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| Journal of the New Zealand Medical Association,
18-August-2006, Vol 119 No 1240
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Metabolic characteristics of patients with apparently normal
fasting plasma glucose
Geoff Braatvedt, Greg Gamble, Cam Kyle
Type 2 diabetes is a growing epidemic in New Zealand with an
estimated 115,000 patients having diagnosed diabetes in 2000.1 Population
screening studies suggest that half of those with diabetes are undiagnosed2 and
many more have impaired glucose tolerance (IGT) and are thus at risk of
developing diabetes.3
The prevalence of IGT and impaired fasting glucose (IFG) in
New Zealand is, however, unknown. Intervention
studies4–6 have shown that
patients with IGT can reduce their risk of developing diabetes by about 60% by
combining exercise with life style changes, and by about 30% with metformin use;
thus diagnosing patients with IGT is worthwhile.
Furthermore, many patients with IGT have coexisting
metabolic abnormalities that cluster as the metabolic syndrome, which increases
the risk of macrovascular disease and again lends itself to intervention
strategies to alter this risk.
In the late 1990s, the American Diabetes Association (ADA)7
and the WHO8 proposed a new category of glucose tolerance called impaired
fasting glucose (IFG). Values of fasting glucose of ≥7 mmol/L were
classified as consistent with diabetes and values 6.1–6.9 mmol/L as
impaired fasting glucose, with values <6.1 mmol/L classified as normal.
A significant minority of subjects with IFG have either IGT
or diabetes on subsequent oral glucose tolerance test (OGTT). Therefore,
proceeding to OGTT was recommended at that time by both the New Zealand and
Australian Diabetes’ Societies for patients with IFG 9,10 (fasting glucose
6.1–6.9 mmol/L) even though the ADA did not take this approach, relying
only on the fasting glucose for classification of patients.
A previous New Zealand study showed that a significant
number of patients with diabetes on OGTT would be misclassified as non-diabetic
using the ADA fasting criteria alone.11
Recently the ADA12 has suggested a new upper limit of normal
fasting glucose of 5.5 mmol/L thus expanding the IFG category from 6.1–6.9
to 5.6–6.9 mmol/L. This was based on the results of studies from Europe
and the USA showing a significant minority of patients with fasting glucose of
between 5.6–6.0 mmol/L (previously classified normal) as having IGT or
even diabetes.
The Australian Diabetes Society has now recommended an OGTT
in all subjects with IFG classified as 5.5–6.9 mmol/L.13 Recently, the New
Zealand (NZ) Guideline Group (NZGG) has published guidelines for the management
of type 2 diabetes14 in New Zealand. They recommend an OGTT for all patients
with a fasting glucose of 6.1–6.9 mmol/L inclusive (previous IFG
limits)—but for those with a fasting glucose between 5.5–6.0 mmol/L,
only if the patient is not of European origin, has a family history of diabetes,
or has “features of the metabolic syndrome.”
The NZ Guideline Group has stated that “a fasting
glucose below 5.5 mmol/L is normal” (Management of Diabetes Guidelines
Page 2), but has at the same time avoided extending the range of impaired
fasting glucose below 6.1 mmol/L.
Therefore patients with fasting glucose in the 5.5–6.0
mmol/L range currently are officially classed as neither normal nor IFG in New
Zealand. Furthermore, unlike Australia where an oral GTT is recommended in all
such patients, many who do not meet the additional risk criteria stated above,
live in a diagnostic “no man’s land” because an oral GTT is
considered unwarranted.
The prevalence of IGT or diabetes in patients in New Zealand
with a fasting glucose between 5.5–6.0 mmol/L is unknown. Furthermore, the
metabolic characteristics of these patients are not described. This study thus
aims to describe the metabolic features of patients with fasting glucose below
6.1 mmol/L.
MethodsNon-pregnant consecutive patients—referred by
their GP (reasons for referral not recorded) between July 2002 and December 2003
for 75 g OGTT to 8 Diagnostic Medlab collection depots spread across the wider
geographical area of Auckland (Orewa to Manurewa)—were invited to
participate.
Height and weight were measured and BMI was calculated.
Ethnicity was self-declared. A standard 75 g OGTT was then carried out.
Fasting samples for lipids, HbA1c, fructosamine, and insulin in addition to
glucose were taken at baseline. Glucose and insulin concentrations were measured
at 60 and 120 minutes after glucose ingestion. Samples for glucose were
collected in fluoride oxalate tubes and serum for insulin frozen at -20°C
for later analysis in one batch.
Serum lipids, glucose, fructosamine and HbA1c were
analysed on the day of collection in one central laboratory. Insulin was
measured on an Abbott Imx (normal range 5–13 mIU/L CV 5.3%), HbA1c by
cation exchange HPLC (Biorad Variant 2 normal range 4–6% CV 2%) and
fructosamine on a Roche Hitachi Modular system (normal range 180–300
umol/L CV 4%).
Estimates of insulin resistance were made from clinical
measurements (BMI) as well as serum cholesterol/HDL ratio and fasting
triglyceride, fasting insulin (higher values imply insulin resistance),
insulin/glucose ratio (higher values imply insulin resistance), and mathematical
indices using homeostasis model assessment (HOMA-IR – higher values imply
more insulin resistance15), the quantitative sensitivity check index (QUICKI16
-a lower score implies more insulin resistance) and McAuley score (lower values
imply insulin resistance and scores<6.3 MmU-1/L defines insulin
resistance),17 which correlate with hyperinsulinamic euglycaemic clamp
studies.18,19 HOMA was calculated as glucose × insulin/ 22.5 and QUICKI as
1/ log (fasting insulin) + log (fasting glucose).
Diabetes was defined as a fasting glucose ≥7.0
and/or 2 hr OGTT ≥11.1 mmol/L; IGT as fasting glucose <7.0
and 2 hour glucose of 7.8–11.0
mmol/L; IFG in 2 categories as fasting glucose 5.5–6.0 mmol/L (“high
fives”), or 6.1–6.9 mmol/L (“old IFG”)
and 2 hour glucose <7.8 mmol/L .
Normal glucose tolerance was defined as a fasting glucose of <5.5
and 2 hour value <7.8 mmol/L.
The study was approved by the Auckland Regional Ethics
Committee.
Comparisons between groups were made using analysis of
variance (ANOVA, proc GLM, SAS Institute Inc, v9.1 software). Should the main
effect reach statistical significance, the post hoc procedure of Dunnett was
used to compare each group against normal. All tests were two-tailed and
p<0.05 was considered significant.
Results310 patients, not previously known to have diabetes, agreed
to participate (90% of those asked). Table 1 displays
the patients’ details. 244 patients (79%) were European, 41 (13%) Maori,
12 (4%) Pacific, and 13 (4.2%) Asian. 72 patients (23%) were classified as
having diabetes and another 74 patients (24%) as IGT following the OGTT.
The 2-hour GTT result (normal, IGT, or diabetes) is compared
with the fasting glucose result (normal, “high fives”,
“old” IFG, diabetes) in Table 2. Whilst similar numbers of patients
with a fasting glucose of <5.5 mmol/L (normal) and 5.5–6.0 mmol/L
(“high fives”) actually had IGT on OGTT (21%), significantly more
patients with “new” IFG had diabetes (13% vs 2%) p≤0.005.
Seventy-two percent of patients with a fasting glucose of 6.1–6.9 mmol/L
(“old” IFG) had IGT (44%) or diabetes (28%) on OGTT and, as
expected, almost all (97%) with diabetic range fasting glucose (≥7 mmol/L)
did indeed have diabetes based on 2-hour OGTT result.
Measures of insulin resistance are shown in Table 1.
Patients with fasting glucose between 6.1–6.9 mmol/L (“old”
IFG) had many features of insulin resistance when compared with patients with a
glucose <5.5 mmol/L with patients with fasting glucose of 5.5–6.0
mmol/L having intermediate features.
The sensitivity, specificity, and positive and negative
predictive value of diagnosing diabetes using a fasting glucose with the lower
IFG category of 5.5–6.0 compared with current IFG category of
6.1–6.9 mmol/L (as compared to OGTT) is shown in Table 3.
DiscussionThis study demonstrates that in patients referred for OGTT,
a significant minority have either IGT or diabetes when the fasting glucose is
below the current IFG threshold (5.5–6.1 mmol/L). Furthermore, many of
these patients have features of the metabolic syndrome (lower McAuley score and
higher HOMA – IR value then those with glucose <5.5 mmol/L) thus
supporting the rationale to proceed to OGTT in all patients with a fasting
glucose of 5.5–6.9 mmol/L inclusive, and not just for those with a fasting
glucose of 6.1–6.9 mmol/L.
Table
2. Percentage of
patients (n=310) with 2-hour OGTT result classified as normal (<7.8 mmol/L),
impaired glucose tolerance (7.8–11.0 mmol/L) or diabetes (≥11.1
mmol/L)—compared to fasting glucose classification result (normal <5.5
mmol/L, “high fives” 5.5–6.0 mmol/L; “old IFG”
6.1–6.9 mmol/L and diabetes≥7.0 mmol/L)
Table 3. Sensitivity, specificity, and positive (PPV)
and negative (NPV) predictive value (95% CI) for diagnosing diabetes on
subsequent OGTT by fasting glucose alone (mmol/L)
In the UKPDS study, diabetes was
diagnosed on the basis of symptoms in only 54% of patients.20 Of more concern,
more than half of those patients had established microvascular complications of
diabetes at diagnosis suggesting a period of 5 – 8 years of preceding
undiagnosed diabetes. Those with the lowest fasting glucose at diagnosis had the
lowest prevalence of microvascular complications at diagnosis and furthermore
had a lower rate of progression of complications at follow up suggesting that
early diagnosis of diabetes improves
outcome.
Detecting patients early, during the IGT (or
‘pre-diabetes’) stage, is also worthwhile. Intervention studies
confirm that the progression of patients with IGT to diabetes can be slowed
significantly by combination of diet, exercise, and metformin use.4–6
Those patients with IGT who had the lowest fasting glucose result had the
greatest success in preventing diabetes in these programmes. These data suggest
that there is a continuum of fasting glucose results wherein patients progress
from normal towards diabetes during which time intervention can delay or prevent
the progression to diabetes or the development of microvascular complications.
Detecting these patients at an early stage relies on the
development of simple screening algorithms that have high sensitivity and
specificity primarily for the detection of diabetes, but which will (as a
consequence) also detect those who are also clearly at risk with
‘pre-diabetes’.
The recent Australian AusDiab study13 used a protocol of
performing a fasting glucose test in patients with one or more risk factors for
diabetes (age >55 years, or >45 years if obese or hypertensive or a family
history of diabetes, non European, established cardiovascular disease, women
with previous gestational diabetes or polycystic ovarian syndrome), then
proceeding to OGTT if the fasting glucose result was between 5.5–6.9
mmol/L. This study had 80% sensitivity and specificity for the detection of
previously undiagnosed type 2 diabetes13 but also detected many patients with
pre-diabetes as well who may potentially benefit from lifestyle change.
Sensitivity for diabetes detection improved from 64% to 80%
by lowering the cutoff from 6.1 to 5.5 mmol/L as the threshold for proceeding to
OGTT , although there was a reduction in specificity from 94% to 80%. The pickup
rate for IGT/IFG also increased from 35% to 52%.13
The current reported study demonstrates that patients with
apparently normal fasting glucose (5.5–6.0 mmol/L) have significantly
higher rates of dysglycaemia compared with those patients with a fasting glucose
of <5.5 mmol/L and that these patients tended to have more features of
insulin resistance (Table 1).
It is acknowledged that the subjects of the current study
were not randomly chosen for OGTT and the pre-test probability of diabetes in
this group was presumably reasonably high for their doctor to have requested the
test in the first place. Nevertheless, this study does provide evidence that
relying on a fasting glucose alone will misclassify a significant number of
patients with dysglycaemia on OGTT as ‘normal’, based on current
fasting thresholds.
Taken together, these data suggest that the upper limit of
normal fasting glucose in New Zealand should be considered to be <5.5 mmol/L
in line with recent Australian recommendations.12 Screening for diabetes should
continue to use the fasting glucose as the first step but all patients with a
fasting glucose of 5.5–6.9 mmol/L should proceed to OGTT testing, also in
line with Australian Diabetes Society guidelines.13
Author information:
Geoff Braatvedt, Associate Professor of Medicine, Department of Medicine,
University of Auckland / Auckland City Hospital; Greg Gamble, Statistician,
Department of Medicine, University of Auckland; Cam Kyle, Biochemist, Diagnostic
Medlab; Auckland
Acknowledgement:
This study was supported by the ELI LILLY GRANT 2003 administered through New
Zealand Society for the Study of Diabetes. Additional support from Roche
diagnostics and Diagnostic Medlab is gratefully acknowledged.
Correspondence:
Associate Professor Geoff Braatvedt, Dept of Medicine, University of Auckland,
Level 12, Auckland Hospital Support Building, Auckland City Hospital, Park Road,
Auckland. Email: g.braatvedt@auckland.ac.nz
References:
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