Dissociation of lipotoxicity and glucotoxicity in a mouse model of obesity associated diabetes: role of forkhead box O1 (FOXO1) in glucose-induced beta cell failure
| Autor: | Stephan Scherneck, Susanne Neschen, Reinhart Kluge, D Kaiser, HG Joost, O Kluth, Annette Schürmann, F. Mirhashemi |
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| Rok vydání: | 2010 |
| Předmět: |
Blood Glucose
Male Maf Transcription Factors Large Endocrinology Diabetes and Metabolism medicine.medical_treatment Apoptosis FOXO1 Proto-Oncogene Mas Diet Carbohydrate-Restricted Mice Insulin-Secreting Cells Insulin Phosphorylation Glucotoxicity Forkhead Box Protein O1 Forkhead Transcription Factors Immunohistochemistry Lipotoxicity Islets Beta cell MIN6 cells endocrine system medicine.medical_specialty Blotting Western Carbohydrates Biology Article Cell Line Islets of Langerhans Internal medicine Diabetes mellitus Transcription factors Diabetes Mellitus Internal Medicine medicine Animals Obesity Transcription factor Homeodomain Proteins medicine.disease Glucose Endocrinology Beta cell failure Hyperglycemia Trans-Activators NZO |
| Zdroj: | Diabetologia |
| ISSN: | 1432-0428 0012-186X |
| DOI: | 10.1007/s00125-010-1973-8 |
| Popis: | Aims/hypothesis Carbohydrate-free diet prevents hyperglycaemia and beta cell destruction in the New Zealand Obese (NZO) mouse model. Here we have used a sequential dietary regimen to dissociate the effects of obesity and hyperglycaemia on beta cell function and integrity, and to study glucose-induced alterations of key transcription factors over 16 days. Methods Mice were rendered obese by feeding a carbohydrate-free diet for 18 weeks. Thereafter, a carbohydrate-containing diet was given. Plasma glucose, plasma insulin and total pancreatic insulin were determined, and forkhead box O1 protein (FOXO1) phosphorylation and the transcription factors pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 protein (NKX6.1) and v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (avian) (MAFA) were monitored by immunohistochemistry for 16 days. Results Dietary carbohydrates produced a rapid and continuous increase in plasma glucose in NZO mice between day 2 and 16 after the dietary challenge. Hyperglycaemia caused a dramatic dephosphorylation of FOXO1 at day 2, followed by a progressive depletion of insulin stores. The loss of beta cells was triggered by apoptosis (detectable at day 8), associated with reduction of crucial transcription factors (PDX1, NKX6.1 and MAFA). Incubation of isolated islets from carbohydrate-restricted NZO mice or MIN6 cells with palmitate and glucose for 48 h resulted in a dephosphorylation of FOXO1 and thymoma viral proto-oncogene 1 (AKT) without changing the protein levels of both proteins. Conclusions/interpretation The dietary regimen dissociates the effects of obesity (lipotoxicity) from those of hyperglycaemia (glucotoxicity) in NZO mice. Obese NZO mice are unable to compensate for the carbohydrate challenge by increasing insulin secretion or synthesising adequate amounts of insulin. In response to the hyperglycaemia, FOXO1 is dephosphorylated, leading to reduced levels of beta cell-specific transcription factors and to apoptosis of the cells. Electronic supplementary material The online version of this article (doi:10.1007/s00125-010-1973-8) contains supplementary material, which is available to authorised users. |
| Databáze: | OpenAIRE |
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