the trends in the prevalence of obesity documented over the last few decades in our country have been alarming , with morbid obesity affecting 5% of our country 's population . hippocrates was among the pioneer scientists who recognized obesity as a medical disorder rather than just being a cosmetic problem leading to many other comorbid conditions such as dyslipidemia , hyperinsulinemia , diabetes , hypertension , cardiovascular diseases and inscribed that  corpulence is not only a disease itself , but the harbinger of others .  type 2 diabetes mellitus ( t2 dm ) is a heterogeneous group of metabolic disorders characterized by chronic hyperglycemia and is a serious implication of obesity . as individuals become obese and their adipocytes enlarge , adipose tissue undergoes molecular and cellular alterations affecting systemic metabolism . first , macrophage numbers in adipose tissue increase with obesity , where they apparently function to scavenge older adipocytes . in fact , adipose tissue macrophages are responsible for almost all adipose tissue tumor necrosis factor  ( tnf- ) expression and significant amounts of interleukin-6 ( il-6 ) . concentrations of acute - phase response markers and mediators of inflammation such as cytokines like tnf- and interleukin-6 are also raised in people with t2 dm . this finding has led to the suggestion that raised concentrations of pro - inflammatory cytokines and the resultant acute - phase response may underlie much of the metabolic clustering due to obesity and diabetes mellitus . therefore it can be conjectured that inflammation is thought to contribute to the development of insulin resistance , a significant sequel of obesity and is evident by studies describing role of tnf- in mediating insulin resistance in obese patients . insulin therapy has a breakthrough role in breaking this vicious cycle of obesity and diabetes as it not only controls chronic hyperglycemia but also regulates inflammatory process central to diabesity ( conjoined term for diabetes and obesity ) due to its anti - inflammatory property . however the effect of insulin therapy on levels of inflammatory markers and difference if any among obese and non - obese diabetics has been inadequately studied . based on above - given background information , the pre- and postinsulin ( 24 weeks and 48 weeks ) effects on circulating levels of tnf- and il-6 in obese and non - obese diabetics were studied . this was a prospective cohort study on 40 patients with t2 dm , aged 4565 years . patients , who did not show improvement in glycemia levels with oral hypoglycemic drugs , were started with insulin therapy and were receiving statins were included in the study . participants were divided into two cohorts , obese diabetic and nonobese diabetic ( n=20 each ) , and obesity was defined as bmi>30 . the average duration of diabetes was 21 months in obese and 34 months in nonobese participants . the study also included age- and sex - matched 10 normal healthy volunteers as controls . insulin dose was titrated by clinician , by measuring fasting plasma glucose ( fpg ) and modifying the dose accordingly . patients were monitored during the study by fpg at monthly intervals , but fpg at 0 , 24 and 48 weeks only were considered for analysis . patients , who had a history of any acute or chronic disease other than t2 dm , either at present or in recent past , or were taking oral hypoglycemic drugs / ace inhibitors , were excluded from the study , to minimize possible confounding of results . all the patients to be included in the study were informed about the objectives of this study and any potential benefits or losses . a standardized patient consent form , approved by institutional ethics committee , was used for this purpose . serum samples were collected before the start of insulin treatment and after 24 and 48 weeks . the concentration of tnf- in various serum samples of diabetes patients and healthy controls was determined by use of a commercial elisa kit ( r and d systems ) . the intraassay and interassay coefficients of variation for tnf were 5.2% and 7.4% , respectively . detection and quantitative measurement of il-6 in serum were done by avibion human il-6 elisa kit ( orgenium laboratories , finland ) . the minimum detectable concentration ( mdc ) was estimated to be 2 pg / ml . the intraassay and interassay coefficients of variation for il-6 were 9.4% and 8.6% , respectively . test was done to compare tnf- and il-6 between two groups ( obese and non - obese ) . analysis of variance ( one- way anova ) was used to compare tnf- and il-6 levels in the same set of groups ( either obese or non - obese ) at two different times . pearson 's coefficient of correlation was done to assess association between tnf- and il-6 levels with glycemic status after insulin therapy in obese and nonobese diabetics . p values < 0.05 were considered significant while p value < 0.001 were extremely significant . the concentration of tnf- in various serum samples of diabetes patients and healthy controls was determined by use of a commercial elisa kit ( r and d systems ) . the intraassay and interassay coefficients of variation for tnf were 5.2% and 7.4% , respectively . detection and quantitative measurement of il-6 in serum were done by avibion human il-6 elisa kit ( orgenium laboratories , finland ) . the minimum detectable concentration ( mdc ) was estimated to be 2 pg / ml . the intraassay and interassay coefficients of variation for il-6 were 9.4% and 8.6% , respectively . test was done to compare tnf- and il-6 between two groups ( obese and non - obese ) . analysis of variance ( one- way anova ) was used to compare tnf- and il-6 levels in the same set of groups ( either obese or non - obese ) at two different times . pearson 's coefficient of correlation was done to assess association between tnf- and il-6 levels with glycemic status after insulin therapy in obese and nonobese diabetics . p values < 0.05 were considered significant while p value < 0.001 were extremely significant . we measured tnf- and il-6 levels [ table 1 ] in patients samples ( n=20 from each group , non - obese diabetics and obese diabetics ) a healthy normal controls ( n=10 ) . as evident from this study a negligible level of tnf- ( 4.46 pg / ml ) and il-6 ( 4.98 pg / ml ) was recorded in normal healthy control . samples of similar age group of nonobese diabetic patients devoid of any insulin treatment ( i.e. , preinsulin samples ) showed an ~20-fold ( 87.8 pg / ml ; p<0.001 ) augmentation in tnf- levels and ~7-fold ( 34.9 pg / ml ; p<0.001 ) augmentation in il-6 levels of preinsulin nonobese diabetics compared to healthy controls . a tremendous augmentation was observed in the levels of tnf- and il-6 by ~25-fold ( 112.1 pg / ml ; p<0.001 ) and ~8.7-fold ( 38.2 pg / ml ; p<0.001 ) respectively compared to healthy controls . tnf- and il-6levels in obese patients , before treatment , after 24 and 48 weeks thereafter , the effect of insulin treatment of nonobese diabetic patients on the expression of tnf- and il-6 was probed after 24 and 48 weeks of insulin administration . a decrease by ~1.28 and ~1.44 fold each was recorded with tnf- and il-6 ( p<0.001 ) after 24 weeks . interestingly , after 48 weeks of insulin administration to nonobese diabetic patients , an appreciably high - magnitude decrease by ~3.63-fold ( p<0.001 ) and 2.82-fold ( p<0.001 ) was observed for tnf- and il-6 respectively . next , the insulin - induced effects in obese diabetic patients on the expression of tnf- and il-6 was probed after 24 weeks and 48 weeks of insulin administration . a decrease by ~1.1 fold each was recorded with tnf- and il-6 respectively ( p<0.05 ) after 24 weeks of insulin administration . similarly , a decrease by ~2.0 fold ( p<0.001 ) and ~1.86 fold ( p<0.001 ) was observed in tnf- and il-6 levels respectively after 48 weeks of insulin administration . a positive correlation was found between postinsulin tnf- and il-6 with fpg levels of non - obese and obese diabetics after 24 and 48 weeks . the correlation coefficient ( r ) for non - obese diabetics between tnf- with fpg levels was 0.97 and 0.98 at 24 and 48 weeks respectively [ figure 1a and b ] while for il-6 with fpg , it was 0.95 and 0.97 [ figure 1c and d ] . however , obese diabetics had a correlation coefficient of 0.93 and 0.96 at 24 and 48 weeks respectively for tnf- with fpg levels [ figure 2a and b ] for il-6 with fpg , it was 0.87 and 0.95 [ figure 2c and d ] . postinsulin tnf- ( pg / ml ) and il-6 ( pg / ml ) correlation with fpg ( mg / dl ) in nonobese diabetics ( detailed description in text ) postinsulin tnf- ( pg / ml ) and il-6 ( pg / ml ) correlation with fpg ( mg / dl ) in obese diabetics ( detailed description in text ) we measured tnf- and il-6 levels [ table 1 ] in patients samples ( n=20 from each group , non - obese diabetics and obese diabetics ) a healthy normal controls ( n=10 ) . as evident from this study a negligible level of tnf- ( 4.46 pg / ml ) and il-6 ( 4.98 pg / ml ) was recorded in normal healthy control . samples of similar age group of nonobese diabetic patients devoid of any insulin treatment ( i.e. , preinsulin samples ) showed an ~20-fold ( 87.8 pg / ml ; p<0.001 ) augmentation in tnf- levels and ~7-fold ( 34.9 pg / ml ; p<0.001 ) augmentation in il-6 levels of preinsulin nonobese diabetics compared to healthy controls . a tremendous augmentation was observed in the levels of tnf- and il-6 by ~25-fold ( 112.1 pg / ml ; p<0.001 ) and ~8.7-fold ( 38.2 pg / ml ; p<0.001 ) respectively compared to healthy controls . tnf- and il-6levels in obese patients , before treatment , after 24 and 48 weeks thereafter , the effect of insulin treatment of nonobese diabetic patients on the expression of tnf- and il-6 was probed after 24 and 48 weeks of insulin administration . a decrease by ~1.28 and ~1.44 fold each was recorded with tnf- and il-6 ( p<0.001 ) after 24 weeks . interestingly , after 48 weeks of insulin administration to nonobese diabetic patients , an appreciably high - magnitude decrease by ~3.63-fold ( p<0.001 ) and 2.82-fold ( p<0.001 ) was observed for tnf- and il-6 respectively . next , the insulin - induced effects in obese diabetic patients on the expression of tnf- and il-6 was probed after 24 weeks and 48 weeks of insulin administration . a decrease by ~1.1 fold each was recorded with tnf- and il-6 respectively ( p<0.05 ) after 24 weeks of insulin administration . similarly , a decrease by ~2.0 fold ( p<0.001 ) and ~1.86 fold ( p<0.001 ) was observed in tnf- and il-6 levels respectively after 48 weeks of insulin administration . a positive correlation was found between postinsulin tnf- and il-6 with fpg levels of non - obese and obese diabetics after 24 and 48 weeks . the correlation coefficient ( r ) for non - obese diabetics between tnf- with fpg levels was 0.97 and 0.98 at 24 and 48 weeks respectively [ figure 1a and b ] while for il-6 with fpg , it was 0.95 and 0.97 [ figure 1c and d ] . however , obese diabetics had a correlation coefficient of 0.93 and 0.96 at 24 and 48 weeks respectively for tnf- with fpg levels [ figure 2a and b ] for il-6 with fpg , it was 0.87 and 0.95 [ figure 2c and d ] . postinsulin tnf- ( pg / ml ) and il-6 ( pg / ml ) correlation with fpg ( mg / dl ) in nonobese diabetics ( detailed description in text ) postinsulin tnf- ( pg / ml ) and il-6 ( pg / ml ) correlation with fpg ( mg / dl ) in obese diabetics ( detailed description in text ) it has been hypothesized that t2 dm is a manifestation of an ongoing acute - phase response that is primarily characterized by alterations of the so - called acute - phase proteins , such as c - reactive protein ( crp ) . elevated levels of il-6 , which is the main stimulator of the production of most acute - phase proteins , increase the risk of diabetes.[911 ] however , in addition to il-6 , other cytokines , such as il-1 and tnf- are central mediators of inflammatory reactions . it is well known that cytokines operate as a network in stimulating the production of acute - phase proteins . obesity , as well as hyperglycemia , contributes to the rise of these inflammatory markers . in the present study attempts were made to probe the difference , if any , between nonobese and obese diabetic patients with respect to pro - inflammatory markers like tnf- and il-6 and effect of insulin treatment on them . we have not come across any study in which levels of inflammatory markers were assessed before and after insulin treatment in obese diabetics . tnf and il-6 are the major cytokines produced by adipose tissue and their circulating levels are increased in diabetics . it is noteworthy to point out here that our results clearly demonstrate preinsulin nonobese diabetics to express augmented tnf- and il-6 when compared to normal controls . as expected and in accordance to earlier studies , we also observed obese diabetics to exhibit a higher magnitude of tnf- and il-6 expressions when compared to nonobese diabetics.[1214 ] previous studies have shown that adipose tissue is the main source of circulating tnf-. the most striking finding of the present study was the insulin - induced downregulation of tnf- and il-6 in nonobese and obese diabetic patients . apart from the above , the other important observation made in this study was of the degree of suppression of tnf- and il-6 after insulin therapy , which was more marked in nonobese compared to obese diabetics . this could be explained by plausible role of the tnf-system in the low - grade systemic inflammation associated with obesity and a supplementary autocrine role in the production of other pro - inflammatory cytokines such as il-6 from adipose depots . the insulin - induced suppression or downregulation after 24 weeks and 48 weeks in tnf- and il-6 at the protein level is highly exciting . a recent study also indicates that there is a relationship between duration of insulin therapy and an acute - phase response . this supports the notion that the relationship between tnf- and il-6 and insulin action may , therefore , be mediated by adiposity . we did not study the relation between individual bmi and levels of tnf- and il-6 . the rising incidence of obesity in our country has made the indian population susceptible to deleterious effects of obesity . there is paucity of data on effects of insulin therapy on inflammation associated with diabesity in indians ; therefore an effort is made to understand interplay of t2 dm , inflammation , and obesity after various durations of insulin therapy , in this study . however , further in - depth investigations at the gene level are warranted in order to reach a conclusive inference from the above observations . there is increased inflammation in obese diabetics in comparison to nonobese diabetics , as shown by greater elevation of tnf- and il-6 levels in the former . insulin treatment leads to reduction in levels of these inflammatory markers in both obese as well as nonobese diabetic patients , but the response is blunted as well as delayed in obese diabetics . in summary , the findings of the present study may help in better understanding the responsiveness of insulin therapy in obese and nonobese diabetic patients .
background : type 2 diabetes ( t2 dm ) mellitus is a serious implication of obesity . the effect of insulin therapy on levels of inflammatory markers among obese and non - obese diabetics has been inadequately studied.aim:the study aimed to analyze the preinsulin and postinsulin levels of tumor necrosis factor  ( tnf- ) and il-6 in nonobese and obese t2 dm patients.materials and methods : we assessed tnf- and il-6 levels in healthy controls ( n=10 ) and diabetic patients ( obese and nonobese ; n=20 each ) and analyzed the postinsulin effect on tnf- and il-6 levels after 24 and 48 weeks . tnf- and 
 il-6 levels were also correlated with fasting plasma glucose of obese and nonobese diabetic patients after insulin therapy.results:there is augmentation of tnf- and il-6 levels in diabetic patients and augmentation is more in obese than in nonobese diabetics . 
 the obese group showed a significant decrease ( p value<0.05 ) after 24 weeks of insulin therapy and an extremely significant decrease ( p<0.001 ) in tnf- and il-6 levels after 48 weeks of therapy . 
 the nonobese group showed an extremely significant decrease ( p<0.001 ) in tnf- and il-6levels after 24 and 48 weeks both.conclusion:there is augmented inflammation in diabetes and it is more in obese diabetics . 
 insulin therapy tends to counter this inflammation , but the response is delayed in obese diabetics .