Selective Insulin Resistance in the Kidney

Abstract

Insulin resistance has been characterized as attenuation of insulin sensitivity at target organs and tissues, such as muscle and fat tissues and the liver. The insulin signaling cascade is divided into major pathways such as the PI3K/Akt pathway and the MAPK/MEK pathway. In insulin resistance, however, these pathways are not equally impaired. For example, in the liver, inhibition of gluconeogenesis by the insulin receptor substrate (IRS) 2 pathway is impaired, while lipogenesis by the IRS1 pathway is preserved, thus causing hyperglycemia and hyperlipidemia. It has been recently suggested that selective impairment of insulin signaling cascades in insulin resistance also occurs in the kidney. In the renal proximal tubule, insulin signaling via IRS1 is inhibited, while insulin signaling via IRS2 is preserved. Insulin signaling via IRS2 continues to stimulate sodium reabsorption in the proximal tubule and causes sodium retention, edema, and hypertension. IRS1 signaling deficiency in the proximal tubule may impair IRS1-mediated inhibition of gluconeogenesis, which could induce hyperglycemia by preserving glucose production. In the glomerulus, the impairment of IRS1 signaling deteriorates the structure and function of podocyte and endothelial cells, possibly causing diabetic nephropathy. This paper mainly describes selective insulin resistance in the kidney, focusing on the proximal tubule.

Figure 1

Typical insulin signaling cascade. Insulin binds to insulin receptor in the cell surface [, –15]. The signal goes via IRS, PI3K, and PDK1 to Akt. Akt is a key regulator of this cascade and triggers various signals of physiological responses such as stimulation of glucose uptake, inhibition of gluconeogenesis, and stimulation of lipogenesis. Insulin also stimulates cell growth and proliferation via MEK and ERK cascade. IRS: insulin receptor substrate, PI3K: isoform of phosphatidylinositol 3′-kinase, PDK1: 3′-phosphoinositide-dependent protein kinase-1, GLUT4: glucose transporter type 4, FoxO1: Forkhead box protein O1, and SREBP-1c: sterol regulatory element-binding protein 1c.

Figure 2

Insulin signaling in insulin resistance in the kidney [, , –21]. In the PT, the expression of IRS1 is suppressed while that of IRS2 is preserved. IRS1 signaling deficiency may cause the upregulation of G6P and PEPCK. In this condition, the inhibition of gluconeogenesis does not work sufficiently, causing enhanced gluconeogenesis and hyperglycemia. On the other hand, the expression of IRS2 is preserved, causing stimulation of sodium reabsorption via NBCe1, leading to sodium retention, hypertension, and edema. In the glomeruli, IRS1 signaling is also impaired similar to the PT. This causes podocyte dysfunction, possibly leading to DM nephropathy. Both the PT and glomeruli have selective insulin resistance, with differences between signaling via IRS1 and signaling via IRS2. IR: insulin receptor, IRS: insulin receptor substrate, FoxO1: Forkhead box protein O1, NBCe1: sodium bicarbonate cotransporter type 1, G6P: glucose-6-phosphatase, and PEPCK: phosphoenolpyruvate carboxykinase.