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Department of Endocrinology (M.-B.T.-N., S.M.), Hvidovre Hospital, University of Copenhagen, DK-2650 Hvidovre, Denmark; and Department of Medical Physiology (M.-B.T.-N., J.J.H.), the Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark
Address all correspondence and requests for reprints to: Prof. Jens Juul Holst, Department of Medical Physiology, The Panum Institute, Blegdamsvej 3, DK- 2200 Copenhagen NV, Denmark. E-mail: holst{at}mfi
Abstract
GLP-1 lowers blood glucose in fasting type 2 diabetic
patients. To clarify the relation of the effect of GLP-1
to obesity, blood glucose, ß-cell function, and insulin sensitivity,
GLP-1 (1.2 pmol/kg·min) was infused iv for 4–6 h into
50 fasting type 2 diabetic patients with a wide range of age, body mass
index, HbA1c, and fasting plasma glucose. The effectiveness of
GLP-1 was evaluated by calculation of a glucose
disappearance constant for each individual (Kg, linear
slope of log-transformed plasma glucose), and by the lowest stable
glucose level (Nadir plasma glucose) obtained during the infusion.
Grouped according to fasting plasma glucose (<10, 10–15, >15
mmol/liter), Kg values were 0.45 ± 0.03, 0.38
± 0.04, and 0.28 ± 0.04%/min (P = 0.005),
and Nadir plasma glucose values were 4.7 ± 0.1 (3.9–5.9),
5.8 ± 0.4 (4.3–8.4), and 8.7 ± 1.4 (6.2–18.7) mmol/liter
(P = 0.0003). Nonresponders were not identified.
Multiple regression analysis with Kg or Nadir plasma
glucose as the dependent parameter and body mass index, age, gender,
diabetes duration, and significantly correlated parameters (in multiple
regression for Kg: fasting plasma glucose, fasting
nonesterified fatty acid, dipeptidyl peptidase activity, peak
insulin, and the logarithm of ß-cell function; and for Nadir plasma
glucose: fasting plasma glucose, fasting nonesterified fatty
acid, dipeptidyl peptidase activity, 
glucagon decrement,
F-GLP-1 total, logarithm of ß-cell function, and
Kg) as independent parameters resulted in fasting plasma
glucose as the only significant predictor of Kg, and
fasting plasma glucose and Kg as predictors of Nadir
plasma glucose. Kg and Nadir plasma glucose were neither
influenced by treatment nor by neuropathy per se. In
conclusion, GLP-1 lowers plasma glucose in type 2 diabetes
regardless of severity, but glucose elimination is faster and obtained
glycemic level lower in patients with the lower fasting plasma glucose.
Not all patients can be expected to reach normoglycemia.
THE INCRETIN HORMONE GLP-1 stimulates glucose-induced insulin secretion and inhibits glucagon secretion (1, 2). As a result of these actions, hepatic glucose production and blood glucose concentrations decrease (3, 4). The ability of GLP-1 to modulate insulin and glucagon secretion is preserved in type 2 diabetic patients (5, 6), and, due to these actions, GLP-1 effectively reduces hyperglycemia in type 2 diabetic patients (7, 8, 9). In nonfasting patients an inhibitory effect on gastric emptying rate adds to the glucose-lowering effect by delaying glucose entry and uptake from the intestine (10, 11).
Several placebo-controlled iv studies have shown that iv GLP-1 infusion in poorly regulated fasting type 2 diabetic patients results in normalization (7, 8) or near-normalization (9) of glucose concentrations. A similar result was obtained in a study with two sc GLP-1 injections given 2 h apart (12). However, all these studies were conducted in small numbers of patients. Pooling the results of three iv studies, and one sc study, Nauck et al. (13) analyzed patient characteristics of a total of 37 patients and found that only the level of fasting glucose and the route (iv vs. sc) but not gender, age, body mass index (BMI), HbA1c, diabetes duration, treatment (sulfonylureas, metformin, and acarbose), were significant predictors of the plasma glucose (PG) level reached after GLP-1 administration. Parameters such as insulin, C-peptide, glucagon, free fatty acids, insulin sensitivity, and ß-cell function were not included in the analysis.
To further investigate individual variations with respect to the blood glucose lowering effect of GLP-1 and to determine patient characteristics predicting these possible variations, we infused GLP-1 iv continuously for 4–6 h in a large group of heterogenous type 2 diabetic patients with a wide range of fasting PG (F-PG) concentrations, BMI, age, diabetes duration, ß-cell function, and insulin sensitivity. The study was not placebo controlled because the glucose-lowering effect of GLP-1 is well established and because the aim of the study was to identify significant determinants of the effectiveness of GLP-1.
Materials and Methods
Subjects
From the diabetes out-clinic 50 type 2 diabetic patients (see
Table 1
for characteristics) with no
history of bowel disease or alcohol abuse were recruited. Whereas
35 patients had no signs of neuropathy, 11 patients were classified as
having manifest diabetic polyneuropathy, 3 of whom had also autonomic
dysfunction while 4 patients could not be classified (see below).
According to the patient’s medical records they had normal serum
creatinine and no albuminuria or impaired hepatic function.
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Infusion protocol
Synthetic human GLP-1(7–36amide) was purchased from Saxon (Haan, Germany; subsidiary of Bachem, Torrance, CA) (GMP grade (catalog no. PGAS242) and from Peninsula Laboratories, Inc. Europe (Merseyside, UK). Both were more than 98% pure and consisted of authentic GLP-1 by high-performance liquid chromatography and sequence analysis. The peptide was dissolved in 0.9% saline containing 1% human serum albumin (Albumin Nordisk, Novo Nordisk, Bagsvaerd, Denmark; guaranteed to be free of hepatitis-B surface antigen and human immunodeficiency virus antibodies), subjected to sterile filtration, dispensed in appropriate amounts into glass ampoules, and stored frozen under sterile conditions until the day of the experiment.
After 3 d of discontinued antidiabetic medication and an overnight fast (10 h), the patients received a 4-h iv infusion of GLP-1 (1.2 pmol/kg·min). Some of the patients continued the GLP-1 infusion for another 30–120 min, corresponding to a maximum infusion time of 6 h. The results of this period are used in the calculations of the lowest glucose value obtained. However, not all patients reached nadir defined as a stable PG level with excursions of 0.2 mmol/liter or less. Only those who did are included in the Nadir PG (Nadir-PG) result section. Blood was sampled from a needle in a forearm vein before start and every half-hour, and distributed into fluoride tubes for analysis of PG and into EDTA/aprotinin tubes (6 mmol/liter EDTA and 500 KIU aprotinin/ml blood) for analysis of plasma concentrations of intact and total GLP-1, glucagon, insulin, C-peptide, dipeptidyl peptidase activity (DPP-IV), nonesterified fatty acid (NEFA), and GAD (GADab) and islet antigen antibodies (IA2ab). Tubes were immediately chilled in ice and centrifuged at 4 C within 10 min. Plasma was stored at -20 C until analysis.
Neuropathy status was evaluated by: 1) medical history; 2) physical examination; 3) biothesiometry (14); 4) cardiologic autonomic tests [i.e. orthostatic blood pressure measurement; and deep breathing, standard 15-sec Valsalva maneuver, and 15-sec Valsalva maneuver with expiration against 40 cm water; the latter three tests evaluated by estimation of beat-to-beat variation (R-R interval) (15)]; and 5) electrophysiological evaluation of peripheral nerve function in 12 patients. The patients were divided into a group having no signs of diabetic neuropathy (class IIA, diabetic polyneuropathy consensus statement of 1993; Ref. 16) and into another group with manifest diabetic neuropathy (class IIB/IIC). Among patients with manifest neuropathy, three also had measurable autonomic dysfunction. Four patients could not be classified—two patients due to signs of incipient but not manifest neuropathy, and two patients due to lack of tests.
Analysis
PG concentrations were analyzed bedside using a Beckman Analyzer (Beckman Coulter, Inc., Fullerton, CA).
Hormone analyses. The glucagon assay (RIA) is directed against the C-terminus of the glucagon molecule (antibody code no. 4305) and, therefore, measures glucagon of mainly pancreatic origin (17). Plasma concentrations of amidated GLP-1 (–36) were measured by means of antibody code no. 89390 (RIA), which is highly specific for the C- terminus of GLP-1 and, therefore, measures the sum of GLP-1(7–36amide) and its metabolite GLP-1(9–36amide) (18). Detection limits and intra-assay coefficients were 1 pmol/liter and less than 6% for both glucagon and amidated GLP-1 (antibody code no. 89390), whereas the interassay coefficient of variation was less than 10% at 20 pmol/liter. Plasma concentrations of intact GLP-1 (the sum of intact amidated and intact glycine-extended GLP-1) were measured using an N-terminally directed antibody (antibody code no. 93242) with a detection limit less than 5 pmol/liter and intra- and interassay coefficients of variation of 6% and 12% at 50 pmol/liter (19). For all three analyses plasma was extracted with ethanol (final concentration, 70% vol/vol) before analysis. Insulin and C-peptide concentrations were measured using commercial ELISA kits (code no. K6219 and K6218, respectively; DAKO Corp., Copenhagen, Denmark).
DPP-IV activity in plasma was assessed with a flourimetric method using H-glycyl-prolyl-AMC (AMC is 7-amino-4-methylcoumarin) as the substrate for the reaction as described previously (20). DPP-IV activity was expressed as mU/ml, where 1 mU corresponds to 1 µmol substrate cleaved per minute, calculated by interpolation from a curve constructed of AMC dissolved in assay buffer.
Antibodies to GAD and IA-2 were measured by a radioligand binding assay, using full-length recombinant human GAD65 or IA-2, as described previously (21). The threshold for positivity was defined as 3 SD above the mean of 276 healthy Danish control individuals with normal glucose tolerance.
Lipids. NEFA were measured by an enzymatic spectrophotometric method as described previously (22).
HbA1c was measured at the laboratory of Steno Diabetes Hospital (Gentofte, Denmark) using an ion exchange high-performance liquid chromatography method endowing the analysis with an interassay coefficient of variation of 0.15 percentage points in the range of 4.7–11.3% (normal range, 4.1–6.4%).
Statistical analysis
Comparisons between two, three, and four groups were carried out by means of multifactor ANOVA with subsequent post hoc analysis (Least Significant Differences). Groups were not matched, and the statistical analyses were corrected for significant covariates. For each individual, a glucose disappearance rate, Kg, was determined as the linear slope of the logarithmically transformed PG concentrations. Correlation analyses were performed by using Spearman’s rho (R), and multiple regression analysis was carried out as forward regression. One-way ANOVA analysis was performed to evaluate the time-related changes of plasma glucagon. The software used for statistical analyses was STATGRAPHICS Plus, version 3.3 for windows (Rockville, MD).
All results are presented as mean ± SEM. The level of statistical significance was set at P less than 0.05.
On the basis of the mean of three values of F-PG and fasting plasma insulin concentrations, insulin sensitivity, Si, and ß-cell function were calculated according to the HOMA 2 model (23).
The designation " insulin" concentrations are used for peak
insulin minus fasting insulin (F-insulin) concentrations and "
glucagon" for fasting glucagon minus nadir glucagon
concentrations.
Results
GAD, IA2
One female patient was marginally positive on IA2ab analysis but was considered a true type 2 diabetic patient on clinical grounds and a fasting C-peptide concentration of 364 pmol/liter. One male patient had a very high level of GADab, and, although fasting C-peptide concentration was 892 pmol/liter, probably has Late Autoimmune Diabetes of the Adult. We did not exclude these two patients from the analysis. No patients was positive for both GADab and IA2ab.
Diabetic neuropathy and autonomic dysfunction results
According to the classification criteria, 11 patients had diabetic polyneuropathy. These patients were characterized by a significantly higher HbA1c and F-PG and a lower F-insulin level and ß-cell function compared with the 35 patients without neuropathy. No difference with respect to age, BMI, diabetes duration, intact GLP-1 levels, C-peptide parameters, NEFA, and Si was found.
Treatment groups
The 19 diet-treated patients (Table 2) had the lowest HbA1c, F-PG, and
F-NEFA and the best ß-cell function, whereas the 5 patients on
combined sulfonylurea plus biguanide (SU+B) had the highest HbA1c,
F-PG, F-NEFA, and a poor ß-cell function. The 10 B-treated patients
were generally the youngest and had the highest BMI, and the 15
SU-treated patients were oldest and had the lowest BMI. The groups had
similar fasting GLP-1, insulin, and C-peptide levels, and
similar area under the curve (AUC) and plateau GLP-1
levels. One patient was treated with insulin and, therefore, excluded
from the calculations.
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PG concentrations decreased in all patients on iv infusion of
GLP-1 (Fig. 1). Mean F-PG
levels were reduced from 12.1 ± 0.6 to a mean of 7.0 ± 0.4
after 240 min of infusion. On dividing the patients into groups with
F-PG lower than 10 (n = 21), F-PG 10–15 (n = 15), and F-PG
15 mmol/liter (n = 14) or higher, F-PG was reduced from 8.0
± 0.3, 12.3 ± 0.4, and 17.9 ± 0.7 mmol/liter,
respectively, to 5.3 ± 0.1, 6.5 ± 0.3, and 10.0 ± 1.0
mmol/liter after a 240-min infusion (P < 0.001).
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Levels of insulin, C-peptide, glucagon, and NEFA are shown in Fig. 2 and Table 1
, the latter also showing
data on intact and total GLP-1, DPP-IV activity, ß-cell
function, and Si. The insulin and C-peptide results
illustrate the glucose-dependent insulinotropic effect of
GLP-1 with early increases of insulin (A) and C-peptide
(B) concentrations, which abated toward the end of infusion as glucose
concentrations approached the normoglycemic level (Fig. 1). As insulin
concentrations increased, NEFA concentrations (C) were suppressed and,
with the declining insulin levels, returned to toward basal levels at
the end of the 4-h infusion. The GLP-1 infusion decreased
glucagon concentrations (D), which, despite remaining below basal
levels in all patients, increased insignificantly at the end of the
infusion in the two groups with the lower F-PG and remained depressed
in the group with the high F-PG (one-way ANOVA of time effect on plasma
glucagon levels in the period from the from the lowest glucagon
concentration to 240 min.).
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Mean Kg was 0.38 ± 0.02%/min (range,
0.11–0.78%/min). Dividing the patients in PG groups as described
above, as shown in Fig. 1, Kg was 0.45 ± 0.03,
0.38 ± 0.04, and 0.28 ± 0.04%/min; P
(ANOVA) = 0.005, Kg being significantly higher in the
F-PG group less than 10 vs. F-PG 15 or more; age, BMI ,and
gender were not significant covariates.
In the four treatment groups, Kg was 0.46 ± 0.03 [diet (D)], 0.42 ± 0.04 (B), 0.32 ± 0.04 (SU), 0.23 ± 0.6 (SU+B) %/min; P(ANOVA) = 0.002. The difference between treatment groups disappeared upon correction for F-PG (P = 0.4) showing that it was caused by the variation of Kg with the F-PG level and not by treatment per se.
In the patients without diabetic neuropathy, Kg was 0.41 ± 0.02 and in the patients with diabetic neuropathy 0.29 ± 0.04%/min; P (ANOVA) = 0.03, but on correction for F-PG no significant difference was present (P = 0.3), indicating that the slower rate of disappearance in the neuropathy group was explained by the higher F-PG.
Table 3 shows that Kg
correlated positively to ß-cell function (expressed logarithmically)
and to insulin (fasting, peak, and ), and inversely to HbA1c, F-PG,
DPP-Iv activity, f-NEFA and AUC NEFA. There was no correlation to BMI,
nor to any GLP-1, C-peptide, or glucagon measure.
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Nadir-PG values
Of the 50 patients, 39 reached a stable nadir (34 within 240 min
and another 5 during continued infusion), and their the individual
results are shown in Fig. 3A. In these 39
patients, mean F-PG in the three F-PG groups was reduced from 7.9
± 0.3 mmol/liter, 12.0 ± 0.5, and 17.7 ± 1.1 mmol/liter to
mean Nadir-PGs of 4.7 ± 0.1 mmol/liter, (range, 3.9–5.9
mmol/liter, n = 19), 5.8 ± 0.4 mmol/liter (4.3–8.4
mmol/liter, n = 11), and 8.7 ± 1.4 mmol/liter (6.2–18.7
mmol/liter, n = 9), corresponding to a maximal reduction of
3.2 ± 0.3, 6.2 ± 0.2 and 9.0 ± 0.5 mmol/liter,
respectively. Gender, BMI, and age were insignificant covariates.
Individual F-PG and end- infusion PG of the 11 patients, who did
not reach a stable nadir during the infusion (i.e. who
continued to show a fall after 4–6 h of infusion) are shown in Fig. 3B.
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shows that Nadir-PG correlated
positively to HbA1c, F-PG, F-NEFA, AUC NEFA, DPP-IV activity,
glucagon, F-GLP-1 of total and intact hormone, and
inversely to Kg and ß-cell function. The correlation to
F-insulin was near significant (r = -0.27; P =
0.10). Nadir-PG did not correlate significantly to AUC/plateau of
intact or total GLP-1, nor to any insulin or C-peptide
parameter.
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glucagon, logarithm of ß-cell function,
and Kg). If F-GLP-1 of total hormone
concentration is included in the analysis R2
value increases slightly (to 77%). GLP-1
GLP-1 concentrations of total and intact hormone are
shown in Fig. 4. Mean plateau level
(30–240 min) of total GLP-1 was 98 ± 6 pmol/liter
and of intact GLP-1 24 ± 1 pmol/liter, consistent
with GLP-1 levels measured in other studies using the same
GLP-1 infusion rate. Neither intact nor total
GLP-1 concentrations correlated with Kg or
Nadir-PG. On dividing the patients into groups with GLP-1
concentrations (total or intact) below 75% of mean in one group and
the rest in a second group no difference with respect to 240 min-PG,
Kg or Nadir-PG was found with or without correction for
F-PG, indicating that differences in the GLP-1
concentration obtained by the infusion were not responsible for the
difference of the glucose lowering effect of GLP-1.
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In this study a heterogeneous group of 50 patients with type 2 diabetes received an iv GLP-1 infusion. No patients could be classified as nonresponders on the GLP-1 infusion. In all patients PG levels were reduced during the infusion to levels below those expected from a placebo infusion (2–3 mmol/liter during 4 h in Ref. 7). At the same time, insulin and C-peptide concentrations were increased and glucagon levels and NEFAs decreased. The combined action of the stimulated insulin and the inhibited glucagon secretion is supposed to be responsible for the glucose lowering effect of GLP-1, but whereas insulin returned to preinfusion levels with the falling plasma glucose, glucagon levels remained below the basal level. Thus, glucagon might be assumed to play an important role for maintaining the glucose level at the new equilibrium, which was also indicated by the strong correlation between Nadir-PG and the degree of suppression of glucagon below basal. Nevertheless, multiple regression analysis only identified F-PG as predictor of the actual Nadir-PG obtained.
Of the 39 patients reaching a stable Nadir-PG, mean F-PG in the three groups was reduced from 7.9 ± 0.3 mmol/liter, 12.0 ± 0.5 and 17.7 ± 1.1 mmol/liter, respectively, to 4.7 ± 0.1 mmol/liter (range, 3.9–5.9 mmol/liter), 5.8 ± 0.4 mmol/liter (range, 4.3–8.4 mmol/liter), and 8.7 ± 1.4 mmol/liter (range, 6.2–18.7 mmol/liter), corresponding to a maximal reduction of 3.2 ± 0.3, 6.2 ± 0.2 and 9.0 ± 0.5 mmol/liter, respectively. Thus, GLP-1 effectively reduced F-PG with the highest absolute value in the most poorly regulated patients. However, not all patients reached normoglycemia or near-normoglycemia in the present study despite the fact that the GLP-1 infusion was continued in the majority of the patients until the glucose lowering effect of GLP-1 had ceased. This contrasts to several other studies with similar mean F-PG levels (11–12 mmol/liter) and GLP-1 infusion rates (1.2 pmol/kg·min) in which all patients were reported to reach normoglycemia (7, 8).
In the present study, in patients with F-PG less than 15 mmol/liter,
all but one (with a Nadir-PG of 8.4 mmol/liter) had Nadir-PGs in the
normoglycemic range. The patients in the this study with F-PG less than
15 mmol/liter generally resemble the patients in previous studies, and
the glucose lowering effect of GLP-1 in our patients with
F-PG less than 15 mmol/liter is comparable with results of previous
studies. The two patients with very high F-PGs and high Nadir-PGs were
also characterized by a very poor ß-cell function and a low
insulin, which seemed to be insufficient to normalize glucose
concentrations. At least, insufficient concentrations of intact
biologically active GLP-1 is unlikely to explain the
inadequate glucose reduction because the patients had levels above mean
and just below mean, respectively.
Multiple regression showed that the only predictors of the level of
Nadir-PG were F-PG and Kg (i.e. high F-PG and low
Kg resulted in higher levels of Nadir-PG). However, the
correlation analysis also showed significant positive correlations to
glucagon suppression and NEFA in addition to the F-PG, and inverse
relationships to ß-cell function and Kg, indicating that
also glucagon inhibition and ß-cell function are important for the
level of Nadir-PG. The insulin response to GLP-1 (either
peak or values) did not seem to affect Nadir-PG. This is probably
because neither patients with very low nor very high F-PG had large
insulin responses but for different reasons; patients with low F-PG
because the stimulation of the glucose dependent insulin secretion
abated quickly as PG decreased and the patients with high F-PG because
they had a poor ß-cell function. In contrast to Nadir-PG,
Kg correlated positively to both fasting levels, peak levels
and increments of insulin, but not to glucagon inhibition. In multiple
regression analysis only F-PG was a significant determinant of
Kg (high F-PG resulted in low rate of glucose
disappearance). However, besides the importance of F-PG for determining
Nadir-PG and Kg, the insulin response, due to the
correlation to Kg, might influence the glucose disappearance
rate, whereas the glucagon inhibition, due to the correlation to
Nadir-PG and due to the prolonged suppression throughout the infusion
period, might be more important for the glycemic levels eventually
obtained.
Kg, Nadir-PG, or 240 min PG were neither related to treatment with diet, sulfonylurea or biguanide, neuropathy status, BMI, age, or gender. Concentrations of intact biologically active GLP-1 did not explain the variations of Kg, 240 min PG or Nadir-PG.
GLP-1 has been suggested as a therapeutic agent in the management of type 2 diabetes. However, suitable means of administration are still to be found. Furthermore, GLP-1 treatment in nonfasting patients is a different situation even though a decreased rate of gastric emptying and possibly a decreased appetite may add to the effectiveness of the glucose lowering effect of GLP-1. According to the present study, one might doubt that monotherapy with GLP-1 will be able to fully normalize glucose concentrations in patients with very high F-PG and poor ß-cell function, whereas GLP-1 treatment in the majority of patients with less severe diabetes is promising. In addition, all patients including the ones with very high F-PG may benefit from a trophic effect of GLP-1 on the ß-cell which in vitro has been shown to exist (24, 25); however, it is not yet known to what extent this effect is clinically important.
In summary, the present study confirmed the glucose-lowering effect of GLP-1 in fasting type 2 diabetic patients. No nonresponders to iv GLP-1 infusion were identified. The majority of fasting type 2 diabetic patients—but not all—can be expected to reach normoglycemia. Levels of Nadir-PG concentration obtained were predicted by F-PG and rate of glucose disappearance (high F-PG and low Kg resulted in high Nadir-PG), and the rate of glucose disappearance was only determined by F-PG (high F-PG resulted in high Nadir-PG). In addition, rate of glucose disappearance might be influenced by the insulin response whereas the glucagon inhibition might be important for the glycemic levels eventually obtained.
Acknowledgments
We thank Gertrud Petersson, Susanne Reimer, and Vladimira Tidsvilde (Hvidovre Hospital); and Lene Albæk and Rigmor Holck (the Panum Institute) for technical assistance. Karina Lykke Rasmussen (Hvidovre Hospital) performed the biothesiometry. Thure Krarup, chief physician at department of internal medicine F, Gentofte University Hospital, kindly allowed us to study six of his patients.
Footnotes
This study was supported by the Danish Diabetes Association, The Foundation of Poul & Erna Sehested Hansen, The Danish Medical Association Research Fund, Danish Medical Research Council, and the NOVO Nordisk Foundation. J.J.H. is a member of the Biotechnology Center for Signal Peptide Research.
Abbreviations: B, Biguanide, BMI, body mass index; D, diet; DPP-IV, dipeptidyl peptidase activity; F-PG, fasting plasma glucose; Kg, glucose disappearance constant; Nadir-PG, Nadir plasma glucose; NEFA, nonesterified fatty acid; PG, plasma glucose; SU, sulfonylurea.
Received January 29, 2001.
Accepted April 18, 2001.
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•), F-PG group
10–15 mmol/liter (n = 15; 
—-
15
mmol/liter (n = 14; 
—
) is
shown. B, Individual F-PG and end- infusion PG (=Final-PG;
