Insulin Signaling Mechanisms in Diabetic Kidney Disease

Worldwide, diabetic kidney disease (DKD) is the leading cause of end-stage renal failure, affecting approximately one third of individuals with diabetes. Central to DKD pathogenesis is insulin signalling within the nephron, particularly in glomerular podocytes, which maintain the filtration barrier and prevent albuminuria. Binding of insulin to its transmembrane receptor triggers autophosphorylation and recruitment of insulin receptor substrates, most notably IRS1, thereby activating downstream kinases such as phosphoinositide 3-kinase and protein kinase B (Akt). These pathways regulate cytoskeletal integrity, mitochondrial function and cell survival. In diabetes, chronic hyperglycaemia, dyslipidaemia and inflammation promote receptor downregulation, aberrant serine phosphorylation of IRS proteins and impaired Akt activation. Concurrent activation of stress pathways—including mechanistic target of rapamycin complex 1 (mTORC1) and IκB kinase β—alongside endoplasmic reticulum stress, exacerbates podocyte injury. Crosstalk with related receptors, such as the insulin-like growth factor 1 receptor, and modulation by metabolic sensors like AMP-activated protein kinase further influence disease progression. A detailed understanding of these interwoven mechanisms has revealed new therapeutic targets to preserve podocyte function and slow DKD advancement.

Research from Nature Portfolio

Studies have demonstrated that exposure to saturated free fatty acids in diabetic models activates IκB kinase β and mTORC1 in podocytes, leading to serine phosphorylation of IRS1 that impairs insulin-stimulated Akt signalling and precipitates albuminuria. Pharmacological or genetic inhibition of either kinase restores IRS1 function and rescues insulin responses. In parallel, enhancing insulin receptor activity—either by receptor overexpression or by knockdown of the negative regulator protein tyrosine phosphatase 1B—protects podocytes from endoplasmic reticulum stress induced by lipid and cytokine-rich diabetic conditions. Protection depends on intact MEK/ERK signalling rather than phosphoinositide 3-kinase alone, underscoring complex pathway interdependencies in maintaining podocyte resilience.

Insulin Signaling Mechanisms in Diabetic Kidney Disease publication trend

The graph below shows the total number of articles in insulin signaling mechanisms in diabetic kidney disease across all publications each year (not limited to Nature Index journals).

Technical terms

Podocyte: A specialised epithelial cell forming part of the glomerular filtration barrier in the kidney.

Insulin receptor (IR): A transmembrane tyrosine kinase that mediates cellular responses to circulating insulin.

Insulin receptor substrate 1 (IRS1): An adaptor protein phosphorylated by the insulin receptor to recruit downstream signalling effectors.

Akt (protein kinase B): A central serine/threonine kinase that regulates metabolism, growth and survival downstream of IRS proteins.

mTOR complex 1 (mTORC1): A multiprotein kinase complex that integrates nutrient and energy signals to regulate cell growth and protein synthesis.

AMP-activated protein kinase (AMPK): A metabolic sensor kinase activated by increased AMP/ATP ratio, promoting energy conservation.

Albuminuria: The abnormal presence of albumin in the urine, indicating glomerular filtration barrier dysfunction.

Endoplasmic reticulum (ER) stress: A cellular state triggered by accumulation of unfolded proteins in the ER lumen.

References

1. The Role of PKGIα and AMPK Signaling Interplay in the Regulation of Albumin Permeability in Cultured Rat Podocytes. International Journal of Molecular Sciences (2023).
2. Contrasting consequences of podocyte insulin-like growth factor 1 receptor inhibition. iScience (2024).
3. GPR43 deficiency protects against podocyte insulin resistance in diabetic nephropathy through the restoration of AMPKα activity. Theranostics (2021).
4. Enhanced insulin receptor, but not PI3K, signalling protects podocytes from ER stress. Scientific Reports (2018).
5. Saturated fatty acids induce insulin resistance in podocytes through inhibition of IRS1 via activation of both IKKβ and mTORC1. Scientific Reports (2020).
6. The Evolving Importance of Insulin Signaling in Podocyte Health and Disease. Frontiers in Endocrinology (2018).