Effects of glucagon-like peptide-1 (7-36)amide on insulin stimulated rat skeletal muscle glucose transport

Glucagon-like peptide-1 binding sites have been reported in peripheral tissues including muscle. However, the potential extra-pancreatic effects of glucagon-like peptide-1(7-36)amide are controversial. To evaluate whether glucagon-like peptide-1(7-36)amide has any effects on skeletal muscle glucose transport, isolated rat soleus muscles were incubated in increasing concentrations of insulin (0–150 nmol/l) in the presence or absence of 1 nmol/l glucagon-like peptide-1(7-36)amide for 3 h. Subsequently glucose transport was measured as uptake of [³H]-O-methylglucose. It was found that glucagon-like peptide-(7-36)amide has a small but significant stimulating effect on skeletal muscle glucose transport independent of the insulin concentration (P<0.01). However, because of the magnitude of the observed effect, the physiological importance of glucagon-like peptide-1 (7-36)amide on skeletal muscle glucose metabolism is questionable. Received: 27 February 1998 / Accepted in revised form: 30 April 1998     

Receptors for glucagon-like peptide-1(7-36) amide on rat insulinoma-derived cells

Specific binding of 125I-labelled glucagon-like peptide-1(7-36)amide (GLP-1(7-36)amide) to rat insulinoma-derived RINm5F cells was dependent upon time and temperature and was proportional to cell concentration. Binding of radioactivity was inhibited in a concentration-dependent manner by GLP-1(7-36) amide consistent with the presence of a single class of binding site with a dissociation constant (Kd) of 204 +/- 8 pmol/l (mean +/- S.E.M.). Binding of the peptide resulted in a dose-dependent increase in cyclic AMP concentrations (half maximal response at 250 +/- 20 pmol/l). GLP-1(1-36)amide was approximately 200 times less potent than GLP-1(7-36)amide in inhibiting the binding of 125I-labelled GLP-1(7-36)amide to the cells (Kd of 45 +/- 6 nmol/l). Binding sites for GLP-1 (7-36)amide were not present on dispersed enterocytes from porcine small intestine.     

Berberine promotes glucagon-like peptide-1 (7-36) amide secretion in streptozotocin-induced diabetic rats

Berberine (BBR), a hypoglycemic agent, has shown beneficial metabolic effects for anti-diabetes, but its precise mechanism was unclear. Glucagon-like peptide-1 (GLP-1) is considered to be an important incretin that can decrease hyperglycemia in the gastrointestinal tract after meals. The aim of this study was to investigate whether BBR exerts its anti-diabetic effects via modulating GCG secretion. Diabetes-like rats induced by streptozotocin received BBR (120 mg/kg per day, i.g) for 5 weeks. Two hours following the last dose, the rats were anaesthetized and received 2.5 g/kg glucose by gavage. At 15-minute and 30-minute after glucose load, blood samples, pancreas, and intestines were obtained to measure insulin and GCG using ELISA kit. The number of L cells in the ileum and beta-cells in the pancreas were identified using immunohistology. The expression of proglucagon mRNA in the ileum was measured by RT-PCR. The results indicated that BBR treatment significantly increased GCG levels in plasma and intestine (P<0.05) accompanied with the increase of proglucagon mRNA expression and the number of L-cell compared with the controls (P<0.05). Furthermore, BBR increased insulin levels in plasma and pancreas as well as beta-cell number in pancreas. The data support the hypothesis that the anti-diabetic effects of BBR may partly result from enhancing GCG secretion.     

Mechanisms involved in glucagon-like peptide-1 (7-36) amide action on the rat hypothalamo-neurohypophysial system

Glucagon-like peptide-1 (7-36) amide (tGLP-1) has been shown to modify the secretory function of the rat hypothalamo-neurohypophysial complex (HNC). However, mechanisms underlying this action are still unclear. Using explants containing the HNC obtained from euhydrated rats, possible interactions of tGLP-1 with angiotensin II (Ang II), forskolin-induced cAMP synthesis or calcium ions were investigated. In addition, explants taken from rats given 2% saline were used in order to examine whether chronic osmotic stimulation affects tGLP-1 action on vasopressin and oxytocin neurons. tGLP-1 did not modify Ang II- or forskolin-evoked hormone release. Incubation of the HNC in calcium-free medium inhibited the tGLP-1-dependent vasopressin/oxytocin secretion. Prolonged salt loading in vivo completely changed the neurohypophysial response to tGLP-1 in vitro; it did not only abolish the stimulatory effect of tGLP-1 on basal hormone release, but reduced K(+)-stimulated vasopressin/oxytocin secretion. Consequently, the neurohypophysial response to tGLP-1 may depend on the functional status of the HNC and on the presence of calcium ions, but not cAMP.     

Differential effects of glucagon-like peptide-1 (7-36)amide versus cholecystokinin on arginine-induced islet hormone release in vivo and in vitro

We compared the effects of two incretin hormones, glucagon-like peptide-1 (7-36)amide (GLP-1) and cholecystokinin (CCK), on islet hormone secretion. GLP-1 strongly potentiated glucose-stimulated insulin secretion in the perfused rat pancreas and in vivo in mice (p < 0.001). In contrast, GLP-1 did not enhance arginine-induced insulin release under these experimental conditions. In the perfused rat pancreas, GLP-1 also potentiated glucose-stimulated somatostatin secretion but, again, had no effect on arginine-induced somatostatin release. However, GLP-1 promptly inhibited the arginine-induced glucagon release (p < 0.02). In contrast, CCK enhanced insulin release in response to arginine both in the perfused rat pancreas and in vivo in mice (p < 0.001). In conclusion, GLP-1, in contrast to CCK, failed to enhance arginine-induced insulin release both in vitro and in vivo. This suggests that a signal generated by nutrient metabolism is required for the potentiation of insulin secretion by GLP-1. Furthermore, GLP-1 directly inhibited arginine-induced glucagon release as no concurrent increase in insulin or somatostatin release was noted.     

Dexamethasone pretreatment of rat insulinoma cells decreases binding of glucagon-like peptide-1(7-36)amide

The effect of dexamethasone on binding of glucagon-like peptide-1(7-36)amide (GLP-1(7-36)amide) to rat insulinoma-derived cells (RINm5F) was investigated. Preincubation of RINm5F cells with dexamethasone (100 nmol/l) for 24 h resulted in a decrease of GLP-1(7-36)amide binding to 55.0 +/- 8.16% (mean +/- S.E.M.), incubation for 48 h to 39.1 +/- 1.76%, and for 72 h to 15.5 +/- 4.35% of maximal binding. The GLP-1(7-36)amide-induced stimulation of cyclic AMP (cAMP) production was significantly decreased to 61.03 +/- 7.4% of maximum production in cells pretreated with dexamethasone (100 nmol/l) for 48 h. The decreased binding was due to a reduction of the receptor number while the receptor affinity remained unchanged. These inhibitory effects on binding and cAMP formation induced by dexamethasone were completely abolished when the antiglucocorticoid RU 38486 (100 nmol/l) was added during preincubation with dexamethasone. RU 38486 alone had no effects. Our data suggest that the biological action of GLP-1(7-36)amide at the B-cell may be modified by glucocorticoids.     

Developmental patterns of glucagon-like peptide-1-(7-36) amide and peptide-YY in rat pancreas and gut.

Glucagon-like peptide-(17-36) amide [GLP-1-(7-36) amide] and peptide tyrosine tyrosine (PYY) are both products of the enteroglucagon cell. To examine the changes occurring during development, we analyzed by RIA the pancreatic concentrations of these two peptides in fetal and neonatal rats. The levels obtained were compared with those of the classical islet hormones, insulin, somatostatin, and glucagon. The total hormone content of the pancreas increased with age for insulin, glucagon, and somatostatin. The amounts of GLP-1-(7-36) amide immunoreactivity (IR) and PYY, however, remained approximately constant in the 3-, 8-, and 30-day-old and adult pancreas. GLP-1-(7-36) amide IR showed only a single peak by gel chromatography, but further analysis by anion exchange chromatography showed that during the fetal period (-18 days) and 3 days postpartum GLP-1-(7-36) amide was the main product, whereas 30 days postpartum and in adult pancreas mainly GLP-1 and an intermediate form were found. Similar analyses of gut extracts revealed that only GLP-1-(7-36) amide is produced during intestinal development. The gut content of GLP-1-(7-36) amide IR and PYY IR increased approximately 100 times between the fetus and the 30-day-old rat. This study reveals a complex and specific regulation of posttranslational processing during maturation for these two peptides.     

Involvement of endogenous glucagon-like peptide-1(7-36) amide on glycaemia-lowering effect of oligofructose in streptozotocin-treated rats

We have evaluated the influence of oligofructose (OFS), a fermentable dietary fibre, on glucose homeostasis, insulin production and intestinal glucagon-like peptide-1 (GLP-1) in streptozotocin-treated diabetic rats. Male Wistar rats received either i.v. streptozotocin (STZ; 40 mg/kg) or vehicle (CT); one week later, they were fed for 6 weeks with either the standard diet (STZ-CT), or with a diet containing 10% oligofructose (STZ-OFS); both diets were available ad libitum. In a second set of experiments (duration 4 weeks), a supplemental group of food-restricted rats (STZ-Res) receiving a similar intake as CT rats, was added. OFS improved glucose tolerance and reduced food intake as compared with STZ-CT rats in both the post-prandial state and after an oral glucose tolerance test. After 6 weeks, portal and pancreatic insulin concentrations were doubled in STZ-OFS rats. Food restriction improved these parameters when compared with STZ-CT rats, but to a lesser extent than in the STZ-OFS group. We have shown that OFS treatment increased portal and colonic GLP-1(7-36) amide levels and doubled colonic proglucagon and prohormone convertase 1 mRNA levels; both OFS and food restriction lowered ileal GLP-1(7-36) amide levels as compared with levels in STZ-CT rats. We propose that OFS, through its fermentation in the colon, promotes the expression and secretion of colonic peptides, namely GLP-1(7-36) amide, with beneficial consequences on glycaemia, insulin secretion and hyperphagia in diabetic rats.     

Effects of glucagon-like peptide-1(7-36)amide on motility and sensation of the proximal stomach in humans

BACKGROUND: Glucagon-like peptide-1(7-36)amide (GLP-1) retards gastric emptying, reduces food intake, and inhibits antroduodenal and stimulates pyloric motility. AIMS: To assess the effects of synthetic GLP-1 on fundus tone and volume waves, gastric compliance, and perception of gastric distension. SUBJECTS: Eleven healthy male volunteers. METHODS: Background infusions were saline, or GLP-1 at 0.3 or 0.9 pmol/ kg/min on separate days in random order. Interdigestive fundus motility was recorded by barostat (maximum capacity of intragastric bag 1200 ml) during basal and peptide periods of 60 minutes each. Thereafter stepwise isobaric distensions were performed with ongoing peptide infusion, and gastric sensation was scored. RESULTS: Low and high loads of GLP-1 induced physiological and supraphysiological plasma immunoreactivities, respectively. GLP-1 dose dependently diminished fundus tone (162.9 (15.0) and 259.5 (17.2) v 121.1 (6.0) ml with saline; p<0.0001). It greatly reduced volume waves and total volume displaced by these events (p<0.0001). Gastric compliance derived from isobaric distension rose in a dose related manner (42.6 (5.5) and 63.6 (7.7) v 27.0 (3.5) ml/mm Hg; p=0.0004) with a concomitant reduction of the pressure at half maximum bag volume (6.4 (0.4) and 5.5 (0.4) v 7.2 (0.1) mm Hg; p<0.0001). GLP-1 did not change perception of isobaric distension but reduced the perception score related to corresponding bag volume (p<0.0001). CONCLUSIONS: GLP-1 is a candidate physiological inhibitory regulator of fundus motility. It allows the stomach to afford a larger volume without increase in sensation.     

Decreased dipeptidyl peptidase-IV activity and glucagon-like peptide-1(7-36)amide degradation in type 2 diabetic subjects

Dipeptidyl peptidase (DPP-IV) rapidly metabolizes hormones such as glucagon-like peptide-1(7-36)amide. This study evaluated circulating DPP-IV activity in type 2 diabetic patients in relation to GLP-1 degradation and metabolic control. Blood samples were collected from type 2 diabetic patients in three main categories: good glycaemic control (HbA(1c) <7%, upper limit of non-diabetic range), moderate glycaemic control (HbA(1c) 7-9%) and poor glycaemic control (HbA(1c) >9%). Age- and sex-matched non-diabetic subjects were used as controls. Circulating DPP-IV activity of healthy control subjects was 22.5+/-0.7 nmol/ml/min (n=70). In the combined groups of type 2 diabetic subjects, circulating DPP-IV activity was significantly decreased at 18.1+/-0.7 nmol/ml/min (p<0.001, n=54). DPP-IV activity was negatively correlated with both glucose (p<0.01) and HbA(1c) (p<0.01) in this population. Furthermore, DPP-IV activity was reduced 1.2-fold (p<0.01, n=25), 1.3-fold (p<0.001, n=19) and 1.3-fold (p<0.05, n=10) in good, moderate and poorly controlled diabetic groups, 18.7+/-1.0, 17.4+/-1.4 and 18.0+/-1.5 nmol/ml/min, respectively. Degradation of GLP-1 by in vitro incubation with pooled plasma samples from healthy and type 2 diabetic subjects revealed decreased degradation to the inactive metabolite, GLP-1(9-36), in the diabetic group. These data indicate decreased DPP-IV activity and GLP-1 degradation in type 2 diabetes. DPP-IV enzyme activity appears to be depressed in response to poor glycaemic control.     

Lys9 for Glu9 substitution in glucagon-like peptide-1(7-36)amide confers dipeptidylpeptidase IV resistance with cellular and metabolic actions similar to those of established antagonists glucagon-like peptide-1(9-36)amide and exendin (9-39)

The incretin hormone glucagon-like peptide-1(7-36)amide (GLP-1) has been deemed of considerable importance in the regulation of blood glucose. Its effects, mediated through the regulation of insulin, glucagon, and somatostatin, are glucose-dependent and contribute to the tight control of glucose levels. Much enthusiasm has been assigned to a possible role of GLP-1 in the treatment of type 2 diabetes. GLP-1's action unfortunately is limited through enzymatic inactivation caused by dipeptidylpeptidase IV (DPP IV). It is now well established that modifying GLP-1 at the N-terminal amino acids, His(7) and Ala(8), can greatly improve resistance to this enzyme. Little research has assessed what effect Glu(9)-substitution has on GLP-1 activity and its degradation by DPP IV. Here, we report that the replacement of Glu(9) of GLP-1 with Lys dramatically increased resistance to DPP IV. This analogue, (Lys(9))GLP-1, exhibited a preserved GLP-1 receptor affinity, but the usual stimulatory effects of GLP-1 were completely eliminated, a trait duplicated by the other established GLP-1-antagonists, exendin (9-39) and GLP-1(9-36)amide. We investigated the in vivo antagonistic actions of (Lys(9))GLP-1 in comparison with GLP-1(9-36)amide and exendin (9-39) and revealed that this novel analogue may serve as a functional antagonist of the GLP-1 receptor.     

Glucagon-like peptide-1-(7-36)amide is transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine.

The insulinotropic hormone glucagon-like peptide-1 (GLP-1) is stored in the intestinal L cell in an active form, GLP-1-(7-36)amide, but more than half of the endogenous peptide circulates in an inactive, N-terminally truncated form, GLP-1-(9-36)amide. This study examined the GLP-1 newly secreted from the porcine ileum, in vitro (isolated perfused preparation) and in vivo (anesthetized pig), to determine where this conversion occurs. Although the GLP-1 extractable from the porcine ileum is predominantly the intact peptide (94.6+/-1.7%), a large proportion of the GLP-1 that is secreted has already been degraded to the truncated form both in vitro (53.8+/-0.9% intact) and in vivo (32.9+/-10.8% intact). In the presence of a specific dipeptidyl peptidase IV (DPP IV) inhibitor (valine-pyrrolidide), the proportion of intact GLP-1 released from the perfused ileum was increased under both basal (99% intact; P < 0.05) and stimulated (86-101% intact; P < 0.05) conditions. Immunohistochemical and histochemical studies revealed specific DPP IV staining in the brush border epithelium as well as in the capillary endothelium. Double staining showed juxtapositioning of DPP IV-positive capillaries and GLP-1-containing L cells. From these results, we suggest that GLP-1 is degraded as it enters the DPP IV containing blood vessels draining the intestinal mucosa.     

A meta-analysis of the effect of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake in humans

Seven studies have now been published pertaining to the acute effect of iv administration of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake. In four of these studies energy intake was significantly reduced following the glucagon-like peptide-1 infusion compared with saline. In the remaining studies, no significant effect of glucagon-like peptide-1 could be shown. Lack of statistical power or low glucagon-like peptide-1 infusion rate may explain these conflicting results. Our aim was to examine the effect of glucagon-like peptide-1 on subsequent energy intake using a data set composed of subject data from previous studies and from two as yet unpublished studies. Secondly, we investigated whether the effect on energy intake is dose dependent and differs between lean and overweight subjects. Raw subject data on body mass index and ad libitum energy intake were collected into a common data set (n = 115), together with study characteristics such as infusion rate, duration of infusion, etc. From four studies with comparable protocol the following subject data were included if available: plasma concentrations of glucagon-like peptide-1, subjective appetite measures, well-being, and gastric emptying rate of a meal served at the start of the glucagon-like peptide-1 infusion. Energy intake was reduced by 727 kJ (95% confidence interval, 548-908 kJ) or 11.7% during glucagon-like peptide-1 infusion. Although the absolute reduction in energy intake was higher in lean (863 kJ) (634-1091 kJ) compared with overweight subjects (487 kJ) (209-764 kJ) (P = 0.05), the relative reduction did not differ between the two groups (13.2% and 9.3%, respectively). Stepwise regression analysis showed that the glucagon-like peptide-1 infusion rate was the only independent predictor of the reduction in energy intake during glucagon-like peptide-1 (7-36) amide infusion (r = 0.4, P < 0.001). Differences in mean plasma glucagon-like peptide-1 concentration on the glucagon-like peptide-1 and placebo day (n = 43) were related to differences in feelings of prospective consumption (r = 0.40, P < 0.01), fullness (r = 0.38, P < 0.05), and hunger (r = 0.26, P = 0.09), but not to differences in ad libitum energy intake. Gastric emptying rate was significantly lower during glucagon-like peptide-1 infusion compared with saline. Finally, well-being was not influenced by the glucagon-like peptide-1 infusion. Glucagon-like peptide-1 infusion reduces energy intake dose dependently in both lean and overweight subjects. A reduced gastric emptying rate may contribute to the increased satiety induced by glucagon-like peptide-1.     

Interaction of glucagon-like peptide-1 (7-36)amide and cholecystokinin-8 in the endocrine and exocrine rat pancreas.

The synergistic impact of glucagon-like peptide-1 (GLP-1) (7-36)amide and cholecystokinin-8 (CCK-8) was studied in the rat pancreas. The GLP-1 (7-36)amide (1 pM-1 microM) had no effect on the basal or CCK-stimulated (1 nM-1 pM) amylase release from isolated pancreatic acini. The insulinotropic action of 0.5 nM GLP-1 (7-36)amide, which weakly stimulated the glucose-induced (6.7 mM) insulin release from the isolated perfused rat pancreas, was strongly potentiated by the addition of CCK-8 (20, 50, and 100 pM) to the perfusate. In concentrations as they occur physiologically after a meal, CCK-8 alone had no significant effect on basal or glucose-stimulated (6.7 mM) insulin secretion. Our data support the assumption that the nutrient-regulated intestinal release of various peptides represents a regulatory system to ensure an adequate insulin response to food intake, at least in rats.     

Glucagon-like peptide-1(7-36) amide stimulates surfactant secretion in human type II pneumocytes

To determine the influence of glucagon-like peptides on the secretion of human pulmonary surfactant, we used human type II pneumocytes. In these cells, GLP-1(7-36) amide and exendin-4 stimulated phosphatidylcholine secretion (PC) and cAMP formation in a concentration-dependent manner; these effects were reversed by exendin(9-39). No changes were observed with other related peptides. The mechanism by which GLP-1(7-36) amide exerts its stimulatory effect was investigated with various agents that are well known to be stimulators or inhibitors of PC secretion. Thus, 8-bromo-cAMP increased and both Rp-cAMPS and H-89, the latter an inhibitor of protein kinase A (PKA), reduced pulmonary surfactant secretion in type II pneumocytes. Also, GLP-1(7-36) amide and TPA exerted additive effects in stimulating PC secretion, and Calph C, a potent inhibitor of protein kinase C (PKC), blocked most of the effect of GLP-1(7-36) amide. By contrast, both the calcium ionophore A23187 and GLP-1(7-36) amide had additive effects in increasing PC secretion, and the specific inhibitor of Ca(2+)-calmodulin-dependent protein kinase (Ca-CM-PK), KN-62, inhibited the effect of A23187 but did not alter the stimulatory action of GLP-1(7-36) amide. Our findings suggest that both PKA and PKC are involved in the stimulatory effects of GLP-1(7-36) amide on PC secretion, whereas this peptide has no effect on PC secretion through a Ca-CM-PK mechanism.     

Interaction of glucagon-like peptide-1(7-36) amide and gastric inhibitory polypeptide or cholecystokinin on insulin and glucagon secretion from the isolated perfused rat pancreas.

The interaction of three incretin candidates, glucagon-like peptide-1(7-36)amide (t-GLP-1), gastric inhibitory polypeptide (GIP), and sulfated COOH-terminal octapeptide of cholecystokinin (CCK-8-S), on insulin and glucagon release from the isolated perfused rat pancreas was studied. Under the perfusate condition of 8.3 mmol/L glucose, coinfusion of 0.1 nmol/L t-GLP-1 and 0.1 nmol/L GIP resulted in an augmented insulin release greater than that obtained by the same dose of each peptide alone. The degree of stimulation elicited by t-GLP-1 and GIP reached a plateau at 0.3 nmol/L for both infusates, and no cooperative effect was observed by coinfusion at 0.3 nmol/L. Coinfusion of 0.1 nmol/L t-GLP-1 and and 0.1 nmol/L CCK-8-S also resulted in an augmented insulin release greater than that obtained by the same dose of each peptide alone. A similar cooperative effect was observed by coinfusion at 0.3 nmol/L, 1 nmol/L, and 3 nmol/L. With the same perfusion experiments, glucagon release was not significantly affected by any peptide at concentrations of 0.1, 0.3, 1, or 3 nmol/L. The coinfusion of 1 nmol/L t-GLP-1 and GIP elicited a transient, but significant, increase in glucagon release. A similar result was obtained by the coinfusion of 0.3 nmol/L and 3 nmol/L t-GLP-1 and GIP, respectively. The coinfusion of t-GLP-1 and CCK-8-S did not affect the glucagon release.(ABSTRACT TRUNCATED AT 250 WORDS)     

N-terminal His(7)-modification of glucagon-like peptide-1(7-36) amide generates dipeptidyl peptidase IV-stable analogues with potent antihyperglycaemic activity

Glucagon-like peptide-1(7-36)amide (GLP-1) possesses several unique and beneficial effects for the potential treatment of type 2 diabetes. However, the rapid inactivation of GLP-1 by dipeptidyl peptidase IV (DPP IV) results in a short half-life in vivo (less than 2 min) hindering therapeutic development. In the present study, a novel His(7)-modified analogue of GLP-1, N-pyroglutamyl-GLP-1, as well as N-acetyl-GLP-1 were synthesised and tested for DPP IV stability and biological activity. Incubation of GLP-1 with either DPP IV or human plasma resulted in rapid degradation of native GLP-1 to GLP-1(9-36)amide, while N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 were completely resistant to degradation. N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 bound to the GLP-1 receptor but had reduced affinities (IC(50) values 32.9 and 6.7 nM, respectively) compared with native GLP-1 (IC(50) 0.37 nM). Similarly, both analogues stimulated cAMP production with EC(50) values of 16.3 and 27 nM respectively compared with GLP-1 (EC(50) 4.7 nM). However, N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 exhibited potent insulinotropic activity in vitro at 5.6 mM glucose (P<0.05 to P<0.001) similar to native GLP-1. Both analogues (25 nM/kg body weight) lowered plasma glucose and increased plasma insulin levels when administered in conjunction with glucose (18 nM/kg body weight) to adult obese diabetic (ob/ob) mice. N-pyroglutamyl-GLP-1 was substantially better at lowering plasma glucose compared with the native peptide, while N-acetyl-GLP-1 was significantly more potent at stimulating insulin secretion. These studies indicate that N-terminal modification of GLP-1 results in DPP IV-resistant and biologically potent forms of GLP-1. The particularly powerful antihyperglycaemic action of N-pyroglutamyl-GLP-1 shows potential for the treatment of type 2 diabetes.     

Effects of glucagon-like peptide-1(7-36) amide on neurohypophysial and cardiovascular functions under hypo- or normotensive hypovolaemia in the rat

To date, glucagon-like peptide 1(7-36) amide (tGLP-1) has been found to affect the neurohypophysial and cardiovascular functions in normotensive and normovolaemic rats. The aim of the present study was to investigate possible effects of tGLP-1 on the mean arterial blood pressure and the release of vasopressin and oxytocin under conditions of blood volume depletion in the rat. In the first series of experiments, the animals were injected i.p. with either 0.15 M saline or 30% polyethylene glycol (PEG). PEG caused an 18% reduction of blood volume 1 h after injection. No significant changes in the mean arterial blood pressure were found in either normo- or hypovolaemic rats during the experiment. tGLP-1 injected i.c.v. at a dose of 1 microg/5 microl 1 h after the i.p. injection increased similarly the arterial blood pressure in normo- and hypovolaemic rats. The plasma vasopressin/oxytocin concentrations were markedly elevated in hypovolaemic animals and tGLP-1 further augmented the release of both hormones. In the second study, hypovolaemia was induced by double blood withdrawal. The haemorrhage resulted in a marked decrease of the mean arterial blood pressure and in the elevated plasma vasopressin/oxytocin concentrations. tGLP-1 injected immediately after the second blood withdrawal increased the arterial blood pressure. In parallel, tGLP-1 enhanced significantly vasopressin and oxytocin secretion when compared with haemorrhaged, saline-injected rats. The results of this study indicate that tGLP-1 may affect the arterial blood pressure and the secretion of neurohypophysial hormones under pathological conditions brought about by blood volume depletion.