The Relationship Between Adrenomedullin, Metabolic Factors, and Vascular Function in Individuals With Type 2 Diabetes

Abstract

CHEE FANG SUM, MBBS1 OBJECTIVE -Subjects with type 2 diabetes are at risk for vascular injury. Several vasoactive factors (e.g., angiotensin) have been implicated. We hypothesize that adrenomedullin, a novel vascoactive factor, is deranged in subjects with type 2 diabetes.RESEARCH DESIGN AND METHODS -Using a new immunoluminometric method, plasma midregional proadrenomedullin (MR-proADM) was measured in four groups of Chinese subjects: healthy (n ϭ 100, fasting plasma glucose [FPG] Ͻ5.6 mmol/l), impaired fasting glucose (IFG) (n ϭ 60, FPG 5.6 -6.9 mmol/l), and diabetic subjects with (n ϭ 100) and without (n ϭ 100) nephropathy. Resting forearm cutaneous microcirculatory perfusion (RCMP) was quantified in vivo using 2-dimensional laser Doppler flowmetry. We investigated the relationship between plasma MR-proADM concentrations, multiple metabolic factors, and vascular function.RESULTS -We observed a stepwise increase in MR-proADM among the groups: healthy group mean Ϯ SD 0.27 Ϯ 0.09, IFG group 0.29 Ϯ 0.13, diabetic group 0.42 Ϯ 0.13, and diabetic nephropathy group 0.81 Ϯ 0.54 nmol/l (diabetic vs. healthy and IFG groups, P ϭ 0.04; and diabetic nephropathy group vs. all, P Ͻ 0.01). Statistical adjustment for sex, age, BMI, and blood pressure did not affect the conclusions. Multiple linear regression analysis revealed that highly sensitive C-reactive protein (␤ ϭ 0.11; P ϭ 0.01), insulin resistance index (␤ ϭ 0.20; P ϭ 0.001), LDL cholesterol (␤ ϭ 0.31; P Ͻ 0.001), and adiponectin (␤ ϭ 0.33; P Ͻ 0.001) were significant predictors of plasma MR-proADM concentrations among nondiabetic individuals. Among subjects with diabetes, plasma MR-proADM concentrations correlated significantly with RCMP (r ϭ 0.43, P ϭ 0.002).CONCLUSIONS -Plasma MR-proADM concentration was elevated in subjects with type 2 diabetes. This was further accentuated when nephropathy set in. MR-proADM was related to multiple metabolic factors and basal microcirculatory perfusion. Adrenomedullin might play a role in the pathogenesis of diabetic vasculopathy. Diabetes Care 30:1513-1519, 2007I ndividuals with type 2 diabetes are at risk for vascular injury. Although major advances have been made in uncovering the mechanism of diabetic vasculopathy, the exact pathophysiology remains incompletely understood (1). In recent years, the importance of endothelial dysfunction has taken central stage (2). By secreting a repertoire of finely regulated vasoactive factors with opposing functions working in autocrine and paracrine fashion, the endothelium is pivotal in maintaining vascular homeostasis (3). Numerous vascoactive factors have been described. Among these factors, adrenomedullin, a 52-amino acid peptide, has been intensively investigated due to its vascular protective properties (e.g., vasodilatory and antiproliferative) and promising potential as a therapeutic target (4). However, understanding of the pathobiology of adrenomedullin in diabetic vasculopathy has only just begun.In healthy states, adrenomedullin circulates at low picomolar concentration, which i...

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“…So far, circulating ADM levels were only investigated in small cohorts of diabetic patients with inconsistent results (26,27,28). In line with our findings, Lim et al (29) reported increased MR-proADM levels in patients with T2D, which were related to chronic inflammation (hsCRP), lipids, and IR. We are the first to demonstrate that MR-proADM levels are highly correlated with MetS, suggesting that ADM may play a role in the pathogenesis of this disorder.…”

Midregional Proadrenomedullin for Prediction of Cardiovascular Events in Coronary Artery Disease: Results from the AtheroGene Study

“…However, in previous studies with groups of healthy individuals (18,23,28 ) and in septic patients (24 ), no sex difference was observed. Interestingly, our data showed that MR-proADM concentrations were lower in current smokers compared to nonsmokers or those having formerly smoked.…”

“…The identification of midregional proadrenomedullin (MR-proADM) has overcome these problems because it is a stable peptide possibly reflecting the concentration of ADM, is theoretically secreted in amounts equimolar to those of ADM, and most likely does not have any physiological effects that might explain its apparent stability (18,22 ). Although its detailed pathological role has not been fully explored, increased plasma concentrations of MR-proADM have been related to cardiac dysfunction, systemic inflammatory status, prevalent type 2 diabetes, and renal failure (22)(23)(24).…”

Hemodynamic and hormonal effects of exogenous adrenomedullin administration in humans and relationship to insulin resistance

“…8,9 As such, plasma concentration of AM was progressively increased in patients with impaired glucose tolerance, diabetes and diabetes with nephropathy. 28 In addition, an increase in AM was related to multiple metabolic factors. 28 AM and insulin resistance may conflict with each other.…”

“…28 In addition, an increase in AM was related to multiple metabolic factors. 28 AM and insulin resistance may conflict with each other. Specifically, decreased reactivity of AM may contribute to increased arterial stiffness during insulin resistance, and this alteration may accelerate the progression of arterial sclerosis in insulin resistance.…”