Insulin: too much of a good thing is bad

Abstract

Background: Insulin shares a limited physiological concentration range with other endocrine hormones. Not only too low, but also too high systemic insulin levels are detrimental for body functions.

Main body: The physiological function and clinical relevance of insulin are usually seen in association with its role in maintaining glucose homeostasis. However, insulin is an anabolic hormone which stimulates a large number of cellular responses. Not only too low, but also excess insulin concentrations are detrimental to the physiological balance. Although the glucoregulatory activity of insulin is mitigated during hyperinsulinemia by dampening the efficiency of insulin signaling ("insulin resistance"), this is not the case for most other hormonal actions of insulin, including the promotion of protein synthesis, de novo lipogenesis, and cell proliferation; the inhibition of lipolysis, of autophagy-dependent cellular turnover, and of nuclear factor E2-related factor-2 (Nrf2)-dependent antioxidative; and other defense mechanisms. Hence, there is no general insulin resistance but selective impairment of insulin signaling which causes less glucose uptake from the blood and reduced activation of endothelial NO synthase (eNOS). Because of the largely unrestricted insulin signaling, hyperinsulinemia increases the risk of obesity, type 2 diabetes, and cardiovascular disease and decreases health span and life expectancy. In epidemiological studies, high-dose insulin therapy is associated with an increased risk of cardiovascular disease. Randomized controlled trials of insulin treatment did not observe any effect on disease risk, but these trials only studied low insulin doses up to 40 IU/day. Proof for a causal link between elevated insulin levels and cardiovascular disease risk comes from Mendelian randomization studies comparing individuals with genetically controlled low or high insulin production.

Conclusions: The detrimental actions of prolonged high insulin concentrations, seen also in cell culture, argue in favor of a lifestyle that limits circadian insulin levels. The health risks associated with hyperinsulinemia may have implications for treatment regimens used in type 2 diabetes.

Keywords: Autophagy; Cardiovascular morbidity and mortality; Hyperinsulinemia; Inflammation; Insulin resistance; Nrf2; Obesity; Oxidative stress; Type 2 diabetes mellitus; eNOS.

Fig. 1

Metabolic signaling of insulin is anabolic. Insulin signaling through the insulin receptor engages several pathways and results in an anabolic state of metabolism. The canonical pathway via phosphokinases PI3K and AKT/PKB promotes glucose uptake and glycogen and lipid syntheses, whereas lipolysis is inhibited in adipocytes, as well as hepatic gluconeogenesis. In addition, AKT kinases activate mTORC1 which supports de novo lipogenesis and protein synthesis. The insulin signaling pathway via SHC and the MAP kinases MEK and ERK promotes cell proliferation and protein synthesis. Another insulin signaling pathway involves NOX4 and the inhibition of PTEN, an inhibitor of the PI3K-AKT pathway

Fig. 2

Insulin promotes obesity. Several independent types of observations support the conclusion that insulin promotes adipogenesis and obesity. For details, see description in the general text

Fig. 3

Signaling of insulin during insulin resistance. During insulin resistance, signaling through AKT kinases is partially impaired. Not all AKT-dependent pathways are affected, as well as other signaling pathways, indicating that insulin resistance is selective. Therefore, hyperinsulinemia, in the presence of insulin resistance, promotes anabolic cell activities via the MEK–ERK pathway and via mTORC1. Although the PI3K/AKT pathway is impaired during insulin resistance, and provides only insufficient translocation of GLUT4 for glucose uptake and deficient activation of eNOS, there appears to be a normal activation of mTORC1. In addition to the anabolic consequences of signaling via the MEK/ERK pathway depicted in the figure, there is enhanced expression of ET-1 and PAI-1 (not shown), as well as inhibition of autophagy and of the nuclear factor Nrf2, which compromises cell constituent turnover and cell defense mechanisms to radical stress, respectively. Hyperinsulinemia downregulates glucose uptake not only via dampening the PI3K/AKT pathway (“insulin resistance”) but also via as yet unknown other pathways

Fig. 4

Hyperinsulinemia, insulin resistance, and cardiovascular disease. High insulin concentrations in the blood may occur due to genetic predisposition, overnutrition, or high-dose insulin treatment of type 2 diabetes. Hyperinsulinemia induces “insulin resistance” as a defense response to maintain glucose homeostasis. Conversely, insulin resistance may be directly induced such as by growth hormone or pro-inflammatory cytokines. Hyperinsulinemia and insulin resistance enhance the risk of cardiovascular disease, by inducing endothelial dysfunction, suppression of endothelial nitric oxide synthase (eNOS), and activation and promotion of calcium ion influx into smooth muscle cells, resulting in increased vascular tone, enhanced reabsorption of sodium ions in renal tubules, adhesion of macrophages to the vessel wall, and development of arterial lesions with increased lipoprotein lipase activity and cardiovascular disease

Fig. 5

Hazard ratio of insulin medication versus different reference medications. Shown are adjusted hazard ratios (HR) for each study with 95% confidence interval. ^#Moderate insulin exposure; ⁺high insulin exposure; *moderate insulin dose (75 to < 100 units per day); ^§high insulin dose (> 100 units per day)