The Effects of Smoking on the Diagnostic Characteristics of Metabolic Syndrome: A Review

Abstract

Metabolic syndrome is a growing epidemic that increases the risk for cardiovascular disease, diabetes, stroke, and mortality. It is diagnosed by the presence of three or more of the following risk factors: 1) obesity, with an emphasis on central adiposity, 2) high blood pressure, 3) hyperglycemia, 4) dyslipidemia, with regard to reduced high-density lipoprotein concentrations, and 5) dyslipidemia, with regard to elevated triglycerides. Smoking is one lifestyle factor that can increase the risk for metabolic syndrome as it has been shown to exert negative effects on abdominal obesity, blood pressure, blood glucose concentrations, and blood lipid profiles. Smoking may also negatively affect other factors that influence glucose and lipid metabolism including lipoprotein lipase, adiponectin, peroxisome proliferator-activated receptors, and tumor necrosis factor-alpha. Some of these smoking-related outcomes may be reversed with smoking cessation, thus reducing the risk for metabolic disease; however, metabolic syndrome risk may initially increase post cessation, possibly due to weight gain. Therefore, these findings warrant the need for more research on the development and efficacy of smoking prevention and cessation programs.

Furthermore, it is important to emphasize that smoking cessation can largely reverse changes to the MetS risk factors; however, it is unknown if structural damage resulting from poor risk factor levels during smoking are fully reversible.

Metabolic syndrome (MetS) is a growing epidemic in the United States that substantially increases the risk for cardiovascular disease, diabetes, stroke, and mortality. ¹ Roughly one-third of the United States population has MetS. ² It is diagnosed by the presence of three or more of the following risk factors: 1) obesity with an emphasis on central adiposity, 2) high blood pressure or current hypertension medication use, 3) hyperglycemia or current blood glucose medication use 4) dyslipidemia with regard to reduced high-density lipoprotein (HDL) concentrations or current HDL boosting medication use, and 5) dyslipidemia with regard to elevated triglycerides or current triglyceride-lowering medication use. ³ While the diagnosis of MetS is straightforward, whether or not there is a distinct pathophysiology or if it is merely a clustering of risk factors remains unknown. The potential for developing MetS is increased by modifiable lifestyle factors such as smoking ⁴ and weight gain caused by physical inactivity and poor dietary habits.^5,6 The focus of this review is to explore the potential role of smoking as a contributing factor to MetS and its possible underlying mechanisms.

While 14% of the adult population in the United States currently smokes, ⁷ cigarette smoking accounts for 1 in 5 deaths every year. ⁸ The relationship between smoking and MetS may explain negative health consequences such as increased mortality risk associated with smoking. ⁴ A meta-analysis by Sun et al ⁴ found that smokers were 1.26 times more likely to develop MetS than non-smokers. The odds of developing MetS increased further to 1.42 in those who were classified as heavy smokers (20 cigarettes per day).

Cessation of smoking may at least partially reverse MetS risk. While there are insufficient studies including females, the aforementioned meta-analysis showed that compared to non-smokers, current male smokers were 1.34 times more likely to develop MetS, but former male smokers (varied cessation periods) were only 1.19 times more likely. ⁴ Paradoxically, there may be a temporary increase in MetS risk after smoking cessation. ⁹ In a 3-year follow-up study, MetS was more prevalent in ex-smokers compared to those who continued smoking for the 3-year period. ⁹ However, the risk is believed to decrease with longer cessation periods. ¹⁰ How long MetS risk is increased in former smokers is not known, but Wada et al ¹⁰ reported that MetS risk persists for about 10 years in those who smoked 20 cigarettes a day. Additionally, non-smokers who are exposed to environmental tobacco smoke have also shown to have increased nicotine and toxic chemical exposure ¹¹ resulting in negative health consequences which include increased MetS risk. ¹²

Conversely, some studies show no relationship between smoking and MetS^13,14 or even a protective effect of smoking on MetS. ¹⁵ However, the preponderance of empirical literature suggests that smoking increases the risk of developing MetS.

The causal relationship between smoking and MetS or the MetS risk factors is not completely understood, as confounding variables—such as study research design differences and individual psychosocial or lifestyle factors—may also explain the relationships or conflicting results. Regarding research design differences, variables such as age, sex, weight, smoking heaviness, years of smoking exposure, duration of smoking cessation, and total nicotine content are accounted (or not accounted for) differently amongst studies. Additionally, smoking is commonly related to certain lifestyle or psychosocial factors such as poor diet, alcohol use, low income, lower education level, and stress. ¹⁶ Finally, it is challenging to determine the extent a risk factor is/is not changed as a result of smoking directly, or as a result of a change in different health outcomes. For example, body weight, which is associated with changes in each metabolic syndrome risk factor may decrease with smoking. ¹⁷ It is important to consider how these confounding variables may mask or worsen changes to the MetS risk factors, complicating interpretations of findings. Furthermore, it is uncertain if smoking leads to a “MetS pathology” that leads to changes in the individual risk factors or if smoking leads directly to the changes in individual risk factors, as a MetS-specific pathophysiology is unknown. However, whether directly or indirectly, it is clear that increased MetS risk in smokers is mirrored by smoking’s effect on the MetS risk factors, including central obesity, blood pressure, blood glucose concentrations, and blood lipid profiles. Thus, the purpose of this review is to explore the potential role of smoking as a contributor to MetS risk factors and the possible underlying mechanisms.

The Relationship Between Smoking and Obesity

Smoking has been shown to have effects on the different measurements that determine obesity such as body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR). While BMI is one of the easiest ways to gauge obesity, the abdominal obesity measurements WC and WHR are used as defining criteria for MetS. Compared to general and gynoid obesity, abdominal obesity is believed to be better correlated with health risks such as cardiovascular disease and chronic diabetes complications. ¹⁸

Despite the hazards associated with smoking, it has often been viewed as a way to control body weight.^17,19 When compared to non-smokers, current smokers have been shown to display a lower BMI.^20,21 Likewise, cigarette smoke exposure has been shown to blunt the increases in body weight that occur with aging. ¹⁷ While smokers generally have lower BMIs compared to non-smokers, a longitudinal study found that smoking more than 20 cigarettes per day independently increased the risk having a high BMI (BMI ≥ 26.4 kg/m²) regardless of gender, ²² suggesting that smoking a higher amount of cigarettes may result in weight gain.

Despite an overall reduction in BMI, smokers are reported to have an increased prevalence of central obesity compared to non-smokers.^20,21,23-25 Jee et al ²⁵ reported that smokers have a greater risk of developing a higher WHR despite a low BMI in both men (2.1-fold) and women (2.5-fold), after adjusting for age, education, height, alcohol consumption, and exercise. Further, a positive association has been established between the number of cigarettes smoked per day and central obesity.^20,23,26 Finally, a meta-analysis by Morris et al ²⁷ studied how smoking status, measured physiologically through a genetic variant, was associated with a .14% increased WC at a given BMI.

While smoking has been shown to aid in the reduction of body weight and BMI, smoking cessation may reverse these effects. ¹¹ Indeed, Stadler et al ²⁸ reported that after 3 months of cessation, participants showed significant increases in BMI, body weight, and body fat percentage along with a decrease in lean mass. A meta-analysis of 62 studies revealed that smoking cessation is associated with an increased body weight of 4–5 kg after 12 months, with the most weight gain occurring within 3 months of smoking cessation. ²⁹ While Williamson et al ³⁰ observed a smaller average weight gain in former smokers of at least 1 year (2.8 kg and 3.8 kg in men and women, respectively), men and women who quit smoking were 8.1 and 5.8, respectively, times more likely to gain more than 13 kg compared to those who continued smoking. These findings have been further supported by additional longitudinal studies lasting less than or equal to 60 days^19,31 and 12 months. ³² Central obesity measurements also may revert after smoking cessation. Time since smoking cessation has been found to be inversely related to WHR when comparing former smokers who quit less than or greater than 20 years prior. ²³ However, WC may initially increase as Pisinger and Jorgenson ³³ found that smoking cessation was associated with increased WC in a 1-year follow-up post cessation - with greater increases in women.

Environmental tobacco smoke has also been shown to negatively affect body composition. In Chinese adult populations, those exposed to environmental tobacco smoke five or more days per week had greater BMI values, WC measures, and WHR compared to those exposed for four or less days per week, when controlled for age, gender, education, income, alcohol drinking, and current smoking status. Likewise, peripheral fat mass was significantly greater in those exposed to five or more days, which was demonstrated in skinfold measurements assessed at the biceps and triceps. ¹² These findings were later supported by a meta-analysis that concluded that second-hand smoke was associated with increased BMI and WC in both children and adults. ³⁴ Thus, unlike smokers who typically have lower BMIs and greater abdominal obesity, those exposed to second-hand smoke may have higher BMIs in addition to greater abdominal obesity at a given BMI. This suggestion is supported by research that used Nutritional Examination Survey (NHANES) data of 6472 adults, which showed that on average, current smokers (26.2 kg/m²; CI: 25.9 to 26.6 kg/m²) had lower BMIs, but those exposed to second-hand smoke (28.3 kg/m²; CI: 27.9 to 28.7 kg/m²) had higher BMIs when compared to non-smokers (27.5 kg/m²; CI: 27.1 to 27.9 kg/m²). ³⁵

Although some studies report that there is no difference in body weight or central adiposity in smokers compared to non-smokers, ³⁶ many studies indicate^27,37-39 that smoking is associated with central fat accumulation. Together, these studies show that while smoking may decrease body weight and thus BMI, it is not without unfavorable effects on fat distribution, as it increases the risk for central obesity. Therefore, smoking could contribute to the onset of MetS through negatively influencing abdominal fat accumulation, despite an overall appearance of weight loss.

The Relationship Between Smoking and Obesity: Mechanisms

Although the mechanisms underlying the changes in body weight and fat distribution with both smoking and cessation are not fully understood, there is evidence to suggest that smoking influences sympathetic nervous system activity, hormones, and inflammatory markers that regulate metabolism, food intake, and visceral fat accumulation.

Nicotine mediates sympathetic activation through binding to nicotinic cholinergic receptors, leading to the release of several neurotransmitters in the central nervous system and peripheral tissues. In the brain, the calcium-induced release of catecholamines^40,41 stimulates lipolysis via activation of beta-adrenoreceptors on the fat cell. ⁴¹ The effect of nicotine on the brain is also associated with complex changes in various substances (i.e., pro-opiomelanocortin, cocaine amphetamine-regulated transcript, neuropeptide Y, and orexin)—some that increase and some that decrease appetite and metabolism; however, the overall resultant acute effect is believed to be appetite suppression and increased metabolism. ¹⁷

While nicotine’s sympathetic activation increases resting metabolism, thus partially explaining weight loss in smokers, nicotine has been shown to have a direct effect on body fat through activation of nicotinic cholinergic receptors on the adipose tissue^41,42 with elevated sympathetic nerve activity associated with increased abdominal adiposity. ⁴³ The cause for increased abdominal fat despite weight loss is still not clearly understood, yet the some of the highlighted changes discussed below may provide insight. Nicotine may promote the release of cortisol and leptin. ¹⁷ Cortisol, which shown to be increased in smokers, ⁴⁴ has been proposed to be associated with abdominal fat distribution as chronic increases in cortisol lead to energy storage, and there is a greater density of glucocorticoid receptors in visceral adipose tissue compared to other adipose tissue. ⁴⁵ Leptin, a hormone released from adipose tissue, has also shown to increase in concentration ⁴⁶ or binding and sensitivity in smokers, thus promoting an increase in energy expenditure and decrease in food intake. ⁴⁷ Furthermore, increases in abdominal obesity may be a result of nicotine’s effect on sex hormone balance ¹⁷ and smoking’s effect of decreasing adiponectin, ⁴⁸ a hormone that is protective against insulin resistance. ⁴⁹ The effect of smoking and its potential mechanisms on body weight is more thoroughly reviewed by Audrain-McGovern and Benowitz. ¹⁷

Inflammation may also play a role in chronic weight gain as cigarette smoking has been positively correlated with C-reactive protein concentrations among adolescents, ⁵⁰ men, and women. ⁵¹ Additionally, C-reactive protein concentrations are positively associated with body fat (r = .41), waist girth (r = .37), and visceral adipose tissue (r = .28). ⁵² Interestingly, this correlation may be more relevant to men than women. Frohlich et al ⁵³ demonstrated that C-reactive protein concentrations were elevated in men (smokers: 1.92 mg/L vs non-smokers: 1.03 mg/L), but not women (smokers: 1.52 mg/L vs non-smokers: 1.41 mg/L) suggesting that women may experience less smoking-related inflammatory reactions.

Although there is uncertainty regarding the mechanisms underlying the changes in body weight and fat distribution due to smoking, changes in metabolic rate and food consumption have been apparent. Contrariwise, weight gain associated with smoking cessation may be attributed to decreased metabolic rate and increased food intake from the absence of nicotine, as well as an increase in the reward value of food to replace the pleasure associated with smoking.^17,54 Smoking 24 cigarettes in a day has shown to increase 24-hour energy expenditure by 10%. ⁵⁵ Furthermore, a 16% reduction in resting metabolic rate has been seen after 30 days of smoking cessation. ¹⁹ Conversely, in a study by Stamford et al, ³¹ acute cigarette smoking did not have significant effects on resting metabolic rate before or after 30 days of smoking cessation; however, they reported that smoking cessation led to an increase of 227 kcals in daily caloric intake, which accounted for 69% of weight gained. Despite lower body weights, smokers still have been reported to consume more calories per day. ⁵⁶ Together, these studies show that smoking likely decreases body weight through increases in energy expenditure that outweigh potential increases in caloric intake.

The Relationship Between Smoking and Blood Pressure

While many of the factors associated with MetS can contribute to raised blood pressure including inactivity and obesity, smoking may be an independent contributor of increased blood pressure, ⁵⁷ yet this relationship is still incompletely understood. Potential differences in blood pressure may explain smoker’s increased health and mortality risk as blood pressure has shown to be associated with increased risk for cardiovascular events ⁵⁸ and mortality. ⁵⁹

Although it is often asserted that smoking effects chronic blood pressure, smoking may only affect daytime blood pressure as a study by Verdecchia et al ⁶⁰ showed that smokers had a higher systolic and diastolic pressure in the day compared to non-smokers (150/97 vs 143/92 mmHg); however, there were no significant differences in nighttime blood pressures. This may be due to the abstinence of smoking throughout the night. Rhee et al ⁶¹ investigated the acute effects of smoking on blood pressure and arterial stiffness after 5, 10, and 15 minutes after smoking one cigarette compared to a baseline measurement. Compared to baseline measurements, normotensive smokers experienced significantly increased arterial stiffness and brachial diastolic blood pressure at all time points but experienced increased brachial systolic blood pressure at 5 and 10 minutes only. Hypertensive smokers, however, experienced differences seen at all 3 time points in the mentioned variables. This suggests that the acute effects of cigarette smoke on aortic stiffness and blood pressure may continue for a longer duration in already hypertensive patients and therefore may be more detrimental to those individuals compared to normotensive smokers.

Regarding chronic increases in blood pressure, a Mendelian randomization meta-analysis that showed how a genetic variant associated with smoking heaviness has no statistically significant relationship with blood pressure. ⁶² However, there are several notable conflicting findings. For example, in an 11-year follow-up study, Niskanen et al ⁶³ showed that men who smoked ≥20 cigarettes a day were more than twice as likely to develop hypertension compared to those who did not smoke. A study by Goa et al ⁶⁴ showed no significant association between smoking and the risk of high blood pressure in individuals younger than 35 years. However, they did see a significant association in participants greater than 35 years, suggesting that the blood pressure changes may be age dependent. Additionally, Zhang et al ⁶⁵ believed cumulative exposure should be better accounted for, rather than just smoking heaviness and thus looked at the relationship between duration of smoking and blood pressure and found that for every additional year of smoking duration, systolic blood pressure was raised .325 mmHg (C.I 0.296–.354). Furthermore, smoking has been related to lower blood pressure in some studies.^66,67 As obesity is associated with higher blood pressure, ⁶⁸ and smoking is associated with weight loss, changes in dietary habits and fat distribution may compensate for any potential changes in blood pressure that occur as a result of smoking or smoking cessation. ⁶⁹

The complexity of the smoking-blood pressure relationship is mirrored in smoking cessation studies. Regarding the acute effects of smoking cessation, Oncken et al ⁷⁰ found that smoking cessation for 6 weeks led to reductions in blood pressure during the daytime, but not nighttime in women. In an 8-year follow-up study, over time, changes in systolic blood pressure remained significantly lower in former smokers compared to smokers after accounting for other potential confounders, such as age, BMI, blood pressure, and heart rate at baseline. However, changes in diastolic pressure were not significantly different. Furthermore, over time, D’Elia et al ⁷¹ showed that blood pressure and risk to develop hypertension in ex-smokers (median years since smoking cessation:3) may become similar to never-smokers. Conversely, in other studies, it has been shown that smoking cessation may lead to increased blood pressure,^72,73 such as Lee et al, ⁷³ who observed an initial decrease in relative risk of hypertension with smoking cessation for <1 year, but then an increase in those who had quit for 1–3, and 3+ years. Both the D’Elia et al ⁷¹ and Lee et al ⁷³ study included only males and adjusted for confounding variables such as changes in BMI and age, illustrating the complexities of understanding this relationship.

Environmental smoke has shown to be associated with higher blood pressure ⁷⁴ with Kim et al ⁷⁴ showing a 13% increased risk of high blood pressure in those exposed to environmental smoke at work or home. To the authors knowledge, there has not been a meta-analysis better clarifying the extent of environmental smoke on blood pressure. However, there has been several epidemiologic studies, with many illustrating that environmental smoke has an adverse effect on blood pressure in both men and women.^74-77 Thus, unlike smokers who have been often reported to have lower blood pressures, those exposed to environmental smoke may have increased blood pressure.

As different cigarettes have different nicotine content, these findings also may help explain inconsistent study results regarding smoking and blood pressure.

Several other confounders may help explain contradictory results. Notably, the role of obesity on blood pressure ⁶⁸ and the effect of smoking or smoking cessation on body weight may contribute to the potential conflicting and sometimes paradoxical blood pressure changes. Thus, efforts to control weight gain post cessation should be considered, especially those at high risk for hypertension. Additional important confounding variables that may contribute to these findings are changes in obesity measurements, age, smoking duration, and nicotine exposure. These findings illustrate the complexity regarding the smoking-blood pressure relationship and the need for more research to further understand the effects of cigarette smoking on blood pressure. In conclusion, most studies are in agreement regarding the acute increase in blood pressure after smoking; however, the chronic effects remain uncertain.

The Relationship Between Smoking and Blood Pressure: Mechanisms

Smoking may affect blood pressure through a variety of mechanisms, mainly through altered sympathetic nerve activity. The resultant sympathetic effect of smoking depends on the net effect on sympathetic excitatory and sympathetic inhibitory responses. Smoking may lead to increased excitatory sympathetic activity, causing an increase in both heart rate and blood pressure.^78,79 Smoking increases nicotine and particulate matter exposure, which may lead to acute increases in sympathetic activation. The increase in sympathetic activity is partially due to increased catecholamines at the neuroeffector junction. ⁸⁰ This smoking-related pressor response may then lead to compensatory inhibition of central sympathetic activity by activating the baroreflex. ⁸⁰ If the baroreflex is intact, this can lead to a net decrease in sympathetic activity in order to bring blood pressure back down. However, if the baroreflex is compromised, a net increase in sympathetic activity is likely to occur. Thus, sympathetic responses may be age-dependent with greater sympathetic vasoconstriction and higher blood pressures observed in middle-aged adults compared to young adults, for whom baroreceptor response is often more compromised. ⁸¹

Because of the inconsistencies in the literature regarding if habitual smoking leads to an increase or decrease in blood pressure, it remains challenging to make definitive conclusions concerning the mechanisms for the effect of smoking on chronic blood pressure. However, several variables that affect blood pressure have been proposed to be altered from chronic smoking-a major factor being oxidative stress. ⁸² Habitual smoking has shown to increase oxidative stress in humans. ⁸³ Oxidative stress may suppress the baroreflex and stimulate lung afferent C-fibers, both of which may stimulate sympathetic activity. ⁸⁴ Furthermore, oxidative stress has been associated with endothelial dysfunction and arterial stiffening, which are both associated with changes in blood pressure.^85,86 Oxidative stress can cause endothelial dysfunction through damage of endothelial cells and resultant decreased nitric oxide bioavailability and reduced function of the vascular smooth muscle cells. ⁸⁷ Talukder et al ⁸⁸ reported increases in reactive oxygen species generation in white blood cells and subsequent impairment in endothelium-dependent vaso-relaxation and hypertension after 32 weeks of cigarette exposure in a mouse model, concluding that smoking-induced endothelial dysfunction may contribute to the elevated blood pressure experienced by smokers. Arterial stiffening has been observed as a result of acute and chronic smoking; however, studies regarding the chronic effects remain inconsistent.^89-91 Other mechanisms for smoking’s role on blood pressure include smoking’s effect on lipid profile, insulin resistance, inflammation, and thrombotic profile, which is further described in a review by Virdis et al. ⁹²

The Relationship Between Smoking and Hyperglycemia

A variety of studies have demonstrated that smoking is associated with hindered glucose regulation and increased risk to develop type 2 diabetes. ⁹³ This is problematic as even prediabetes is associated with a 1.3-fold increase in risk of all-cause mortality. ⁹⁴ While in healthy individuals, temporary increases in blood glucose concentrations lead to insulin secretion from the pancreas which aids the glucose delivery into cells, smoking has shown to lead to insulin resistance and thus disturbances in this process. Whereas glucose may initially be elevated due to insulin resistance, insulin levels may then increase in an attempt to compensate for increased blood glucose levels, which can lead to further reductions in insulin sensitivity. Indeed, clinical evidence supports the association between smoking with hyperglycemia, hyperinsulinemia, insulin resistance, and diabetes.^93,95,96

The relationship between smoking and glucose control has been demonstrated with both non-fasted and fasted testing. Piatti et al ⁹⁷ reported that smokers had higher glucose compared to non-smokers (129.3 ± 40.2 vs 117.7 ± 37.6 mg/dl, P < .01) and insulin levels (57.4 ± 47.8 vs 48.9 ± 41.4, P < .001) at the end of an oral glucose tolerance test. Additionally, insulin concentrations have shown to be higher after glucose loading in otherwise healthy male smokers, even when controlling for other factors known to impact insulin resistance and sensitivity.^98,99 There is evidence that smoking has a dose-dependent relationship with several glucose regulation variables such as fasted plasma glucose concentrations^100,101 and measures of insulin resistance.^{95,96,102,103} Several studies have also found a link between cigarette smoking and the risk for developing diabetes, with a meta-analysis showing that diabetes risk increases with smoking heaviness; Pan et al ⁹³ determined that compared to never-smokers, the relative risk for moderate smokers (10–20 cigarettes) and heavy smokers (>20 cigarettes a day) was 1.34 (C.I 1.27–1.41) and 1.57 (C.I 1.47–1.66) respectively. Of note, the authors of the aformentioned meta-analysis acknowledged that not all studies controlled for lifestyle confounders such as physical activity and diet; however, differences were not substantial when they were controlled for.

Fortunately, smoking’s negative consequences on glucose regulation may be reversed with smoking cessation. The Pan et al ⁹³ meta-analysis mentioned above also examined relative risk of diabetes after smoking cessation; compared to never-smokers, the relative risk of developing diabetes was 1.54 (C.I 1.36–1.74) in new quitters (<5 years), but only 1.11 (CI 1.02–1.20) in long-term quitters (>10 years). Thus, although long-term smoking cessation likely decreases the risk of glucose dysregulation and diabetes, the risk may be at least temporally increased. More specifically, Yeh and colleagues ¹⁰⁴ found that among smokers who quit, the relative risk for diabetes was highest after 3 years of smoking cessation and suggested it was most likely due to increased inflammation and weight gain; risk for diabetes gradually decreased to zero by the 12th year following smoking cessation. Interestingly, despite initial increased risk for the first few years post smoking cessation, insulin sensitivity has shown to improve after just an 8-week follow-up, notwithstanding an increase in body fat. ¹⁰⁵

Environmental tobacco smoke exposure may also place an individual at a higher risk for disrupted glucose control. The Pan et al meta-analysis examined the association between passive smoking and diabetes risk found a pooled relative risk of 1.22 (C.I 1.10–1.35) for diabetes in those exposed to passive smoking compared to those who were not. ⁹³ Data by Kermah et al ³⁵ also demonstrated how second-hand smoke is associated with worsened glycemic control, but after adjusting for BMI, the authors showed that higher BMIs in second-hand smokers mediated the glycemic effects considerably. A meta-analysis by Chen et al ³⁴ showed the second-hand smoke was associated with increased fasting blood glucose and increased insulin levels in adults.

While a link between cigarette smoking and insulin resistance has been established, several studies have found no relationship between these two variables. Henkin et al ¹⁰⁶ reported no association between smoking and insulin resistance but found that environmental smoke exposure was associated with decreased insulin sensitivity. A large sample size of 24,389 men and 35,078 women indicated no relationship between the amount of tobacco smoked and glucose tolerance. ⁸ Onat et al ¹⁵ found an inverse relationship between cigarette smoking and both MetS and diabetes in women with those who smoked 11 or more cigarettes, thus implying a “protective” effect. The researchers noted that this may be due to the potential protective effect of smoking on obesity since smoking may suppress appetite. Therefore, other risk factors for diabetes and MetS such as weight gain should be addressed in smoking cessation programs. Furthermore, discrepancies among research studies may also be related to nicotine content in various cigarette brands since nicotine is likely the main ingredient affecting insulin resistance.^107,108 All in all, smoking is associated with insulin resistance and worsening glycemic control; however, some of the negative consequences on glycemic control may be mediated because smoking often leads to confounding changes, namely weight loss.

The Relationship Between Smoking and Hyperglycemia: Mechanisms

When examining the effects of smoking on glycemic control, it is important to look at both the production and effectiveness of insulin. At first glance, it is easy to assume that if blood glucose is elevated, insulin concentrations may be down. Indeed, nicotine has been shown to damage pancreatic beta-cell function^109,110 and increase beta-cell apoptosis. ¹¹¹ This is believed to be partially mediated through increases in oxidative stress. ¹¹¹ However, as mentioned before, smokers have been reported to have hyperinsulinemia. ⁹⁸ Thus, it is important to also focus on how smoking affects the response of the cell to insulin. Insulin resistance is a major factor believed to lead to diabetes progression and can occur before apparent hyperglycemia. While the body may try to increase insulin to compensate for the increased glucose, negative feedback mechanisms such as decreased insulin receptor quantity and affinity may occur and result in even more insulin resistance. ¹¹²

Smoking likely affects glycemic control through indirect and direct mechanisms on insulin resistance. ¹⁰² Smoking causes insulin resistance indirectly largely through its effect on abdominal obesity, which is greatly associated with insulin resistance. Briefly, while the specific link between abdominal obesity and insulin resistance is uncertain, abdominal obesity is associated with visceral obesity, which correlates with liver fat accumulation and increased inflammation; this relationship is more thoroughly discussed in a review by Hardy et al. ¹¹³

It is suspected that smoking can also directly affect insulin resistance, with nicotine likely being the major culprit. ¹⁰⁸ How smoking directly affects insulin resistance is not fully understood, but disturbances in glucose regulation as a result of smoking and nicotine alone have been observed. For example, nicotine from cigarette smoke has been shown to directly affect increases in phosphorylation of insulin receptor substrate 1 (IRS-1^ser636) via the mechanistic target of the rapamycin (mTOR) pathway. ¹¹⁴ Further, this overactivation of the mTOR pathway can decrease the strength of the insulin signaling along the rest of the pathway, ¹¹⁵ leading to insulin resistance. Smoking has also shown to be associated with decreased concentrations of adiponectin ¹¹⁶ and decreased lipoprotein lipase (LPL) activity, ¹¹⁷ both of which have shown to be postulated to affect glycemic control. ¹¹⁸ Furthermore, cigarette smoking has been shown to promote the secretion of cortisol, catecholamines, and growth hormone, which may be antagonistic to the effects of insulin. These secretions could result in increased lipolysis, resulting in elevated concentrations of free fatty acids. ¹¹⁹ Indeed, increased lipolysis in adipose tissue from the release of epinephrine and norepinephrine due to nicotine has been reported. ¹⁷ Further, these results have been shown to occur with the chronic chewing of nicotine gum. ¹⁰⁸ Other smoking byproducts such as carbon monoxide have been shown to influence insulin resistance. ²⁴ Although much is left to be determined regarding the mechanisms, smoking’s effect on glycemic control is blatant.

The Relationship Between Smoking and Blood Lipids

While elevated triglyceride concentrations and reduced HDL concentrations are determining criteria for MetS diagnosis, this paper will also briefly discuss elevated low-density lipoprotein (LDL) levels, given the close relationship between them and their association with increased risk for heart disease, stroke, and death. ¹²⁰ Small modifications in these factors can promote substantial changes in health status, as it has been suggested that a 1% decrease in LDL cholesterol or a 1 mg/dL increase in HDL cholesterol may decrease the risk for cardiovascular disease by 2–3%.^121,122 Furthermore, a 1 mg/dL increase in triglycerides is associated with a 14% and 37% increase risk of cardiovascular disease in men and women respectively after adjustment for HDL and other risk factors. ¹²³

A meta-analysis that included over 50 studies that looked at the long-term effects of cigarette smoking reported that compared to non-smokers, smokers had higher serum concentrations of triglycerides (9.1%), higher LDL (1.7%), and lower HDL (−5.7%). Furthermore, a dose-dependent relationship was shown with each of these variables when comparing non-smokers and light, moderate, and heavy smokers. ¹²⁴

While blood lipid profiles may be unfavorably altered with the addition of cigarette smoking, the cessation of smoking may reverse these changes. Maeda et al ¹²⁵ performed a meta-analysis that examined the effects of smoking cessation on lipid profile; the eligible studies included former smokers whose cessation period ranged from at least 30 days to 72 months. It was found that while HDL levels increased significantly (+.100, CI: .074 to .127 mmol/L (=3.9 mg/dl)), LDL and triglyceride levels did significantly improve with smoking cessation. More recent studies have shown agreement with these findings. Moffatt et al ¹²⁶ found that HDL concentrations were reversed in as little as 14 days of cessation. A 1-year follow-up assessment to a smoking cessation program indicated that those who abstained from smoking experienced a significant rise in HDL concentration as well as an increase in HDL particle size and a total number of HDL particles; however, no changes in LDL cholesterol were observed. ¹²⁷ These results are supported by a study done by Chen et al ³⁶ who demonstrated no differences in HDL concentrations between former smokers (abstained from smoking ≥1 year) and non-smokers, indicating that HDL concentrations may be restored to pre-smoking concentrations. Triglyceride concentrations have shown to be lower in former smokers compared to current smokers, while still being higher than never-smokers, suggesting that if triglyceride concentrations may improve, they may not fully recover to baseline values or that may take longer to do so. ³⁶ Furthermore, while the Maeda et al ¹²⁵ meta-analysis suggests that LDL levels may not improve post cessation, LDL has shown to be paradoxically higher in former smokers compared to current smokers; however, in the mentioned study, former smokers only needed to be smoke-free for 1 month. ¹²⁸ Thus, the length of time that LDL is elevated is unknown. Overall, the literature suggests that cessation from smoking helps ameliorate the negative alterations in cholesterol and triglyceride concentrations caused by cigarette smoking, but all lipid variables may not completely return to pre-smoking levels.

Individuals exposed to environmental smoke may be more susceptible to dyslipidemia, but the literature remains inconsistent. Several studies have shown that environmental smoke may increase triglycerides, decrease HDL and increase LDL; however, a meta-analysis by Chen et al ³⁴ concluded that second-hand smoke was not associated with changes in triglycerides, HDL, or LDL in adults (18–60 years), but second-hand smoke did impact HDL and LDL in adolescents (10–18 years). The authors suspected that since HDL decreases and LDL increases with increasing age, the effects of second-hand smoke on lipid profile might have been masked by age-related effects. While the aforementioned meta-analysis included studies examining the chronic effects of second-hand smoke, acute changes still occur. For example, just one six-hour of exposure to environmental smoke led to decreased HDL levels for at least 24 hours. ¹²⁹

Despite these findings, there have been contradictory findings. For example, Yan-ling et al ¹³⁰ reported conflicting data in elderly populations living 90 or more years; they found that the current smokers had lower concentrations of total cholesterol compared to non-smokers. While this may be inconsistent with other findings, the authors suggest that a high mortality rate in those who smoked in combination with dyslipidemia would leave only those with normal or low cholesterol concentrations to live 90 years. These results suggest that some individuals may not be as susceptible to alterations in blood lipids that occur from smoking, and they are therefore at a lower risk for both MetS and mortality compared to smokers with high cholesterol.

Despite some conflicting studies, smoking appears to have a negative impact on lipid profiles. However, the extent of smoking’s impact is not fully known as several other variables such as age and genetics undoubtfully play a role in lipid profile. Additionally, behaviors that are more common in smokers, such as drinking, ¹³¹ may mask ¹³² or worsen ¹³³ lipid profile changes, likely depending on the heaviness of alcohol consumption. ¹³⁴ Furthermore, it is important to note that smoking has been shown to increase the relative risk for coronary heart disease, cardiovascular disease, and all-cause mortality in men and in women despite low cholesterol values and absence of elevated blood pressure. ¹³⁵ The combination of smoking, high blood pressure, and high cholesterol was associated with an almost 10 times greater risk for coronary heart disease mortality in men and 16 times greater risk in women compared to those without the three risk factors. ¹³⁵

The Relationship Between Smoking and Blood Lipids: Mechanisms

While the mechanisms underlying changes in blood lipid profile as a result of smoking are far from being fully understood, several mechanisms responsible for lipid profile changes are interconnected with one other and other MetS risk factors.

As previously mentioned, smoking promotes catecholamine release; this can promote elevated free fatty acid levels and thus promote very low-density lipoproteins (VLDL) and LDL accumulation in the blood, and ultimately lower HDL concentrations.^136,137 The increase in free fatty acids should stimulate LPL release to promote hydrolysis and clearing of triglycerides. ¹³⁸ However, in smokers, LPL may be decreased, which is believed to be partially due to increased insulin among smokers. ¹³⁹

Several other theories regarding HDL metabolism have been proposed to explain why smoking leads to reduced HDL concentrations and are reviewed by He et al. ¹⁴⁰ Briefly, smoking may disrupt HDL biosynthesis and maturation through decreasing apolipoprotein A-1 and lecithin cholesterol acyltransferase concentrations. Smoking may also impact HDL remodeling through increases in cholesterol ester transfer protein and hepatic lipase, although evidence on this remains controversial. Finally, while HDL has a role in reverse cholesterol transport, smoking make impair HDL uptake by the liver, the major site of HDL uptake. ¹⁴⁰

While the absolute concentrations of lipids are important, it is critical to also see how smoking alters the properties and function of the lipids. Smoking can lead to oxidative stress, which is proposed to alter lipid function. For example, oxidative modifications of HDL may lead to loss of protective functions such as reverse cholesterol transport ¹⁴⁰ and oxidized LDL is a major precursor to atherosclerosis. ¹⁴¹ Blood samples from smokers show increased concentrations of oxidative stress biomarkers such as malondialdehyde (MDA) and F2-isoprostane, products of lipid peroxidation.^142,143 Isik and colleagues ¹⁴² found that serum MDA was significantly higher in smokers than non-smokers. Similarly, Morrow et al ¹⁴³ found that smokers had significantly higher concentrations of circulating F2-isoprostane in comparison to non-smokers. Cessation of smoking decreased these concentrations, suggesting that smoking contributes to oxidative modifications in blood lipids. In addition, LDL cholesterol from smokers is more susceptible to oxidation in comparison to non-smokers. ¹⁴²

Cigarette smoke can also hinder the effectiveness of the antioxidant protective system. Compared to non-smokers, smokers have been found to possess a lower concentration and activity of the enzyme paraoxonase (PON), an enzyme that is linked to HDL that functions as an antioxidant.^142,144 Likewise, an inverse relationship has been observed between the concentrations of PON in HDL with LDL oxidation with a 10% reduction in PON content associated with a significantly higher concentration of LDL hyperperoxides. ¹⁴⁴ Additionally, former smokers showed higher PON activity and concentrations than smokers, and a longer duration of smoking cessation was associated with greater improvements in these concentrations. ¹⁴⁴ Thus, smoking’s effect on both the concentration and function likely explain increased health risk in smokers.

Notable Factors Indirectly Affecting Characteristics of Metabolic Syndrome

Lipoprotein Lipase

Regulation of lipids and lipoproteins in the blood is further influenced by the enzyme LPL through hydrolyzing triglycerides in chylomicrons and VLDL to promote the uptake of fatty acids by skeletal muscle and adipose tissue for storage or energy. ¹⁴⁵ LPL production is influenced by feeding conditions. LPL is produced in adipose tissue as feeding increases and decreases production in the skeletal muscle. Serum LPL generally reflects the balance between skeletal muscle and adipose LPL. ¹¹⁷ Administration of heparin releases membrane-bound lipase into plasma, and post-heparin lipolytic activity can be measured. Higher pre-heparin and post-heparin LPL mass is associated with high HDL cholesterol and low triglyceride concentrations.^146-148 In addition, increased pre-heparin LPL mass was shown to be negatively correlated with fasting blood glucose concentrations and HbA1C values. ¹⁴⁸ Hirano et al ¹⁴⁹ reported lower serum LPL concentrations in diabetic patients along with a positive association with insulin resistance in patients with hypercholesterolemia. Saiki et al ¹⁴⁸ suggested that pre-heparin LPL mass may serve as a marker for MetS as it decreases with an increase in the number of symptoms for MetS.

Smoking has been shown to influence LPL expression as smokers have shown higher adipose LPL activity compared to non-smokers^139,150 along with lower post-heparin plasma LPL concentrations. ¹¹⁷ Therefore, the lower LPL concentrations may serve as a factor contributing to the lower HDL and higher triglyceride concentrations seen in smokers, as fewer triglycerides will be stored in adipose tissue. LPL may also be linked to the insulin resistance observed in smokers as findings from an oral glucose test resulted in a 30% decrease in adipose LPL activity in smokers compared to the 2-fold increase observed in non-smokers. ¹³⁹ Further evidence shows that 4 weeks of smoking cessation is associated with an increase in gluteal adipose tissue LPL activity and weight gain in premenopausal women. While this study utilized a small sample size of 5 women, it suggests that LPL activity may play a role in the changes in body weight and blood lipids with smoking cessation. ¹⁵¹

Adiponectin

Adiponectin, a protein produced and released into the blood from adipocytes, has been shown to reduce the production of hepatic glucose and promote the oxidation of fatty acids in skeletal muscle, resulting in the regulation of glucose and fatty acids. ¹⁵² By enhancing the metabolism of lipids and glucose, adiponectin also functions to increase insulin sensitivity.^49,153 Administration of adiponectin can reverse insulin resistance in both obese and diabetic mouse models, ¹⁵³ further suggesting adiponectin’s role in increasing insulin sensitivity.

Supporting the actions of adiponectin are the peroxisome proliferator-activated receptors (PPARs) α, β, and γ. PPARs are transcription factors that promote glucose and lipid metabolism and insulin sensitivity. PPAR-α and β specifically reduce triglycerides in the blood and increase fatty acid metabolism, respectively. ¹⁵⁴ PPAR-γ increases glucose metabolism and insulin sensitivity and is in the promoter region of the gene coding for adiponectin, making it essential for the production of adiponectin. ¹⁵⁴

Cross-sectional studies have found that smokers have lower adiponectin concentrations compared to non-smokers in both healthy men^{48,116,155-157} and women. ⁴⁸ This association remained after controlling for age, BMI, hyperglycemia, and cholesterol.^155-157 Kawamoto et al ¹¹⁶ and Takefuji et al ⁴⁸ have reported a dose-response inverse relationship between the number of cigarettes smoked per day and adiponectin concentrations. In addition, a 14.5% decrease in adiponectin concentrations was observed 12 hours following the exposure to 1 cigarette by 5 non-smokers. ¹⁵⁵ Smoking cessation contributes to a rise in adiponectin concentrations as 8 weeks of smoking cessation in healthy Greek men and women was reported to significantly increase adiponectin concentrations while the adiponectin concentrations of smokers did not change. ¹⁵⁸ Similar results were reported by Otsuka et al ¹⁵⁹ who found that adiponectin concentrations significantly increased within 6 months of smoking cessation. There was also a positive relationship between the percent increase in plasma adiponectin concentrations and the percent increase in HDL concentrations. Takefuji and colleagues ⁴⁸ found that adiponectin concentrations may return to normal with cessation as there was no difference in adiponectin concentrations in former smokers and non-smokers. Additionally, adiponectin concentrations continued to increase with time since smoking cessation ⁴⁸ suggesting that the effects of cigarette smoke on adiponectin and lipids may persist for some time following smoking cessation. While more research is needed to determine the effects of cigarette smoking on PPAR-γ in adipocytes, there is evidence showing that PPAR-γ expression in human monocyte–derived dendritic cells of the lungs is reduced. Therefore, cigarette smoke may alter adiponectin concentrations by suppressing PPAR-γ expression in adipocytes. ¹⁶⁰

Tumor Necrosis Factor-Alpha

Tumor necrosis factor-alpha (TNF-α), an inflammatory cytokine produced predominantly by macrophages, is inversely associated with adiponectin and has been shown to suppress LPL activity. ¹⁶¹ This inflammatory cytokine released by adipocytes is elevated in obese individuals and has been found to induce insulin resistance.^162,163 TNF-α activity was found to be elevated in healthy smokers compared to non-smokers. Additionally, when controlling for obesity, there was a positive relationship between TNF-α activity and the number of cigarettes smoked (r = .33). ¹⁶⁴ Likewise, serum concentrations of TNF-α have been shown to be significantly higher in smokers compared to non-smokers. ¹⁶⁵ Additionally, those who smoked more than one pack per day had greater concentrations than those who smoked less than one pack per day. A positive correlation between total pack-years and TNF-α concentrations in the blood was also reported ¹⁶⁵ together suggesting a dose-dependent relationship between cigarette smoking and TNF-α concentrations. Conversely, Keatings et al ¹⁶⁶ found that only smokers with chronic obstructive pulmonary disease (COPD) had elevated TNF-α with no difference in concentrations between healthy smokers and non-smokers, suggesting that disease status may have a greater influence on TNF-α than smoking status. However, Tanni et al ¹⁶⁷ concluded that current smoking status regardless of pulmonary disease was related to TNF-α activity as current healthy smokers and smokers with COPD had higher TNF-α concentrations compared to healthy non-smokers and COPD patients that were previous smokers. Therefore, through the elevation of TNF-α activity, smoking may further contribute to the increased inflammation, elevated lipids, and increased insulin resistance that contribute to the development of MetS

Conclusion

In conclusion, cigarette smokers are at a greater risk for the development of MetS through the direct and indirect effects that smoking has on the diagnostic criteria for MetS. While there is strong evidence suggesting that cigarette smoking negatively affects obesity measures, blood pressure, blood glucose concentrations, and blood lipids, more research is needed to understand the underlying mechanisms associated with these modifications. Inconsistencies in results from research studies may have been due to a lack of uniformity in the definition of smoking status. Thus, clearer definitions and criteria need to be determined for smoking status to allow for better comparisons and conclusions. While smoking cessation has shown to improve risk factors, not all risk factors may improve completely to levels of never-smokers. More so, some risk factors may temporarily worsen, with initial weight gain likely playing a significant role. To better understand the timeline for risk factor alterations after smoking cessation, more longitudinal studies are needed. Furthermore, it is important to emphasize that smoking cessation can largely reverse changes to the MetS risk factors; however, it is unknown if structural damage resulting from poor risk factor levels during smoking are fully reversible. Literature regarding improvements of the risk factors in non-smoking related studies suggests that while several pathological and structural changes may be reversed, some consequences can be permanent. While preventing smoking is ideal, smoking cessation can still make a huge impact. Although it takes time, former smokers may have similar cardiovascular disease risk as non-smokers after 10 to 15 years of smoking cessation; with the risk being considerably reduced within the first 5 years of cessation compared to smokers. ¹⁶⁸ Therefore, these results warrant the need for more research on the development and efficacy of smoking cessation programs.