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.

Keywords: cancer; cardiovascular disease; diabetes; growth hormone; hyperinsulinemia; insulin clearance; insulin resistance; insulin secretion; insulin-like growth factor-I; longevity; obesity.

Figure 1

The insulin–growth hormone–IGF-I (insulin–GH–IGF-I) axis plays a central role in metabolism. (A) In healthy subjects, the insulin–GH–IGF-I axis is in balance: insulin and GH both stimulate IGF-I production in the liver, while after secretion IGF-I feeds back to suppress both insulin and GH. (B) The continuous food intake and energy surplus (Western diet) in modern societies has disturbed the normal balance of the insulin–GH–IGF-I axis. As a consequence, a shift of the insulin : GH ratio towards insulin (and IGF-I) and away from GH has occurred. The higher insulin : GH ratio lowers energy expenditure and induces fat accumulation. 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 (see text for more details on how continuous foods intake and Western diet may influence the balance of the insulin–GH axis).

Figure 1

The insulin–growth hormone–IGF-I (insulin–GH–IGF-I) axis plays a central role in metabolism. (A) In healthy subjects, the insulin–GH–IGF-I axis is in balance: insulin and GH both stimulate IGF-I production in the liver, while after secretion IGF-I feeds back to suppress both insulin and GH. (B) The continuous food intake and energy surplus (Western diet) in modern societies has disturbed the normal balance of the insulin–GH–IGF-I axis. As a consequence, a shift of the insulin : GH ratio towards insulin (and IGF-I) and away from GH has occurred. The higher insulin : GH ratio lowers energy expenditure and induces fat accumulation. 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 (see text for more details on how continuous foods intake and Western diet may influence the balance of the insulin–GH axis).

Figure 2

(A). The Traditional Model vs. The New Model of the pathogenesis of type 2 diabetes. The Traditional Model posits that insulin resistance is the primary abnormality leading to hyperinsulinemia, which is followed by β-cell dysfunction. When β-cells are no longer able to sustain sufficient insulin secretion to compensate hyperglycemia, they become exhausted and frank type 2 diabetes will develop. The Traditional Model has been called into question since it cannot explain that hyperinsulinemia can already be found in subjects with normal glucose tolerance (see text for details). In the (alternative) New Model, chronic hypersecretion of insulin (due to genetics and environmental factors) is the primary abnormality leading to hyperinsulinemia. Hyperinsulinemia initiates and sustains the development of insulin resistance (and obesity), until the β-cells fail and become exhausted and ultimately frank type 2 diabetes develops. (B) The Traditional Model vs. The New Model of the pathogenesis of type 2 diabetes. In the Traditional Model, insulin resistance (1) precedes hyperinsulinemia (2), which is followed by β-cell exhaustion and finally frank type 2 diabetes. In the New Model, hypersecretion of insulin and the resulting hyperinsulinemia (1) primarily cause insulin resistance (2), which is followed by β-cell exhaustion and finally frank type 2 diabetes. Note that in The New Model hyperinsulinemia is already present when there is a normal glucose tolerance.

Figure 3

Kaplan–Meier curves for the development of diabetes according to sex-specific tertiles of C-peptide at baseline in 5176 participants of the PREVEND study. Low = M: <642, F: <592 pmol/L; medium = M: 642–890, F: 592–803 pmol/L; high = M: >890, F: >803 pmol/L; PREVEND: Prevention of Renal and Vascular End-Stage Disease. Note that in this population-based cohort, C-peptide levels in the highest tertile were associated with a higher incidence of type 2 diabetes during a median follow-up of 7, 2 years, compared to lower C-peptide levels (p < 0.001), and this association was independent of age, sex, BMI, family history of diabetes, blood pressure, triglycerides, HDL cholesterol, and fasting plasma glucose. Reproduced from S. Sokooti, L.M. Kieneker, M.H. de Borst, A. Muller Kobold, J.E. Kootstra-Ros, J. Gloerich, A.J. van Gool, H.J. Lambers Heerspink, R.T. Gansevoort, R.P.F. Dullaart, S.J.L. Bakker. Plasma C-Peptide and Risk of Developing Type 2 Diabetes in the General Population. J Clin Med. 2020 Sep 17; 9(9):3001. doi:10.3390/jcm9093001.

Figure 4

Some factors involved in hyperinsulinemia. Certain genes, hepatic insulin clearance, excess food intake, quality of nutrition, fetal/metabolic programming and exposure to endocrine disrupting chemicals have all been suggested as possible etiological factors in the development of hyperinsulinemia. Loss of pulsatile insulin secretion may contribute to changes in hepatic insulin clearance, hyperinsulinemia and insulin resistance. Note: genes, excess food intake and loss of pulsatile insulin secretion may modify hepatic insulin clearance (see also text for more details).

Figure 5

Interactions between insulin, IGFBP-1, IGFBP-2, SHBG, IGF-I bioavailability, the insulin receptor-A, the IGF-I receptor, estradiol and the estradiol receptor. Inhibitory effects are shown in red and stimulatory effects in green. Insulin stimulates the insulin receptor A (directly) and increases bioavailable IGF-I and estradiol (indirectly). Note that there is also bidirectional cross-talk between the IGF-I receptor and the estradiol receptor. IGFBP-1 = insulin-like growth factor binding protein-1, IGFBP-2 = insulin-like growth factor binding protein-2, SHBG= sex hormone binding globulin, ↑ levels increase, ↓ levels decrease.

Figure 6

In the view of Parr, nutritionally driven “normal” insulin exposure is central to imbalance of the insulin–growth hormone axis (insulin–GH axis) [157,158]. (A) At young age there is balance in the insulin–GH axis. However, when there is (excessive) food intake ad libitum, a progressive imbalance develops in the insulin–GH axis with aging. This imbalance is the direct consequence of a food-induced increase in insulin secretion and the five-fold decline in GH secretion, which normally occurs between the age of 18 and 80. Due to the progressive imbalance in the insulin–GH axis with aging the decline in reserve capacity of cells and organ functions is accelerated. (B) Calorie restriction started at a young age will cause (a lifelong) lower insulin and GH secretion. As a consequence of calorie restriction, cumulative lifetime exposure to insulin at the same age will be less and lifespan will be extended by better maintaining the balance in the insulin–GH axis: this will result in long-term low (but functional) insulin levels and a high insulin receptor sensitivity (see text for more details).