| 1. |
- Ahlkvist, Linda, et al.
(författare)
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Synergism by individual macronutrients explains the marked early GLP-1 and islet hormone responses to mixed meal challenge in mice
- 2012
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Ingår i: Regulatory Peptides. - : Elsevier. - 0167-0115 .- 1873-1686. ; 178:1-3, s. 29-35
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Tidskriftsartikel (refereegranskat)abstract
- Apart from glucose, proteins and lipids also stimulate incretin and islet hormone secretion. However, the glucoregulatory effect of macronutrients in combination is poorly understood. We therefore developed an oral mixed meal model in mice to 1) explore the glucagon-like peptide-1 (GLP-1) and islet hormone responses to mixed meal versus isocaloric glucose, and 2) characterize the relative contribution of individual macronutrients to these responses. Anesthetized C57BL/6J female mice were orally gavaged with 1) a mixed meal (0.285 kcal; glucose, whey protein and peanut oil; 60/20/20% kcal) versus an isocaloric glucose load (0.285 kcal), and 2) a mixed meal (0.285 kcal) versus glucose, whey protein or peanut oil administered individually in their mixed meal caloric quantity, i.e., 0.171, 0.055 and 0.055 kcal, respectively. Plasma was analyzed for glucose, insulin and intact GLP-1 before and during oral challenges. Plasma glucose was lower after mixed meal versus after isocaloric glucose ingestion. In spite of this, the peak insulin response (P=0.02), the peak intact GLP-1 levels (P=0.006) and the estimated β-cell function (P=0.005) were higher. Furthermore, the peak insulin (P=0.004) and intact GLP-1 (P=0.006) levels were higher after mixed meal ingestion than the sum of responses to individual macronutrients. Compared to glucose alone, we conclude that there is a marked early insulin response to mixed meal ingestion, which emanates from a synergistic, rather than an additive, effect of the individual macronutrients in the mixed meal and is in part likely caused by increased levels of GLP-1.
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| 2. |
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| 3. |
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| 4. |
- Andersson, Sofia A, et al.
(författare)
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Glucose-dependent docking and SNARE protein-mediated exocytosis in mouse pancreatic alpha-cell
- 2011
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Ingår i: Pflügers Archiv. - : Springer. - 0031-6768 .- 1432-2013. ; 462:3, s. 443-454
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Tidskriftsartikel (refereegranskat)abstract
- The function of alpha-cells in patients with type 2 diabetes is often disturbed; glucagon secretion is increased at hyperglycaemia, yet fails to respond to hypoglycaemia. A crucial mechanism behind the fine-tuned release of glucagon relies in the exocytotic machinery including SNARE proteins. Here, we aimed to investigate the temporal role of syntaxin 1A and SNAP-25 in mouse alpha-cell exocytosis. First, we used confocal imaging to investigate glucose dependency in the localisation of SNAP-25 and syntaxin 1A. SNAP-25 was mainly distributed in the plasma membrane at 2.8 mM glucose, whereas the syntaxin 1A distribution in the plasma membrane, as compared to the cytosolic fraction, was highest at 8.3 mM glucose. Furthermore, following inclusion of an antibody against SNAP-25 or syntaxin 1A, exocytosis evoked by a train of ten depolarisations and measured as an increase in membrane capacitance was reduced by ~50%. Closer inspection revealed a reduction in the refilling of granules from the reserve pool (RP), but also showed a decreased size of the readily releasable pool (RRP) by ~45%. Disparate from the situation in pancreatic beta-cells, the voltage-dependent Ca²⁺ current was not reduced, but the Ca²⁺ sensitivity of exocytosis decreased by the antibody against syntaxin 1A. Finally, ultrastructural analysis revealed that the number of docked granules was >2-fold higher at 16.7 mM than at 1 mM glucose. We conclude that syntaxin 1A and SNAP-25 are necessary for alpha-cell exocytosis and regulate fusion of granules belonging to both the RRP and RP without affecting the Ca²⁺ current.
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| 5. |
- Bjärsholm, Daniel, et al.
(författare)
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A longitudinal study on exercise habits and mental health among Swedish police students
- 2023
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Konferensbidrag (refereegranskat)abstract
- IntroductionIn Sweden, police education should promote students’ physical activity and mental health. According to national goals, police students should be provided with sufficient conditions to develop and maintain advantageous exercise habits and tools to handle various mentally and physically demanding tasks. The national goals also state that students’ physical fitness must be better at graduation than what the requirements are for admission (see Krugly et al., 2022). Although the improvement of students’ physical fitness and mental health are national goals, there is a general lack of knowledge regarding: 1) police students physical and mental health, especially from a Swedish perspective; and 2) how well police education promotes students’ level of physical activity during education. Against this background, the aim is to explore police students’ mental health and level of physical activity during police education in Sweden.MethodsThe data derives from the largest project in Sweden on police students’ physical and mental health, and consists of longitudinal data on police students answers of a self-rated questionnaire about exercise habits and mental health (N = 785). The data used in this study was gathered between 2019–2021, and consisted of four data collection points, from two police educations in Sweden. The analysis was conducted in two steps. First, exploratory- and confirmatory factor analyses were conducted to create scales for mental health orientation. Second, these scales, together with the variable exercise habits, were used as outcome variables in t-tests, X2 test and ANOVA. Effect size measurements were calculated and interpreted based on established guidelines.ResultsThe results show high psychometric support for two scales named positive health orientation and negative health orientation. Based on the scales and the variable of exercise habits, three primarily results emerge: 1) the levels of physical training for men decrease during education; 2) there are gender differences showing that women have a more negative health orientation; and, 3) the positive mental health orientation decreases during education for both men and women.DiscussionSwedish police education should prepare students for physically and mentally demanding work. However, as this study concludes, this tends to not be the case, especially given that both the level of physical activity and the positive mental health orientation decrease during education. This raises questions on whether the Swedish police education is doing “enough” to provide the students with adequate conditions for improving their mental and physical health.Krugly, S., Bjärsholm, D., Jansson, A., Rosendal Hansen, A., Hansson, O., Brehm, K., Datmo, A., Hafsteinsson Östenberg, A., & Vikman, J. (2022). A retrospective study of physical fitness and mental health among police students in Sweden. The Police Journal: Theory, Practice and Principles. doi.org/10.1177/0032258X221089576
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| 6. |
- Carr, Richard D, et al.
(författare)
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Secretion and Dipeptidyl Peptidase-4-Mediated Metabolism of Incretin Hormones after a Mixed Meal or Glucose Ingestion in Obese Compared to Lean, Nondiabetic Men.
- 2010
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 95, s. 872-878
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Tidskriftsartikel (refereegranskat)abstract
- Context: Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are cleaved by dipeptidyl peptidase-4 (DPP-4); plasma activity of DPP-4 may be increased in obesity. The impact of this increase on incretin hormone secretion and metabolism is not known. Objective: The aim of the study was to assess incretin hormone secretion and degradation in lean and obese nondiabetic subjects. Design, Settings, and Participants: We studied the ingestion of a mixed meal (560 kcal) or oral glucose (2 g/kg) in healthy lean (n = 12; body mass index, 20-25 kg/m(2)) or obese (n = 13; body mass index, 30-35 kg/m(2)) males at a University Clinical Research Unit. Main Outcome Measures: We measured the area under the curve of plasma intact (i) and total (t) GIP and GLP-1 after meal ingestion and oral glucose. Results: Plasma DPP-4 activity was higher in the obese subjects (38.5 +/- 3.0 vs. 26.7 +/- 1.6 mmol/min . mul; P = 0.002). Although GIP secretion (AUCtGIP) was not reduced in obese subjects after meal ingestion or oral glucose, AUCiGIP was lower in obese subjects (8.5 +/- 0.6 vs. 12.7 +/- 0.9 nmol/liter x 300 min; P < 0.001) after meal ingestion. GLP-1 secretion (AUCtGLP-1) was reduced in obese subjects after both meal ingestion (7.3 +/- 0.9 vs. 10.0 +/- 0.6 nmol/liter x 300 min; P = 0.022) and oral glucose (6.6 +/- 0.8 vs. 9.6 +/- 1.1 nmol/liter x 180 min; P = 0.035). iGLP-1 was reduced in parallel to tGLP-1. Conclusions: 1) Release and degradation of the two incretin hormones show dissociated changes in obesity: GLP-1 but not GIP secretion is lower after meal ingestion and oral glucose, whereas GIP but not GLP-1 metabolism is increased after meal ingestion. 2) Increased plasma DPP-4 activity in obesity is not associated with a generalized augmented incretin hormone metabolism.
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| 7. |
- Jansson, Alexander, et al.
(författare)
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Mental health and exercise habits among police students in Sweden : a three-year retrospective study
- 2023
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Ingår i: Abstracts from the First European Conference on Law Enforcement and Public Health, Umeå 2023. - : Enheten för polisutbildning, Umeåuniversitet. - 9789180701099
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Working as a police officer involves mentally and physically demanding tasks. During the Swedish police education, students should be provided with sufficient conditions to develop and maintain advantageous exercise habits and tools to handle mentally and physically demanding tasks (see Krugly et al., 2022). However, there is a lack of knowledge regarding Swedish police students exercise habits and overall mental- and physical health.The aim is to explore police students’ mental health and physical activity levels during police education in Sweden.The data consisted of police students answers of a self-rated questionnaire about their physical and mental health. The data used in this study was gathered between 2019–2021, and consist of four data collection points, from two police educations in Sweden. The analysis was conducted in two steps. First, exploratory- and confirmatory factor analyses were conducted to create scales for health orientation. Second, these scales were used as outcome variables in t-tests, X2 test and ANOVA. Effect size measurements (Cohens, d, Crames V and Phi) were calculated and interpreted based on well establish guidelines.Two scales were developed (i.e. positive health orientation and negative health orientation), and both showed high psychometric support. Based on the scales, two primarily results emerged: 1) results showed that women had a more negative health orientation in general and that positive health orientation, for both genders, decreased between semesters one to four; and 2) more women conducted two hours (or more) per week of physical exercise. Moreover, physical training among men decreased continuously during their education.Conclusions and ImplicationsBased on the results, this study questions whether police education in Sweden doing enough to prepare students for a mentally and physically demanding profession.
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| 8. |
- Jansson, Alexander, et al.
(författare)
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Mental health and exercise habits among police students in Sweden : A three-year retrospective study
- 2023
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Ingår i: The Police Journal. - : Sage Publications. - 0032-258X .- 1740-5599.
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Tidskriftsartikel (refereegranskat)abstract
- This study aims to explore police students’ self-rated mental health and physical activity levels and the relationship between them. Based on longitudinal and cross-sectional data (N = 722), two scales on mental health orientation were developed. The scales and levels of physical activity were analyzed using t-test, ANOVA, and X2. During police education, (1) the level of physical activity decreases for men, (2) there is a decline in positive health orientation for both sexes, and (3) women report a more negative health orientation. This raises questions regarding whether “enough” is done to provide police students with sufficient conditions for improving their health.
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| 9. |
- Jansson, Alexander, et al.
(författare)
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Mental health and exercise habits among police students in Sweden : A three-year retrospective study
- 2023
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Ingår i: The Police Journal. - : Sage Publications. - 0032-258X .- 1740-5599. ; , s. 1-16
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Tidskriftsartikel (refereegranskat)abstract
- This study aims to explore police students’ self-rated mental health and physical activity levels and the relationship between them. Based on longitudinal and cross-sectional data (N = 722), two scales on mental health orientation were developed. The scales and levels of physical activity were analyzed using t-test, ANOVA, and X2. During police education, (1) the level of physical activity decreases for men, (2) there is a decline in positive health orientation for both sexes, and (3) women report a more negative health orientation. This raises questions regarding whether “enough” is done to provide police students with sufficient conditions for improving their health.
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| 10. |
- Jansson, Alexander, et al.
(författare)
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Träningsråd till dig som ska genomföra tester av fysisk förmåga på Plikt- och prövningsverket
- 2023
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- På Plikt- och prövningsverket genomförs flera olika tester. När det kommer till att testa de prövandes fysiska förmåga används bland annat ett konditionstest på cykel och ett isokinetiskt styrketest som kallas Isokai. I den här texten ges information om testerna, grundläggande träningsråd för att klara dessa samt råd inför fortsatt träning. Råden är uppdelade i två delar. I den första delen beskrivs träningsråd för styrketräning och i den andra för konditionsträning.
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| 11. |
- Jeans, Alexander F., et al.
(författare)
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A dominant mutation in Snap25 causes impaired vesicle trafficking, sensorimotor gating, and ataxia in the blind-drunk mouse
- 2007
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 104:7, s. 2431-2436
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Tidskriftsartikel (refereegranskat)abstract
- The neuronal soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex is essential for synaptic vesicle exocytosis, but its study has been limited by the neonatal lethality of murine SNARE knockouts. Here, we describe a viable mouse line carrying a mutation in the b-isoform of neuronal SNARE synaptosomal-associated protein of 25 kDa (SNAP-25) The causative I67T missense mutation results in increased binding affinities within the SNARE complex, impaired exocytotic vesicle recycling and granule exocytosis in pancreatic beta-cells, and a reduction in the amplitude of evoked cortical excitatory postsynaptic potentials. The mice also display ataxia and impaired sensorimotor gating, a phenotype which has been associated with psychiatric disorders in humans. These studies therefore provide insights into the role of the SNARE complex in both diabetes and psychiatric disease.
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| 12. |
- Jones, Helena, et al.
(författare)
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beta-cell PDE3B regulates Ca(2+)-stimulated exocytosis of insulin.
- 2007
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Ingår i: Cellular Signalling. - : Elsevier BV. - 1873-3913 .- 0898-6568. ; 19:Feb 12, s. 1505-1513
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Tidskriftsartikel (refereegranskat)abstract
- cAMP signaling is important for the regulation of insulin secretion in pancreatic beta-cells. The level of intracellular cAMP is controlled through its production by adenylyl cyclases and its breakdown by cyclic nucleotide phosphodiesterases (PDEs). We have previously shown that PDE3B is involved in the regulation of nutrient-stimulated insulin secretion. Here, aiming at getting deeper functional insights, we have examined the role of PDE3B in the two phases of insulin secretion as well as its localization in the beta-cell. Depolarization-induced insulin secretion was assessed and in models where PDE3B was overexpressed [islets from transgenic RIP-PDE3B/7 mice and adenovirally (AdPDE3B) infected INS-I (832/13) cells], the first phase of insulin secretion, occurring in response to stimulation with high K+ for 5 min, was significantly reduced (similar to 25% compared to controls). In contrast, in islets from PDE3B(-/-) mice the response to high K+ was increased. Further, stimulation of isolated beta-cells from RIP-PDE3B/7 islets, using successive trains of voltage-clamped depolarizations, resulted in reduced Ca2+-triggered first phase exocytotic response as well as reduced granule mobilization-dependent second phase, compared to wild-type beta-cells. Using sub-cellular fractionation, confocal microscopy and transmission electron microscopy of isolated mouse islets and INS-1 (832/13) cells, we show that endogenous and overexpressed PDE3B is localized to insulin granules and plasma membrane. We conclude that PDE3B, through hydrolysis of cAMP in pools regulated by Ca2+, plays a regulatory role in depolarization-induced insulin secretion and that the enzyme is associated with the exocytotic machinery in beta-cells. (c) 2007 Elsevier Inc. All rights reserved.
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| 13. |
- Krugly, Sandra, et al.
(författare)
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A retrospective study of physical fitness and mental health among police students in Sweden
- 2023
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Ingår i: The Police Journal. - : Sage Publications. - 0032-258X .- 1740-5599. ; 96:3, s. 430-450
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about the physical and mental health among police students. Based on data on Swedish police students’ physical fitness (N = 1736) and mental health (N = 407), the results show that: (a) there are gender differences; (b) the physical fitness changes during police education; in general, the students get stronger but less flexible, and the aerobic endurance increases for women but decreases for men; and (c) students’ self-reported physical activity and mental health affect their perceived police ability differently in re- lation to gender. Consequently, this study questions if the Swedish police education is preparing the students adequately for their future profession.
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| 14. |
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| 15. |
- Lindgren, Ola, et al.
(författare)
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Differential Islet and Incretin Hormone Responses in Morning vs. Afternoon after Standardized Meal in Healthy Men.
- 2009
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 94:8, s. 2887-2892
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Tidskriftsartikel (refereegranskat)abstract
- Context: The insulin response to meal ingestion is more rapid in the morning than in the afternoon. Whether this is explained by a corresponding variation in the incretin hormones is not known. Objective: Assess islet and incretin hormones after meal ingestion in the morning versus afternoon. Design, Settings and Participants: Ingestion at 8am and at 5pm of a standardized meal (524 kcal) in healthy lean males (n=12) at a University Clinical Research Unit. Main Outcome Measures: 1)Early (30 min) area under the curve (AUC30) of plasma levels of insulin and intact (i) and total (t) glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) after meal ingestion. 2)Estimation of ss-cell function by model analysis of glucose and C-peptide. Results: Peak glucose was lower in the morning than in the afternoon (6.1+/-0.2 vs. 7.4+/-0.3 mmol/l, P=0.001). AUC30insulin (4.9+/-0.6 vs 2.8+/-0.4 nmol/l*30 min; P=0.012), AUC30tGLP-1 (300+/-40 vs. 160+/-30 pmol/l*30 min, P=0.002), AUC30iGIP (0.7+/-0.1 vs. 0.3+/-0.1 nmol/l* 30 min, P=0.002) and AUC30tGIP (1.1+/-0.1 vs. 0.6+/-0.1nmol/l*min, P=0.007) were all higher in the morning. AUC30iGLP-1 (r=0.68, P=0.021) and AUC39iGIP (r=0.78, P=0.001) both correlated to AUC30insulin. Model analysis of ss-cell function showed a higher first hour potentiation factor in the morning (P=0.009). This correlated negatively with the 60 min glucose level (r=-0.63, P<0.001). Conclusions: The early release of GLP-1 and GIP are more pronounced in the morning than in the afternoon. This may contribute to the more rapid early insulin response, more pronounced potentiation of ss-cell function and lower glucose after the morning meal.
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| 16. |
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| 17. |
- Ma, Xiaosong, et al.
(författare)
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Glucagon stimulates exocytosis in mouse and rat pancreatic {alpha} cells by binding to glucagon receptors.
- 2005
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Ingår i: Molecular Endocrinology. - : The Endocrine Society. - 0888-8809 .- 1944-9917. ; 19:1, s. 198-212
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Tidskriftsartikel (refereegranskat)abstract
- Glucagon, secreted by the pancreatic alpha-cells, stimulates insulin secretion from neighboring beta-cells by cAMP- and protein kinase A (PKA)-dependent mechanisms, but it is not known whether glucagon also modulates its own secretion. We have addressed this issue by combining recordings of membrane capacitance (to monitor exocytosis) in individual alpha-cells with biochemical assays of glucagon secretion and cAMP content in intact pancreatic islets, as well as analyses of glucagon receptor expression in pure alpha-cell fractions by RT-PCR. Glucagon stimulated cAMP generation and exocytosis dose dependently with an EC50 of 1.6-1.7 nm. The stimulation of both parameters plateaued at concentrations beyond 10 nm of glucagon where a more than 3-fold enhancement was observed. The actions of glucagon were unaffected by the GLP-1 receptor antagonist exendin-(9-39) but abolished by des-His1-[Glu9]-glucagon-amide, a specific blocker of the glucagon receptor. The effects of glucagon on alpha-cell exocytosis were mimicked by forskolin and the stimulatory actions of glucagon and forskolin on exocytosis were both reproduced by intracellular application of 0.1 mm cAMP. cAMP-potentiated exocytosis involved both PKA-dependent and -independent (resistant to Rp-cAMPS, an Rp-isomer of cAMP) mechanisms. The presence of the cAMP-binding protein cAMP-guanidine nucleotide exchange factor II in alpha-cells was documented by a combination of immunocytochemistry and RT-PCR and 8-(4-chloro-phenylthio)-2'-O-methyl-cAMP, a cAMP-guanidine nucleotide exchange factor II-selective agonist, mimicked the effect of cAMP and augmented rapid exocytosis in a PKA-independent manner. We conclude that glucagon released from the alpha-cells, in addition to its well-documented systemic effects and paracrine actions within the islet, also represents an autocrine regulator of alpha-cell function.
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| 18. |
- MacDonald, Patrick, et al.
(författare)
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Regulated Exocytosis and Kiss-and-Run of Synaptic-Like Microvesicles in INS-1 and Primary Rat {beta}-Cells.
- 2005
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 54:3, s. 736-743
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Tidskriftsartikel (refereegranskat)abstract
- We have applied cell-attached capacitance measurements to investigate whether synaptic-like microvesicles (SLMVs) undergo regulated exocytosis in insulinoma and primary pancreatic beta-cells. SLMV and large dense-core vesicle (LDCV) exocytosis was increased 1.6- and 2.4-fold upon stimulation with 10 mmol/l glucose in INS-1 cells. Exocytosis of both types of vesicles was coupled to Ca(2+) entry through l-type channels. Thirty percent of SLMV exocytosis in INS-1 and rat beta-cells was associated with transient capacitance increases consistent with kiss-and-run. Elevation of intracellular cAMP (5 micromol/l forskolin) increased SLMV exocytosis 1.6-fold and lengthened the duration of kiss-and-run events in rat beta-cells. Experiments using isolated inside-out patches of INS-1 cells revealed that the readily releasable pool (RRP) of SLMVs preferentially undergoes kiss-and-run exocytosis (67%), is proportionally larger than the LDCV RRP, and is depleted more quickly upon Ca(2+) stimulation. We conclude that SLMVs undergo glucose-regulated exocytosis and are capable of high turnover. Following kiss-and-run exocytosis, the SLMV RRP may be reloaded with gamma-aminobutyric acid and undergo several cycles of exo- and endocytosis. Our observations support a role for beta-cell SLMVs in a synaptic-like function of rapid intra-islet signaling.
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| 19. |
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| 20. |
- Omar, Bilal, et al.
(författare)
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Enhanced beta cell function and anti-inflammatory effect after chronic treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin in an advanced-aged diet-induced obesity mouse model
- 2013
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 56:8, s. 1752-1760
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Studies have shown that dipeptidyl peptidase-4 (DPP4) inhibitors stimulate insulin secretion and increase beta cell mass in rodents. However, in these models hyperglycaemia has been induced early on in life and the treatment periods have been short. To explore the long-term effects of DPP4 inhibition on insulin secretion and beta cell mass, we have generated a high-fat diet (HFD)-induced-obesity model in mice of advanced age (10 months old). METHODS: After 1 month of HFD alone, the mice were given the DPP4 inhibitor vildagliptin for a further 11 months. At multiple time points throughout the study, OGTTs were performed and beta cell area and long-term survival were evaluated. RESULTS: Beta cell function and glucose tolerance were significantly improved by vildagliptin with both diets. In contrast, in spite of the long treatment period, beta cell area was not significantly different between vildagliptin-treated mice and controls. Mice of advanced age chronically fed an HFD displayed clear and extensive pancreatic inflammation and peri-insulitis, mainly formed by CD3-positive T cells, which were completely prevented by vildagliptin treatment. Chronic vildagliptin treatment also improved survival rates for HFD-fed mice. CONCLUSIONS/INTERPRETATION: In a unique advanced-aged HFD-induced-obesity mouse model, insulin secretion was improved and the extensive peri-insulitis prevented by chronic DPP4 inhibition. The improved survival rates for obese mice chronically treated with vildagliptin suggest that chronic DPP4 inhibition potentially results in additional quality-adjusted life-years for individuals with type 2 diabetes, which is the primary goal of any diabetes therapy.
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| 21. |
- Salunkhe, Vishal A., et al.
(författare)
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Dual Effect of Rosuvastatin on Glucose Homeostasis Through Improved Insulin Sensitivity and Reduced Insulin Secretion
- 2016
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 10, s. 185-194
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Tidskriftsartikel (refereegranskat)abstract
- Statins are beneficial in the treatment of cardiovascular disease (CVD), but these lipid-lowering drugs are associated with increased incidence of new on-set diabetes. The cellular mechanisms behind the development of diabetes by statins are elusive. Here we have treated mice on normal diet (ND) and high fat diet (HFD) with rosuvastatin. Under ND rosuvastatin lowered blood glucose through improved insulin sensitivity and increased glucose uptake in adipose tissue. In vitro rosuvastatin reduced insulin secretion and insulin content in islets. In the beta cell Ca(2+) signaling was impaired and the density of granules at the plasma membrane was increased by rosuvastatin treatment. HFD mice developed insulin resistance and increased insulin secretion prior to administration of rosuvastatin. Treatment with rosuvastatin decreased the compensatory insulin secretion and increased glucose uptake. In conclusion, our data shows dual effects on glucose homeostasis by rosuvastatin where insulin sensitivity is improved, but beta cell function is impaired.
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| 22. |
- Vikman, Jenny, et al.
(författare)
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Antibody inhibition of synaptosomal protein of 25 kDa (SNAP-25) and syntaxin 1 reduces rapid exocytosis in insulin-secreting cells.
- 2006
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Ingår i: Journal of Molecular Endocrinology. - : Bioscientifica. - 1479-6813 .- 0952-5041. ; 36:3, s. 503-515
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Tidskriftsartikel (refereegranskat)abstract
- SNARE-proteins (soluble NSF-attachment protein receptor) are important for Ca2+-dependent exocytosis. We have used capacitance measurements and confocal imaging to dissect the role of synaptosomal protein of 25 kDa (SNAP-25) and syntaxin 1 in rapid exocytosis in insulin-secreting pancreatic ß-cells. Following immunoneutralization of syntaxin 1 and SNAP-25, exocytosis was strongly reduced and associated with a marked reduction in the size of the readily releasable pool (RRP) by 65% and 86% in the presence of the anti-SNAP-25 and anti-syntaxin 1 antibodies respectively. The size of the immediately releasable pool (IRP), a subset of RRP in close association with the voltage-dependent Ca2+-channels, was reduced to an equal extent. The reduction in IRP correlated with slowed release kinetics and the time constant ({tau}) increased from a control value of 16 to 36 ms and 51 ms after inclusion of anti-SNAP-25 and anti-syntaxin 1 antibodies respectively in the pipette solution. We further show that SNAP-25 and syntaxin 1 aggregate in clusters along the plasma membrane. The size of these clusters was estimated to be ~300 nm and every ß-cell contained ~400 SNAP-25/syntaxin 1 clusters. Whereas the inhibitory action of the anti-syntaxin 1 antibody on exocytosis could be attributed almost entirely to suppression of the voltage-dependent Ca2+-current (–40%), the effect of the anti-SNAP-25 antibody was not mediated by decreased Ca2+-entry and is more likely due to a direct interference with the exocytotic machinery. Our data are consistent with the concept that both syntaxin 1 and SNAP-25 are required for rapid exocytosis in ß-cells.
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| 23. |
- Vikman, Jenny
(författare)
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Exocytosis in insulin secreting cells - role of SNARE-proteins
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 2 diabetes is marked by deterioration in pancreatic β-cell function. SNARE-proteins are crucial for the fusion of insulin granules with the plasma membrane, a prerequisite for insulin secretion. The aim of this thesis has been to investigate the exocytotic process in β-cells with a specific focus on the function and significance of the two SNARE-proteins SNAP-25 and syntaxin 1. SNAP-25 and syntaxin 1 was discovered to be situated in clusters along the plasma membrane. Immunoneutralization of syntaxin 1 and SNAP-25 resulted in a strongly reduced exocytotic response of primed granules in close association with the voltage-dependent calcium channels. Cholesterol is an essential component of the plasma membrane. Desorption of cholesterol from the plasma membrane in β-cells were accompanied with an overall reduction in the response of β-cells, from insulin secretion to exocytosis. We believe this is due to disturbance of a basic mechanism. Indeed, we found that SNAP-25 migrated from the plasma membrane out to the cytosol. The stimulating effect of cAMP on insulin secretion is implemented through different pathways. One pathway is through cAMP-GEFII and its downstream affector RIM2. We show that SNAP-25 binds to both cAMP-GEFII and RIM2, and that this binding mediates the effects of cAMP on exocytosis. The blind-drunk mouse carries a mutation in SNAP-25 that results in increased binding affinities within the SNARE-complex and the consequence in pancreatic β-cells are impaired vesicle recycling and granule exocytosis. These results together demonstrate the significance of a functional exocytotic machinery for β-cells to respond satisfying to an elevation in blood glucose.
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| 24. |
- Vikman, Jenny, et al.
(författare)
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Inhibitory effect of kisspeptins on insulin secretion from isolated mouse islets.
- 2009
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 11 Suppl 4, s. 197-201
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Tidskriftsartikel (refereegranskat)abstract
- Islet hormone secretion is regulated by a variety of factors, and many of these signal through G protein-coupled receptors (GPCRs). A novel islet GPCR is GPR54, which couples to the Gq isoform of G proteins, which in turn signal through the phospholipase C pathway. Ligands for GPR54 are kisspeptins, which are peptides encoded in the KISS1 gene and also expressed in islet beta-cells. The KISS1 gene encodes a hydrophobic 145-amino acid protein that is cleaved into a 54-amino acid protein, kisspeptin-54 or KP54. Shorter kisspeptins also exist, such as kisspeptin-10 (KP10) and kisspeptin-13 (KP13). The involvement of GPR54 and kisspeptins in the regulation of islet function is not known. To address this problem, we incubated isolated mouse islets in the presence of KP13 and KP54 for 60 min and measured insulin secretion. We found that both KP13 and KP54 at 10 nM, 100 nM and 1microM inhibited insulin secretion in the presence of 2.8 mM glucose. However, by increasing the glucose concentration, this inhibitory action of the kisspeptins vanished. Thus, at 11.1 mM glucose, KP13 and KP54 inhibited insulin secretion only at high doses, and at 16.7 mM they no longer inhibited insulin secretion in any of the doses. We conclude that kisspeptins inhibit insulin secretion at glucose concentrations below 11.1 mM. This suggests that kisspeptins are regulating insulin secretion at physiological concentrations of glucose. The mechanisms by which kisspeptins regulate islet function and insulin secretion are unknown and will be further investigated.
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| 25. |
- Vikman, Jenny, et al.
(författare)
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Insulin secretion is highly sensitive to desorption of plasma membrane cholesterol.
- 2009
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Ingår i: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860. ; 23:1, s. 58-67
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Tidskriftsartikel (refereegranskat)abstract
- Cholesterol-rich clusters of SNARE (soluble NSF attachment protein receptor) proteins have been implicated as being important for exocytosis. Here we demonstrate the significance of cholesterol for normal biphasic insulin secretion in mouse beta cells by removal of cholesterol from the plasma membrane using methyl-beta-cyclodextrin (MBCD). Maximal inhibition of insulin secretion in static incubations was achieved using 0.1 mM MBCD. In in situ pancreatic perfusion measurements, both first and second phase insulin secretions were reduced by approximately 50% (P<0.05). This was accompanied by a reduced number of docked large dense core vesicles (LDCVs) ( approximately 40%; P<0.01) and a reduced exocytotic response (>50%; P<0.01). Further, subcellular fractionations demonstrated movement of the synaptosomal protein of 25 kDa (SNAP-25) from the plasma membrane to the cytosol after MBCD treatment. The inhibitory actions of MBCD were counteracted by subsequent addition of cholesterol. We hypothesize that desorption of cholesterol leads to the disturbance of a basic exocytotic mechanism partly due to migration of SNAP-25, and we conclude that insulin secretion is highly sensitive to changes in plasma membrane cholesterol.-Vikman, J., Jimenez-Feltström, J., Nyman, P., Thelin, J., Eliasson, L. Insulin secretion is highly sensitive to desorption of plasma membrane cholesterol.
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| 26. |
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| 27. |
- Vikman, Jenny, et al.
(författare)
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Truncation of SNAP-25 reduces the stimulatory action of cAMP on rapid exocytosis in insulin-secreting cells.
- 2009
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Ingår i: American Journal of Physiology: Endocrinology and Metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 297, s. 452-461
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Tidskriftsartikel (refereegranskat)abstract
- SNAP-25 is important for Ca(2+)-dependent fusion of Large Dense Core Vesicles (LDCVs) in insulin-secreting cells. Exocytosis is further enhanced by cAMP-increasing agents such as GLP-1 and this augmentation includes interaction with both PKA and cAMP-GEFII. To investigate the coupling between SNAP-25 and cAMP-dependent stimulation of insulin exocytosis we have used capacitance measurements, protein-binding assays and Western blot analysis. In insulin secreting INS-1 cells overexpressing wild-type SNAP-25 (SNAP-25WT) rapid exocytosis was stimulated >3-fold by cAMP, similar to the situation in non-transfected cells. However, cAMP failed to potentiate rapid exocytosis in INS-1 cells overexpressing a truncated form of SNAP-25 (SNAP-251-197) or Botulinum neurotoxin A (BoNT/A). Close dissection of the exocytotic response revealed that the inability of cAMP to stimulate exocytosis in presence of a truncated SNAP-25 was confined to the release of primed LDCVs within the Readily Releasable Pool (RRP), especially from the Immediately Releasable Pool (IRP), whereas cAMP enhanced mobilization of granules from the Reserve Pool (RP) in both SNAP-251-197 (P<0.01) and SNAP-25WT (P<0.05) cells. This was supported by hormone release measurements. Augmentation of IRP by cAMP has been suggested to act through the cAMP-GEFII-dependent, PKA-independent pathway. Indeed, we were able to verify an interaction between SNAP-25 with both cAMP-GEFII and RIM2, two proteins involved in the PKA-independent pathway. Thus, we hypothesize that SNAP-25 is a necessary partner in the complex mediating cAMP-enhanced rapid exocytosis in insulin secreting cells. Key words: cAMP, SNAP-25, insulin, INS-1.
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