Aging is associated with an increased incidence of type 2 diabetes mellitus. On looking at the characteristics of the age-related decline in insulin secretion that occurs with aging, it appears that the abnormality in insulin secretion from beta cells of the pancreas that occurs in diabetes is an exaggeration of normal aging processes, coupled with increasing demand for insulin release in the setting of insulin resistance. Of great interest is the new information that these changes can be reversed. We treated young (3 months) and old (23 months) Wistar rats with an infusion of human recombinant GLP-1 (1.5 pmol per kg body weight per minute), a naturally-occurring gut peptide, using an ALZET osmotic pump (1003D) implanted subcutaneously in the neck for 5 days. Insulin mRNA was increased 3 fold in the GLP-1 infused animals. Even the old rats which have a lower amount of mRNA (50% lower) for insulin than young rats had a 3 fold increase in insulin mRNA. The abnormality in insulin secretion with aging was also normalized by this treatment. Of great interest is the fact that there is an increase in beta cell mass after chronic treatment with GLP-1. GLP-1 causes stem cells to proliferate which then differentiate into insulin-producing cells. This occurs in stem cells in the acinar and ductal tissue. This phenomenon has not been shown with any previous treatment. It will require further study to determine the mechanism by which GLP-1 activates beta cell specific genes and it has implications for treating pancreatitis and type 1 diabetes, also. Using a ductal cell line, AR42J cells, we have shown that the cells can become insulin- producing when treated with GLP-1, and they become responsive to glucose. We have investigated the intracellular signals involved in the GLP-1 induced differentiation of AR42J cells and found that it is dependent on the continuous activation of the MAP kinase pathway. We plan to do studies in primary duct cell lines to see if the same pathways are involved.
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