The incretin hormone glucagon-like polypeptide-1 (GLP-1) stimulates pancreatic neogenesis and increases β-cell mass. Therefore its administration to rat pups who have undergone 90% partial pancreatectomy results in an increase in both β-cell mass and improved glucose homeostasis. Exendin-4 is a long-acting GLP-1 which in addition to the aforementioned activities stimulates expression of Pancreatic Duodenal Homeobox (PDX) protein in the pancreas. PDX is critical for the early development of both the endocrine and exocrine pancreas and mediates glucose responsive stimulation of transcription of the insulin gene.

Stoffers and colleagues treated IUGR rat pups with exendin-4 during the early postnatal period to study its effects on the subsequent development of type 2 diabetes. Four groups of rat pups were studied: (1) control pups given vehicle injection, (2) control pups given exendin-4 injections, (3) IUGR pups given vehicle injections, and (4) IUGR pups given exendin-4 injections. Injections were administered on postnatal days 1 through 6. Glucose tolerance, β-cell mass, β-cell proliferation and PDX gene expression were measured at 14 days and 3 months of age. Glucose tolerance was also determined at 7 weeks and 8 months of age.

Exendin–4 decreased weights in both control and IUGR pups (Groups 2 and 4) at 2 weeks. This decrease persisted into adulthood (Table). At day 14, glucose tolerance in the IUGR pups treated with exendin-4 was similar to that in control animals. The treated animals remained euglycemic at 8 months. Vehicle–treated IUGR pups (Group 3) developed diabetes by 3 months and died by 8 months of age. Exendin-4 treated IUGR pups (Group 4) had normal β-cell mass comparable to that in Group 1 as the result of normalized replication rates. While Pdx-1 mRNA levels were reduced by 60% in IUGR rats not receiving exendin-4 at 14 days, those treated with exendin-4 had normal levels.

The authors state their major finding is that a short treatment with exendin-4 during the early newborn period prevents the development of diabetes in the IUGR rat. It is not clear whether this effect is through the stimulation of Pdx-1. However, the effect is independent of β-cell mass, since its effects were observed prior to any reduction in the IUGR pancreatic mass. They suggest that the permanent improvement in maintenance of β-cell mass by exendin-4 may mean that similar drugs could be effective in reducing the risk or preventing type 2 diabetes mellitus in individuals born with IUGR. The negative part of the study was the growth inhibiting effect of exendin-4.

Stoffers DA, et al. Diabetes 2003;52:734-740.