Phenotypic Characterization of MIP-CreERT1Lphi Mice With Transgene-Driven Islet Expression of Human Growth Hormone

Oropeza, Daniel; Jouvet, Nathalie; Budry, Lionel; Campbell, Jonathan E.; Bouyakdan, Khalil; Lacombe, Julie; Perron, Gabrielle; Bergeron, Valérie; Neuman, Joshua C.; Brar, Harpreet K.; Fenske, Rachel J.; Meunier, Clémence; Sczelecki, Sarah; Kimple, Michelle E.; Drucker, Daniel J.; Screaton, Robert A.; Poitout, Vincent; Ferron, Mathieu; Alquier, Thierry; Estall, Jennifer L.

doi:10.2337/db15-0272

Cited by 77 publications

(122 citation statements)

References 41 publications

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“…Interestingly, Oropeza et al (12) did not observe impaired glucose-stimulated insulin secretion and decreased GLUT2 levels as was shown before in the Pdx1-Cre model that also expresses hGH in islets (17). This suggests that these impairments are independent of hGH bioactivity.…”

supporting

confidence: 52%

“…In addition, no adverse effects on glucose tolerance and glucose-stimulated Ca 2+ release were observed (19). However, Oropeza et al (12) provide a more extensive and detailed analysis of this mouse model. First, strong evidence is provided using higher resolution techniques and the mT/mG reporter line (20) that Cre activity is indeed exclusively found in b-cells and not in hypothalamic or hindbrain nuclei, as was reported before in other strains (7,8).…”

mentioning

confidence: 98%

“…In this issue of Diabetes, Oropeza et al (12) describe yet another concern in the tamoxifen-inducible MIP-CreERT 1Lphi mouse line caused by transgenic human growth hormone (hGH) expression. In the 1980s, a pioneering study described that the presence of introns induces more efficient transgene expression (13).…”

mentioning

confidence: 99%

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Human Growth Hormone in Transgenesis: A Growing Problem?

Brouwers

Creemers

2015

Diabetes

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supporting

confidence: 52%

mentioning

confidence: 98%

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Human Growth Hormone in Transgenesis: A Growing Problem?

Brouwers

Creemers

2015

Diabetes

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“…The MIP-CCK mice are therefore a model of ␤-cell-derived CCK overexpression, with ␤-cell CCK expression levels similar to those found in obese models. Recently, several reports have described expression of human growth hormone (hGH) protein from the hGH minigene, which is included in many murine transgene constructs to increase transgene expression (3,6,45). As our MIP-CCK construct contained the same hGH minigene, we needed to examine whether we also had expression of hGH protein.…”

Section: E821mentioning

confidence: 99%

Cholecystokinin expression in the β-cell leads to increased β-cell area in aged mice and protects from streptozotocin-induced diabetes and apoptosis

Lavine

Kibbe

Baan

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Lavine JA, Kibbe CR, Baan M, Sirinvaravong S, Umhoefer HM, Engler KA, Meske LM, Sacotte KA, Erhardt DP, Davis DB. Cholecystokinin expression in the ␤-cell leads to increased ␤-cell area in aged mice and protects from streptozotocin-induced diabetes and apoptosis. Am J Physiol Endocrinol Metab 309: E819 -E828, 2015. First published September 22, 2015; doi:10.1152/ajpendo.00159.2015.-Cholecystokinin (CCK) is a peptide hormone produced in the gut and brain with beneficial effects on digestion, satiety, and insulin secretion. CCK is also expressed in pancreatic ␤-cells, but only in models of obesity and insulin resistance. Whole body deletion of CCK in obese mice leads to reduced ␤-cell mass expansion and increased apoptosis. We hypothesized that islet-derived CCK is important in protection from ␤-cell apoptosis. To determine the specific role of ␤-cell-derived CCK in ␤-cell mass dynamics, we generated a transgenic mouse that expresses CCK in the ␤-cell in the lean state (MIP-CCK). Although this transgene contains the human growth hormone minigene, we saw no expression of human growth hormone protein in transgenic islets. We examined the ability of MIP-CCK mice to maintain ␤-cell mass when subjected to apoptotic stress, with advanced age, and after streptozotocin treatment. Aged MIP-CCK mice have increased ␤-cell area. MIP-CCK mice are resistant to streptozotocin-induced diabetes and exhibit reduced ␤-cell apoptosis. Directed CCK overexpression in cultured ␤-cells also protects from cytokineinduced apoptosis. We have identified an important new paracrine/ autocrine effect of CCK in protection of ␤-cells from apoptotic stress. Understanding the role of ␤-cell CCK adds to the emerging knowledge of classic gut peptides in intraislet signaling. CCK receptor agonists are being investigated as therapeutics for obesity and diabetes. While these agonists clearly have beneficial effects on body weight and insulin sensitivity in peripheral tissues, they may also directly protect ␤-cells from apoptosis.cholecystokinin; islet; ␤-cell; apoptosis; aging; streptozotocin TYPE 1 AND TYPE 2 DIABETES MELLITUS are both diseases of reduced ␤-cell mass. In type 1 diabetes, autoimmune destruction of ␤-cells results in an absolute ␤-cell mass deficit. In type 2 diabetes, obesity increases insulin resistance, resulting in a relative insulin deficiency. In patients with type 2 diabetes, ␤-cell mass is lost via increased ␤-cell apoptosis (7, 16). Therefore, there has been wide interest in the development of diabetes therapeutics that preserve ␤-cell mass and prevent ␤-cell apoptosis.Cholecystokinin (CCK) is a gastrointestinal peptide produced by duodenal I cells and secreted in response to fat and protein (31). CCK signals through two G protein-coupled receptors, the CCK1(A) receptor [CCK1(A)R] and the CCK2(B) receptor [CCK2(B)R]. In healthy and diabetic patients, CCK infusion increases insulin secretion and decreases glucose excursion after a meal, suggesting that CCK is a potential diabetes therapeutic (1, 2). CCK also increases satiety by ...

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“…Recently it has been reported that glucose tolerance is altered in MIP-CreERT mice under certain conditions. 41 In pooling female littermate control data, it was determined that MIP-CreERT mice did not differ from wildtype or PKA-CaR littermates in either body weight (P > 0.05, 1-way ANOVA) or in glucose tolerance (P > 0.05, 2-way ANOVA). The PKA-CaR allele was induced by administering tamoxifen at 10 weeks of age by injecting 3 mg i.p.…”

Section: Animalsmentioning

confidence: 99%

Long-term activation of PKA inβ-cells provides sustained improvement to glucose control, insulin sensitivity and body weight

Levine

Kaihara

Layden

et al. 2016

Islets

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(2016) Long-term activation of PKA in β-cells provides sustained improvement to glucose control, insulin sensitivity and body weight, Islets, 8:5, 125-134, DOI: 10.1080/19382014.2016 To link to this article: https://doi.org/10. 1080/19382014.2016 ABSTRACTType 2 diabetes is associated with obesity, insulin resistance and b-cell failure. Therapeutic aims are to reduce adiposity, improve insulin sensitivity and enhance b-cell function. However, it has been proposed that chronically increasing insulin release leads to b-cell exhaustion and failure. We previously developed mice to have increased activity of the cAMP-dependent protein kinase (PKA), specifically in b-cells (b-caPKA mice). b-caPKA mice have enhanced acute phase insulin release, which is the primary determinant of the efficacy of glucose clearance. Here these mice were used to determine the sustainability of enhanced insulin secretion, and to characterize peripheral effects of enhanced b-cell function. Increased PKA activity was induced by tamoxifen administration at 10 weeks of age. Male mice were aged to 12 months of age and female mice to 16 months. Glucose control in both male and female b-caPKA mice was significantly improved relative to littermate controls with ad libitum feeding, upon refeeding after fasting, and in glucose tolerance tests. In female mice insulin release was both greater and more rapid than in controls. Female mice were more insulin sensitive than controls. Male and female b-caPKA mice had lower body weights than controls. DEXA analysis of male mice revealed that this was due to reduced adiposity and not due to changes in lean body mass. This study indicates that targeting b-cells to enhance insulin release is sustainable, maintains insulin sensitivity and reduces body weight. These data identify b-cell PKA activity as a novel target for obesity therapies.

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Phenotypic Characterization of MIP-CreERT1Lphi Mice With Transgene-Driven Islet Expression of Human Growth Hormone

Cited by 77 publications

References 41 publications

Human Growth Hormone in Transgenesis: A Growing Problem?

Human Growth Hormone in Transgenesis: A Growing Problem?

Cholecystokinin expression in the β-cell leads to increased β-cell area in aged mice and protects from streptozotocin-induced diabetes and apoptosis

Long-term activation of PKA inβ-cells provides sustained improvement to glucose control, insulin sensitivity and body weight

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