Glucolipotoxicity age-dependently impairs beta cell function in rats despite a marked increase in beta cell mass

• Published in: Diabetologia Vol. 53; no. 11; pp. 2369 - 2379
• Main Authors: Fontés, G., Zarrouki, B., Hagman, D. K., Latour, M. G., Semache, M., Roskens, V., Moore, P. C., Prentki, M., Rhodes, C. J., Jetton, T. L., Poitout, V.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.11.2010; Springer; Springer Nature B.V
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; biosynthesis; Cell Proliferation; Cell Proliferation - drug effects; Cells, Cultured; Diabetes. Impaired glucose tolerance; Disorders of blood lipids. Hyperlipoproteinemia; drug effects; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty Acids; Fatty Acids - toxicity; gene expression; Glucose; Glucose - toxicity; Human Physiology; hyperlipidemia; Immunohistochemistry; In Vitro Techniques; insulin; Insulin - metabolism; Insulin-Secreting Cells; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Internal Medicine; islets of Langerhans; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; metabolism; pathology; Proinsulin; Proinsulin - metabolism; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; toxicity; Hyperglycaemia; Ageing; Glucose clamp; Biosynthesis; Hyperlipidaemia; Islets of Langerhans; Gene expression; Insulin; Endocrinopathy; Pancreatic hormone; Senescence; Rat; Lipids; Glucose; Hyperglycemia; Hyperlipemia; β Cell; Dyslipemia; Age; Endocrine pancreas; Diabetes mellitus; Rodentia; Langerhans islet; Metabolic diseases; Vertebrata; Mammalia; Animal
• ISSN: 0012-186X; 1432-0428; 1432-0428
• DOI: 10.1007/s00125-010-1850-5

Aims/hypothesis Prolonged exposure of pancreatic beta cells to excessive levels of glucose and fatty acids, referred to as glucolipotoxicity, is postulated to contribute to impaired glucose homeostasis in patients with type 2 diabetes. However, the relative contribution of defective beta cell function vs diminished beta cell mass under glucolipotoxic conditions in vivo remains a subject of debate. We therefore sought to determine whether glucolipotoxicity in rats is due to impaired beta cell function and/or reduced beta cell mass, and whether older animals are more susceptible to glucolipotoxic condition. Methods Wistar rats (2 and 6 months old) received a 72 h infusion of glucose + intravenous fat emulsion or saline control. In vivo insulin secretion and sensitivity were assessed by hyperglycaemic clamps. Ex vivo insulin secretion, insulin biosynthesis and gene expression were measured in isolated islets. Beta cell mass and proliferation were examined by immunohistochemistry. Results A 72 h infusion of glucose + intravenous fat emulsion in 2-month-old Wistar rats did not affect insulin sensitivity, insulin secretion or beta cell mass. In 6-month-old rats by contrast it led to insulin resistance and reduced insulin secretion in vivo, despite an increase in beta cell mass and proliferation. This was associated with: (1) diminished glucose-stimulated second-phase insulin secretion and proinsulin biosynthesis; (2) lower insulin content; and (3) reduced expression of beta cell genes in isolated islets. Conclusions/interpretation In this in vivo model, glucolipotoxicity is characterised by an age-dependent impairment of glucose-regulated beta cell function despite a marked increase in beta cell mass.