tobacco use has fallen in many high - income countries , at least in men , but is now rising rapidly in many low- and middle - income countries such as china .
thirty - eight percent of the world 's smokers are chinese , especially chinese men who smoke one - third of the world 's cigarettes , with 52.9% smoking prevalence and 50.4% current cigarette use [ 2 , 3 ] .
tobacco use has become the number one killer in china and is responsible for 1.2 million deaths annually , and this number is expected to rise to 3.5 million deaths annually by the year 2030 .
diabetes is another major public health problem in china . according to 2010 china noncommunicable disease surveillance
, the overall prevalence of diabetes and prediabetes was estimated to be 11.6% ( 12.1% among men ) and 50.1% ( 52.1% among men ) in chinese adults , respectively , representing up to 113.9 million adults with diabetes and 493.4 million with prediabetes .
furthermore , the current prevalence of diabetes in the chinese population is very similar to the us population even though overweight and obesity are much more common in the latter .
it is of urgent need to illuminate associated risk factors so as to develop effective strategies to prevent the development of diabetes in china .
the association between smoking and increased risk for type 2 diabetes mellitus ( type 2 dm ) has been well documented [ 5 , 6 ] . both active and passive
smoking have been demonstrated to be associated with an increased risk of type 2 dm [ 7 , 8 ] .
recent study also reported that current smokers were dose - dependently associated with increased risk for incident metabolic syndrome in chinese men .
insulin resistance ( ir ) and declining -cell function have proven to be potential mechanisms in the development of type 2 dm and can be demonstrated long before overt diabetes is diagnosed [ 10 , 11 ] .
chronic smoking was reported to markedly and in a dose - dependent manner aggravate ir observed in type 2 dm patients . however , when the metabolic effects of smoking , especially chronic smoking , were studied in persons without diabetes , the findings were controversial .
smoking was reported to acutely impair insulin action and led to ir in normal subjects .
chronic smoking was also shown to be associated with ir and its degree [ 5 , 1417 ] .
nevertheless , some studies found no difference in ir between smokers and nonsmokers in population without diabetes [ 1823 ] . on the other hand ,
few available studies failed to provide conclusive evidence [ 18 , 19 , 23 ] .
even opposite effects on -cell function were reported in current and former smokers , when compared with nonsmokers .
homeostatic model assessment ( homa ) using steady - state glucose and insulin is a method for assessing ir and -cell function and is more appropriate for use in large epidemiological studies .
but few studies applying homa method are currently available for assessing the associations of chronic smoking in asians who exhibit lower levels of the homa of insulin resistance ( homa - ir ) than western populations [ 1719 ] .
moreover , a dynamic evaluation of -cell function , such as oral glucose tolerance test ( ogtt ) , according to smoking status was rare .
this population - based study aims to elucidate the effects of chronic smoking on ir and -cell function in a large sample of chinese men without diabetes using both homa analysis and ogtt .
on the basis of china noncommunicable disease surveillance in 2010 , the study population in this cross - sectional study was a subset population recruited in jiangsu province , using a complex , multistage , probability sampling design . in brief , we first selected 6 counties from 106 counties using stratified random sampling according to the population , gross domestic product ( gdp ) , degree of urbanization , and geographic setting . secondly , 4 towns from each county and 3 villages from each town were selected with the probability proportional to the population size , using cluster random sampling .
thirdly , 1 residential group including at least 50 households was selected from each village using simple random cluster sampling .
random digit function in excel was applied in selection of these households from each residential group . finally , one family member aged 18 years or over was randomly selected from each household using the kish grid method [ 25 , 26 ] . the subjects who were diagnosed as diabetes according to the american diabetes association criteria
the data collected during the face - to - face interview included demographic characteristics , lifestyle factors , and medical history .
the investigated smoking history included age at smoking initiation , years of smoking , number of cigarettes smoked per day , and smoking cessation .
briefly , an individual who never smoked or smoked less than 100 cigarettes in his lifetime was defined as a never smoker .
an individual who smoked at least 100 cigarettes in his lifetime but quit smoking more than 12 months before the interview was considered as a former smoker .
current smokers included those currently smoking and those who quit smoking less than 12 months before interview .
the pack - year of smoking was calculated according to the number of packs of cigarettes smoked per day and smoking duration ( years ) .
an individual who never consumed alcohol or consumed less than or equal to one drink per month was defined as a never drinker , otherwise as an ever drinker .
the global physical activity questionnaire was used to evaluate physical activities by calculating the total weekly volume ( metabolic equivalents ( met ) min / wk ) across three separate domains ( work / home , during commuting , and during leisure time ) , by applying met values to the time variables according to the intensity of the activity [ 4 , 29 , 30 ] .
height and weight were measured in light underclothes without shoes . in the standing position of participants in light clothing , waist circumference
was measured at the midway between the lower edge of the costal arch and the upper edge of the iliac crest .
body mass index ( bmi ) was calculated as weight ( kg)/height ( m ) .
kg / m was considered as overweight , and waist circumference  90  cm as central obesity for chinese men [ 4 , 31 ] .
blood pressure was measured by trained physicians using calibrated electronic sphygmomanometer ( hem-7071 , omron corporation , japan ) , on the nondominant arm in precordial level after at least 5  min of rest and with the subjects in sitting position .
three readings were taken 2  min apart and the averaged values of systolic blood pressure ( sbp ) and diastolic blood pressure ( dbp ) were calculated .
the participants were identified as hypertensive subjects if they had high blood pressure values of sbp  140  mmhg and/or dbp  90  mmhg or if they had a history of hypertension or if they were under antihypertensive medications therapy . a venous blood sample ( 4 - 5  ml )
plasma samples for glucose test were collected with the tubes containing sodium fluoride at 0  h and 2  h after administration of a standard 75  g glucose solution during ogtt test .
plasma glucose was measured using glucose oxidase or hexokinase methods within 24  h. capillary blood samples for glycated hemoglobin ( hba1c ) detection were collected by the hemoglobin capillary collection system .
hba1c was measured within 4  w by high - performance liquid chromatography using the variant ii hemoglobin testing system ( bio - rad laboratories ) .
serum insulin was measured by the electrochemiluminescence immunoassay on an automatic electrochemiluminescence analyzer ( cobas - e601 , roche company ) .
serum total cholesterol ( tc ) , triglyceride ( tg ) , low density lipoprotein cholesterol ( ldl ) , and high density lipoprotein cholesterol ( hdl ) were detected with the enzymatic methods using an automatic biochemistry analyzer ( abbott laboratories ) .
on the basis of fasting glucose and insulin levels , insulin resistance and secretion were evaluated using homa method with the formulas as homa - ir = fasting insulin ( mu / l )  fasting glucose ( mmol / l)/22.5 and -cell function ( homa- ) % = [ 20  fasting insulin ( mu / l)]/[fasting glucose ( mmol / l )  3.5 ] .
individuals with fasting glucose of 3.5  mmol / l or less were excluded from analysis .
the cutoff points for ir and -cell deficiency were homa - ir  2.6 and homa- ( % ) < 50 , respectively [ 24 , 32 ] .
dyslipidemia was defined by the presence of at least one abnormal serum lipid : tc  5.18  mmol / l , tg  1.7 
mmol / l , ldl  3.37  mmol / l , and hdl in men < 1.04  mmol / l .
all the data were double entered in the database and corrected for errors using epi - info 6.0 software .
the statistical analyses were performed using the sas software version 9.2 ( sas institute , cary , nc ) .
the differences in the distributions of demographic characteristics among never , former , and current smokers were compared by an unpaired student 's t - test for continuous variables and a  test for categorical variables , using never smokers as references . to improve skewness , fasting insulin , glucose , hba1c , homa - ir , and homa- were logarithmically transformed for statistical analyses .
unadjusted and adjusted geometric means ( adjustment for age , education level , drinking status , bmi , waist circumference , level of physical activity , hypertension , and dyslipidemia ) with 95% confidence interval ( ci ) were calculated by general linear model and back transformed to natural units for presentation .
the associations between smoking status and ir and -cell deficiency were evaluated under univariate and multivariate unconditional logistic regression model after adjustment for covariates .
odds ratio ( or ) with 95% ci was used to estimate the strength of association .
dose - dependent effect of smoking intensity on -cell function was also analyzed as a continuous variable using fractional polynomial regression model .
all the statistical tests were two - sided , and p < 0.05 was considered as statistically significant .
the 1,568 chinese men without diabetes in this study included 598 never smokers , 120 former smokers , and 850 current smokers ( table 1 ) .
there was no significant difference in age between current and never smokers ; however , the former smokers were younger than never smokers ( p = 0.0430 ) .
higher percentages of ever drinkers were observed in both current ( 72.35% ) and former ( 75.83% ) smokers , compared with the percentage of 55.52% in never smokers ( p < 0.0001 ) . moreover , current smokers with a median equivalent combination of physical activity of 3360 met min / wk were more physically active , compared to never smokers ( 2520 met min / wk , p = 0.0063 ) .
although there were more subjects with hypertension and dyslipidemia in current smokers , and more participants who had a higher level of education , bmi , and waist circumference in former smokers , the differences were not statistically significant .
there was no statistical difference in fasting glucose ; however , the levels of 2  h glucose for ogtt were significantly higher in current smokers than in never smokers ( p = 0.0493 ) ( table 2 ) . compared to never smokers ,
current smokers had significantly decreased fasting insulin , after adjustment for covariates ( p = 0.0335 ) .
the adjusted means with 95% ci for homa- ( % ) were 54.86 ( 52.1057.78 ) in current smokers and 58.81 ( 55.5762.24 ) in never smokers ( p = 0.0257 ) .
no significant difference in hba1c and homa - ir was observed when comparing current or former smoker with never smokers . as shown in table 3 , there were 57.42% current smokers with a homa- value less than 50 .
current smoking was associated with -cell deficiency ( or 1.23 , 95% ci 1.001.52 ) , compared to never smoking .
the association was still statistically significant ( or 1.29 , 95% ci 1.011.64 ) after adjustment for age , education level , drinking status , bmi , waist circumference , level of physical activity , hypertension , and dyslipidemia .
no association was observed between former smoking and -cell deficiency , as well as between smoking status and homa - ir .
the strength of association with -cell deficiency was further analyzed after categorizing current smokers according to their pack - year of smoking and using never smokers as references .
a dose - dependent effect of smoking intensity was observed to be associated with impaired -cell function , however , not with homa - ir .
the -cell function gradually decreased with increasing smoking intensity ( ptrend < 0.0001 and 0.0026 after adjustment for covariates ) , and the differences were statistically significant when the pack - year of smoking was 20 or above ( figure 1 ) .
to evaluate the observed association between smoking intensity and -cell function in a more dynamic manner , we further analyzed the dose - dependent effect of smoking intensity as a continuous variable on -cell deficiency using fractional polynomial regression model .
a significant linear trend of increasing ors along with increasing smoking intensity was observed ( figure 2 , ptrend < 0.0001 ) , which was consistent with the results under logistic regression analysis of smoking intensity as a categorical variable .
in addition , fasting glucose increased with cumulative intensity of smoking ; the adjusted means ( 95% ci ) were 5.65 ( 5.565.74 ) , 5.58 ( 5.445.73 ) ( p = 0.3857 ) , 5.55 ( 5.425.69 ) ( p = 0.1806 ) , 5.72 ( 5.595.86 ) ( p = 0.3271 ) , and 5.78 ( 5.665.91 ) ( p = 0.0384 ) , respectively , for never smokers and current smokers with the pack - year of smoking < 10 , 10~ , 20~ , and 30 ( ptrend = 0.2177 ) .
in this population - based study , we evaluated the associations between chronic smoking and ir and -cell function in chinese men without diabetes .
our results showed that current smoking was associated with decreased -cell function in a dose - dependent manner , and the levels of 2  h glucose were significantly higher in current smokers than in never smokers .
the metabolic effects of smoking have generally been studied in persons without diabetes , in order to avoid the impacts from the medications or changed behaviors in patients with diabetes .
ir and -cell function are usually determined by the hyperinsulinemic - euglycemic clamp and the hyperglycemic clamp . using the euglycemic clamp technique , eliasson et al .
[ 14 , 33 ] observed ir in middle - aged men who chronically smoke and its normalization eight weeks after smoking cessation . however , in the insulin resistance atherosclerosis study , smoking was not associated with ir as assessed by a modified glucose tolerance test with minimal model analysis . although referred to as the gold standard tests , clamps are complex stress tests with insulin and glucose concentrations and flux well outside the normal range .
moreover , clamp techniques are only suitable to be applied in studies with relatively small numbers of subjects .
alternately , homa , a method for assessing ir and -cell function from basal glucose and insulin concentration , correlates well with estimates using other methods including clamps and is more appropriate for use in large epidemiological studies .
the relationship between glucose and insulin in the basal state reflects the balance between hepatic glucose output and insulin secretion , which is maintained by a feedback loop between the liver and -cells .
but recent studies using the homa method reported inconsistent effects of smoking in caucasians , such as high -cell values and ir in normoglycaemic persons , lower -cell function in men without hypertension and diabetes , or no association in men without diabetes .
the study of ko et al .   in chinese men without diabetes showed that no statistical difference in homa - ir or homa- was observed among current , former , and never smokers .
but in this study smokers merely accounted for 22.53% ( 178 out of 790 ) of subjects without diabetes , and men with newly diagnosed impaired glucose tolerance ( igt ) were excluded .
our study including 1,568 men without diabetes found impaired -cell secretion in current smokers , which was signified by both low values of homa- and fasting insulin .
the inconsistency among these studies using homa method may be attributable to the differences in study design , subject recruit , ethnic origin , gender stratification , involved covariates , and sample size .
animal experiments showed that both prenatal and postnatal exposure to nicotine could directly induce imbalance of metabolic control .
the studies using rodent models demonstrated that nicotine exposure could cause -cell dysfunction , elevated pancreatic -cell apoptosis , and loss of -cell mass , which was mediated via the mitochondrial and/or death receptor pathway .
smoking cessation could possibly reverse the unfavorable effects from nicotine . a recent study by stadler et al .  
reported that smoking cessation was associated with metabolic changes including increased -cell secretion in response to glucose .
all these findings provided consistent evidence and biological plausibility for the decreased insulin secretion in smokers , especially heavy smokers in our study . in the dynamic evaluation of -cell function using ogtt test
, we also found higher levels of 2  h glucose in current smokers , which may be attributed to long - term effects of nicotine exposure or may be from acute stress due to nicotine withdrawal .
either acute or chronic nicotine exposure was reported to negatively affect insulin action in smokers preceded before type 2 dm .
long - term use of nicotine - containing chewing gum in nonsmoking men was associated with ir and hyperinsulinemia . however
, no association was observed between smoking and homa - ir in the current study .
it is noteworthy that homa - ir , based on fasting insulin and glucose measurements to determine whole - body ir , primarily reflects hepatic ( central ) insulin sensitivity rather than impaired glucose uptake and consumption in skeletal muscle and adipose tissue ( peripheral ) , thus limiting its ability to assess ir , especially in individuals with igt [ 4043 ] .
it was suggested that insulin responses during the ogtt may be a better surrogate measure for ir , particularly those that occurred in peripheral insulin - sensitive tissues such as muscle [ 42 , 44 , 45 ] .
also pointed out that none of the surrogate estimates of insulin sensitivity in their study was superior to simple measurement of fasting plasma insulin concentrations in predicting insulin sensitivity . in our study , increased 2  h plasma glucose during ogtt test indicated probably insulin resistance in current smokers .
in the present study based on the national survey , the subjects recruited using random sampling methods were representative .
physical activities were investigated using standard questionnaires and evaluated by metabolic equivalent - minutes per week .
first , we only detected 2  h plasma glucose after administration of a standard glucose solution .
area under the curve which is more important in dynamic measurement could not be calculated and compared in this study .
second , due to few former smokers available , we did not further analyze when -cell dysfunction in smokers would return to normal after smoking cessation .
third , our study lacked information on other major confounders such as socioeconomic factors , psychosocial stress , and dietary patterns .
fourth , the participants in this study were chinese men , which restricted the generalization of our results to other ethnicities and gender .
last , cross - sectional design could not provide a causal relationship between smoking and -cell deficiency .
therefore , large - scale prospective studies are warranted to confirm our findings . in conclusion ,
our study suggested that chronic smoking impaired insulin secretion and probably brought about insulin resistance in chinese men without diabetes .
taking into consideration the increased risk of development of type 2 dm related to -cell dysfunction in current smokers , tobacco control should be considered the most urgent and immediate priority in china , especially in chinese men .
 the aim of this study was to evaluate the associations between chronic smoking and insulin resistance and -cell function in chinese men without diabetes . 
 a total of 1,568 participants were recruited by multistage sampling . 
 using homeostatic model assessment ( homa ) , geometric means of insulin resistance ( homa - ir ) and -cell function ( homa- ) with 95% confidence interval ( ci ) were calculated by general linear model . 
 odds ratios ( ors ) with 95% ci were estimated to evaluate the associations between smoking status and insulin resistance and -cell deficiency under a logistic regression model . 
 current smokers had higher levels of 2  h glucose ( 6.66 versus 6.48  mmol / l ) for oral glucose tolerance test and lower levels of fasting insulin ( 5.68 versus 6.03  
 mu / l ) than never smokers . 
 the adjusted means for homa- ( % ) were 54.86 in current smokers and 58.81 in never smokers ( p = 0.0257 ) . 
 current smoking was associated with -cell deficiency ( or 1.29 , 95% ci 1.011.64 ) compared to never smoking . 
 the -cell function gradually decreased with increasing smoking intensity ( ptrend = 0.0026 ) , and the differences were statistically significant when the pack - year of smoking was 20 or above . 
 no association was observed between smoking status and homa - ir . 
 our study suggested that chronic smoking may dose - dependently suppress insulin secretion in chinese men . 
1. Introduction
2. Subjects and Methods
3. Results
4. Discussion