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Similar Elimination Rates of Glucagon-Like Peptide-1 in Obese Type 2 Diabetic Patients and Healthy Subjects

Department of Internal Medicine F (T.V., T.K.), Gentofte Hospital, DK-290 Hellerup, Denmark; Department of Medical Physiology (T.V., J.J.H.), Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark; and Ferring Pharmaceuticals A/S (H.A.), DK-2300 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Tina Vilsbøll, M.D., Department of Internal Medicine F, Gentofte Hospital, University of Copenhagen, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark. E-mail: tivi{at}gentoftehosp.kbhamt.dk.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We have previously shown that type 2 diabetic patients have decreased plasma concentrations of glucagon-like peptide 1 (GLP-1) compared with healthy subjects after ingestion of a standard mixed meal. This decrease could be caused by differences in the metabolism of GLP-1. The objective of this study was to examine the pharmacokinetics of GLP-1 in healthy subjects and type 2 diabetic patients after iv bolus doses ranging from 2.5–25 nmol/subject. Bolus injections iv of 2.5, 5, 15, and 25 nmol of GLP-1 and a meal test were performed in six type 2 diabetic patients [age, mean (range): 56 (48–67) yr; body mass index: 31.2 (27.0–37.7) kg/m²; fasting plasma glucose: 11.9 (8.3–14.3) mmol/liter; hemoglobin A_1C: 9.6 (7.0–12.5)%]. For comparison, six matched healthy subjects were examined. Peak plasma GLP-1 concentrations increased linearly with increasing doses of GLP-1 and were similar for type 2 diabetic patients and healthy subjects. The peak concentrations of total GLP-1 (C-terminal) after 2.5, 5, 15, and 25 nmol of GLP-1 were 357 ± 56, 647 ± 141, 1978 ± 276, 3435 ± 331 pmol/liter in the type 2 diabetic patients and 315 ± 37, 676 ± 64, 1848 ± 146, 3168 ± 358 pmol/liter, respectively, in the healthy subjects (not statistically significant). Peak concentrations of the intact GLP-1 peptide (N-terminal) were: 69 ± 17, 156 ± 44, 703 ± 77, and 1070 ± 117 pmol/liter in the type 2 diabetic patients and 75 ± 14, 160 ± 40, 664 ± 79, 974 ± 87 in the healthy subjects (not statistically significant). GLP-1 was eliminated rapidly with clearances of intact GLP-1 after 2.5, 5, 15, and 25 nmol of GLP-1 amounting to: 9.0 ± 5.0, 8.1 ± 6.0, 4.0 ± 1.0, 4.0 ± 1.0 liter/min in type 2 diabetic patients and 8.4 ± 4.2, 7.6 ± 4.5, 5.0 ± 2.0, 5.0 ± 1.0 liter/min in healthy subjects. The volume of distribution ranged from 9–26 liters per subject. No significant differences were found between healthy subjects and type 2 diabetic subjects. We conclude that elimination of GLP-1 is the same in obese type 2 diabetic patients and matched healthy subjects. The impaired incretin response seen after ingestion of a standard breakfast meal must therefore be caused by a decreased secretion of GLP-1 in type 2 diabetic patients.

	Introduction

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GLUCAGON-LIKE-PEPTIDE-1 (GLP-1) is an intestinal incretin hormone that arises from tissue specific posttranslational processing of the glucagon precursor, proglucagon, within the intestinal mucosal L-cells (1, 2). In humans, most of the L-cell product is C-terminally amidated GLP-1-(7–36)amide. It is released in response to ingestion of a mixed meal and, in contrast to the N-terminally extended GLP-1-(1–36)amide, the GLP-1-(7–36)amide is highly potent in stimulating insulin and inhibiting glucagon secretion (3). GLP-1-(7–36)amide thus contributes to the incretin effect, i.e. the potentiation of insulin release in response to oral ingestion (as opposed to parenteral administration) of glucose or a food stimulus (4). After secretion, GLP-1-(7–36)amide is rapidly degraded in plasma by the enzyme dipeptidyl peptidase IV (DPP-IV) to form an N-terminally truncated biologically inactive peptide, GLP-1-(9–36)amide (5), which is mainly eliminated by the kidney (6). The half-life of this transformation of GLP-1 is approximately 1–1.5 min in pigs following iv administration (6) and 1 h after sc injection in human beings (7). The half-life of intact GLP-1 after iv administration has never been determined in humans. Previous studies have shown that the incretin effect is abolished or severely reduced in patients with type 2 diabetes (8), and we recently presented data showing reduced postprandial concentrations of GLP-1 in type 2 diabetic patients (9). These decreased GLP-1 concentrations in the patients might, therefore, explain part of the impaired incretin effect in type 2 diabetes. Theoretically, the lower GLP-1 concentrations could be caused by either an increased elimination of GLP-1 or a decreased secretion of GLP-1 in type 2 diabetic patients compared with healthy subjects. The aim of the present investigation was to compare the pharmacokinetics of GLP-1 in obese type 2 diabetic patients and in matched healthy subjects after four different doses of iv injected GLP-1, to elucidate which mechanism was responsible for the reduced GLP-1 concentrations in type 2 diabetic patients [preliminary data have been published in abstract form (10) and metabolic responses after the GLP-1 stimulation is previously published (11)].

	Subjects and Methods

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Patients

We studied six type 2 diabetic patients (four men, two women); mean (range) age: 56 (48–67) yr; body mass index (BMI): 31.2 (27.0–37.7) kg/m²; hemoglobin A_1C: 9.6 (7.0–12.5)%; fasting plasma glucose: 11.9 (8.3–14.3) mmol/liter; Duration of diabetes: 55 (33–97 months), and 6 matched healthy subjects: age: 56 (51–70) yr; BMI: 31.6 (26.4–37.9) kg/m²; fasting plasma glucose: 5.4 (5.2–5.8) mmol/liter); hemoglobin A_1C: 5.5 (5.2–5.8) %. Two patients were treated with diet alone, whereas four were treated with diet and oral antidiabetics (biguanides and/or sulfonylureas). Three patients had a history of hypertension and were treated with thiazides or angiotensin converting enzyme inhibitors. The diabetic patients studied represent typical outpatient obese type 2 diabetic patients and they were all diagnosed according to the criteria of World Health Organization (12, 13). None of the patients had impaired renal function (serum creatinine levels less than 130 µmol/liter and no microalbuminuria), proliferative retinopathy or impaired liver function. None of the healthy subjects had a family history of diabetes and all had normal oral glucose tolerance test. All agreed to participate and gave oral and written consent. The study was approved by the Copenhagen County Ethical Committee, and the study was conducted according to the principles of the Helsinki Declaration.

Methods

All oral antidiabetics were discontinued 3 d before the study. After an overnight fast (from 2200 h), the subjects were studied recumbent with two cannulas inserted into the cubital veins, one for injection of GLP-1, and one for blood sampling. All participants were examined on 4 separate days in randomized order, and received an iv bolus injection of four different doses of GLP-1 (2.5, 5, 15, 25 nmol). All experiments were performed within 5 months. Venous blood was sampled 15, 10, and 0 min before and 2, 3, 4, 6, 8, 10, 15, 20, 30, and 45 min after GLP-1 administration. Synthetic GLP-1 (7–36)amide was purchased from Peninsula Europe (Merseyside, UK). The peptide was dissolved in sterilized water containing 2% human serum albumin (Human Albumin, Statens Serum Institute, Copenhagen, Denmark, guaranteed to be free of hepatitis B surface antigen, hepatitis C virus antibodies and human immunodeficiency virus antibodies), and subjected to sterile filtration. Appropriate amounts of peptide for each experimental subject were dispensed into glass ampoules and stored frozen under sterile conditions until the day of the experiment. The peptide was demonstrated to be more than 97% pure and identical to the natural human peptide by HPLC, mass, and sequence analysis.

Blood was sampled into fluoride tubes for plasma glucose analysis and into EDTA tubes (6 mmol/liter) with aprotinin (500 KIU/ml blood; Trasylol, Bayer Corp., Leverkusen, Germany) for hormone analyses. Tubes were immediately cooled on ice and centrifuged at 4 C within 20 min. Plasma was stored at minus 20 C until analysis.

Analysis

Plasma samples were assayed for GLP-1 immunoreactivity using RIAs that are specific for each terminus of the GLP-1 molecule: the C-terminal assay measuring the sum of the intact peptide plus the primary metabolite, GLP-1 (9–36)amide, and the N-terminal assay measuring the concentration of intact surviving GLP-1. The C-terminal immunoreactivity of GLP-1 was measured as described previously (14), using standards of synthetic GLP-1 (7–36)amide (= proglucagon 78–107amide) and antiserum no 89390. The assay cross-reacts less than 0.01% with C-terminally truncated fragments, and 83% with GLP-1 (9–36)amide and has a detection limit less than 1 pmol/liter. N-terminal immunoreactivity was measured using antiserum 93242 (15), which cross-reacts approximately 10% with GLP-1 (1–36) amide, and less than 0.1% with GLP-1 (8–36)amide and GLP-1 (9–36)amide. The assay has a detection limit of 2 pmol/liter. For both assays, intraassay and interassay coefficients of variation were less than 6% and 15%, respectively, at 40 pmol/liter. The concentration of the metabolite was calculated as the concentration of total GLP-1 (C-terminal) minus intact GLP-1 (N-terminal).

Statistical analysis and calculations

All results are presented as the mean ± SEM. The significance of the difference between the different tests within the groups was estimated by repeated measures ANOVA for parametric data followed by a Bonferroni test for multiple comparisons. The level of statistical significance was set at P < 0.05.

Pharmacokinetic analysis

GLP-1 levels in plasma obtained after iv injections were corrected for the baseline concentration before the pharmacokinetic parameters were estimated. The baseline level was set to the mean concentration of the three blood samples collected before dosing at -15, -10, and 0 min. The metabolism of GLP-1 and of the metabolite in plasma was assessed for the individual subjects in each group by use of noncompartmental methods using standard equations (16). The areas under the plasma concentration vs. time curves were calculated according to the linear trapezoidal rule. Pharmacokinetic parameters were assessed by noncompartmental methods using the commercially available software WinNonlin (Pharsight Corp., Mountain View, CA).

The infinite part of the curve was determined as C_last/_z, with C_last = the last measurable concentration and _z = the slope for the terminal phase. The area under the first moment curve was calculated as the area under the curve of the product of time (t) and plasma concentration (C_p), from zero time to infinity:

The infinite part of the first moment curve was calculated as:

with t_last = the last sample time.

The peak concentration (C_max) and times (t_max) were read from the individual plasma concentrations vs. time curves.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Fasting plasma GLP-1 concentrations (C-terminal and N-terminal (in parentheses, mean ± SEM) were 10 ± 4 (11 ± 6), 4 ± 1 (3 ± 1), 5 ± 3 (6 ± 2) and 6 ± 2 (7 ± 2) pmol/liter at the day of 2.5, 5, 15 and 25 nmol of GLP-1 stimulation in type 2 diabetic patients [not statistically significant (NS)]. Corresponding results were 9 ± 3 (11 ± 6), 5 ± 2 (8 ± 5), 9 ± 6 (9 ± 6) and 6 ± 2 (10 ± 6) pmol/liter in healthy subjects. Basal concentrations of intact GLP-1 were reached again 10–30 min after iv injection of the four different GLP-1 doses (Fig. 1). Peak plasma GLP-1 concentrations increased linearly with increasing doses of GLP-1 and were similar for type 2 diabetic patients and healthy subjects. The peak concentrations of total GLP-1 (C-terminal) in type 2 diabetic patients and healthy subjects (in parentheses) were 357 ± 56 (315 ± 37), 647 ± 141 (675 ± 64), 1978 ± 276 (1849 ± 146), 3435 ± 331 (3168 ± 358) pmol/liter after respectively 2.5, 5, 15, and 25 nmol of GLP-1 (NS). Corresponding measurements of the intact GLP-1 peptide (N-terminal) were: 69 ± 17 (75 ± 14), 156 ± 44 (160 ± 40), 703 ± 77 (664 ± 79) and 1070 ± 117 (974 ± 87) pmol/liter (NS). Peak plasma concentrations of the metabolite (total GLP-1 minus intact GLP-1) in type 2 diabetic patients and healthy subjects (in brackets) after 2.5, 5, 15, and 25 nmol of GLP-1 were: 299 ± 50 (241 ± 35), 554 ± 134 (516 ± 39), 1274 ± 224 (1204 ± 114) and 2511 ± 262 (2194 ± 348) pmol/liter, respectively (NS). Areas under the curve appear in Table 1.

View larger version (16K): [in this window] [in a new window]   Figure 1. A, Plasma concentrations of total GLP-1; B, intact GLP-1 concentrations after 2.5 nmol of GLP-1 [type 2 diabetic patients (—), healthy subjects (—)], 5 nmol of GLP-1 [patients (—), healthy subjects (—)], 15 nmol of GLP-1 [patients (•—•), healthy subjects (—)], and 25 nmol of GLP-1 [patients (—), healthy subjects (—)]. Data are raw data.

View larger version (8K): [in this window] [in a new window]   Figure 2. Clearance plotted against dose after iv administration of four dose levels of GLP-1 to type 2 diabetic patients () and healthy subjects ().

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

We have previously shown that type 2 diabetic patients have significantly decreased total and intact GLP-1 levels after ingestion of a standard breakfast meal compared with healthy subjects, and the same was true for the subjects investigated here (9). Because the present investigation revealed similar pharmacokinetics for intact GLP-1 as well as the primary metabolite in both the patients and in the healthy subjects, the decreased plasma concentrations of both peptides seen after ingestion of a standard breakfast meal in type 2 diabetic patients is, most likely, caused by a decreased secretion of GLP-1 in the patients. Previous studies have shown that GLP-1 significantly stimulates insulin secretion in patients with diabetes (19, 20), and iv infusion of GLP-1 has been demonstrated to normalize blood glucose completely, even in patients with long-standing disease and secondary failure of oral antidiabetic drugs (21). Thus, decreased secretion rather than increased elimination of GLP-1 in type 2 diabetic patients is likely to contribute to their impaired secretion of insulin.

	Acknowledgments

 
We thank Jytte Purtoft, Lene Albæk, and Susanne Reimer for technical assistance.

	Footnotes

 
Abbreviations: BMI, Body mass index; C_max, the maximum observed plasma concentration; DPP-IV, dipeptidyl peptidase IV; GLP-1, glucagon-like peptide-1; NS, not statistically significant; t_max, time to reach C_max; t_1/2, half-life.

Received July 8, 2002.

Accepted September 13, 2002.

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