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The oral glucose tolerance test (OGTT) revisited
European Journal of Internal Medicine 22 (2011) 8–12
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European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Review article
The oral glucose tolerance test (OGTT) revisited E. Bartoli, G.P. Fra ⁎, G.P. Carnevale Schianca Clinica Medica, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi del Piemonte Orientale “Amedeo Avogadro”, Via Solaroli 17, 28100 Novara, Italy
a r t i c l e
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Article history: Received 22 March 2010 Received in revised form 6 July 2010 Accepted 12 July 2010 Available online 17 August 2010 Keywords: OGTT Glycosylated haemoglobin Diabetes Insulin β-cell function
a b s t r a c t The oral glucose tolerance test (OGTT) has been the mainstay for diagnosing diabetes for decades. Recently, the American Diabetes Association (ADA) suggested abandoning the OGTT, while resorting to a simpler screening test, exclusively based on baseline fasting blood glucose concentration. This review article rewinds the history of OGTT and its recent advancements, and compares its power in detecting early diabetes with that of fasting blood glucose alone. The key point is that there are more diabetics originating from a population with normal fasting blood glucose than from subjects with impaired fasting glucose, those who can be detected by the new ADA recommendations. Conversely, the OGTT detects more efficiently early diabetes as well as subjects with IGT, as the glycemia at the second hour seems crucial as a diagnostic tool. We discuss the different significance of fasting versus second hour glycemia during OGTT, according to different mechanisms of glucose homeostasis. Finally, we provide recent evidence on very simple additional information that can be obtained from the OGTT, which renders this test even more useful, discussing pathophysiologic significance. © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Globally, the prevalence of type 2 diabetes is increasing at an alarming rate. The number of people with type 2 diabetes worldwide is projected to increase from 171 million in 2000 to 366 million by the year 2030 [1]. This increase, closely linked to the upsurge of obesity [2], represents a global health care problem for the related micro- and macro-vascular complications. In this perspective view, recognizing high-risk subjects is mandatory, as recent trials suggested that primary prevention by lifestyle modifications [3,4] and drug administration [4,5] could be an effective strategy to restrain the epidemic increase in disease prevalence. Thus, the question arises on how to recognize normal subjects who are at risk for type 2 diabetes in their future. This review shall focus on the traditional diagnostic tool for diabetes, hurriedly considered obsolete and unsuitable, which deserves revisiting with proper improvements and more modern interpretations.
2. The history of OGTT Plasma glucose concentration, measured either after an overnight fast (FPG) or after glucose loading, has been the mainstay to diagnose diabetes for a century. It has been debated, however which cut-off values should be considered diagnostic. These numbers have been ⁎ Corresponding author. Tel.: +39 0321 3733361; fax: +39 0321 3733600. E-mail address: [email protected] (G.P. Fra).
changed several times, but it is apparent that fasting hyperglycemia is too late a criterion for the early diagnosis of type 2 diabetes. The history of OGTT is instructive in this regard. The recognition that many subjects had obvious diabetes when their glucose was measured after a test meal led to the development, by the 1960s, of at least six different recommendations for standardized oral glucose loads, ranging from 50 to 100 g, based on body size, or independent from this [6,7]. Analyses based on bimodal plasma glucose distribution, first observed among Pima Indians [8], were subsequently used by the National Diabetes Data Group in 1979 [9] and the American Diabetes Association (ADA) Expert Committee in 1997 [10] to establish the fasting and 2 h post-glucose load criteria for diabetes. These reports spread a worldwide recognition of the diagnostic values, and, while helping in the early identification of diabetes, made the experts of the field aware of the limits and implications of their enforcement. In fact: 1) The procedure to execute the OGTT was standardized by establishing a glucose load of 75 g p.o. 2) By FPG and 2 hours post-glucose load glycemia (2hPG), two intermediate stages of glucose intolerance, possible intermediate steps between normal glucose tolerance (NGT) and diabetes, were recognized: a) the impaired glucose tolerance (IGT), defined by a 2hPG of 140–199 mg/dl in 1979 and: b) the impaired fasting glycemia (IFG) defined by an FPG between 110 and 125 mg/dl in 1997. 3) In 1997 the ADA amended the previous criteria to diagnose diabetes, lowering the FPG cut-off value from 140 to 126 mg/dl.
0953-6205/$ – see front matter © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2010.07.008
E. Bartoli et al. / European Journal of Internal Medicine 22 (2011) 8–12
4) This revisited value of FPG, based on epidemiologic data [11], made clear that ADA hoped to render the OGTT unnecessary. Thus, the test just developed and standardized was about to become obsolete. It is interesting to analyze the reasoning of the ADA about the OGTT. The rationale was that by lowering the FPG levels (126 mg/dl for diabetes and 110 for IFG), the ADA was expecting to include most subjects whose OGTT would have been conclusive for diabetes or IGT, thus making the OGTT unnecessary. The hope was that by eliminating the OGTT, which the ADA considered time consuming, poorly reproducible and not well accepted by patients, would lead a greater number of individuals to be screened, diagnosed and treated. Unfortunately, more thorough epidemiologic data [12] demonstrated that the FPG cut-off values for diabetes and/or IFG were far from being equivalent to their corresponding 2hPG values. In particular, IFG was not at all equivalent to IGT. We supplied evidence pointing to the diversity of these pre-diabetic stages: we found that an impairment in insulin secretion is more relevant in IFG, while a faltering insulin sensitivity is peculiar of IGT [13]. Furthermore, in addition to the evidence that FPG cannot be equated to 2hPG, it has been demonstrated that the 2hPG predicts the risk of heart disease more effectively than FPG [12,14]. To further improve the diagnostic power of FPG alone, in 2003 the ADA lowered the cut-off value of FPG from 110 to 100 mg/dl, thus recognizing the IFG stage within the range of 100 to125 mg/dl [15]. This newly amended criterion will allow the recruitment of more pre-diabetic subjects, while most of these will never become affected by type 2 diabetes. At variance with one single study involving three ethnic groups in the United Kingdom [16], that reported a better prediction for diabetes from FPG with respect to 2hPG, several epidemiologic studies demonstrated, instead, that diabetes prevalence by using FPG underestimated that obtained from 2hPG [12,17]. Although substituting FPG for 2hPG seems convenient both on an epidemiologic and clinical ground, it does not supply any metabolically relevant information. In fact, tight glucose homeostasis is ensured by a prompt and efficient biochemical and hormonal regulatory system, such that a number of studies [18,19] evidenced that alterations in insulin secretion and sensitivity are already present when FPG is still within the “normal” range (b100 mg/dl). If we accepted the ADA rationale, the necessary conclusion drawn from these data would be to lower even further the FPG cut-off value. However, this would be to no avail, as the majority of diabetics still originate from patients within the NGT range. The point is that it is misleading to try to assess glucose homeostasis without information on post-prandial glucose metabolism. Actually, the majority of subjects with FPG N 100 mg/dl display normal or non-diabetic 2hPG and, even more important, a consistent proportion of subjects with IGT display an FPG b 100 mg/dl [20,21]. To compare the relative importance of FPG vs 2hPG in detecting diabetes, we studied different FPG cut-off values in ruling out glucose intolerance separately identified by OGTT [22]. Out of 202 subjects with FPG ≥ 100 mg/dl, 121 (60%) had 2hPG b 140 mg/dl; conversely, out of 452 subjects with FPG b 100 mg/dl, 61 (14%) had a 2hPG ≥ 140 mg/dl. Choosing arbitrarily an FPG cut-off of 90 mg/dl, 33 out of 266 subjects (12%) still had abnormal 2hPG. These data clearly prove that any reduction of FPG threshold produces a progressive increase in sensitivity coupled to a progressive decline in specificity to detect high-risk subjects for type 2 diabetes. Only the simultaneous information obtained from 2hPG (i.e. OGTT) allows the screening to become effective. 3. Advantages of OGTT In synthesis, in our opinion, the OGTT offers several advantages: 1) It allows establishing whether a subject has an NGT or unknown type 2 diabetes.
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2) It discloses whether a subject has IGT, an essential diagnostic step, especially when FPG is within the normal range, as these subjects are at high risk not only for type 2 diabetes, but in particular for cardiovascular disease [12,14]. Thus, using solely FPG to rule out abnormal glucose tolerance, would deceitfully reassure a large proportion of individuals as having NGT, without warning them on the benefits of preventive treatments. 3) It establishes whether an IFG subject has normal 2hPG. This is essential, as we demonstrated above that the majority of IFG subjects are probably endowed with a better preserved glucose homeostasis with respect to those IFG subjects who, having an abnormal 2hPG, belong to a different subgroup named IFG/IGT, faring a worse prognosis. These latter subjects have more pronounced alterations in insulin secretion and sensitivity [13,19] and they should gain more benefit from preventive strategies. The critical issue on OGTT is represented by its reproducibility [10,15]. This represents a necessary consequence of the physiologic context of OGTT. In essence, plasma glucose levels during OGTT are determined by both insulin sensitivity and secretion. However the influence of other factors is also important, among which are the enteric hormones and neural responses to nutrient ingestion, as well as gastrointestinal motility and gastric emptying. All these factors vary widely among individuals [23], influence post-load glucose metabolism and plasma concentration, and are too many to be individually and simultaneously measured. However, as OGTT was definitely standardized by considering only FPG and 2hPG [10,15], the variability of OGTT has been reduced by this simplification, since it has been demonstrated that the intermediate glycemic OGTT values suffer from a coefficient of variation larger than that affecting FPG and 2hPG [24]. Finally, all trials aimed at type 2 diabetes prevention included IGT subjects [3–5], who could not be possibly recognized without OGTT. It seems therefore evident that the routine execution of OGTT is presently the one and only possible answer. Finally, the data on the regression from pre-diabetes (IGT, IFG or both) to NGT following the Diabetes Prevention Program were recently published [25]: they strengthen our contention that only OGTT can permit testing the effective clinical weight of preventive strategies. 4. The role of glycosylated haemoglobin (A1C) In its relentless attempt to dissuade from OGTT, at the beginning of the current year, the ADA suggested to resort to A1C to diagnose diabetes [26]. An A1C ≥ 6.5% should be diagnostic of diabetes, while a subject with an A1C between 5.7 and 6.4% should be considered as at high risk for developing diabetes in the future [26]. We believe, analyzing a series of epidemiological studies [27–31], that using A1C in screening diabetes cannot substitute for the information derived from OGTT. Although A1C represents a screening test less demanding than OGTT, as it is not influenced by fasting, drinking a glucose solution, or waiting hours for blood drawing, its usefulness is limited by important considerations. First of all, the contribution of both fasting and post-prandial plasma glucose to A1C levels [32], does not lend support to the recent contention that A1C is superior to FPG in predicting diabetes [27]: in that study, the diagnosis of diabetes was self-reported, and the fasting glucose measurements during follow-up were limited. The major impact of this report is the confirmation that very high A1C values are equivalent to overt diabetes in compounding the cardiovascular risk. Also the NHANES study [28] reported that A1C ≥ 6.5% demonstrates reasonable agreement with FPG for diagnosing diabetes. Unfortunately, contrary to that report, the New Hoorn Study [29] demonstrated strong correlations between plasma glucose values and A1C in subjects with known diabetes, but not in the general population. Moreover, in
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the Rancho Bernardo Study [30], 85% of participants with A1C ≥ 6.5% were not classified as diabetics by ADA criteria and one-third of the participants with diabetes by ADA criteria would be classified as normoglycemic by A1C. Thus, this study demonstrated that 30% of subjects who are already diabetic or pre-diabetic would have been missed if A1C had been used instead of OGTT. In conclusion, the data confirmed, in agreement with an Australian study [31], that an A1C ≤5.5 or ≥7% can predict the absence or presence of diabetes respectively, while intermediate values are inconclusive. Both FPG and post-prandial glucose contribute to A1C levels, although the contribution of FPG is prominent at higher A1C levels [32]. In this contest, the simple and easy FPG, available readily worldwide, would be more sensitive and specific than A1C to diagnose diabetes. Conversely, borderline A1C values just above the upper limits of normal, depend upon post-prandial glycemias (i.e. 2hPG), still requiring the OGTT to be correctly interpreted. These unclear correlations between plasma glucose and A1C indicate that they reflect a different process, especially in the non-diabetic range of glucose tolerance. Finally, the fact that the ADA recommends using A1C while emphasising the importance of IFG and IGT, which cannot be diagnosed without OGTT, to disclose high-risk subjects for diabetes, clearly shows that A1C would be of little value without OGTT and that pre-diabetes includes different entities [12–14,33]. Only the practice of OGTT can disclose unknown diabetes when FPG b 126 mg/dl, and screen efficiently within the range of the rather heterogeneous pre-diabetic values. 5. Revival of the OGTT Given its importance and strengthened by the above discussion, revisiting the OGTT requires substantial improvements to make it more effective by endowing it with an additional power of information. This necessary improvement is based on considerations stemming from available evidence. Only preventive strategies can reduce the incidence of type 2 diabetes together with the expected, related excess in cardiovascular morbidity and mortality [1]. It is obvious that the greater is the accuracy in selecting high-risk subjects, the better is the preventive effectiveness. However, not all subjects with IGT, IFG, or both go on to develop diabetes [34]: in fact only 30–40% of IGT subjects will eventually convert to type 2 diabetes [35]. Furthermore, in longitudinal epidemiological studies, ~40% of subjects who develop type 2 diabetes exhibit NGT at baseline blood glucose testing, indicating that there is a large number of NGT subjects who constitute the larger reservoir of future type 2 diabetes [34]. Thus, the present format and data analysis of OGTT, like methods using non-OGTT data [36,37], do not recognize most of high-risk subjects for type 2 diabetes. The fact is that diabetes risk screening, independent from the method used, is still hampered by a large number of false-positive data. Therefore, a larger number of subjects need to be treated with preventive interventions. Thus, new prediction models should be aimed at optimizing the sensitivity and specificity rather than replacing existing models. Unfortunately, relying solely on IGT detection to recognize “future” diabetics, would miss a large fraction of high-risk individuals not affected by IGT, who could still benefit from preventive interventions. Recently it has been proposed that the 1-h plasma glucose concentration during OGTT (≥ 155 mg/dl) has better predictive power to disclose future diabetics than either FPG or 2hPG [38]. This was known even before, when the whole OGTT profile was used with hourly measurements, and it would be a true surprise if the glycemia measured after 1 h of oral glucose loading was meaningless. It was abandoned because of its larger variability with respect to the 2nd hour glycemia, and this source of error was not disclaimed by the report [38], such that we are still more confident on the more reproducible 2nd hour value. However, as our paper purports to
enforce the validity of OGTT, this is further strengthened by the additional information supplied by a 1st hour measurement, which still pertains to the OGTT as a whole. It ushers the critical question: is it possible to modify the present format of OGTT in order to obtain further information to identify high-risk subjects? Probably a dynamic interpretation of FPG and 2hPG could offer surprising and unexpected considerations. As an example, let us consider the case of a patient whose OGTT yielded FPG = 85 and 2hPG = 102 mg/dl, and let us compare him with another subject whose OGTT gave FPG = 73 and 2hPG = 128 mg/dl. Both subjects are, by definition, NGT. Are they truly similar? To understand the important difference between these two patients, we should address pertinent pathophysiologic correlates. FPG and 2hPG do closely correlate with β-cell function, the principal factor responsible for the development of type 2 diabetes [19]. Consequently, changes in β-cell function will influence not only FPG and 2hPG, but also the shape of plasma glucose concentration profile during OGTT. An important component of this profile is the time required for the plasma glucose concentration to return to the fasting level [39]. Recently, in a prospective study derived from the San Antonio Heart Study, it has been reported that NGT subjects whose post-load plasma glucose concentration returned quickly to baseline, had a lower risk of developing type 2 diabetes after a follow-up of 8 years, when compared to subjects with a slower fall to baseline [40]. This behaviour suggests that the faster the post-load glucose drops towards FPG, or the lower the rise in post-load glucose, the more efficient is β-cell function. We recently tested the possibility that OGTT could identify NGT subjects with more subtle and specific metabolic phenotypes, endowed with direct and specific implications on glucose homeostasis [41]. We did this by computing the percentage increment of 2hPG with respect to FPG (PG%), using the formula [(2hPG − FPG) / FPG] × 100. Adding to glycemic measurements the simultaneous determinations of plasma insulin to estimate β-cell function [23], we demonstrated that NGT subjects with 2hPG near or below FPG value, i.e. lower PG%, are more sensitive to insulin: these do not need, then, an enhanced insulin secretion. Conversely, increased secretion seems instead necessary for NGT subjects with 2hPG higher than FPG value, i.e. higher PG% (though still within the normal range), where there is a fall in insulin sensitivity (a rise in insulin resistance). Since glucose tolerance deteriorates when the fall in insulin sensitivity is not compensated by a sufficient increase in secretion, NGT subjects with higher PG% could herald a risk of worsening glucose tolerance more important than those NGT subjects whose PG% is lower. These data are in agreement with the finding that subjects with a 2hPG within 120–140 mg/dl do exhibit an approximate 40–50% relative fall in β-cell function compared with subjects with 2hPG b 100 mg/dl: yet, both groups are considered to have NGT [19]. Recently, in a retrospective analysis of the San Antonio Heart Study and the Botnia Study, in which the incidence of type 2 diabetes in NGT subjects was examined, the 1-h plasma glucose concentration was reported to be more predictive than the 2hPG [42]. In fact, stratifying NGT subjects based on their 1-h plasma glucose concentration, the group with a 1-h plasma glucose N 155 mg/dl had a 13.1-fold increased odds ratio for type 2 diabetes with respect to the group with a 1-NGTh plasma glucose b 125 mg/dl. Computing, according to our formula, the PG%, the first group, with mean FPG and 2hPG values of 83 ± 6 and 109 ± 21 mg/dl respectively, shows a PG% of 31.3%, while the second group, with mean FPG and 2hPG values of 81 ± 1 and 87 ± 11 mg/dl respectively, reaches a PG% of 7.4%, in full agreement with our contention. Thus, the simple use of the PG%, as an adjunctive dynamic interpretation of FPG and 2hPG, can expand the clinical use of the OGTT from a tool to investigate glucose tolerance to a more powerful and informative method capable of disclosing the efficiency of β-cell
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function: a high, although still “normal”, PG% probably pinpoints a higher risk of worsening glucose homeostasis. This very simple calculation could also replace the more expensive and demanding 1st hour sampling for glucose measurement. We have now the instrument to detect the pathophysiologic difference between the two NGT subjects of the above example: the first patient has a PG% = 20%, the second one = 75%. Very likely, this latter subject has a deterioration of β-cell function bearing consequences in the future which could be amenable to preventive treatments. Beside the calculation of PG%, the OGTT could offer further metabolic information on glucose homeostasis. The simultaneous measurements of glucose and insulin during standard OGTT represent the favourable opportunity to establish, in a single test, not only the stage of glucose tolerance, but also β-cell function [23]. This seems particularly promising as, in the near future, a low insulin sensitivity (i.e. high insulin resistance) and/or an alteration in its secretion could become targets of specific treatments even within the NGT range. Also the simple plasma glucose/plasma insulin ratios demonstrate β-cell dysfunction when the PG% is higher. Fig. 1 and Table 1 show glucose and insulin values during fasting, and then 1 and 2 h during OGTT in 136 NGT subjects. When compared to 72 NGT subjects whose PG% was ≤20%, NGT subjects with PG% N 20% have a significantly lower FPG, whereas 2hPG, fasting insulin and 2 h-insulin are significantly higher. On the contrary, the 1st hour insulin and glucose values are not significantly different considering the two NGT groups (b and NPG 20%): this further underlines the lack of information of 1st hour intermediate glucose and insulin values as opposed to the baseline and final measurements. When considering the glycemia/ insulin ratios during fasting and at 2 h post-glucose load, it is readily apparent that the lower ratios of NGT subject with higher PG% disclose
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Table 1 Glycemic and insulinemic values (M± S.D.) during OGTT in NGT subjects with PG% ≤ 20% or with PG% N 20%.
FPG mg/dl 1hPG mg/dl 2hPG mg/dl Fasting insulin μU/ml 1hInsulin μU/ml 2hInsulin μU/ml Fasting glucose/insulin 2 h glucose/insulin
PG% ≤ 20% n = 72
PG% N 20% n = 64
“t” Student p
94.4 ± 5.7 146.1 ± 34.5 89.6 ± 20.1 9.4 ± 3.7 102.1 ± 46.8 43.7 ± 30.3 11.6 ± 5.1 3.4 ± 2.5
90.8 ± 3.7 145.8 ± 18.8 127.6 ± 7.3 11.1 ± 5.1 119.1 ± 62.3 81.8 ± 41.2 9.8 ± 4.6 2.1 ± 1.6
b0.0001 n.s. b0.0001 b0.03 n.s. b0.0001 b 0.04 b0.001
For the meaning of symbols see Fig. 1.
the important impairment of their β-cell function, which could herald the occurrence of a late phase of type 2 diabetes. Prospective studies designed to test the clinical weight of PG% are necessary. Independent from the results of future observations, OGTT, even though underrated and considered aged and costly, lengthy, poorly reproducible and informative, seems, on the contrary, rejuvenated, surprising and fascinating when implemented with a simple, grammar school calculation, even more informative when coupled to insulin measurements. 6. Learning points • Approximately 40% of subjects who will develop type 2 diabetes are within the NGT range at OGTT, indicating that there is a large number of NGT subjects who constitute the larger reservoir of future type 2 diabetes. • OGTT detects diabetes more efficiently than FPG as it recognizes altered post-prandial metabolism. • OGTT establishes whether an IFG subject has normal 2hPG. This is essential, as the majority of IFG subjects display a preserved glucose homeostasis with respect to those IFG subjects with abnormal 2hPG. • FPG does not supply any metabolically relevant information, to the point that it is misleading to try to assess glucose homeostasis without information on post-prandial glucose metabolism. • IGT subjects, who are always included in trials concerning type 2 diabetes prevention, cannot be recognized without OGTT. • Using A1C in diabetes screening does not substitute for the information derived from OGTT, because they are not equivalent tests. • OGTT lends itself to simple calculations, like the % change of 2 h with respect baseline glycemia, capable of detecting additional subjects at risk for type 2 diabetes. References
Fig. 1. Legend: Glycemic (over panel) and insulinemic (inferior panel) values during OGTT in NGT subjects with PG% ≤ 20% (continuous line) and PG N 20% (hatched line). FPG = fasting plasma glucose, 1hPG = 1 hour post-glucose load glycemia, 2hPG = 2 hours post-glucose load glycemia, FPIns = fasting plasma insulin, 1hPIns = 1 hour post-glucose load insulin, 2hPIns = 2 hours post-glucose load insulin.
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European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Review article
The oral glucose tolerance test (OGTT) revisited E. Bartoli, G.P. Fra ⁎, G.P. Carnevale Schianca Clinica Medica, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi del Piemonte Orientale “Amedeo Avogadro”, Via Solaroli 17, 28100 Novara, Italy
a r t i c l e
i n f o
Article history: Received 22 March 2010 Received in revised form 6 July 2010 Accepted 12 July 2010 Available online 17 August 2010 Keywords: OGTT Glycosylated haemoglobin Diabetes Insulin β-cell function
a b s t r a c t The oral glucose tolerance test (OGTT) has been the mainstay for diagnosing diabetes for decades. Recently, the American Diabetes Association (ADA) suggested abandoning the OGTT, while resorting to a simpler screening test, exclusively based on baseline fasting blood glucose concentration. This review article rewinds the history of OGTT and its recent advancements, and compares its power in detecting early diabetes with that of fasting blood glucose alone. The key point is that there are more diabetics originating from a population with normal fasting blood glucose than from subjects with impaired fasting glucose, those who can be detected by the new ADA recommendations. Conversely, the OGTT detects more efficiently early diabetes as well as subjects with IGT, as the glycemia at the second hour seems crucial as a diagnostic tool. We discuss the different significance of fasting versus second hour glycemia during OGTT, according to different mechanisms of glucose homeostasis. Finally, we provide recent evidence on very simple additional information that can be obtained from the OGTT, which renders this test even more useful, discussing pathophysiologic significance. © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Globally, the prevalence of type 2 diabetes is increasing at an alarming rate. The number of people with type 2 diabetes worldwide is projected to increase from 171 million in 2000 to 366 million by the year 2030 [1]. This increase, closely linked to the upsurge of obesity [2], represents a global health care problem for the related micro- and macro-vascular complications. In this perspective view, recognizing high-risk subjects is mandatory, as recent trials suggested that primary prevention by lifestyle modifications [3,4] and drug administration [4,5] could be an effective strategy to restrain the epidemic increase in disease prevalence. Thus, the question arises on how to recognize normal subjects who are at risk for type 2 diabetes in their future. This review shall focus on the traditional diagnostic tool for diabetes, hurriedly considered obsolete and unsuitable, which deserves revisiting with proper improvements and more modern interpretations.
2. The history of OGTT Plasma glucose concentration, measured either after an overnight fast (FPG) or after glucose loading, has been the mainstay to diagnose diabetes for a century. It has been debated, however which cut-off values should be considered diagnostic. These numbers have been ⁎ Corresponding author. Tel.: +39 0321 3733361; fax: +39 0321 3733600. E-mail address: [email protected] (G.P. Fra).
changed several times, but it is apparent that fasting hyperglycemia is too late a criterion for the early diagnosis of type 2 diabetes. The history of OGTT is instructive in this regard. The recognition that many subjects had obvious diabetes when their glucose was measured after a test meal led to the development, by the 1960s, of at least six different recommendations for standardized oral glucose loads, ranging from 50 to 100 g, based on body size, or independent from this [6,7]. Analyses based on bimodal plasma glucose distribution, first observed among Pima Indians [8], were subsequently used by the National Diabetes Data Group in 1979 [9] and the American Diabetes Association (ADA) Expert Committee in 1997 [10] to establish the fasting and 2 h post-glucose load criteria for diabetes. These reports spread a worldwide recognition of the diagnostic values, and, while helping in the early identification of diabetes, made the experts of the field aware of the limits and implications of their enforcement. In fact: 1) The procedure to execute the OGTT was standardized by establishing a glucose load of 75 g p.o. 2) By FPG and 2 hours post-glucose load glycemia (2hPG), two intermediate stages of glucose intolerance, possible intermediate steps between normal glucose tolerance (NGT) and diabetes, were recognized: a) the impaired glucose tolerance (IGT), defined by a 2hPG of 140–199 mg/dl in 1979 and: b) the impaired fasting glycemia (IFG) defined by an FPG between 110 and 125 mg/dl in 1997. 3) In 1997 the ADA amended the previous criteria to diagnose diabetes, lowering the FPG cut-off value from 140 to 126 mg/dl.
0953-6205/$ – see front matter © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2010.07.008
E. Bartoli et al. / European Journal of Internal Medicine 22 (2011) 8–12
4) This revisited value of FPG, based on epidemiologic data [11], made clear that ADA hoped to render the OGTT unnecessary. Thus, the test just developed and standardized was about to become obsolete. It is interesting to analyze the reasoning of the ADA about the OGTT. The rationale was that by lowering the FPG levels (126 mg/dl for diabetes and 110 for IFG), the ADA was expecting to include most subjects whose OGTT would have been conclusive for diabetes or IGT, thus making the OGTT unnecessary. The hope was that by eliminating the OGTT, which the ADA considered time consuming, poorly reproducible and not well accepted by patients, would lead a greater number of individuals to be screened, diagnosed and treated. Unfortunately, more thorough epidemiologic data [12] demonstrated that the FPG cut-off values for diabetes and/or IFG were far from being equivalent to their corresponding 2hPG values. In particular, IFG was not at all equivalent to IGT. We supplied evidence pointing to the diversity of these pre-diabetic stages: we found that an impairment in insulin secretion is more relevant in IFG, while a faltering insulin sensitivity is peculiar of IGT [13]. Furthermore, in addition to the evidence that FPG cannot be equated to 2hPG, it has been demonstrated that the 2hPG predicts the risk of heart disease more effectively than FPG [12,14]. To further improve the diagnostic power of FPG alone, in 2003 the ADA lowered the cut-off value of FPG from 110 to 100 mg/dl, thus recognizing the IFG stage within the range of 100 to125 mg/dl [15]. This newly amended criterion will allow the recruitment of more pre-diabetic subjects, while most of these will never become affected by type 2 diabetes. At variance with one single study involving three ethnic groups in the United Kingdom [16], that reported a better prediction for diabetes from FPG with respect to 2hPG, several epidemiologic studies demonstrated, instead, that diabetes prevalence by using FPG underestimated that obtained from 2hPG [12,17]. Although substituting FPG for 2hPG seems convenient both on an epidemiologic and clinical ground, it does not supply any metabolically relevant information. In fact, tight glucose homeostasis is ensured by a prompt and efficient biochemical and hormonal regulatory system, such that a number of studies [18,19] evidenced that alterations in insulin secretion and sensitivity are already present when FPG is still within the “normal” range (b100 mg/dl). If we accepted the ADA rationale, the necessary conclusion drawn from these data would be to lower even further the FPG cut-off value. However, this would be to no avail, as the majority of diabetics still originate from patients within the NGT range. The point is that it is misleading to try to assess glucose homeostasis without information on post-prandial glucose metabolism. Actually, the majority of subjects with FPG N 100 mg/dl display normal or non-diabetic 2hPG and, even more important, a consistent proportion of subjects with IGT display an FPG b 100 mg/dl [20,21]. To compare the relative importance of FPG vs 2hPG in detecting diabetes, we studied different FPG cut-off values in ruling out glucose intolerance separately identified by OGTT [22]. Out of 202 subjects with FPG ≥ 100 mg/dl, 121 (60%) had 2hPG b 140 mg/dl; conversely, out of 452 subjects with FPG b 100 mg/dl, 61 (14%) had a 2hPG ≥ 140 mg/dl. Choosing arbitrarily an FPG cut-off of 90 mg/dl, 33 out of 266 subjects (12%) still had abnormal 2hPG. These data clearly prove that any reduction of FPG threshold produces a progressive increase in sensitivity coupled to a progressive decline in specificity to detect high-risk subjects for type 2 diabetes. Only the simultaneous information obtained from 2hPG (i.e. OGTT) allows the screening to become effective. 3. Advantages of OGTT In synthesis, in our opinion, the OGTT offers several advantages: 1) It allows establishing whether a subject has an NGT or unknown type 2 diabetes.
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2) It discloses whether a subject has IGT, an essential diagnostic step, especially when FPG is within the normal range, as these subjects are at high risk not only for type 2 diabetes, but in particular for cardiovascular disease [12,14]. Thus, using solely FPG to rule out abnormal glucose tolerance, would deceitfully reassure a large proportion of individuals as having NGT, without warning them on the benefits of preventive treatments. 3) It establishes whether an IFG subject has normal 2hPG. This is essential, as we demonstrated above that the majority of IFG subjects are probably endowed with a better preserved glucose homeostasis with respect to those IFG subjects who, having an abnormal 2hPG, belong to a different subgroup named IFG/IGT, faring a worse prognosis. These latter subjects have more pronounced alterations in insulin secretion and sensitivity [13,19] and they should gain more benefit from preventive strategies. The critical issue on OGTT is represented by its reproducibility [10,15]. This represents a necessary consequence of the physiologic context of OGTT. In essence, plasma glucose levels during OGTT are determined by both insulin sensitivity and secretion. However the influence of other factors is also important, among which are the enteric hormones and neural responses to nutrient ingestion, as well as gastrointestinal motility and gastric emptying. All these factors vary widely among individuals [23], influence post-load glucose metabolism and plasma concentration, and are too many to be individually and simultaneously measured. However, as OGTT was definitely standardized by considering only FPG and 2hPG [10,15], the variability of OGTT has been reduced by this simplification, since it has been demonstrated that the intermediate glycemic OGTT values suffer from a coefficient of variation larger than that affecting FPG and 2hPG [24]. Finally, all trials aimed at type 2 diabetes prevention included IGT subjects [3–5], who could not be possibly recognized without OGTT. It seems therefore evident that the routine execution of OGTT is presently the one and only possible answer. Finally, the data on the regression from pre-diabetes (IGT, IFG or both) to NGT following the Diabetes Prevention Program were recently published [25]: they strengthen our contention that only OGTT can permit testing the effective clinical weight of preventive strategies. 4. The role of glycosylated haemoglobin (A1C) In its relentless attempt to dissuade from OGTT, at the beginning of the current year, the ADA suggested to resort to A1C to diagnose diabetes [26]. An A1C ≥ 6.5% should be diagnostic of diabetes, while a subject with an A1C between 5.7 and 6.4% should be considered as at high risk for developing diabetes in the future [26]. We believe, analyzing a series of epidemiological studies [27–31], that using A1C in screening diabetes cannot substitute for the information derived from OGTT. Although A1C represents a screening test less demanding than OGTT, as it is not influenced by fasting, drinking a glucose solution, or waiting hours for blood drawing, its usefulness is limited by important considerations. First of all, the contribution of both fasting and post-prandial plasma glucose to A1C levels [32], does not lend support to the recent contention that A1C is superior to FPG in predicting diabetes [27]: in that study, the diagnosis of diabetes was self-reported, and the fasting glucose measurements during follow-up were limited. The major impact of this report is the confirmation that very high A1C values are equivalent to overt diabetes in compounding the cardiovascular risk. Also the NHANES study [28] reported that A1C ≥ 6.5% demonstrates reasonable agreement with FPG for diagnosing diabetes. Unfortunately, contrary to that report, the New Hoorn Study [29] demonstrated strong correlations between plasma glucose values and A1C in subjects with known diabetes, but not in the general population. Moreover, in
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the Rancho Bernardo Study [30], 85% of participants with A1C ≥ 6.5% were not classified as diabetics by ADA criteria and one-third of the participants with diabetes by ADA criteria would be classified as normoglycemic by A1C. Thus, this study demonstrated that 30% of subjects who are already diabetic or pre-diabetic would have been missed if A1C had been used instead of OGTT. In conclusion, the data confirmed, in agreement with an Australian study [31], that an A1C ≤5.5 or ≥7% can predict the absence or presence of diabetes respectively, while intermediate values are inconclusive. Both FPG and post-prandial glucose contribute to A1C levels, although the contribution of FPG is prominent at higher A1C levels [32]. In this contest, the simple and easy FPG, available readily worldwide, would be more sensitive and specific than A1C to diagnose diabetes. Conversely, borderline A1C values just above the upper limits of normal, depend upon post-prandial glycemias (i.e. 2hPG), still requiring the OGTT to be correctly interpreted. These unclear correlations between plasma glucose and A1C indicate that they reflect a different process, especially in the non-diabetic range of glucose tolerance. Finally, the fact that the ADA recommends using A1C while emphasising the importance of IFG and IGT, which cannot be diagnosed without OGTT, to disclose high-risk subjects for diabetes, clearly shows that A1C would be of little value without OGTT and that pre-diabetes includes different entities [12–14,33]. Only the practice of OGTT can disclose unknown diabetes when FPG b 126 mg/dl, and screen efficiently within the range of the rather heterogeneous pre-diabetic values. 5. Revival of the OGTT Given its importance and strengthened by the above discussion, revisiting the OGTT requires substantial improvements to make it more effective by endowing it with an additional power of information. This necessary improvement is based on considerations stemming from available evidence. Only preventive strategies can reduce the incidence of type 2 diabetes together with the expected, related excess in cardiovascular morbidity and mortality [1]. It is obvious that the greater is the accuracy in selecting high-risk subjects, the better is the preventive effectiveness. However, not all subjects with IGT, IFG, or both go on to develop diabetes [34]: in fact only 30–40% of IGT subjects will eventually convert to type 2 diabetes [35]. Furthermore, in longitudinal epidemiological studies, ~40% of subjects who develop type 2 diabetes exhibit NGT at baseline blood glucose testing, indicating that there is a large number of NGT subjects who constitute the larger reservoir of future type 2 diabetes [34]. Thus, the present format and data analysis of OGTT, like methods using non-OGTT data [36,37], do not recognize most of high-risk subjects for type 2 diabetes. The fact is that diabetes risk screening, independent from the method used, is still hampered by a large number of false-positive data. Therefore, a larger number of subjects need to be treated with preventive interventions. Thus, new prediction models should be aimed at optimizing the sensitivity and specificity rather than replacing existing models. Unfortunately, relying solely on IGT detection to recognize “future” diabetics, would miss a large fraction of high-risk individuals not affected by IGT, who could still benefit from preventive interventions. Recently it has been proposed that the 1-h plasma glucose concentration during OGTT (≥ 155 mg/dl) has better predictive power to disclose future diabetics than either FPG or 2hPG [38]. This was known even before, when the whole OGTT profile was used with hourly measurements, and it would be a true surprise if the glycemia measured after 1 h of oral glucose loading was meaningless. It was abandoned because of its larger variability with respect to the 2nd hour glycemia, and this source of error was not disclaimed by the report [38], such that we are still more confident on the more reproducible 2nd hour value. However, as our paper purports to
enforce the validity of OGTT, this is further strengthened by the additional information supplied by a 1st hour measurement, which still pertains to the OGTT as a whole. It ushers the critical question: is it possible to modify the present format of OGTT in order to obtain further information to identify high-risk subjects? Probably a dynamic interpretation of FPG and 2hPG could offer surprising and unexpected considerations. As an example, let us consider the case of a patient whose OGTT yielded FPG = 85 and 2hPG = 102 mg/dl, and let us compare him with another subject whose OGTT gave FPG = 73 and 2hPG = 128 mg/dl. Both subjects are, by definition, NGT. Are they truly similar? To understand the important difference between these two patients, we should address pertinent pathophysiologic correlates. FPG and 2hPG do closely correlate with β-cell function, the principal factor responsible for the development of type 2 diabetes [19]. Consequently, changes in β-cell function will influence not only FPG and 2hPG, but also the shape of plasma glucose concentration profile during OGTT. An important component of this profile is the time required for the plasma glucose concentration to return to the fasting level [39]. Recently, in a prospective study derived from the San Antonio Heart Study, it has been reported that NGT subjects whose post-load plasma glucose concentration returned quickly to baseline, had a lower risk of developing type 2 diabetes after a follow-up of 8 years, when compared to subjects with a slower fall to baseline [40]. This behaviour suggests that the faster the post-load glucose drops towards FPG, or the lower the rise in post-load glucose, the more efficient is β-cell function. We recently tested the possibility that OGTT could identify NGT subjects with more subtle and specific metabolic phenotypes, endowed with direct and specific implications on glucose homeostasis [41]. We did this by computing the percentage increment of 2hPG with respect to FPG (PG%), using the formula [(2hPG − FPG) / FPG] × 100. Adding to glycemic measurements the simultaneous determinations of plasma insulin to estimate β-cell function [23], we demonstrated that NGT subjects with 2hPG near or below FPG value, i.e. lower PG%, are more sensitive to insulin: these do not need, then, an enhanced insulin secretion. Conversely, increased secretion seems instead necessary for NGT subjects with 2hPG higher than FPG value, i.e. higher PG% (though still within the normal range), where there is a fall in insulin sensitivity (a rise in insulin resistance). Since glucose tolerance deteriorates when the fall in insulin sensitivity is not compensated by a sufficient increase in secretion, NGT subjects with higher PG% could herald a risk of worsening glucose tolerance more important than those NGT subjects whose PG% is lower. These data are in agreement with the finding that subjects with a 2hPG within 120–140 mg/dl do exhibit an approximate 40–50% relative fall in β-cell function compared with subjects with 2hPG b 100 mg/dl: yet, both groups are considered to have NGT [19]. Recently, in a retrospective analysis of the San Antonio Heart Study and the Botnia Study, in which the incidence of type 2 diabetes in NGT subjects was examined, the 1-h plasma glucose concentration was reported to be more predictive than the 2hPG [42]. In fact, stratifying NGT subjects based on their 1-h plasma glucose concentration, the group with a 1-h plasma glucose N 155 mg/dl had a 13.1-fold increased odds ratio for type 2 diabetes with respect to the group with a 1-NGTh plasma glucose b 125 mg/dl. Computing, according to our formula, the PG%, the first group, with mean FPG and 2hPG values of 83 ± 6 and 109 ± 21 mg/dl respectively, shows a PG% of 31.3%, while the second group, with mean FPG and 2hPG values of 81 ± 1 and 87 ± 11 mg/dl respectively, reaches a PG% of 7.4%, in full agreement with our contention. Thus, the simple use of the PG%, as an adjunctive dynamic interpretation of FPG and 2hPG, can expand the clinical use of the OGTT from a tool to investigate glucose tolerance to a more powerful and informative method capable of disclosing the efficiency of β-cell
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function: a high, although still “normal”, PG% probably pinpoints a higher risk of worsening glucose homeostasis. This very simple calculation could also replace the more expensive and demanding 1st hour sampling for glucose measurement. We have now the instrument to detect the pathophysiologic difference between the two NGT subjects of the above example: the first patient has a PG% = 20%, the second one = 75%. Very likely, this latter subject has a deterioration of β-cell function bearing consequences in the future which could be amenable to preventive treatments. Beside the calculation of PG%, the OGTT could offer further metabolic information on glucose homeostasis. The simultaneous measurements of glucose and insulin during standard OGTT represent the favourable opportunity to establish, in a single test, not only the stage of glucose tolerance, but also β-cell function [23]. This seems particularly promising as, in the near future, a low insulin sensitivity (i.e. high insulin resistance) and/or an alteration in its secretion could become targets of specific treatments even within the NGT range. Also the simple plasma glucose/plasma insulin ratios demonstrate β-cell dysfunction when the PG% is higher. Fig. 1 and Table 1 show glucose and insulin values during fasting, and then 1 and 2 h during OGTT in 136 NGT subjects. When compared to 72 NGT subjects whose PG% was ≤20%, NGT subjects with PG% N 20% have a significantly lower FPG, whereas 2hPG, fasting insulin and 2 h-insulin are significantly higher. On the contrary, the 1st hour insulin and glucose values are not significantly different considering the two NGT groups (b and NPG 20%): this further underlines the lack of information of 1st hour intermediate glucose and insulin values as opposed to the baseline and final measurements. When considering the glycemia/ insulin ratios during fasting and at 2 h post-glucose load, it is readily apparent that the lower ratios of NGT subject with higher PG% disclose
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Table 1 Glycemic and insulinemic values (M± S.D.) during OGTT in NGT subjects with PG% ≤ 20% or with PG% N 20%.
FPG mg/dl 1hPG mg/dl 2hPG mg/dl Fasting insulin μU/ml 1hInsulin μU/ml 2hInsulin μU/ml Fasting glucose/insulin 2 h glucose/insulin
PG% ≤ 20% n = 72
PG% N 20% n = 64
“t” Student p
94.4 ± 5.7 146.1 ± 34.5 89.6 ± 20.1 9.4 ± 3.7 102.1 ± 46.8 43.7 ± 30.3 11.6 ± 5.1 3.4 ± 2.5
90.8 ± 3.7 145.8 ± 18.8 127.6 ± 7.3 11.1 ± 5.1 119.1 ± 62.3 81.8 ± 41.2 9.8 ± 4.6 2.1 ± 1.6
b0.0001 n.s. b0.0001 b0.03 n.s. b0.0001 b 0.04 b0.001
For the meaning of symbols see Fig. 1.
the important impairment of their β-cell function, which could herald the occurrence of a late phase of type 2 diabetes. Prospective studies designed to test the clinical weight of PG% are necessary. Independent from the results of future observations, OGTT, even though underrated and considered aged and costly, lengthy, poorly reproducible and informative, seems, on the contrary, rejuvenated, surprising and fascinating when implemented with a simple, grammar school calculation, even more informative when coupled to insulin measurements. 6. Learning points • Approximately 40% of subjects who will develop type 2 diabetes are within the NGT range at OGTT, indicating that there is a large number of NGT subjects who constitute the larger reservoir of future type 2 diabetes. • OGTT detects diabetes more efficiently than FPG as it recognizes altered post-prandial metabolism. • OGTT establishes whether an IFG subject has normal 2hPG. This is essential, as the majority of IFG subjects display a preserved glucose homeostasis with respect to those IFG subjects with abnormal 2hPG. • FPG does not supply any metabolically relevant information, to the point that it is misleading to try to assess glucose homeostasis without information on post-prandial glucose metabolism. • IGT subjects, who are always included in trials concerning type 2 diabetes prevention, cannot be recognized without OGTT. • Using A1C in diabetes screening does not substitute for the information derived from OGTT, because they are not equivalent tests. • OGTT lends itself to simple calculations, like the % change of 2 h with respect baseline glycemia, capable of detecting additional subjects at risk for type 2 diabetes. References
Fig. 1. Legend: Glycemic (over panel) and insulinemic (inferior panel) values during OGTT in NGT subjects with PG% ≤ 20% (continuous line) and PG N 20% (hatched line). FPG = fasting plasma glucose, 1hPG = 1 hour post-glucose load glycemia, 2hPG = 2 hours post-glucose load glycemia, FPIns = fasting plasma insulin, 1hPIns = 1 hour post-glucose load insulin, 2hPIns = 2 hours post-glucose load insulin.
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