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Free access

David P Sonne, Jens F Rehfeld, Jens J Holst, Tina Vilsbøll, and Filip K Knop

Objective

Recent preclinical work has suggested that postprandial flow of bile acids into the small intestine potentiates nutrient-induced glucagon-like peptide 1 (GLP1) secretion via bile acid-induced activation of the G protein-coupled receptor TGR5 in intestinal L cells. The notion of bile-induced GLP1 secretion combined with the findings of reduced postprandial gallbladder emptying in patients with type 2 diabetes (T2DM) led us to speculate whether reduced postprandial GLP1 responses in some patients with T2DM arise as a consequence of diabetic gallbladder dysmotility.

Design and methods

In a randomised design, 15 patients with long-standing T2DM and 15 healthy age-, gender- and BMI-matched control subjects were studied during 75-g oral glucose tolerance test (OGTT) and three isocaloric (500 kcal) and isovolaemic (350 ml) liquid meals: i) 2.5 g fat, 107 g carbohydrate and 13 g protein; ii) 10 g fat, 93 g carbohydrate and 11 g protein; and iii) 40 g fat, 32 g carbohydrate and 3 g protein. Basal and postprandial plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP1, glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin and gastrin were measured. Furthermore, gallbladder emptying and gastric emptying were examined.

Results

Gallbladder emptying increased with increasing meal fat content, but no intergroup differences were demonstrated. GIP and GLP1 responses were comparable among the groups with GIP levels being higher following high-fat meals, whereas GLP1 secretion was similar after both OGTT and meals.

Conclusions

In conclusion, patients with T2DM exhibited normal gallbladder emptying to meals with a wide range of fat content. Incretin responses were similar to that in controls, and an association with postprandial gallbladder contraction could not be demonstrated.

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.

Free access

Signe Harring Østoft, Jonatan Ising Bagger, Torben Hansen, Bolette Hartmann, Oluf Pedersen, Jens Juul Holst, Filip Krag Knop, and Tina Vilsbøll

Objective

The role of the incretin hormones in the pathophysiology of maturity onset diabetes of the young (MODY) is unclear.

Design

We studied the postprandial plasma responses of glucagon, incretin hormones (glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP)) and dipeptidyl-peptidase 4 (DPP4) enzymatic activity in patients with glucokinase (GCK) diabetes (MODY2) and hepatocyte nuclear factor 1α (HNF1A) diabetes (MODY3) as well as in matched healthy individuals (CTRLs).

Subjects and methods

Ten patients with MODY2 (mean age±s.e.m. 43±5 years; BMI 24±2 kg/m2; fasting plasma glucose (FPG) 7.1±0.3 mmol/l: HbA1c 6.6±0.2%), ten patients with MODY3 (age 31±3 years; BMI 24±1 kg/m2; FPG 8.9±0.8 mmol/l; HbA1c 7.0±0.3%) and ten CTRLs (age 40±5 years; BMI 24±1 kg/m2; FPG 5.1±0.1 mmol/l; HbA1c 5.3±0.1%) were examined with a liquid test meal.

Results

All of the groups exhibited similar baseline values of glucagon (MODY2: 7±1 pmol/l; MODY3: 6±1 pmol/l; CTRLs: 8±2 pmol/l, P=0.787), but patients with MODY3 exhibited postprandial hyperglucagonaemia (area under the curve (AUC) 838±108 min×pmol/l) as compared to CTRLs (182±176 min×pmol/l, P=0.005) and tended to have a greater response than did patients with MODY2 (410±154 min×pmol/l, P=0.063). Similar peak concentrations and AUCs for plasma GIP and plasma GLP1 were observed across the groups. Increased fasting DPP4 activity was seen in patients with MODY3 (17.7±1.2 mU/ml) vs CTRLs (13.6±0.8 mU/ml, P=0.011), but the amount of activity was similar to that in patients with MODY2 (15.0±0.7 mU/ml, P=0.133).

Conclusion

The pathophysiology of MODY3 includes exaggerated postprandial glucagon responses and increased fasting DPP4 enzymatic activity but normal postprandial incretin responses both in patients with MODY2 and in patients with MODY3.

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.

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.

Restricted access

Signe Stensen, Lærke S Gasbjerg, Liva L. Krogh, Kirsa Skov-Jeppesen, Alexander H. Sparre-Ulrich, Mette H. Jensen, Flemming Dela, Bolette Hartmann, Tina Vilsbøll, Jens J Holst, Mette M. Rosenkilde, Mikkel B. Christensen, and Filip K Knop

Objective: The insulinotropic effect of exogenous, intravenously infused glucose-dependent insulinotropic polypeptide (GIP) is impaired in patients with type 2 diabetes. We evaluated the effects of endogenous GIP in relation to glucose and bone metabolism in patients with type 2 diabetes using a selective GIP receptor antagonist and hypothesized that the effects of endogenous GIP were preserved.

Design: A randomized, double-blinded, placebo-controlled, crossover study.

Methods: Ten patients with overweight/obesity and type 2 diabetes (mean±SD; HbA1c 52±11 mmol/mol; BMI 32.5±4.8 kg/m2) were included. We infused a selective GIP receptor antagonist, GIP(3-30)NH2 (1,200 pmol × kg-1 × min-1), or placebo (saline) during two separate, 230-minute, standardized, liquid mixed meal tests followed by an ad libitum meal. Subcutaneous adipose tissue biopsies were analyzed.

Results: Compared with placebo, GIP(3-30)NH2 reduced postprandial insulin secretion (Δbaseline-subtracted area under the curve (bsAUC)C-peptide%±SEM; -14±6%, p=0.021) and peak glucagon (Δ%±SEM; -11±6%, p=0.046), but had no effect on plasma glucose (p=0.692). Suppression of bone resorption (assessed by circulating carboxy-terminal collagen crosslinks (CTX)) was impaired during GIP(3-30)NH2 infusion compared with placebo (ΔbsAUCCTX;±SEM; -4.9±2 ng/ml × min, p=0.005) corresponding to a ~50% reduction. Compared with placebo, GIP(3-30)NH2 did not affect plasma lipids, ad libitum meal consumption or adipose tissue triglyceride content.

Conclusions: Using a selective GIP receptor antagonist during a meal, we show that endogenous GIP increases postprandial insulin secretion with little effect on postprandial glycemia but is important for postprandial bone homeostasis in patients with type 2 diabetes.

Restricted access

Niels B Dalsgaard, Lærke S Gasbjerg, Laura S Hansen, Nina L Hansen, Signe Stensen, Bolette Hartmann, Jens F Rehfeld, Jens J Holst, Tina Vilsbøll, and Filip K Knop

Aims

The alpha-glucosidase inhibitor acarbose is believed to reduce plasma glucose by delaying hydrolysis of carbohydrates. Acarbose-induced transfer of carbohydrates to the distal parts of the intestine increases circulating glucagon-like peptide 1 (GLP-1). Using the GLP-1 receptor antagonist exendin(9–39)NH2, we investigated the effect of acarbose-induced GLP-1 secretion on postprandial glucose metabolism in patients with type 2 diabetes.

Methods

In a double-blinded, placebo-controlled, randomized, crossover study, 15 participants with metformin-treated type 2 diabetes (age: 57–85 years, HbA1c: 40–74 mmol/mol) were subjected to two 14-day treatment periods with acarbose or placebo, respectively, separated by a 6-week wash-out period. At the end of each period, two randomized 4-h liquid mixed meal tests with concomitant infusion of exendin(9–39)NH2 and saline, respectively, were performed.

Results

Compared to placebo, acarbose increased postprandial GLP-1 concentrations and decreased postprandial glucose. We observed no absolute difference in the exendin(9–39)NH2-induced increase in postprandial glucose excursions between placebo and acarbose periods, but relatively, postprandial glucose was increased by 119 ± 116% (mean ± s.d.) during exendin(9–39)NH2 infusion in the acarbose period vs a 39 ± 27% increase during the placebo period (P = 0.0163).

Conclusions

We confirm that acarbose treatment stimulates postprandial GLP-1 secretion in patients with type 2 diabetes. Using exendin(9–39)NH2, we did not see an impact of acarbose-induced GLP-1 secretion on absolute measures of postprandial glucose tolerance, but relatively, the effect of exendin(9–39)NH2 was most pronounced during acarbose treatment.

Restricted access

Mia Demant, Malte Palm Suppli, Signe Foghsgaard, Lise Gether, Magnus Frederik Gluud Grøndahl, Niels Bjørn Dalsgaard, Sigrid S Bergmann, Amalie Rasmussen Lanng, Lærke S Gasbjerg, Martin Thomasen, Jonatan Ising Bagger, Charlotte Strandberg, Merete Juhl Kønig, Henning Grønbæk, Ulrik Becker, Jens J Holst, Joachim Knop, Matthew Paul Gillum, Tina Vilsbøll, and Filip K. Knop

Aims/hypothesis. Metabolic effects of intermittent unhealthy lifestyle in young adults are poorly studied. We investigated the gluco-metabolic and hepatic effects of participation in Roskilde Festival (one week of binge drinking and junk food consumption) in young, healthy males.

Methods. Fourteen festival participants (FP) were studied before, during and after one week’s participation in Roskilde Festival. Fourteen matched controls (CTRL) who did not participate in Roskilde Festival or change their lifestyle in other ways were investigated along a similar timeline.

Results. The FP group consumed more alcohol compared to their standard living conditions (2.0±3.9 vs 16.3±8.3 units/day, p<0.001). CTRLs did not change their alcohol consumption. AUC for glucose during OGTT did not change in either group. C-peptide responses increased in the FP group (320±31 vs 376±25 nmol/l×min, p=0.055) and the Matsuda index of insulin sensitivity decreased (6.2±2.4 vs 4.7±1.4, p = 0.054). AUC for glucagon during OGTT increased in the FP group (1,115±114 vs 1,599±183 pmol/l×min, p=0.003) together with fasting fibroblast growth factor 21 (FGF21) (62±30 vs 132±72 pmol/L, p<0.001), growth differentiation factor 15 (GDF5) (276±78 vs 330±83 pg/mL, p=0.009) and aspartate aminotransferase (AST) levels (37.6±6.8 vs 42.4±11 U/l, p=0.043). Four participants (29%) developed ultrasound-detectable steatosis and mean strain elastography-assessed liver stiffness increased (p=0.026) in the FP group.

Conclusions/interpretation. Participation in Roskilde Festival did not affect oral glucose tolerance, but was associated with a reduction in insulin sensitivity, increases in glucagon, FGF21, GDF15 and AST and lead to increased liver stiffness and, in 29% of the participants, ultrasound-detectable hepatic steatosis.