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The impact of insulin resistance on the kidney and vasculature

Key Points

  • In addition to classical insulin target tissues (liver, skeletal muscle and white adipose tissue) insulin acts on most human organs and cell types, including the arterial vasculature and the kidney

  • In insulin-resistant states such as obesity or type 2 diabetes mellitus, not only are the classical insulin effects impaired, but also the effects of insulin on the vasculature and the kidney

  • Insulin stimulates its own delivery to target cells by actions on the vasculature involving increased capillary recruitment and endothelial transcytosis; these effects are impaired in insulin-resistant states

  • Insulin resistance affects many aspects of kidney function, including renal haemodynamics, podocyte viability and tubular function

  • The action of insulin on renal sodium handling is preserved in insulin resistance and contributes to sodium retention and arterial hypertension

  • Renal and vascular insulin resistance can be improved through an integrated approach including lifestyle interventions and pharmacological agents

Abstract

Insulin resistance is a systemic disorder that affects many organs and insulin-regulated pathways. The disorder is characterized by a reduced action of insulin despite increased insulin concentrations (hyperinsulinaemia). The effects of insulin on the kidney and vasculature differ in part from the effects on classical insulin target organs. Insulin causes vasodilation by enhancing endothelial nitric oxide production through activation of the phosphatidylinositol 3-kinase pathway. In insulin-resistant states, this pathway is impaired and the mitogen-activated protein kinase pathway stimulates vasoconstriction. The action of insulin on perivascular fat tissue and the subsequent effects on the vascular wall are not fully understood, but the hepatokine fetuin-A, which is released by fatty liver, might promote the proinflammatory effects of perivascular fat. The strong association of salt-sensitive arterial hypertension with insulin resistance indicates an involvement of the kidney in the insulin resistance syndrome. The insulin receptor is expressed on renal tubular cells and podocytes and insulin signalling has important roles in podocyte viability and tubular function. Renal sodium transport is preserved in insulin resistance and contributes to the salt-sensitivity of blood pressure in hyperinsulinaemia. Therapeutically, renal and vascular insulin resistance can be improved by an integrated holistic approach aimed at restoring overall insulin sensitivity and improving insulin signalling.

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Figure 1: The insulin signalling pathway.
Figure 2: Organ crosstalk in the insulin-resistant state.
Figure 3: The effects of insulin on the arterial vasculature.
Figure 4: Transendothelial transport of insulin in a skeletal muscle capillary.
Figure 5: Insulin signal transduction in the endothelial cells of resistance arterioles.
Figure 6: Perivascular adipose tissue influences vascular function.
Figure 7: Insulin signalling in the principal cell of the aldosterone-sensitive distal nephron.

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Acknowledgements

We acknowledge the meticulous work of Marketa Kovarova (Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University Hospital Tübingen, Germany) in designing the figures. The authors' work is funded by a grant from the German Federal Ministry of Education and Research to the German Centre for Diabetes Research (DZD), München-Neuherberg, Germany.

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All authors researched the data for the article, discussed the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Hans-Ulrich Häring.

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Glossary

Impaired glucose tolerance

Defined as a plasma glucose concentration of 140–200 mg/dl (7.77–11.1 mmol/l) measured 2 h after an oral glucose load of 75 g.

Visceral obesity

Increased waist circumference as a result of an accumulation of fat in the intra-abdominal compartments, such as the omentum majus.

Hepatokines

Factors that are secreted from the liver and act on other tissues.

Hyperinsulinaemic–euglycaemic clamp

Test used to quantify insulin resistance on a whole-body level. Continuous insulin infusion is used to maintain plasma insulin levels, whilst variable glucose infusion is used to maintain plasma glucose concentration at basal levels. When a stable plasma glucose concentration is achieved, the rate of glucose infusion is equal to the rate of glucose uptake by all of the body tissues.

Renal resistive index

A measure of intrarenal vascular resistance.

Kimmelstiel–Wilson lesions

The typical histopathological hallmark of diabetic nephropathy, which is characterized by nodular glomerulosclerosis.

Impaired fasting glucose

Defined as a plasma glucose concentration of 110–126 mg/dl (6.11–6.99 mmol/l) in the fasting state.

Oral glucose tolerance test

Test used to screen for disturbances in glucose metabolism and insulin resistance.

Liver steatosis

Accumulation of excess fat in the liver.

Homeostasis model assessment of insulin resistance

A simple quantitative measure of insulin resistance calculated from the plasma fasting glucose level and insulin concentration.

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Artunc, F., Schleicher, E., Weigert, C. et al. The impact of insulin resistance on the kidney and vasculature. Nat Rev Nephrol 12, 721–737 (2016). https://doi.org/10.1038/nrneph.2016.145

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