Review
Relationship between autonomic dysfunction, insulin resistance and hypertension, in diabetes

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Abstract

Sympathovagal imbalance and insulin resistance are the common underlying disorders linking hypertension and diabetes. The role of hyperinsulinemia, however, on sympathovagal balance and blood pressure has never been clearly dissected from that of hyperglycemia. Nevertheless, the study of animal models of hypertension showed that hypertension does not invariably result in the onset of insulin resistance. This suggests that insulin resistance precedes the onset of hypertension and (possibly) contributes to its pathogenesis, mainly through sympathetic activation. To examine this hypothesis, recent studies investigated the relationship between insulin sensitivity and sympathetic activity in subjects with insulin resistance but free of overt hyperglycemia and obesity, i.e., insulin-resistant offspring of type 2 diabetic patients, demonstrating a prevalence of sympathetic over vagal activity. Therefore insulin resistance and sympathovagal imbalance come before hypertension, but a clear causative role cannot be demonstrated since other mechanisms, including an inappropriate lifestyle, must be taken into account to determine clinical hypertension. Finally, several experiments in human healthy volunteers suggest that the modulation of autonomic regulation at the forearm level can regulate insulin sensitivity, tempting us to speculate that it is the primary autonomic imbalance, through vasoconstriction, that results in both insulin resistance and hypertension. In conclusion, the close relationship between autonomic imbalance, insulin resistance and hypertension is unquestionable; although logical hypothesis can be constructed, which of the three is the earliest event is still not understood, and further research is required.

Introduction

Hypertension is approximately twice as common in diabetic subjects as in the general population [1]. The frequent association of impaired glucose tolerance, diabetes mellitus, obesity and hypertension was first reported in 1929 [2]. The presence of insulin resistance with compensatory hyperinsulinemia is considered as the common underlying metabolic disorder that links these conditions. However, hypertension per se may be associated with insulin resistance independently of other factors, as first demonstrated by Ferrannini et al. [3]. These authors showed a severe impairment of insulin-mediated glucose uptake in a group of lean hypertensive subjects with normal glucose tolerance. Since this first report, the relationship between hypertension and insulin resistance in human essential hypertension has stimulated great interest and debate [4]. In particular, during the last 20 years several studies investigated the pathogenesis of the association between hypertension and insulin resistance, substantially trying to validate at least three different possibilities:

  • •

    hypertension precedes the onset of insulin resistance and contributes to its pathogenesis through metabolic and/or hemodynamic disorders;

  • •

    insulin resistance/hyperinsulinemia precedes the onset of hypertension and contributes to its pathogenesis, mainly through sympathetic activation;

  • •

    autonomic imbalance represents the earliest event and contributes to the pathogenesis of both insulin resistance and hypertension.

Section snippets

Is hypertension responsible for the development of insulin resistance?

Insulin resistance with compensatory hyperinsulinemia are commonly described in non obese patients with essential hypertension [2], [5]; however, the relationship between hypertension and insulin resistance is still not completely understood, since the impact of high blood pressure per se on insulin-mediated glucose metabolism is not easily distinguishable. Nevertheless, if the decreased insulin sensitivity described in hypertensive individuals is the consequence of metabolic or hemodynamic

Does insulin resistance/hyperinsulinemia precede the onset of hypertension?

The alternative hypothesis is that insulin resistance and compensatory hyperinsulinemia represent the primary event and that the deriving enhanced sympathetic activity plays the pathogenic role in the increased prevalence of hypertension in the diabetic population [3], [19]. Among the various mechanisms postulated to link insulin resistance/hyperinsulinemia to hypertension sympathetic activation seems, in fact, to be the most important, as suggested by the finding that insulin infusion

Does autonomic imbalance represent the primary factor that, in turn, leads to insulin resistance and hypertension?

There is substantial evidence that sympathetic overactivity may be involved in the development of the metabolic alterations of the insulin resistance syndrome, such as dyslipidemia and the abnormalities in insulin-mediated glucose disposal at the skeletal muscle level [36], [37]. A primary autonomic imbalance could result in insulin resistance in several ways. The first possibility is that sympathetic overactivity could determine vasoconstriction [36], [37]. In this hemodynamic model of insulin

References (57)

  • S. Frontoni et al.

    Increased insulin sensitivity in the high-sodium, one-kidney, one figure-8 hypertensive rats

    Hypertension August

    (1992)
  • E.L. Bravo

    Metabolic factors and the sympathetic nervous system

    Am J Hypertens

    (1989)
  • D.C. Deibert et al.

    Epinephrine-induced insulin resistance in man

    J Clin Invest

    (1980)
  • D. Porte

    Sympathetic regulation of insulin secretion

    Arch Intern Med

    (1969)
  • R.A. Rizza et al.

    Adrenergic mechanisms for the effects of epinephrine on glucose production and clearance in man

    J Clin Invest

    (1980)
  • G.A. Werther et al.

    Physiological insulin action is opposed by β-adrenergic mechanisms in dogs

    Am J Physiol

    (1988)
  • D.A. Young et al.

    Effect of catecholamines on glucose uptake and glycogenolysis in rat skeletal muscle

    Am J Physiol

    (1985)
  • J.L. Chiasson et al.

    Inhibitory effect of epinephrine on insulin-stimulated glucose uptake by rat skeletal muscle

    J Clin Invest

    (1981)
  • J.R. Lupien et al.

    Effects of norepinephrine infusion on in vivo insulin sensitivity and responsiveness

    Am J Physiol

    (1990)
  • J.E. Hall et al.

    Chronic hyperinsulinemia and blood pressure regulation

    Am J Physiol

    (1990)
  • C. Berne et al.

    The sympathetic response to euglycemic hyperinsulinemia: the evidence from microelectrode nerve recordings in healthy subjects

    Diabetologia

    (1992)
  • E.A. Anderson et al.

    Insulin increases sympathetic activity but not blood pressure in borderline hypertensive humans

    Hypertension

    (1992)
  • E.A. Anderson et al.

    Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans

    J Clin Invest

    (1991)
  • R.A. DeFronzo et al.

    Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease

    Diabetes Care

    (1991)
  • Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology

    Heart rate variability. Standards of measurement, physiological interpretation, and clinical use

    Eur Heart J

    (1996)
  • L. Landsberg

    Insulin-mediated sympathetic stimulation: role in the pathogenesis of obesity-related hypertension (or, how insulin affects blood pressure, and why)

    J Hypertens

    (2001)
  • R.J. Troisi et al.

    Relation of obesity and diet to sympathetic nervous system activity

    Hypertension

    (1991)
  • E. Muscelli et al.

    Autonomic and haemodynamic responses to insulin in lean and obese humans

    J Clin Endocrinol Metab

    (1998)

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