| 1. |
- Adriani, O., et al.
(författare)
-
Design of an Antimatter Large Acceptance Detector In Orbit (ALADInO)
- 2022
-
Ingår i: Instruments. - : MDPI AG. - 2410-390X. ; 6:2
-
Tidskriftsartikel (refereegranskat)abstract
- A new generation magnetic spectrometer in space will open the opportunity to inves-tigate the frontiers in direct high-energy cosmic ray measurements and to precisely measure the amount of the rare antimatter component in cosmic rays beyond the reach of current missions. We propose the concept for an Antimatter Large Acceptance Detector In Orbit (ALADInO), designed to take over the legacy of direct measurements of cosmic rays in space performed by PAMELA and AMS-02. ALADInO features technological solutions conceived to overcome the current limi-tations of magnetic spectrometers in space with a layout that provides an acceptance larger than 10 m2 sr. A superconducting magnet coupled to precision tracking and time-of-flight systems can provide the required matter–antimatter separation capabilities and rigidity measurement resolution with a Maximum Detectable Rigidity better than 20 TV. The inner 3D-imaging deep calorimeter, designed to maximize the isotropic acceptance of particles, allows for the measurement of cosmic rays up to PeV energies with accurate energy resolution to precisely measure features in the cosmic ray spectra. The operations of ALADInO in the Sun–Earth L2 Lagrangian point for at least 5 years would enable unique revolutionary observations with groundbreaking discovery poten-tials in the field of astroparticle physics by precision measurements of electrons, positrons, and antiprotons up to 10 TeV and of nuclear cosmic rays up to PeV energies, and by the possible unam-biguous detection and measurement of low-energy antideuteron and antihelium components in cosmic rays.
|
|
| 2. |
- Ahlkvist, Linda, et al.
(författare)
-
Evidence for neural contribution to islet effects of DPP-4 inhibition in mice
- 2016
-
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 780, s. 46-52
-
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.
|
|
| 3. |
- Ahrén, Bo, et al.
(författare)
-
Improved meal-related beta-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year.
- 2005
-
Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 28:8, s. 1936-1940
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE—To examine the effects of dipeptidyl peptidase-IV (DPP-4) inhibition on meal-related β-cell function and insulin sensitivity over 52 weeks in type 2 diabetes. RESEARCH DESIGN AND METHODS—In a 12-week core study, placebo (n = 51) or vildagliptin (n = 56; 50 mg OD) was added to metformin treatment (1.5–3.0 mg/day). A 40-week extension followed in 71 patients. Meal tests were performed at 0, 12, 24, and 52 weeks; glucose, insulin, and C-peptide were evaluated. RESULTS—In subjects completing 52 weeks with participation in all meal tests (n = 57), HbA1c (A1C) decreased in the vildagliptin/metformin group (VM group, n = 31) but increased in the placebo/metformin group (PM group, n = 26; between-group difference −1.0 ± 0.2%; P < 0.001; baseline of all subjects combined 7.7 ± 0.1%). Also, fasting glucose decreased in the VM group but increased in the PM group (difference −0.9 ± 0.3 mmol/l, P = 0.016; baseline 9.8 ± 0.3 mmol/l). Insulin secretion (postmeal suprabasal area under the 0- to 30-min C-peptide curve divided by the 30-min increase in glucose) was increased in the VM group but was reduced in the PM group (difference +0.011 ± 0.03 pmol/l 30 min/mmol/l, P = 0.018; baseline 0.036 ± 0.02). Insulin sensitivity during meal ingestion (oral glucose insulin sensitivity) increased in the VM group but was not altered in the PM group (difference +27 ± 4 ml · min−1 · m−2, P = 0.036; baseline 246 ± 6). Insulin secretion related to insulin sensitivity (adaptation index) increased in the VM group but decreased in the PM group (difference +3.2 ± 1.0, P = 0.040; baseline 9.1 ± 0.5). The change in adaptation index correlated to the change in A1C (r = −0.39, P = 0.004). CONCLUSIONS—This study presents evidence that DPP-4 inhibition by vildagliptin when added to metformin in type 2 diabetes over 52 weeks improves β-cell function along with improved postmeal insulin sensitivity.
|
|
| 4. |
- Ahrén, Bo, et al.
(författare)
-
The augmenting effect on insulin secretion by oral versus intravenous glucose is exaggerated by high-fat diet in mice.
- 2008
-
Ingår i: Journal of Endocrinology. - 1479-6805. ; 197:1, s. 181-187
-
Tidskriftsartikel (refereegranskat)abstract
- To study whether the incretin effect is involved in adaptively increased insulin secretion in insulin resistance, glucose was infused at a variable rate to match glucose levels after oral glucose (25 mg) in normal anesthetized C57BL/6J female mice or in mice rendered insulin resistant by 8 weeks of high-fat feeding. Insulin response was markedly higher after oral than i.v. glucose in both groups, and this augmentation was even higher in high-fat fed than normal mice. In normal mice, the area under the curve (AUC(insulin)) was augmented from 4.0+/-0.8 to 8.0+/-1.8 nmol/lx60 min by the oral glucose, i.e. by a factor of 2 (P=0.023), whereas in the high-fat fed mice, AUC(insulin) was augmented from 0.70+/-0.4 to 12.4+/-2.5 nmol/lx60 min, i.e. by a factor of 17 (P<0.001). To examine whether the incretin hormone glucagon-like peptide-1 (GLP-1) is responsible for this difference, the effect of i.v. GLP-1 was compared in normal and high-fat fed mice. The sensitivity to i.v. GLP-1 in stimulating insulin secretion was increased in the high-fat diet fed mice: the lowest effective dose of GLP-1 was 650 pmol/kg in normal mice and 13 pmol/kg in the high-fat diet fed mice. We conclude that 1) the incretin effect contributes by approximately 50% to insulin secretion by the oral glucose in normal mice, 2) this effect is markedly exaggerated in insulin-resistant mice fed a high-fat diet, and 3) this augmented incretin contribution in the high-fat fed mice may partially be explained by GLP-1.
|
|
| 5. |
- Alsalim, Wathik, et al.
(författare)
-
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
-
Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 20:4, s. 1080-1085
-
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.
|
|
| 6. |
- Alsalim, Wathik, et al.
(författare)
-
Incretin and islet hormone responses to meals of increasing size in healthy subjects.
- 2015
-
Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 100:2, s. 561-568
-
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.
|
|
| 7. |
|
|
| 8. |
- Alsalim, Wathik, et al.
(författare)
-
Persistent whole day meal effects of three dipeptidyl peptidase-4 inhibitors on glycaemia and hormonal responses in metformin-treated type 2 diabetes
- 2020
-
Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 22:4, s. 590-598
-
Tidskriftsartikel (refereegranskat)abstract
- Aim: Dipeptidyl peptidase-4 (DPP-4) inhibition has effects on both fasting and postprandial glucose. However, the extent of this effect over the whole day and whether different DPP-4 inhibitors have the same effects have not been established. We therefore explored the whole day effects of three different DPP-4 inhibitors versus placebo on glucose, islet and incretin hormones after ingestion of breakfast, lunch and dinner in subjects with metformin-treated and well-controlled type 2 diabetes. Methods: The study was single-centre and crossover designed, involving 24 subjects [12 men, 12 women, mean age 63 years, body mass index 31.0 kg/m2, glycated haemoglobin 44.7 mmol/mol (6.2%)], who underwent four test days in random order. Each whole day test included ingestion of standardized breakfast (525 kcal), lunch (780 kcal) and dinner (560 kcal) after intake of sitagliptin (100 mg) or vildagliptin (50 mg twice), or saxagliptin (5 mg) or placebo. Results: Compared with placebo, DPP-4 inhibition reduced glucose levels, increased beta-cell function (insulin secretory rate in relation to glucose), suppressed glucagon, increased intact glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) but suppressed total GLP-1 and GIP after all three meals. The effects were sustained throughout the daytime period with similar changes after each meal and did not differ between the DPP-4 inhibitors. Conclusions: DPP-4 inhibition has persistent daytime effects on glucose, islet and incretin hormones with no difference between three different DPP-4 inhibitors.
|
|
| 9. |
- Chan, Hui Min, et al.
(författare)
-
Effects of increasing doses of glucagon-like peptide-1 on insulin-releasing phases during intravenous glucose administration in mice
- 2011
-
Ingår i: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 300:5, s. 1126-1133
-
Tidskriftsartikel (refereegranskat)abstract
- Chan HM, Jain R, Ahren B, Pacini G, D'Argenio DZ. Effects of increasing doses of glucagon-like peptide-1 on insulin-releasing phases during intravenous glucose administration in mice. Am J Physiol Regul Integr Comp Physiol 300: R1126-R1133, 2011. First published February 9, 2010; doi:10.1152/ajpregu.00687.2010.-The increase in insulin secretion caused by glucagon-like peptide-1 (GLP-1) and GLP-1 mimetics observed during an intravenous glucose test (IVGTT) has been reported in both normal and disease animal models, as well as in humans. In this study, a hierarchical population modeling approach is used, together with a previously reported model relating glucose to insulin appearance, to determine quantitative in vivo dose-response relationships between GLP-1 dose level and both first-and second-phase insulin release. Parameters of the insulin kinetic model were estimated from the complete set of glucose and insulin data collected in 219 anesthetized nonfasted NMR-imaged mice after intravenous injection of glucose (1 g/kg) alone or with GLP-1 (0.03-100 nmol/kg). The resulting dose-response curves indicate a difference in GLP-1 effect on the two release phases, as is also evident from the different ED50 parameter values (0.107 vs. 6.65 nmol/kg for phase 1 vs. phase 2 insulin release parameters). The first phase of insulin release is gradually augmented with increasing GLP-1 dose, reaching saturation at a dose of similar to 1 nmol/kg, while the second-phase release changes more abruptly at GLP-1 doses between 3 and 10 nmol/kg and shows a more pronounced 100-fold increase between control and the high GLP-1 dose of 100 nmol/kg Moreover, separate disposition indices calculated for phase 1 and 2 insulin release, show a different pattern of increase with increasing GLP-1 dose.
|
|
| 10. |
- Færch, Kristine, et al.
(författare)
-
Insulin resistance is accompanied by increased fasting glucagon and delayed glucagon suppression in individuals with normal and impaired glucose regulation
- 2016
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 65:11, s. 3473-3481
-
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.
|
|
