Jan Fog Pedersen

Glucagon-like peptide-2 inhibits antral emptying in man, but is not as potent as glucagon-like peptide-1

Background: GLP‐1 (glucagon‐like peptide‐1) and GLP‐2 (glucagon‐like peptide‐2) are released in equimolar amounts in response to meal ingestion. GLP‐1 inhibits gastric emptying and reduces postprandial gastric and exocrine pancreatic secretion and may play a physiological regulatory role in controlling appetite and energy intake in humans. The role of GLP‐2 is more uncertain. Based on the results of animal studies, it has been suggested that GLP‐2 may induce intestinal epithelial growth and inhibit gastric motility. The aim of this study was to determine to what extent GLP‐2 alone or together with GLP‐1 inhibits gastric emptying and the sensation of hunger in man. Methods: Eight healthy volunteers were tested in a double‐blind, placebo‐controlled fashion. Antral emptying of a liquid meal and hunger ratings were determined using ultrasound technology and visual analogue scales scoring during infusions of saline, GLP‐2 (0.5, and 1.0 pmol kg body wt −1 min −1 ), GLP‐1 (0.5 pmol kg body wt −1 min −1 ) or GLP‐1 and GLP‐2 (0.5 pmol kg body wt −1 min −1 ). Results: The GLP‐2 infusions resulted in a dose‐dependent increase in antral emptying time (35%;u2005ns and 75%; Pu2005=u20050.049) compared to saline, but GLP‐2 was less potent than GLP‐1, which increased the antral emptying time by 192% (Pu2005<u20050.001). Addition of GLP‐2 to the GLP‐1 infusion did not alter the antral emptying time compared with GLP‐1 alone. The GLP‐1 infusion decreased the sensation of hunger compared with saline (Pu2005=u20050.023), whereas the two GLP‐2 infusions had no significant effect. Addition of GLP‐2 to the GLP‐1 infusion did not decrease the sensation of hunger further. Conclusions: Both GLP‐1 and GLP‐2 inhibit antral emptying in man, but GLP‐1 is more potent.

Human placental lactogen and pregnancy-associated plasma protein A in first trimester and subsequent fetal growth

Objective. To study in an optimized design the possible relation between serum levels in weeks 8‐14 of human placental lactogen and pregnancy‐associated plasma protein A and fetal size at delivery.

Serum levels of human placental lactogen, pregnancy‐associated plasma protein A and endometrial secretory protein PP14 in first trimester of diabetic pregnancy

OBJECTIVEnTo study maternal serum levels of human placental lactogen (hPL), pregnancy-associated plasma protein A (PAPP-A) and endometrial secretory protein PP14 (PP14) in first trimester of diabetic pregnancy.nnnMETHODSnSeventy-nine insulin-dependent diabetic women and 93 normal pregnant women had a venous blood sample drawn in weeks 8-14, ultrasound age. Serum levels were measured by radioimmunoassays and expressed in multiples of the median serum value in normal pregnancy at that ultrasound age.nnnRESULTSnLevels of hPL were significantly lower in diabetic mothers than in controls, z= -5.502, p<0.00001. Levels of PAPP-A were also significantly lower, z =2.263, p=0.024, but were significantly less depressed than those of hPL, z=2.41, p=0.015. The PP14 levels did not deviate from normal.nnnCONCLUSIONnIn first trimester of diabetic pregnancy there appears to be both a more general depression of trophoblast function, and also a specific depression of the hPL release.

Oral 2‐oleyl glyceryl ether improves glucose tolerance in mice through the GPR119 receptor

The intestinal G protein-coupled receptor GPR119 is a novel metabolic target involving glucagon-like peptide-1 (GLP-1)-derived insulin-regulated glucose homeostasis. Endogenous and diet-derived lipids, including N-acylethanolamines and 2-monoacylglycerols (2-MAG) activate GPR119. The purpose of this work is to evaluate whether 2-oleoyl glycerol (2-OG) improves glucose tolerance through GPR119, using wild type (WT) and GPR 119 knock out (KO) mice. We here show that GPR119 is essential for 2-OG-mediated release of GLP-1 and CCK from GLUTag cells, since a GPR119 specific antagonist completely abolished the hormone release. Similarly, in isolated primary colonic crypt cultures from WT mice, GPR119 was required for 2-OG-stimulated GLP-1 release while there was no response in crypts from KO mice. In vivo, gavage with 2-oleyl glyceryl ether ((2-OG ether), a stable 2-OG analog with a potency of 5.3 µM for GPR119 with respect to cAMP formation as compared to 2.3 µM for 2-OG), significantly (Pu2009<u20090.05) improved glucose clearance in WT littermates, but not in GPR119 KO mice. Finally, deletion of GPR119 in mice resulted in lower glucagon levels, whereas the levels of insulin and GIP were unchanged. In the present study we show that 2-OG stimulates GLP-1 secretion through GPR119 activation in vitro, and that fat-derived 2-MAGs are potent candidates for mediating fat-induced GLP-1 release through GPR119 in vivo.

Increased postprandial response of glucagon-like peptide-2 in patients with chronic pancreatitis and pancreatic exocrine insufficiency.

Background/Aims: Glucagon-like peptide-2 (GLP-2) is a nutrient-released gastrointestinal (GI) hormone that acts as an intestinal growth factor, and exogenous GLP-2 has been shown to increase superior mesenteric artery (SMA) blood flow. We aimed to investigate how assimilation of nutrients affects postprandial GLP-2 responses and to correlate these with postprandial SMA blood flow. Methods: Responses of the GI hormone glucose-dependent insulinotropic polypeptide (GIP) and GLP-2 were measured following an 80-min liquid meal test in 8 patients (6 males) with chronic pancreatitis (CP) and pancreatic exocrine insufficiency (PEI) and 8 healthy control subjects (5 males). Postprandial GI hormone responses were correlated with change in SMA flow as assessed by the resistance index. Results: Patients with CP and PEI exhibited the greatest postprandial GLP-2 responses (1,870 ± 249 vs. 1,199 ± 108 pM·80 min, p = 0.027). No difference was observed with regard to GIP. GLP-2, but not GIP, responses correlated significantly with postprandial SMA flow. Conclusion: These results suggest that delayed assimilation of nutrients in patients with CP and PEI increases the secretion of GLP-2 – possibly due to delivery of a larger nutrient load to the distal part of the small intestine, where GLP-2 secreting L-cells are abundant – and that this hypersecretion of GLP-2 is associated with a higher SMA flow.

The antagonistic metabolite of GLP-1, GLP-1 (9-36)amide, does not influence gastric emptying and hunger sensations in man

Objective. Glucagon-like peptide-1 (GLP-1 (7-36)amide) is an intestinal hormone that is released in response to meal ingestion. GLP-1 reduces postprandial gastric and exocrine pancreatic secretion and is believed to inhibit gastric emptying. Furthermore, GLP-1 may play a role in hunger and thirst regulation. In vivo, GLP-1 is rapidly (within minutes) converted into a metabolite, GLP-1 (9-36)amide, which has been shown to act as a GLP-1 receptor antagonist in vitro and in anaesthetized pigs. The purpose of this study was to assess the effect of infusion of GLP-1 (9-36)amide on hunger ratings and antral emptying of a meal. Material and methods. Six healthy volunteers were tested in a double-blind, placebo-controlled fashion. Antral emptying of a liquid meal and hunger ratings were determined using ultrasound technology and visual analogue scale scoring during infusions of saline or GLP-1 (9-36)amide (5 pmol/kg body wt/min) resulting in supraphysiological concentrations. Results. Infusion of GLP-1 (9-36)amide had no effect on gastric emptying or the sensation of hunger compared to saline. Conclusions. Our findings suggests that the rapid formation of the antagonistic metabolite does not influence gastric emptying and hunger ratings in humans even when it is present in supraphysiological concentrations.

Pregnancy-associated plasma protein A in first trimester of diabetic pregnancy and subsequent fetal growth.

In the first trimester of normal pregnancy we have observed a significant positive correlation between pregnancy-associated plasma protein A (PAPP-A) levels and relative birth weight (1), so that the PAPP-A level in first trimester gives some crude prediction of subsequent fetal growth. Here we examine whether there is a similar association in pregnancies complicated by maternal diabetes, a situation in which fetal growth is known to deviate from normal.

Ultrasound Demonstration of the Amniotic Membrane

Abstract. Ultrasound scanning in the first trimester of pregnancy occasionally revealed a thin linear echo in the gestational sac. A total of 360 examinations, which had shown a live fetus with a crown‐rump length of 7–82 mm, equivalent to a menstrual age of 6–14 weeks, were reviewed. The linear echo was seen in 51 of the examinations, at an ultrasound age of 6–12 weeks. Most frequently it was seen in the 9th week, where it was recorded in 28 of 61 (46%) of the examinations. The origin of the linear echo is believed to be the very thin amniotic membrane, which from the 8th to the 12th week is lined by fluid on both sides. Other intra‐uterine membranes which all give stronger echo reflections are listed.