Metabolic syndrome,adiponectin and proinflammatory status in patients with type 1 diabetes mellitus

Abstract

Objectives

To assess the prevalence of metabolic syndrome and evaluate proinflammatory status in patients with type 1 diabetes, and to analyse the relationship between inflammation, metabolic control and insulin resistance in these patients.

Methods

Patients with type 1 diabetes were stratified according to the presence or absence of metabolic syndrome. Serum adiponectin, leptin, tumour necrosis factor (TNF)-α, interleukin (IL)-6 and high-sensitivity C-reactive protein (hsCRP) were quantified.

Results

The prevalence of metabolic syndrome was 28.6% (22/77). Patients with metabolic syndrome had lower adiponectin concentrations and higher leptin, TNF-α, IL-6 and hsCRP concentrations compared with patients without metabolic syndrome. In addition, metabolic syndrome was associated with higher glycosylated haemoglobin and insulin dose, and increased insulin resistance.

Conclusions

The proinflammatory state associated with metabolic syndrome in patients with type 1 diabetes leads to deterioration of glycaemic control and an increase in the required daily dose of insulin. Early and proactive diagnosis of metabolic syndrome in these patients will allow medication and lifestyle optimization, in order to prevent the occurrence of diabetes complications and improve health-related quality-of-life.

Keywords

Metabolic syndrome type 1 diabetes obesity adiponectin leptin

Introduction

The presence of metabolic syndrome significantly increases cardiovascular risk^1,2 and impaired glycaemic control.³ The World Health Organization first described metabolic syndrome in 1998 as a condition characterized by several risk factors, which together have increased predictive power for the development of impaired glycaemic control and atherosclerotic disease, compared with each factor taken separately.⁴ Metabolic syndrome has been associated with both type 2 and type 1 diabetes mellitus, thereby augmenting cardiovascular risk even in younger patients with type 1 diabetes.^5–7

Patients with metabolic syndrome have increased abdominal adipose tissue, especially visceral fat.⁸ Visceral adipocytes have intense secretory activity and can be considered equivalent to endocrine organs.⁹ Obesity is associated with increased adipocyte secretion of factors that reduce insulin-mediated glucose uptake, including free fatty acids and proinflammatory cytokines such as tumour necrosis factor (TNF)-α, interleukin (IL)-β1, and IL-6.¹⁰ Obesity is also associated with low levels of adiponectin (the only adipocytokine that increases insulin-mediated glucose uptake), and has an anti-inflammatory action.^11,12 Cytokines released by adipose tissue are involved in initiating and promoting a proinflammatory status, contributing to greater insulin resistance and cardiovascular risk.^9,13,14 Leptin and adiponectin decrease triglyceride synthesis, promoting the catabolism of fatty acids and enhancing insulin action in both skeletal muscle and liver.¹⁵ In patients with obesity, leptin levels are increased and adiponectin levels are decreased, suggesting that obesity leads to a state of leptin resistance and adiponectin deficiency.¹⁵ Cell exposure to TNF-α stimulates inhibitory phosphorylation of the serine residues of insulin receptor substrate 1, which is recognized as the major pathway in insulin resistance promotion.¹⁶ TNF-α is an important link between inflammation, obesity and insulin resistance.¹⁷ IL-6 reduces the expression of insulin receptor substrate 1 via extracellular signal-regulated kinases, thereby impairing insulin signalling and action.¹⁸ High sensitivity C-reactive protein (hsCRP; the most important acute-phase protein) also plays a role in leptin resistance by acting as a leptin-interacting protein. In addition, CRP is considered to be an important link between atherosclerosis, cardiovascular disease and insulin resistance.¹⁸

Studies have described an increased prevalence of abdominal obesity and metabolic syndrome in children and adults with type 1 diabetes, suggesting an association between metabolic syndrome, insulin resistance, and the risk of developing chronic diabetes complications in these people.^19–21

The primary aim of the present study was to assess the prevalence of metabolic syndrome in patients with type 1 diabetes mellitus. In addition, proinflammatory status was evaluated by quantifying each patient’s adiponectin, leptin, TNF-α, IL-6 and hs-CRP concentrations, and the relationship between proinflammatory status and quality of metabolic control, daily insulin dose, and prevalence of diabetes complications was examined.

Patients and methods

Study population

The study enrolled patients with type 1 diabetes, treated between April 2012 and May 2013 at the Diabetes Clinic of the Emergency Hospital, Timisoara, Romania. Inclusion criteria were aged <45 years; basal–bolus insulin analogue monotherapy (without any other antidiabetic or insulin sensitizer agents). Data regarding history of diabetes, daily insulin requirement (per kg body weight), dietary habits, alcohol intake, smoking profile and physical activity were obtained from medical records. Height, weight, blood pressure (according to European Society of Cardiology Guidelines²²) and abdominal and hip circumference were measured for each patient; body mass index (BMI; kg/m²) and waist-to-hip ratio (WHR) were calculated. Metabolic syndrome was diagnosed according to AHA/NHLBI 2009 consensus criteria.²³

All patients provided written informed consent and the study was approved by the Ethics Committee of the Emergency Hospital, Timisoara, Romania.

Laboratory analyses

Peripheral blood (5 ml) was taken from each patient after an overnight fast, for quantification of concentrations of serum triglyceride, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) (all via enzymatic methods), glycosylated haemoglobin (HbA1c) (immunoturbidimetric method; Abbot Architect c8000 clinical chemistry analyser, Abbot Laboratories, Irving, TX, USA), adiponectin, leptin, TNF-α, IL-6 (all via enzyme-linked immunosorbent assay, Biovendor Laboratory Medicine, Candler, NC, USA), and hs-CRP (nephelometry method). Insulin resistance was assessed using the estimated glucose disposal rate (eGDR), according to the following formula: eGDR = 24.31–(12.22 × WHR)–(3.29 × presence of hypertension: 0 for no and 1 for yes)–(0.57 × HbA1c) (mg × kg⁻¹× min⁻¹). There is an inverse correlation between insulin resistance and eGDR.²⁴

Statistical analyses

Data were presented as mean ± SD (for continuous variables with Gaussian distribution), median (interquartile range [IQR]; for continuous variables without Gaussian distribution), or n (%) (categorical variables). The 95% confidence intervals for prevalence were calculated according to Wilson’s procedure.

Patients were stratified according to the presence or absence of metabolic syndrome. Between-group comparisons were made using Student’s t-test, Mann–Whitney U-test or χ²-test with Yates correction, as appropriate. The distribution of continuous variables was tested for normality using Shapiro–Wilk test and Levene’s test for equality of variances. Pearson’s correlation coefficient was used to evaluate correlations and regression strength in the study population as a whole, with statistical significance assessed using t-distribution test.

Statistical analyses were performed using SPSS® version 17.0 (SPSS Inc., Chicago, IL, USA) for Windows®. P-values <0.05 were considered statistically significant.

Results

The study included 77 patients with type diabetes (37 [48.1%] male/40 [51.9%] female; mean age 34 ± 8 years; age range 21–55 years). Clinical and demographic characteristics of the study population are shown in Table 1.

Table 1.

Demographic and clinical characteristics of patients included in a study investigating the prevalence of metabolic syndrome and proinflammatory status in type 1 diabetes mellitus (n = 77).

Characteristic	Value
Age, years	34 (8)
Males	37 (48.1%)
Diabetes duration, years	7 (5)
BMI, kg/m²	27.6 ± 7.1
Abdominal circumference, cm – males	90.4 ± 6.9
Abdominal circumference, cm – females	74.3 ± 6.7
HbA1c, %	7.9 ± 0.9
Daily insulin dose, IU/kg	0.74 ± 0.15
Systolic blood pressure, mmHg	124.3 ± 11.4
Diastolic blood pressure, mmHg	67.3 ± 10.4
Triglyceride, mg/dl	116.1 ± 38.3
HDL-C, mg/dl	48.3 ± 6.9
hs-CRP, mg/l	5.3 ± 1.6
Adiponectin, µg/l	11.2 ± 4.8
Leptin, ng/ml	8.5 ± 3.5
TNF-α, pg/ml	13.4 ± 2.1
IL-6, pg/ml	3.6 ± 0.9

Data presented as median (interquartile range), n (%) or mean ± SD.

BMI, body mass index; HbA1c, glycosylated haemoglobin; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; TNF, tumour necrosis factor; IL, interleukin.

A total of 22/77 (28.6%) patients were diagnosed with metabolic syndrome (12/40 [30.0%] female vs 10/37 male [27.0%]; difference not statistically significant). Median age was significantly higher in patients with metabolic syndrome than in those without (36 [5] vs 32 [7]; P = 0.022). As expected, there were significant between-group differences in all criteria included in the definition of metabolic syndrome (P < 0.0001 for each comparison; Table 2).

Table 2.

Metabolic syndrome criteria components in patients with type 1 diabetes mellitus, stratified according to the presence or absence of metabolic syndrome.

Parameter	Metabolic syndrome present n = 22	Metabolic syndrome absent n = 55	Statistical significance^a
Abdominal circumference, cm
Male patients	102.0 ± 6.8	86. 1 ± 7.0	P < 0.0001
Female patients	86.2 ± 5.3	70.5 ± 7.3	P < 0.0001
Triglyceride, mg/dl	192.6 ± 37.0	155. 6 ± 33.2	P < 0.001
HDL-C, mg/dl
Male patients	38.5 ± 4.1	49.6 ± 4.7	P < 0.0001
Female patients	46.8 ± 4.5	51.1 ± 7.1	P < 0.001
Systolic blood pressure, mmHg	133.3 ± 7.6	120.6 ± 10.7	P < 0.0001
Diastolic blood pressure, mmHg	77.7 ± 7.9	62.7 ± 7.9	P < 0.0001

Data presented as mean ± SD.

^aStudent’s t-test.

HDL-C, high-density lipoprotein cholesterol.

Data regarding adiponectin and leptin concentrations are shown in Table 3. Adiponectin concentrations were significantly lower and leptin concentrations significantly higher in patients with metabolic syndrome compared to those without (P < 0.0001 for both comparisons). There was a significant inverse correlation between serum adiponectin levels and BMI in both males (r = −0.61; P < 0.001) and females (r = −0.54; P < 0.001). Serum leptin values correlated directly and significantly with BMI in both male (r = 0.77; P < 0.001) and female (r = 0.72; P < 0.001) patients.

Table 3.

Serum adipocytokine and proinflammatory cytokine concentrations and clinical parameters in patients with type 1 diabetes mellitus, stratified according to the presence or absence of metabolic syndrome.

Parameter	Metabolic syndrome present n = 22	Metabolic syndrome absent n = 55	Statistical significance^a
Adiponectin, µg/ml	7.64 ± 2.56	12.58 ± 4.73	P < 0.0001
Leptin, ng/ml	11.23 ± 2.37	7.36 ± 3.22	P < 0.0001
TNF-α, pg/ml	7.5 ± 1.82	5.36 ± 1.89	P < 0.0001
IL-6, pg/ml	4.32 ± 0.84	3.36 ± 0.89	P < 0.0001
hs-CRP, mg/l	6.64 ± 1.33	4.76 ± 1.29	P < 0.0001
eGDR	7.22 ± 1.91	8.13 ± 1.61	P = 0.037
HbA1c, %	8.82 ± 2.2	7.53 ± 1.8	P = 0.009
Daily insulin dose, IU/kg	0.93 ± 0.24	0.66 ± 0.12	P < 0.001

Data presented as mean ± SD.

^aStudent’s t-test.

TNF: tumour necrosis factor; IL: interleukin; hs-CRP: high-sensitivity C-reactive protein; eGDR: estimated glucose disposal rate; HbA1c: glycosylated haemoglobin.

Patients with metabolic syndrome had significantly higher TNF-α, IL-6 and hs-CRP concentrations (P < 0.0001 for each comparison; Table 3), decreased eGDR (increased insulin resistance; P = 0.037), increased HbA1c (P = 0.009) and higher insulin dose (P < 0.001) than patients without metabolic syndrome (Table 3).

Body mass index was positively correlated with TNF-α and IL-6 in both male patients (r = 0.55, P < 0.001 and r = 0.51, P < 0.001, respectively) and female patients (r = 0.56, P < 0.001 and r = 0.53, P < 0.001, respectively).

Concentrations of TNF-α, IL-6 and hs-CRP were inversely correlated with adiponectin concentrations, and directly correlated with leptin concentrations (Table 4).

Table 4.

Pearson’s correlation coefficient analysis of the relationships between serum adiponectin or leptin and proinflammatory cytokine concentrations, in patients with type 1 diabetes mellitus (n = 77).

Parameter	Adiponectin		Leptin
Parameter	r	Statistical significance	r	Statistical significance
TNF-α
Male patients	−0.71	P < 0.001	0.52	P = 0.001
Female patients	−0.68	P < 0.001	0.48	P = 0.002
IL-6
Male patients	−0.67	P < 0.001	0.61	P < 0.001
Female patients	−0.64	P < 0.001	0.55	P < 0.001
hs-CRP
Male patients	−0.65	P < 0.001	0.42	P = 0.009
Female patients	−0.61	P < 0.001	0.47	P = 0.002

TNF, tumour necrosis factor; IL, interleukin; hs-CRP, high-sensitivity C-reactive protein.

Discussion

The prevalence of metabolic syndrome in patients with type 1 diabetes in the present study was similar to that found in the general population,^25,26 in spite of the relatively young age of our study group. This suggests that metabolic syndrome is more prevalent at younger ages in patients with type 1 diabetes than in the general population of a similar age group. The presence of metabolic syndrome in patients with type 1 diabetes was associated with increased insulin resistance and proinflammatory state in the present study. This leads to a premature increase in global cardiovascular risk,^2,27,28 rendering young patients with type 1 diabetes as vulnerable to cardiovascular disease as the older population without diabetes.

Metabolic syndrome is less common in patients with type 1 diabetes than in those with type 2 diabetes,²⁹ possibly because insulin resistance caused by abdominal obesity is one of the main pathogenic mechanisms in type 2 diabetes.³⁰ However, if a patient with type 1 diabetes develops abdominal obesity, the risk of developing metabolic syndrome becomes similar to that of a patient with type 2 diabetes, because both present the same clinical characteristics, including a proinflammatory state.³¹

Patients with type 1 diabetes and metabolic syndrome in the present study had elevated proinflammatory cytokine concentrations and decreased adiponectin concentrations compared with patients without metabolic syndrome. A proinflammatory state promotes insulin resistance and increases cardiovascular risk.^2,3,8,32 In addition, the presence of metabolic syndrome in patients with type 1 diabetes promotes insulin resistance and leads to increased insulin requirements, with subsequent deterioration of glycaemic control and weight gain.³³

Adiponectin concentrations were inversely correlated with BMI and proinflammatory cytokine (TNF-α and IL-6) and inflammatory marker (hs-CRP) concentrations in the present study. This finding underlines the important role of adiponectin in reducing inflammation the atherogenic process, which is known to have a considerable inflammatory component.³⁴ Leptin was elevated in the presence of metabolic syndrome in the present study and was directly correlated with BMI. This suggests that abdominal obesity (a characteristic of metabolic syndrome) is associated with hyperleptinaemia, and that these patients may have developed leptin resistance. IL-6 and TNF-α are correlated with abdominal obesity,³⁵ thus linking obesity and metabolic syndrome in type 1 diabetes to proinflammatory status and atherosclerosis.

The present study is unusual in that it analyses the relationship between metabolic syndrome, adipocytokines, glycaemic control and inflammation in adults (median age 34 years) with type 1 diabetes. Other studies have generally focused on children or younger adults.³⁶ The inflammatory and metabolic states of patients with type 1 diabetes and metabolic syndrome in the present study were similar to patients of a similar age with type 2 diabetes.³⁷ In addition, the present study assessed directly the relationship between the components of metabolic syndrome and adipocytokines and glycaemic control.

In conclusion, the proinflammatory state associated with metabolic syndrome in patients with type 1 diabetes leads to further deterioration of glycaemic control and an increase in the daily dose of insulin needed. Since the development of chronic diabetic complications is strictly related to the quality of glycaemic control, the presence of metabolic syndrome would lead to an increased risk of developing chronic complications. Early and proactive diagnosis of metabolic syndrome in patients with type 1 diabetes will allow medication and lifestyle optimization in order to prevent the occurrence of microvascular and macrovascular complications of diabetes and improve quality of life.

Footnotes

Declaration of conflicting interest

The authors declare that there are no conflicts of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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