Ins1 Cre knock-in mice for beta cell-specific gene recombination

Abstract

Aims/hypothesisPancreatic beta cells play a central role in the control of glucose homeostasis by secreting insulin to stimulate glucose uptake by peripheral tissues. Understanding the molecular mechanisms that control beta cell function and plasticity has critical implications for the pathophysiology and therapy of major forms of diabetes. Selective gene inactivation in pancreatic beta cells, using the Cre-lox system, is a powerful approach to assess the role of particular genes in beta cells and their impact on whole body glucose homeostasis. Several Cre recombinase (Cre) deleter mice have been established to allow inactivation of genes in beta cells, but many show non-specific recombination in other cell types, often in the brain.MethodsWe describe the generation of Ins1Cre and Ins1CreERT2 mice in which the Cre or Cre-oestrogen receptor fusion protein (CreERT2) recombinases have been introduced at the initiation codon of the Ins1 gene.ResultsWe show that Ins1Cre mice induce efficient and selective recombination of floxed genes in beta cells from the time of birth, with no recombination in the central nervous system. These mice have normal body weight and glucose homeostasis. Furthermore, we show that tamoxifen treatment of adult Ins1CreERT2 mice crossed with Rosa26-tdTomato mice induces efficient recombination in beta cells.Conclusions/interpretationThese two strains of deleter mice are useful new resources to investigate the molecular physiology of pancreatic beta cells.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-014-3468-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Autocrine Action of IGF2 Regulates Adult β-Cell Mass and Function

“…1A), and inactivation of the Igf2 gene was achieved by crossing male Igf2 lox/+ mice with female Ins1Cre mice (29) to induce recombination only in islet b-cells (Fig. 1B).…”

A causal role for hyperinsulinemia in obesity

“…Ins2 can be detected earlier in murine development and has a broader tissue distribution (Deltour et al 1993, Fan et al 2009, Mehran et al 2012. Murine Ins1 expression and promoter activity are largely restricted to the pancreas (Mehran et al 2012, Thorens et al 2015, and it does not contribute as much to pancreatic insulin production as Ins2, except in the mouse embryo during the early stages of pancreatic development (Wentworth et al 1986, Linde et al 1989, Deltour et al 1993, Bengtsson et al 2005. Complete inactivation of both Ins genes in mice (i.e.…”

Zinc and diabetes

“…Thus, expression of ZnT8 in extra-pancreatic tissue seems to be crucial for regulating bodyweight. In this laboratory, we deleted ZnT8 using a highly 10 specific β cell Ins1Cre driver line, which produces no detectable recombination in the hypothalamus [84], thus avoiding potential complications resulting from deletion in appetite centres which occurs after the use of the rat insulin promoter (RIP2Cre) driver line [85].…”

“…Thus, expression of ZnT8 in extra-pancreatic tissue seems to be crucial for regulating bodyweight. In this laboratory, we deleted ZnT8 using a highly 10 specific β cell Ins1Cre driver line, which produces no detectable recombination in the hypothalamus [84], thus avoiding potential complications resulting from deletion in appetite centres which occurs after the use of the rat insulin promoter (RIP2Cre) driver line [85].Confirming previous observations, these animals, depleted for ZnT8 highly specifically in the β cell, presented with impaired glucose tolerance, abnormal granule morphology, reduced cytosolic zinc concentration in the β cells and lower zinc secretion [60]. These findings thus confirm a β cell autonomous action of ZnT8 manipulation.…”