumulation and insulin sensitivity/glucose tolerance in, both, normal conditions and after a high fat diet. We have analyzed the endocrine pancreas functionality in four months-old male mice overexpressing the rate limiting enzyme in the polyamine catabolism, spermidine/spermine N 1-acetyltransferase (SSAT). The pancreatic SSAT activity was 37-fold elevated in the transgenic mice, which reduced the total pancreatic and islet pools of spermidine (71%) and spermine (69%), and increased putrescine and N 1-acetyl spermidine. Reduction in the islet ATP levels (65%) was accompanied with increased transcription of 5′-AMP-activated protein kinase (AMPK) (1.5-fold) and Foxa2 (2.7-fold), and reduced HNF4α (67%) and HNF1α (92%), insulin 1 (47%), insulin 2 (50%), and Glut2 (57%). Moreover, the SSAT transgenic mice also presented increased beta cell area, decreased insulin production, and altered glucose-stimulated insulin secretion. It has been hypothesized that the acute activation of the polyamine catabolism produces a futile cycle that greatly decreases the energy reserves of the cell. The lower energy status would activate the energy expenditure regulator, AMPK, which would consequently repress the PI3K/Akt pathway, and activate the transcription factor Foxa2.