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Restored insulin-sensitivity in IRS-1-deficient mice treated by adenovirus-mediated gene therapy
K Ueki1, T Yamauchi, H Tamemoto
1Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Abstract:
Insulin resistance is commonly observed both in overt diabetes and in individuals prone to, but not yet manifesting, diabetes. Hence the maintenance or restoration of insulin sensitivity may prevent the onset of this disease. We previously showed that homozygous disruption of insulin receptor substrate-1 (IRS-1) in mice resulted in insulin resistance but not diabetes. Here, we have explored the mechanism of systemic insulin resistance in these mice and used adenovirus-mediated gene therapy to restore their insulin sensitivity. Mice expressing the IRS-1transgene showed almost normal insulin sensitivity. Expression of an IRS-1 mutant (IRS-1Deltap85) lacking the binding site for the p85 subunit of phosphatidylinositol 3-kinase (PI3K) also restored insulin sensitivity, although PI3K is known to play a crucial role in insulin's metabolic responses. Protein kinase B (PKB) activity in liver was decreased in null mice compared with the wild-type and the null mice expressing IRS-1 or IRS-1Deltap85. In primary hepatocytes isolated from null mice, expression of IRS-1 enhanced both PI3K and PKB activities, but expression of IRS-1Deltap85 enhanced only PKB. These data suggest that PKB in liver plays a pivotal role in systemic glucose homeostasis and that PKB activation might be sufficient for reducing insulin resistance even without full activation of PI3K.
Insights
Restoring insulin sensitivity may prevent diabetes. In mice lacking insulin receptor substrate-1 (IRS-1), activating Protein Kinase B (PKB) in the liver improved insulin sensitivity, even without fully activating phosphatidylinositol 3-kinase (PI3K).
Area of Science:
- Molecular Biology
- Metabolic Diseases
- Genetics
Background:
- Insulin resistance is a precursor to type 2 diabetes.
- Insulin receptor substrate-1 (IRS-1) plays a key role in insulin signaling.
- Previous studies showed IRS-1 disruption causes insulin resistance but not diabetes.
Purpose of the Study:
- To investigate the mechanism of systemic insulin resistance in IRS-1 deficient mice.
- To explore the potential of gene therapy to restore insulin sensitivity.
- To elucidate the roles of phosphatidylinositol 3-kinase (PI3K) and Protein Kinase B (PKB) in insulin resistance.
Main Methods:
- Adenovirus-mediated gene therapy was used to reintroduce IRS-1 or a mutant IRS-1 (IRS-1Deltap85) lacking the PI3K binding site.
- Insulin sensitivity was assessed in genetically modified mice.
- PKB and PI3K activities were measured in liver tissue and primary hepatocytes.
Main Results:
- Mice expressing IRS-1 or IRS-1Deltap85 showed restored insulin sensitivity.
- PKB activity in the liver was reduced in IRS-1 deficient mice but restored upon IRS-1 or IRS-1Deltap85 expression.
- IRS-1Deltap85 expression enhanced PKB activity in hepatocytes without significantly enhancing PI3K activity.
Conclusions:
- PKB activation in the liver is crucial for systemic glucose homeostasis.
- PKB activation may be sufficient to reduce insulin resistance, independent of full PI3K activation.
- Targeting PKB could be a therapeutic strategy for managing insulin resistance and preventing diabetes.
