Journal of the New Zealand Medical Association, 18-August-2006, Vol 119 No 1240
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.
Non-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.
310 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.
This 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: email@example.com
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