Abstract
BackgroundType 2 diabetes (T2D) is associated with reduced numbers and impaired function of circulating angiogenic cells (CAC) which contributes to the progression of atherosclerosis and microvascular disease. Previous studies suggest that short-term infusion of unacylated ghrelin (UAG) normalizes CAC number in patients with T2D. To determine dose-dependent effects of short-term infusion of UAG in T2D patients using a cross-over model, and of long-term infusion of UAG in obese mice, on differentiation of monocyte progenitors into CAC.MethodsEight overweight T2D patients were infused overnight with 3 and 10 µg/kg/h of UAG in a double-blind, placebo-controlled cross-over study. To assess the effects of long-term UAG treatment, obese mice were infused with UAG for 4 weeks. Monocyte progenitors were assessed for their ability to differentiate into CAC in vitro.ResultsIn T2D patients, UAG treatment caused a reduction in differentiation of CAC, dependent on UAG dose and differentiation method. However, mice treated with UAG showed a significant increase in differentiation of bone marrow progenitors into CAC.ConclusionUAG causes a minor suppressive effect on CAC development after short-term treatment in humans, but experiments in mice suggest that long-term treatment has beneficial effects on CAC formation.The Netherlands Trial Register: TC=2487
Highlights
Type 2 diabetes (T2D) is associated with reduced numbers and impaired function of circulating angiogenic cells (CAC) which contributes to the progression of atherosclerosis and microvascular disease
Assessment of dose‐dependent effects of unacylated ghrelin (UAG) in humans Baseline values of generated EBM-CAC, Toyo-CAC and macrophages are shown in Fig. 1, representing the retrieval of these cell types from cultures of Peripheral blood mononuclear cells (PBMC) obtained before the initiation of treatment
These baseline findings indicate that both types of CAC cultures and macrophage cultures measure essentially distinct parameters. This is confirmed by a correlation analysis of the culture yields before and after treatment (Figs. 2, 3). This shows that a significant correlation exists only between the quantity of EBM-CAC and macrophages at baseline (Fig. 2b), but this correlation is lost after treatment with UAG (Fig. 3b)
Summary
Type 2 diabetes (T2D) is associated with reduced numbers and impaired function of circulating angiogenic cells (CAC) which contributes to the progression of atherosclerosis and microvascular disease. Previous studies suggest that short-term infusion of unacylated ghrelin (UAG) normalizes CAC number in patients with T2D. To determine dose-dependent effects of short-term infusion of UAG in T2D patients using a cross-over model, and of long-term infusion of UAG in obese mice, on differentiation of monocyte progenitors into CAC. Ghrelin is a 28 amino acid peptide that is secreted predominantly by X/A-like cells in the stomach. It circulates in two different forms: acylated ghrelin (AG) and unacylated ghrelin (UAG; named des-acyl ghrelin) [1, 2]. Since UAG only activates GHSR1a at supra-physiological concentrations [6], and has no physiological effect on GH secretion [7], it has long been considered not to have a physiological role.
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