Vous êtes sur la page 1sur 5

Pathophysiology/Complications

O R I G I N A L A R T I C L E

Contributions of Fasting and


Postprandial Plasma Glucose Increments
to the Overall Diurnal Hyperglycemia of
Type 2 Diabetic Patients
Variations with increasing levels of HbA1c
LOUIS MONNIER, MD1 the same type of patients, it has been re-
1
HELENE LAPINSKI, MD ported (3) that preprandial PG concentra-
CLAUDE COLETTE, PHD2 tions were related to HbA1c more strongly
than postprandial concentrations. How-
ever, a better correlation was observed be-
tween HbA1c and mean daily glucose
concentrations, confirming that HbA1c is
OBJECTIVE The exact contributions of postprandial and fasting glucose increments to a function of both fasting and postpran-
overall hyperglycemia remain controversial. The discrepancies between the data published pre- dial hyperglycemia (3). Although it seems
viously might be caused by the interference of several factors. To test the effect of overall glycemic
control itself, we analyzed the diurnal glycemic profiles of type 2 diabetic patients investigated at
from the results of previous studies (4,5)
different levels of HbA1c. that postprandial hyperglycemia contrib-
utes to 30 40% of the total daytime
RESEARCH DESIGN AND METHODS In 290 noninsulin- and nonacarbose- hyperglycemia, the debate remains wide
using patients with type 2 diabetes, plasma glucose (PG) concentrations were determined at open. The discrepancies between the data
fasting (8:00 A.M.) and during postprandial and postabsorptive periods (at 11:00 A.M., 2:00 P.M., published over the last years seem to in-
and 5:00 P.M.). The areas under the curve above fasting PG concentrations (AUC1) and 6.1 dicate that the answer to the question of
mmol/l (AUC2) were calculated for further evaluation of the relative contributions of postpran- the relative contribution of fasting and
dial (AUC1/AUC2, %) and fasting [(AUC2 AUC1)/AUC2, %] PG increments to the overall postprandial hyperglycemia to the overall
diurnal hyperglycemia. The data were compared over quintiles of HbA1c. diabetic disequilibrium might be more
complex and subtle than expected. For
RESULTS The relative contribution of postprandial glucose decreased progressively from
the lowest (69.7%) to the highest quintile of HbA1c (30.5%, P 0.001), whereas the relative instance, the magnitude of the relative
contribution of fasting glucose increased gradually with increasing levels of HbA1c: 30.3% in the contribution of postprandial glucose ex-
lowest vs. 69.5% in the highest quintile (P 0.001). cursions to overall hyperglycemia might
be influenced both by the circumstances
CONCLUSIONS The relative contribution of postprandial glucose excursions is predom- under which blood glucose has been
inant in fairly controlled patients, whereas the contribution of fasting hyperglycemia increases monitored in the postprandial period and
gradually with diabetes worsening. These results could therefore provide a unifying explanation by the degree of the overall diabetic con-
for the discrepancies as observed in previous studies. trol itself (1). The aim of the present study
was to extend our knowledge on the latter
Diabetes Care 26:881 885, 2003
point. For that purpose, we were led to
analyze the diurnal glycemic profiles of
noninsulin-using type 2 diabetic pa-

T
he exact contribution of postpran- insulin-treated type 2 diabetic patients, tients investigated at different levels of
dial blood glucose excursions to the we found that postlunch and extended HbA1c.
overall glycemic control of patients postlunch plasma glucose (PG) concen-
with type 2 diabetes remains largely un- trations were better correlated to HbA1c
determined (1). A few years ago in non than fasting values (2). More recently in RESEARCH DESIGN AND
METHODS

From the 1Department of Metabolism, Lapeyronie Hospital, Montpellier, France; and the 2University Insti- Patients
tute of Clinical Research, Montpellier, France.
Address correspondence and reprint requests to Prof. L. Monnier, Department of Metabolism, Lapeyronie A total of 290 patients (139 men, 151
Hospital, 34295 Montpellier Cedex 5, France. E-mail: l-monnier@chu-montpellier.fr. women) participated in the study and
Received for publication 29 March 2002 and accepted in revised form 20 November 2002. were entered consecutively. Eligibility for
Abbreviations: AUC, area under the curve; AUC1, AUC above fasting PG concentrations; AUC2, AUC the study was based on a diagnosis of di-
6.1 mmol/l; CGMS, continuous glucose monitoring system; CV, coefficient of variation; PG, plasma
glucose.
abetes for at least 6 months. The subjects
A table elsewhere in this issue shows conventional and Systeme International (SI) units and conversion could be treated by diet alone or with a
factors for many substances. stable dose of metformin (1,700 mg/day),

DIABETES CARE, VOLUME 26, NUMBER 3, MARCH 2003 881


Contribution of diurnal postprandial glycemia to HbA1c

glyburide (515 mg/day), or both, pro- tended postlunch at 5:00 P.M.) is a marker dents t test. Correlation analyses were
vided that the weight-controlling diet of a postabsorptive period (7,8). On the performed by using the least-square
and/or the drug regimen had been kept study day, patients were maintained on method, and strengths of the relation-
constant for at least 3 months before the their usual treatment with oral antidia- ships were given by coefficients of deter-
study. Because insulin or acarbose treat- betic drugs. HbA1c measurement was mination (r2).
ments can or do exert specific effects on made at 8:00 A.M. on the first blood sam-
postprandial glucose excursions, patients ple by using a high-performance liquid Validation of the model using a four-
who were being treated with acarbose or chromatography assay (Menarini Diag- point glucose profile
insulin were excluded to avoid any bias in nostics, Florence, Italy). The intra- and In the 290 patients, a significant correla-
the interpretation of the contribution of interassay CVs were 3% at values 8%. tion (r2 0.48, P 0.0001) was found
postprandial glucose increments to over- between HbA1c and AUC2, this area inte-
all hyperglycemia. The study was con- Calculation of the relative grating both fasting and postprandial glu-
ducted after the patients had given their contributions of fasting and cose increments and being considered a
informed consent. The patients were fur- postprandial plasma glucose to the reflection of the average exposure to high
ther divided into five equal groups ac- overall hyperglycemia over the glucose over the diurnal period of the
cording to the quintiles of HbA1c. For that diurnal period of daytime study day. Furthermore, to know more
purpose, the 290 HbA1c values were The diurnal PG response to meals was es- precisely whether the areas calculated
ranked in increasing order, with random timated as a whole by calculating the in- from the fourtime point diurnal glucose
ranking when two or several HbA1c mea- cremental area under the daytime PG profiles provide an objective reflection of
surements were equal. curve from 8:00 A.M. to 5:00 P.M. Two variations in fasting and postprandial glu-
areas were calculated geometrically from cose levels during real life, we investi-
Protocol of the study the four-point curve, the area below the gated an additional subgroup of 20 type 2
All patients were submitted to a protocol baseline value being ignored. The first, diabetic patients who were selected ac-
that has been previously described (6). the area under the curve (AUC) above cording to the same criteria as the 290
After an overnight fast, all patients were fasting PG concentrations (AUC1), was patients included in the study. The values
admitted at the outpatient clinic of the calculated above a baseline level equal to (mean SE) in this subgroup were
Department of Metabolism, Lapeyronie the fasting plasma value and was therefore 62.4 1.2 years for age, 10.3 0.9 years
Hospital. Patients were asked to eat a test considered a reflection of the postpran- for diabetes duration, 30.2 0.6 kg/m2
breakfast at 8:00 A.M. and a test lunch at dial glycemic responses to breakfast and for BMI, and 8.77 0.26% for HbA1c. In
12:00 P.M. The energy and macronutrient lunch. The second, the AUC 6.1 mmol/l the 20 patients, the subcutaneous inter-
content of each test meal were standard- (AUC2), was calculated above a baseline stitial glucose level was monitored on an
ized according to a dietary program, as level equal to 6.1 mmol/l (110 mg/dl), re- ambulatory basis and over 24 h using the
previously described (6). Four venous flecting the increases in both fasting and Minimed continuous glucose monitoring
blood samples were collected into tubes postprandial PG. The baseline value of system (CGMS; Northridge, CA) (12,13).
containing EDTA and fluoride at 8:00 6.1 mmol/l was chosen because this The glucose patterns as obtained were
A.M., 11:00 A.M., 2:00 P.M., and 5:00 P.M. threshold has been defined as the upper submitted to the following readings and
Plasma was separated from the cells limit of normal PG at fasting or prepran- calculations, which are illustrated in Fig.
within 1 h after withdrawal, and glu- dial times by the American Diabetes As- 1. First, for each patient, four glucose val-
cose concentrations in plasma were deter- sociation (9,10). Therefore, the difference ues were read on the time curves at 8:00
mined by an hexokinase method using a (AUC2 AUC1) can be considered an A.M., 11:00 A.M., 2:00 P.M., and 5:00 P.M.
Synchro CX4/CX5 glucose analyzer assessment of the increment in fasting PG The four time points were connected by
(Beckman Instruments, Fullerton, CA). values. As a result, the relative contribu- straight lines over time, and then trape-
Both the intra- and interassay coefficients tions of postprandial and fasting PG to the zoidal areas were calculated from 8:00
of variation (CVs) were 2% at values 7 total PG increment were calculated, re- A.M. to 5:00 P.M. according to the method
mmol/l. The rationale for the timing of the spectively, by using the following equa- as described above. These areas were
four PG determinations (i.e., of the so- tions: (AUC 1 /AUC 2 ) 100 for the termed as AUC1 4-pt, AUC2 4-pt, and
called diurnal PG profiles) was initially postprandial contribution and [(AUC2 (AUC2 AUC1) 4-pt. Second, incremen-
determined by giving a priority choice to AUC1)/AUC2] 100 for the fasting con- tal areas under continuous glucose mon-
the two PG values that are usually consid- tribution. itoring were calculated from the CGMS
ered to reflect a real fasting state (pre- patterns both over the diurnal 9-h period
breakfast PG at 8:00 A . M .) and a Statistical analysis (from 8:00 A.M. to 5:00 P.M.) and over
nonquestionable postprandial period All results are given as the mean SE. All 24 h. These areas were termed AUCs 9-h
(2-h postlunch PG at 2:00 P.M.). The two data, particularly those concerning the and AUCs 24-h. Areas under continuous
remaining time points were chosen to re- relative contributions of fasting and post- glucose monitoring were determined by
spect a regular 3-h time interval between prandial PG to the total glucose incre- dividing the entire daytime period into
blood samplings. The 3-h postbreakfast ments, were compared over quintiles of three periods, each starting with the main
PG at 11:00 A.M. can therefore be consid- HbA1c by using one-way ANOVA, fol- meals (breakfast, lunch, and dinner) and
ered as a compromise between a late post- lowed by a Bonferronis test (11). Relative ending with the subsequent meal. Over
breakfast and an early prelunch value, contributions of postprandial and fasting each period, AUC1s continuous were de-
whereas the 5-h postlunch PG value (ex- PG were compared by using a paired Stu- fined as the incremental areas above pre-

882 DIABETES CARE, VOLUME 26, NUMBER 3, MARCH 2003


Monnier and Associates

Figure 1Description in a typical pa-


tient of the calculations used for deter-
mining the incremental AUCs of glucose.
a: Diurnal four-point profiles. b: Diurnal
9-h continuous profile. c: 24-h continu-
ous profile. BF, breakfast; D, dinner; and
L, lunch. Measurements were respec-
tively taken at 8:00 A.M., 12:00 P.M., and
7:00 P.M. AUC1: white areas (lower part
of the figure); AUC2: shaded areas (upper
part of the figure). AUC 2 AUC 1 :
hatched areas (lower part of the figure).
F, values transcribed from the CGMS
pattern for establishing the four-point
profile and prebreakfast values; E, pre-
prandial values before lunch and dinner.

prandial glucose values that were read fasting state and therefore served for eval- Relative contributions of fasting and
just before starting breakfast, lunch, and uating the fasting and postprandial glu- postprandial glucose to the overall
dinner. AUC1s 9-h and 24-h were calcu- cose increments, we calculated the CV of diurnal hyperglycemia
lated by summing the areas up to 5:00 P.M. glucose fluctuations obtained from the The values of AUC1 and AUC2 are given
and over 24 h, respectively. AUC2s 9-h CGMS over the 30-min interval that pre- in Fig. 2 with the differences (AUC2
and 24-h were measured by calculating ceded the starting glucose level before AUC1). AUC1, which reflects postpran-
the total areas under the CGMS values breakfast. For each of the 20 patients, in- dial glucose increments, was significantly
6.1 mmol/l. The differences in AUC2 dividual means and CVs were calculated decreased in the lowest quintile of HbA1c
AUC1 were calculated and termed as by averaging seven glucose values that when compared with all of the remaining
(AUC2 AUC1) 9-h and 24-h. were obtained from 5-min interval read- quintiles. The AUC1 value exhibited a
In the 20 patients, highly significant ings over the 30-min prebreakfast period. threefold increase from quintile 1 to 3,
correlations were found between AUC2 reached a quasi-plateau at quintile 3, and
The mean within-subject CV for the 20
4-pt and either AUC2 9-h over the diurnal remained stable over quintiles 4 and 5.
patients was further calculated from the
period (r2 0.93, P 0.0001) or AUC2 The difference (AUC2 AUC1), which
24-h (r2 0.82, P 0 0.0001). Less sig- individual data and was estimated at reflects fasting glucose increments, in-
nificant correlations were observed be- 5.1%. creased progressively with increasing lev-
tween AUC1 4-pt and either AUC1 9-h (r2 els of HbA1c, with significant differences
0.40, P 0.002) or AUC1 24-h (r2 being found between each quintile taken
0.21, P 0.041). However, correlations RESULTS individually and all of the following upper
remained highly significant when (AUC2 quintiles.
AUC1) 4-pt was tested against either Main clinical data and diurnal As shown in Fig. 3, the relative con-
(AUC2 AUC1) 9-h (r2 0.89, P plasma glucose profiles tribution of postprandial PG decreased
0.0001) or 24-h (r2 0.86, P 0.0001). All results are indicated in Table 1 and progressively from the lowest to the high-
Fig. 2. As expected, all PG values both at est quintile of HbA1c. By contrast, the rel-
Evaluation of glucose stability over fasting and during postprandial or post- ative contribution of fasting PG showed a
the prebreakfast period absorptive periods were increasing signif- gradual increase with increasing levels of
Because prebreakfast glucose values were icantly and progressively from the lowest HbA1c.
used as reference for estimating the real to the highest quintiles of HbA1c. For each relative postprandial or fast-
Table 1Clinical data

Quintiles of HbA1c 1 2 3 4 5 Entire population


Patients tested (n) 58 58 58 58 58 290
Sex ratio (M/F) 31/27 34/24 22/36 27/31 25/33 139/151
Age (years) 62.6 1.1 56.5 1.4 62.3 1.3 60.7 1.3 58.3 1.4 60.1 0.6
Diabetes duration (years) 8.4 1.3 10.0 1.1 13.8 1.7 11.7 1.2 8.3 1.1 10.5 0.6
BMI (kg/m2) 30.6 0.8 31.7 0.9 29.9 0.7 30.3 0.9 29.6 0.8 30.4 0.4
HbA1c (%) 6.45 0.08 7.93 0.04 8.85 0.03 9.76 0.04 11.32 0.13 8.86 0.10
Data are means SE.

DIABETES CARE, VOLUME 26, NUMBER 3, MARCH 2003 883


Contribution of diurnal postprandial glycemia to HbA1c

was only significant (r2 0.40, P


0.002) for the contribution over 24 h. As
expected, [(AUC2 AUC1)/AUC2] 9-h
and 24-h correlated with HbA1c at the
same level of significance, but in a positive
manner.

CONCLUSIONS The present re-


sults suggest that postprandial glycemic
excursions play a major role in the meta-
bolic disequilibrium of patients suffering
from mild or moderate hyperglycemia.
On the contrary, fasting hyperglycemia
appears as a main contributor to the over-
all diurnal hyperglycemia in poorly con-
trolled diabetic patients, whereas the role
of postprandial glucose elevations de-
creases as patients progress toward poor
diabetic control. Because this relationship
was confirmed in the 20 patients investi-
gated with the CGMS, all periods that are
not accounted for in the fourtime point
glucose profile do not seem to affect the
validity of the results given by our four-
point sampling model, which integrates
markers during the three main (fasting,
postprandial, and postabsorptive) peri-
ods of daytime.
The importance of postprandial gly-
cemic excursions in fairly well-controlled
type 2 diabetic patients is in agreement
with the results of all epidemiological
studies (14,15), which have shown that
Figure 2Fourtime point diurnal profiles of plasma glucose concentrations (A) and AUCs (B) postchallenge hyperglycemia was a stron-
over quintiles of HbA1c. E, AUC1; F, AUC2; , AUC2 AUC1 (differences between the two ger predictor of cardiovascular disease
areas). Methods of calculation and meanings for each area are provided in the text; and results are than elevation of glucose at fasting. How-
given as the means SE. *Significant differences from all following upper quintiles. All P values ever, these findings were solely observed
are 0.001 after Bonferroni adjustment, except for comparisons between quintiles 1 and 2 of in diabetic patients with mild or moderate
AUC1 (P 0.015) or AUC2 AUC1 (P 0.032) and between quintiles 2 and 3 (P 0.047) of alterations of diabetic control and mostly
AUC2 AUC1. in subjects who were only suffering from

ing contribution, analyzed individually,


comparisons over quintiles of HbA 1c
showed significant differences first be-
tween the lowest quintile and all of the
following upper quintiles, and second be-
tween the 2nd and the 5th quintile. Fur-
thermore, significant differences were
found in quintiles 1, 4, and 5 when rela-
tive postprandial and fasting contribu-
tions were compared within the same
quintile. Figure 3Relative contributions of post-
In the 20 patients investigated with prandial () and fasting (f) hyperglycemia
(%) to the overall diurnal hyperglycemia
the CGMS, the relative contributions of
over quintiles of HbA1c. a, significant differ-
postprandial glucose to the overall hyper- ence was observed between fasting and post-
glycemia, as estimated from the ratios of prandial plasma glucose (paired t test); b,
AUC1 9-h to AUC2 9-h and AUC1 24-h to significantly different from all other quintiles
AUC2 24-h, were negatively correlated (ANOVA); c, significantly different from
with HbA1c levels, but the relationship quintile 5 (ANOVA).

884 DIABETES CARE, VOLUME 26, NUMBER 3, MARCH 2003


Monnier and Associates

impaired tolerance to glucose (15). On a reference for determinations of AUCs 707713, 1992
the contrary, fasting hyperglycemia plays seems to be sufficiently reduced (CV 8. Monnier L: Is postprandial glucose a ne-
a major role as soon as the HbA1c level 5.1%) for meaningful interpretation of glected cardiovascular risk factor in type 2
rises above 8.4%. This finding results the data, since this relatively small impre- diabetes? Europ J Clin Invest 30 (Suppl. 2):
311, 2000
mainly from the fact that AUC2 AUC1 cision in fasting PG is compensated by the
9. The Expert Committee in the Diagnosis
(a reflection of fasting glucose exposure) size of the investigated population. and Classification of Diabetes Mellitus:
increased steadily from quintile 1 to 5, In conclusion, our results indicate Report of the Expert Committee on the
whereas AUC1 (a reflection of postpran- that there exists a progressive shift in the Diagnosis and Classification of Diabetes
dial exposure) remained stable over the respective contributions of fasting and Mellitus. Diabetes Care 25 (Suppl. 1):S5
three upper quintiles. These observations postprandial hyperglycemia when the pa- S20, 2002
are consistent with U.K. Prospective Dia- tients progress from moderate to high 10. American Diabetes Association: Standards
betes Study data (16), which have pro- hyperglycemia, the contribution of post- of medical care for patients with diabetes
vided cogent evidence for the deleterious prandial glucose excursions being pre- mellitus (Position Statement). Diabetes Care
dominant in patients with moderate 25 (Suppl. 1):S33S49, 2002
effect of fasting hyperglycemia in the pro-
diabetes, whereas the contribution of fast- 11. Miller RG: Simultaneous Statistical Interfer-
gression and development of vascular ence, 2nd ed. New York, Springer-Verlag,
complications in patients suffering from ing hyperglycemia increases with diabetes 1981
overt diabetes with frank elevations of worsening. Such observations seem to 12. Monsod TP, Flanagan DE, Rife F, Saenz R,
glucose values at fasting. However, even conciliate the different results that were Caprio S, Sherwin RS, Tamborlane WV:
in this type of patient, the role of post- observed in the literature because the shift Do sensor glucose levels accurately pre-
prandial glycemic excursions remains in the respective contributions of fasting dict plasma glucose concentrations dur-
possible because in the quintile of our pa- and postprandial hyperglycemia appears ing hyperglycemia and hyperinsulinemia?
tients who had the highest levels of as a continuous spectrum from fairly to Diabetes Care 25:889 893, 2002
poorly controlled patients with type 2 13. Sacks DB, Bruns DE, Goldstein DE, Ma-
HbA1c, postprandial hyperglycemia ac-
diabetes. claren NK, McDonald JM, Parrott M:
counted for approximately one-fourth of Guidelines and recommendations for lab-
the total diurnal hyperglycemia. Such an oratory analysis in the diagnosis and man-
observation can explain the specific dele- References agement of diabetes mellitus. Diabetes
terious effect of postprandial hyperglyce- 1. American Diabetes Association: Postpran- Care 25:750 786, 2002
mia as reported in the subset of poorly dial blood glucose (Consensus State- 14. The DECODE Study group on behalf of
controlled type 2 diabetic patients who ment). Diabetes Care 24:775778, 2001 the European Diabetes Epidemiology
were included in the Diabetes Interven- 2. Avignon A, Radauceanu A, Monnier L: Group: Glucose tolerance and mortality:
tion Study (17). Nonfasting plasma glucose is a better comparison of WHO and American Dia-
All of these interpretations are tena- marker of diabetic control than fasting betes Association diagnostic criteria. Lan-
plasma glucose in type 2 diabetes. Diabe- cet 354:617 621, 1999
ble, provided that the validity of the ob- 15. Bonora E, Muggeo M: Postprandial blood
tes Care 20:18221826, 1997
servations on a fourtime point diurnal 3. Bonora E, Calcaterra F, Lombardi S, Bon- glucose as a risk factor for cardiovascular
glucose profile in standard conditions fante N, Formentini G, Bonadonna RC, disease in type II diabetes: the epidemio-
with standardized meals on a specific Muggeo M: Plasma glucose levels logical evidence. Diabetologia 44:2107
study might be extended to the chronic throughout the day and HbA1c interrela- 2114, 2001
variations of plasma glucose in real life. tionships in type 2 diabetes: implications 16. UK Prospective Diabetes Study (UKPDS)
An answer to refute all these possible lim- for treatment and monitoring of meta- group: Intensive blood glucose control
itations is given by the finding of signifi- bolic control. Diabetes Care 24:2023 with sulphonylureas or insulin compared
cant correlations between the areas under 2029, 2001 with conventional treatment and risk of
4. Reaven GM, Hollenbeck C, Jeng CY, Wu complications in patients with type 2 di-
the fourtime point diurnal glucose pro-
MS, Chen YD: Measurement of plasma abetes (UKPDS 33). Lancet 352:837 853,
files and several parameters, such as glucose, free fatty acid, lactate, and insulin 1998
HbA 1c measurements, which usually for 24 h in patients with NIDDM. Diabetes 17. Hanefeld M, Fischer S, Julius U, Schulze J,
evaluate the chronic variations of plasma 37:1020 1024, 1988 Schwanebeck U, Schmechel H, Ziegel-
glucose (18), and the incremental areas 5. Riddle MC: Evening insulin strategy (Re- asch HJ, Lindner J: Risk factors for myo-
with the CGMS data, which provide in- view). Diabetes Care 13:676 686, 1990 cardial and death in newly detected
formation on continuous changes of glu- 6. Monnier L, Colette C, Rabasa-Lhoret R, NIDDM: the Diabetes Intervention Study,
cose levels in real life. These findings are Lapinski H, Caubel C, Avignon A, Boni- 11-year follow-up. Diabetologia 39:1577
in accordance with our a priori hypothe- face H: Morning hyperglycemic excur- 1583, 1996
sions: a constant failure in the metabolic 18. Rohlfing CL, Wiedmeyer HM, Little RR,
sis that the areas calculated from the four
control of noninsulin-using patients England JD, Tennill A, Goldstein DE: De-
time point profiles can be used as a proxy with type 2 diabetes. Diabetes Care 25: fining the relationship between plasma
for the areas under both diurnal and 24-h 737741, 2002 glucose and HbA1c: analysis of glucose
continuous glucose monitoring. Further- 7. Dinneen S, Gerich JE, Rizza R: Carbohy- profiles and HbA1c in the Diabetes Con-
more, the intraindividual variability of the drate metabolism in non-insulin-depen- trol and Complications Trial. Diabetes
prebreakfast glucose values that served as dent diabetes mellitus. N Engl J Med 327: Care 25:275278, 2002

DIABETES CARE, VOLUME 26, NUMBER 3, MARCH 2003 885