Leptin, discovered in 1994, is a 16 kDa cytokine that contains 167 amino acids and is produced predominantly by white adipose tissue; its circulating levels correlate positively with white adipose tissue mass. Therefore, leptin is considered a proinflammatory adipokine that contributes to a low-grade inflammatory state in overweight and obese individuals 1. Leptin is an adipokine encoded on the ob gene and is associated with appetite regulation and energy homeostasis. Also, it has been implicated in the regulation of the cardiovascular functions 2.
Leptin regulates hepatic gluconeogenesis and has insulin-sensitizing effects. High leptin levels and leptin resistance are often found in prediabetic patients 3. Leptin resistance is associated independently with early markers of cardiovascular disease (CVD), including increased carotid intimal media thickness and decreased arterial distensibility, which may reflect the relation between hyperleptinemia and CVD 4.
Thyroid hormones have profound effects on lipid metabolism. Hypothyroidism is associated with increased total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL) levels, which increase the risk of CVD. Also, hypothyroidism results in increased vascular resistance, decreased cardiac output, myocardial injuries, and pericardial effusion. Thus, hypothyroid patients show a higher prevalence of cardiovascular risk factors and often have features of metabolic syndrome, including hypertension, increased waist circumference (WC), and dyslipidemia 5.
Thyroid dysfunction and diabetes mellitus are the two most common endocrine disorders encountered in clinical practice and they have been shown to influence each other mutually. Prediabetes is an intermediate metabolic state between normoglycaemia and diabetes. It includes those with impaired glucose tolerance and impaired fasting blood glucose. It has been shown that prediabetes is associated with an increased risk of CVD 6.
Patients and methods
This study was carried out on 240 hypothyroid male patients (levels of serum leptin vary during the menstrual cycle, being the lowest during the follicular phase, and 50% highest in the luteal phase; thus, women were not included in the study), who attended the endocrine outpatient clinic of the Main Alexandria University Hospital. Their ages ranged from 20 to 55 years. They were divided into two groups: group A included 120 hypothyroid patients with normal glucose tolerance and group B included 120 hypothyroid prediabetic patients. The study included a third group: group C, which included 120 healthy individuals matched for age and sex as a control group.
Exclusion criteria included drug-induced hypothyroidism, coronary heart disease (CHD), and patients with WC of more than 102 cm.
All patients and controls were subjected to an assessment of history, clinical examination (included WC), and laboratory investigations. Routine laboratory investigations included complete blood count, liver function tests, renal function tests, and specific investigations included fasting and 2 h postprandial blood glucose, basal serum TC, TG, LDL, and HDL, serum free T3 (FT3) (2.3–4.2 pg/ml), free T4 (FT4) (0.8–1.7 ng/dl), thyroid-stimulating hormone (TSH) (0.35–5.5 mIU/l), and fasting serum leptin level using an enzyme-linked immunosorbent assay 7. Blood samples were collected by venipuncture from all participants following 12 h of fasting.
All procedures performed in this study were in accordance with the ethical standards of the Declaration of Helsinki. Informed consent was obtained from all individual participants included in the study and ethical permission was granted from the local ethics committee at the Faculty of Medicine, Alexandria University.
All statistical analyses were carried out on IBM SPSS, version 21 (IBM Corporation; Chicago, USA). On the basis of the distribution of data, normally distributed data were analyzed using analysis of variance with a post-hoc test. The Kruskal–Wallis test was used for nonparametric data. Correlations between two quantitative variables were assessed using Pearson’s coefficients (logarithmic normalization was performed for abnormally distributed data). All tests were considered two-tailed and a P value of less than 0.05 was considered to be statistically significant.
The study included 240 hypothyroid male patients and 120 healthy men; their ages ranged from 20 to 55 years. They were divided into three groups: group A included 120 hypothyroid male patients with normal glucose tolerance with a mean age of 41.40±11.91 years, group B included 120 hypothyroid prediabetic male patients with a mean age of 40.13±10.55 years, and group C included 120 healthy males with a mean age of 40.15±12.21 years.
Diastolic blood pressure (DBP) was significantly higher in groups A and B in comparison with group C (Table 1). However, there was no significant difference in DBP between groups A and B.
WC was significantly higher in groups A and B compared with group C (Table 2). Yet, there was no significant difference in WC between groups A and B.
As shown in Table 3 and Fig. 1, there was a significant increase in serum leptin in groups A and B compared with the control group. However, there was no significant difference in serum leptin between groups A and B.
In comparison with group C, patients in group A had significantly higher serum TC, TG, LDL, and lower serum HDL. In group B, serum TC and LDL were significantly higher, whereas serum HDL was significantly lower than that in groups A and C. Serum TG was significantly higher in group B than in group C, whereas there was no significant difference in relation to group A (Fig. 2).
In group A, serum leptin showed a significant positive correlation with TSH (P=0.0001), TC (P=0.0001), and DBP (0.026), whereas it showed a significant negative correlation with FT3 (P=0.0001) and FT4 (P=0.004).
In the patients in group B, serum leptin showed a significant positive correlation with serum TC (P=0.0001), TG (P=0.041), and LDL (P=0.036) (Fig. 3), and a significant negative correlation with serum HDL (P=0.039).
Since its discovery over a decade ago, leptin has been established as a key regulator of energy balance. In addition, leptin plays an important role in the development of atherosclerosis and CVD 8.
Serum levels of lipids are found to increase in hypothyroidism and adipocytes express high levels of TSH receptors. As shown by many studies, serum levels of leptin were significantly higher in hypothyroidism 9.
Both overt and subclinical hypothyroidism are correlated with endothelial dysfunction, diastolic hypertension, dyslipidemia, atherosclerotic plaque progression, and instability 10.
In the current study, serum leptin was significantly higher in hypothyroid patients with normal glucose tolerance and hypothyroid prediabetic patients in comparison with the control group (P=0.0001). Similarly, Ibrahim et al. 11 showed that serum leptin in hypothyroid patients was significantly higher than that in euthyroid controls (P<0.05). Also, Kar and Sinha 12 found that serum leptin was significantly higher in hypothyroid patients than in controls (P<0.05).
The present study showed that serum leptin was significantly high in hypothyroid patients with prediabetes. In agreement with the results of the current study, Al-Daghri et al. 13 found that among men and women, serum leptin was significantly higher in those with prediabetes than in the controls (P=0.004 and 0.046, respectively). Also, Yang et al. 14 showed that plasma leptin levels were significantly higher in patients with impaired fasting glucose than in those with normal glucose tolerance (P<0.05). Li et al. 15 showed that a significant inverse association existed between serum leptin and β-cell function, and suggested that leptin plays a role in the development of insulin resistance and diabetes independent of metabolic syndrome.
In line with the present results, Chen et al. 9 showed that hypothyroid patients presented with significantly higher serum levels of TC, TG, LDL, and leptin compared with controls (P<0.05).
The current results showed that in hypothyroid prediabetic patients, serum TC, TG, and LDL were significantly higher and serum HDL was significantly lower than that in hypothyroid patients with normal glucose tolerance. In agreement with the results of the lipid profile of prediabetics in the present study, Kansal and Kamble 16 found that TC, LDL, TG, very-low-density lipoprotein, the TG/HDL ratio, and the LDL/HDL ratio were significantly increased in prediabetic individuals compared with normal healthy individuals, whereas HDL was significantly lower in prediabetic individuals compared with normal healthy individuals.
In addition to the dyslipidemia found in prediabetic hypothyroid patients, the present study showed that serum uric acid, DBP, and WC were significantly higher in hypothyroid patients with normal glucose tolerance and prediabetic hypothyroid ones in comparison with the control group, whereas there was no significant difference in serum uric acid, DBP, and WC between hypothyroid patients with normal glucose tolerance and those with prediabetes.
In the present study, in hypothyroid patients with normal glucose tolerance, serum leptin showed a significant positive correlation with TSH (P=0.0001), TC (P=0.0001), and DBP (P=0.026) and a significant negative correlation with FT3 (P=0.0001) and FT4 (P=0.004); also, TSH showed a significant positive correlation with LDL (P=0.001) and DBP (P=0.01) and a significant negative correlation with uric acid (P=0.03), whereas in hypothyroid prediabetic patients, serum leptin showed a significant positive correlation with serum TC (P=0.0001), TG (P=0.041), and LDL (P=0.036), whereas it showed a significant negative correlation with serum HDL (P=0.039).
In conjunction with these results, Balgi et al. 17 showed that TC, LDL, TG, and very-low-density lipoprotein were significantly increased in prediabetics, whereas HDL was significantly decreased in prediabetics compared with normal healthy individuals and concluded that prediabetics are highly prone to cardiovascular complications. Gutch et al. 18 found that serum TSH levels in participants with metabolic syndrome were significantly higher than those of the controls (P<0.001), suggesting a significant relation between TSH and metabolic syndrome, and highlights the association between hypothyroidism and metabolic syndrome.
The first limitation of this study is its small sample size. The second limitation is that thyroid status was classified in all patients on the basis of one blood test. Thus, some individuals with transient TSH elevations might have been misclassified. The third the causality between TSH and lipid levels can not be fully established.
A well-designed prospective research study will be necessary to address the relationship between TSH and lipid levels in prediabetics.
In the treatment of dyslipidemia in hypothyroid patients with prediabetes, thyroid function, especially the serum TSH level, should be monitored and maintained in the relatively low-normal range.
The author thanks the nursing staff and laboratory technicians in Endocrinology Unit, Internal Medicine Department, Faculty of Medicine, Alexandria University, for their sincere cooperation.
Conflicts of interest
There are no conflicts of interest.
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