Abstract
ABSTRACTType 2 diabetes mellitus is a complex metabolic disease and its pathogenesis involves abnormalities in both peripheral insulin action and insulin secretion. Previous in vitro data showed that insulin receptor isoform A, but not B, favours basal glucose uptake through its specific association with endogenous GLUT1/2 in murine hepatocytes and beta cells. With this background, we hypothesized that hepatic expression of insulin receptor isoform A in a mouse model of type 2 diabetes could potentially increase the glucose uptake of these cells, decreasing the hyperglycaemia and therefore ameliorating the diabetic phenotype. To assure this hypothesis, we have developed recombinant adeno-associated viral vectors expressing insulin receptor isoform A (IRA) or isoform B (IRB) under the control of a hepatocyte-specific promoter. Our results demonstrate that in the long term, hepatic expression of IRA in diabetic mice is more efficient than IRB in ameliorating glucose intolerance. Consequently, it impairs the induction of compensatory mechanisms through beta cell hyperplasia and/or hypertrophy that finally lead to beta cell failure, reverting the diabetic phenotype in about 8 weeks. Our data suggest that long-term hepatic expression of IRA could be a promising therapeutic approach for the treatment of type 2 diabetes mellitus.
Highlights
Owing to the central role of the liver in the control of glucose homeostasis, hepatic insulin resistance becomes a hallmark of Type 2 diabetes mellitus (T2DM) (Michael et al, 2000; Cook et al, 2015), and, precise regulation of glucose homeostasis is a major challenge in diabetes management (Callejas et al, 2003)
Generation and analysis of inducible liver insulin receptor knockout mice iLIRKO mice were created by breeding mice carrying insulin receptor alleles modified with loxP sites flanking exon 4 (Brüning et al, 1998) with mice in which the tamoxifen-dependent CreERT2 recombinase gene was located under the albumin promoter (Schuler et al, 2004)
Deletion of insulin receptor (Insr) exon 4 was analysed by quantitative real-time PCR of genomic DNA samples isolated from the total pool of the liver from control or iLIRKO mice, showing that IR was sufficiently reduced in iLIRKO mice as compared with controls (Fig. 1B)
Summary
Type 2 diabetes mellitus (T2DM) results from a combination of insulin resistance and impaired insulin secretion, where insulin. Insulin resistance affects several tissues that are relevant in glucose homeostasis such as liver, skeletal muscle and the adipose organ (Muoio and Newgard, 2008). Owing to the central role of the liver in the control of glucose homeostasis, hepatic insulin resistance becomes a hallmark of T2DM (Michael et al, 2000; Cook et al, 2015), and, precise regulation of glucose homeostasis is a major challenge in diabetes management (Callejas et al, 2003)
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