Type 1 Diabetes Manifested Solely by 2-h Oral Glucose Tolerance ...

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Type 1 Diabetes Manifested Solely by 2-h Oral
Glucose Tolerance Test Criteria
Carla J. Greenbaum, David Cuthbertson, Jeffrey P. Krischer, and the Diabetes Prevention Trial
of Type 1 Diabetes Study Group

The clinical presentation of type 1 diabetes usually
involves symptoms such as polyuria and polydipsia.
However, investigators in the Diabetes Prevention Trial
of Type 1 Diabetes (DPT-1) have detected a group of
subjects with type 1 diabetes who have a different phe-

The clinical manifestation of type1 diabetes usually
involves symptoms such as polyuria and polydip-
sia and is thought to occur after autoimmune
notype. These subjects are asymptomatic, have normal
destruction of most of the pancreatic -cells,
(<6.1 mmol/l) (group A) or impaired (6.1– <7.0 mmol/l)
resulting in severe insulin deficiency and fasting hypergly-
(group B) fasting glucose, but have 2-h glucose values
>11.1 mmol/l on their oral glucose tolerance tests

cemia. However, investigators in the Diabetes Prevention
(OGTT). Of the 585 OGTTs performed on islet cell anti-
Trial of Type 1 Diabetes (DPT-1) (1,2) have detected a group
body (ICA)-positive relatives with insulin autoanti-
of subjects with type 1 diabetes who have a different pheno-
bodies (IAA) or low first-phase insulin response
type. These subjects are asymptomatic, have normal
(FPIR), normal glucose tolerance (NGT) was found in
(<6.1 mmol/l) or impaired (6.1–<7.0 mmol/l) fasting glucose
427 subjects; impaired glucose tolerance (IGT) was
on their oral glucose tolerance tests (OGTTs), but have 2-h glu-
found in 87 subjects, and diabetes was found by 2-h
cose values >11.1 mmol/l, thus meeting one of the American
OGTT criteria alone in 61 subjects. Despite marked dif-
Diabetes Association’s (3) new criteria for the diagnosis of dia-
ferences in 2-h glucose values (NGT 5.8 ± 1.1 mmol/l,
betes. Importantly, these subjects have characteristics plac-
IGT 8.9 ± 0.9 mmol/l, and group A 13.5 ± 2.5 mmol/l),
ing them at increased risk for type 1 diabetes; i.e., they are rel-
there were no significant differences in fasting glucose
values among NGT (4.8 ± 0.5 mmol/l), IGT (5.03 ±

atives of patients with type 1 diabetes, they are <45 years of
0.5 mmol/l), and group A (4.99 ± 0.7 mmol/l) categories.
age, and they are islet cell antibody (ICA)-positive.
Mean FPIR was higher in subjects with NGT compared
The DPT-1 is a multicenter randomized trial designed to
with subjects with IGT and subjects diagnosed by 2-h
determine if type 1 diabetes can be prevented or delayed.
OGTT criteria alone. However, the correlation between
First- or second-degree relatives of type 1 diabetic patients ≤45
FPIR and 2-h glucose value was low (r2 = 0.14). Multi-
years of age are screened for the presence of ICAs. Then,
variate analysis demonstrated that additional inde-
those who are ICA+ enter the staging part of the DPT-1, dur-
pendent variables provide smaller contributions to the
ing which they undergo tests to estimate their risk for devel-
2-h glucose value. In conclusion, there are asympto-
oping diabetes more precisely. The last staging test per-
matic type 1 diabetic subjects whose diabetes was diag-
formed before randomization into the treatment part of the
nosed by the 2-h criteria on OGTT alone. Despite the
importance of -cell dysfunction in the pathogenesis of

study is an OGTT to rule out the presence of diabetes (1,2).
type 1 diabetes, factors other than impaired FPIR must
Those with fasting or postprandial hyperglycemia on this
also contribute to postprandial glucose tolerance in
OGTT are excluded from further participation. This report
these subjects. Diabetes 50:470–476, 2001
describes the population of subjects with type 1 diabetes
identified by the 2-h OGTT criteria alone at the time of the
DPT-1 staging OGTT. Demographic data (age, sex, and rela-
tionship to proband), immune activity (antibody status), and
tests of -cell function (first-phase insulin response [FPIR] and
From the Department of Veterans Affairs (C.J.G.), Puget Sound Health Care
OGTT) are described for these subjects and compared with
System and the Department of Medicine (C.J.G.), University of Washington,
those subjects whose staging OGTT for DPT-1 classified
Seattle, Washington; and the H. Lee Moffitt Cancer Center and Research Insti-
them as having normal glucose tolerance (NGT) or impaired
tute (D.C., J.P.K.), University of South Florida, Tampa, Florida.
Address correspondence and reprint requests to Carla Greenbaum MD,
glucose tolerance (IGT).
Diabetes Clinical Research Unit, Clinical Research Center, Virginia Mason
Research Center, 1201 9th Ave., Seattle, WA 98101. E-mail: [email protected]
Subjects. All of the subjects were participants in the DPT-1 who underwent
Received for publication 18 August 1999 and accepted in revised form
an OGTT during the period from February 1994 through December 1998
16 October 2000.
(Fig. 1). Protocols were approved at participating locations nationwide, and
AUC, area under the curve; DPT-1, Diabetes Prevention Trial of Type 1
all subjects (and/or parents of minors) gave written informed consent for
Diabetes; FPIR, first-phase insulin response; HOMA- , homeostasis model
each part of the study.
assessment of -cell function; HOMA-IR, homeostasis model assessment of
Screening. As of 31 December 1998, 65,758 first-degree (
insulin resistance; IAA, insulin autoantibody; ICA, islet cell antibody; IDS,
≤45 years of age) and
second-degree (
Immunology of Diabetes Society; IGT, impaired glucose tolerance; IVGTT,
≤20 years of age) relatives of patients with type 1 diabetes were
intravenous glucose tolerance test; JDF U, Juvenile Diabetes Foundation
screened for the presence of ICAs. Those subjects whose ICA titer was ≥10
units; NDDG, National Diabetes Data Group; NGT, normal glucose tolerance;
Juvenile Diabetes Foundation units (JDF U) were invited to participate in stag-
NIH, National Institutes of Health; OGTT, oral glucose tolerance test.
ing (n = 2,350).

FIG. 1. DPT-1 screening and staging as of 31 December 1998. *OGTT results on eligible, consenting subjects whose results were available by
December 1998. Exclusions were interim diagnosis of diabetes, presence of HLA DQB1*0602, medications or illness that may interfere with
glucose metabolism or study compliance, and unable or unwilling to consent.

Staging. ICA+ relatives underwent intravenous glucose tolerance testing
Homeostasis model assessment of insulin resistance. The homeostasis
(IVGTT) to determine FPIR. In addition, repeat testing was performed for ICAs,
model assessment of insulin resistance (HOMA-IR) (7) was calculated as fol-
and the presence of insulin autoantibodies (IAAs) was determined. Subjects
lows: [fasting insulin (pmol)
fasting glucose (mmol/l)]/22.5.
with IVGTT insulin results below threshold (see below) on two occasions (n =
OGTT. After an overnight fast and insertion of an antecubital intravenous line,
420) or who had ICAs as well as IAAs present (n = 469) were eligible for OGTT.
samples were drawn at –10 and 0 min. An oral glucose load was then adminis-
Autoantibody assays. ICA values were determined on frozen sections of
tered (Fisherbrand Sun-dex) (1.75 g/kg, maximum 75 g). Blood samples were
human pancreas in the DPT-1 ICA core laboratory (Gainesville, FL, February
drawn at 30, 60, 90, and 120 min after glucose consumption. C-peptide and glu-
1994 to September 1997; and New Orleans, LA, September 1997 to December
cose were measured in the DPT-1 -Cell Function core laboratory (Seattle, WA).
1998). Values ≥10 JDF U were considered positive. In the 1995 Immunology of
Statistical analysis. Variables that were not normally distributed (autoan-
Diabetes Society (IDS) workshop, this ICA assay had a specificity of 100% with
tibody titers, HOMA- , HOMA-IR, C-peptide area under the curve (AUC), fast-
a sensitivity of 74.4% for recent onset patients <30 years of age.
ing insulin, FPIR, and fasting and 2-h glucose) were log-transformed for analy-
Insulin autoantibody. IAA values were determined at the DPT-1 IAA core lab-
sis. However, for clarity of interpretation, results are expressed as untrans-
oratory (Boston, MA) by a fluid-phase radioassay using 600 µl of sera with
formed mean and SD values.
duplicate determinations with and without unlabeled insulin for competition.
Differences in means of continuous variables were tested using analysis of
The interassay coefficient of variation for the IAA assay is 10.3% at low posi-
variance. Tukey’s studentized range test was used to control the experiment-
tive values. In the 1995 IDS workshop, this IAA assay had a specificity of 91%
wise error rate for pair-wise comparisons. Differences in categorical vari-
and a sensitivity of 49% for recent onset patients <30 years of age.
ables were tested using the 2 statistic and Fisher’s exact test. Pair-wise com-
GAD65 and ICA512 antibodies. GAD65 and ICA512 antibodies (GAD65ab,
parisons were performed, altering the accepted level of statistical signifi-
ICA512ab) were determined in Denver, Colorado, on DPT-1 samples as part of
cance by a Bonferroni adjustment; with four groups, the acceptance level is
an ancillary study. A combined GAD65ab and ICA512ab radioassay was per-
0.0083; with three groups, the acceptance level is 0.0167. Trends were
formed (4). Labeled recombinant GAD65 and ICA512 were produced by in vitro
assessed using Spearman’s rho correlation analysis. Multivariate step-wise lin-
transcription/translation with differential labeling (3H-GAD65 and 35S-
ear regression was performed using variables determined to be statistically
ICA512). The levels of both antibodies were expressed as an index. The
significant by univariate analysis. Statistical significance for the regression
interassay coefficients of variation are 6 and 9.6% for GAD65ab and ICA512ab,
analyses was accepted at 5%.
respectively. The upper limits of normal (0.032 for GAD65ab; 0.071 for
ICA512ab) were established as the 99th percentile for GAD65ab and as the 100th
percentile for ICA512ab from receiver-operating characteristic curves in 198
healthy control subjects and 50 patients with recent- onset diabetes. In the 1995
Glucose. As of 31 December 1998, there were 585 subjects
IDS workshop, sensitivity for the GAD65ab assay was 82%, and specificity
who underwent a staging OGTT. NGT was found in 427 sub-
was 99%. Sensitivity for the ICA512ab assay was 73%, and specificity was 100%.
jects, IGT was found in 87 subjects, and type 1 diabetes was
-cell function. IVGTTs were performed according to the Islet Cell Antibody
diagnosed solely by the 2-h OGTT criteria in 61 subjects. The
Register User’s Study protocol (5,6). Fasting samples were drawn at –10 and
–4 min through an intravenous line. A solution of 25% glucose (0.5 g/kg, max-
American Diabetes Association has also defined a category
imum 35 g) was then given intravenously over 3 min. Samples were drawn at
of impaired fasting glucose in which the fasting glucose value
1, 3, 5, 7, and 10 min after the end of the glucose infusion. Insulin and glucose
is between 6.1 and <7.0 mmol/l, and the 2-h value is
were measured in the DPT-1 -Cell Function core laboratory (Seattle, WA).
<7.8 mmol/l. Because only three subjects had this glucose pro-
FPIR was calculated as the sum of the IVGTT insulin values at 1 and 3 min.
file, they were not included in the analysis. However, the dis-
The 10th percentile of normal control subjects for siblings and offspring >8
years of age is 600 pmol/l. The 10th percentile for siblings and offspring <8
tinction between normal and impaired fasting glucose was
years of age and the first percentile for parents is 360 pmol/l. FPIR below these
applied to the subjects with diabetes diagnosed by their 2-h
values are defined as low and are used as the thresholds for eligibility for the
OGTT value, thus defining group A and group B categories
parental insulin intervention trial.
(described below). There were an additional seven subjects
Homeostasis model assessment of -cell function. The homeostasis
model assessment of -cell function (HOMA- ) (7) was calculated as fol-
excluded from the analysis who had fasting glucose
lows: fasting insulin (pmol)/[fasting glucose (mmol) – 3.5]
≥7.0 mmol/l and 2-h glucose ≥11.1 mmol/l (Table 1 and Fig. 2).

Classification of ICA+ and IAA/low FPIR relatives according to OGTT results
OGTT ≥11.1 mol/l
Group A
Group B
Group criterion
Fasting glucose (mmol/l)
2-h glucose (mmol/l)
≥7.8, <11.1
Baseline characteristics
Fasting glucose (mmol/l)
4.80 ± 0.46
5.03 ± 0.5
4.99 ± 0.67
6.47 ± 0.28*
2-h glucose (mmol/l)
5.82 ± 1.12*
8.93 ± 0.89*
13.54 ± 2.51*
15.19 ± 3.39*
Age (years)
12.6 ± 9.5 (2–44)
13.9 ± 11.0 (1–45)
11.8 ± 9.5 (2–40)
21.0 ± 14.1 (3–44)*
243 (56.9)
50 (57.5)
16 (44.4)
14 (56.0)
184 (43.1)
37 (42.5)
20 (55.6)
11 (44.0)
Relationship to proband†
266 (62.3)
61 (71.1)
20 (55.6)
16 (64.0)
113 (26.5)
19 (21.8)
10 (27.8)
4 (16.0)
15 (3.5)
3 (3.5)
2 (5.6)
5 (20.0)
Second-degree relative
33 (7.7)
4 (4.6)
4 (11.1)
0 (0.0)
381 (89.2)
80 (92)
34 (94.4)
22 (88.0)
6 (1.4)
3 (3.5)
0 (0.0)
0 (0.0)
22 (5.2)
2 (2.3)
2 (5.6)
1 (4.0)
11 (2.6)
0 (0.0)
0 (0.0)
2 (8.0)
7 (1.6)
2 (2.3)
0 (0.0)
0 (0.0)
Type 1 diabetes haplotypes‡
288 (66.8)
62 (71.3)
27 (75)
19 (73.1)
ICA titer (JDF U; median)
80 (10–40,960)
160 (10–2,560)
160 (10–5,120)
320 (20–2,560)
303 (71.0)
66 (75.9)
28 (77.8)
13 (52)
184 (75.7)
33 (76.7)
14 (66.7)
9 (75.0)
113 (40.5)
30 (62.5)
11 (50.0)
7 (58.3)
Fasting insulin (pmol/l)
77.4 ± 51.6
72.2 ± 57.0
73.8 ± 32.4
117.6 ± 75.0*
59.4 ± 70.1
56.1 ± 37.0
50.9 ± 32.2
42.9 ± 24.2
17.7 ± 17.8
19.2 ± 14.4
16.5 ± 8.5
32.8 ± 22.7*
FPIR (pmol/l)§
724 ± 485*
462 ± 388
365 ± 215
279 ± 154
Data are means ± SD, means ± SD (range), and n (%). *Significantly different from other group by analysis of variance (F test and
Duncan’s range test); †statistically significant by 2 analysis; ‡DQA1*0501/DQB1*0201 and DQA1*0301/DQB1*0302; §statistically signi-
ficant trend by Spearman’s rho.
Groups were defined according to 2-h glucose value.
described in this study. However, analysis of data obtained on
Therefore, as expected, the mean values were different
subjects undergoing OGTT since that date indicates no signi-
among those with NGT (5.8 ± 1.1 mmol/l), those with IGT
ficant difference in either trend or average among groups
(8.9 ± 0.9 mmol/l), and those with diabetes diagnosed by the
with respect to BMI, although the number is small.
2-h glucose criteria (14.2 ± 3.0 mmol/l) (P < 0.001). When the
Genetic data. The haplotypes DQA1*0501/DQB1*0201 and
latter group was divided between subjects with normal fast-
DQA1*0301/DQB1*0302 are commonly associated with type 1
ing glucose (group A) and subjects with impaired fasting glu-
diabetes. There were no differences in the frequency of these
cose (group B), there was also a difference in 2-h glucose val-
haplotypes between glucose tolerance groups (Table 1).
ues (group A 13.5 ± 0.4 mmol/l and group B 15.2 ± 3.4 mmol/l;
Antibody data. IAA and ICA data were available on all
P < 0.001). Despite these marked differences in 2-h glucose
585 subjects, as they were obtained as part of DPT-1 proto-
values, the difference in fasting glucose values among NGT
col. GAD65ab and ICA512ab were obtained as part of a
(4.8 ± 0.5 mmol/l), IGT (5.02 ± 0.5 mmol/l), and group A
DPT-1 ancillary study; therefore, results were available for
(4.99 ± 0.7 mmol/l) diabetes groups was not significant.
only 323 of these samples. For both IAA and GAD65 anti-
Demographic data. Univariate analysis demonstrated no
bodies, there were no differences in the percent positive
differences with respect to age, ethnic affiliation, relationship
(Table 1) or in titers (data not shown) between OGTT
of subject to proband with diabetes, or sex among groups
groups. Similarly, the median ICA titers were the same
defined as NGT, IGT, or diabetes by 2-h criteria only. However,
between groups. There was also no significant trend relat-
those in group B were older (P < 0.001), more likely to be a
ing any of these antibodies with worsening glucose toler-
parent of the proband with diabetes, and less likely to be a sec-
ance. Though the percent of subjects that were ICA512ab+
ond-degree relative of the diabetic proband (P = 0.012) than
in each group was statistically different by 2 analysis (P =
those with NGT (Table 1). Height and weight data was not col-
0.017), there was no significant trend with worsening glucose
lected on subjects in the staging part of DPT-1 until early
tolerance, and the median titers were not different by OGTT
1999; therefore, this data is not available for the population
group (data not shown).

0.001). There were no significant differences among the lat-
ter three groups as categories; however, there was a signifi-
cant trend of decreasing FPIR with worsening glucose intol-
erance (Fig. 3) (r = –0.27, P < 0.001). Comparing only those
subjects in each glucose tolerance group who had a low
FPIR (n = 304; 52% of subjects), there was a difference in
mean FPIR between those with NGT (392.3 ± 127.9 pmol/l)
and IGT (310.7 ± 108.8 pmol/l), group A (289.0 ± 140.5 pmol/l),
and group B (266.5 ± 135.5 pmol/l) (P < 0.001).
To explore the relationship between FPIR and glucose val-
ues further, we compared FPIR with fasting glucose or 2-h glu-
cose as continuous variables. Though there was a statistically
significant relationship between FPIR and each glucose mea-
sure, the correlation of these measures was weak (Figs. 4 and
5). A similar relationship was found when only those with low
FPIR were examined (data not shown). Similar results were
obtained using C-peptide measurements during the OGTT
as a measure of insulin secretion; i.e., there was a statistically
FIG. 2. Relationship between fasting and 2-h glucose value from
OGTT in 585 ICA+ relatives with IAA and/or low FPIR. A, group A;

significant relationship (P = 0.0001) between the 2-h glucose
B, group B.
value and the C-peptide AUC or the increment from 0–30 min.
However, the correlations were low (R2 = 0.03 for AUC and
0.11 for the 0–30 min increment).
Metabolic data
We then analyzed the correlations between variables
Basal insulin secretion. Fasting insulin values were not dif-
(Table 2) and performed multivariate stepwise linear regres-
ferent among subjects with NGT (77.4 ± 51.6 pmol/l), IGT
sion analysis to determine the independent contribution of
(82.2 ± 57 pmol/l), and diabetes diagnosed by 2-h criteria
variables of interest in explaining the 2-h glucose values.
alone (90.8 ± 56.8 pmol/l), although there was a difference
Because of the close correlation (R = 0.84) between glucose
between group A (73.8 ± 32.4 pmol/l) and group B (117.6 ±
AUC and 2-h glucose value, glucose AUC was not considered
75 pmol/l). Similarly, though the HOMA-
indexes were the
an independent variable. The independent variables tested
same by OGTT group (NGT 59.4 ± 70.1, IGT 56.1 ± 37.0, and
diabetes by 2-h OGTT criteria 49.2 ± 29.4), there was a weak
but statistically significant correlation among each of these
variables and categories of worsening glucose tolerance (fast-
ing insulin r = 0.09, P = 0.04; and HOMA- r = –0.09, P = 0.03).
There were no differences in the HOMA-IR index among
NGT (17.7 ± 17.8), IGT (19.2 ± 14.4), and group A (16.5 ± 8.5)
categories. However, the HOMA-IR index in group B was signi-
ficantly increased (32.8 ± 22.7), and there was a weak but sta-
tistically significant trend between the HOMA-IR values and the
categories of worsening glucose tolerance (r = 0.13, P = 0.001).
Stimulated insulin secretion. Fewer of the relatives with
NGT had low FPIR compared with the other OGTT groups
(P < 0.001). This was also reflected in the mean values for each
group, with a significantly higher FPIR in those with NGT
(724 ± 485 pmol/l) than in those with IGT (462 ± 338 pmol/l),
group A (365 ± 215 pmol/l) or group B (279 ± 154 pmol/l) (P <
FIG. 4. A: FPIR vs. fasting glucose from OGTT; R2 = 0.06. B: FPIR vs.
FIG. 3. Means ± SE FPIR according to OGTT group.
2-h glucose from OGTT; R2 = 0.14.

Type 1 diabetes is believed to occur because of an autoim-
mune-mediated process resulting in progressive -cell
destruction. Loss of first-phase insulin release occurs before
the onset of clinical disease, and it is the most powerful pre-
dictor for the development of overt hyperglycemia and asso-
ciated symptoms. Our data indicate a statistically significant
but weak correlation of FPIR with categories of worsening
glucose tolerance. This supports the concept that subjects
with diabetes diagnosed solely by their 2-h OGTT glucose
value represent a previously undescribed intermediate step
on the path from NGT to overt diabetes. Interestingly, post-
prandial hyperglycemia seen in relatives of type 2 diabetic sub-
jects before overt diabetes was also associated with alter-
ations in -cell function (8), even though those subjects also
had slight elevations in fasting glucose as compared with the
type 1 diabetic subjects described in this study.
However, the relationship between FPIR and glucose status
is not entirely straightforward, as we were unable to find a
FIG. 5. Log-transformed FPIR vs. 2-h glucose from OGTT; R2 = 0.14.
robust direct relationship between FPIR and 2-h glucose
value. At the extremes of the curves, subjects with the high-
include FPIR, fasting insulin, fasting glucose, HOMA-IR,
est glucose values had low FPIR, and subjects with high FPIR
HOMA- , IAA titer, relationship to proband, ethnicity, incre-
had lower glucose values. However, among subjects with a low
mental C-peptide between 0–30 min, and C-peptide AUC. In
FPIR (600 pmol/l), 2-h glucose values ranged between 2.8 and
addition to FPIR, the variables that significantly, though
30.5 mmol/l. This suggests that low FPIR is necessary, but not
weakly, contributed to 2-h glucose were fasting glucose, IAA
sufficient for postprandial hyperglycemia. Though statisti-
titer, HOMA-IR, and OGTT C-peptide values (both incre-
cally significant, the low R2 value of 0.14 suggests that 86% of
mental C-peptide between 0 and 30 min and C-peptide AUC).
the variance is due to factors other than FPIR.
Together, these independent variables were only moderately
If not fully accounted for by FPIR, then what additionally
correlated with 2-h glucose (model R2 = 0.39).
accounts for the state of glucose intolerance in these subjects?
Although stepwise linear regression analysis identified other
factors, the ability of all variables to predict 2-h glucose was
This study describes a previously unrecognized group of sub-
only moderate (R2 = 0.39), suggesting that 61% of variance in
jects with asymptomatic type 1 diabetes. These subjects have
2-h glucose remains unexplained based on these data. There
normal or impaired fasting glucose values and elevated 2-h glu-
are several possibilities. Because the -cell’s response to glu-
cose values on OGTT. The validity of our observation is indi-
cose is only one measure of -cell function, further -cell
cated by the fact that there is no absolute difference or trend
destruction manifested by a lack of insulin release to nonglu-
of higher values in fasting glucose among those with NGT, IGT,
cose secretagogues may be required before postprandial
and diabetes diagnosed by 2-h glucose alone, despite moder-
hyperglycemia is seen. In this scenario, it may be that the
ate (IGT) or marked (diabetic) 2-h hyperglycemia. In addition,
-cell’s inability to respond to the incretin hormones (GLP-1,
repeat OGTT was performed on 14 subjects with diabetes
GIP) would result in postprandial hyperglycemia.
diagnosed by 2-h OGTT criteria alone, and either IGT or dia-
Alternatively, though the primary defect in these subjects
betes with normal fasting glucose was confirmed in 13 of the
is impairment in insulin secretion, it is possible that variations
subjects. Importantly, these subjects have characteristics
in insulin or glucose action could contribute to the 2-h hyper-
associated with type 1 diabetes; they are relatives of subjects
glycemia. The older age, increased fasting insulin, and
with type 1 diabetes, they are between 3 and 45 years of age,
increased HOMA-IR values among the subjects in group B sug-
they are ICA+, and 53% have markedly abnormal first-phase
gests that the mild elevation in fasting hyperglycemia may be
insulin release.
due to a relatively greater degree of insulin resistance com-
Correlations (r values on log-transformed variables)
Fasting C-peptide
change 2-h
0–30 min
Fasting insulin
Fasting glucose


C-peptide AUC

C-peptide change 0–30 min


2-h Glucose

Glucose AUC


pared with the younger subjects. Because the difference
existed. In this context, it is important to note that subjects
between group A and group B is primarily the fasting glucose
in our study with diabetes diagnosed by 2-h glucose criteria
values, the HOMA-IR data support the concept that failing
are no different from subjects with NGT with respect to age.
-cell secretion is reflected in an inability to handle an oral
Additionally, though we do not have BMI data on the subjects
glucose load, but that fasting hyperglycemia in this popula-
described in this study, analysis of a smaller number of sub-
tion occurs only with the additional burden of insulin resis-
jects studied since 1999 suggests no differences between
tance. Though we do not have information about the presence
OGTT groups. Thus, having postprandial hyperglycemia and
of type 2 diabetes in the families of these subjects, the geno-
normal fasting glucose is not a finding related to age or
typing data suggest that these subjects are not genetically
weight, but rather is seen in people at risk for type 1 diabetes,
unusual type 1 diabetic patients, and implies that insulin
even into adulthood.
resistance may contribute to the manifestation of type 1 dia-
There are several implications to the identification of this
betes in some people. In this regard, they share characteris-
subset of subjects with type 1 diabetes. First, it is not clear
tics with the group of antibody-positive adults clinically pre-
what the natural history of these subjects will be over time.
senting with type 2 diabetes (latent autoimmune disease in
All of these subjects were identified through the DPT-1 as
adults) (9–11), who may also represent part of the continuum
being in the population of subjects at a 25% or greater risk of
of the autoimmune diabetes disease process modified by
developing clinical type 1 diabetes over a 5-year period; thus,
insulin resistance and other unknown factors.
we are not suggesting that postprandial hyperglycemia is
The observation that some relatives of type 1 diabetic
commonly present in normal healthy subjects without islet
patients have abnormal glucose responses to OGTT is not
cell autoimmunity. In addition, a prospective study of relatives
new. Almost 30 years ago Burkeholder et al. (12) described
with IGT defined by NDDG criteria demonstrated a threefold
significant nonfasting OGTT abnormalities in 25 children
greater risk for subsequent type 1 diabetes than relatives
after testing 138 asymptomatic siblings of type 1 diabetic
with a normal OGTT (23). Nonetheless, whether these sub-
patients, of whom only 2 subsequently developed overt dia-
jects will rapidly progress to overt symptomatic diabetes
betes. Fajans et al. (13,14) mentioned that some patients
with fasting hyperglycemia, remain with postprandial hyper-
manifest diabetes only by their postprandial glucose value.
glycemia, or revert to normal glucose tolerance is unknown.
Several authors noted that abnormalities in postprandial glu-
A prospective study to answer these questions is underway
cose tolerance (chemical diabetes) were often associated
and will assist clinicians in making therapeutic decisions.
with normal or elevated insulin values. In these subjects,
Second, until results from the ongoing DPT-1 and other inter-
reversion to NGT was frequent (15–18) Thus, the clinical
vention studies are available, we will not know whether early
significance of postprandial glucose elevation or episodes
intervention is beneficial for preventing the progression of dis-
of transient hyperglycemia was unclear.
ease. Third, as expressed by the NDDG team in 1978, we still
In 1978, the National Diabetes Data Group (NDDG) set
do not know whether early diagnosis is beneficial regarding
criteria for the diagnosis of diabetes. Adults under that clas-
prevention of long-term complications of diabetes. There-
sification were defined as having diabetes when there was a
fore, because our data show that some asymptomatic type 1
2-h and one other value on an OGTT that was ≥11.1 mmol/l
diabetic subjects develop postprandial hyperglycemia in the
in the presence of normal fasting glucose. In contrast, for chil-
presence of normal fasting glucose, we suggest that treatment
dren, abnormal postprandial glucose values alone were not
in nonpregnant subjects is not necessary at this stage. Fre-
sufficient to classify a child as having diabetes; instead, these
quent re-evaluation and counseling for the potential future
children were defined as having IGT. Thus, the children with
progression of their disease should be recommended.
diabetes described in this report would not have been diag-
Importantly, the identification of this group of subjects
nosed with diabetes according to the previous criteria. The
also allows for further investigation as to the mechanisms con-
reason for developing more precise criteria for the diagnosis
tributing to postprandial hyperglycemia while normal fasting
of diabetes in children relates to the lack of either retro-
glucose is maintained. If abnormalities in other components
spective or prospective data indicating the “significance of IGT
of glucose homeostasis, i.e., insulin sensitivity, glucose dis-
in children and its relationship to the development of frank
posal, or incretin response, are found to contribute to type 1
disease and diabetic complications” (19).
diabetes, it would suggest heterogeneity in this disease anal-
Recently established American Diabetes Association cri-
ogous to type 2 diabetes, with implications for genetic inves-
teria for the diagnosis of diabetes require having one of the
tigations and development of pharmacological treatments, in
following on two occasions: 1) symptoms of diabetes and
addition to insulin therapy.
plasma glucose ≥11.1 mmol/l, 2) fasting glucose ≥7.0 mmol/l,
or 3) 2-h plasma glucose ≥11.1 mmol/l during an OGTT. Sub-
jects with fasting glucose values of 6.1–6.9 mmol/l would be
DPT-1 is supported through cooperative agreements by the
classified as having impaired fasting glucose and those with
Division of Diabetes, Endocrinology and Metabolic Diseases,
2-h values of 7.8–11 mmol/l as having IGT. It is important to
National Institute of Diabetes and Digestive and Kidney Dis-
note that similar to the data used for the 1978 NDDG criteria
eases, the National Institutes of Health (NIH); the National
(19), these values are based on data from the Pima Indian
Institute of Allergy and Infectious Disease, NIH; the National
Study (20), the National Health and Nutrition Examination
Institute of Child Health and Human Development, NIH; the
Survey III, the Paris Prospective Study (21), and an Egyptian
National Center for Research Resources, NIH; the American
study (22) (all adult populations who are at risk for type 2 dia-
Diabetes Association; the Juvenile Diabetes Foundation
betes). These committees did not consider the significance of
International; and various corporate sponsors.
postprandial hyperglycemia alone in children because there
Additional support was obtained from an American Dia-
was no clear evidence that this population of subjects
betes Association Clinical Research Award and a Research

Associate Career Development Award from the Department
MR, Groop LC: Clinical and genetic characteristics of type 2 diabetes with and
of Veterans Affairs. These investigations also relied on the
without GAD antibodies. Diabetes 48:150–157, 1999
Clinical Research Centers at DPT-1 sites, including the Uni-
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WJ: Autoantibodies to glutamic acid decarboxylase and insulin in islet cell anti-
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