Effects of galanin on the release of insulin, glucagon and somatostatin from the isolated, perfused dog pancreas

1988 ◽  
Vol 119 (1) ◽  
pp. 91-98 ◽  
Author(s):  
K. Hermansen

Abstract. Galanin is a 29 amino acid peptide which has been found in intrapancreatic nerves. The effects of galanin, adrenergic and cholinergic blockade as well as somatostatin on the hormone release from the isolated perfused dog pancreas were studied. It was found that galanin dose-dependently inhibited insulin (P < 0.001) and somatostatin (P < 0.001) but not glucagon secretion at normal glucose levels. The lowest galanin concentration that caused a significant suppression of insulin and somatostatin secretion was 10−11and 10−10 mol/l, respectively. Similar effects were evident during stimulation with 2.5 mmol/l arginine. Galanin (10−9 mol/l) caused a more pronounced inhibition of insulin and somatostatin secretion at high (10 mmol/l) and normal (5 mmol/l) than at low glucose (1.3 mmol/l). In contrast, suppression of the glucagon secretion was only seen at low glucose (1.3 mmol/l). Perfusion of 10−6 mol/l of atropine, phentolamine and propranolol had no effect on the galanin-mediated (10−10 mol/l) inhibition of insulin and somatostatin secretion. Galanin (10−12–10−10 mol/l) and somatostatin (10−12 – 10−10 mol/l) were equipotent in inhibiting insulin secretion whereas only somatostatin exerted a suppression of the glucagon secretion at normal glucose. Thus, galanin exerts a differential effect on islet hormone secretion and may participate in the hormonal control of insulin, glucagon and somatostatin secretion.

1982 ◽  
Vol 99 (1) ◽  
pp. 86-93 ◽  
Author(s):  
Kjeld Hermansen

Abstract. We studied the actions of tolbutamide on the release of somatostatin, insulin, and glucagon from the isolated, perfused dog pancreas. Tolbutamide (180 μm) elicited a biphasic response of all three islet hormones in the absence of glucose. In the presence of normal glucose (5.5 mm), 180 μm tolbutamide was again stimulatory, however, now the D cell response appeared uniphasic and the relative increase of somatostatin was lower than in the absence of glucose. At the highest perfusate glucose of 11 mm, no augmentation of the somatostatin output was seen to 180 μm tolbutamide, whereas the B and A cell secretion was still stimulated. In dose-response studies with tolbutamide (1.8–1800 μm) it was found that the D cell threshold to tolbutamide was 18 μm, Furthermore, that maximal D cell secretion was attained in the presence of 180 μm tolbutamide at low glucose (1.4 mm) and of 18 μm tolbutamide at normal glucose (5.5 mm), respectively. The insulin and glucagon responses showed clearcut dose-dependency over the range of tolbutamide doses applied. The B and A cell threshold to tolbutamide was 1.8 μm when the prevailing glucose level was stimulatory for the B and A cell, respectively. The finding that D and B cell responses to tolbutamide were eliminated during calcium deprivation indicates a key role of calcium in the events that proceeds to tolbutamide-mediated somatostatin and insulin release. In conclusion, the primary effect of tolbutamide on the islet cells is to stimulate hormone secretion, however, pertubations in terms of appearance and magnitude of D, B, and A cell responses depend on the balance between the concentrations of tolbutamide and glucose.


1989 ◽  
Vol 121 (4) ◽  
pp. 545-550 ◽  
Author(s):  
Kjeld Hermansen ◽  
Noboru Yanaihara ◽  
Bo Ahrén

Abstract. Galanin, a 29 amino acid peptide, inhibits insulin and somatostatin secretion from the isolated, perfused dog pancreas. To assess the nature of the influences of galanin on the endocrine pancreas, we examined the effects of porcine galanin and six different galanin analogues at the equimolar concentration of 1 nmol/l on the hormone release from the isolated, perfused dog pancreas. It was found that galanin2–29 (by 75 ± 4%), like the native galanin1–29 (by 90 ± 3%) potently inhibited insulin secretion (p < 0.001). In contrast, galanin3–29 did not significantly affect insulin secretion. This indicates that removal of the two N-terminal amino acids markedly reduces the potency of galanin. Also, the replacement of the amino acid number 2 (Trp) by Tyr or Phe was followed by a loss of the insulin lowering effect of galanin at this dose level. Likewise, galanin 10–29 had no significant effect on insulin secretion. In contrast, the C-terminally deleted galanin1–15 significantly inhibited insulin secretion (by 24 ± 5%; p < 0.01), though with a lower potency than did native galanin (p < 0.05). Consequently, the C-terminal end of galanin is also of importance for the effect. Somatostatin secretion was inhibited by galanin (p < 0.001), but not by any of the other investigated peptides. Glucagon secretion was not affected by galanin. It is concluded that the two N-terminal amino acids of galanin are essential for the inhibitory action on the insulin secretion. The removal of the N-terminal Gly residue decreases the action of galanin on insulin secretion to a much smaller extent than does the removal of, in addition, the Trp residue. However, the remainder of the molecule seems necessary for full potency. It is also concluded that the inhibition by galanin of somatostatin secretion seems to require the entire molecule.


1995 ◽  
Vol 269 (6) ◽  
pp. G852-G860 ◽  
Author(s):  
R. S. Heller ◽  
G. W. Aponte

Glucagon-like peptide (GLP)-1-(7--36) amide, a peptide product of the posttranslational processing of pancreatic and intestinal proglucagon, has been shown to regulate insulin secretion. Monoclonal antibodies to glucagon and GLP-1-(7--36) amide were generated to localize GLP-1-(7--36) amide in the pancreatic islets by immunocytochemistry and radioimmunoassay. GLP-1-(7--36) amide immunoreactivity was found in some, but not all, glucagon-containing alpha-cells. Displaceable receptor binding for GLP-1-(7--36) amide and nonamidated GLP-1-(7--37) on hormone secretion were investigated using isolated pancreatic islet preparations. GLP-1-(7--37) and -(7--36) amide significantly increased insulin and somatostatin release in the concentration range of 0.01-100 nM in 11.0 mM glucose. GLP-1-(7--37) and -(7--36) amide had no effect on glucagon secretion in the presence of 11.0 mM glucose. GLP-1-(7--36) amide was released from isolated islets in response to 2.25, 5.5, and 11.0 mM glucose. These results suggest that pancreatic GLP-1 may be important in the regulation of intra-islet hormone secretion.


2013 ◽  
Vol 2 (2) ◽  
pp. 69-78 ◽  
Author(s):  
L Ahlkvist ◽  
K Brown ◽  
B Ahrén

We previously demonstrated that the overall incretin effect and the β-cell responsiveness to glucagon-like peptide-1 (GLP1) are increased in insulin-resistant mice and may contribute to the upregulated β-cell function. Now we examined whether this could, first, be explained by increased islet GLP1 receptor (GLP1R) protein levels and, secondly, be leveraged by G-protein-coupled receptor 119 (GPR119) activation, which stimulates GLP1 secretion. Female C57BL/6J mice, fed a control (CD, 10% fat) or high-fat (HFD, 60% fat) diet for 8 weeks, were anesthetized and orally given a GPR119 receptor agonist (GSK706A; 10 mg/kg) or vehicle, followed after 10 min with gavage with a liquid mixed meal (0.285 kcal). Blood was sampled for determination of glucose, insulin, intact GLP1, and glucagon, and islets were isolated for studies on insulin and glucagon secretion and GLP1R protein levels. In HFD vs CD mice, GPR119 activation augmented the meal-induced increase in the release of both GLP1 (AUCGLP1 81±9.6 vs 37±6.9 pM×min, P=0.002) and insulin (AUCINS 253±29 vs 112±19 nM×min, P<0.001). GPR119 activation also significantly increased glucagon levels in both groups (P<0.01) with, however, no difference between the groups. By contrast, GPR119 activation did not affect islet hormone secretion from isolated islets. Glucose elimination after meal ingestion was significantly increased by GPR119 activation in HFD mice (0.57±0.04 vs 0.43±0.03% per min, P=0.014) but not in control mice. Islet GLP1R protein levels was higher in HFD vs CD mice (0.8±0.1 vs 0.5±0.1, P=0.035). In conclusion, insulin-resistant mice display increased islet GLP1R protein levels and augmented meal-induced GLP1 and insulin responses to GPR119 activation, which results in increased glucose elimination. We suggest that the increased islet GLP1R protein levels together with the increased GLP1 release may contribute to the upregulated β-cell function in insulin resistance.


1995 ◽  
Vol 268 (6) ◽  
pp. E1128-E1134 ◽  
Author(s):  
Z. K. Krowicki ◽  
P. J. Hornby

Until recently, the dorsal vagal complex (DVC) was considered as the only brain stem regulatory center for the vagal control of the endocrine pancreas. Because the nucleus raphe obscurus (NRO) maintains anatomic connections via the DVC to the pancreas, a functional significance of these findings was investigated in the present study. Kainic acid and vehicle were microinjected into the right DVC and the NRO of alpha-chloralose-anesthetized rats, and plasma concentrations of rat insulin, glucagon, and glucose were determined before and 5, 15, 30, and 60 min after injections. Chemical stimulation of neurons in the DVC by kainic acid at a dose of 200 pmol evoked increases in concentrations of insulin, with a peak at 15 min, and glucagon, with a peak at 30 min. Microinjection of kainic acid into the NRO at a dose of 200 pmol, but not at a dose of 20 pmol, produced increases in plasma concentrations of insulin, with a peak at 30 min, and glucagon, with a peak at 60 min. Plasma glucose levels on microinjection of kainic acid into the NRO at a dose of 20 pmol were decreased, whereas no changes on microinjection of kainic acid at a dose of 200 pmol were observed. The effects of kainic acid on insulin and glucagon secretion in the NRO were abolished by bilateral vagotomy. The study demonstrates for the first time that the NRO can contribute to vagal control of pancreatic endocrine function, although the exact circuitry and neurotransmitters involved in this response remain unknown.


Author(s):  
Marine L. Croze ◽  
Marcus F. Flisher ◽  
Arthur Guillaume ◽  
Caroline Tremblay ◽  
Glyn M. Noguchi ◽  
...  

ABSTRACTObjectiveMaintenance of glucose homeostasis requires the precise regulation of hormone secretion from the endocrine pancreas. Free-fatty acid receptor 4 (FFAR4/GPR120) is a G protein-coupled receptor whose activation in islets of Langerhans promotes insulin and glucagon secretion and inhibits somatostatin secretion. However, the contribution of individual islet cell types (α, β, and δ cells) to the insulinotropic and glucagonotropic effects of GPR120 remains unclear. As gpr120 mRNA is enriched in somatostatin-secreting δ cells, we hypothesized that GPR120 activation stimulates insulin and glucagon secretion via inhibition of somatostatin release.MethodsGlucose tolerance tests were performed in mice after administration of the selective GPR120 agonist Compound A. Insulin, glucagon and somatostatin secretion were measured in static incubations of isolated mouse islets in response to endogenous (ω-3 polyunsaturated fatty acids) and/or pharmacological (Compound A and AZ-13581837) GPR120 agonists. The effect of Compound A on hormone secretion was tested further in islets isolated from mice with global or somatostatin cell-specific knockout of gpr120. Gpr120 expression was assessed in pancreatic section by RNA in situ hybridization and immunohistochemistry. Cyclic AMP (cAMP) and calcium dynamics in response to pharmacological GPR120 agonists were measured specifically in α, β and δ cells in intact islets using cAMPER and GCaMP6 reporter mice, respectively.ResultsAcute exposure to Compound A increased glucose tolerance and circulating insulin and glucagon levels in vivo. Endogenous and/or pharmacological and GPR120 agonists reduced somatostatin secretion in isolated islets and concomitantly demonstrated dose-dependent potentiation of glucose-stimulated insulin secretion and arginine-stimulated glucagon secretion. GPR120 was enriched in δ cells and pharmacological GPR120 agonists reduced cAMP and calcium levels in δ cells, but increased these signals in α and β cells. Compound A-mediated inhibition of somatostatin secretion was insensitive to pertussis toxin. The effect of Compound A on hormone secretion was completely absent in islets from mice with either global or somatostatin cell-specific deletion of gpr120 and was partially reduced upon blockade of somatostatin receptor signaling by cyclosomatostatin.ConclusionsInhibitory GPR120 signaling in δ cells contributes to both insulin and glucagon secretion in part via mitigating somatostatin release.


1985 ◽  
Vol 63 (10) ◽  
pp. 1308-1311 ◽  
Author(s):  
Suzanne Rousseau-Migneron ◽  
Sophie Nadeau ◽  
André Nadeau

The influence of dobutamine on glucoregulation has been assessed in the rat during and after an intravenous infusion given at the following doses: 0, 0.1, 1.0, 10, 100, and 1000 μg∙kg−1∙min−1. Plasma glucose, insulin, and glucagon levels were measured at 15-min intervals in unanesthetized previously cannulated rats. Basal glucose levels were preserved with the ≤10 μg∙kg−1∙min−1 doses. At the ≥100 μg∙kg−1∙min−1 doses, a marked hyperglycemic effect was observed, partly attributable to some inhibitory effect of dobutamine on glucose-induced insulin secretion and to its stimulatory effect on glucagon secretion. Such data suggest that dobutamine may disturb the normal glucose homeostasis, particularly in situations of deficient insulin reserve.


2020 ◽  
Vol 3 ◽  
Author(s):  
William Phillips ◽  
Marcella Brissova ◽  
Julie Kilburn ◽  
Joyce Niland ◽  
Carmella Evans-Molina

Background/Objective:   The Integrated Islet Distribution Program (IIDP) distributes islets from five isolation Centers and serves as the main source of human islets for research in the U.S.  In 2016, the IIDP initiated the Human Islet Phenotyping Program (HIPP), which provides standardized post-shipment assessment of islet hormone secretion and endocrine cell composition for each IIDP-supported islet isolation.  To date, islets from 276 non-diabetic donors have been analyzed.  We hypothesized that analysis of this unique resource will provide novel insights into how demographic and clinical features impact islet health.     Methods:  Relationships between insulin and glucagon secretion assessed by perifusion and islet composition (% of β- and α-cells) were analyzed using SAS Version 9.4.  For each analysis, the isolation center was used as a covariate.      Results:    Of the 276 donors, 60% were male; 59% of donors were Caucasian, 28% were Hispanic, 9% were African-American; 4% were Asian; and 0.36% were American Indian.  The % of β-cells was moderately correlated with insulin responses to 16.7 mM glucose (r=0.2785; p<0.0001) and 20 mM KCL (r=0.3109, p<0.0001).  Similarly, the α-cell% was moderately correlated with total glucagon content (r=0.3362, p<0.0001) and glucagon responses to 1.7 mM glucose + 1mM epinephrine (r=0.2015, p=0.0001). The % of β -cells was negatively correlated with glucagon total content (r=-.243,p=.0001), while the α-cell% was negatively correlated with insulin stimulation index to KCL (r=-0.2573, p<0.0001). Notably, Asian donors exhibited a significantly higher β-cell% compared to other groups (p<0.05).  Consistent with this, glucose-stimulated insulin secretion was higher in Asian donors compared to responses observed in islets from African American donors (p<0.01).    Conclusion:   These data indicate that islet cell composition influences insulin and glucagon secretory responses and suggests that race may impact islet composition and hormone secretion. Continued analysis of the HIPP dataset may aid in our understanding of risk factors for the development islet dysfunction in diabetes.   


1973 ◽  
Vol 72 (3) ◽  
pp. 475-494 ◽  
Author(s):  
Svein Oseid

ABSTRACT Six cases of congenital generalized lipodystrophy have been studied at different ages from infancy to adolescence with regard to glucose tolerance, insulin secretion, and insulin sensitivity. During the first few years of life there is normal glucose tolerance. The fasting immuno-reactive insulin (IRI) levels are either slightly elevated or normal. The IRI response to glucose is exaggerated and prolonged, at least from the third year of life. Some degree of insulin resistance is already present in infancy. From the age of 8–10 years glucose tolerance decreases rapidly. The fasting IRI levels are usually grossly elevated, while fasting plasma glucose levels are only moderately elevated or normal. The IRI responses to oral and iv administered glucose, and to tolbutamide are exaggerated; the insulinogenic indices are high. Cortisone primed glucose tolerance tests become abnormal. Insulin resistance is marked, and increases with age. After cessation of growth at approximately 12 years of age, frank diabetes with fasting hyperglycaemia and diabetic glucose tolerance curves developed in the one patient followed beyond this age. Her fasting IRI was increased, but there was a poor IRI response to glucose stimulation, suggesting a partial exhaustion of the β-cells. Her initial IRI response to tolbutamide was still good, but not as brisk as in the younger patients. This type of diabetes is quite different from the juvenile form, and also from the diabetes of older age. It may be causally related to the lack of an adequate adipose organ necessary for the disposal of excesses of glucose, or possibly related to another anti-insulin mechanism.


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