Highlights
|
• IRS proteins and cardiovascular disease |
• IRS proteins and diabetic nephropathy |
• IRS proteins in diabetic retinopathy |
• IRS proteins in the brain |
• IRS proteins in diabetic neuropathy |
Introduction
IRS proteins and cardiovascular disease
IRS involved | Mouse model | Organ affected | Main findings | Reference |
---|---|---|---|---|
IRS1, IRS2 | Myocardium-specific Irs1
−/−; Irs2
−/− mice | Heart | In the absence of both Irs1 and Irs2, thinning walls, global dilatation, diastolic failure and decreased systolic activity were evident. Heart failure markers such as β-myosin heavy chain increased and interstitial fibrosis was associated with increased TGFβ1 and collagen 1 mRNA. Myocardium-specific Irs1
−/−; Irs2
−/− mice died at 6–8 weeks of age, yet heterozygous myocardium Irs1
+/−; Irs2
+/− mice survived to at least 6 months of age before fatal cardiac dysfunction developed | Qi et al (2013) [78] |
Mice with specific hepatic deletion of Irs1 and Irs2
| Liver | Hepatic deletion of Irs1 and Irs2 caused a decrease in cardiac IRS1 and IRS2, and similar, albeit less severe, effects on the heart were observed. These mice showed p38MAPK activation, which mediated IRS protein degradation in response to chronic insulin stimulation. These data suggest a new link between hepatic insulin signalling and IRS protein levels in the heart | Qi et al (2013) [78] | |
IRS1 |
ob/ob mice (model of type 2 diabetes) | Heart | Myocardial IRS1–PI3K activity was significantly increased in ob/ob mice vs control. These data were similar to IRS1–PI3K activity in both individuals with type 2 diabetes and those with left ventricular dysfunction, whose myocardium was insulin resistant. IR-β, IRS1 and total and phospho-Akt were also increased in ob/ob mice; however, total IRS1 was unchanged in individuals with type 2 diabetes and left ventricular dysfunction. Insulin-induced Akt phosphorylation was greater in control mice than in ob/ob mice with no alterations in total Akt | Cook et al (2010) [17]a
|
IRS proteins and diabetic nephropathy
IRS protein involved | Rodent genotype/phenotype | Kidney region/cell affected | Main findings | Reference |
---|---|---|---|---|
IRS1 | OLETF rats that developed diabetes and overt nephropathy | Renal cortex | IRS1 protein expression significantly reduced vs control LETO rats | Nakamura et al (2015) [79] |
IRS1 | ROP mice | Isolated mesangial cells | High glucose increased total IRS1 protein expression and IRS1 phosphorylation in mesangial cells from glomerulosclerosis-prone ROP mice, and levels of IGF-1 receptor and IGF-1 also increased. This is consistent with previous data implicating IRS1 as the main IRS protein involved in IGF-1 signalling. ROP mesangial cells expressed less IGFBP-2 vs control mice, and individuals with DN presented with reduced IGFBP-2 in glomeruli vs control individuals, indicating the potential for IGFBP-2 as a marker identifying patient susceptibility to DN. Low levels of IGFBP-2 may play a partial role in increased IGF-1 signalling via IRS1, as treatment of ROP mesangial cells with exogenous IGFBP-2 reduced glucose-induced increases in IRS1 phosphorylation, protecting cells from further damage | |
IRS1 | NOD mice | Isolated mesangial cells | Mesangial cells from NOD mice (model of type 1 diabetes) with nephropathy displayed phenotypic changes such as IGF-1 signalling pathway activation | Fornoni et al (2006) [80] |
IRS1 |
db/db mice | Isolated mesangial cells | Mesangial cells from db/db mice (model of type 2 diabetes) also displayed phenotypic changes, such as IGF-1 signalling pathway activation | Fornoni et al (2006) [80] |
IRS1 | C57BL/6 mice | Isolated mesangial cells | High glucose treatment of control mesangial cells from glomerulosclerosis-resistant C57BL/6 mice yielded changes that were similar to those observed with mesangial cells from NOD and db/db mice. These data suggest that both type 1 and type 2 diabetes stimulate the IGF-1 pathway | Fornoni et al (2006) [80] |
IRS2 | Wild-type, Irs1
−/− and Irs2
−/− mice | Proximal tubule epithelial cells | Insulin-induced increases in tubular bicarbonate ion absorption and Akt phosphorylation were seen in wild-type mice, and this effect was decreased in Irs2
−/− mice. No defects in bicarbonate absorption were seen in Irs1
−/− mice, suggesting that IRS2 coordinates the effects of insulin upon tubular epithelial cell bicarbonate transport | Zheng et al (2005) [82] |
IRS2 | Wild-type mice | Tubular epithelial cells | IRS2 expression detected in embryonic kidney tubules, adult proximal and distal tubules and cortical collecting duct. BMP-7 increased IRS2 signalling in HK-2 proximal tubule epithelial cells | Hookham et al (2013) [37] |
IRS2 |
Irs2
−/− mice | Podocytes |
Irs2
−/− podocytes were found to be insulin resistant with respect to Akt signalling and GLUT4-mediated glucose uptake in response to insulin | Santamaria et al (2015) [36] |
IRS proteins in diabetic retinopathy
IRS involved | Rodent genotype/phenotype | Organ affected | Main findings | Reference |
---|---|---|---|---|
IRS2 |
Irs2
−/− mice | Eye (retina) |
Irs2 gene deletion triggered photoreceptor apoptosis with a 50% reduction in cells by day 14, with almost complete photoreceptor loss by 16 months of age. In contrast, normal retinal morphology was maintained in Irs1
−/− mice at up to 2 years of age. Retinas from Irs2
−/− mice displayed higher caspase-3 cleavage and activation, and lower Akt phosphorylation, consistent with apoptotic cell death. Expression of rhodopsin (the light-sensing G-protein-coupled receptor in the retina) was reduced in Irs2
−/− retinas and retinal electrical function showed that Irs2
−/− mice had reduced dark- and light-adapted responses, suggesting lower rod and cone activity, respectively | Yi et al (2005) [45] |
IRS2 | 9- and 12-week-old Irs2
−/− mice | Eye (retina) | At 9 weeks, activation of Müller glial cells was apparent, as demonstrated by outer retinal layers that were considerably thinner than their wild-type counterparts. Thinning extended to each retinal layer in 12-week-old Irs2
−/− mice. Changes in microglia were also detected at 9 weeks with swelling/retraction of microglial processes observed. In both age groups, shortened rod segments were apparent, and rhodopsin distribution in the rod photoreceptors of the outer nuclear layer was abnormal. Photoreceptor atrophy, as well as synaptic changes at the outer plexiform layer were also observed. Retinal ganglion cell degeneration was present in 12-week-old Irs2
−/− mice with the progressive loss of these cells observed | |
IRS1, IRS2 | STZ-induced model of type 1 diabetes in Sprague–Dawley rats | Eye (retina) | At 1 month post STZ-induced diabetes, retinal IRS1/2-associated PI3K activity, Akt1 and Akt3 kinase activity, and p70S6K/pGSK3β were decreased with no change in retinal IRS1/2 expression or tyrosine phosphorylation. Such rapid signalling changes and alterations in p70S6K and GSK3β as a result of hyperglycaemia provide further evidence of a role for insulin signalling in retinal cell survival. After 3 months, IR-β expression, autophosphorylation and kinase activity was decreased in diabetic retina. Moreover, IRS2 protein expression was decreased whereas IRS1 was unchanged. These data suggest that IR signalling is compromised relatively early in the diabetic retina, and suggests a critical role for reduced insulin in IRS2 signalling in progressive retinal degeneration | Reiter et al (2006) [85] |
IRS proteins in the brain
IRS proteins in diabetic neuropathy
IRS involved | Rodent genotype/phenotype | Organ affected | Main finding(s) | Reference |
---|---|---|---|---|
IR, IRS1 |
ob/ob mice (model of type 2 diabetes) | Spinal dorsal horn region of the spinal cord | Diabetic ob/ob mice displayed PDN in the form of mechanical hyperalgesia, as demonstrated by low paw-withdrawal thresholds. This decrease in withdrawal threshold coincided with reduced p-IRS1 and IR-positive spinal dorsal horn neurons in these mice. As PDN progresses, IR and p-IRS1 levels decline. Also, with progression of PDN, pJAK2 and p-STAT3 levels increase, with specific activation of JAK2/STAT3 occurring in this area. Administration of a JAK2/STAT3 pathway inhibitor reverts the pain threshold to normal levels in ob/ob mice. The JAK/STAT inhibitor also prevented the decrease in IR and p-IRS1, suggesting a link between JAK/STAT, IR/IRS1 signalling and PDN | Kou et al (2013) [73] |
IRS2 | Diabetic GK rats | Neurons | Oral administration of vildagliptin reduced neuronal atrophy and improved neuropathy as evaluated by motor and sensory nerve conduction velocity. Vildagliptin preserved intra-epidermal nerve fibre density in GK rats, which indicates beneficial neuropathic effects. Vildagliptin increased GLP-1 signals such as CREB; PKB/Akt phosphorylation in the dorsal root ganglion, with changes in IRS2Tyr/IRS2Ser phosphorylation also seen. Crosstalk exists between insulin and GLP-1 at least in part through CREB phosphorylation, which promotes IRS2 expression. Of note, hyperglycaemia in these diabetic GK rats was unchanged following vildagliptin treatment, suggesting that vildagliptin functions to inhibit neuropathy development independently of hyperglycaemia | Tsuboi et al (2015) [77] |
IR-β, IRS1, IRS2 | ZDF rats, a long-term model of PDN | Sensory neurons and dorsal root ganglion | Progressive slowing of nerve conduction in the ZDF rats is detected. ZDF rats are more sensitive to mechanical withdrawal (similar to ob/ob mice), suggesting pain sensation from a non-painful stimulation of the skin. Dorsal root ganglion mRNA levels of IR-β, IRS1 and IRS2, Akt, PI3K and GLUT4 were preserved or slightly increased in ZDF rats | Brussee et al (2008) [86] |
IRS2 |
ob/ob mice (model of type 2 diabetes), and STZ C57BL/6 mice (model of type 1 diabetes) | Dorsal root ganglion | Total IRS2 levels decreased in diabetic ob/ob dorsal root ganglion neurons. IRS2 Ser phosphorylation increases in dorsal root ganglion neurons from diabetic ob/ob mice and dorsal root ganglion neurons from an STZ mouse model. Suboptimal dorsal root ganglion insulin signalling may be caused by increased IRS serine phosphorylation, leading to IRS degradation, decreasing IR/IRS interaction. In healthy neurons, insulin increases neurite outgrowth. Neurons from ob/ob mice were unable to efficiently respond to insulin. Increased IRS2 serine phosphorylation and subsequent insulin resistance may modulate neuronal insulin signalling to promote peripheral nerve dysfunction leading to PDN. |