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Mechanisms of Disease: pathway-selective insulin resistance and microvascular complications of diabetes

Nature Clinical Practice Endocrinology & Metabolism volume 1, pages 100–110 (2005)Cite this article

Abstract

Resistance to the actions of insulin is strongly associated with the microvascular complications of diabetes. To the extent that insulin resistance leads to hyperglycemia, dyslipidemia and hypertension, this association is not surprising. It is now clear that insulin also has direct actions in the microvasculature that influence the development and progression of microvascular disease. In the healthy state, insulin appears to have only minor effects on vascular function, because of the activation of opposing mediators such as nitric oxide and endothelin-1. Diabetes and obesity, however, are associated with selective insulin resistance in the phosphatidylinositol-3-kinase signaling pathway, which leads to reduced synthesis of nitric oxide, impaired metabolic control and compensatory hyperinsulinemia. By contrast, insulin signaling via extracellular signal-regulated kinase dependent pathways is relatively unaffected in diabetes, tipping the balance of insulin's actions so that they favor abnormal vasoreactivity, angiogenesis, and other pathways implicated in microvascular complications and hypertension. In addition, preferential impairment of nonoxidative glucose metabolism leads to increased intracellular formation of advanced glycation end products, oxidative stress and activation of other pathogenic mediators. Despite a strong temporal association, a causal link between pathway-selective insulin resistance and microvascular damage remains to be established. It is possible that this association reflects a common genotype or phenotype. Nonetheless, insulin resistance remains an important marker of risk and a key target for intervention, because those patients who achieve a greater improvement of insulin sensitivity achieve better microvascular outcomes.

Key Points

  • Resistance to the actions of insulin is strongly associated with the microvascular complications of diabetes, independently of metabolic control and hypertension

  • Insulin resistance is an important marker of risk and a key target for intervention, as those patients who achieve a greater improvement of insulin sensitivity achieve better microvascular outcomes

  • Diabetes and obesity are associated with pathway-selective insulin resistance in the phosphatidylinositol-3-kinase signaling pathway, while signaling via extracellular signal-regulated kinase dependent pathways is comparatively unaffected, tipping the balance of insulin's actions in favor of abnormal vasoreactivity, angiogenesis, and other pathways implicated in microangiopathy

  • Insulin resistance is able to enhance key pathways involved in hyperglycemia-induced microvascular damage and to exacerbate hypertension

  • The strong association between insulin resistance and microvascular disease might also reflect a common genotype or phenotype

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Figure 1: Some of the opposing actions of insulin that are balanced in healthy individuals, but uncoupled in diabetes and obesity
Figure 2: The insulin-receptor signaling pathway
Figure 3: Selective impairment of nonoxidative glucose metabolism (shown by the total height of bars) in patients with diabetes, with or without microalbuminuria and/or hypertension

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  1. Per-Henrik Groop
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  2. Carol Forsblom
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  3. Merlin C Thomas
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Groop, PH., Forsblom, C. & Thomas, M. Mechanisms of Disease: pathway-selective insulin resistance and microvascular complications of diabetes. Nat Rev Endocrinol 1, 100–110 (2005). https://doi.org/10.1038/ncpendmet0046

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