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.
Highlights
Subjects with insulin resistance and hyperinsulinemia are at high risk of developing obesity, type 2 diabetes, cardiovascular disease, cancer and premature mortality [1,2,3,4,5,6,7,8,9]
Insulin resistance was considered to be the primary etiological factor in the development of obesity, type 2 diabetes, cardiovascular disease and cancer, whereas the compensatory hyperinsulinemia was thought to be a direct consequence of insulin resistance [11]
This opens the possibility that interventions able to normalize/reduce plasma insulin concentrations might play a key role in the prevention and treatment of obesity, type 2 diabetes, cardiovascular disease, cancer and premature mortality [10,17]
Summary
Subjects with insulin resistance and hyperinsulinemia are at high risk of developing obesity, type 2 diabetes, cardiovascular disease, cancer and premature mortality [1,2,3,4,5,6,7,8,9]. It has even been proposed that hyperinsulinemia per se is primary and causes (and is not a consequence of) insulin resistance [13] In this new concept, insulin resistance is proposed to be a physiological defense mechanism of the body that tries to prevent the development of hypoglycemia and to protect critical tissues from metabolic stress and nutrient-induced injury [15,16]. Insulin resistance is proposed to be a physiological defense mechanism of the body that tries to prevent the development of hypoglycemia and to protect critical tissues from metabolic stress and nutrient-induced injury [15,16] This opens the possibility that (early) interventions able to normalize/reduce plasma insulin concentrations might play a key role in the prevention and treatment of obesity, type 2 diabetes, cardiovascular disease, cancer and premature mortality [10,17]. It discusses how insulin might play a pivotal role in health, disease and longevity and (potential) strategies to prevent and manage hyperinsulinemia
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