leptin , an adipocyte derived cytokine , primarily was known to be involved in the regulation of food intake and energy expenditure ( dardeno et al . , 2010 ) . later on studies showed the role of leptin in the immune system modulation ( lord et al . , 1998 ) . the studies describing the role of leptin in diabetes are so conflicting and no one could classify it into either pro - inflammatory or anti - inflammatory groups ( lam and lu , 2007 ; weisberg et al . , 2003 ; xu et al . , 2003 ) . similarly heat shock proteins ( hsps ) are endogenous highly conserved molecules produced by various cells , including macrophage , monocyte and polymorphonuclears when exposed to high temperature , inflammatory cytokines and oxidative stress ( kalmar and greensmith , 2009 ) . the hsp genes are considered as vitagenes , which are involved in preserving cellular homeostasis during stressful conditions , which are induced by co - ordinating information flow along its convergent , divergent and multiply branched signaling pathways ( calabrese et al . , 2010 , 2011 ) . more importantly both hsp70 and leptin are correlated with c reactive protein ( crp ) ( molvarec et al . , 2009 , 2011 ) . the purpose of the present study was to study the correlation between serum hsp70 and leptin levels in patients with type 2 diabetes stratified according to gender . we performed a cross sectional study on the established groups of patients with type 2 diabetes defined as 1 : patients with long standing diabetes for more than 3  years ; and 2 : patients with newly diagnosed diabetes within recent 6  months who were not on any glucose lowering treatment other than by dietary means alone and 3 : healthy controls . patient recruitment was from the diabetes clinic of vali - asr hospital , affiliated with tehran university of medical sciences . healthy controls were selected from those without any known disease including type 2 diabetes , hyperlipidemia , ischemic heart disease , and malignancy . patients and controls were matched according to age , sex and body mass index ( bmi ) . diabetes was diagnosed according to the criteria of the american diabetes association ( seo et al . , 2009 ) . exclusion criteria were smoking , pregnancy , creatinine >  1.5  mg / dl or gfr <  70  cc / min , glomerulonephritis , congestive heart failure , use of antioxidant , statins , hormone replacement therapy and hospital admission in previous 6  months . demographic and anthropometric data including age , sex , duration of diabetes , height , weight in light clothing , and blood pressure in sitting position were recorded . the local ethics review committee of tehran university of medical science approved the study protocol . blood samples were collected after 12  h of fasting , centrifuged and were kept at   70  c until analysis . serum creatinine , fasting blood sugar ( fbs ) , total cholesterol , triglycerides , high - density lipoprotein- ( hdl ) cholesterol , low - density lipoprotein ( ldl ) cholesterol , and hba1c were measured for all participants . glucose measurements ( intra - assay coefficient of variation [ cv ] 2.1% , inter - assay cv 2.6% ) were carried out using the glucose oxidase method . cholesterol , hdl , ldl and triglycerides were determined using direct enzymatic methods ( parsazmun , karaj , iran ) . measurements of hsp70 were performed using a quantitative sandwich elisa immunoassay ( eks-715 , stressgen , usa ) . serum leptin concentration was determined by an enzyme - linked immunosorbent assay ( drg instruments gmbh , germany ) with an intra - assay cv of 5.96.9% and an inter - assay cv of 8.611.5% . crp was assessed using a two - site , enzyme - linked immunosorbent assay ( elisa ) ( diagnostic biochem , london , ontario , canada ) . the statistical package spss 17 for windows ( chicago , illinois , usa ) was used for analysis . pearson 's correlation test was employed to study the correlation between leptin , hsp70 , crp , bmi and waist circumference . partial correlation coefficient was employed to study the correlation between the studied variables after adjustment for bmi . primary characteristics of the groups of patients and controls are presented in table  1 . patients with long standing diabetes had higher leptin , hsp70 , hba1c and triglyceride than controls . serum leptin levels were significantly lower in patients with newly diagnosed diabetes , compared to other groups ( table  1 ) . women with newly diagnosed diabetes had higher leptin and crp levels compared to men ( table  2 ) . table  2 presents the characteristics of patients with newly diagnosed diabetes , stratified according to gender . we studied the correlation between serum hsp70 , leptin , bmi , and waist circumference ( table  3 ) . while hsp70 was significantly correlated in women with newly diagnosed diabetes , there were not such correlations in men with newly diagnosed diabetes , men and women in long standing diabetes and controls . 1 shows the correlation coefficient between leptin and hsp70 in the studied groups stratified according to gender . the greatest difference exists between patients with newly diagnosed diabetes and patients with long standing diabetes ( fig .  1 ) . the correlation was highest in women with newly diagnosed diabetes and was attenuated in women who were on treatment . there was no correlation between leptin and hsp70 in men ( both newly diagnosed and long standing disease ) . most of the studies which have shown a positive correlation are carried out in disease states . however , while some have shown a positive correlation , others have shown a negative one . in consistent with our findings rong quan and collaborators showed that leptin activates hsp70 expression in a dose dependent manner in mcf-7 breast cancer cell line ( xue et al . , 2012 ) . similarly bonior and collaborators showed that leptin administration stimulates the expression of hsp60 in pancreatic acinar and beta cell lines . leptin protects pancreatic acinar cell line from the damage of acute pancreatitis ( bonior et al . , 2006 ) . on the other hand , figueiredo et al . showed that leptin administration would decrease food intake and hsp70 levels in the liver and hypothalamus of chickens but not in the muscle . the effect of leptin on hsp70 levels was independent of the inhibition of food intake ( figueiredo et al . , 2007 ) . in another study , geranylgeranylacetone ( gga ) administration induced hsp70 expression in liver , which rendered physiologic protection against high fat diet in mice , while decreased leptin levels ( adachi et al . , 2010 ) . sirotken et al . showed that leptin administration inhibited the transcription of hsp70 in ovarian follicular granulosa cells . heat stress , but not malnutrition can promote depletion of hsp70 in ovarian cells , which is partly reversed by leptin ( sirotkin and bauer , 2011 ) . we hypothesized that the answer is the duality of hsp70 behavior in different inflammatory or non - inflammatory environments ( nakhjavani et al . , 2012 ) . as stated , the positive correlation between leptin and hsp is observed in chronic inflammation such as type 2 diabetes ( our findings ) and breast cancer ; while all other studies , which have shown a negative correlation , are carried out in the normal cells , without any chronic inflammatory state . we have previously shown the positive correlation of hsp70 with adma , a nitric oxide inhibitor , in chronic inflammatory states while it was negatively correlated to adma in normal physiology ( nakhjavani et al . one could argue that this correlation is only present in women , while we do not observe such a correlation in men . both leptin and hsp70 have been shown to be higher in women ( nakhjavani et al . , 2010a , 2010b ; nakhjavani et al . , 2011 ; rossi et al . , 2012 ; samara et al . , 2010 ) earlier studies on leptin deficient mouse have shown marked reduced number of lymphocytes with impaired humoral response and thymic atrophy ( gruver and sempowski , 2008 ; mancuso et al . , 2002 ) . lipoatrophy in hiv infected patients is assumed to be a result of reduced leptin in these patients ( papaevangelou et al . , 2007 ) . serum leptin levels were significantly elevated in patients with multiple myeloma and chronic lymphatic leukemia ( pamuk et al . , 2006 ) . serum leptin levels are increased in women with type 2 diabetes ( nakhjavani et al . one explanation was that a greater adipose tissue in women is the underlying reason ( rossi et al . , 2012 ) . on the other hand , studies have repeatedly shown that women with type 2 diabetes and metabolic syndrome have higher serum leptin levels , after adjustment for body fat composition ( meyers et al . , 2008 ; thomas et al . , 2000 ) . the other explanation could be that an increased serum leptin level is associated with accelerated immune cell activation in women with type 2 diabetes . interestingly we have previously shown that women with long standing diabetes have higher serum hsp70 levels ( nakhjavani et al . rodrigues - krause and collaborators have suggested a role of bmi on extracellular hsp70 levels ( rodrigues - krause et al . , 2012 ) . while intracellular hsp70 induction in response to pro - inflammatory stimuli can exert anti - inflammatory effects , extracellular hsps may signal danger , activating immune cells ( atalay et al . since immune system is more active in women compared to men ( de leon - nava and morales - montor , 2006 ; grimaldi , 2006 ) , one would argue that the observed correlation between serum hsp70 and leptin implies a higher state of chronic inflammation . in consistent with our findings zulkit et al . showed that food restriction induces leptin and hsp70 protein expression in female broiler chicken ( zulkifli et al . , 2002 ) . the principal limitation of the present study is its cross sectional nature which precludes the determination of the direction of causality , however we took advantage of a relatively large sample size and close similarity between groups in most of the potentially confounding variables . in conclusion