Importance of Impaired Insulin-Gene Expression in Occurrence of Diabetes in Obese Rats

To investigate the role of the β-cell in the occurrence of diabetes in obesity, longitudinal changes of insulingene expression and pancreatic insulin content were compared among genetically obese diabetic (Wistar fatty) rats, genetically obese nondiabetic (Zucker fatty) rats, and ventromedial hypothalamus (VMH)-lesioned obese rats. Plasma glucose levels were significantly elevated with age in Wistar fatty rats, whereas they were virtually unchanged in VMH-lesioned and Zucker fatty rats. Obesity and hyperinsulinemia were evident in VMH-lesioned rats 1 wk after the operation and in Zucker and Wistar fatty rats at 5 wk of age. In VMHlesioned rats, the pancreatic preproinsulin I mRNA (pplmRNA) level and pancreatic insulin content markedly increased approximately two- to threefold (P < 0.001) with the development of hyperinsulinemia, whereas sham-operated rats showed no significant change. In Zucker and Wistar lean rats, the pplmRNA level and pancreatic insulin content increased with age, corresponding to increases in body weight. In Zucker fatty rats, the pplmRNA level and pancreatic insulin content at 5 and 14 wk of age were significantly higher than those of lean littermates. The pplmRNA level in Zucker fatty rats at 14 wk of age reached 290% of that of their lean littermates (P < 0.001). On the other hand, the pplmRNA level and pancreatic insulin content in Wistar fatty rats at 5 and 14 wk of age did not increase more than those of their lean littermates at the corresponding ages and were therefore significantly lower than in Zucker fatty rats, which had a higher grade of hyperinsulinemia at 14 wk of age. The pplmRNA level in Wistar fatty rats at 14 wk of age was found to be 41% of that of Zucker fatty rats at corresponding age (P < 0.001). Increased pplmRNA level in association with hyperinsulinemia in VMHlesioned and Zucker fatty rats suggests that the activation of insulin-gene expression for adaptation to a large demand for insulin is common to obesity without diabetes (both experimental and genetic). Furthermore, the inability to augment pplmRNA level to meet a large demand for insulin in Wistar fatty rats is associated with the occurrence of diabetes. These findings suggest that obesity induces diabetes only when a primary defect exists in the β-cell.