Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review

Abstract

Renal proximal tubules reabsorb glucose from the glomerular filtrate and release it back into the circulation. Modulation of glomerular filtration and renal glucose disposal are some of the insulin actions, but little is known about a possible insulin effect on tubular glucose reabsorption. This review is aimed at synthesizing the current knowledge about insulin action on glucose handling by proximal tubules. Method. A systematic article selection from Medline (PubMed) and Embase between 2008 and 2019. 180 selected articles were clustered into topics (renal insulin handling, proximal tubule glucose transport, renal gluconeogenesis, and renal insulin resistance). Summary of Results. Insulin upregulates its renal uptake and degradation, and there is probably a renal site-specific insulin action and resistance; studies in diabetic animal models suggest that insulin increases renal SGLT2 protein content; in vivo human studies on glucose transport are few, and results of glucose transporter protein and mRNA contents are conflicting in human kidney biopsies; maximum renal glucose reabsorptive capacity is higher in diabetic patients than in healthy subjects; glucose stimulates SGLT1, SGLT2, and GLUT2 in renal cell cultures while insulin raises SGLT2 protein availability and activity and seems to directly inhibit the SGLT1 activity despite it activating this transporter indirectly. Besides, insulin regulates SGLT2 inhibitor bioavailability, inhibits renal gluconeogenesis, and interferes with Na⁺K⁺ATPase activity impacting on glucose transport. Conclusion. Available data points to an important insulin participation in renal glucose handling, including tubular glucose transport, but human studies with reproducible and comparable method are still needed.

Figure 1

Literature flow diagram.

Figure 2

(a) Insulin effect on renal proximal tubule cells. (b) Diabetes, hyperinsulinaemia, and insulin resistance impact on renal proximal tubule cells. Grey arrows = flux; black continuous arrows = stimulatory effect; black interrupted arrows = inhibitory effect; thicker arrows = increased activity. I: insulin; GLU: glucose; ROS: reactive oxygen species; NHE3: Na⁺H⁺ exchanger type 3; NKA: Na⁺K⁺ATPase; IRecs: insulin receptors; IRS: insulin receptor substrate proteins; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; TNFα: tumor necrosis factor alpha; IL-6 and IL-10: interleukins. ^?Scanty or conflicting data; ^//reduced effect; ∗enhanced in animal models but conflicting human data; ∗∗enhanced in murine models but reduced in cultures; ^§temporal dual action according to exposition (short time = stimulatory and sustained = inhibitory); ^#total NKA function increased despite inhibitory GLU effect and mitochondrial dysfunction.