Altered beta-cell distribution of pdx-1 and GLUT-2 after a short-term challenge with a high-fat diet in C57BL/6J mice.
Mechanisms involved in the islet adaptation to insulin resistance were examined in mice of the C57BL/6J strain challenged with a high-fat (58%) diet for 8 weeks. Basal hyperglycemia commenced after 1 week, whereas hyperinsulinemia evolved after 8 weeks. Glucose elimination after an intravenous glucose challenge (1 g/kg) was significantly delayed after 1, 4, and 8 weeks on the high-fat diet compared with normal-diet-fed mice. This result was associated with unchanged insulin responses. However, glucose-stimulated insulin secretion from isolated islets was increased in a compensatory fashion at all glucose levels over a wide range (3.3-22 mmol/l) after 8 weeks on the high-fat diet, whereas no compensatory hypersecretion of insulin was evident after 1 or 4 weeks, except at 22 mmol/l glucose. Immunohistochemistry revealed that the islet architecture of insulin and glucagon cells remained intact in islets from mice fed a high-fat diet. However, the nuclear translocation of the homeobox transcription factor, pdx-1, and the plasma membrane translocation of GLUT2 were both impaired in high-fat-fed animals after 1 week. In contrast, the expression of the full-length leptin receptor (ObRb) was not affected by high-fat feeding. The study thus shows that 8 weeks are required for the development of a compensatory hypersecretion of insulin after high-fat feeding in mice, and even then the in vivo insulin secretion is insufficient to normalize impaired glucose tolerance. The early-onset islet dysfunction is accompanied by impaired beta-cell trafficking of two factors, pdx-1 and GLUT-2, which are involved in beta-cell proliferation and glucose recognition. The mechanisms compromising this beta-cell trafficking remain to be established.
Reimer
Martina Kvist
MK
Department of Medicine, Lund University, Lund, Sweden. martina.kvist_reimer@med.lu.se
Ahrén
Bo
B
D000818:Animals; D001786:Blood Glucose; D001835:Body Weight; D004041:Dietary Fats / Q000494:pharmacology*; D005260:Female; D005951:Glucose Tolerance Test; D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009004:Monosaccharide Transport Proteins / Q000032:analysis / Q000378:metabolism*; D015534:Trans-Activators / Q000032:analysis / Q000378:metabolism*
D001786:Blood Glucose; D004041:Dietary Fats; D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein