Elsevier

Peptides

Volume 30, Issue 2, February 2009, Pages 256-261
Peptides

Significant lower VVH7-like immunoreactivity serum level in diabetic patients: Evidence for independence from metabolic control and three key enzymes in hemorphin metabolism, cathepsin D, ACE and DPP-IV

https://doi.org/10.1016/j.peptides.2008.11.004Get rights and content

Abstract

Low circulating VVH7-like immunoreactivity (VVH7 i.r) level was amazingly observed in human diabetic sera. Here, we examined the impact of diabetes type, clinico-biological features and metabolic control on circulating VVH7 i.r level in this disease. ELISA test was used to measure VVH7 i.r in sera of 120 diabetic patients (type 1 diabetes in 64, type 2 diabetes in 56). Three enzymatic tests were also applied to determine serum cathepsin D (CD), dipeptidyl peptidase IV (DPP-IV) and angiotensin-converting enzyme (ACE) activities. A subgroup of 24 type 1 diabetic patients negative for microalbuminuria and hypertension were submitted to an ambulatory blood pressure monitoring to evaluate the relationship between VVH7 i.r level and blood pressure parameters. The mean serum concentration of VVH7 i.r was drastically reduced in diabetic patients (0.91 ± 0.93 μmol/l versus 5.63 ± 1.11 μmol/l in controls) (p < 0.001). A negative correlation between VVH7 i.r level and daytime diastolic blood pressure existed in type 1 diabetic patients. There was no association of low VVH7 i.r with either type of diabetes or HbA1c level. An increase of cathepsin D activity was found in serum of diabetic patients compared to controls (0.47 U/ml versus 0.15 U/ml, respectively) whereas DPPIV activity was significantly decreased in diabetic sera (50.81 U/ml versus 282.10 U/l respectively). Diminution of VVH7 i.r in sera of diabetic patients was confirmed but still remained unexplained. Relationships between higher systolic blood pressure and decrease of VVH7 i.r reinforce the need to investigate this pathway in this disease to elucidate its role in macro- and micro-angiopathy.

Introduction

We previously made the observation that VVH7 i.r level in blood of a short series of 31 diabetic patients was drastically decreased in comparison to controls [9]. In addition, glycated hemoglobin submitted to cathepsin D hydrolysis released three to five times less hemorphin-7 (H7) like peptides than native hemoglobin [9]. These in vitro data suggested that the glycation of hemoglobin could be a cause of the decrease of VVH7 i.r observed in serum of diabetics by interfering with the cleavage site of cathepsin D on globin beta chain. The clinical significance and mechanisms of such hemorphin decrease associated with diabetes mellitus remained unknown. The hemorphins are peptides which derived from the CD-induced cellular proteolysis of beta chain of hemoglobin [33]. Those peptides exhibit biological properties such as analgesic, anti-inflammatory and hypotensive activities [27], [34]. They exert a hypotensive property by specifically inhibiting ACE [8], [18] and mimicking angiotensin IV cellular actions [11], [24]. Such potential activities could be particularly relevant in natural history of diabetes and its complications as high blood pressure is a major risk factor for both macro- and micro-angiopathy [30] in type 2 and type 1 as well [7], [22].

The aim of the present study is to confirm the previous observation on a larger series of patients, to evaluate the relationship between plasma VVH7 i.r level with degree of glucose control, body mass index and type of diabetes. We also analysed the possible association between this parameter and some markers of diabetes-related complications such as high blood pressure and microalbuminuria. Finally, as the role of glycation of hemoglobin in the decrease of plasma VVH7 i.r cannot resume the mechanism observed, we tested other hypothesis. Circulating hemorphin decrease could be the result of either a defect of production rate from cathepsin D [33], an excess of catabolism rate by various peptidases such as DPP-IV [4] and ACE [8], [11] or structural changes modifying the clearance rate or masking VVH7 i.r to specific antibodies. Thus, we evaluated activity of some of those enzymes involved in metabolism of hemorphins, i.e. cathepsin D, DPPIV and ACE in the serum of diabetic patients and correlated those measures with hemorphin levels.

Section snippets

Description of patients

A population of 120 patients was enrolled. Diabetic patients were classified as suffering from either type 1 diabetes (64 patients) or type 2 diabetes (56 patients) according to ADA classification [1]. Diabetic patients were treated according to the standards of practice. Type 1 diabetic patients received intensified insulin therapy with basal insulin analogue (glargine or detemir) and pre-meal rapid insulin analog (Lispro or aspart) injections. Type 2 diabetic patients were treated by diet and

VVH7 i.r level in various populations

Characteristics of the diabetic and control populations are summarized on Table 1. Type 1 diabetic patients represented 53% of the entire diabetic population (n = 120). In comparison to type 1 diabetic patients, type 2 diabetic subjects were characterized by a tendency to higher age (p = 0.09), BMI (p < 0.001), prevalence of high blood pressure (p < 0.001), higher plasma haptoglobulin level (p < 0.001), and lower plasma creatinin level (p < 0.001).

The mean HbA1c level of the whole diabetic population was

Discussion

This study on a larger series of patients definitively confirms the previous preliminary observation made by our group of a drastically reduced level of circulating VVH7 i.r in plasma of diabetic patients [9]. This anomaly is only related to the diabetic state as it was observed in both forms of the disease, type 1 and type 2 diabetes. H7-like peptides are short peptides released specifically by cellular proteolysis of beta-chain of human hemoglobin. Various biological activities have been

Acknowledgements

This investigation was funded by University Hospital of Marseille (Assistance Publique-Hôpitaux de Marseille) and French Ministry of Health. We are grateful to the staff of the Department of Nutrition, Metabolic diseases and Endocrinology of the University Hospital La Timone (Marseille, France) for assistance in recruiting patients and Hospital of La Rochelle for technical support, particularly the Biological Laboratories Platform. The authors also thank the French Ministry of Research for

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