Genetic manipulation of insulin signaling, action and secretion in mice

Baudry, Anne; Leroux, Loïc; Jackerott, Malene; Joshi, Rajiv L.

doi:10.1093/embo-reports/kvf078

Cited by 33 publications

(14 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, insulin receptor inactivation in the liver also resulted in hyperinsulinemia, hepatic insulin resistance, and peripheral insulin resistance (Michael et al . 2000, Baudry et al . 2002, Mauvais-Jarvis et al .…”

Section: Current Understanding Of T2dmmentioning

confidence: 99%

Current views on type 2 diabetes

Yan

Sun

2009

Journal of Endocrinology

386

253

View full text Add to dashboard Cite

Type 2 diabetes mellitus (T2DM) affects a large population worldwide. T2DM is a complex heterogeneous group of metabolic disorders including hyperglycemia and impaired insulin action and/or insulin secretion. T2DM causes dysfunctions in multiple organs or tissues. Current theories of T2DM include a defect in insulin-mediated glucose uptake in muscle, a dysfunction of the pancreatic b-cells, a disruption of secretory function of adipocytes, and an impaired insulin action in liver. The etiology of human T2DM is multifactorial, with genetic background and physical inactivity as two critical components.The pathogenesis of T2DM is not fully understood. Animal models of T2DM have been proved to be useful to study the pathogenesis of, and to find a new therapy for, the disease. Although different animal models share similar characteristics, each mimics a specific aspect of genetic, endocrine, metabolic, and morphologic changes that occur in human T2DM. The purpose of this review is to provide the recent progress and current theories in T2DM and to summarize animal models for studying the pathogenesis of the disease.

show abstract

Section: Current Understanding Of T2dmmentioning

confidence: 99%

Current views on type 2 diabetes

Yan

Sun

2009

Journal of Endocrinology

386

253

View full text Add to dashboard Cite

show abstract

“…Impaired action and/or secretion of insulin cause diabetes [1][2][3]. PTEN (phosphatase and tensin homolog deleted on chromosome 10), originally discovered as a tumor suppressor [4,5], was increasingly found to be impor-tant in insulin signaling [6].…”

Section: Introductionmentioning

confidence: 99%

Pancreas-specific Pten deficiency causes partial resistance to diabetes and elevated hepatic AKT signaling

et al. 2009

View full text Add to dashboard Cite

PTEN, a negative regulator of the phosphatidylinositol-3-kinase/AKT pathway, is an important modulator of insulin signaling. To determine the metabolic function of pancreatic Pten, we generated pancreas-specific Pten knockout (PPKO) mice. PPKO mice had enlarged pancreas and elevated proliferation of acinar cells. They also exhibited hypoglycemia, hypoinsulinemia, and altered amino metabolism. Notably, PPKO mice showed delayed onset of streptozotocin (STZ)-induced diabetes and sex-biased resistance to high-fat-diet (HFD)-induced diabetes. To investigate the mechanism for the resistance to HFD-induced hyperglycemia in PPKO mice, we evaluated AKT phosphorylation in major insulin-responsive tissues: the liver, muscle, and fat. We found that Pten loss in the pancreas causes the elevation of AKT signaling in the liver. The phosphorylation of AKT and its downstream substrate GSK3b was increased in the liver of PPKO mice, while PTEN level was decreased without detectable excision of Pten allele in the liver of PPKO mice. Proteomics analysis revealed dramatically decreased level of 78-kDa glucose-regulated protein (GRP78) in the liver of PPKO mice, which may also contribute to the lower blood glucose level of PPKO mice fed with HFD. Together, our findings reveal a novel response in the liver to pancreatic defect in metabolic regulation, adding a new dimension to understanding diabetes resistance.

show abstract

“…Signaling of insulin through its cell surface receptor (insulin receptor [IR]) and downstream substrates (IRS isoforms) has been highlighted in recent genetically engineered mouse models (5). These studies emphasize the importance of insulin signaling in the control of glycemia and demonstrate the intricacies involved in glucose metabolism.…”

mentioning

confidence: 99%

Insulin Hypersensitivity and Resistance to Streptozotocin-Induced Diabetes in Mice Lacking PTEN in Adipose Tissue

Kurlawalla-Martinez¹,

Stiles

Wang

et al. 2005

Molecular and Cellular Biology

172

135

View full text Add to dashboard Cite

In adipose tissue, insulin controls glucose and lipid metabolism through the intracellular mediators phosphatidylinositol 3-kinase and serine-threonine kinase AKT. Phosphatase and a tensin homolog deleted from chromosome 10 (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/AKT pathway, is hypothesized to inhibit the metabolic effects of insulin. Here we report the generation of mice lacking PTEN in adipose tissue. Loss of Pten results in improved systemic glucose tolerance and insulin sensitivity, associated with decreased fasting insulin levels, increased recruitment of the glucose transporter isoform 4 to the cell surface in adipose tissue, and decreased serum resistin levels. Mutant animals also exhibit increased insulin signaling and AMP kinase activity in the liver. Pten mutant mice are resistant to developing streptozotocin-induced diabetes. Adipose-specific Pten deletion, however, does not alter adiposity or plasma fatty acids. Our results demonstrate that in vivo PTEN is a potent negative regulator of insulin signaling and insulin sensitivity in adipose tissue. Furthermore, PTEN may be a promising target for nutritional and/or pharmacological interventions aimed at reversing insulin resistance.

show abstract

Genetic manipulation of insulin signaling, action and secretion in mice

Cited by 33 publications

References 38 publications

Current views on type 2 diabetes

Current views on type 2 diabetes

Pancreas-specific Pten deficiency causes partial resistance to diabetes and elevated hepatic AKT signaling

Insulin Hypersensitivity and Resistance to Streptozotocin-Induced Diabetes in Mice Lacking PTEN in Adipose Tissue

Contact Info

Product

Resources

About