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Free access

Jakob Ryskjær, Carolyn F Deacon, Richard D Carr, Thure Krarup, Sten Madsbad, Jens Holst and Tina Vilsbøll

Objective: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide are incretin hormones, secreted in response to meal ingestion. The incretin hormones stimulate insulin secretion and are essential for the maintenance of normal plasma glucose concentrations. Both incretin hormones are metabolized quickly by the enzyme dipeptidyl peptidase-IV (DPP-IV). It is well known that type-2 diabetic patients have an impaired incretin effect. Therefore, the aim of the present study was to investigate plasma DPP-IV activity in the fasting and the postprandial state in type-2 diabetic patients and control subjects.

Design: The study included two protocols. Protocol one involved 40 fasting type-2 diabetic patients (28 men); age 61 ± 1.4 (mean ± s.e.m.) years; body mass index (BMI) 31 ± 0.6 kg/m2; HbAlc 7.2 ± 0.2%; and 20 matched control subjects (14 men) were studied. Protocol two involved eight type-2 diabetic patients (six men); age 63 ± 1.2 years; BMI 33 ± 0.5 kg/m2; HbAlc 7.5 ± 0.4%; eight matched control subjects were included.

Methods: In protocol one, fasting values of DPP-IV activity were evaluated and in protocol two, postprandial DPP-IV activity during a standard meal test (566 kcal) was estimated.

Results: Mean fasting plasma DPP-IV activity (expressed as degradation of GLP-1) was significantly higher in this patient group compared with the control subjects (67.5 ± 1.9 vs 56.8 ± 2.2 fmol GLP-1/h (mean ± s.e.m.); P=0.001). In the type-2 diabetic patients, DPP-IV activity was positively correlated to FPG and HbAlc and negatively to the duration of diabetes and age of the patients. No postprandial changes were seen in plasma DPP-IV activity in any of the groups.

Conclusions: Plasma DPP-IVactivity increases in the fasting state and is positively correlated to FPG and HbAlc levels, but plasma DPP-IV activity is not altered following meal ingestion and acute changes in plasma glucose.

Open access

Astrid Plamboeck, Simon Veedfald, Carolyn F Deacon, Bolette Hartmann, André Wettergren, Lars B Svendsen, Søren Meisner, Claus Hovendal, Filip K Knop, Tina Vilsbøll and Jens J Holst

Objective

Glucagon-like peptide 1 (GLP1) is rapidly inactivated by dipeptidyl peptidase 4 (DPP4), but may interact with vagal neurons at its site of secretion. We investigated the role of vagal innervation for handling of oral and i.v. glucose.

Design and methods

Truncally vagotomised subjects (n=16) and matched controls (n=10) underwent 50 g-oral glucose tolerance test (OGTT)±vildagliptin, a DPP4 inhibitor (DPP4i) and isoglycaemic i.v. glucose infusion (IIGI), copying the OGTT without DPP4i.

Results

Isoglycaemia was obtained with 25±2 g glucose in vagotomised subjects and 18±2 g in controls (P<0.03); thus, gastrointestinal-mediated glucose disposal (GIGD) – a measure of glucose handling (100%×(glucoseOGTT−glucoseIIGI/glucoseOGTT)) – was reduced in the vagotomised compared with the control group. Peak intact GLP1 concentrations were higher in the vagotomised group. Gastric emptying was faster in vagotomised subjects after OGTT and was unaffected by DPP4i. The early glucose-dependent insulinotropic polypeptide response was higher in vagotomised subjects. Despite this, the incretin effect was equal in both groups. DPP4i enhanced insulin secretion in controls, but had no effect in the vagotomised subjects. Controls suppressed glucagon concentrations similarly, irrespective of the route of glucose administration, whereas vagotomised subjects showed suppression only during IIGI and exhibited hyperglucagonaemia following OGTT. DPP4i further suppressed glucagon secretion in controls and tended to normalise glucagon responses in vagotomised subjects.

Conclusions

GIGD is diminished, but the incretin effect is unaffected in vagotomised subjects despite higher GLP1 levels. This, together with the small effect of DPP4i, is compatible with the notion that part of the physiological effects of GLP1 involves vagal transmission.

Free access

Monika J Bak, Nicolai Wewer Albrechtsen, Jens Pedersen, Bolette Hartmann, Mikkel Christensen, Tina Vilsbøll, Filip K Knop, Carolyn F Deacon, Lars O Dragsted and Jens J Holst

Aim

To determine the specificity and sensitivity of assays carried out using commercially available kits for glucagon and/or oxyntomodulin measurements.

Methods

Ten different assay kits used for the measurement of either glucagon or oxyntomodulin concentrations were obtained. Solutions of synthetic glucagon (proglucagon (PG) residues 33–61), oxyntomodulin (PG residues 33–69) and glicentin (PG residues 1–69) were prepared and peptide concentrations were verified by quantitative amino acid analysis and a processing-independent in-house RIA. Peptides were added to the matrix (assay buffer) supplied with the kits (concentration range: 1.25–300 pmol/l) and to human plasma and recoveries were determined. Assays yielding meaningful results were analysed for precision and sensitivity by repeated analysis and ability to discriminate low concentrations.

Results and conclusion

Three assays were specific for glucagon (carried out using the Millipore (Billerica, MA, USA), Bio-Rad (Sundbyberg, Sweden), and ALPCO (Salem, NH, USA) and Yanaihara Institute (Shizuoka, Japan) kits), but none was specific for oxyntomodulin. The assay carried out using the Phoenix (Burlingame, CA, USA) glucagon kit measured the concentrations of all three peptides (total glucagon) equally. Sensitivity and precision were generally poor; the assay carried out using the Millipore RIA kit performed best with a sensitivity around 10 pmol/l. Assays carried out using the BlueGene (Shanghai, China), USCN LIFE (Wuhan, China) (oxyntomodulin and glucagon), MyBioSource (San Diego, CA, USA) and Phoenix oxyntomodulin kits yielded inconsistent results.