Mice with targeted knockout of insulin receptor from the proximal tubule have impaired glucose tolerance

Abstract

Recently, we demonstrated basolateral and brush border staining for the insulin receptor (IR) in the proximal tubule (PT) of rodents by immunofluoresence. Expression of IR was reduced in the PT of insulin resistant rats. In order to evaluate the physiological relevance of the IR in PT, we generated PT IR knockout mice using a Cre‐ loxP recombination strategy. Mice homozygous for loxP‐flanked IR gene were crossed with mice heterozygous for Cre‐recombinase driven by the type I gamma glutamyltransferase promoter, PT‐specific promoter. Young male PTKO mice exhibited a mild diabetic phenotype as indicated by their significantly higher plasma glucose levels relative to their wild‐type (WT) littermates (mmol/L): 7.8 ± 0.2 vs. 10.5 ± 1.1 for WT and PTKO respectively, p = 0.03. To determine whether these mice had slower/impaired rate of glucose clearance, mice were injected with 5 ml/kg.bw of 20% dextrose intraperitoneally followed by measurement of blood glucose levels at 15, 30, 60, 90 and 120 minutes. PTKO mice showed impaired GT as evidenced by significantly higher area under the curve for glucose over time: 15.5 ± 1.1 vs. 19.6 ± 1.4 mmol/L·hour for WT and PTKO mice respectively, p = 0.04. PTKO mice excreted significantly higher insulin levels in their urine than WT under basal state (pmol/24 hours): 0.05 ± 0.02 vs. 0.19 ± 0.05, p=0.04. Plasma insulin levels however were not significantly different 210 ± 56 vs. 361 ± 84 pmol/L, p=0.2. These results support a physiologic role for IR in the proximal tubule to affect whole body glucose tolerance; and furthermore, suggest that down regulation of IR in renal PT in obesity may have a causative influence on whole‐body glucose utilization. Supported by HL074142