the dpt-1 screened 103,391 relatives of individuals with type 1 diabetes who had been diagnosed before age 45 years . to have been eligible for screening , an individual must have been a first - degree relative of a patient with type 1 diabetes aged between 3 and 45 years or a second - degree relative aged between 3 and 20 years . the 3,483 relatives who were found to be islet cell antibody ( ica ) positive were staged to quantify the projected 5-year risk of diabetes ( 13 ) . staging consisted of ica confirmation , hla - dq typing , determination of insulin autoantibodies , and oral ( ogtt ) and intravenous glucose tolerance testing . relatives with hla - dqa 1 * 0102/dqb1 * 0602 were excluded ( 16 ) . those considered to be at a > 50% 5-year risk were eligible for entry into the parenteral insulin trial if either the first - phase insulin response to intravenous glucose was below the 1st10th percentile ( depending on age and relation to the proband ) on two occasions or there were abnormalities ( other than diabetes ) on the ogtt ( 17 ) . if none of these metabolic abnormalities were present , first - phase insulin response was above threshold ( 10th percentile for siblings , offspring , and second - degree relatives and 1st percentile for parents ) , insulin autoantibodies were positive , and the 5-year risk was 2550% , participants were entered for the oral insulin trial ( 18 ) . subjects were randomly assigned to receive insulin intervention or matched placebo / observation , respectively . neither intervention showed a statistically significant difference between the treatment arms in terms of progression to diabetes ( 17,18 ) . we report here on the 180 participants in the oral insulin trial ( moderate - risk group ) and the 148 subjects in the parenteral trial ( high - risk group ) who were randomized to the placebo / observation arms of the study . at baseline and follow up , the ogtt was performed using a dose of glucose of 1.75 g / kg body wt ( maximum 75 g ) . after an overnight fast , blood samples were obtained through indwelling catheters for plasma glucose and serum c - peptide measurements in the fasting state and 30 , 60 , 90 , and 120 min later . after the baseline study , subjects received an ogtt every 6 months until development of diabetes ( median 2.2 years ) or study end ( median 3.2 years ) . mmol / l , with confirmation by either an elevated fasting or 2-h glucose level at a special follow - up visit or a random plasma glucose 11.1 mmol / l accompanied by symptoms of polyuria , polydipsia , or weight loss . impaired glucose tolerance ( igt ) was defined as a fasting glucose < 7.0 mmol / l and a 2-h glucose between 7.8 and 11.1 serum c - peptide was determined by radioimmunoassay as previously described ( 20 ) , with an interassay coefficient of variation of 6.9% in a reference pool with relatively high values and 7.8% in a reference pool with relatively low values . modeling methods are described in detail in an online appendix , available at http://diabetes.diabetesjournals.org/cgi/content/full/db09-1378/dc1 . in brief , -cell function parameters were obtained from the ogtt using a model ( 21 ) that describes the relationship between insulin secretion and glucose concentration . characteristic -cell function parameters reported here are fasting insulin secretion rate ( in picomoles per min per square meter of body surface area ) ; insulin output , i.e. , the integral of insulin secretion during the 2-h ogtt ; and -cell glucose sensitivity , i.e. , the mean slope of the dose response relating insulin secretion to glucose concentration within the observed glucose range . as defined and used here , in vivo -cell glucose sensitivity quantifies an overall relationship and does reflect specifically the cellular processes governing glucose sensing ( glucose transport through glut2 , phosphorylation by glucokinase , etc . ) . insulin sensitivity was calculated using the oral glucose  derived insulin sensitivity index ( ogis ) ( 22 ) , which provides a validated estimate of the glucose clearance ( in milliliters per min per square meter of body surface area ) during the insulin - stimulated conditions of the euglycemic - hyperglycemic clamp . the time trajectories of glucose concentration and the model - derived parameters were analyzed using a function of time capable of representing a biphasic pattern , with an initial phase in which the variable changes slowly with time and a late phase in which the change is accelerated . group comparisons were performed using the mann - whitney u or wilcoxon signed - rank test ( for unpaired and paired observations , respectively ) and the  test for categorical variables . kaplan - meier plots were used to compare diabetes - free survival curves by means of the log - rank  statistic . cox proportional hazards models were used to estimate hazard ratios ( hrs ) ( 95% ci ) . p values are two sided , and p < 0.05 was accepted as statistically significant . all analyses were performed using jmp , version 3.1 ( sas institute , cary , nc ) . at baseline and follow up , the ogtt was performed using a dose of glucose of 1.75 g / kg body wt ( maximum 75 g ) . after an overnight fast , blood samples were obtained through indwelling catheters for plasma glucose and serum c - peptide measurements in the fasting state and 30 , 60 , 90 , and 120 min later . after the baseline study , subjects received an ogtt every 6 months until development of diabetes ( median 2.2 years ) or study end ( median 3.2 years ) . diabetes was diagnosed if the fasting glucose was 7.0 mmol / l or the 2-h glucose was 11.1 mmol / l , with confirmation by either an elevated fasting or 2-h glucose level at a special follow - up visit or a random plasma glucose 11.1 mmol / l accompanied by symptoms of polyuria , polydipsia , or weight loss . impaired glucose tolerance ( igt ) was defined as a fasting glucose < 7.0 mmol / l and a 2-h glucose between 7.8 and 11.1 serum c - peptide was determined by radioimmunoassay as previously described ( 20 ) , with an interassay coefficient of variation of 6.9% in a reference pool with relatively high values and 7.8% in a reference pool with relatively low values . modeling methods are described in detail in an online appendix , available at http://diabetes.diabetesjournals.org/cgi/content/full/db09-1378/dc1 . in brief , -cell function parameters were obtained from the ogtt using a model ( 21 ) that describes the relationship between insulin secretion and glucose concentration . characteristic -cell function parameters reported here are fasting insulin secretion rate ( in picomoles per min per square meter of body surface area ) ; insulin output , i.e. , the integral of insulin secretion during the 2-h ogtt ; and -cell glucose sensitivity , i.e. , the mean slope of the dose response relating insulin secretion to glucose concentration within the observed glucose range . as defined and used here , in vivo -cell glucose sensitivity quantifies an overall relationship and does reflect specifically the cellular processes governing glucose sensing ( glucose transport through glut2 , phosphorylation by glucokinase , etc . ) . insulin sensitivity was calculated using the oral glucose  derived insulin sensitivity index ( ogis ) ( 22 ) , which provides a validated estimate of the glucose clearance ( in milliliters per min per square meter of body surface area ) during the insulin - stimulated conditions of the euglycemic - hyperglycemic clamp . the time trajectories of glucose concentration and the model - derived parameters were analyzed using a function of time capable of representing a biphasic pattern , with an initial phase in which the variable changes slowly with time and a late phase in which the change is accelerated . group comparisons were performed using the mann - whitney u or wilcoxon signed - rank test ( for unpaired and paired observations , respectively ) and the  test for categorical variables . kaplan - meier plots were used to compare diabetes - free survival curves by means of the log - rank  statistic . cox proportional hazards models were used to estimate hazard ratios ( hrs ) ( 95% ci ) . p values are two sided , and p < 0.05 was accepted as statistically significant . all analyses were performed using jmp , version 3.1 ( sas institute , cary , nc ) . subjects who progressed to diabetes ( progressors ) were younger and leaner than those who remained diabetes free over the follow - up period and were more often igt than nonprogressors , as manifested by their higher 2-h plasma glucose levels ( table 1 ) . the insulin secretion / plasma glucose dose - response curve was considerably flatter in progressors than in nonprogressors . its descriptive parameter , the slope or -cell glucose sensitivity , was 45% lower in progressors , whereas fasting insulin secretion rate , total insulin output , and insulin sensitivity were similar in the two groups . after excluding subjects with igt ( 30 progressors and 18 nonprogressors ) , glucose sensitivity was still significantly impaired in subjects converting to diabetes ( median 54 pmol / min per m per mmol / l [ interquartile range 38 ] vs. 90 pmol / min per m per mmol / l   of nonprogressors ; p < 0.0001 ) ( fig . anthropometric and metabolic parameters at baseline data are median ( interquartile range ) or n unless otherwise indicated . dose - response curve of insulin secretion rates vs. plasma glucose levels during the ogtt in 280 subjects with normal glucose tolerance according to whether ( progressors ) or not ( nonprogressors ) they developed diabetes . full lines , baseline data ; dotted lines , data at follow - up . in female subjects , younger age and higher bmi were positive predictors of incident diabetes , whereas a good -cell glucose sensitivity was a strong protective factor . in male subjects , only a younger age was a risk factor , while both -cell glucose sensitivity and insulin sensitivity were protective ( table 2 ) . of note is that a high a priori risk ( assessed at staging as a composite of relation to proband and reduced acute insulin response to intravenous glucose ) was a significant predictor of conversion to diabetes only in female subjects and did not replace either glucose sensitivity or insulin sensitivity . with regard to plasma glucose levels themselves , in univariate analysis 2-h glucose levels predicted incident diabetes , with hrs ( 1.81 [ 95% ci 1.372.40 ] ,  = 16 in male subjects and 2.35 [ 1.723.21 ] ,  = 29 in female subjects ) that were lower than the univariate hrs carried by -cell glucose sensitivity ( 0.32 [ 0.170.56 ] ,  = 20 in male subjects and 0.24 [ 0.140.38 ] ,  = 46 in female subjects ) . thus , in the multivariate models of table 2 , neither fasting nor 2-h glucose was a significant independent predictor in male subjects and only 2-h glucose was an additional predictor in female subjects ( p = 0.03 ) . even in subjects with normal glucose tolerance ( n = 280 ) , diabetes - free survival was strongly dependent on baseline -cell glucose sensitivity in both sexes ( fig . 2 ) . predictors of incident type 1 diabetes multivariate analysis ; risk ratios for age , bmi , -cell glucose sensitivity , and insulin sensitivity were calculated for the sex - specific interquartile range of their respective values . kaplan - meier plots of diabetes - free survival in 280 subjects with normal glucose tolerance at baseline according to tertile of baseline -cell glucose sensitivity ( log - rank  = 25.5 , p < 0.0001 , and 13.2 , p = 0.0003 , in female [ a ] and male [ b ] subjects , respectively ) . the risk ratio of subjects in the bottom tertile of -cell glucose sensitivity ( dotted line ) is 2.40 ( 95% ci 1.763.30 ) , p < 0.0001 vs. the top tertile , adjusted for sex , age , and bmi . fasting and 2-h plasma glucose concentrations had risen slightly in nonprogressors , who now counted as 41 subjects in the igt category . both fasting insulin secretion rate and insulin output were higher than at baseline , whereas insulin sensitivity and -cell glucose sensitivity were slightly but significantly worse . in progressors , the marked rise in fasting and 2-h plasma glucose levels was accompanied by a fall in insulin output and insulin sensitivity and a further , drastic decline in glucose sensitivity ( table 3 ) . anthropometric and metabolic parameters at follow - up data are median ( interquartile range ) or n unless otherwise indicated . ns , not significant . in the subjects with four or more sequential ogtts ( n = 208 ) , the individual time series could generally be described as approximately linear with time ( i.e. , a monophasic time course ) or as biphasic ( i.e. , displaying a definite change in slope at an identifiable transition time ) ( fig . 3 ) . for the 2-h plasma glucose concentrations , both the raw values and their fitting functions revealed a predominantly biphasic pattern in progressors ( n = 52 ) and a mostly monophasic one among nonprogressors ( n = 156 ) ( fig . the statistical analysis of all the ogtt - derived parameters is given in supplemental table a1 . for 2-h glucose concentrations , glucose sensitivity , and insulin sensitivity , the average time course was significantly better described by a biphasic than a monophasic fit in progressors compared with nonprogressors . accordingly , the initial and final slopes of the respective time series were not different from one another in nonprogressors , whereas the final slopes were much steeper than the initial slopes in the progressors . example of a monophasic ( a ) ( subject yw3599 ) and a biphasic ( b ) ( subject hr2920 ) time course of 2-h plasma glucose concentrations ; note the change in slope at transition time in the biphasic time pattern . half - yearly averages of 2-h plasma glucose concentrations ( left panel ) and individual fits of their time series ( right panel ) in nonprogressors and progressors . the thick lines are the mean of the individual fitting functions . among progressors , 36 subjects ( or 70% ) had a biphasic time course for 2-h glucose levels ( on a median of 6 [ interquartile range 2 ] tests ) , while for glucose sensitivity a similar pattern was present in 30 subjects . in these individuals , the transition time for 2-h glucose was positively correlated with the transition time for glucose sensitivity (  = 0.43 ; p = 0.020 ) . in addition , the transition to an increased rate of decrease in glucose sensitivity occurred earlier than the corresponding 2-h glucose transition ( 1.3 [ 1.2 ] vs. 0.77 [ 1.0 ] years ; p = 0.035 ) ( fig . when 2-h glucose levels were synchronized on the individual transition times , it became clear that plasma glucose levels changed little until 0.78 years before diagnosis , when they started to rise at a rate of 13 mmol / l per year . when the time series of the metabolic parameters were synchronized with the glucose time series , it was found that glucose sensitivity had begun to decline ( at a rate of 29 pmol / min per m per mmol / l ) 1.45 years before diagnosis , i.e. , significantly ( p < 0.0001 ) earlier than the plasma glucose surge . during this anticipation phase  lasting a median 4.3 months ( n = 30 ) with an unequivocally biphasic time course of 2-h glucose concentrations , the transition times of -cell glucose sensitivity were positively associated with the transition times of 2-h plasma glucose concentration ( supplemental fig . time course of 2-h plasma glucose concentrations , glucose sensitivity , fasting insulin secretion , and insulin sensitivity in the progressor group . subjects who progressed to diabetes ( progressors ) were younger and leaner than those who remained diabetes free over the follow - up period and were more often igt than nonprogressors , as manifested by their higher 2-h plasma glucose levels ( table 1 ) . the insulin secretion / plasma glucose dose - response curve was considerably flatter in progressors than in nonprogressors . its descriptive parameter , the slope or -cell glucose sensitivity , was 45% lower in progressors , whereas fasting insulin secretion rate , total insulin output , and insulin sensitivity were similar in the two groups . after excluding subjects with igt ( 30 progressors and 18 nonprogressors ) , glucose sensitivity was still significantly impaired in subjects converting to diabetes ( median 54 pmol / min per m per mmol / l [ interquartile range 38 ] vs. 90 pmol / min per m per mmol / l   of nonprogressors ; p < 0.0001 ) ( fig . anthropometric and metabolic parameters at baseline data are median ( interquartile range ) or n unless otherwise indicated . dose - response curve of insulin secretion rates vs. plasma glucose levels during the ogtt in 280 subjects with normal glucose tolerance according to whether ( progressors ) or not ( nonprogressors ) they developed diabetes . full lines , baseline data ; dotted lines , data at follow - up . in female subjects , younger age and higher bmi were positive predictors of incident diabetes , whereas a good -cell glucose sensitivity was a strong protective factor . in male subjects , only a younger age was a risk factor , while both -cell glucose sensitivity and insulin sensitivity were protective ( table 2 ) . of note is that a high a priori risk ( assessed at staging as a composite of relation to proband and reduced acute insulin response to intravenous glucose ) was a significant predictor of conversion to diabetes only in female subjects and did not replace either glucose sensitivity or insulin sensitivity . with regard to plasma glucose levels themselves , in univariate analysis 2-h glucose levels predicted incident diabetes , with hrs ( 1.81 [ 95% ci 1.372.40 ] ,  = 16 in male subjects and 2.35 [ 1.723.21 ] ,  = 29 in female subjects ) that were lower than the univariate hrs carried by -cell glucose sensitivity ( 0.32 [ 0.170.56 ] ,  = 20 in male subjects and 0.24 [ 0.140.38 ] ,  = 46 in female subjects ) . thus , in the multivariate models of table 2 , neither fasting nor 2-h glucose was a significant independent predictor in male subjects and only 2-h glucose was an additional predictor in female subjects ( p = 0.03 ) . even in subjects with normal glucose tolerance ( n = 280 ) , diabetes - free survival was strongly dependent on baseline -cell glucose sensitivity in both sexes ( fig . 2 ) . predictors of incident type 1 diabetes multivariate analysis ; risk ratios for age , bmi , -cell glucose sensitivity , and insulin sensitivity were calculated for the sex - specific interquartile range of their respective values . kaplan - meier plots of diabetes - free survival in 280 subjects with normal glucose tolerance at baseline according to tertile of baseline -cell glucose sensitivity ( log - rank  = 25.5 , p < 0.0001 , and 13.2 , p = 0.0003 , in female [ a ] and male [ b ] subjects , respectively ) . the risk ratio of subjects in the bottom tertile of -cell glucose sensitivity ( dotted line ) is 2.40 ( 95% ci 1.763.30 ) , p < 0.0001 vs. the top tertile , adjusted for sex , age , and bmi . fasting and 2-h plasma glucose concentrations had risen slightly in nonprogressors , who now counted as 41 subjects in the igt category . both fasting insulin secretion rate and insulin output were higher than at baseline , whereas insulin sensitivity and -cell glucose sensitivity were slightly but significantly worse . in progressors , the marked rise in fasting and 2-h plasma glucose levels was accompanied by a fall in insulin output and insulin sensitivity and a further , drastic decline in glucose sensitivity ( table 3 ) . anthropometric and metabolic parameters at follow - up data are median ( interquartile range ) or n unless otherwise indicated . in the subjects with four or more sequential ogtts ( n = 208 ) , the individual time series could generally be described as approximately linear with time ( i.e. , a monophasic time course ) or as biphasic ( i.e. , displaying a definite change in slope at an identifiable transition time ) ( fig . 3 ) . for the 2-h plasma glucose concentrations , both the raw values and their fitting functions revealed a predominantly biphasic pattern in progressors ( n = 52 ) and a mostly monophasic one among nonprogressors ( n = 156 ) ( fig . the statistical analysis of all the ogtt - derived parameters is given in supplemental table a1 . for 2-h glucose concentrations , glucose sensitivity , and insulin sensitivity , the average time course was significantly better described by a biphasic than a monophasic fit in progressors compared with nonprogressors . accordingly , the initial and final slopes of the respective time series were not different from one another in nonprogressors , whereas the final slopes were much steeper than the initial slopes in the progressors . example of a monophasic ( a ) ( subject yw3599 ) and a biphasic ( b ) ( subject hr2920 ) time course of 2-h plasma glucose concentrations ; note the change in slope at transition time in the biphasic time pattern . half - yearly averages of 2-h plasma glucose concentrations ( left panel ) and individual fits of their time series ( right panel ) in nonprogressors and progressors . the thick lines are the mean of the individual fitting functions . among progressors , 36 subjects ( or 70% ) had a biphasic time course for 2-h glucose levels ( on a median of 6 [ interquartile range 2 ] tests ) , while for glucose sensitivity a similar pattern was present in 30 subjects . in these individuals , the transition time for 2-h glucose was positively correlated with the transition time for glucose sensitivity (  = 0.43 ; p = 0.020 ) . in addition , the transition to an increased rate of decrease in glucose sensitivity occurred earlier than the corresponding 2-h glucose transition ( 1.3 [ 1.2 ] vs. 0.77 [ 1.0 ] years ; p = 0.035 ) ( fig . when 2-h glucose levels were synchronized on the individual transition times , it became clear that plasma glucose levels changed little until 0.78 years before diagnosis , when they started to rise at a rate of 13 mmol / l per year . when the time series of the metabolic parameters were synchronized with the glucose time series , it was found that glucose sensitivity had begun to decline ( at a rate of 29 pmol / min per m per mmol / l ) 1.45 years before diagnosis , i.e. , significantly ( p < 0.0001 ) earlier than the plasma glucose surge . during this anticipation phase  lasting a median 4.3 months  both insulin secretion and insulin sensitivity were essentially stable . in progressors ( n = 30 ) with an unequivocally biphasic time course of 2-h glucose concentrations , the transition times of -cell glucose sensitivity were positively associated with the transition times of 2-h plasma glucose concentration ( supplemental fig . time course of 2-h plasma glucose concentrations , glucose sensitivity , fasting insulin secretion , and insulin sensitivity in the progressor group . by selection , our subjects were at enhanced risk of progressing to diabetes by genetic makeup ( kinship and lack of protective genotype ) as well as clinical phenotype ( presence of ica and insulin autoantibodies or reduced acute insulin response to intravenous glucose ) . accordingly , 35% developed diabetes over the follow - up period , a crude rate of 13% per year ( in the range of that of similar cohorts ) . insulin secretion rates and insulin sensitivity were no different between progressors and nonprogressors while -cell glucose sensitivity was markedly impaired ( by 45% ) . 1 ) , and was only reflected in a 0.78 mmol / l difference in 2-h glucose concentrations while fasting glucose was virtually identical ( median 4.83 mmol / l [ interquartile range 0.72 ] vs. 4.80 , some deterioration of all metabolic parameters was seen in the whole cohort ; emergence of overt diabetes , however , was marked by a further , drastic ( 70% ) decline in -cell glucose sensitivity ( table 2 ) . consistent with these time - related changes are the predictive models of incident diabetes : younger age and worse -cell glucose sensitivity were the strongest independent predictors of progression in both sexes , with bmi ( in female subjects ) and insulin resistance ( in male subjects ) as additional risk factors ( table 2 ) . first , absolute rates of insulin secretion ( or plasma insulin concentrations ) do not track a failing -cell function . in fact , fasting insulin secretion increased over time in progressors and nonprogressors alike , while even in progressors insulin output was diminished by only 20% at the time of diagnosis ( table 2 ) . 5 ) is reminiscent of the inverted - u shape of plasma insulin concentrations in individuals progressing to type 2 diabetes ( 25 ) , which is also termed the starling curve of the pancreas ( 26 ) . on the other hand , -cell glucose sensitivity was specifically associated with glucose tolerance across groups and over time , was the strongest predictor of the diabetes outcome , and declined as a monotonical function of time in progressors ( fig . thus , absolute insulin secretion rates can be viewed as reflecting the secretory tone of the -cell , which adapts to chronically raised glucose levels by upregulating release of the hormone . glucose sensitivity , in contrast , expresses the ability of the -cell to quickly respond to acute changes in plasma glucose levels in vivo , thereby directly controlling glucose tolerance . it is this latter function that we found to be compromised long ( years ) before the onset of type 1 diabetes . at this time other than a younger age ( 2 years ) and a 15% increase in 2-h glucose concentrations that differentiated subjects who were to become diabetic from those who remained nondiabetic over the observation period . thus , in vivo -cell glucose insensitivity is an early defect in type 1 diabetes . the question stands whether the whole dpt-1 cohort  and not just the subjects who progressed within 3 years  was one characterized by a defect in -cell glucose sensitivity . however , from data collected in the risc study ( 27 ) we selected 90 young ( median age 32 years [ interquartile range 3 ] ) , lean ( bmi 22.6 kg / m [ 4.2 ] ) volunteers with a negative family history of diabetes in whom -cell function and insulin sensitivity were assessed with the same methodology as used in the present study . in these historical controls , median -cell glucose sensitivity was 138 pmol / min per m per mmol / l ( interquartile range 72 ) and insulin sensitivity was 460 ml / min per m ( 69 ) . thus , this comparison suggests that both -cell glucose sensitivity and insulin sensitivity may have been less than normal even in the nonprogressors of dpt-1 at the time of staging . whether the dpt-1 population had entirely normal metabolic functions prior to the autoimmune attack on the -cell secondly , the tight association between -cell glucose insensitivity and glucose tolerance does not per se establish a cause - effect link : a primary -cell defect can clearly cause loss of glucose tolerance but might also result from toxic effects of mild but persistent hyperglycemia on -cells . it should be stressed that the primary -cell defect could consist in a reduction in number of normally functioning -cells , a dysfunction of a normal number of -cells , or a combination of the two . in vivo assessment of -cell glucose sensitivity glucose toxicity , on the other hand , can acutely depress both the insulin secretory response to glucose ( 28 ) and insulin sensitivity ( 29 ) . the time series analysis of our data shows that in two - thirds of the progressors , the trajectory of plasma glucose concentrations was distinctly biphasic , with a slow rise turning into a brisk surge 0.7 years before diagnosis ( research design and methods ) . in these individuals , a transition of -cell glucose sensitivity from a flat time course to a clear decline occurred 1.4 years prior to diagnosis and consistently anticipated the transition of glucose levels ( fig . were shifted with respect to one another by 68 months , during which time neither absolute insulin secretion nor insulin sensitivity was changing appreciably . these findings provide strong support for the conclusion that a loss of -cell glucose sensitivity effectively is a potent drive for the acceleration of hyperglycemia in high - risk subjects rapidly progressing to diabetes . of note is that recent work carried out in nondiabetic patients undergoing pancreatectomy ( 30 ) has revealed a curvilinear reciprocal association between 2-h plasma glucose concentration and -cell relative volume , suggesting that -cell function / mass may decrease initially without much impact on glucose levels but then  beyond a certain critical level  cause an exponential rise in glycemia . finally , the characteristic biphasic time pattern of conversion in dpt-1 screenees is consistent with a previous preliminary finding from dpt-1 ( 15 ) and is reminiscent of what happens in type 2 diabetes . in three prospective analyses of incident type 2 diabetes ( 3133 ) , an acceleration of plasma glucose increments the similarity is striking : a few years ( type 2 diabetes [ 3133 ] ) or months ( type 1 diabetes [ present study ] ) before diagnosis , glucose tolerance characteristically begins to deteriorate at a much faster rate than during the preceding years . the fact that the pathogenesis and natural history of the two forms of diabetes are distinct suggests that a more general factor may be at play . glucose homeostasis relies on multiple controls : to name only the main ones , insulin sensitivity of liver , fat , and skeletal muscle tissues as well as -cell and -cell function . in the individual who is destined to become diabetic  whether type 2 or type 1 diabetes several of the factors that govern glucose tolerance are more or less altered , generating a critical state of instability . in such a condition , phase transition can be triggered by small further changes in the controlling variables and occurs relatively rapidly . for type 1 diabetes ( 34 ) , this instability paradigm  borrowed from physics ( 35)has been formulated mathematically by rate equations describing the changes in numbers of -cells , macrophages , and th - lymphocytes eventually leading to self - sustained -cell elimination . the conclusion of this theoretical study was that onset of type 1 diabetes is due to a collective , dynamical instability rather than being caused by a single etiological factor ( 34 ) . transition to the phase of rapid plasma glucose increases was characterized by a precipitous fall in insulin sensitivity plus an acceleration of glucose insensitivity ; in the meantime , insulin secretion was failing to keep up with the rising glucose ( fig . thus , a state of critical instability transitioned to a phase of impending global failure . different time patterns , linear or erratic , could be equally explained by different combinations of rates of failure of the determinants of glucose tolerance . in summary , a defect in -cell glucose sensitivity is detectable in at - risk subjects years before diagnosis , anticipates plasma glucose increments , and in combination with progressive insulin resistance and secretory insufficiency produces the acute hyperglycemia of type 1 diabetes .
objectiverelatives of type 1 diabetic patients are at enhanced risk of developing diabetes . 
 we investigated the mode of onset of hyperglycemia and how insulin sensitivity and -cell function contribute to the progression to the disease.research design and methodsin 328 islet cell autoantibody 
 positive , nondiabetic relatives from the observational arms of the diabetes prevention trial-1 study ( median age 11 years [ interquartile range 8 ] , sequential ogtts ( 2,143 in total ) were performed at baseline , every 6 months , and 2.7 years [ 2.7 ] later , when 115 subjects became diabetic . 
 -cell glucose sensitivity ( slope of the insulin - secretion / plasma glucose dose - response function ) and insulin sensitivity were obtained by mathematical modeling of the ogtt glucose / c - peptide responses.resultsin progressors , baseline insulin sensitivity , fasting insulin secretion , and total postglucose insulin output were similar to those of nonprogressors , whereas -cell glucose sensitivity was impaired ( median 48 
 pmol / min per m2 per mmol / l [ interquartile range 36 ] vs. 87 pmol / min per m2 per mmol / l [ 67 ] ; p < 0.0001 ) and predicted incident diabetes ( p < 0.0001 ) independently of sex , age , bmi , and clinical risk . in progressors , 
 2-h glucose levels changed little until 0.78 years before diagnosis , when they started to rise rapidly ( 13 mmol  l1  year1 ) ; glucose sensitivity began to decline significantly ( p < 0.0001 ) earlier ( 1.45 years before diagnosis ) than the plasma glucose surge . during this anticipation phase , 
 both insulin secretion and insulin sensitivity were essentially stable.conclusionsin high - risk relatives , -cell glucose sensitivity is impaired and is a strong predictor of diabetes progression . 
 the time trajectories of plasma glucose are frequently biphasic , with a slow linear increase followed by a rapid surge , and are anticipated by a further deterioration of -cell glucose sensitivity .