Insulin: Trigger and Target of Renal Functions

Abstract

Kidney function in metabolism is often underestimated. Although the word "clearance" is associated to "degradation", at nephron level, proper balance between what is truly degraded and what is redirected to de novo utilization is crucial for the maintenance of electrolytic and acid-basic balance and energy conservation. Insulin is probably one of the best examples of how diverse and heterogeneous kidney response can be. Kidney has a primary role in the degradation of insulin released in the bloodstream, but it is also incredibly susceptible to insulin action throughout the nephron. Fluctuations in insulin levels during fast and fed state add another layer of complexity in the understanding of kidney fine-tuning. This review aims at revisiting renal insulin actions and clearance and to address the association of kidney dysmetabolism with hyperinsulinemia and insulin resistance, both highly prevalent phenomena in modern society.

Keywords: albuminuria; diabetic nephropathy; insulin; insulin clearance; insulin resistance.

FIGURE 1

Canonical insulin signaling cascade. Insulin (gray circle) binds to its transmembrane kinase receptor at cell membrane and triggers insulin signaling cascade. Insulin receptor present two isoforms with distinct affinity for insulin already associated to differential insulin internalization (INSR A and INSR B; Calzi et al., 1997). Binding of insulin auto-phosphorylates INSR at Tyr-960. Further recruitment and phosphorylation of insulin receptor substrate (IRS) 1 and 2 will mostly result in subsequent activation of phosphoinositide-dependent kinase 1 (PDK1) through phosphoinositide-3 kinase (PI3K; Yamada et al., 2002). PDK1 is responsible for propagation of insulin signal to one of the most important downstream effectors, Akt. Importantly, Akt has two distinct phosphorylation sites, Thr308 activated by PDK1 (Alessi et al., 1997) and Ser473 phosphorylated by mammalian target of rapamycin complex (mTORC) 2 protein (Bayascas and Alessi, 2005). Finally, fully activated Akt can interact with different proteins, eliciting different effects as stimulation of glucose uptake and glycogen synthesis by AS160 and glycogen synthase kinase 3 (GSK3), respectively (Ng et al., 2008). On the other hand, INRS activation also promote growth factor receptor-bound protein 2 (GRB2) interaction with Shc proteins and activation of mitogen activated protein kinases (MAPK; Skolnik et al., 1993; Xu et al., 2006). This as part of the insulin-mediated proliferative stimuli. PIP2, phosphatidylinositol 4,5 biphosphate; PIP3, phosphatidylinositol 3,4,5 triphosphate.

FIGURE 2

Schematic representation of renal insulin handling. Insulin is depicted in gray circles at different portions of the nephron. As insulin is a small molecule, it will be fully filtered by the glomerular system until it reaches the proximal tubule. At proximal tubule cells, almost all the filtered insulin will be absorbed at the luminal membrane. In physiological conditions, only a small percentage will be excreted in urine. Beyond glomerular filtration, insulin also raise from the perivenous capillaries. In a closer look to the proximal tubule cells is represented both mechanisms of insulin clearance. The increased levels of insulin receptor (INSR) and consequent increased uptake of insulin at the basolateral membrane is also depicted.

FIGURE 3

Podocyte insulin signaling. Podocytes are the first cells to interact with insulin at the nephron and express several proteins of the canonical insulin signaling pathway. However, here the podocyte-specific protein nephrin is known to have a role in the trafficking of glucose transporters (GLUT1 or GLUT4) to podocyte membrane and consequently promote glucose uptake. The trafficking seems to involve Vamp2 and actin remodeling. On the other branch of insulin signaling, an effect in the large-conductance Ca²⁺-activated K⁺ channels (BK_Ca) is also important for maintenance of podocyte integrity and proper glomerular filtration. GRB2, growth factor receptor-bound protein 2; GSV, GLUT storage vesicle; VAMP2, Vesicle-associated membrane protein 2.

FIGURE 4

Dynamics of proximal tubule cells at fasting, fed and insulin resistant states. Proximal tubule cells are subjected to distinct microenvironments (lumen and interstitium) and the regulation of absorption and reabsorption of molecules is complex. Although all the described processes occur in every cell of the proximal tubule simultaneously, each specific process is illustrated in a different cell. At fasting (A), low levels of insulin allow expression of gluconeogenic enzymes whereas sodium reabsorption is downregulated. Expression of glucose transporter 2 (GLUT2) at basolateral membrane is mostly associated to glucose output and not to its uptake. Moreover, albumin absorption is performed by megalin and cubilin at luminal membrane and transcytosis allow albumin to be rerouted back to the organism. At fed state (B), increased availability of insulin and glucose promote drastic changes in proximal tubule dynamics. In the case of insulin, luminal uptake is mostly associated to degradation and basolateral to signaling activation. Insulin receptor (INSR) activation downregulates gluconeogenesis and increases sodium reabsorption by different proteins as type 3 Na-H exchanger (NHE-3) and sodium-glucose transport protein 2 (SGLT2). Together with sodium, SGLT2 also co-transport glucose from the lumen. Finally, hyperinsulinemia is linked to perturbations of proximal tubule cells in many aspects (C). As in many other organs, insulin signaling desensitization is associated to inefficient inhibition of gluconeogenesis contributing to maintenance of increased levels of glucose. Derangements at podocyte level increases filtration of albumin and overloads luminal capacity of reabsorption. Such impairment in albumin reabsorption culminates with albuminuria, frequent observed in hyperinsulinemic states.