type 1 diabetes is characterized by insulin deficiency resulting from destruction of pancreatic cells and subclassified into type 1a ( autoimmune ) and type 1b ( idiopathic ) diabetes .
we previously reported a novel subtype of type 1b diabetes that we referred to fulminant type 1 diabetes . in fulminant type 1 diabetes
, remarkably acute and almost complete cell destruction occurs and nearly no insulin secretion remains , even just after the disease onset .
measurement of serum cpeptide level is effective for assessing the ability of endogenous insulin secretions . in particular , it is valuable to presume residual cell capability for type 1 diabetic patients . with a conventional method , enzyme immunoassays ( eia ) , low levels ( usually < 0.07 
nmol / l [ 0.2  ng / ml ] ) of serum cpeptide are difficult to detect .
however , we can now detect up to 0.003  nmol / l ( 0.01  ng / ml ) serum cpeptide levels using a high sensitivity method , chemiluminescent enzyme immunoassay ( cleia ) .
it enables us to know more precise levels of serum cpeptide in patients who have almost no insulin secretion , such as patients with fulminant type 1 diabetes . in the present study
, we evaluated serum cpeptide levels measured by cleia and clarified the clinical features of fulminant type 1 diabetic patients based on residual endogenous insulin secretions .
we studied 12 patients with fulminant type 1 diabetes ( 5 males and 7 females ) .
these patients were diagnosed as having fulminant type 1 diabetes between 19882006 , and had been followed in our hospital for more than 0.5  years since the disease onset .
the diagnosis of fulminant type 1 diabetes was established according to the inclusion criteria proposed by the committee of the japan diabetes society .
namely : ( i ) the presence of ketosis or ketoacidosis within a week after the onset of hyperglycemic symptoms ; ( ii ) urinary cpeptide excretion < 10  g / day or fasting serum cpeptide level < 0.10  nmol / l ( 0.3  ng / ml ) and peak serum cpeptide level < 0.17  nmol / l ( 0.5  ng / ml ) after glucagon ( 1  mg ) or a meal load soon after disease onset ; and ( iii ) plasma glucose level 16.0  mmol / l ( 288  mg / dl ) and hba1c level < 8.5% at first visit .
patients characteristics were as follows : they were aged 2278  years ( 44.2    18.4 ) , duration of the disease was 0.819  years ( 4.8    5.2 ) , body mass index ( bmi ) was 18.524.8 ( 20.8    1.9 ) , hba1c was 5.710.4% ( 7.2    1.5 ) , and glycoalbumin was 19.032.5% ( 25.1    4.1 ) .
eight of the 12 patients were receiving multiple daily injections and three patients were receiving continuous subcutaneous insulin infusion .
every patient was usually followed every month in our outpatient clinic and insulin doses were adjusted for targeting nearly normal glucose levels ( hba1c  <  6.5% , fasting glucose level < 5.6  mmol / l [ 100  mg / dl ] , 120min postprandial glucose level < 7.8  mmol / l [ 140  mg / dl ] ) . the data of hba1c , glycoalbumin , bodyweight and daily dosages of insulin were measured every 9  months ( from january to september in 2006 ) and expressed as mean of 9  months measurements .
sevenpoint ( fasting and 120  min postprandial for each meal and bedtime ) capillary blood glucose concentrations were measured in seven of the 12 patients for at least two days , and mean mvalue was calculated in each patient .
mvalue is a logarithmic transformation of the deviation of blood glucose from a selected standard .
we used 5.6  mmol / l ( 100  mg / dl ) as the selected standard . the deviation index (  ) of each individual glucose value (  ) is first calculated as   =  ( 10    log[/5.0 ] ) .
serum cpeptide levels were measured by cleia ( lumipulse f , lumipulse cpeptide ; fujirevio , tokyo , japan ) and two different eia , aia21 ( e test cpeptide ; tosoh , tokyo , japan ) and eclusys 2010 ( eclusis cpeptide ; roche diagnostics , basel , switzerland ) simultaneously by using the same serum samples . serum cpeptide level
was also followed for 9  months by cleia , and the maximal value was determined in each patient .
the present study was carried out with patients approvals and informed consent was obtained from every patient .
the significance of differences between the two groups was evaluated by pearson s correlation coefficient and mvalue was evaluated by mann 
we studied 12 patients with fulminant type 1 diabetes ( 5 males and 7 females ) .
these patients were diagnosed as having fulminant type 1 diabetes between 19882006 , and had been followed in our hospital for more than 0.5  years since the disease onset .
the diagnosis of fulminant type 1 diabetes was established according to the inclusion criteria proposed by the committee of the japan diabetes society .
namely : ( i ) the presence of ketosis or ketoacidosis within a week after the onset of hyperglycemic symptoms ; ( ii ) urinary cpeptide excretion < 10  g / day or fasting serum cpeptide level < 0.10  nmol / l ( 0.3  ng / ml ) and peak serum cpeptide level < 0.17  nmol / l ( 0.5  ng / ml ) after glucagon ( 1  mg ) or a meal load soon after disease onset ; and ( iii ) plasma glucose level 16.0  mmol / l ( 288  mg / dl ) and hba1c level < 8.5% at first visit .
patients characteristics were as follows : they were aged 2278  years ( 44.2    18.4 ) , duration of the disease was 0.819  years ( 4.8    5.2 ) , body mass index ( bmi ) was 18.524.8 ( 20.8    1.9 ) , hba1c was 5.710.4% ( 7.2    1.5 ) , and glycoalbumin was 19.032.5% ( 25.1    4.1 ) .
eight of the 12 patients were receiving multiple daily injections and three patients were receiving continuous subcutaneous insulin infusion .
every patient was usually followed every month in our outpatient clinic and insulin doses were adjusted for targeting nearly normal glucose levels ( hba1c  <  6.5% , fasting glucose level < 5.6  mmol / l [ 100  mg / dl ] , 120min postprandial glucose level < 7.8  mmol / l [ 140  mg / dl ] ) . the data of hba1c , glycoalbumin , bodyweight and daily dosages of insulin were measured every 9  months ( from january to september in 2006 ) and expressed as mean of 9  months measurements .
sevenpoint ( fasting and 120  min postprandial for each meal and bedtime ) capillary blood glucose concentrations were measured in seven of the 12 patients for at least two days , and mean mvalue was calculated in each patient .
mvalue is a logarithmic transformation of the deviation of blood glucose from a selected standard .
we used 5.6  mmol / l ( 100  mg / dl ) as the selected standard . the deviation index (  ) of each individual glucose value (  ) is first calculated as   =  ( 10    log[/5.0 ] ) .
serum cpeptide levels were measured by cleia ( lumipulse f , lumipulse cpeptide ; fujirevio , tokyo , japan ) and two different eia , aia21 ( e test cpeptide ; tosoh , tokyo , japan ) and eclusys 2010 ( eclusis cpeptide ; roche diagnostics , basel , switzerland ) simultaneously by using the same serum samples . serum cpeptide level
was also followed for 9  months by cleia , and the maximal value was determined in each patient .
the present study was carried out with patients approvals and informed consent was obtained from every patient .
the significance of differences between the two groups was evaluated by pearson s correlation coefficient and mvalue was evaluated by mann 
maximal concentrations of serum cpeptide evaluated by cleia were 0.020.10  nmol / l ( 0.060.29  ng / ml ) in four patients and < 0.003  nmol / l ( 0.01  ng / ml ) in eight patients .
serum cpeptide concentrations of the former four patients ranged from 0.007 to 0.10  nmol / l ( 0.020.29  ng / ml ) and those of the latter eight patients were always less than 0.003 
in contrast , serum cpeptide was detectable in just two patients ( 0.090.10  nmol / l , respectively ) by conventional eia . 
detectable serum cpeptide levels in 4 patients (  ,  ,  ,  ) ranged from 0.007 to 0.10  nmol / l , however serum cpeptide levels in eight patients were always < 0.003  nmol / l .
patients who kept more serum cpeptide levels needed significantly fewer daily dosages of insulin ( p  <  0.01 ; figure  2 ) .
the patients with detectable serum cpeptide levels showed a significantly lower mvalue ( median 2.94 , range 0.966.15 ,
n  =  4 ) than those without detectable serum cpeptide levels ( median 16.62 , range 5.3627.10 , n  =  3 ; p  =  0.01 ) . 
relationship between maximal serum cpeptide level(nmol / l ) and daily dosages of insulin ( unit / kg ) .
residual insulin secreting capacity shown as serum cpeptide level and daily dosages of insulin indicated a significant negative correlation ( * p  <  0.01 ) .
there were no significant correlations between hba1c , glycoalbumin , bmi , duration of disease and serum cpeptide levels .
in the present study , we clarified a significant negative correlation between serum cpeptide levels and daily dosages of insulin .
the patients who had more residual endogenous insulin secreting capacity needed fewer daily dosages of insulin injection .
in addition , the patients whose serum cpeptide levels were < 0.003  nmol / l had a significantly higher mvalue than the patients whose serum cpeptide levels were 0.0070.10  nmol / l .
these results suggest that even very low endogenous insulin secreting capacity would improve the doses of required insulin and stability of blood glucose controls in patients with fulminant type 1 diabetes .
fukuda et  al . have reported a negative correlation between endogenous insulin secreting capacity and degree of blood glucose instability in 20 patients with type 1 diabetes whose fasting serum cpeptide levels were 0.010.13  nmol / l . in the present study , compared with the report from fukuda et  al .
, not fasting but maximal postprandial cpeptide levels were 0.020.10  nmol / l or less , showing that a negative correlation was observed even in the patients with lower levels of serum cpeptide .
second , serum cpeptides were detectable and ranged from 0.007 to 0.10  nmol / l in four patients with fulminant type 1 diabetes throughout the followup period of 9  months .
pathophysiology of fulminant type 1 diabetes is known as almost complete cell destruction around the disease onset , resulting in nearly no cpeptide secretion .
however , our results also suggest that endogenous insulin secreting capacity would be preserved by intensive insulin therapy , as shown in data from the diabetes control and complications trial , even in patients with fulminant type 1 diabetes .
it is important because preserving cell function , even at a low level , could help to stabilize blood glucose levels in patients with fulminant type 1 diabetes . in conclusion ,
our present results suggest that even very low levels of serum cpeptide could reduce daily dosages of insulin and stabilize blood glucose controls in fulminant type 1 diabetes .
 abstractfulminant type 1 diabetes is characterized by almost complete cell destruction , resulting in scarce insulin secretion . in the present study 
 , we aimed to clarify clinical features related to serum cpeptide levels measured by a high sensitivity method , chemiluminescent enzyme immunoassay , in 12 patients with fulminant type 1 diabetes . 
 serum cpeptide was detected ( 0.0070.10  
 nmol / l ) in four patients and was not detected in eight patients . a negative correlation was observed between serum cpeptide levels and daily dosages of insulin ( p  <  0.01 ) . 
 the patients with detectable cpeptide showed a significantly lower mvalue than those without ( p  =  0.01 ) . in conclusion , 
 our present results suggest that even very low levels of endogenous insulin secreting capacity can improve daily dosages of insulin and stabilize blood glucose levels . 
 ( j diabetes invest , doi : 10.1111/j.20401124.2010.0059.x , 2010 ) 