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An Early Insulin Intervention Accelerates Pancreatic ß-Cell Dysfunction in Young Goto-Kakizaki Rats, a Model of Naturally Occurring Noninsulin-Dependent Diabetes¹

Departments of Geriatrics, Endocrinology, and Metabolism (N.S., T.A., N.A., Y.S., M.K., K.Y., K.H.), Laboratory Medicine (H.H.), and Pathology (N.I.), Shinshu University School of Medicine, Matsumoto, Nagano-ken, Japan

Address all correspondence and requests for reprints to: Toru Aizawa, M.D., Department of Geriatrics, Endocrinology, and Metabolism, Shinshu University School of Medicine, 3–1-1 Asahi, Matsumoto, Nagano-ken, Japan.

This study was designed to delineate the nature of ß-cell dysfunction in a model of genetically determined nonobese diabetes, the Goto-Kakizaki (GK) rat. Pancreatic ß-cell function was analyzed immediately after weaning and 5 weeks thereafter, comparing animals with or without insulin treatment during the interval. In 3.5-week-old GK rats, fasting plasma glucose was mildly elevated with normoinsulinemia, and the islet insulin content was reduced by 33%. When incubated with 3–30 mM glucose in vitro, the GK rat islets showed reduced glucose sensitivity, i.e. the EC₅₀ values were 19.5 and 15.9 mM, and the Hill constants for the positive cooperativity 2.1 and 4.2, in the islets of GK and the control rats, respectively. On the other hand, the maximum response to glucose was not attenuated when reduced islet insulin content was considered. In 8.5-week-old GK rats, hyperglycemia worsened and glucose-stimulated insulin release by the islets more severely impaired. A daily insulin injection from the 3.5–8.5 weeks of age significantly lowered plasma glucose in the GK rat, accompanied by a marked suppression of both basal (with 3 mM glucose) and glucose (6–30 mM)-stimulated insulin release by the islets. In the GK rat, ß-cell dysfunction develops by the age of 3.5 weeks, and insulin treatment during the subsequent 5 weeks accelerates its progression.

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