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Glucagon-like peptide (7-36) amide (GLP-1) is an incretin hormone of the enteroinsular axis released rapidly after meals despite the fact that GLP-1 secreting cells (L-cells) occur predominantly in the distal gut. The importance of these colonic L-cells for postprandial GLP-1 was determined in healthy control subjects and in ileostomy patients with minimal small bowel resection (<5 cm). Subjects were fed a high complex carbohydrate test meal (15.3 g starch) followed by two carbohydrate-free, high fat test meals (25 g and 48.7 g fat respectively). Circulating levels of glucose, insulin, glucagon, glucose insulinotrophic peptide (GIP) and GLP-1 were measured over a 9-h postprandial period. For both subject groups the complex carbohydrate test meal failed to elicit a rise in either GIP or GLP-1. However, both hormones were elevated after the fat load although the GLP-1 concentration was significantly reduced in the ileostomist group when compared with controls (P=0.02). Associated with this reduction in circulating GLP-1 was an elevation in glucagon concentration (P=0.012) and a secondary rise in the plasma glucose concentration (P=0.006). These results suggest that the loss of colonic endocrine tissue is an important determinant in the postprandial GLP-1 concentration. Ileostomists should not be assumed to have normal enteroinsular function as the colon appears to have an important role in postprandial metabolism.
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ABSTRACT
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 (K d) 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 (K d of 45±6 nmol/l). Binding sites for GLP-1 (7–36)amide were not present on dispersed enterocytes from porcine small intestine.
J. Endocr. (1988) 116, 357–362
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ABSTRACT
Pancreatic somatostatin-like immunoreactivity (SLI), immunoreactive insulin (IRI) and glucagon-like immunoreactivity (GLI) were measured during growth in ducks. The content of each hormone increased progressively but at different rates in the dorsal, ventral and splenic lobes of the pancreas. In the almost fully grown duck, the splenic lobe contained 80 and 63% of the total content of GLI and SLI respectively but low levels of IRI (23%), which were highest in the dorsal lobe (53%). In contrast to the hormonal content, only total GLI concentrations increased during development, the SLI concentrations remaining stable and IRI concentrations declining during growth. Gel filtration of pancreatic extracts indicated that most of the SLI in the pancreas of young and adult birds was somatostatin-14, although somatostatin-28 was present in the ventral lobe of young birds and larger molecular forms were present in the ventral and dorsal lobes. These changes in pancreatic hormonal content and concentration are dissimilar to age-related changes in SLI, GLI and IRI previously observed in the plasma of ducks. Plasma levels of pancreatic hormones may thus be controlled by hormonal and/or neural factors during post-hatch growth.
J. Endocr. (1987) 113, 65–70
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ABSTRACT
The effects of i.v. glucagon-like peptide-1-(7–36)amide (GLP-1; 10 μg) on starved sheep given an i.v. glucose load (5 g) were studied. Plasma insulin concentrations rose significantly more after glucose administration in fed than in starved sheep. Giving GLP-1 to starved sheep increased the insulin response to the glucose load. The rise in plasma insulin concentrations in starved sheep given GLP-1 was similar to that observed in fed sheep. Plasma glucose concentrations returned to normal values more quickly in the starved sheep given GLP-1 than in starved sheep not given gut hormone. Plasma concentrations of free fatty acid, urea and α-amino nitrogen decreased more quickly following glucose administration in starved sheep given GLP-1 than in those not given GLP-1. The data suggest a role for GLP-1 in regulating plasma insulin concentrations and hence metabolism in ruminant animals. The possible role of gut hormones in ruminants is discussed.
Journal of Endocrinology (1991) 129, 55–58
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Abstract
Food ingestion induces a rapid increase in the insulinotropic glucagon-like peptide-1 (GLP-1) in plasma. Paradoxically, GLP-1 originates from the lower intestines and therefore a complex regulation of postprandial GLP-1 secretion must exist. This was addressed in the present study by utilizing an isolated vascularly perfused rat ileum preparation. Peptides and neurotransmitters thought to be candidate mediators triggering GLP-1 secretion were arterially infused and GLP-1 was measured in the venous effluent. Arterial infusion of cholinergic agonists strongly enhanced GLP-1 secretion which was counteracted by the addition of atropine. Histamine, dopamine, 5-hydoxytryptamine, γ-aminobutyric acid, and norepinephrine had no effect. Peptides of the bombesin family were strong stimulants whereas tachykinins, enkephalins, dynorphin, TRH, calcitonin-gene-related peptide and members of the secretin family, vasoactive intestinal peptide, peptide histidine isoleucine and neuropeptide Y, were less effective. The second incretin hormone, gastric inhibitory polypeptide (GIP), was the most potent stimulant of GLP-1 secretion in our study. It enhanced GLP-1 release up to sixfold above basal during the early phase followed by a sustained secretion at 400% above basal. This stimulation remained unaffected by atropine. In conclusion, in addition to luminal stimulation of nutrients, a cholinergic impulse as well as peptidergic mediators (among them possibly GIP and GRP) may have an impact on postprandial GLP-1 secretion from the rat ileum.
Journal of Endocrinology (1995) 147, 25–31
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Liraglutide, an analog of the incretin hormone, glucagon-like peptide 1 (GLP-1), is widely used for obesity and type 2 diabetes treatment. However, there is scarce information about its effects on testicular function. Within the testis, Sertoli cells (SCs) provide nutritional support for germ cells: they metabolize glucose to lactate, which is delivered to germ cells to be used as a preferred energy substrate. Besides, SCs use fatty acids (FAs) as an energy source and store them as triacylglycerols (TAGs) within lipid droplets (LDs), which serve as an important energy reserve. In the present study, twenty-day-old rat SC cultures were used to assess whether liraglutide affects their metabolic functions related to nutritional support and lipid storage. The results show that liraglutide does not modify glucose consumption or lactate production. However, it increases TAG levels and LD content. These effects are accompanied by an increase in the mRNA levels of the fatty acid transporter FAT/CD36, glycerol-3-phosphate-acyltransferases 3, and perilipins 1 and 4. Then, the participation of the cAMP/PKA signaling pathway was explored. We observed that H89 (PKA inhibitor) decreases LD upregulation elicited by liraglutide, and that dibutyryl cAMP increases LD content and the expression of related genes. In summary, liraglutide promotes lipid storage in SCs through the regulation of key regulatory genes involved in FA transport, TAG synthesis, and LD formation. Considering the importance of lipid storage in SC energetic homeostasis maintenance, we postulate that liraglutide might improve the overall energetic status of the seminiferous tubule.
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The present study evaluates the possibility that an extra-pancreatic source of insulin exists in chickens. The effect of pancreatectomy on plasma levels of immunoreactive insulin (IRI), glucagon (IRG) and pancreatic polypeptide (IRAPP) was examined. Plasma levels of IRI, IRG and IRAPP were measured both in the basal state and after an i.v. challenge with known secretogogues at several times after pancreatectomy. The nature of the avian plasma immunoreactivity was further characterized by gel filtration.
Results indicated that plasma IRI and IRG persisted for 5 h, 24 h and 5 days after pancreatectomy. Furthermore, plasma levels of IRI and IRG remained responsive to the stimulus of i.v. arginine. The Sephadex G-50 elution profiles for IRI and IRG were similar for plasma obtained from both depancreatized and intact chickens. Postmortem tissue analyses indicated that the persistence of IRI and IRG in the depancreatized animals was not due to the presence of pancreatic remnants.
Plasma IRAPP decreased to undetectable levels 5 h after pancreatectomy. Although plasma IRAPP was measurable 1 and 5 days after pancreatectomy, these levels were not responsive to i.v. pentagastrin. Furthermore, gel filtration experiments indicated that the only form of IRAPP remaining after pancreatectomy had an apparent mol. wt of greater than 100 000. Such a compound was not secreted by the pancreas in vitro.
Evidence presented herein indicates that pancreatic polypeptide is the only pancreatic hormone to be eliminated from the circulation after pancreatectomy in chickens. It is suggested that the depancreatized chicken might be useful as a model of a 'selective' pancreatic polypeptide deficiency.
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Glucagon-like peptide-1 (GLP-1) is the most potent endogenous insulin-stimulating hormone. In the present study the plasma stability and biological activity of a GLP-1 analog, [Ser]GLP-1(7-36)amide, in which the second N-terminal amino acid alanine was replaced by serine, was evaluated in vitro and in vivo. Incubation of GLP-1 with human or rat plasma resulted in degradation of native GLP-1(7-36)amide to GLP-1(9-36)amide, while [Ser]GLP-1(7-36)amide was not significantly degraded by plasma enzymes. Using glucose-responsive HIT-T15 cells, [Ser]GLP-1(7-36)amide showed strong insulinotropic activity, which was inhibited by the specific GLP-1 receptor antagonist exendin-4(9-39)amide. Simultaneous i.v. injection of [Ser]GLP-1(7-36)amide and glucose in rats induced a twofold higher increase in plasma insulin levels than unmodified GLP-1(7-36)amide with glucose and a fivefold higher increase than glucose alone. [Ser]GLP-1(7-36)amide induced a 1.5-fold higher increase in plasma insulin than GLP-1(7-36)amide when given 1 h before i.v. application of glucose. The insulinotropic effect of [Ser]GLP-1(7-36)amide was suppressed by i.v. application of exendin-4(9-39)amide. The present data demonstrate that replacement of the second N-terminal amino acid alanine by serine improves the plasma stability of GLP-1(7-36)amide. The insulinotropic action in vitro and in vivo was not impaired significantly by this modification.
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SMUMARY
Concentrations of thyroxine above 10-7 m inhibited the activity of the 'usual' and 'atypical' human plasma cholinesterase in vitro. The 'atypical' enzy mewas more readily inhibited and the ratio of the I50 atypical: I50 usual indicates that the hormone can be used as a differential inhibitor to identify the two phenotypes. Similar results were obtained with thiourea, but the action of thiouracil appeared to differ in so far as this inhibited both enzymes to the same extent. Neither glucagon nor thyroid stimulating hormone had any effect.
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A method is described for the isolation of viable hepatocytes from sheep liver. The characteristics of insulin and glucagon binding to the cells were investigated by the use of mono-iodinated hormone, and from these data the optimum in-vitro incubation conditions for hormone-receptor binding were established. Glucagon and insulin receptors were examined in relation to plasma concentrations of hormones and metabolites in non-mated, and 20- and 50-day-lactating ewes (six animals/group). Measurements of insulin, growth hormone and non-esterified fatty acids in the circulation, together with a fall in body weight, suggested that at peak lactation (20 days) the ewes were in energy-deficit and were mobilizing body tissue. The percentage binding of insulin was higher in hepatocytes after 50 days of lactation when compared with that in both the unmated (P < 0·05) and 20-day-lactating animals. No changes in insulin binding were found between the unmated and 20-day-lactating groups. Glucagon binding was reduced in the 20- (P < 0·02) and increased in the 50-day-lactating group (P < 0·001) when compared with the unmated control animals. The binding of glucagon was higher at 50 days as compared with 20 days of lactation (P < 0·001). The changes in insulin binding resulted primarily from altered receptor numbers whereas changes in the binding of glucagon were due to alterations in both receptor numbers and affinity. Our results indicated that the binding of insulin and glucagon to isolated hepatocytes was altered during lactation in sheep and that these changes might modulate the sensitivity of the cells to the actions of the hormones.
