Islet neogenesis associated protein transgenic mice are resistant to hyperglycemia induced by streptozotocin

Abstract

Islet neogenesis associated protein (INGAP) is a protein factor that can stimulate new islet mass from adult pancreatic progenitor cells. In models of islet neogenesis, INGAP expression is elevated in pancreatic acinar cells. Using a transgenic model to drive a sustained expression of INGAP in pancreatic acinar cells, we have identified a protection to chemical-induced hyperglycemia. A sustained expression of INGAP during development did not perturb islet development or basal blood glucose homeostasis, although b-cell mass and pancreatic insulin content were significantly increased in the INGAP transgenic mice. When challenged with a diabetogenic dose of streptozotocin (STZ), mice carrying the INGAP transgene did not become hyperglycemic. In contrast, wild-type mice became and remained hyperglycemic, blood glucoseO 550 mg/dl. The serum insulin levels and islet morphology were preserved in the transgenic mice after STZ treatment. These data suggest that the sustained expression of INGAP in the acinar pancreas confers resistance to a diabetogenic insult. The INGAP transgenic mouse provides a new model to uncover factors that are protective to diabetes onset and biomarkers to track b-cell pathology.

Pancreatic acinar-specific overexpression of Reg2 gene offered no protection against either experimental diabetes or pancreatitis in mice

“…4G and 5F). Reg2 expression was significant but patchy, similar to that of INGAP transgenic mice (26). This report was derived from data obtained using founder 4, which were subsequently confirmed in founder 1 of Ela-Reg2 mice.…”

“…Indeed, overexpressed Reg2 protected insulinoma cells against streptozotocin-induced apoptosis (L. Liu et al, unpublished observations); early vaccination with intact Reg2 or the COOH-terminal portion of Reg2 delayed the onset of diabetes in nonobese diabetic (NOD) mice (10). Similarly, overexpressed Reg3␣ increased cyclin D1 and CDK4 levels and the rate of proliferation in insulinoma cells (5), and INGAP, when overexpressed in acinar cells, induced pancreatic islet hyperplasia and protected transgenic mice from streptozotocin-induced diabetes (26). In the acinar cells, the levels of Reg1 and Reg3␤ were drastically increased in edematous or necrotizing pancreatitis (2,11).…”

β-Cell regeneration: the pancreatic intrinsic faculty

“…Whole pancreatic extracts after injury appear to promote b-cell mass augmentation in mice treated with STZ [91,92]. Specifically, two proteins of the Reg family, Reg3 (formerly named INGAP) and PSP/Reg, isolated from pancreatic extracts after cellophane wrapping or 90% partial PX, respectively, were shown to stimulate b-cell growth [93][94][95][96]. Recent clinical studies suggest that INGAP promotes insulin production in T1D patients and ameliorates glycemic control in T2D patients [97].…”

The Role of Reg Proteins, a Family of Secreted C-Type Lectins, in Islet Regeneration and as Autoantigens in Type 1 Diabetes

“…These studies found enhanced glucose tolerance, partial protection from streptozotocin (STZ)-induced diabetes and alterations in gene expression profiles when compared to non-transgenic mice. Overexpression of mRegII targeted to the exocrine pancreas with an elastase-1 promoter failed to provide protection from streptozotocininduced diabetes (Li, Wang et al 2010), whereas hamINGAP targeted to the exocrine pancreas with the same promoter did confer resistance to STZ-induced diabetes and increased the -cell mass (expressed as insulin positive cells and the total pancreatic insulin/protein ratio) as well as the number of smaller islets compared to non transgenic littermates (Taylor-Fishwick, Bowman et al 2006). The findings obtained from the two transgenic models with exocrine targeting of mRegII or hamINGAP were interpreted to indicate that different Reg members could have different effects.…”