Hyperinsulinemia and Its Pivotal Role in Aging, Obesity, Type 2 Diabetes, Cardiovascular Disease and Cancer

Abstract

For many years, the dogma has been that insulin resistance precedes the development of hyperinsulinemia. However, recent data suggest a reverse order and place hyperinsulinemia mechanistically upstream of insulin resistance. Genetic background, consumption of the “modern” Western diet and over-nutrition may increase insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing hyperinsulinemia. Hyperinsulinemia disturbs the balance of the insulin–GH–IGF axis and shifts the insulin : GH ratio towards insulin and away from GH. This insulin–GH shift promotes energy storage and lipid synthesis and hinders lipid breakdown, resulting in obesity due to higher fat accumulation and lower energy expenditure. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer and premature mortality. It has been further hypothesized that nutritionally driven insulin exposure controls the rate of mammalian aging. Interventions that normalize/reduce plasma insulin concentrations might play a key role in the prevention and treatment of age-related decline, obesity, type 2 diabetes, cardiovascular disease and cancer. Caloric restriction, increasing hepatic insulin clearance and maximizing insulin sensitivity are at present the three main strategies available for managing hyperinsulinemia. This may slow down age-related physiological decline and prevent age-related diseases. Drugs that reduce insulin (hyper) secretion, normalize pulsatile insulin secretion and/or increase hepatic insulin clearance may also have the potential to prevent or delay the progression of hyperinsulinemia-mediated diseases. Future research should focus on new strategies to minimize hyperinsulinemia at an early stage, aiming at successfully preventing and treating hyperinsulinemia-mediated diseases.

Predictive link between systemic metabolism and cytokine signatures in the brain of apolipoprotein E ε4 mice

“…However, observation of glucose levels at finer time resolution and earlier than the 15 minute GTT time point will shine further light on any changes in the peak and shape of the insulin spike. Our results suggest that aged APOE3 mice tend toward hyperinsulinemia with aging, similar to effects seen in humans 77 . Young APOE3 females had the best glucose tolerance, while old APOE3 mice had the worst tolerance.…”

Insulin sensitivity in mesolimbic pathways predicts and improves with weight loss in older dieters

“…It is also, to our knowledge, the first study that demonstrates positive effects of caloric restriction on central insulin function in humans using a longitudinal within-subject design. The observation of such an effect in older adults is particularly important given age-related metabolic and neural changes and the potential, detrimental consequences of hyperinsulinemia, overweight and obesity in later life (Janssen, 2021).…”

“…Our data extend these beneficial neural effects of caloric restriction in animals to improved central insulin functioning in the human brain. This is particularly intriguing with regard to our pre-diabetic sample of elderlies, in whom weight-related brain dysfunction is not only a risk factor for metabolic disorders but also for cognitive decline and neurodegeneration (Ekblad et al, 2017; Janssen, 2021; Mattson and Arumugam, 2018).…”

“…There is consensus that improvement of hyperinsulinemia and insulin resistance, as achieved by caloric restriction, is key in the prevention and treatment of obesity, type 2 diabetes or cardiovascular diseases in aging (Janssen, 2021; Ryan, 2000). Evidence from human studies for such effects, however, are sparse, especially when it comes to central nervous insulin signaling.…”

“…The mechanisms and directions of these interactions are under debate. For instance, it has long been assumed that insulin resistance in aging precedes the development of hyperinsulinemia, while recent data suggest a reverse direction (Janssen, 2021). Moreover, there is evidence from animal and human research of an weight-independent effect of aging on insulin sensitivity (Ehrhardt et al, 2019; Petersen et al, 2003).…”