Table 1.

Key messages

• Insulin employs at least three different pathways of signal transduction. One pathway involves phosphorylation steps via IRS–PI3K–AKT, another is the MAP kinases Ras–MEP–ERK, and third leads to the activation of NOX4.

• Insulin resistance is selective because it partially mitigates the PI3K/AKT pathway for limiting glucose uptake and eNOS activation despite hyperinsulinemia, but many other hormonal actions of insulin are not suppressed.

• Signaling via mTOR and the MEP/ERK pathway causes suppression of autophagy and NRF2, leading to deficient turnover and impaired cell defense.

• Moderate to high normal insulin levels inhibit lipolysis and promote lipogenesis/obesity.

• Insulin resistance and hyperinsulinemia are interdependent. Diet-induced hyperinsulinemia precedes insulin resistance.

• In epidemiological studies, insulin therapy of type 2 diabetes is associated with a higher risk of cardiovascular events or death.

• Randomized trials of insulin therapy and associated risks only studied dosages up to 40 IU/day.

• Mendelian randomization studies found that genetically determined high insulin levels lead to cardiovascular disease.

• Suppression of hyperinsulinemia and concomitant “insulin resistance” provides substantial health benefits.