Clinical Endocrinology (2014)
doi: 10.1111/cen.12404
ORIGINAL ARTICLE
Circulating Apelin is increased in patients with type 1 or type 2 diabetes and is associated with better glycaemic control Marana Habchi*, Laurence Duvillard†, Vanessa Cottet†, Marie-Claude Brindisi*,†, Benjamin Bouillet*,†, Maud Beacco*, Elodie Crevisy*, Perrine Buffier*, Sabine Baillot-Rudoni*, Bruno Verges*,† and Jean-Michel Petit*,† *Services de diabetologie et endocrinologie Universite de Bourgogne and †Centre de Recherche INSERM Unite 866 CHU du Bocage, Dijon Cedex, France
Introduction Summary Context Apelin is an adipokine expressed in several tissues and it appears to be involved in energy metabolism. Objective The aim of this study was to determine serum apelin levels in a large cohort of patients with type 1 and type 2 diabetes and control subjects and to correlate the results with glycaemic control. Design and Participants One hundred and thirty patients with type 1 diabetes, 98 patients with type 2 diabetes and 162 controls were enrolled in the study. Apelin levels were measured by enzyme-linked immunosorbent assay. Results Serum apelin levels were significantly higher in type 1 and type 2 diabetic patients than in controls (P < 00001). Serum apelin levels were higher in type 1 than in type 2 diabetic patients (P = 002). In multivariate analysis, serum apelin levels were higher in patients with type 1 diabetes and in patients with type 2 diabetes versus controls. We found a negative correlation between glycosylated haemoglobin and serum apelin levels in all diabetic patients (r = 017, P = 0008) and in patients with type 2 diabetes (r = 024 P = 001). No correlation was found in type 1 diabetic patients. Conclusion Our study showed that apelin concentrations were increased in diabetic patients. This rise, which was greater in type 1 than in type 2 diabetic patients, suggests that obesity is not the main determinant of plasma apelin levels. The negative correlation with glycosylated haemoglobin in patients with type 2 diabetes could indicate that apelin plays a role in glycaemic balance and even insulin sensitivity. (Received 7 November 2013; returned for revision 24 November 2013; finally revised 6 January 2014; accepted 7 January 2014)
Correspondence: Dr Marana Habchi and Dr Jean-Michel Petit, Service de Diabetologie et d’Endocrinologie, CHU du Bocage, BP 77908, 21079 Dijon Cedex, France. Tel.: 33 3 80 29 34 53; Fax: 33 3 80 29 35 19; E-mails: [email protected] and [email protected] © 2014 John Wiley & Sons Ltd
Apelin is a bioactive peptide, first isolated from bovine stomach.1 This peptide is the endogenous ligand of the G-protein-coupled receptor APJ. Apelin is derived from preproapelin, a 77-amino-acid precursor, which is subsequently cleaved by endopeptidases into several active molecular forms, such as apelin-36, apelin-13 and apelin-12.1,2 Apelin mRNA is expressed in several tissues: including several regions of the central nervous system, in the heart, placenta, lung, mammary gland and gastrointestinal tract.3–7 It has been shown that apelin is an adipokine produced and secreted by white adipose tissue in humans and mice.8 Given its hypotensive effect and its effect on cardiac contractility, apelin also appears to be involved in cardiovascular function.2,9,10 Other studies suggest that apelin plays a role in the central nervous system and particularly in the regulation of food intake and water balance but the results of the different studies are conflicting.11–15 Moreover, apelin is involved in energy metabolism: it has been demonstrated that this adipokine improves insulin sensitivity in insulin-resistant obese mice, and that this effect is explained by an increase in glucose uptake in skeletal muscle.16,17 Apelin synthesis is stimulated by insulin and plasma apelin levels were reported to be increased in obesity in association with hyperinsulinaemia.8 In humans, several studies have evaluated the relationship between the serum concentration of apelin and diabetes and the results are still controversial. Indeed, some studies found an increased apelin level in obese subjects and in type 2 diabetic patients whereas other authors reported lower plasma apelin in obese subjects with newly-diagnosed type 2 diabetes than in nondiabetic subjects.18–22 In type 1 diabetes, only three studies have assessed plasma apelin concentrations. Two studies reported higher circulating apelin levels in type 1 diabetic patients than in healthy controls: one study in children 23 and one study in adult patients.24 In contrast, a recent study reported no difference in the circulating apelin levels between patients with type 1 diabetic patients and controls.25 Thus, the aim of our study was (i) to determine serum apelin levels in a large cohort of subjects with type 1 diabetes, type 2 diabetes and in nondiabetic controls; (ii) to investigate whether there was any relationship between serum apelin levels and glycaemic balance.
1
2 M. Habchi et al. measured using a commercial enzyme-linked immunosorbent assay (Phoenix Pharmaceuticals Inc., Burlingame, CA, USA.)
Research design and methods This single-centre study was approved by our regional ethics committee. Written informed consent was obtained from all patients prior to inclusion in the study. Patients with type 1 or type 2 diabetes were screened prospectively at the endocrinology department for the following inclusion criteria: the absence of acute or chronic disease based on the patient’s medical history, physical examination and standard laboratory tests (blood counts, electrolyte concentrations); and alcohol consumption of less than 20 g/day. Patients who had received thiazolidinediones were excluded. One hundred and thirty patients with type 1 diabetes and 98 patients with type 2 diabetes were included in the study. In the group of type 2 diabetic patients, 55 (561%) patients were treated with sulfonylurea, 65 (663%) with metformin and 53 (54%) with insulin. Only 5 patients were treated with diet alone. In the group of type 1 diabetic patients 99 (761%) patients were treated with basal-bolus insulin therapy, 5 (38%) with premix insulin therapy and 26 (200%) with insulin pumps. In type 1 diabetic patients, the mean daily insulin dose was 533 253 IU/day. One hundred and sixty-two control subjects were selected from a population undergoing a standard annual physical examination and biological measurements for medical insurance purposes. Body mass index (BMI) at baseline was calculated as weight in kilograms (kg) divided by squared height in meters (m), and individuals were classified as underweight (BMI < 185 kg/m²), normal weight [BMI (185–25) kg/m²], overweight [BMI (25–30) kg/m²] or obese (BMI ≥ 30 kg/m²). Given the low number of underweight people, the categories of underweight and normal weight were combined in a single category. Laboratory determinations Plasma glucose, HA1c, fasting serum HDL cholesterol, fasting LDL cholesterol and fasting serum triglycerides were determined by standard procedures. Serum Apelin-12 concentrations were
Statistical analysis Continuous variables were described as medians with interquartile ranges (25th and 75th percentiles) and categorical variables as numbers and percentages. Univariate comparisons between groups were performed using chi-square tests or Fisher exact tests, when appropriate, for qualitative variables, and using the Kruskal-Wallis test for quantitative variables. The Spearman correlation coefficient was used to test associations between quantitative variables. All variables associated with level of apelin or with diabetes group with a P-value
doi: 10.1111/cen.12404
ORIGINAL ARTICLE
Circulating Apelin is increased in patients with type 1 or type 2 diabetes and is associated with better glycaemic control Marana Habchi*, Laurence Duvillard†, Vanessa Cottet†, Marie-Claude Brindisi*,†, Benjamin Bouillet*,†, Maud Beacco*, Elodie Crevisy*, Perrine Buffier*, Sabine Baillot-Rudoni*, Bruno Verges*,† and Jean-Michel Petit*,† *Services de diabetologie et endocrinologie Universite de Bourgogne and †Centre de Recherche INSERM Unite 866 CHU du Bocage, Dijon Cedex, France
Introduction Summary Context Apelin is an adipokine expressed in several tissues and it appears to be involved in energy metabolism. Objective The aim of this study was to determine serum apelin levels in a large cohort of patients with type 1 and type 2 diabetes and control subjects and to correlate the results with glycaemic control. Design and Participants One hundred and thirty patients with type 1 diabetes, 98 patients with type 2 diabetes and 162 controls were enrolled in the study. Apelin levels were measured by enzyme-linked immunosorbent assay. Results Serum apelin levels were significantly higher in type 1 and type 2 diabetic patients than in controls (P < 00001). Serum apelin levels were higher in type 1 than in type 2 diabetic patients (P = 002). In multivariate analysis, serum apelin levels were higher in patients with type 1 diabetes and in patients with type 2 diabetes versus controls. We found a negative correlation between glycosylated haemoglobin and serum apelin levels in all diabetic patients (r = 017, P = 0008) and in patients with type 2 diabetes (r = 024 P = 001). No correlation was found in type 1 diabetic patients. Conclusion Our study showed that apelin concentrations were increased in diabetic patients. This rise, which was greater in type 1 than in type 2 diabetic patients, suggests that obesity is not the main determinant of plasma apelin levels. The negative correlation with glycosylated haemoglobin in patients with type 2 diabetes could indicate that apelin plays a role in glycaemic balance and even insulin sensitivity. (Received 7 November 2013; returned for revision 24 November 2013; finally revised 6 January 2014; accepted 7 January 2014)
Correspondence: Dr Marana Habchi and Dr Jean-Michel Petit, Service de Diabetologie et d’Endocrinologie, CHU du Bocage, BP 77908, 21079 Dijon Cedex, France. Tel.: 33 3 80 29 34 53; Fax: 33 3 80 29 35 19; E-mails: [email protected] and [email protected] © 2014 John Wiley & Sons Ltd
Apelin is a bioactive peptide, first isolated from bovine stomach.1 This peptide is the endogenous ligand of the G-protein-coupled receptor APJ. Apelin is derived from preproapelin, a 77-amino-acid precursor, which is subsequently cleaved by endopeptidases into several active molecular forms, such as apelin-36, apelin-13 and apelin-12.1,2 Apelin mRNA is expressed in several tissues: including several regions of the central nervous system, in the heart, placenta, lung, mammary gland and gastrointestinal tract.3–7 It has been shown that apelin is an adipokine produced and secreted by white adipose tissue in humans and mice.8 Given its hypotensive effect and its effect on cardiac contractility, apelin also appears to be involved in cardiovascular function.2,9,10 Other studies suggest that apelin plays a role in the central nervous system and particularly in the regulation of food intake and water balance but the results of the different studies are conflicting.11–15 Moreover, apelin is involved in energy metabolism: it has been demonstrated that this adipokine improves insulin sensitivity in insulin-resistant obese mice, and that this effect is explained by an increase in glucose uptake in skeletal muscle.16,17 Apelin synthesis is stimulated by insulin and plasma apelin levels were reported to be increased in obesity in association with hyperinsulinaemia.8 In humans, several studies have evaluated the relationship between the serum concentration of apelin and diabetes and the results are still controversial. Indeed, some studies found an increased apelin level in obese subjects and in type 2 diabetic patients whereas other authors reported lower plasma apelin in obese subjects with newly-diagnosed type 2 diabetes than in nondiabetic subjects.18–22 In type 1 diabetes, only three studies have assessed plasma apelin concentrations. Two studies reported higher circulating apelin levels in type 1 diabetic patients than in healthy controls: one study in children 23 and one study in adult patients.24 In contrast, a recent study reported no difference in the circulating apelin levels between patients with type 1 diabetic patients and controls.25 Thus, the aim of our study was (i) to determine serum apelin levels in a large cohort of subjects with type 1 diabetes, type 2 diabetes and in nondiabetic controls; (ii) to investigate whether there was any relationship between serum apelin levels and glycaemic balance.
1
2 M. Habchi et al. measured using a commercial enzyme-linked immunosorbent assay (Phoenix Pharmaceuticals Inc., Burlingame, CA, USA.)
Research design and methods This single-centre study was approved by our regional ethics committee. Written informed consent was obtained from all patients prior to inclusion in the study. Patients with type 1 or type 2 diabetes were screened prospectively at the endocrinology department for the following inclusion criteria: the absence of acute or chronic disease based on the patient’s medical history, physical examination and standard laboratory tests (blood counts, electrolyte concentrations); and alcohol consumption of less than 20 g/day. Patients who had received thiazolidinediones were excluded. One hundred and thirty patients with type 1 diabetes and 98 patients with type 2 diabetes were included in the study. In the group of type 2 diabetic patients, 55 (561%) patients were treated with sulfonylurea, 65 (663%) with metformin and 53 (54%) with insulin. Only 5 patients were treated with diet alone. In the group of type 1 diabetic patients 99 (761%) patients were treated with basal-bolus insulin therapy, 5 (38%) with premix insulin therapy and 26 (200%) with insulin pumps. In type 1 diabetic patients, the mean daily insulin dose was 533 253 IU/day. One hundred and sixty-two control subjects were selected from a population undergoing a standard annual physical examination and biological measurements for medical insurance purposes. Body mass index (BMI) at baseline was calculated as weight in kilograms (kg) divided by squared height in meters (m), and individuals were classified as underweight (BMI < 185 kg/m²), normal weight [BMI (185–25) kg/m²], overweight [BMI (25–30) kg/m²] or obese (BMI ≥ 30 kg/m²). Given the low number of underweight people, the categories of underweight and normal weight were combined in a single category. Laboratory determinations Plasma glucose, HA1c, fasting serum HDL cholesterol, fasting LDL cholesterol and fasting serum triglycerides were determined by standard procedures. Serum Apelin-12 concentrations were
Statistical analysis Continuous variables were described as medians with interquartile ranges (25th and 75th percentiles) and categorical variables as numbers and percentages. Univariate comparisons between groups were performed using chi-square tests or Fisher exact tests, when appropriate, for qualitative variables, and using the Kruskal-Wallis test for quantitative variables. The Spearman correlation coefficient was used to test associations between quantitative variables. All variables associated with level of apelin or with diabetes group with a P-value
