a total of 99 japanese individuals ( 61 men and 38 women ) who underwent pancreatic surgery and whose resected pancreas sample contained adequate normal pancreas for histological analysis were included in the study ( table 1 and supplemental figure 1 ) . written informed consent was obtained from each patient , whereas it was waived for patients who had discontinued hospital visits at the time of study enrollment ( n = 40 ) . characteristics of subjects abbreviations : ipmn , intraductal papillary mucinous neoplasm ; n / a , not available ; oha , oral hypoglycemic agent . data with normal distribution are expressed as mean  sd , and nonnormally distributed data are expressed as median ( interquartile range ) . cpr index was calculated as cpr ( nanomoles per liter)/pg ( millimoles per liter ) . of these , 41 patients had been diagnosed with type 2 diabetes before the diagnosis of pancreatic tumors , and eight patients were diagnosed with pancreatic cancer ( pc ) and diabetes at the same time . there was no case of type 1 diabetes or a case in which glutamic acid decarboxylase antibody was positive . information on each patient including glycated hemoglobin ( hba1c ) , glycated albumin ( ga ) , plasma glucose , and serum c - peptide immunoreactivity ( cpr ) levels were obtained from the medical records . hba1c was measured by hplc and expressed as national glycohemoglobin standardization program and international federation of clinical chemistry values . ga and cpr were measured by an enzymatic method and chemiluminescent enzyme immunoassay , respectively . -cell function was assessed by serum cpr to plasma glucose ratio ( cpr index ) calculated as cpr ( nanomoles per liter ) per plasma glucose ( millimoles per liter ) , as previously reported ( 9 ) . in addition , a questionnaire on a family history of diabetes and history of obesity was conducted in 59 patients . the questionnaire consisted of the following categories : 1 ) history of obesity in childhood and adolescence , 2 ) body weight at age 20 years and every decade thereafter , 3 ) maximum body weight in life , and 4 ) first - degree family history of diabetes . the cases were classified into four groups according to the presence or absence of diabetes and obesity . obesity was defined as body mass index ( bmi ) of 25 kg / m or greater ( 10 ) . the surgically resected pancreas was immediately fixed in formaldehyde and embedded in paraffin for subsequent analysis . in eight subjects who underwent total pancreatectomy , pancreas samples were obtained from the head in three cases and the body or tail in five cases . five - micrometer sections were cut from the tumor - free region and stained for light microscopy as follows : 1 ) with hematoxylin - eosin , 2 ) for insulin ( peroxidase staining ) with hematoxylin , 3 ) for glucagon with hematoxylin , 4 ) for insulin and ki67 for assessment of -cell replication , and 5 ) for insulin and single - stranded dna or cleaved poly(adp - ribose ) polymerase-1 for the assessment of -cell apoptosis , as previously described ( 7 , 8) . to quantify fractional -cell area ( bca ) , the entire pancreatic section was imaged at the original magnification of 200 ( 20 objective ) using a mirax scan and mirax viewer ( carl zeiss microimaging gmbh ) . the ratio of bca to total pancreas area was digitally measured using image pro plus software ( media cybernetics ) , as previously reported ( 7 , 8) . likewise , the ratio of -cell area to total pancreas area ( aca ) was also digitally measured , and the ratio of aca to bca was determined in each case . all measurements were conducted by a single investigator ( j.i . ) , and the intraobserver coefficient of variance was 7% . all measurements were conducted twice , and the mean of the two measurements was used . at the time of measurement , the investigator was blinded to both the glycemic and obesity status for each specimen . to conduct further morphometric analysis , size and density of islets , density of scattered -cells , and insulin - positive duct cells were quantified in randomly selected areas of the pancreas that contained approximately 100 islets in each case ( 106  6 islets , total 10 491 islets ) using a mirax viewer ( carl zeiss microimaging gmbh ) ( 7 , 8) . scattered -cells were defined as a cluster of three or fewer -cells in acinar tissue . in addition , -cell replication and apoptosis were quantified and expressed as percentage of islets . data are presented as mean  sd or , if nonnormally distributed , median ( interquartile range ) in the text and tables . a mann - whitney u test was used to assess difference between two groups , and spearman correlation coefficient was used to assess the correlation between two parameters . a total of 99 japanese individuals ( 61 men and 38 women ) who underwent pancreatic surgery and whose resected pancreas sample contained adequate normal pancreas for histological analysis were included in the study ( table 1 and supplemental figure 1 ) . written informed consent was obtained from each patient , whereas it was waived for patients who had discontinued hospital visits at the time of study enrollment ( n = 40 ) . characteristics of subjects abbreviations : ipmn , intraductal papillary mucinous neoplasm ; n / a , not available ; oha , oral hypoglycemic agent . data with normal distribution are expressed as mean  sd , and nonnormally distributed data are expressed as median ( interquartile range ) . cpr index was calculated as cpr ( nanomoles per liter)/pg ( millimoles per liter ) . of these , 41 patients had been diagnosed with type 2 diabetes before the diagnosis of pancreatic tumors , and eight patients were diagnosed with pancreatic cancer ( pc ) and diabetes at the same time . there was no case of type 1 diabetes or a case in which glutamic acid decarboxylase antibody was positive . information on each patient including glycated hemoglobin ( hba1c ) , glycated albumin ( ga ) , plasma glucose , and serum c - peptide immunoreactivity ( cpr ) levels were obtained from the medical records . hba1c was measured by hplc and expressed as national glycohemoglobin standardization program and international federation of clinical chemistry values . ga and cpr were measured by an enzymatic method and chemiluminescent enzyme immunoassay , respectively . -cell function was assessed by serum cpr to plasma glucose ratio ( cpr index ) calculated as cpr ( nanomoles per liter ) per plasma glucose ( millimoles per liter ) , as previously reported ( 9 ) . in addition , a questionnaire on a family history of diabetes and history of obesity was conducted in 59 patients . the questionnaire consisted of the following categories : 1 ) history of obesity in childhood and adolescence , 2 ) body weight at age 20 years and every decade thereafter , 3 ) maximum body weight in life , and 4 ) first - degree family history of diabetes . the cases were classified into four groups according to the presence or absence of diabetes and obesity . obesity was defined as body mass index ( bmi ) of 25 kg / m or greater ( 10 ) . the surgically resected pancreas was immediately fixed in formaldehyde and embedded in paraffin for subsequent analysis . in eight subjects who underwent total pancreatectomy , pancreas samples were obtained from the head in three cases and the body or tail in five cases . five - micrometer sections were cut from the tumor - free region and stained for light microscopy as follows : 1 ) with hematoxylin - eosin , 2 ) for insulin ( peroxidase staining ) with hematoxylin , 3 ) for glucagon with hematoxylin , 4 ) for insulin and ki67 for assessment of -cell replication , and 5 ) for insulin and single - stranded dna or cleaved poly(adp - ribose ) polymerase-1 for the assessment of -cell apoptosis , as previously described ( 7 , 8) . to quantify fractional -cell area ( bca ) , the entire pancreatic section was imaged at the original magnification of 200 ( 20 objective ) using a mirax scan and mirax viewer ( carl zeiss microimaging gmbh ) . the ratio of bca to total pancreas area was digitally measured using image pro plus software ( media cybernetics ) , as previously reported ( 7 , 8) . likewise , the ratio of -cell area to total pancreas area ( aca ) was also digitally measured , and the ratio of aca to bca was determined in each case . all measurements were conducted by a single investigator ( j.i . ) , and the intraobserver coefficient of variance was 7% . all measurements were conducted twice , and the mean of the two measurements was used . at the time of measurement , the investigator was blinded to both the glycemic and obesity status for each specimen . to conduct further morphometric analysis , size and density of islets , density of scattered -cells , and insulin - positive duct cells were quantified in randomly selected areas of the pancreas that contained approximately 100 islets in each case ( 106  6 islets , total 10 491 islets ) using a mirax viewer ( carl zeiss microimaging gmbh ) ( 7 , 8) . scattered -cells were defined as a cluster of three or fewer -cells in acinar tissue . in addition , -cell replication and apoptosis were quantified and expressed as percentage of islets . data are presented as mean  sd or , if nonnormally distributed , median ( interquartile range ) in the text and tables . a mann - whitney u test was used to assess difference between two groups , and spearman correlation coefficient was used to assess the correlation between two parameters . representative photomicrographs of the pancreas of patients with and without diabetes are shown in figure 1 . in patients with diabetes mellitus ( dm group ) , bca was decreased by 46% compared with age- and bmi - matched nondiabetic patients ( ndm group ) ( 1.48%  1.08% vs. 0.80%  0.54% , p < .001 , supplemental figure 2 ) . there was no difference in aca between the two groups ( 0.49%  0.44% vs 0.35%  0.31% , p = .09 ) . aca to bca ratio in the dm group was thus increased compared with that in the ndm group ( 0.35  0.18 vs 0.46  0.30 , p = .045 ) . representative photomicrographs of pancreas immunostained for insulin ( brown ) ( a , c , e , and g ) or glucagon ( brown ) ( b , d , f , and h ) and with hematoxylin ( 20 objective ) . examples of lean ( 65 y old woman , bmi 21.5 kg / m , hba1c 5.7% [ 38 mmol / mol ] ) ( a and b ) and obese ( 63 y old man , bmi 26.0 kg / m , hba1c 5.6% [ 37 mmol / mol ] ) ( c and d ) subjects without diabetes , and lean ( 63 y old woman , bmi 19.6 kg / m , hba1c 8.2% [ 66 mmol / mol ] ) ( e and f ) , and obese ( 70 y old man , bmi 29.0 kg / m , hba1c 7.7% [ 60 mmol / mol ] ) ( g and h ) subjects with diabetes . mean islet size ( 5297  2115 vs 4486  1990 m , p = .03 ) and islet density ( 4.52  3.05 vs 3.09  2.04 /mm , p = .003 ) were both decreased in the dm group compared with the ndm group . on the other hand , there was no difference in the density of scattered -cells , density of insulin - positive duct cells , and -cell replication between the two groups . -cell apoptosis ( ie , single stranded dna and/or cleaved poly(adp - ribose ) polymerase-1-positive -cells ) was not found in either group ( supplemental figure 2 ) . reduced bca in the dm group was also observed when patients diagnosed with pc and diabetes at the same time ( n = 8) were excluded from the analysis ( 0.81%  0.55% , p < .001 vs ndm ) . furthermore , a similar reduction in bca was observed in patients with diabetes duration of longer than 3 years and those with diabetes duration of 3 years or less ( p = .65 , supplemental figure 3a ) . there was no difference in bca among patients treated with different medications ( supplemental figure 3d ) . there was no difference in either bca or aca according to the pancreas regions from which the samples had been obtained ( ie , pancreas head vs body or tail , supplemental figure 4 , d i ) . however , the bca of subjects with pc was significantly lower than that of those with other tumors , irrespective of the presence or absence of diabetes ( supplemental figure 4a ) . patients with or without diabetes were further classified according to presence or absence of obesity ( table 1 ) . in the ndm group , there was no difference in bca ( 1.42%  1.09% vs 1.71%  1.07% , p = .21 ) , aca ( 0.48%  0.46% vs 0.55%  0.37% , p = .33 ) , and aca to bca ratio ( 0.33  0.16 vs 0.41  0.26 , p = .56 ) between lean and obese subjects ( figure 2 ) . similarly , no differences in bca , aca , and aca to bca ratio between lean and obese subjects were observed in the dm group . accordingly , bca was similarly decreased with diabetes in the lean and obese groups ( p = .001 and p = .04 , respectively ) . there were no correlations between bmi and bca , aca , or aca to bca ratio in either the ndm or dm group ( figure 2 , d no increase in bca in obese subjects was also confirmed by the analysis of covariance model including age , sex , diabetes , and pc ( adjusted mean [ 95% confidence interval 1.20% [ 1.01%1.40% ] ] vs 1.20% [ 0.77%1.62% ] in lean vs obese , respectively ) . c , effects of obesity on bca , aca , and aca to bca ratio in cases with and without diabetes . bars indicate mean . * , 
 p < .05 vs lean cases without diabetes ; # , p < .05 vs obese cases without diabetes . d  i , correlations between bmi and bca , aca , or aca to bca ratio in cases with and without diabetes . in the dm group , but not the ndm group , mean islet size in obese subjects was increased compared with that in lean subjects ( 6220  2219 vs 4096  1736 m , p = .01 , supplemental figure 5a ) , and was positively correlated with bmi ( r = 0.43 , p = .002 , supplemental figure 5h ) . in both the ndm and dm groups , there was no difference in islet density and -cell turnover between the lean and obese groups ( supplemental figure 5 , b cases that answered the questionnaire on history of obesity ( n = 59 ) were divided into three groups according to the duration of obesity ( lean [ ie , no history of obesity ] , 10 y , and > 10 y , supplemental table 1 ) . among the three groups , no difference in bca and aca was found in either the ndm or dm group ( figure 3 ) . neither bca nor aca was correlated with maximum bmi in life ( figure 3 , e , there was a positive correlation between mean islet size and maximum bmi ( r = 0.48 , p = .003 ) . cases that answered the questionnaire ( n = 59 ) were divided into three groups according to the duration of obesity ( lean [ ie , no history of obesity ] , 10 y , and > 10 y ) . e  h , correlations between maximum bmi in life and bca or aca in cases with and without diabetes . gray and white circles show cases with and without diabetes , respectively . among the 59 patients , three subjects in the ndm group ( 12% ) and 11 subjects in the dm group ( 33% ) had a first - degree family history of diabetes . although there was no significant difference in bca and aca between patients with and without a family history of diabetes , in the dm group islet density was significantly decreased and mean islet size was increased with borderline significance in patients with a family history compared with those without ( figure 4 ) . effects of first - degree family history of diabetes ( fh ) on bca ( a and b ) , aca ( c and d ) , and islet morphology ( e  h ) . bca was negatively correlated with hba1c and ga before surgery ( r = 0.42 , p < .001 , and r = 0.49 , p = .003 , respectively , figure 5 , a and b ) , whereas aca was not ( r = 0.15 , p = .15 , and r = 0.20 , p = .25 , respectively ) . the relationship between bca and hba1c remained significant after adjustment for age , sex , bmi , and the presence of pc (  = 0.21 , p = .04 ) . bca was correlated with the cpr index before surgery ( r = 0.37 , p = .005 , supplemental figure 6c ) . a and b , correlations between bca and preoperative hba1c ( n = 93 ) or ga ( n = 35 ) . c and d , correlations between bca and hba1c ( n = 77 ) or ga ( n = 32 ) at 6 months after surgery . c and d , cases who underwent total pancreatectomy were excluded . a negative correlation between bca and hba1c or ga was also observed at 3 and 6 months after surgery ( figure 5 , c and d , and supplemental figure 6 , a and b ) . in contrast , the aca was not correlated with postoperative hba1c or ga at any time point ( data not shown ) . the same results were observed when only the cases with distal pancreatectomy were included in the analysis ( data not shown ) . representative photomicrographs of the pancreas of patients with and without diabetes are shown in figure 1 . in patients with diabetes mellitus ( dm group ) , bca was decreased by 46% compared with age- and bmi - matched nondiabetic patients ( ndm group ) ( 1.48%  1.08% vs. 0.80%  0.54% , p < .001 , supplemental figure 2 ) . there was no difference in aca between the two groups ( 0.49%  0.44% vs 0.35%  0.31% , p = .09 ) . aca to bca ratio in the dm group was thus increased compared with that in the ndm group ( 0.35  0.18 vs 0.46  0.30 , p = .045 ) . representative photomicrographs of pancreas immunostained for insulin ( brown ) ( a , c , e , and g ) or glucagon ( brown ) ( b , d , f , and h ) and with hematoxylin ( 20 objective ) . examples of lean ( 65 y old woman , bmi 21.5 kg / m , hba1c 5.7% [ 38 mmol / mol ] ) ( a and b ) and obese ( 63 y old man , bmi 26.0 kg / m , hba1c 5.6% [ 37 mmol / mol ] ) ( c and d ) subjects without diabetes , and lean ( 63 y old woman , bmi 19.6 kg / m , hba1c 8.2% [ 66 mmol / mol ] ) ( e and f ) , and obese ( 70 y old man , bmi 29.0 kg / m , hba1c 7.7% [ 60 mmol / mol ] ) ( g and h ) subjects with diabetes . mean islet size ( 5297  2115 vs 4486  1990 m , p = .03 ) and islet density ( 4.52  3.05 vs 3.09  2.04 /mm , p = .003 ) were both decreased in the dm group compared with the ndm group . on the other hand , there was no difference in the density of scattered -cells , density of insulin - positive duct cells , and -cell replication between the two groups . -cell apoptosis ( ie , single stranded dna and/or cleaved poly(adp - ribose ) polymerase-1-positive -cells ) was not found in either group ( supplemental figure 2 ) . reduced bca in the dm group was also observed when patients diagnosed with pc and diabetes at the same time ( n = 8) were excluded from the analysis ( 0.81%  0.55% , p < .001 vs ndm ) . furthermore , a similar reduction in bca was observed in patients with diabetes duration of longer than 3 years and those with diabetes duration of 3 years or less ( p = .65 , supplemental figure 3a ) . there was no difference in bca among patients treated with different medications ( supplemental figure 3d ) . there was no difference in either bca or aca according to the pancreas regions from which the samples had been obtained ( ie , pancreas head vs body or tail , supplemental figure 4 , d however , the bca of subjects with pc was significantly lower than that of those with other tumors , irrespective of the presence or absence of diabetes ( supplemental figure 4a ) . patients with or without diabetes were further classified according to presence or absence of obesity ( table 1 ) . in the ndm group , there was no difference in bca ( 1.42%  1.09% vs 1.71%  1.07% , p = .21 ) , aca ( 0.48%  0.46% vs 0.55%  0.37% , p = .33 ) , and aca to bca ratio ( 0.33  0.16 vs 0.41  0.26 , p = .56 ) between lean and obese subjects ( figure 2 ) . similarly , no differences in bca , aca , and aca to bca ratio between lean and obese subjects were observed in the dm group . accordingly , bca was similarly decreased with diabetes in the lean and obese groups ( p = .001 and p = .04 , respectively ) . there were no correlations between bmi and bca , aca , or aca to bca ratio in either the ndm or dm group ( figure 2 , d no increase in bca in obese subjects was also confirmed by the analysis of covariance model including age , sex , diabetes , and pc ( adjusted mean [ 95% confidence interval 1.20% [ 1.01%1.40% ] ] vs 1.20% [ 0.77%1.62% ] in lean vs obese , respectively ) . c , effects of obesity on bca , aca , and aca to bca ratio in cases with and without diabetes . bars indicate mean . * , 
 p < .05 vs lean cases without diabetes ; # , p < .05 vs obese cases without diabetes . d  i , correlations between bmi and bca , aca , or aca to bca ratio in cases with and without diabetes . in the dm group , but not the ndm group , mean islet size in obese subjects was increased compared with that in lean subjects ( 6220  2219 vs 4096  1736 m , p = .01 , supplemental figure 5a ) , and was positively correlated with bmi ( r = 0.43 , p = .002 , supplemental figure 5h ) . in both the ndm and dm groups , there was no difference in islet density and -cell turnover between the lean and obese groups ( supplemental figure 5 , b to examine the effect of history of obesity on islet morphology , cases that answered the questionnaire on history of obesity ( n = 59 ) were divided into three groups according to the duration of obesity ( lean [ ie , no history of obesity ] , 10 y , and > 10 y , supplemental table 1 ) . among the three groups , no difference in bca and aca was found in either the ndm or dm group ( figure 3 ) . neither bca nor aca was correlated with maximum bmi in life ( figure 3 , e h ) . in the dm group , there was a positive correlation between mean islet size and maximum bmi ( r = 0.48 , p = .003 ) . cases that answered the questionnaire ( n = 59 ) were divided into three groups according to the duration of obesity ( lean [ ie , no history of obesity ] , 10 y , and > 10 y ) . e  h , correlations between maximum bmi in life and bca or aca in cases with and without diabetes . gray and white circles show cases with and without diabetes , respectively . among the 59 patients , three subjects in the ndm group ( 12% ) and 11 subjects in the dm group ( 33% ) had a first - degree family history of diabetes . although there was no significant difference in bca and aca between patients with and without a family history of diabetes , in the dm group islet density was significantly decreased and mean islet size was increased with borderline significance in patients with a family history compared with those without ( figure 4 ) . effects of first - degree family history of diabetes ( fh ) on bca ( a and b ) , aca ( c and d ) , and islet morphology ( e  h ) . bca was negatively correlated with hba1c and ga before surgery ( r = 0.42 , p < .001 , and r = 0.49 , p = .003 , respectively , figure 5 , a and b ) , whereas aca was not ( r = 0.15 , p = .15 , and r = 0.20 , p = .25 , respectively ) . the relationship between bca and hba1c remained significant after adjustment for age , sex , bmi , and the presence of pc (  = 0.21 , p = .04 ) . bca was correlated with the cpr index before surgery ( r = 0.37 , p = .005 , supplemental figure 6c ) . a and b , correlations between bca and preoperative hba1c ( n = 93 ) or ga ( n = 35 ) . c and d , correlations between bca and hba1c ( n = 77 ) or ga ( n = 32 ) at 6 months after surgery . c and d , cases who underwent total pancreatectomy were excluded . a negative correlation between bca and hba1c or ga was also observed at 3 and 6 months after surgery ( figure 5 , c and d , and supplemental figure 6 , a and b ) . in contrast , the aca was not correlated with postoperative hba1c or ga at any time point ( data not shown ) . the same results were observed when only the cases with distal pancreatectomy were included in the analysis ( data not shown ) . in this study , we report the following : 1 ) bca in individuals with diabetes was decreased by approximately 45% compared with that in those without diabetes , whereas there was no difference in aca ; 2 ) there was little effect of obesity or history of obesity on bca and aca irrespective of the presence or absence of diabetes ; and 3 ) bca , but not aca , was significantly correlated with preoperative and postoperative glycemic control . the findings of this study extend the current knowledge on the pathophysiological changes in bcm and acm in humans , as discussed below . first , the reduction in bca by approximately 45% in japanese patients with t2 dm was consistent with our prior report using autopsy pancreas ( 8) . although it is often difficult to distinguish t2 dm and pc - associated diabetes in patients with pc , we confirmed the same results in patients with diabetes duration of longer than 3 years , in whom t2 dm was likely to have preceded the development of pancreatic tumors ( 11 ) . a recent study suggested that -cell loss in patients with t2 dm is overestimated due to the presence of degranulated -cells ( 12 ) ; however , the comparable reduction in islet size and density in this study supports the idea that the number of -cells is indeed reduced in those with t2 dm , as reported by prior observations ( 5 , 8 , 1315 ) . reduced insulin secretion and a paradoxical increase in glucagon secretion is a hallmark of t2 dm ( 16 ) ; however , the change in acm in patients with diabetes is controversial . acm has been reported to increase in patients with t2 dm ( 14 ) , but this was not found in other studies ( 8 , 17 , 18 ) . a recent rodent study has suggested -cell to -cell transdifferentiation as a mechanism of increased acm in diabetes ( 2 ) . in the present study , we observed no significant increase in aca in patients with t2 dm , although the relative proportion of aca to bca was significantly increased compared with that in nondiabetic patients . thus , the present study indicates that the relative increase in acm compared with bcm in patients with t2 dm is mainly driven by reduced bcm , but not an increase in acm . the reduced islet size and density observed in patients with diabetes also reflect reduced total endocrine cells in patients with diabetes . the second objective of this study was to clarify the effects of obesity on bcm and acm in patients with and without diabetes . we have previously reported no increase in bcm in japanese obese nondiabetic individuals compared with lean controls by using autopsy samples ( 7 ) . in contrast , in the caucasian population , autopsy studies have shown that bcm is increased by approximately 2050% in obese nondiabetic individuals ( 4 , 5 ) . a recent study in the caucasian population using surgically resected pancreas has also shown a significant increase in bca in nondiabetic individuals with insulin resistance ( 19 ) . these inconsistent findings suggest the possibility that the adaptive change in bcm in response to obesity differs among ethnicities . in this study , using surgically resected pancreas , we confirmed no increase in bca in japanese obese individuals with or without diabetes , in line with recent japanese studies ( 20 , 21 ) . because it has been reported that -cell replication rapidly decreases postmortem ( 22 , 23 ) , -cell turnover might be underestimated in autopsy pancreas . here we found that -cell replication and surrogate markers of -cell neogenesis in the surgically resected pancreas were also not changed in obese individuals . furthermore , we here showed that there was no effect of either duration of obesity or maximum bmi in life on bca in these subjects . similarly to bca , aca was also not changed in obese individuals irrespective of the presence or absence of diabetes . although studies have shown that -cell function adjusted for insulin sensitivity is comparable between japanese and caucasians ( 24 , 25 ) , considering the similar incidence of t2 dm despite less degree of obesity in japanese compared with caucasians ( 26 ) , our results suggest that the ethnic difference in bcm could be attributable to lower maximum insulin secretory ability in asians compared with caucasians . further studies are needed to determine genetic and environmental factors regulating bcm in humans and clarify the underlying mechanisms of the ethnic difference in -cell change in response to obesity . although the mean islet size was reduced in patients with t2 dm compared with nondiabetic subjects , there was a positive correlation between mean islet size and bmi in patients with t2 dm . considering the lack of significant change in bca or aca with obesity , the increase in islet size possibly resulted from an increase in other endocrine cells , amyloid deposits , or other components . it has been reported that islet amyloid deposition is positively correlated with bmi in patients with t2 dm ( 27 ) . it would be of interest to clarify the underlying mechanism of islet remodeling with obesity in patients with t2 dm , which may cause further -cell loss in these patients . it is also of note that we assessed the effect of a first - degree family history of diabetes on bcm . as a result , in patients with diabetes , reduced islet density with greater islet size was observed in patients with a family history of diabetes . we have previously reported that islet number rather than islet size is a major determinant of bcm , and islet density was negatively correlated with plasma glucose level in nondiabetic humans ( 28 ) . reduced islet density with greater islet size has also been reported in nondiabetic subjects with the tcf7l2 polymorphism who are susceptible to t2 dm ( 29 ) . together with these prior studies , the present study suggests that a genetic factor is associated with t2 dm susceptibility through reduced islet number . finally , we investigated the clinical significance of bcm , ie , the relationship between bca and plasma glucose level , and found a negative correlation between bca and hba1c , consistent with our and prior reports ( 8 , 14 , 30 , 31 ) . we also confirmed the association between bca and plasma glucose level using another glycemic index , ga . intriguingly , the relationships between bca and glycemic markers remained significant , even 6 months after surgery in patients with pancreatoduodenectomy or distal pancreatectomy in which a half of the pancreas had been resected , indicating that bca predicts glycemic control before and after surgery . the present study and others have also observed a significant correlation between bca and endogenous insulin secretion assessed by cpr or the cpr index ( 21 , 31 ) , which have been shown to predict future glycemic control ( 32 ) . these findings underpin the importance of bcm rather than acm in the regulation of glucose metabolism in humans . another unexpected and novel finding of this study was the reduced bca in patients with pc compared with those with other pancreatic tumors . it is known that pc is associated with new - onset or worsening of diabetes ( 33 ) . however , the mechanisms by which pc causes deterioration of glucose metabolism remain largely unknown . it has been reported that -cell function is impaired in patients with pc ( 34 ) . one study reported reduced bca in patients with pc and diabetes ( 35 ) , whereas others did not ( 21 , 31 ) . these inconsistent results might have been due to the small sample size in these studies . in this study , reduced bca in patients with pc was observed irrespective of the presence or absence of diabetes , suggesting that the reduction in bcm is independent of the effect of diabetes . the reduced bca in the tumor - free region supports the concept that pc may affect endocrine cells indirectly through humoral factors such as adrenomedullin ( 36 ) . further study will be needed to clarify the underlying mechanisms by which pc induces glucose intolerance through a reduction in endocrine cells . the strengths of the present study include the following : 1 ) the relatively large sample size with well - matched controls , 2 ) detailed medical information before and after surgery , and 3 ) detailed information on the history of obesity and family history of diabetes obtained by questionnaire . the major limitation of this study was that the cases had pancreatic diseases , which might have affected pancreatic morphology . however , we confirmed the same results in cases with and without pc , and the findings of this study were consistent with our prior report using autopsy pancreas in which cases with pancreatic disease were excluded ( 7 , 8 , 28 ) . second , the pancreas samples were obtained from different portions of the pancreas according to the operative procedures . however , it has been reported that the proportion of endocrine cells is constant throughout the pancreas with the exception of the ventral portion of the pancreatic head ( 37 ) , and we confirmed that there was no difference in either bca or aca between samples from the head and those from the body or tail . another limitation of the study was that we evaluated bca as a surrogate for bcm . thus , the different pancreas mass in each case might have affected our findings , although it was difficult to determine pancreas mass because of the presence of pancreatic tumors . nonetheless , estimates of bcm based on reference data ( 38 ) did not change our conclusion ( data not shown ) , and an increase in bca in obese subjects has been observed in both autopsy and surgically resected pancreas in the caucasian population ( 4 , 19 ) , supporting our conclusion that the change in bca in response to obesity is limited in japanese . finally , although we evaluated the history of obesity , none of the cases had a history of childhood obesity . because postnatal -cell replication is more frequently observed in the first 5 years of life ( 39 , 40 ) , we were not able to exclude the possibility that childhood obesity may promote bcm expansion in the japanese population . in conclusion , there was no increase in bcm in japanese obese individuals who underwent pancreatic surgery , and bcm was not related to bmi , history of obesity , or maximum bmi . these findings suggest that the increase in bcm in the face of insulin resistance is extremely limited in japanese . bcm was reduced by approximately 45% in patients with t2 dm , and bcm , but not acm , was associated with preoperative and postoperative glycemic control . these findings support the concept that bcm rather than acm has a major role in regulating blood glucose level in humans .
context : the ethnic difference in -cell regenerative capacity in response to obesity may be attributable to different phenotypes of type 2 diabetes among ethnicities.objective:this study aimed to clarify the effects of diabetes and obesity on - ( bcm ) and -cell mass ( acm ) in the japanese population.design , setting , and participants : we obtained the pancreases of 99 individuals who underwent pancreatic surgery and whose resected pancreas sample contained adequate normal pancreas for histological analysis . 
 questionnaires on a family history of diabetes and history of obesity were conducted in 59 patients . 
 pancreatic sections were stained for insulin or glucagon , and fractional - and -cell area were measured . 
 islet size and density as well as -cell turnover were also quantified.results:in patients with diabetes , bcm was decreased by 46% compared with age- and body mass index - matched nondiabetic patients ( 1.48%  1.08% vs 0.80%  0.54% , p < 
 .001 ) , whereas there was no difference in acm between the groups . 
 there was no effect of obesity or history of obesity on bcm and acm irrespective of the presence or absence of diabetes . 
 there was a negative correlation between bcm , but not acm , and glycated hemoglobin before and after pancreatic surgery . 
 in addition , reduced bcm was observed in patients with pancreatic cancer compared with those with other pancreatic tumors.conclusions:these findings suggest that the increase in bcm in the face of insulin resistance is extremely limited in the japanese , and bcm rather than acm has a major role in regulating blood glucose level in humans .