Insulin resistance underlies the elevated cardiovascular risk associated with kidney disease and glomerular hyperfiltration

Abstract

The curve that describes the relationship between glomerular filtration rate (GFR) and cardiovascular risk is U-shaped, indicating that both reduced GFR (kidney failure) and elevated GFR (glomerular hyperfiltration) are equivalent cardiovascular risk factors. The elevated cardiovascular risk associated with abnormal GFR is not explained by standard cardiovascular risk factors. The relationship between GFR and all-cause mortality follows a similar pattern, so that altered GFR (either low or high) increases the risk for overall mortality. Glomerular hyperfiltration is an adaptive process that arises under conditions that demand improved kidney excretory capacity, such as animal protein ingestion and kidney failure. Unlike vegetable protein, animal protein consumption increases dietary acid load and requires an elevation of the GFR to restore acid-base balance. The loss of functioning nephrons in diseased kidneys requires a compensatory increase of the GFR in the nephrons that remain working to enhance whole-kidney GFR. A major factor that raises GFR is the pancreatic hormone glucagon. Glucagon infusion and endogenous glucagon release increase GFR in healthy subjects and patients with kidney failure. In addition to its kidney hemodynamic effect, glucagon causes insulin resistance. Like hyperglucagonemia, insulin resistance develops across the entire spectrum of abnormal GFR, from glomerular hyperfiltration to advanced kidney disease. Insulin resistance is associated with subclinical vascular injury in the general population and patients with diabetes and kidney failure, being a strong cardiovascular risk factor in these population groups. Animal protein consumption activates glucagon secretion and promotes insulin resistance, having a detrimental effect on cardiovascular disease and renal outcomes.

Keywords: Glucagon; animal protein; cardiovascular risk; glomerular filtration rate; glomerular hyperfiltration; insulin resistance; kidney disease; renal plasma flow; vascular disease; vegetable protein.