A method by which to reverse the process that leads to destruction of pancreatic islet cells and type 1 diabetes mellitus is the "Holy Grail" that all diabetologists seek.  In the present report from Barcelona, the investigators of the School of Veterinary Medicine and Gene Therapy Center succeeded in doing just that in an animal model in which the key is selective overexpression of IGF-I in β-cells. 

Transgenic mice were developed in which mouse IGF-I was linked to the rat insulin promoter and thus targeted to the β-cell, where IGF-I expression was many fold greater than in control animals.  In these mice, at 6 months of age there was a 1.5 fold increase in β-cell mass but normal pancreatic insulin content.  Circulating concentrations of IGF-I were comparable in control and transgenic animals.  The latter did not develop hypoglycemia, hyperinsulinemia, or neoplasms and had normal life span and reproduction. 

At two months of age, administration of streptozotocin (STZ) led to the development of insulitis, hyperglycemia, hypoinsulinemia, and death at four months of age in the control groups from two strains of mice (C57BL and CD-1) utilized.  In the C57BL mice which overexpressed IGF-I only in the β-cell, STZ lead to transient modest hyperglycemia, impaired insulin secretion, mild but reversible insulitis, and subsequent normal life span.  In the CD-1 transgenic mice, hyperglycemia and hypoinsulinemia following STZ were extreme, but again transient with long term survival (Figure).  After recovery from hyperglycemia, the growth was normal in the β-cell-targeted IGF-I transgenic animals. 

Histological examination in C57BL mice revealed a mild decrease in islet β-cells and budding of insulin containing cells from pancreatic ductal epithelium.  Thus, IGF-I appeared to at least partially protect β-cells from destruction while also increasing generation of new β-cell precursors.  Since the β-cell IGF-I receptor is found on the β-cell membrane, the high levels of IGF-I synthesized by the β-cell specific IGF-I transgenic mice must be acting in a paracrine or autocrine manner to protect β-cells insulted by STZ.

Histological examination in the CD-1 mice revealed much less severe insulitis in the transgenic STZ treated mice than in the control STZ treated animals.  There was slow recovery from insulitis, but with β-cell proliferation and neogenesis, blood sugar and insulin serum levels were restored to normal. 

The authors concluded that co-expression of IGF-I and insulin in β-cells protected these cells from permanent destruction by STZ by increasing resistance to the inflammatory insult itself, augmenting β-cell division, and encouraging differentiation of new β-cells.  They suggest that IGF-I may be a candidate gene for transfer to pancreatic β-cells in the gene therapy of patients developing type 1 diabetes mellitus.

Editor’s Comment:  This exciting paper raises the possibility that IGF-I might be capable of halting the progression of β-cell loss in patients developing type 1 diabetes mellitus if a method can be found to target this growth factor to the insulted β-cell in the intact patient.  Perhaps equally feasible, and possibly even more beneficial, might be the insertion of IGF-I into the β-cells of patients at risk for development of type 1 diabetes mellitus to "protect" or to help them recover from the anticipated insults in the future that will lead to insulinitis.  The latter objective may be more useful because the present experiments, which were successful, were conducted in animals that had high IGF-I pancreatic islet contact before the STZ insult.  Such an approach would, hopefully, simulate the successful experiment recorded in this article.

Allen Root, MD

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