High serum phosphate and triglyceride levels in smoking women and men with CVD risk and type 2 diabetes

Optimal serum phosphate (S-P) is an important condition for effective glucose metabolism. In glucose intolerance, there is a negative association between S-Glucose (S-Glu) and S-P [1‐4]. The low S-P in connection with obesity indicates an association with biomarkers for metabolic syndrome and cardiovascular disease (CVD) risk factors [4‐6]; however, high levels of phosphate, although within normal limits, can be an even stronger marker for CVD risk with or without renal disease [7‐10]. Thus, defining normal S-P levels may be important in understanding early metabolic disturbances. Reducing high S-P in patients with Chronic Kidney Disease (CKD) is an important therapy as well as a possible preventive strategy in other patients and individuals with high S-P levels [10]. Therefore, phosphate binders could be used in non-uremic vascular disease to reduce S-P levels [11]. The CVD risk of high levels of phosphate with respect to CKD relative to the risk of low S-P due to obesity has been described as a double-edge sword [4, 8, 12]. If this U-shaped relationship between S-P and CVD risk is true, the possible links, causes, and mechanisms need more study. Defining the level of S-P that influences CVD risk, either low or high, needs to be determined and used as the normal reference interval in future investigations. As smoking increases risk for type 2 diabetes (as shown by dyslipidemia and hyperglycemia), we wanted to study whether smoking and type 2 diabetes were associated with serum triglycerides and phosphate levels independently from other CVD risk factors.

We found a higher level of S-P and S-TG in smokers compared to non-smokers in non- type 2 diabetes women and men. These associations still existed after adjusting for age and CVD risk factors in the multiple linear regression analysis. No interaction between smoking and type 2 diabetes in the association with S-P levels was revealed while interaction between S-Glu and type 2 diabetes was positively associated with S-P. This indicates an existence of high but normal S-P levels in type 2 diabetes as well (Figure 1). The adverse and combined association between CVD risk with smoking in type 2 diabetes may partly be due to high S-P levels in addition to a high S-TG levels.

An inverse relationship between S-Glu and S-P in non-type 2 diabetes women and men, between age and S-P in men, and BMI and S-P in women indicate the need to adjust for sex, age, and BMI in the assessment of CVD risk factors associated with S-P levels. Age-related differences in S-P between women and men may be due to differences in renal thresholds for phosphate [15]. The comparison of smokers with non-smokers after stratification for sex reveals higher S-P as well as higher S-TG levels and a lower SBP and DBP in both women and men. In a community study, a higher prevalence of smokers was seen in the highest quartile of serum phosphate [9]. Some studies have reported higher but within normal levels of S-P for smokers without a discussion of the importance of S-P with respect to either CVD risk or insulin resistance for smokers [9, 16]. The present study highlights associations between some conventional CVD-risk factors and high but normal S-P levels and as such expands our knowledge of the U-shaped risk pattern related to CVD risk, not including patients with kidney disease and hyperphosphatemia. In chronic kidney disease, a pathological level of S-P (hyperphosphatemia) is frequently reported as S-P may interact with calcium, which increases CVD risk [8].

Increased levels of S-TG and S-P in smokers and type 2 diabetes patients compared with non-smokers and non-type 2 diabetes patients indicate a common disturbance of metabolism linked to CVD risk associated with insulin resistance. A high level of glycosylated haemoglobin (HbA1c) in smokers may be an indicator for insulin resistance, but the mechanism behind this is still unclear [17]. In an earlier study, S-P was shown to be a marker for glycaemia control [18].

In light of this study, future research should address the following question: Does the high normal level of S-P signal insulin resistance in smokers and in patients with type 2 diabetes? Factors contributing to a high level of S-P in smokers are largely unknown and sources and mechanisms responsible for an increase in S-P in smokers and the association between level of S-Glu and level of S-P in type 2 diabetes needs further investigation.

There are three possible mechanisms or explanations for a high level of S-P that may be present in smokers and in patients with type 2 diabetes: 1) an increased threshold for reabsorption of phosphate in the kidney tubules can partly be explained by a decrease in the level of parathyroid hormone (PTH) [15, 19]; 2) low bone mineral content (BMC) analysis has shown that smokers have greater bone loss than non-smokers perhaps as a result of mobilization of phosphate from bone by either increased resorption or decreased mineralisation revealed [20]; and 3) a decreased cellular uptake of glucose for intracellular energy metabolism (i.e., phosphorylation) may be related to both low oxygen consumption and the level of S-P, described as affinity hypoxia [3].

We believe that the higher S-P may be associated with intracellular depletion of Pi, oxygen, and glucose. A disturbed oxidative phosphorylation may explain lower ATP production in offspring who have parents with type 2 diabetes [21] and this may also explain why recovery from exercise in smokers involves a delay in adenosine triphosphate (ATP) resynthesis [22]. Intracellular phosphate depletion may also underlie hyperinsulinemia [23].

The important findings that type 2 diabetes was associated with S-TG – although in opposite directions in women (-) and men (+) and stronger for women than men (p = 0.000 vs. p = 0.047) – may be associated with the level of other risk factors in the model and, for women, associated with the level of S-Cholesterol. In women only, the interaction between type 2 diabetes and cholesterol and S-TG could explain the opposite directions of associations. Smoking was strongly associated with S-TG after control for the other CVD risk factors resembling metabolic syndrome.

Another important finding that links these two conditions (metabolic disturbance in smokers and in type 2 diabetes) to insulin resistance and CVD risk is dyslipidemia (i.e., high S-TG). We found that high S-TG in type 2 diabetes men but not women was further accentuated by smoking (i.e., higher S-TG in smokers vs. non-smokers). Smokers had higher visceral obesity as shown by a high waist/hip ratio [24]. Thus smoking is associated with dyslipidemia and central fat accumulation [25]. A study on men with and without cardiovascular disease found that S-TG levels were higher in smokers than non-smokers [26]. Smoking and very high levels of TG were associated with myocardial infarction in women with diabetes mellitus [27]. The higher S-TG might indicate (in addition to an increase in S-Glu) that insulin dependent glucose transport is affected and the increased risk of metabolic syndrome with smoking may be associated with high S-TG but not linked to insulin resistance [28]. The higher S-TG in smokers indicates a disturbed metabolism of fat (i.e., disturbed β-oxidation). In addition, the lack of oxygen entering a cell (affinity hypoxia) may negatively affect glucose transport and oxidative phosphorylation [12], eventually contributing to reduced combustion of fat. Nocturnal intermittent hypoxia was associated with increased risk of developing type 2 diabetes, a finding that supports the present hypothesis [29].

The weakness of this study was the cross-sectional design – descriptive data from a non-randomly selected population. Another limitation was the lack of adjustments of alcohol consumption and social differences. In addition, we had no access to information regarding insulin levels or measures for insulin resistance.

This study reveals that smoking is associated with higher although within normal limits of S-P levels and that S-Glu is negatively associated with S-P in non-type 2 diabetes patients, indicating glucose intolerance. Increased levels of S-TG and S-P in smokers and type 2 diabetes patients compared with non-smokers and non-type 2 diabetes patients indicate a common disturbance of metabolism linked to CVD risk associated with insulin resistance. Future studies on the causal relation between cigarette smoking and risk for insulin resistance should address S-P levels and include the possible effects of smoking cessation on reducing S-P and S-TG levels.

In every study of metabolic syndrome and obesity in relation to CVD risk, associations and influences from smoking need to be considered as smoking independently contributes to both high S-TG and high S-P levels. Although the smoking-S-TG association was stronger than what was found for S-P, this result provides information for future studies on CVD risk and high S-P levels in general. As our study shows, smoking needs to be considered as a confounder if not a causative factor.