Etiopathogenesis of Hypertension with Insulin Resistance in Children: History
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Veronica Maria Tagi
,
,
Francesco Chiarelli

Insulin resistance (IR) is a key component in the etiopathogenesis of hypertension (HS) in patients with diabetes mellitus (DM). The higher risk of developing cardiovascular morbidity in children with a youth-onset Type 2 DM (T2D) is well known. Longitudinal data from the Treatment Options for T2D in Adolescents and Youth (TODAY) study revealed that in a group of 677 participants with a mean age of 14 ± 2 years the cumulative incidence of HS, LDL-C dyslipidemia, and hypertriglyceridemia was 59%, 33%, and 37% respectively and at the end of a mean 10.2 ± 4.5 years follow-up 54% had ≥2 cardiovascular risk factors in addition to T2D.

  • hypertension
  • insulin resistance
  • diabetes mellitus

1. Introduction

Insulin resistance (IR) is the principal mechanism responsible for the development of HS in patients with DM [1]. In fact, it contributes to an increase blood pressure (BP) in several ways, including the enhanced tissue angiotensin II (AngII) and aldosterone activities [2][3], the increased sympathetic nervous system activity [4], and oxidative stress [5]. Nevertheless, the hypothesis of the “endothelial IR” has been postulated, according to which endotelial disfunction precedes peripheric IR due to the impairment of blood flow in peripheral tissues. This mechanism is mediated by increased oxidative stress, through a protein kinase C β-dependent pathway. In fact, the suppression of reactive oxygen species-dependent pathways in the endothelium has been shown to restore insulin delivery to peripheral organs by preserving nitric oxide (NO) availability [6][7].
The higher risk of developing cardiovascular morbidity in children with a youth-onset Type 2 DM (T2D) is well known. Longitudinal data from the Treatment Options for T2D in Adolescents and Youth (TODAY) study revealed that in a group of 677 participants with a mean age of 14 ± 2 years the cumulative incidence of HS, LDL-C dyslipidemia, and hypertriglyceridemia was 59%, 33%, and 37% respectively and at the end of a mean 10.2 ± 4.5 years follow-up 54% had ≥2 cardiovascular risk factors in addition to T2D. Male sex, non-Hispanic white race/ethnicity, obesity, poor glycemic control, lower insulin sensitivity, and reduced β-cell function were identified as the main risk factors [8].
Agbaje et al. investigated the temporal causal longitudinal associations of carotid-femoral pulse wave velocity (cfPWV), an index of arterial stiffness, with the risk of developing IR, measured with the homeostatic model assessment (HOMA) index, in a group of 3862 followed-up 17.7-year-old participants from the Avon Longitudinal Study of Parents and Children. HOMA index is a paradigm model which allows for determining the IR rate using only the fasting glucose and insulin values. Levels above 2.9 signal significant insulin resistance. A higher value of HOMAIR corresponds to a more severe IR. The research showed that a higher cfPWV at 17.7 years was associated with higher HOMA index at age 24.5 years, supporting the hypothesis according to which arterial stiffness in adolescence may be a causal risk factor for hyperinsulinemia and IR in young adulthood [9].
Adults with DM are two to four times more likely to die from heart disease than those who do not have DM [10].
The prevalence of HS is higher in patients with DM than in the general population. In fact, it is estimated that about 69.0% have a systolic blood pressure of 140 mmHg or higher or diastolic blood pressure of 90 mmHg or higher or are on prescription medication for their high blood pressure [11]. If HS and DM are both present, the incidences of cardiovascular diseases (CVD) and mortality increase, such as the risks of nephropathy and retinopathy [12][13][14].
Given these premises, specific management of HS in children affected by DM is mandatory. The two most relevant societies that have recently proposed a peculiar treatment and follow-up of children with DM in their guidelines are the European Society of HS [15] and the American Academy of Pediatrics [16].

2. Etiopathogenesis

The association between IR and HS is multifactorial [1].
IR is involved in the development of HS and atherosclerotic cardiovascular disease through three main mechanisms [17]: the basic molecular etiology of IR [18][19][20][21][22][23][24][25][26][27], the compensatory hyperinsulinemia that occurs in response to IR [24][28][29][30][31][32][33][34], and the association between IR and some cardiometabolic abnormalities [28][29][30][35][36].
Insulin acts on its target organs phosphorylating a transmembrane-spanning tyrosine kinase receptor, the insulin receptor (IR). It binds to the α subunit of its receptor activating the tyrosine kinase of the β subunit of the receptor, causing autophosphorylation and phosphorylation of several IR substrates (IRS), such as IRS-1 and IRS-2 [37]. These substrates activate phosphatidylinositol 3-kinase (PI3K), which stimulates Akt, a serine/theronine kinase, which in turn stimulates the glucose uptake through the translocation of GLUT-4, the major glucose transporter to the cell membrane [38]. Akt is also responsible for the activation of nitric oxide synthase, which leads to the production of NO. If this pathway is impaired, NO, which is a potent vasodilator and antiatherogenic agent [28][29], is not produced, favouring vascular resistance, HS and atherogenesis (Figure 1).
Figure 1. Pathophysiological mechanisms linking IR and hypertension in children with DM. The signaling is impaired at the level of IRS-1, therefore, glucose transport is decreased and nitric oxide synthase activation is impaired, leading to decreased NOS production and therefore vasoconstriction. At the same time, insulin signalling through the MAPK pathway remains normally sensitive to insulin. For this reason, compensatory hyperinsulinemia (secondary to insulin resistance in the IRS-1/PI3K pathway) causes excessive stimulation of the MAPK pathway, which is involved in inflammation, vascular smooth muscle cell proliferation, and atherogenesis. Ab—Abbreviations: NOS—nitric oxide synthase; SHC—Src homology collagen.
One of the mechanisms through which hyperinsulinemia causes an increase of BP is dysregulation of peripheral vascular resistance, stimulating the sympathetic system and therefore causing vasoconstriction [4]; furthermore, hyperinsulinemia contributes to the development of HS-related target organ damage, in particular: impairment of cell membrane ion exchange, enhanced sympathetic nervous and renin-angiotensin systems, suppressed atrial natriuretic peptide activities, sodium retention, and plasma volume expansion lead to chronic kidney disease, left ventricular hypertrophy and carotid atherosclerosis [1].
Moreover, insulin-resistant states, such as T2D, are associated with several cardiometabolic abnormalities factor abnormalities, including elevated PAI-1, increased fibrinogen, and higher platelet stickiness, which are important cardiovascular risk factors [39][40].
Obesity is one of the leading causes of IR [14][28][29], and is strongly associated to atherosclerotic cardiovascular disease [41][42][43].
IR in obese subjects is mainly determined by lipotoxicity: the effect of excessive lipid accumulation which occurs when energy intake exceeds energy consumption [28][29][30]. Elevated free fatty acids in blood promote lipid deposition in tissues, including vessels [44][45][46][47][48][49] and activation of inflammatory pathways [43]. Excessive fat in adipocytes induces enhances the secretion of proinflammatory/prothrombotic cytokines, such as TNFa, PAI-1 and resistin, which promote atherogenesis [50][51][52][53].

This entry is adapted from the peer-reviewed paper 10.3390/ijms23105814

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