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Department of Endocrinology, Hvidovre Hospital, University of Copenhagen (M.-B.T.-N., M.B.D., S.M.), DK-2650 Hvidovre, Denmark; Department of Medical Physiology, Panum Institute, University of Copenhagen (M.-B.T.-N., J.J.H.), DK-2200 Copenhagen N, Denmark; Department of Clinical Chemistry, Rigshospitalet, University of Copenhagen (L.M.H.), DK-2100 Copenhagen Ø, Denmark; Metabolic and Cardiovascular Diseases Research, Novartis Institute for Biochemical Research (T.E.H.), Summit, New Jersey 08901; and Department of Diabetes Autoimmunity, Hagedorn Research Institute (B.K.M.), DK-2820 Gentofte, Denmark
Address all correspondence and requests for reprints to: Jens Juul Holst, M.D., Department of Medical Physiology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. E-mail: holst{at}mfi.ku.dk
Abstract
To elucidate the causes of the diminished incretin effect in type 2 diabetes mellitus we investigated the secretion of the incretin hormones, glucagon-like peptide-1 and glucose- dependent insulinotropic polypeptide and measured nonesterified fatty acids, and plasma concentrations of insulin, C peptide, pancreatic polypeptide, and glucose during a 4-h mixed meal test in 54 heterogeneous type 2 diabetic patients, 33 matched control subjects with normal glucose tolerance, and 15 unmatched subjects with impaired glucose tolerance. The glucagon-like peptide-1 response in terms of area under the curve from 0–240 min after the start of the meal was significantly decreased in the patients (2482 ± 145 compared with 3101 ± 198 pmol/liter·240 min; P = 0.024). In addition, the area under the curve for glucose-dependent insulinotropic polypeptide was slightly decreased. In a multiple regression analysis, a model with diabetes, body mass index, male sex, insulin area under the curve (negative influence), glucose-dependent insulinotropic polypeptide area under the curve (negative influence), and glucagon area under the curve (positive influence) explained 42% of the variability of the glucagon-like peptide-1 response. The impaired glucose tolerance subjects were hyperinsulinemic and generally showed the same abnormalities as the diabetic patients, but to a lesser degree. We conclude that the meal-related glucagon-like peptide-1 response in type 2 diabetes is decreased, which may contribute to the decreased incretin effect in type 2 diabetes.
TYPE 2 DIABETES is characterized by hyperglycemia, insulin resistance, absolute or relative insulin deficiency, hyperglucagonemia, increased hepatic glucose production, and frequently accelerated gastric emptying and obesity (1). The positive influence of the incretin hormone glucagon-like peptide-1 (GLP-1) on the metabolic disturbances of type 2 diabetes, including stimulation of insulin secretion (2, 3) and inhibition of glucagon secretion (3, 4), hepatic glucose production (5, 6), gastric emptying (7, 8), and appetite (9, 10), has provided a rationale for its therapeutic use in type 2 diabetes. Furthermore, GLP-1 seems to exert trophic effects on the ß-cell (11).
Several studies have documented the importance of GLP-1 for maintenance of normal glucose tolerance. Thus, GLP-1 receptor-deficient mice exhibit increased glucose levels and diminished insulin levels after an oral glucose challenge (12, 13). In healthy subjects, infusion of the GLP-1 receptor antagonist exendin-(9–39), during an oral glucose tolerance test, increased incremental glucose area under the curves (AUCs), and peak postprandial glucose levels (14). In type 2 diabetic patients the incretin effect is reduced or lost (15, 16). Glucose-dependent insulinotropic polypeptide (GIP) studies are inconclusive to date, with reports of both increased and decreased secretion in studies of diabetic patients compared with nondiabetic subjects (17), but the GIP effect on insulin secretion is decreased in type 2 diabetic patients (18, 19). In contrast, type 2 diabetic patients show a pronounced insulin response to parenterally administered GLP-1 (3, 19). The GLP-1 secretion patterns in type 2 diabetes and type 2 diabetes-related conditions are not clear. They has been reported to be increased (20) or reduced (21, 22) in obese subjects, to be higher in women than in men (23, 24), and to be increased (25, 26), decreased (24), or unaltered (19, 23, 27) in subjects with impaired or diabetic glucose tolerance. However, the early GLP-1 assays were unable to distinguish between GLP-1 from the gut and GLP-1-immunoreactive molecules from the pancreas [i.e. GLP-1-(1–36)amide or -(1–37) and major proglucagon fragment] as inactive by-products of glucagon secretion.
To determine the secretion and possible pathophysiological role of the incretins, GLP-1 and GIP, in type 2 diabetes, we subjected a heterogeneous group of type 2 diabetic (T2DM) patients and matched healthy subjects with normal glucose tolerance (NGT) as well as subjects with impaired glucose tolerance (IGT) to a meal test. We show that the GLP-1 response to a standard meal test in patients with T2DM is decreased, probably as a consequence of the diabetic state.
Subjects and Methods
Subjects
The T2DM group was recruited from the diabetes out-clinic, whereas the groups with NGT or IGT, classified after an oral glucose tolerance test according to the WHO criteria of 1985, responded to an advertisement in a local newspaper. None had a history of bowel disease, alcohol abuse, or, for the NGT/IGT subjects, diabetes among first degree relatives. According to the patients’ medical records, they had normal serum creatinine, normal hepatic function, and no albuminuria.
The T2DM group consisted of 54 type 2 diabetic patients with a mean
diabetes duration of 4.9 ± 5.6 yr (mean ± SD;
see Table 1
for anthropometric data).
Thirty-three control subjects with NGT were matched to the T2DM group
(Table 1). A person to person match was not attempted, but when the
subjects were divided according to body mass index (BMI; 20–25,
25–30, 30–35, and >35 kg/m2) similar means,
medians, and ranges for age, male/female ratios, and BMIs were obtained
in each of the 4 groups for patients compared with volunteers. The IGT
subjects had significantly higher BMI, but similar age and male/female
ratio compared with the T2DM and NGT groups (Table 1).
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Procedure
After 3 d of discontinued antidiabetic medication and an
overnight fast (10 h), the subjects consumed a mixed breakfast meal
containing 2250 kJ (41.8% fat, 40.7% carbohydrate, and 17.5%
protein; fiber content, 6.7 g). The meal was served with coffee or
tea and ingested within 10–15 min. Blood was sampled from a needle in
a forearm vein before the start and during the next 4 h as
indicated in Figs. 1-3 and was
distributed into fluoride tubes for analysis of plasma glucose (PG) and
into EDTA/aprotinin tubes (6 mmol/liter EDTA and 500 kallikrein
inhibitor units aprotinin/ml blood) for analysis of plasma
concentrations of GLP-1, GIP, glucagon, insulin, C
peptide, and pancreatic polypeptide (PP); fasting plasma concentration
of nonesterified fatty acids (NEFA); glutamic acid decarboxylase
(GAD) antibodies (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.
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Analytical methods
Plasma glucose concentrations were analyzed bedside using an 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 (25). Plasma concentrations of amidated GLP-1-(7–36) 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-(7–36)amide and its metabolite GLP-1-(9–36)amide (31). The detection limits and intraassay coefficients of the assays employed are 1 pmol/liter and less than 6% for both glucagon and amidated GLP-1 (antibody 89390), whereas the interassay coefficient of variation was less than 10%. GIP was measured using a C-terminally directed antibody (code no. R65; RIA), reacting 100% with human GIP, but not with so-called 8-kDa GIP (32, 33). The detection limit is 5 pmol/liter, the intraassay coefficient of variation is 9%, and the interassay coefficient of variation is 15–20%. 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). PP concentrations were measured using a previously described specific RIA (34). Intra- and interassay coefficients of variation were less than 13% in the range of 16–50 and 30–75 pmol/liter, respectively.
Antibodies to GAD and IA-2 were measured by a radioligand binding assay, using full-length recombinant human GAD65 or IA-2 as previously described (35). 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 previously described (36).
Hemoglobin A1c was measured at the laboratory of Steno Diabetes Hospital (Gentofte, Denmark), using an ion exchange HPLC method 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 and calculations
Nonparametric statistical methods were generally used, i.e. Mann-Whitney’s test for comparison of two groups (T2DM vs. NGT and neuropathy vs. nonneuropathy T2DM patients) and Kruskal-Wallace test for comparison of three groups (T2DM, NGT, and IGT). However, in the case of comparison of nonmatched groups in which correction for covariates would seem necessary (comparison between the different T2DM treatment groups; T2DM vs. NGT vs. IGT; neuropathy vs. nonneuropathy T2DM patients), we used multiple comparison ANOVA followed by a post-hoc test, least significant differences, and correction for significant covariates, such as BMI, gender, and age. Multiple regression analysis with the GLP-1 and the GIP response as the dependent variable was carried out as forward and backward regressions for T2DM and NGT separately, together, and with IGT included. No colinearity was apparent for the variables included in the regression analysis. In the case of non-Gaussian distribution in the ANOVA or of the dependent variable in the multiple regression analysis, data were logarithmically transformed.
AUC was calculated as incremental areas above zero, and incremental AUC was calculated as AUC above basal.
Results are presented as the mean ± 1 SD or as the mean ± SEM. The level of statistical significance was set at P < 0.05.
Results
GAD, IA2
Upon IA2ab analysis, 1 female patient of the 102 subjects (54 T2DM, 33 NGT, and 15 IGT) was marginally positive, but was most likely a true type 2 diabetic patient (fasting C peptide concentration of 534 pmol/liter). Upon GADab analysis, two subjects with NGT were marginally positive, and 1 male T2DM patient had a very high level of GADab. Although he had a fasting C peptide concentration of 1119 pmol/liter, he probably has late autoimmune diabetes of the adult. Neither of the subjects was excluded from the analysis.
NEFA
Fasting NEFA concentrations were the same for T2DM and NGT,
whereas the level in IGT was a little higher (Table 1
). There was no
significance between groups.
Glucose
Plasma glucose concentrations (Fig. 1, upper panel) at
all time points, including the fasting state, were significantly higher
for T2DM compared with NGT and IGT and so were the AUCs. IGT values
were higher than NGT values, however, significantly so only at 75 min
(Tables 1 and 2).
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T2DM and NGT had similar insulin and C peptide fasting levels
(Table 1) and AUCs (Table 2), whereas IGT
had higher levels. After correcting for BMI, only the difference
between AUCs of IGT vs. T2DM remained significant. Peak
insulin concentrations, insulin concentrations at 20–60 min, and C
peptide concentrations at 20–105 min were significantly lower in T2DM
compared with NGT and IGT (Fig. 1). The time to reach the peak C
peptide concentration was significantly delayed in T2DM compared with
those in NGT and IGT. The delay in C peptide levels for IGT was not
significant.
Glucagon
T2DM had significantly higher glucagon concentrations at all time
points and significantly higher AUCs compared with NGT (Tables 1 and 2
and Fig. 2, upper panel). IGT
tended to have higher values than NGT, significantly so at 20–75, 210,
and 240 min.
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Fasting levels and AUCs of PP were similar for all groups, but in
the curve for T2DM the early peak was reduced (Table 2 and Fig. 2, middle panel).
GIP
As shown in Table 1, the fasting GIP level in the T2DM was
insignificantly higher than those in the NGT and IGT group. The GIP
meal response (Table 2 and Fig. 2) was slightly, but significantly
(P = 0.047), decreased in the T2DM compared with the
NGT group, but this difference was absent in the BMI and
gender-corrected ANOVA analysis for all three groups. Peak values were
similar in all groups.
GLP-1
Fasting GLP-1 concentrations were significantly
higher in T2DM than in NGT (Table 1), but there was no difference
between the three groups upon ANOVA, and no significant covariates were
found. Postprandial GLP-1 levels (Fig. 3) and AUC were significantly decreased
in T2DM compared with NGT (Table 2), and, upon ANOVA analysis
correcting for BMI and gender, they were also decreased compared with
IGT values. The GLP-1 AUC of the IGT group ranged between
those of T2DM and NGT. The GLP-1 AUC was lower in males
and decreased with increasing BMI. BMI- and gender-corrected
GLP-1 AUC means were 2464 (T2DM), 2907 (IGT), and 3066
(NGT) pmol/liter·240 min (P = NS for NGT
vs. IGT group). The incremental GLP-1 response
in the T2DM group was even more impaired (Table 2), and here also IGT
levels ranged between T2DM and NGT values.
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The 15 (13 men and 2 women) patients with and the 35 (27 men and 8 women) patients without diabetic neuropathy had similar age, BMI, and hemoglobin A1c. The patients with diabetic neuropathy had significantly higher fasting PG (13.5 ± 1.2 vs. 11.0 ± 0.6; P = 0.09, by Wilcoxon; P = 0.015, by ANOVA correcting for gender) and significantly lower insulin and C peptide responses (not shown). The GLP-1 meal response tended to be higher in the patients with neuropathy (2752 ± 285 vs. 2371 ± 176; P = 0.26 without and P = 0.28 with correction for BMI and gender). Incremental AUCs were similar. The GIP and PP responses did not differ significantly between groups. Of the 15 patients with neuropathy, 5 patients also had autonomic nerve dysfunction; of these, 1 had a GLP-1 AUC below, and 4 had a GLP-1 AUC above the group mean.
Treatment groups in T2DM
The 54 T2DM patients were treated with diet (D), sulfonylurea (SU), biguanide (B), or sulfonylurea and biguanide (SU+B; n = 19/16/12/7). In these groups SU patients were the oldest, had the lowest BMI, and, together with SU+B, had the highest fasting glucose. Group B patients were the youngest, and group D patients were the most well regulated. There was no difference with respect to diabetes duration. The GLP-1 responses in terms of AUC were significantly different between groups (D, 1964 ± 216; SU, 3151 ± 238; B, 2504 ± 337; SU+B, 2318 ± 283 pmol/liter·240 min), with the D group being significantly lower than the SU group and, after correcting for BMI, also significantly lower than the B group. Thus, the most well regulated T2DM patients had the lowest GLP-1 response. Multiple regression with GLP-1 AUC as the dependent factor showed that BMI (negative influence), fasting glucose (positive influence), and glucagon AUC (positive influence), but not any treatment modality, were determining factors of the GLP-1 response. The incremental GLP-1 response was not significantly different between any of the treatment groups after adjusting for BMI, age, and gender.
Covariates
As shown in Table 2, BMI was a significant covariate for fasting
levels and AUCs of insulin, C peptide, glucagon (higher values with
higher BMI), and for AUC for GIP and for AUC and incremental AUC for
GLP-1 (lower values with increasing BMI). Gender was a
significant covariate for fasting and AUC of glucose due to higher
glucose values in T2DM females than in T2DM males and for AUC for GIP,
AUC for GLP-1, and incremental AUC for GLP-1,
for which females had higher values than males. Finally, PP increased
with age.
Multiple regression analysis
Multiple regression analysis for the combined groups, T2DM/NGT, was conducted with GLP-1 AUC, incremental AUC for GLP-1, or GIP AUC as dependent variables. The independent variables were diabetic state, age, BMI, gender, NEFA, and AUCs of PG, insulin, glucagon, PP, and GLP-1/GIP, respectively. The AUC for C peptide could not be included due to colinearity. Fasting glucose was not included because the subjects were denoted T2DM or NGT. However, by Spearmann correlation analysis in the T2DM there was a significant positive correlation between GLP-1 AUC and fasting glucose (r = 0.44; P = 0.0013), i.e. the higher the PG, the higher the GLP-1 response.
With GLP-1 AUC as dependent parameter, forward and backward regression showed that a model with diabetes, male sex, BMI, insulin AUC, GIP AUC, and glucagon AUC explained 42% (adjusted r2) of the variation of the GLP-1 response. Except for glucagon, which had a positive coefficient and thus was increasing the GLP-1 response, the rest of the parameters had negative coefficients, resulting in a negative influence on the GLP-1 response. The model of multiple regression analysis with incremental GLP-1 AUC as the dependent parameter differed only by leaving out insulin AUC and GIP AUC. With GIP AUC as the dependent parameter, a model with BMI, male sex, diabetes and GLP-1 AUC (all with negative coefficients) explained only 15% of the variation.
Discussion
In the present study the meal-stimulated GLP-1 response was measured in patients with type 2 diabetes and compared with that in carefully matched subjects with NGT. In addition, a group of subjects with IGT was investigated. We found that the meal-stimulated GLP-1 response, expressed as both the total AUC and the incremental AUC, was significantly decreased in patients with type 2 diabetes. Consistent with this, the subjects with IGT had GLP-1 responses in between those of the controls and the patients regardless of whether significant covariates (gender and BMI) were taken into account. A slight impairment of GIP secretion was also observed in the patients. As demonstrated in animal experiments, and for GLP-1 also in healthy volunteers, the incretin effect, for which GLP-1 and GIP are normally responsible, is important for the maintenance of NGT (12, 14, 37). Decreased incretin secretion, therefore, may worsen already existing diabetes mellitus or, theoretically, may contribute to the development of diabetes.
Because of the large number of very heterogeneous patients studied, it
was possible to search for factors influencing GLP-1
secretion. Hyperglycemia per se is unlikely to be
responsible for the decreased GLP-1 response, as indicated
by an unexpected positive correlation between blood glucose and
GLP-1 response in the T2DM group. Consistent with the
significantly lower GLP-1 response in the T2DM compared
with the NGT, diabetes was found to be a significant determinant for
the GLP-1 response by multiple regression analysis. This
is in agreement with results obtained by Vaag et al.
(24), who studied a small group of monozygotic twins
discordant for diabetes. Furthermore, gender and BMI turned out to both
be determinants of the GLP-1 response in the multiple
regression analysis and significant covariates in the ANOVA analysis.
Males had a smaller response than females, in agreement with results
presented by Nauck et al. (23) and Vaag
et al. (24). The GLP-1 response
decreased with the degree of obesity, consistent with the results
reported by Ranganath et al. (21) and
Näslund et al. (22). The negative
relation between insulin AUC and the GLP-1 response was
unexpected, but may illustrate a hitherto undescribed negative feedback
effect of insulin on GLP-1 secretion. By multiple
regression analysis, GIP had a barely significant, negative influence
on the GLP-1 response. Thus, we found no support for a
positive feedback mechanism of GIP on the L cell and, therefore, no
support for the hypothesis that GIP promotes GLP-1
secretion as observed in rats (38). The strong positive
influence of glucagon on the GLP-1 response found in the
multiple regression analysis is also difficult to explain. It may be
caused by a factor in the meal stimulating both the intestinal L cell
and the pancreatic 
cell. A glucose challenge does not promote
glucagon secretion, but the protein content of meals does. Peptones
(protein hydrolysates) have recently been shown to stimulate the L cell
(39), and therefore, the relatively high protein content
(17.5%) in the meal may be the link between the parallel glucagon and
GLP-1 secretion.
In this study several factors were excluded as determinants of the GLP-1 response; hence, treatment with sulfonylureas or biguanides, neuropathy, and fasting NEFA concentrations did not seem to affect the GLP-1 response to a detectable level. The diet-treated patients had the lowest GLP-1 response (total AUC), whereas the incremental GLP-1 response was not significantly different between any of the treatment groups, after adjusting for BMI, age, and gender differences. In the present study the 15 patients with diabetic neuropathy had an insignificantly higher GLP-1 response both with and without correction for covariates, and four of five patients with autonomic nerve dysfunction, who may have defective neural signaling, had GLP-1 responses above the mean. We conclude that the decreased GLP-1 responses are unlikely to be related to neural dysfunction in this patient group and, thus, do not support the results of Rocca et al. (40), who reported that vagal activity was important for GLP-1 secretion in rats. Recently, it was hypothesized that NEFA inhibit the L cell (41). However, in this study the fasting concentrations of NEFA were similar in the diabetic and NGT groups, and NEFA were not a significant determinant either in the multiple regression analysis including T2DM alone or in the total T2DM plus NGT group, apparently excluding NEFA as a major regulator of GLP-1 secretion.
A possible explanation for the decreased GLP-1 secretion
may be a decreased gastric emptying rate, which hypothetically might
increase the absorption in the proximal intestine resulting in less
food reaching the distal intestine where the L cells are more numerous.
Indeed, the opposite situation, increased exposure of carbohydrates to
the distal intestinal mucosa by -glucosidase inhibitors or
accelerated gastric emptying, increases GLP-1 secretion
(42, 43). However, the gastric emptying rate does not seem
to exhibit consistent changes in T2DM and obesity, but is more often
reported as delayed (44, 45). The gastric emptying rate in
males is believed to be faster than that in premenopausal females, but
this sex difference may disappear (46) (but probably not
revert to the opposite) in the postmenopausal state. Almost all of the
women participating in this study were postmenopausal, and therefore,
gastric emptying rates would not be expected to explain the sex
difference observed here. However, proximal absorption rates could
hypothetically explain a decreased GLP-1 secretion in the
patients. Obese subjects may have an increased proximal absorption rate
(47), which could thus provide an explanation for the
decreased GLP-1 secretion with increasing BMI. Proximal
absorption rates in diabetic patients compared with nondiabetic
subjects and in males compared with females have not been investigated
to our knowledge.
Our finding of a decreased GLP-1 response in T2DM contrasts to earlier reports of unaltered (19, 23, 27) or even increased (24, 26) GLP-1 secretion in subjects with impaired or diabetic glucose tolerance. The discrepancy can at least partly be explained by use of different GLP-1 assays. The assays used in the studies by Fukase et al. (20, 26) and Ørskov et al. (25) were nonspecific and cross-reacted with several pancreatic GLP-1-containing peptide moieties such as the major proglucagon fragment and GLP-1-(1–37). Patients with type 2 diabetes and obesity have hyperglucagonemia, and as glucagon secretion is paralleled by a release of pancreatic GLP-1-containing proglucagon-processing products, the high levels of GLP-1 immunoreactivity in these two studies were probably due to hypersecretion of such products. The assay employed in the present study cross-reacts very little with other proglucagon products. It measures the COOH-terminus and, therefore, the sum of the biologically active intact molecule GLP-1-(7–36)amide and the primary inactive metabolite GLP-1-(9–36) amide. The use of this assay rather than an NH-terminal assay measuring only the intact, biologically active GLP-1 (48) is essential to estimate the rate of secretion of GLP-1, because the hormone is metabolized intravascularly and extremely rapidly (with an apparent half-life of 1–1.5 min and a clearance rate that greatly exceeds cardiac output). Thus, it is the sum of the concentrations of the primary metabolite and the intact hormone that reflects the secretory rate of the L cell. In fact, under certain circumstances peripheral concentrations of intact GLP-1 may remain constant despite increasing concentrations of metabolite (49). In agreement with this observation, recent research has demonstrated that the majority of GLP-1 secreted from the intestine in pigs is metabolized in the intestinal capillary bed before it enters the systemic circulation (50). Presumably, in this situation GLP-1 acts as a paracrine transmitter acting on mucosal nerve endings before being degraded (51), with the potential of activating pancreatic insulin secretion reflexly (52, 53). These recent findings underscore the importance of measuring the intact hormone as well as the primary metabolite for estimation of L cell activity.
We conclude that GLP-1 secretion is significantly impaired in type 2 diabetes, most likely as a consequence of the disease.
Acknowledgments
We thank Gertrud Petersson, Susanne Reimer, and Vladimira Tidsvilde (Hvidovre Hospital) and Hanne Mathiesen and Lene Albæk (Panum Institute) for technical assistance. Karina Lykke Rasmussen (Hvidovre Hospital) performed the biothesiometry, and Grete Hansen (Hvidovre Hospital) composed the meal. Thure Krarup, chief physician at Department of Internal Medicine F, Gentofte University Hospital, kindly allowed us to study six of his patients.
Footnotes
This work was supported by the Danish Diabetes Association, the Foundation of Poul and Erna Sehested Hansen, the Danish Medical Association Research Fund, the Danish Medical Research Council, and the NOVO Nordisk Foundation.
J.J.H. is a member of the Biotechnology Center for Signal Peptide Research.
Abbreviations: AUC, Area under the curve; B, biguanide treatment; BMI, body mass index; D, treated with diet; GAD, glutamic acid decarboxylase; GADab, GAD antibodies; GIP, glucose-dependent insulinotropic polypeptide; IGT, impaired glucose tolerance; NEFA, nonesterified fatty acids; NGT, normal glucose tolerance; PG, plasma glucose; PP, pancreatic polypeptide; SU, sulfonylurea treatment; T2DM, type 2 diabetes mellitus.
Received December 1, 2000.
Accepted April 20, 2001.
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 E. T. Parlevliet, J. P. S.-v. d. Elst, E. P. M. Corssmit, K. Picha, K. O'Neil, V. Stojanovic-Susulic, T. Ort, L. M. Havekes, J. A. Romijn, and H. Pijl CNTO736, a Novel Glucagon-Like Peptide-1 Receptor Agonist, Ameliorates Insulin Resistance and Inhibits Very Low-Density Lipoprotein Production in High-Fat-Fed Mice J. Pharmacol. Exp. Ther., January 1, 2009; 328(1): 240 - 248. [Abstract] [Full Text] [PDF]
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M. Salehi, T. P. Vahl, and D. A. D'Alessio Regulation of Islet Hormone Release and Gastric Emptying by Endogenous Glucagon-Like Peptide 1 after Glucose Ingestion J. Clin. Endocrinol. Metab., December 1, 2008; 93(12): 4909 - 4916. [Abstract] [Full Text] [PDF]
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 W. Kim and J. M. Egan The Role of Incretins in Glucose Homeostasis and Diabetes Treatment Pharmacol. Rev., December 1, 2008; 60(4): 470 - 512. [Abstract] [Full Text] [PDF]
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J. J. Holst Pharmacology of GLP-1-based therapies The British Journal of Diabetes & Vascular Disease, November 1, 2008; 8(2_suppl): S10 - S18. [Abstract] [PDF]
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C. W. Chia and J. M. Egan Incretin-Based Therapies in Type 2 Diabetes Mellitus J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 3703 - 3716. [Abstract] [Full Text] [PDF]
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B. Laferrere, J. Teixeira, J. McGinty, H. Tran, J. R. Egger, A. Colarusso, B. Kovack, B. Bawa, N. Koshy, H. Lee, et al. Effect of Weight Loss by Gastric Bypass Surgery Versus Hypocaloric Diet on Glucose and Incretin Levels in Patients with Type 2 Diabetes J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2479 - 2485. [Abstract] [Full Text] [PDF]
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 M. Salehi, B. A. Aulinger, and D. A. D'Alessio Targeting {beta}-Cell Mass in Type 2 Diabetes: Promise and Limitations of New Drugs Based on Incretins Endocr. Rev., May 1, 2008; 29(3): 367 - 379. [Abstract] [Full Text] [PDF]
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E. Muscelli, A. Mari, A. Casolaro, S. Camastra, G. Seghieri, A. Gastaldelli, J. J. Holst, and E. Ferrannini Separate Impact of Obesity and Glucose Tolerance on the Incretin Effect in Normal Subjects and Type 2 Diabetic Patients Diabetes, May 1, 2008; 57(5): 1340 - 1348. [Abstract] [Full Text] [PDF]
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M. Ferdaoussi, S. Abdelli, J.-Y. Yang, M. Cornu, G. Niederhauser, D. Favre, C. Widmann, R. Regazzi, B. Thorens, G. Waeber, et al. Exendin-4 Protects {beta}-Cells From Interleukin-1{beta}-Induced Apoptosis by Interfering With the c-Jun NH2-Terminal Kinase Pathway Diabetes, May 1, 2008; 57(5): 1205 - 1215. [Abstract] [Full Text] [PDF]
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 C. L. Martin Beyond Glycemic Control: The Effects of Incretin Hormones in Type 2 Diabetes The Diabetes Educator, May 1, 2008; 34(Supplement_3): 66S - 72S. [Abstract] [Full Text] [PDF]
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 L R Ranganath Incretins: pathophysiological and therapeutic implications of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 J. Clin. Pathol., April 1, 2008; 61(4): 401 - 409. [Abstract] [Full Text] [PDF]
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 D. Q. Pham, A. Nogid, and R. Plakogiannis Sitagliptin: A novel agent for the management of type 2 diabetes mellitus Am. J. Health Syst. Pharm., March 15, 2008; 65(6): 521 - 531. [Abstract] [Full Text] [PDF]
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K. Vollmer, J. J. Holst, B. Baller, M. Ellrichmann, M. A. Nauck, W. E. Schmidt, and J. J. Meier Predictors of Incretin Concentrations in Subjects With Normal, Impaired, and Diabetic Glucose Tolerance Diabetes, March 1, 2008; 57(3): 678 - 687. [Abstract] [Full Text] [PDF]
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S. P. Choukem and J.-F. Gautier Comment on: Knop et al. (2007) Reduced Incretin Effect in Type 2 Diabetes: Cause or Consequence of the Diabetic State? Diabetes 56:1951 1959 Diabetes, January 1, 2008; 57(1): e1 - e1. [Full Text] [PDF]
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F. K. Knop, T. Vilsboll, S. Madsbad, T. Krarup, and J. J. Holst Response to Comment on: Knop et al. (2007) Reduced Incretin Effect in Type 2 Diabetes: Cause or Consequence of the Diabetic State? Diabetes 56:1951 1959 Diabetes, January 1, 2008; 57(1): e2 - e3. [Full Text] [PDF]
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A. Karamanlis, R. Chaikomin, S. Doran, M. Bellon, F D. Bartholomeusz, J. M Wishart, K. L Jones, M. Horowitz, and C. K Rayner Effects of protein on glycemic and incretin responses and gastric emptying after oral glucose in healthy subjects Am. J. Clinical Nutrition, November 1, 2007; 86(5): 1364 - 1368. [Abstract] [Full Text] [PDF]
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W. J. Lu, Q. Yang, W. Sun, S. C. Woods, D. D'Alessio, and P. Tso The regulation of the lymphatic secretion of glucagon-like peptide-1 (GLP-1) by intestinal absorption of fat and carbohydrate Am J Physiol Gastrointest Liver Physiol, November 1, 2007; 293(5): G963 - G971. [Abstract] [Full Text] [PDF]
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 J. J. Holst The Physiology of Glucagon-like Peptide 1 Physiol Rev, October 1, 2007; 87(4): 1409 - 1439. [Abstract] [Full Text] [PDF]
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A. N. Pilichiewicz, R. Chaikomin, I. M. Brennan, J. M. Wishart, C. K. Rayner, K. L. Jones, A. J. P. M. Smout, M. Horowitz, and C. Feinle-Bisset Load-dependent effects of duodenal glucose on glycemia, gastrointestinal hormones, antropyloroduodenal motility, and energy intake in healthy men Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E743 - E753. [Abstract] [Full Text] [PDF]
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S. Porksen, L. B. Nielsen, A. Kaas, M. Kocova, F. Chiarelli, C. Orskov, J. J. Holst, K. B. Ploug, P. Hougaard, L. Hansen, et al. Meal-Stimulated Glucagon Release Is Associated with Postprandial Blood Glucose Level and Does Not Interfere with Glycemic Control in Children and Adolescents with New-Onset Type 1 Diabetes J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 2910 - 2916. [Abstract] [Full Text] [PDF]
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F. K. Knop, T. Vilsboll, P. V. Hojberg, S. Larsen, S. Madsbad, A. Volund, J. J. Holst, and T. Krarup Reduced Incretin Effect in Type 2 Diabetes: Cause or Consequence of the Diabetic State? Diabetes, August 1, 2007; 56(8): 1951 - 1959. [Abstract] [Full Text] [PDF]
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 R. E. Amori, J. Lau, and A. G. Pittas Efficacy and Safety of Incretin Therapy in Type 2 Diabetes: Systematic Review and Meta-analysis JAMA, July 11, 2007; 298(2): 194 - 206. [Abstract] [Full Text] [PDF]
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 B. Laferrere, S. Heshka, K. Wang, Y. Khan, J. McGinty, J. Teixeira, A. B. Hart, and B. Olivan Incretin Levels and Effect Are Markedly Enhanced 1 Month After Roux-en-Y Gastric Bypass Surgery in Obese Patients With Type 2 Diabetes Diabetes Care, July 1, 2007; 30(7): 1709 - 1716. [Abstract] [Full Text] [PDF]
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C. D. Lauster, T. P. McKaveney, and S. V. Muench Vildagliptin: A novel oral therapy for type 2 diabetes mellitus Am. J. Health Syst. Pharm., June 15, 2007; 64(12): 1265 - 1273. [Abstract] [Full Text] [PDF]
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D. Kim, L. MacConell, D. Zhuang, P. A. Kothare, M. Trautmann, M. Fineman, and K. Taylor Effects of Once-Weekly Dosing of a Long-Acting Release Formulation of Exenatide on Glucose Control and Body Weight in Subjects With Type 2 Diabetes Diabetes Care, June 1, 2007; 30(6): 1487 - 1493. [Abstract] [Full Text] [PDF]
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G. Xu, H. Kaneto, D. R. Laybutt, V. F. Duvivier-Kali, N. Trivedi, K. Suzuma, G. L. King, G. C. Weir, and S. Bonner-Weir Downregulation of GLP-1 and GIP Receptor Expression by Hyperglycemia: Possible Contribution to Impaired Incretin Effects in Diabetes Diabetes, June 1, 2007; 56(6): 1551 - 1558. [Abstract] [Full Text] [PDF]
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Y.-S. Lee, S. Shin, T. Shigihara, E. Hahm, M.-J. Liu, J. Han, J.-W. Yoon, and H.-S. Jun Glucagon-Like Peptide-1 Gene Therapy in Obese Diabetic Mice Results in Long-Term Cure of Diabetes by Improving Insulin Sensitivity and Reducing Hepatic Gluconeogenesis Diabetes, June 1, 2007; 56(6): 1671 - 1679. [Abstract] [Full Text] [PDF]
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B. E. Dunning and J. E. Gerich The Role of {alpha}-Cell Dysregulation in Fasting and Postprandial Hyperglycemia in Type 2 Diabetes and Therapeutic Implications Endocr. Rev., May 1, 2007; 28(3): 253 - 283. [Abstract] [Full Text] [PDF]
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 Y.-L. He, Y. Wang, J. M. Bullock, C. F. Deacon, J. J. Holst, B. E. Dunning, M. Ligueros-Saylan, and J. E. Foley Pharmacodynamics of Vildagliptin in Patients With Type 2 Diabetes During OGTT J. Clin. Pharmacol., May 1, 2007; 47(5): 633 - 641. [Abstract] [Full Text] [PDF]
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B. L. Wajchenberg {beta}-Cell Failure in Diabetes and Preservation by Clinical Treatment Endocr. Rev., April 1, 2007; 28(2): 187 - 218. [Abstract] [Full Text] [PDF]
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B. Ahren Insulin Secretion and Insulin Sensitivity in Relation to Fasting Glucose in Healthy Subjects Diabetes Care, March 1, 2007; 30(3): 644 - 648. [Abstract] [Full Text] [PDF]
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R. Iakoubov, A. Izzo, A. Yeung, C. I. Whiteside, and P. L. Brubaker Protein Kinase C{zeta} Is Required for Oleic Acid-Induced Secretion of Glucagon-Like Peptide-1 by Intestinal Endocrine L Cells Endocrinology, March 1, 2007; 148(3): 1089 - 1098. [Abstract] [Full Text] [PDF]
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 R K. Campbell Rationale for Dipeptidyl Peptidase 4 Inhibitors: A New Class of Oral Agents for the Treatment of Type 2 Diabetes Mellitus Ann. Pharmacother., January 1, 2007; 41(1): 51 - 60. [Abstract] [Full Text] [PDF]
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E. Muscelli, A. Mari, A. Natali, B. D. Astiarraga, S. Camastra, S. Frascerra, J. J. Holst, and E. Ferrannini Impact of incretin hormones on beta-cell function in subjects with normal or impaired glucose tolerance Am J Physiol Endocrinol Metab, December 1, 2006; 291(6): E1144 - E1150. [Abstract] [Full Text] [PDF]
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G. E. Lim and P. L. Brubaker Glucagon-Like Peptide 1 Secretion by the L-Cell: The View From Within Diabetes, December 1, 2006; 55(Supplement_2): S70 - S77. [Abstract] [Full Text] [PDF]
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 S. R. Gambert and S. Pinkstaff Emerging Epidemic: Diabetes in Older Adults: Demography, Economic Impact, and Pathophysiology Diabetes Spectr, October 1, 2006; 19(4): 221 - 228. [Abstract] [Full Text] [PDF]
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R. E Pratley, A. Salsali, and G. Matfin Review: Inhibition of dipeptidyl peptidase-4 with vildagliptin: a potential new treatment for type 2 diabetes The British Journal of Diabetes & Vascular Disease, July 1, 2006; 6(4): 150 - 156. [Abstract] [PDF]
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D. F. Kruger, C. L. Martin, and C. E. Sadler New insights into glucose regulation. The Diabetes Educator, March 1, 2006; 32(2): 221 - 228. [Abstract] [Full Text] [PDF]
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M. J. Theodorakis, O. Carlson, S. Michopoulos, M. E. Doyle, M. Juhaszova, K. Petraki, and J. M. Egan Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP Am J Physiol Endocrinol Metab, March 1, 2006; 290(3): E550 - E559. [Abstract] [Full Text] [PDF]
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P. T. Schmidt, E. Naslund, P. Gryback, H. Jacobsson, J. J. Holst, L. Hilsted, and P. M. Hellstrom A Role for Pancreatic Polypeptide in the Regulation of Gastric Emptying and Short-Term Metabolic Control J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5241 - 5246. [Abstract] [Full Text] [PDF]
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R. Chaikomin, S. Doran, K. L. Jones, C. Feinle-Bisset, D. O'Donovan, C. K. Rayner, and M. Horowitz Initially more rapid small intestinal glucose delivery increases plasma insulin, GIP, and GLP-1 but does not improve overall glycemia in healthy subjects Am J Physiol Endocrinol Metab, September 1, 2005; 289(3): E504 - E507. [Abstract] [Full Text] [PDF]
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J. H. Schou, K. Pilgaard, T. Vilsboll, C. B. Jensen, C. F. Deacon, J. J. Holst, A. Volund, S. Madsbad, and A. A. Vaag Normal Secretion and Action of the Gut Incretin Hormones Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide in Young Men with Low Birth Weight J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4912 - 4919. [Abstract] [Full Text] [PDF]
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C. A Schnabel The incretin mimetic, exenatide: a novel treatment option for type 2 diabetes The British Journal of Diabetes & Vascular Disease, July 1, 2005; 5(4): 227 - 235. [Abstract] [PDF]
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M. A. Nauck, B. Baller, and J. J. Meier Gastric Inhibitory Polypeptide and Glucagon-Like Peptide-1 in the Pathogenesis of Type 2 Diabetes Diabetes, December 1, 2004; 53(suppl_3): S190 - S196. [Abstract] [Full Text] [PDF]
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J. J. Holst and C. Orskov The Incretin Approach for Diabetes Treatment: Modulation of Islet Hormone Release by GLP-1 Agonism Diabetes, December 1, 2004; 53(suppl_3): S197 - S204. [Abstract] [Full Text] [PDF]
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Z. T. Bloomgarden Gut-Derived Incretin Hormones and New Therapeutic Approaches Diabetes Care, October 1, 2004; 27(10): 2554 - 2559. [Full Text] [PDF]
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K. B. Degn, B. Brock, C. B. Juhl, C. B. Djurhuus, J. Grubert, D. Kim, J. Han, K. Taylor, M. Fineman, and O. Schmitz Effect of Intravenous Infusion of Exenatide (Synthetic Exendin-4) on Glucose-Dependent Insulin Secretion and Counterregulation During Hypoglycemia Diabetes, September 1, 2004; 53(9): 2397 - 2403. [Abstract] [Full Text] [PDF]
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J. J. Holst and J. Gromada Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans Am J Physiol Endocrinol Metab, August 1, 2004; 287(2): E199 - E206. [Abstract] [Full Text] [PDF]
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S. L. Aronoff, K. Berkowitz, B. Shreiner, and L. Want Glucose Metabolism and Regulation: Beyond Insulin and Glucagon Diabetes Spectr, July 1, 2004; 17(3): 183 - 190. [Abstract] [Full Text] [PDF]
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D. A. D'Alessio and T. P. Vahl Glucagon-like peptide 1: evolution of an incretin into a treatment for diabetes Am J Physiol Endocrinol Metab, June 1, 2004; 286(6): E882 - E890. [Abstract] [Full Text] [PDF]
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G. S. Meneilly, N. Greig, H. Tildesley, J. F. Habener, J. M. Egan, and D. Elahi Effects of 3 Months of Continuous Subcutaneous Administration of Glucagon-Like Peptide 1 in Elderly Patients With Type 2 Diabetes Diabetes Care, October 1, 2003; 26(10): 2835 - 2841. [Abstract] [Full Text] [PDF]
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T. Vilsboll, T. Krarup, J. Sonne, S. Madsbad, A. Volund, A. G. Juul, and J. J. Holst Incretin Secretion in Relation to Meal Size and Body Weight in Healthy Subjects and People with Type 1 and Type 2 Diabetes Mellitus J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2706 - 2713. [Abstract] [Full Text] [PDF]
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), and IGT subjects (
) during a 240-min meal test. The meal was
started at time zero and finished in the 10- to 15-min period.
