Insulin Resistance the Hinge Between Hypertension and Type 2 Diabetes

Abstract

Epidemiological studies have documented a high incidence of diabetes in hypertensive patients.Insulin resistance is defined as a less than expected biologic response to a given concentration of the hormone and plays a pivotal role in the pathogenesis of diabetes. However, over the last decades, it became evident that insulin resistance is not merely a metabolic abnormality, but is a complex and multifaceted syndrome that can also affect blood pressure homeostasis. The dysregulation of neuro-humoral and neuro-immune systems is involved in the pathophysiology of both insulin resistance and hypertension. These mechanisms induce a chronic low grade of inflammation that interferes with insulin signalling transduction. Molecular abnormalities associated with insulin resistance include the defects of insulin receptor structure, number, binding affinity, and/or signalling capacity. For instance, hyperglycaemia impairs insulin signalling through the generation of reactive oxygen species, which abrogate insulin-induced tyrosine autophosphorylation of the insulin receptor. Additional mechanisms have been described as responsible for the inhibition of insulin signalling, including proteasome-mediated degradation of insulin receptor substrate 1/2, phosphatase-mediated dephosphorylation and kinase-mediated serine/threonine phosphorylation of both insulin receptor and insulin receptor substrates. Insulin resistance plays a key role also in the pathogenesis and progression of hypertension-induced target organ damage, like left ventricular hypertrophy, atherosclerosis and chronic kidney disease. Altogether these abnormalities significantly contribute to the increase the risk of developing type 2 diabetes.

Keywords: Atherosclerosis; Cardiovascular risk; Left ventricular hypertrophy; Microalbuminuria; Vascular inflammation.

Fig. 1

The pleiotropic action of insulin. Insulin regulates different physiological process including the glucose, protein and lipid metabolism, the cell cycle, growth and survival, the vascular tone and inflammation, the ions and amino-acid exchange/transport, and neuro-hormonal activity. Na⁺, sodium; Ca⁺⁺, calcium; RAAS, Renin–angiotensin–aldosterone system; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; IL-1, interleukin-1; PAI-1, plasminogen activator inhibitor-1

Fig. 2

Regulation of peripheral vascular resistances by insulin and effects of insulin resistance. In physiological conditions, insulin antagonizes (green arrows) the effects of vasoconstrictor mediators (red arrows), contributing to maintain the normal vascular tone. Insulin resistance (red arrows), impairs the capability of insulin to counterbalance the action of vasoconstrictor mediators, resulting in the increase of vascular peripheral resistances. TNF-α, tumor necrosis factor-α; IL-6, interleukin-6

Fig. 3

Molecular mechanisms that account for angiotensin II-induced insulin resistance. The binding of insulin to its own receptor evokes the tyrosine autophosphorylation of the β subunit, which, in turn activates, in sequence, the insulin receptor substrate-1 and phosphatidylinositol 3-kinase (green arrows). This cascade, accounts for the biological effects of insulin. Angiotensin II stimulation, through the activation of NADPH oxidase, stimulates the generation of reactive oxygen species, which, in turn promote the threonine phosphorylation of insulin receptor substrate-1 (red arrows). This induces the proteasome-dependent degradation of insulin receptor substrate-1, interrupting the insulin signalling cascade. Ser, serine; P, phospho; Tyr, tyrosine; ROS, reactive oxygen species; PI3K, phosphatidylinositol 3-kinase; IRS-1, insulin receptor substrate-1

Fig. 4

Relationship between microalbuminuria and insulin resistance in the continuum of cardiovascular disease. Microalbuminuria, is clinical marker of activation of the insulin resistance-dependent pathogenic mechanisms involved in the genesis and progression of hypertension and hypertension-induced target organ damage

Fig. 5

Insulin resistance is a time-dependent organ and tissue specific phenomenon. Insulin resistance contributes to the dysregulation of peripheral vascular resistance, resulting in an increase of blood pressure. In arterial hypertension, insulin resistance participates to the development of target organ damage. The persistence of insulin resistance induces the metabolic abnormalities that account for development of type 2 diabetes. The increased caloric intake and the sedentary habit are the principal environmental factors that account for the development and progression of insulin resistance