| 1. |
- Ahlkvist, Linda, et al.
(författare)
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Evidence for neural contribution to islet effects of DPP-4 inhibition in mice
- 2016
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 780, s. 46-52
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Tidskriftsartikel (refereegranskat)abstract
- It has been suggested that neural mechanisms may contribute to effects of the incretin hormones, and, therefore, also to the effects of dipeptidyl peptidase (DPP-4) inhibition. We therefore examined whether muscarinic mechanisms are involved in the stimulation of insulin secretion by DPP-4 inhibition. Fasted, anesthetized mice were given intraperitoneal saline or the muscarinic antagonist atropine (5mg/kg) before duodenal glucose (75mg/mouse), with or without the DPP-4 inhibitor NVPDPP728 (0.095mg/mouse), or before intravenous glucose (0.35g/kg) with or without co-administration with GLP-1 or glucose-dependent insulinotropic polypeptide (GIP) (both 3nmol/kg). Furthermore, isolated islets were incubated (1h) in 2.8 and 11.1mM glucose, with or without GIP or GLP-1 (both 100nM), in the presence or absence of atropine (100µM). Duodenal glucose increased circulating insulin and this effect was potentiated by DPP-4 inhibition. The increase in insulin achieved by DPP-4 inhibition was reduced by atropine by approximately 35%. Duodenal glucose also elicited an increase in circulating intact GLP-1 and GIP and this was augmented by DPP-4 inhibition, but these effects were not affected by atropine. Atropine did also not affect the augmentation by GLP-1 and GIP on glucose-stimulated insulin secretion from isolated islets. Based on these findings, we suggest that muscarinic mechanisms contribute to the stimulation of insulin secretion by DPP-4 inhibition through neural effects induced by GLP-1 and GIP whereas neural effects do not affect the levels of GLP-1 or GIP or the islet effects of the two incretin hormones.
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| 2. |
- Alsalim, Wathik, et al.
(författare)
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Effect of single-dose DPP-4 inhibitor sitagliptin on β-cell function and incretin hormone secretion after meal ingestion in healthy volunteers and drug-naïve, well-controlled type 2 diabetes subjects
- 2018
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 20:4, s. 1080-1085
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Tidskriftsartikel (refereegranskat)abstract
- To explore the effects of a single dose of the DPP-4 inhibitor sitagliptin on glucose-standardized insulin secretion and β-cell glucose sensitivity after meal ingestion, 12 healthy and 12 drug-naïve, well-controlled type 2 diabetes (T2D) subjects (mean HbA1c 43mmol/mol, 6.2%) received sitagliptin (100mg) or placebo before a meal (525kcal). β-cell function was measured as the insulin secretory rate at a standardized glucose concentration and the β-cell glucose sensitivity (the slope between glucose and insulin secretory rate). Incretin levels were also monitored. Sitagliptin increased standardized insulin secretion, in both healthy and T2D subjects, compared to placebo, but without increasing β-cell glucose sensitivity. Sitagliptin also increased active glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) and reduced total (reflecting the secretion) GIP, but not total GLP-1 levels. We conclude that a single dose of DPP-4 inhibition induces dissociated effects on different aspects of β-cell function and incretin hormones after meal ingestion in both healthy and well-controlled T2D subjects.
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| 3. |
- Alsalim, Wathik, et al.
(författare)
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Incretin and islet hormone responses to meals of increasing size in healthy subjects.
- 2015
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 100:2, s. 561-568
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Tidskriftsartikel (refereegranskat)abstract
- Context: Postprandial glucose homeostasis is regulated through the secretion of glucagon-like peptide 1 (GLP-1) through stimulation of insulin secretion and inhibition of glucagon secretion. However, how these processes dynamically adapt to demands created by caloric challenges achieved during daily life is not known. Objective: To explore adaptation of incretin and islet hormones after mixed meals of increasing size in healthy subjects. Design: Twenty-four healthy lean subjects ingested a standard breakfast after an overnight fast followed, after four hours, by a lunch of different size (511, 743 and 1034 kcal) but with identical nutrient composition together with 1.5g paracetamol. Glucose, insulin, C-peptide, glucagon, intact glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and paracetamol were measured after the meals. Main outcome measure: Area under the 180 min curve (AUC) for insulin, C-peptide, glucagon, GLP-1 and GIP and model- derived ß-cell function and paracetamol appearance. Results: Glucose profiles were similar after the two larger meals whereas after the smaller meal, there was a post-peak reduction below baseline to nadir of 3.8±0.1mmol/l after 75min (p<0.001). AUC for GLP-1, GIP, insulin and C-peptide were significantly higher by increasing the caloric load as was β-cells sensitivity to glucose. In contrast, AUC glucagon was the same for all three meals, although there was an increase in glucagon after the postpeak glucose reduction in the smaller meal. The 0-20 min paracetamol appearance was increased by increasing meal size. Conclusion: Mixed lunch meals of increasing size elicit a caloric dependent insulin response due to increased β-cell secretion achieved by increased GIP and GLP-1 levels. The adaptation at larger meals results in identical glucose excursions, whereas after a lower caloric lunch the insulin response is high resulting in postpeak suppression of glucose below baseline.
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| 4. |
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| 5. |
- Færch, Kristine, et al.
(författare)
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Insulin resistance is accompanied by increased fasting glucagon and delayed glucagon suppression in individuals with normal and impaired glucose regulation
- 2016
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 65:11, s. 3473-3481
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Tidskriftsartikel (refereegranskat)abstract
- Hyperinsulinemia is an adaptive mechanism that enables the maintenance of normoglycemia in the presence of insulin resistance. We assessed whether glucagon is also involved in the adaptation to insulin resistance. A total of 1,437 individuals underwent an oral glucose tolerance test with measurements of circulating glucose, insulin, and glucagon concentrations at 0, 30 and 120 min. Early glucagon suppression was defined as suppression in the period from 0 to 30 min, and late glucagon suppression as 30 to 120 min after glucose intake. Insulin sensitivity was estimated by the validated insulin sensitivity index. Individuals with screen-detected diabetes had 30% higher fasting glucagon levels and diminished early glucagon suppression, but greater late glucagon suppression when compared with individuals with normal glucose tolerance (P 0.014). Higher insulin resistance was associated with higher fasting glucagon levels, less early glucagon suppression, and greater late glucagon suppression (P < 0.001). The relationship between insulin sensitivity and fasting glucagon concentrations was nonlinear (P < 0.001). In conclusion, increased fasting glucagon levels and delayed glucagon suppression, together with increased circulating insulin levels, develop in parallel with insulin resistance. Therefore, glucose maintenance during insulin resistance may depend not only on hyperinsulinemia but also on the ability to suppress glucagon early after glucose intake.
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| 6. |
- Frid, Anders, et al.
(författare)
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Effect of oral pre-meal administration of betaglucans on glycaemic control and variability in subjects with type 1 diabetes
- 2017
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 9:9
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a double-blind placebo-controlled crossover pilot study to investigate the effect of oat betaglucans (β-glucan) on glycaemic control and variability in adults with type 1 diabetes (T1D; n = 14). Stomacol® tablets (1.53 g of β-glucan) or placebo (Plac) were administered three times daily before meals for two weeks. Glucose levels were monitored during the second week by continuous glucose monitoring (CGM). There was an increase in basic measures of glycaemic control (maximal glucose value 341 ± 15 vs. 378 ± 13 mg/dL for Plac and β-glucan, p = 0.004), and average daily risk range (62 ± 5 vs. 79 ± 4 mg/dL for Plac and β-glucan, p = 0.003) favouring Plac over β-glucan, but no increase in the M-value (the weighted average of the glucose values) or other more complex measures. Basic measures of glucose variability were also slightly increased during β-glucan treatment, with no difference in more complex measures. However, glycaemic variability increased between the first and last two CGM days on Plac, but remained unchanged on β-glucan. In conclusion, in this pilot study we were unable to demonstrate a general positive effect of β-glucan before meals on glucose control or variability in T1D.
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| 7. |
- Lindgren, Ola, et al.
(författare)
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Incretin Effect after Oral Amino Acid Ingestion in Humans.
- 2015
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 100:3, s. 1172-1176
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Tidskriftsartikel (refereegranskat)abstract
- Context: The incretin effect is the augmented insulin secretion by oral versus intravenous glucose at matching glucose levels. We previously demonstrated an augmented insulin secretion when fat is given orally rather than intravenously, suggesting an incretin effect also after fat. However, whether there is an incretin effect is also present after amino acid ingestion is not known. Objective: To explore insulin secretion and islet hormones after oral and intravenous amino acid administration at matched total amino acid concentrations in healthy subjects. Design: Amino acid mixture (Vaminolac(R)) was administered orally or intravenously at a rate resulting in matching total amino acid concentrations to twelve male volunteers with age 22.5±1.4 yr and BMI 22.4±1.4 kg/m(2), who had no history of diabetes. Main outcome measures: Area under the 120 min curve (AUC) for insulin, C-peptide, glucagon, intact and total glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and insulin secretory rate and insulin clearance. Results: Insulin, C-peptide and glucagon levels increased after both oral and intravenous administration, but insulin secretion was 25% higher after oral than after intravenous amino acid challenges (P=0.006), whereas there was no significant difference in the glucagon response. Intact and total GIP rose after oral but not after intravenous amino acid administration, whereas intact and total GLP-1 levels did not change significantly in either test. Conclusion: Oral amino acid mixture ingestion elicits a stronger insulin secretory response than intravenous amino acid at matching amino acid levels and that this is associated with increased GIP level, suggesting that an incretin effect exists also after oral amino acids, possibly mediated by GIP.
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| 8. |
- 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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| 9. |
- 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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| 10. |
- Song, Gina, et al.
(författare)
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Glucagon increases insulin levels by stimulating insulin secretion without effect on insulin clearance in mice
- 2017
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Ingår i: Peptides. - : Elsevier BV. - 0196-9781. ; 88, s. 74-79
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Tidskriftsartikel (refereegranskat)abstract
- Circulating insulin is dependent on a balance between insulin appearance through secretion and insulin clearance. However, to what extent changes in insulin clearance contribute to the increased insulin levels after glucagon administration is not known. This study therefore assessed and quantified any potential effect of glucagon on insulin kinetics in mice. Prehepatic insulin secretion in mice was first estimated following glucose (0.35 g/kg i.v.) and following glucose plus glucagon (10 μg/kg i.v.) using deconvolution of plasma C-peptide concentrations. Plasma concentrations of glucose, insulin, and glucagon were then measured simultaneously in individual mice following glucose alone or glucose plus glucagon (pre dose and at 1, 5, 10, 20 min post). Using the previously determined insulin secretion profiles and the insulin concentration-time measurements, a population modeling analysis was applied to estimate the one-compartment kinetics of insulin disposition with and without glucagon. Glucagon with glucose significantly enhanced prehepatic insulin secretion (Cmax and AUC0-20) compared to that with glucose alone (p < 0.0001). From the modeling analysis, the population mean and between-animal SD of insulin clearance was 6.4 ± 0.34 mL/min for glucose alone and 5.8 ± 1.5 mL/min for glucagon plus glucose, with no significant effect of glucagon on mean insulin clearance. Therefore, we conclude that the enhancement of circulating insulin after glucagon administration is solely due to stimulated insulin secretion.
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