Increased β-Cell Mass by Islet Transplantation and PLAG1 Overexpression Causes Hyperinsulinemic Normoglycemia and Hepatic Insulin Resistance in Mice

• Published in: Diabetes (New York, N.Y.) Vol. 59; no. 8; pp. 1957 - 1965
• Main Authors: DECLERCQ, Jeroen, KUMAR, Anujith, VERFAILFLE, Catherine M, VAN DIEPEN, Janna A, VROEGRIJK, Irene O. C. M, GYSEMANS, Conny, DI PIETRO, Caterina, VOSHOL, Peter J, MATHIEU, Chantal, ECTORS, Nadine, VAN DE VEN, Wim J. M
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.08.2010
• Subjects: Animals; Biological and medical sciences; Blood Glucose - metabolism; Care and treatment; Cell Division; Diabetes. Impaired glucose tolerance; DNA-Binding Proteins - genetics; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gene Expression Regulation; Glucagon - blood; Glucose Clamp Technique; Glucose Tolerance Test; Health aspects; Homeostasis; Hyperinsulinism - genetics; Insulin - blood; Insulin resistance; Insulin Resistance - genetics; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - transplantation; Islet cell transplantation; Islet Studies; Islets of Langerhans Transplantation - physiology; Medical sciences; Metabolic diseases; Mice; Mice, Inbred C57BL; Mice, Transgenic; Risk factors; Belgium; United Kingdom; Endocrinopathy; Hyperinsulinemia; Diabetes mellitus; Langerhans islet; Rodentia; Gene overexpression; Metabolic diseases; Transplantation; Target tissue resistance; Vertebrata; Mammalia; Mouse; Animal; Insulin resistance; β Cell; Endocrine pancreas
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db09-1446

It is believed that an organism remains normoglycemic despite an increase in the beta-cell mass because of decreased insulin production by beta-cells on a per-cell basis. However, some transgenic mouse models with beta-cell hyperplasia suggest that insulin production remains excessive and that normoglycemia is maintained by insulin resistance. Here, we investigated the effect of an increased beta-cell mass on glycemia and insulin resistance by grafting excess normal islets in normoglycemic mice, as well as using targeted PLAG1 expression in beta-cells, which leads to beta-cell expansion. In both models, fasting plasma insulin levels were increased, even though animals were normoglycemic. After an intraperitoneal glucose tolerance test, plasma insulin levels increased, which was associated with improved glucose clearing. Under these conditions, normoglycemia is maintained by hepatic insulin resistance as demonstrated by hyperinsulinemic euglycemic clamp experiments. In conclusion, we demonstrate that when excess beta-cells are grafted, insulin production on a per beta-cell basis is not sufficiently decreased, leading to hyperinsulinemia and hepatic insulin resistance. This observation might be important for the design of stem cell-based islet replacement therapies.