children with new - onset type 1 diabetes were recruited for a randomized , placebo - controlled trial of low - dose oral interferon- for preservation of -cell function ( the primary outcome of which will be published in a separate report ) . patients had a mean age of 9.4  4.6 years , were enrolled within 6 weeks of diagnosis , and were free of other significant illness ( n = 23 , 30% female , 91% caucasian ) . study approval was obtained from the institutional review board at the national institute of diabetes and digestive and kidney diseases ( niddk ) at the national institutes of health ( nih ) . basal rates were continued but morning bolus injections were withheld . for patients on multiple daily injections of insulin , morning doses were withheld . the meal consisted of boost high protein , 7 ml / kg ( maximum 400 ml ) , ingested over 5 min . blood samples were drawn at 10 , 0 , 30 , 60 , 90 , and 120 min . ng / l , with an interassay coefficient of variation ( cv ) of 18% and an intra - assay cv of 15% . c - peptide concentrations were determined with a competitive chemiluminescence assay at the nih clinical center laboratory . nmol / l , with an intra - assay cv of 3.4% ( at 1.45 nmol / l ) and inter - assay cvs of 7.7 and 8.3% at 0.37 and 1.98 nmol / l , respectively area under the curve ( auc ) for glucagon and c - peptide were calculated using the trapezoidal method . the mean of values obtained at 10 and 0 min was used as the baseline value . net glucagon and c - peptide secretion following the mixed meal were expressed as auc . statistical analyses were performed using sas version 9.1 ( sas institute , cary , nc ) . results were described using frequency distributions , pearson 's correlation coefficients , and repeated - measures anova using proc mixed for testing change over time . opposing change ( i.e. , positive for glucagon vs. negative for c - peptide , or vice versa ) was assessed using a sign test based on the sign of the product of the slopes over time for glucagon and c - peptide . all tests were two - sided , with statistical significance defined as p  0.05 . there were no differences between treatment groups ( interferon vs. placebo ) for glucagon or c - peptide auc ; therefore , all 23 subjects were combined for subsequent analyses . subjects showed an increase in glucagon secretion following the mixed meal , with peak glucagon levels at 30 min ( fig . glucagon auc progressively increased over the 12-month observation period ( p = 0.0008 ) , whereas c - peptide auc progressively declined ( p < 0.0001 ) ( fig . the magnitude of change was similar for both hormones ( 37% rise in glucagon vs. 45% decline in c - peptide auc over 12 months ) . of the 23 subjects , 18 ( 78% ) showed opposing changes in glucagon and c - peptide auc over time ( p = 0.01 ) . the percent rise in meal - stimulated c - peptide [ 100  ( peak  fasting)/fasting ] declined over time , from 147  22% at month 0 to 85  12% at month 12 . in contrast , the percent rise in meal - stimulated glucagon increased over time , from 63  12% at month 0 to 82  9% at month 12 . fasting glucagon rose from 40  3 ng / l at month 0 to 46  3 ng / l at month 12 . no significant correlations were found between glucagon auc and a1c , insulin dose , or insulin dose - adjusted a1c ( data not shown ) . the phenomenon of elevated glucagon in response to oral glucose or mixed meal testing has been described cross - sectionally in patients with type 1 and type 2 diabetes , generally of several years duration ( 25 ) . more recently , porksen et al . ( 6 ) reported a 17% rise in post mixed meal glucagon ( measured as a single value at 90 min ) from 1 to 12 months after diagnosis of type 1 diabetes . in the present study , we demonstrate a progressive , 37% rise in meal - stimulated glucagon secretion over 12 months after diagnosis of type 1 diabetes , paralleled by a 45% decline in c - peptide secretion . fasting glucagon rose only 15% over 12 months and remained within the normal range of the assay , suggesting that hyperglucagonemia may not be recognized if only fasting blood samples are obtained . as seen in previous studies ( 7,8 ) , the ability of -cells to secrete insulin in response to a stimulus declined over time in our patients with type 1 diabetes . in contrast , the ability of -cells to secrete glucagon in response to a stimulus increased over time . this suggests that -cell secretory reserve is not diminished by the ongoing autoimmune process in type 1 diabetes . although the pathophysiology of glucagon excess during hyperglycemia in type 1 diabetes is not well understood , the opposing directions of abnormal glucagon and c - peptide secretion over time support the link between dysregulated glucagon secretion and declining -cell function . these data represent the most detailed time course to date of the progression of abnormal glucagon secretion in type 1 diabetes . we did not observe a significant correlation between glucagon auc and a1c or insulin dose ; however , this may be related to small sample size . nevertheless , the timing and rapid progression shown here suggest that excess glucagon secretion may represent a distinct therapeutic target early in the course of type 1 diabetes .
objective  to determine the time course of changes in glucagon and insulin secretion in children with recently diagnosed type 1 diabetes.research design and methods  glucagon and c - peptide concentrations were determined in response to standard mixed meals in 23 patients with type 1 diabetes aged 9.4  4.6 years , beginning within 6 weeks of diagnosis , and every 3 months thereafter for 1 year.resultsglucagon secretion in response to a physiologic stimulus ( mixed meal ) increased by 37% over 12 months , while c - peptide secretion declined by 45% . 
 fasting glucagon concentrations remained within the normal ( nondiabetic ) reference range.conclusionspostprandial hyperglucagonemia worsens significantly during the first year after diagnosis of type 1 diabetes and may represent a distinct therapeutic target . 
 fasting glucagon values may underestimate the severity of hyperglucagonemia . 
 the opposing directions of abnormal glucagon and c - peptide secretion over time support the link between dysregulated glucagon secretion and declining -cell function .