| 281. |
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| 282. |
- Pacini, Giovanni, et al.
(författare)
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Glucagon and GLP-1 exhibit no synergistic enhancement of glucose-stimulated insulin secretion in mice.
- 2015
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Ingår i: Peptides. - : Elsevier BV. - 1873-5169 .- 0196-9781. ; 71:Jun 26, s. 66-71
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Tidskriftsartikel (refereegranskat)abstract
- The combination of glucagon and glucagon-like peptide-1 (GLP-1) has been suggested as an approach to target obesity, since the two hormones have complementary action on body weight. We examined whether complementary action of the two hormones also exist on insulin secretion. Female C57BL/6 mice were injected intravenously with glucose with or without GLP-1, glucagon or the combination of GLP-1 and glucagon at three different dose levels. Furthermore, freshly isolated mouse islets were incubated for 30min in with the presence of 2.8, 11.1 or 16.7mmol/l glucose or with 11.1mmol/l glucose in the presence of 100 nmol/l glucagon and/or GLP-1. It was found that at 1min after glucose injection alone, insulin rose to a peak level and this peak, as well as the 50min area under the insulin curve (AUC insulin) were dose-dependently augmented by GLP-1 and glucagon. However, peak insulin with the two hormones together (with glucose) was not higher than after either single administration at any of the tested doses, i.e., no additive of synergistic action was observed by the combination on glucose-stimulated insulin secretion. Similar results were observed when calculating insulin for the whole test period. Also in vitro, both glucagon and GLP-1 augmented insulin secretion; however, there was no difference between the combined stimulation of insulin secretion by GLP-1 and glucagon together compared with either hormone alone. Insulin sensitivity did not exhibit significant changes from the glucose only condition. We conclude that the acute combined administration of the strongly insulinotropic GLP-1 and glucagon, both in vivo and in vitro, did not induce any additive or synergistic action on glucose-stimulated insulin secretion. This shows that the risk of a marked insulinotropic action when the two compounds are given together most likely does not result in increased risk of hypoglycemia.
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| 283. |
- Pacini, Giovanni, et al.
(författare)
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Glucagon-like peptide-1 and glucose-dependent insulinotropic peptide : effects alone and in combination on insulin secretion and glucose disappearance in mice
- 2017
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Ingår i: Physiological Reports. - : Wiley. - 2051-817X. ; 5:11
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Tidskriftsartikel (refereegranskat)abstract
- Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) stimulate insulin secretion. They are both released after meal ingestion, and therefore they might cooperate in their actions. However, whether there is a cooperative action of the two incretins is not known. This study therefore investigated the effects on insulin secretion and glucose disappearance of GLP-1 and GIP when given together with intravenous glucose both alone and in combination in mice. Four different doses were used (0.003, 0.03, 0.3 and 3.0 nmol/kg), which ranged from subthreshold to maximal doses to stimulate first-phase insulin secretion as evident from initial dose–response studies. It was found that at 0.03 nmol/kg and higher doses, glucose-stimulated insulin secretion was augmented by both incretins. When they were given in combination, no further increase was observed, indicating no synergistic effect. Also, glucose disappearance rate was increased by 0.03 and 3.0 nmol/kg of the two incretins, both when they were given alone and in combination with, again, no synergy. Finally, glucose effectiveness (an index of noninsulin-mediated processes) was enhanced by the two incretins, in particular GIP. We also found that insulin-dependent and insulin-independent mechanisms contributed 38% and 62%, respectively, to glucose tolerance after glucose alone; with GIP, the contribution by noninsulin-dependent processes was remarkably dominant and with GLP-1, insulin-dependent processes were prevailing. In conclusion, GIP and GLP-1 stimulate insulin secretion and glucose effectiveness in mice with no synergistic action, but with a dissociated contributory effector on glucose disposal: with GLP-1 being more active on insulin-dependent processes and GIP more active on noninsulin-dependent processes.
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| 284. |
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| 285. |
- Pacini, G., et al.
(författare)
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Methods and Models for Metabolic Assessment in Mice
- 2013
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Ingår i: Journal of Diabetes Research. - : Hindawi Limited. - 2314-6753 .- 2314-6745.
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Tidskriftsartikel (refereegranskat)abstract
- The development of new therapies for the treatment of type 2 diabetes requires robust, reproducible and well validated in vivo experimental systems. Mice provide the most ideal animal model for studies of potential therapies. Unlike larger animals, mice have a short gestational period, are genetically similar, often give birth to many offspring at once and can be housed as multiple groups in a single cage. The mouse model has been extensively metabolically characterized using different tests. This report summarizes how these tests can be executed and how arising data are analyzed to confidently determine changes in insulin resistance and insulin secretion with high reproducibility. The main tests for metabolic assessment in the mouse reviewed here are the glucose clamp, the intravenous and the oral glucose tolerance tests. For all these experiments, including some commonly adopted variants, we describe: (i) their performance; (ii) their advantages and limitations; (iii) the empirical formulas and mathematical models implemented for the analysis of the data arising from the experimental procedures to obtain reliable measurements of peripheral insulin sensitivity and beta cell function. Finally, a list of previous applications of these methods and analytical techniques is provided to better comprehend their use and the evidences that these studies yielded.
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| 286. |
- Pacini, Giovanni, et al.
(författare)
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Reappraisal of the intravenous glucose tolerance index for a simple assessment of insulin sensitivity in mice
- 2009
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Ingår i: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 296:5, s. 1316-1324
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Tidskriftsartikel (refereegranskat)abstract
- Pacini G, Ahren M, Ahren B. Reappraisal of the intravenous glucose tolerance index for a simple assessment of insulin sensitivity in mice. Am J Physiol Regul Integr Comp Physiol 296: R1316-R1324, 2009. First published February 11, 2009; doi: 10.1152/ajpregu.90575.2008.- Mice are increasingly used in studies where measuring insulin sensitivity (IS) is a common procedure. The glucose clamp is labor intensive, cannot be used in large numbers of animals, cannot be repeated in the same mouse, and has been questioned as a valid tool for IS in mice; thus, the minimal model with 50-min intravenous glucose tolerance test (IVGTT) data was adapted for studies in mice. However, specific software and particular ability was needed. The aim of this study was to establish a simple procedure for evaluating IS during IVGTT in mice (CSI). IVGTTs (n = 520) were performed in NMRI and C57BL/6J mice (20-25g). After glucose injection (1 g/kg), seven samples were collected for 50 min for glucose and insulin measurements, analyzed with a minimal model that provided the validated reference IS (S-perpendicular to). By using the regression CS perpendicular to = alpha(1) + alpha(2) x K-G/AUC(D), where K-G is intravenous glucose tolerance index and AUC(D) is the dynamic area under the curve, IS was calculated in 134 control animals randomly selected (regression CSI vs. S-I: r = 0.66, P < 0.0001) and yielded alpha(1) = 1.93 and alpha(2) = 0.24. KG is the slope of log (glucose(5-20)) and AUCD is the mean dynamic area under insulin curve in the IVGTT. By keeping fixed alpha(1) and alpha(2), CSI was validated in 143 control mice (4.7 +/- 0.2 min . mu U- . ml(-1), virtually identical to S-I: 4.7 +/- 0.3, r = 0.89, P < 0.0001); and in 123 mice in different conditions: transgenic, addition of neuropeptides, incretins, and insulin (CSI: 6.0 +/- 0.4 vs. SI: 6.1 +/- 0.4, r = 0.94, P < 0.0001). In the other 120 animals, CSI revealed its ability to segregate different categories, as does S-I. This easily usable formula for calculating CSI overcomes many experimental obstacles and may be a simple alternative to more complex procedures when large numbers of mice or repeated experiments in the same animals are required.
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| 287. |
- Pacini, Giovanni, et al.
(författare)
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The dual incretin co-agonist tirzepatide increases both insulin secretion and glucose effectiveness in model experiments in mice
- 2024
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Ingår i: Peptides. - 0196-9781. ; 171
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Tidskriftsartikel (refereegranskat)abstract
- Tirzepatide is a dual GIP and GLP-1 receptor co-agonist which is approved for glucose-lowering therapy in type 2 diabetes. Here, we explored its effects on beta cell function, insulin sensitivity and insulin-independent glucose elimination (glucose effectiveness) in normal mice. Anesthetized female C57/BL/6 J mice were injected intravenously with saline or glucose (0.125, 0.35 or 0.75 g/kg) with or without simultaneous administration of synthetic tirzepatide (3 nmol/kg). Samples were taken at 0, 1, 5, 10, 20 and 50 min. Glucose elimination rate was estimated by the percentage reduction in glucose from min 5 to min 20 (KG). The 50 min areas under the curve (AUC) for insulin and glucose were determined. Beta cell function was assessed as AUCinsulin divided by AUCglucose. Insulin sensitivity (SI) and glucose effectiveness (SG) were determined by minimal model analysis of the insulin and glucose data. Tirzepatide glucose-dependently reduced glucose levels and increased insulin levels. The slope for the regression of AUCinsulin versus AUCglucose was increased 7-fold by tirzepatide from 0.014 ± 0.004 with glucose only to 0.099 ± 0.016 (P < 0.001). SI was not affected by tirzepatide, whereas SG was increased by 78% (P < 0.001). The increase in SG contributed to an increase in KG by 74 ± 4% after glucose alone and by 67 ± 8% after glucose+ tirzepatide, whereas contribution by SI times AUCinsulin insulin (i.e., disposition index) was 26 ± 4% and 33 ± 8%, respectively. In conclusion, tirzepatide stimulates both insulin secretion and glucose effectiveness, with stimulation of glucose effectiveness being the prominent process to reduce glucose.
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| 288. |
- Persson, Kristin, et al.
(författare)
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Islet function phenotype in gastrin-releasing Peptide receptor gene-deficient mice.
- 2002
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 143:10, s. 3717-3726
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Tidskriftsartikel (refereegranskat)abstract
- Gastrin-releasing peptide (GRP) is an islet neuropeptide that stimulates insulin secretion. To explore whether islet GRP contributes to neurally mediated insulin secretion, we studied GRP receptor (GRPR)-deleted mice. By using RT-PCR we showed that GRPR mRNA is expressed in islets of wild-type mice, but is lost in GRPR-deleted mice. Functional studies revealed that GRP potentiates glucose-stimulated insulin secretion in wild-type animals, but not in GRPR-deleted mice. This shows that GRPR is the receptor subtype mediating GRP-induced insulin secretion and that GRPR-deleted mice are tools for studying the physiological role of islet GRP. We found that GRPR-deleted mice display 1) augmentation of the insulin response to glucose by a mechanism inhibited by ganglionic blockade; 2) increased insulin responsiveness also to the cholinergic agonist carbachol, but not to arginine; 3) impaired insulin and glucagon responses to autonomic nerve activation by 2-deoxyglucose; 4) normal islet adaptation to high fat-induced insulin resistance and fasting; and 5) normal islet cytoarchitecture, as revealed by immunocytochemistry of insulin and glucagon. In conclusion, 1) GRPR is the receptor subtype mediating the islet effects of GRP; 2) GRP contributes to insulin secretion induced by activation of the autonomic nerves; and 3) deletion of GRPR is compensated by increased cholinergic sensitivity.
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| 289. |
- Persson, K, et al.
(författare)
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The neuropeptide PACAP contributes to the glucagon response to insulin-induced hypoglycaemia in mice.
- 2002
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Ingår i: Acta Physiologica Scandinavica. - 0001-6772. ; 175:1, s. 25-28
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Tidskriftsartikel (refereegranskat)abstract
- The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide in the autonomic nerves innervating the pancreatic islets and previous studies have shown that it stimulates insulin and glucagon secretion. It is known that autonomic nerve activation contributes to the glucagon response to hypoglycaemia. In the present study, we evaluated whether PACAP is involved in this glucagon response by examining the glucagon response to insulin-induced hypoglycaemia in mice genetically deleted of the specific PACAP receptor, the PAC1 receptor. We found that insulin (1 U kg-1 ip) reduced circulating glucose to a hypoglycaemic level of approximately 2.5 mmol L-1 in PAC1R-/- mice and their wild-type counterparts with no difference between the groups. However, the glucagon response to this hypoglycaemia was markedly impaired in the PAC1R-/- mice. Thus, after 120 min, plasma glucagon was 437 +/- 79 ng L-1 in wild-type mice vs. only 140 +/- 36 ng L-1 in PAC1R-/- mice (P=0.004). In contrast, the glucagon response to intravenously administered arginine (0.25 g kg-1) was the same in the two groups of mice. We conclude that PACAP through activation of PAC1 receptors contribute to the glucagon response to insulin-induced hypoglycaemia. Therefore, the glucagon response to hypoglycaemia is dependent not only on the classical neurotransmitters but also on the neuropeptide PACAP.
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| 290. |
- Petersen, Astrid H, et al.
(författare)
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The impact of large tidal volume ventilation on the absorption of inhaled insulin in rabbits.
- 2007
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 1879-0720 .- 0928-0987. ; 30:3-4, s. 351-357
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have shown that ventilation patterns affect absorption of inhaled compounds. Thus, the aim of this study was to investigate the effect of large tidal volume ventilation (LTVV) on the absorption of inhaled insulin in rabbits. Mechanically ventilated rabbits were given human insulin via a nebuliser system, and plasma insulin was measured for the following 120 min. Ventilation was adjusted to (1) normal tidal volume ventilation (NTVV) for the entire period after dosing (NTVV group), to (2) LTVV for the entire period after dosing (LTVV group), to (3) NTVV except for 15 min LTVV immediately after dosing (Early LTVV group), or to (4) NTVV except for 15 min LTVV starting at 60 min after dosing (late LTVV group). Insulin absorption (AUC(ins(0-120min))) was increased by 149% for the LTVV group compared to NTVV group (p < 0.01) with increased maximal insulin concentration (106%, p = 0.03). The Early LTVV group showed a changed absorption profile. For the late LTVV group an increase in insulin levels was observed after the LTVV period (not significant compared to the NTVV group). These data could potentially have implications for patients using inhaled insulin in situations where a change in breathing pattern is seen, such as exercise.
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