title: A general and islet cell-enriched overexpression of IGF-I results in normal islet cell growth, hypoglycemia, and significant resistance to experimental diabetes.
abstract: Insulin-like growth factor I (IGF-I) is normally produced from hepatocytes and various other cells and tissues, including the pancreas, and is known to stimulate islet cell replication in vitro, prevent Fas-mediated beta-cell destruction and delay the onset of diabetes in nonobese diabetic mice. Recently, however, the notion that IGF-I stimulates islet cell growth has been challenged by the results of IGF-I and receptor gene targeting. To test the effects of a general, more profound increase in circulating IGF-I on islet cell growth and glucose homeostasis, we have characterized MT-IGF mice, which overexpress the IGF-I gene under the metallothionein I promoter. In early reports, a 1.5-fold-elevated serum IGF-I level caused accelerated somatic growth and pancreatic enlargement. We demonstrated that the transgene expression, although widespread, was highly concentrated in the beta-cells of the pancreatic islets. Yet, islet cell percent and pancreatic morphology were unaffected. IGF-I overexpression resulted in significant hypoglycemia, hypoinsulinemia, and improved glucose tolerance but normal insulin secretion and sensitivity. Pyruvate tolerance test indicated significantly suppressed hepatic gluconeogenesis, which might explain the severe hypoglycemia after fasting. Finally, due to a partial prevention of beta-cell death against onset of diabetes and/or the insulin-like effects of IGF-I overexpression, MT-IGF mice (which overexpress the IGF-I gene under the metallothionein I promoter) were significantly resistant to streptozotocin-induced diabetes, with diminished hyperglycemia and prevention of weight loss and death. Although IGF-I might not promote islet cell growth, its overexpression is clearly antidiabetic by improving islet cell survival and/or providing insulin-like effects.
authors.affiliation: Fraser Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Katie
authors.initials: K
authors.lastname: Robertson
authors.forename: Yarong
authors.initials: Y
authors.lastname: Lu
authors.forename: Kristine
authors.initials: K
authors.lastname: De Jesus
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.forename: Qing
authors.initials: Q
authors.lastname: Su
authors.forename: P Kay
authors.initials: PK
authors.lastname: Lund
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Liu
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005455:Fluorescent Antibody Technique; D005943:Gluconeogenesis / Q000235:genetics; D005951:Glucose Tolerance Test; D006801:Humans; D007003:Hypoglycemia / Q000378:metabolism*; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis* / Q000235:genetics; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D008668:Metallothionein / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D011773:Pyruvates / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D007328:Insulin; D011773:Pyruvates; D012313:RNA; D007334:Insulin-Like Growth Factor I; D008668:Metallothionein