Sensory nerves contribute to insulin secretion by glucagon-like peptide-1 in mice

2004 ◽  
Vol 286 (2) ◽  
pp. R269-R272 ◽  
Author(s):  
Bo Ahrén
Keyword(s):  
Insulin Secretion ◽  
Direct Action ◽  
Insulin Response ◽  
Sensory Nerves ◽  
High Dose ◽  
Intravenous Glucose ◽  
Insulin Response To Glucose ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

It has been hypothesized that the potent insulinotropic action of the gut incretin hormone glucagon-like peptide-1 (GLP-1) is exerted not only through a direct action on the beta cells but may be partially dependent on sensory nerves. We therefore examined the influence of GLP-1 in mice rendered sensory denervated by neonatal administration of capsaicin performed at days 2 and 5 (50 mg/kg). Control mice were given vehicle. Results show that at 10-16 wk of age in control mice, intravenous GLP-1 at 0.1 or 10 nmol/kg augmented the insulin response to intravenous glucose (1 g/kg) in association with improved glucose elimination. In contrast, in capsaicin-pretreated mice, GLP-1 at 0.1 nmol/kg could not augment the insulin response to intravenous glucose and no effect on glucose elimination was observed. Nevertheless, at the high dose of 10 nmol/kg, GLP-1 augmented the insulin response to glucose in capsaicin-pretreated mice as efficiently as in control mice. The insulin response to GLP-1 from isolated islets was not affected by neonatal capsaicin, and, furthermore, the in vivo insulin response to glucose was augmented whereas that to arginine was not affected by capsaicin. It is concluded that GLP-1-induced insulin secretion at a low dose in mice is dependent on intact sensory nerves and therefore indirectly mediated and that this distinguishes GLP-1 from other examined insulin secretagogues.

GLP-1-(9–36) amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion

2002 ◽  
Vol 282 (4) ◽  
pp. E873-E879 ◽  
Author(s):  
Carolyn F. Deacon ◽  
Astrid Plamboeck ◽  
Søren Møller ◽  
Jens J. Holst
Keyword(s):  
Insulin Secretion ◽  
Therapeutic Potential ◽  
Intravenous Glucose ◽  
Dpp Iv ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Independent Effects ◽  
Insulinotropic Effect ◽  
Insulin Responses

Glucagon-like peptide 1 (GLP-1) is a potent anti-hyperglycemic hormone currently under investigation for its therapeutic potential. However, due to rapid degradation by dipeptidyl peptidase IV (DPP IV), which limits its metabolic stability and eliminates its insulinotropic activity, it has been impossible to assess its true efficacy in vivo. In chloralose-anesthetized pigs given valine-pyrrolidide (to block endogenous DPP IV activity), the independent effects of GLP-1-(7–36) amide on glucose and insulin responses to intravenous glucose were assessed, and the metabolite generated by DPP IV, GLP-1-(9–36) amide, was investigated for any ability to influence these responses. GLP-1-(7–36) amide enhanced insulin secretion ( P < 0.03 vs. vehicle), but GLP-1-(9–36) amide was without effect, either alone or when coinfused with GLP-1-(7–36) amide. In contrast, GLP-1-(9–36) amide did affect glucose responses ( P < 0.03). Glucose excursions were greater after saline (121 ± 17 mmol · l−1 · min) than after GLP-1-(9–36) amide (73 ± 19 mmol · l−1 · min; P < 0.05), GLP-1-(7–36) amide (62 ± 13 mmol · l−1 · min; P < 0.02) or GLP-1-(7–36) amide + GLP-1-(9–36) amide (50 ± 13 mmol · l−1 · min; P < 0.005). Glucose elimination rates were faster after GLP-1-(7–36) amide + (9–36) amide (10.3 ± 1.2%/min) than after GLP-1-(7–36) amide (7.0 ± 0.9%/min; P < 0.04), GLP-1-(9–36) amide (6.8 ± 1.0%/min; P < 0.03), or saline (5.4 ± 1.2%/min; P < 0.005). Glucagon concentrations were unaffected. These results demonstrate that GLP-1-(9–36) amide neither stimulates insulin secretion nor antagonizes the insulinotropic effect of GLP-1-(7–36) amide in vivo. Moreover, the metabolite itself possesses anti-hyperglycemic effects, supporting the hypothesis that selective DPP IV action is important in glucose homeostasis.

Glucagon-like peptide-1(7-36)-amide confers glucose sensitivity to previously glucose-incompetent beta-cells in diabetic rats: in vivo and in vitro studies

1997 ◽  
Vol 155 (2) ◽  
pp. 369-376 ◽  
Author(s):  
N Dachicourt ◽  
P Serradas ◽  
D Bailbe ◽  
M Kergoat ◽  
L Doare ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Beta Cells ◽  
Insulin Release ◽  
Insulin Response ◽  
Diabetic Rats ◽  
Insulin Response To Glucose ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The effects of glucagon-like peptide-1(7-36)-amide (GLP-1) on cAMP content and insulin release were studied in islets isolated from diabetic rats (n0-STZ model) which exhibited impaired glucose-induced insulin release. We first examined the possibility of re-activating the insulin response to glucose in the beta-cells of the diabetic rats using GLP-1 in vitro. In static incubation experiments, GLP-1 amplified cAMP accumulation (by 170%) and glucose-induced insulin release (by 140%) in the diabetic islets to the same extent as in control islets. Using a perifusion procedure, GLP-1 amplified the insulin response to 16.7 mM glucose by diabetic islets and generated a clear biphasic pattern of insulin release. The incremental insulin response to glucose in the presence of GLP-1, although lower than corresponding control values (1.56 +/- 0.37 and 4.53 +/- 0.60 pg/min per ng islet DNA in diabetic and control islets respectively), became similar to that of control islets exposed to 16.7 mM glucose alone (1.09 +/- 0.15 pg/min per ng islet DNA). Since in vitro GLP-1 was found to exert positive effects on the glucose competence of the residual beta-cells in the n0-STZ model. we investigated the therapeutic effect of in vivo GLP-1 administration on glucose tolerance and glucose-induced insulin release by n0-STZ rats. An infusion of GLP-1 (10 ng/min per kg; i.v.) in n0-STZ rats enhanced significantly (P < 0.01) basal plasma insulin levels, and, when combined with an i.v. glucose tolerance and insulin secretion test, it was found to improve (P < 0.05) glucose tolerance and the insulinogenic index, as compared with the respective values of these parameters before GLP-1 treatment.

PACAP contributes to insulin secretion after gastric glucose gavage in mice

2000 ◽  
Vol 279 (2) ◽  
pp. R424-R432 ◽  
Author(s):  
Karin Filipsson ◽  
Jens Juul Holst ◽  
Bo Ahrén
Keyword(s):  
Insulin Secretion ◽  
Insulin Response ◽  
Gastric Inhibitory Polypeptide ◽  
Inhibitory Effect ◽  
Intravenous Glucose ◽  
Parasympathetic Nerves ◽  
Prandial Insulin ◽  
Pituitary Adenylate Cyclase ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Pituitary adenylate cyclase-activating polypeptide (PACAP) is localized to pancreatic ganglia governing the parasympathetic nerves, which contribute to prandial insulin secretion. We hypothesized that this contribution involves PACAP and show here that the PACAP receptor antagonist PACAP-(6—27) (1.5 nmol/kg iv) reduces the 15-min insulin response to gastric glucose (150 mg/mouse) by 18% in anesthetized mice ( P = 0.041). The reduced insulinemia was not due to inhibited release of the incretin factor glucagon-like peptide 1 (GLP-1) because PACAP-(6—27) enhanced the GLP-1 response to gastric glucose. Furthermore, the GLP-1 antagonist exendin-3-(9—39) (30 nmol/kg) exerted additive inhibitory effect on the insulin response when combined with PACAP-(6—27). The PACAP antagonism was specific because intravenous PACAP-(6—27) inhibited the insulin response to intravenous PACAP-27 plus glucose without affecting the insulin response to intravenous glucose alone (1 g/kg) or glucose together with other insulin secretagogues of potential incretin relevance of intestinal (GLP-1, gastric inhibitory polypeptide, cholecystokinin) and neural (vasoactive intestinal peptide, gastrin-releasing peptide, cholinergic agonism) origin. We conclude that PACAP contributes to the insulin response to gastric glucose in mice and suggest that PACAP is involved in the regulation of prandial insulin secretion.

scholarly journals Disruption of the Dopamine D2 Receptor Impairs Insulin Secretion and Causes Glucose Intolerance

Endocrinology ◽  
2010 ◽  
Vol 151 (4) ◽  
pp. 1441-1450 ◽  
Author(s):  
Isabel García-Tornadú ◽  
Ana M. Ornstein ◽  
Astrid Chamson-Reig ◽  
Michael B. Wheeler ◽  
David J. Hill ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Intolerance ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Insulin Response ◽  
Wild Type ◽  
Β Cell ◽  
Insulin Response To Glucose

The relationship between antidopaminergic drugs and glucose has not been extensively studied, even though chronic neuroleptic treatment causes hyperinsulinemia in normal subjects or is associated with diabetes in psychiatric patients. We sought to evaluate dopamine D2 receptor (D2R) participation in pancreatic function. Glucose homeostasis was studied in D2R knockout mice (Drd2−/−) mice and in isolated islets from wild-type and Drd2−/− mice, using different pharmacological tools. Pancreas immunohistochemistry was performed. Drd2−/− male mice exhibited an impairment of insulin response to glucose and high fasting glucose levels and were glucose intolerant. Glucose intolerance resulted from a blunted insulin secretory response, rather than insulin resistance, as shown by glucose-stimulated insulin secretion tests (GSIS) in vivo and in vitro and by a conserved insulin tolerance test in vivo. On the other hand, short-term treatment with cabergoline, a dopamine agonist, resulted in glucose intolerance and decreased insulin response to glucose in wild-type but not in Drd2−/− mice; this effect was partially prevented by haloperidol, a D2R antagonist. In vitro results indicated that GSIS was impaired in islets from Drd2−/− mice and that only in wild-type islets did dopamine inhibit GSIS, an effect that was blocked by a D2R but not a D1R antagonist. Finally, immunohistochemistry showed a diminished pancreatic β-cell mass in Drd2−/− mice and decreased β-cell replication in 2-month-old Drd2−/− mice. Pancreatic D2Rs inhibit glucose-stimulated insulin release. Lack of dopaminergic inhibition throughout development may exert a gradual deteriorating effect on insulin homeostasis, so that eventually glucose intolerance develops.

scholarly journals Leptin inhibits insulin secretion induced by cellular cAMP in a pancreatic B cell line (INS-1 cells)

1999 ◽  
Vol 277 (4) ◽  
pp. R959-R966 ◽  
Author(s):  
Bo Ahrén ◽  
Peter J. Havel
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Insulin Response ◽  
Signal Transduction Pathway ◽  
Intracellular Camp ◽  
Intracellular Content ◽  
Pituitary Adenylate Cyclase ◽  
Insulin Response To Glucose ◽  
Glucagon Like Peptide 1 ◽  
Activate Protein Kinase

The effect of leptin on insulin secretion is controversial due to conflicting results in the literature. In the present study, we incubated insulin-producing rat insulinoma INS-1 cells for 60 min and examined the effects of recombinant murine leptin (20 nmol/l). We found that leptin (0.1–100 nmol/l) did not affect the insulin response to glucose (1–20 mmol/l). However, when cells were incubated with agents that increase the intracellular content of cAMP, i.e., glucagon-like peptide-1 (100 nmol/l), pituitary adenylate cyclase activating polypeptide (100 nmol/l), forskolin (2.5 μmol/l), dibutyryl-cAMP (1 mmol/l), or 3-isobutyl-1-methylxanthine (100 μmol/l), leptin significantly reduced insulin secretion (by 34–58%, P < 0.05–0.001). In contrast, when insulin secretion was stimulated by the cholinergic agonist carbachol (100 μmol/l) or the phorbol ester 12- O-tetradecanoylphorbol 13-acetate (1 μmol/l), both of which activate protein kinase C, leptin was without effect. We conclude that leptin inhibits insulin secretion from INS-1 cells under conditions in which intracellular cAMP is increased. This suggests that the cAMP-protein kinase A signal transduction pathway is a target for leptin to inhibit insulin secretion in insulin-producing cells.

Involvement of capsaicin-sensitive nerves in regulation of insulin secretion and glucose tolerance in conscious mice

1994 ◽  
Vol 267 (4) ◽  
pp. R1071-R1077 ◽  
Author(s):  
S. Karlsson ◽  
A. J. Scheurink ◽  
A. B. Steffens ◽  
B. Ahren
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Insulin Response ◽  
Secretory Response ◽  
Sensory Nerves ◽  
Plasma Norepinephrine ◽  
Plasma Catecholamine ◽  
Intravenous Glucose ◽  
The Impact ◽  
Insulin Secretory Response

The impact of sensory nerves in glucose-stimulated insulin secretion and glucose tolerance was investigated in conscious mice treated neonatally with either capsaicin (Cap) or vehicle (Veh). At 10-12 wk after Cap, both the early (1 min) insulin secretory response to intravenous glucose (2.8 mmol/kg) (by 67%) and glucose elimination were potentiated (P < 0.05). In contrast, basal insulin, glucagon, and glucose were not affected by Cap. Plasma norepinephrine and epinephrine levels did not differ between Cap- and Veh-treated animals, whereas the increase in plasma insulin levels normally induced by alpha-adrenoceptor blockade by phentolamine was absent after Cap treatment. In isolated islets, the insulin secretory response to glucose (20 mmol/l), carbachol (0.1 mmol/l), or phentolamine (0.5 mmol/l) was not affected after Cap. It is concluded that sensory denervation by Cap results in increased glucose tolerance, which is in part because of a potentiated early insulin response to glucose. This potentiation does not seem secondary to altered plasma catecholamine levels or to altered islet secretory capacity. The results suggest rather that Cap-sensitive nerves, by a local effector function and/or as the afferent loop of a neural reflex, exert inhibitory influences on insulin secretion.

Measurements of insulin responses as predictive markers of pancreatic β-cell mass in normal and β-cell-reduced lean and obese Göttingen minipigs in vivo

2006 ◽  
Vol 290 (4) ◽  
pp. E670-E677 ◽  
Author(s):  
Marianne O. Larsen ◽  
Bidda Rolin ◽  
Jeppe Sturis ◽  
Michael Wilken ◽  
Richard D. Carr ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Mass ◽  
Insulin Response ◽  
Study Groups ◽  
Β Cell ◽  
Intravenous Glucose ◽  
Body Weights ◽  
In Vivo Tests ◽  
Insulin Responses

At present, the best available estimators of β-cell mass in humans are those based on measurement of insulin levels or appearance rates in the circulation. In several animal models, these estimators have been validated against β-cell mass in lean animals. However, as many diabetic humans are obese, a correlation between in vivo tests and β-cell mass must be evaluated over a range of body weights to include different levels of insulin sensitivity. For this purpose, obese ( n = 10) and lean ( n = 25) Göttingen minipigs were studied. β-Cell mass had been reduced ( n = 16 lean, n = 5 obese) with a combination of nicotinamide (67 mg/kg) and streptozotocin (125 mg/kg), acute insulin response (AIR) to intravenous glucose and/or arginine was tested, pulsatile insulin secretion was evaluated by deconvolution ( n = 30), and β-cell mass was determined histologically. AIR to 0.3 ( r2= 0.4502, P < 0.0001) or 0.6 g/kg glucose ( r2= 0.6806, P < 0.0001), 67 mg/kg arginine ( r2= 0.5730, P < 0.001), and maximum insulin concentration ( r2= 0.7726, P < 0.0001) were all correlated to β-cell mass when evaluated across study groups, and regression lines were not different between lean and obese groups except for AIR to 0.3 g/kg glucose. Baseline pulse mass was not significantly correlated to β-cell mass across the study groups ( r2= 0.1036, NS), whereas entrained pulse mass did show a correlation across groups ( r2= 0.4049, P < 0.001). This study supports the use of in vivo tests of insulin responses to evaluate β-cell mass over a range of body weights in the minipig. Extensive stimulation of insulin secretion by a combination of glucose and arginine seems to give the best correlation to β-cell mass.

scholarly journals Increased insulin clearance in mice with double deletion of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors

2018 ◽  
Vol 314 (5) ◽  
pp. R639-R646 ◽  
Author(s):  
Andrea Tura ◽  
Roberto Bizzotto ◽  
Yuchiro Yamada ◽  
Yutaka Seino ◽  
Giovanni Pacini ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Clearance ◽  
Second Phase ◽  
Incretin Hormones ◽  
Intravenous Glucose ◽  
C Peptide ◽  
Double Deletion ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
First Phase Insulin Secretion

To establish whether incretin hormones affect insulin clearance, the aim of this study was to assess insulin clearance in mice with genetic deletion of receptors for both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), so called double incretin receptor knockout mice (DIRKO). DIRKO ( n = 31) and wild-type (WT) C57BL6J mice ( n = 45) were intravenously injected with d-glucose (0.35 g/kg). Blood was sampled for 50 min and assayed for glucose, insulin, and C-peptide. Data were modeled to calculate insulin clearance; C-peptide kinetics was established after human C-peptide injection. Assessment of C-peptide kinetics revealed that C-peptide clearance was 1.66 ± 0.10 10−3 1/min. After intravenous glucose administration, insulin clearance during first phase insulin secretion was markedly higher in DIRKO than in WT mice (0.68 ± 0.06 10−3 l/min in DIRKO mice vs. 0.54 ± 0.03 10−3 1/min in WT mice, P = 0.02). In contrast, there was no difference between the two groups in insulin clearance during second phase insulin secretion ( P = 0.18). In conclusion, this study evaluated C-peptide kinetics in the mouse and exploited a mathematical model to estimate insulin clearance. Results showed that DIRKO mice have higher insulin clearance than WT mice, following intravenous injection of glucose. This suggests that incretin hormones reduce insulin clearance at physiological, nonstimulated levels.

scholarly journals Dual-acting peptide with prolonged glucagon-like peptide-1 receptor agonist and glucagon receptor antagonist activity for the treatment of type 2 diabetes

2007 ◽  
Vol 192 (2) ◽  
pp. 371-380 ◽  
Author(s):  
Thomas H Claus ◽  
Clark Q Pan ◽  
Joanne M Buxton ◽  
Ling Yang ◽  
Jennifer C Reynolds ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Receptor Agonist ◽  
Antagonist Activity ◽  
Glucagon Receptor ◽  
Glucagon Receptor Antagonist ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Type 2 diabetes is characterized by reduced insulin secretion from the pancreas and overproduction of glucose by the liver. Glucagon-like peptide-1 (GLP-1) promotes glucose-dependent insulin secretion from the pancreas, while glucagon promotes glucose output from the liver. Taking advantage of the homology between GLP-1 and glucagon, a GLP-1/glucagon hybrid peptide, dual-acting peptide for diabetes (DAPD), was identified with combined GLP-1 receptor agonist and glucagon receptor antagonist activity. To overcome its short plasma half-life DAPD was PEGylated, resulting in dramatically prolonged activity in vivo. PEGylated DAPD (PEG-DAPD) increases insulin and decreases glucose in a glucose tolerance test, evidence of GLP-1 receptor agonism. It also reduces blood glucose following a glucagon challenge and elevates fasting glucagon levels in mice, evidence of glucagon receptor antagonism. The PEG-DAPD effects on glucose tolerance are also observed in the presence of the GLP-1 antagonist peptide, exendin(9–39). An antidiabetic effect of PEG-DAPD is observed in db/db mice. Furthermore, PEGylation of DAPD eliminates the inhibition of gastrointestinal motility observed with GLP-1 and its analogues. Thus, PEG-DAPD has the potential to be developed as a novel dual-acting peptide to treat type 2 diabetes, with prolonged in vivo activity, and without the GI side-effects.

scholarly journals PACAP stimulates insulin secretion but inhibits insulin sensitivity in mice

1998 ◽  
Vol 274 (5) ◽  
pp. E834-E842 ◽  
Author(s):  
Karin Filipsson ◽  
Giovanni Pacini ◽  
Anton J. W. Scheurink ◽  
Bo Ahrén
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Elimination Rate ◽  
Insulin Response ◽  
Area Under The Curve ◽  
Glucose Disposal ◽  
Sensitivity Index ◽  
Maximal Effect ◽  
Intravenous Glucose

Although pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates insulin secretion, its net influence on glucose homeostasis in vivo has not been established. We therefore examined the action of PACAP-27 and PACAP-38 on insulin secretion, insulin sensitivity, and glucose disposal as derived from the minimal model of glucose disappearance during an intravenous glucose tolerance test in anesthetized mice. PACAP-27 and PACAP-38 markedly and equipotently potentiated glucose-stimulated insulin secretion, with a half-maximal effect at 33 pmol/kg. After PACAP-27 or PACAP-38 (1.3 nmol/kg), the acute (1–5 min) insulin response was 3.8 ± 0.4 nmol/l (PACAP-27) and 3.3 ± 0.3 nmol/l (PACAP-38), respectively, vs. 1.4 ± 0.1 nmol/l after glucose alone ( P < 0.001), and the total area under the curve for insulin (AUCinsulin) was potentiated by 60% ( P < 0.001). In contrast, PACAP-27 and PACAP-38 reduced the insulin sensitivity index (SI) [0.23 ± 0.04 10−4min−1/(pmol/l) for PACAP-27 and 0.29 ± 0.06 10−4min−1/(pmol/l) for PACAP-38 vs. 0.46 ± 0.02 10−4min−1/(pmol/l) for controls ( P < 0.01)]. Furthermore, PACAP-27 or PACAP-38 did not affect glucose elimination determined as glucose half-time or the glucose elimination rate after glucose injection or the area under the curve for glucose. Moreover, glucose effectiveness and the global disposition index (AUCinsulin times SI) were not affected by PACAP-27 or PACAP-38. Finally, when given together with glucose, PACAP-27 did not alter plasma glucagon or norepinephrine levels but significantly increased plasma epinephrine levels. We conclude that PACAP, besides its marked stimulation of insulin secretion, also inhibits insulin sensitivity in mice, the latter possibly explained by increased epinephrine. This complex action explains why the peptide does not enhance glucose disposal.

Sign in / Sign up

Export Citation Format

Share Document