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11.
  • Barg, Sebastian, et al. (författare)
  • Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting alpha-cells
  • 2000
  • Ingår i: Diabetes. - : American Diabetes Association Inc.. - 1939-327X .- 0012-1797. ; 49:9, s. 1500-1510
  • Tidskriftsartikel (refereegranskat)abstract
    • alpha-Cells were identified in preparations of dispersed mouse islets by immunofluorescence microscopy. A high fraction of alpha-cells correlated with a small cell size measured as the average cell diameter (10 microm) and whole-cell capacitance (<4 pF). The alpha-cells generated action potentials at a low frequency (1 Hz) in the absence of glucose. These action potentials were reversibly inhibited by elevation of the glucose concentration to 20 mmol/l. The action potentials originated from a membrane potential more negative than -50 mV, had a maximal upstroke velocity of 5 V/s, and peaked at +1 mV. Voltage-clamp experiments revealed the ionic conductances underlying the generation of action potentials. alpha-Cells are equipped with a delayed tetraethyl-ammonium-blockable outward current (activating at voltages above -20 mV), a large tetrodotoxin-sensitive Na+ current (above -30 mV; peak current 200 pA at +10 mV), and a small Ca2+ current (above -50 mV; peak current 30 pA at +10 mV). The latter flowed through omega-conotoxin GVIA (25%)- and nifedipine-sensitive (50%) Ca(2+)-channels. Mouse alpha-cells contained, on average, 7,300 granules, which undergo Ca(2+)-induced exocytosis when the alpha-cell is depolarized. Three functional subsets of granules were identified, and the size of the immediately releasable pool was estimated as 80 granules, or 1% of the total granule number. The maximal rate of exocytosis (1.5 pF/s) was observed 21 ms after the onset of the voltage-clamp depolarization, which is precisely the duration of Ca(2+)-influx during an action potential. Our results suggest that the secretory machinery of the alpha-cell is optimized for maximal efficiency in the use of Ca2+ for exocytosis.
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12.
  • Barker, Adam, et al. (författare)
  • Association of genetic loci with glucose levels in childhood and adolescence a meta-analysis of over 6,000 children
  • 2011
  • Ingår i: Diabetes. - 0012-1797 .- 1939-327X. ; 60:6, s. 1805-1812
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE-To investigate whether associations of common genetic variants recently identified for fasting glucose or insulin levels in nondiabetic adults are detectable in healthy children and adolescents. RESEARCH DESIGN AND METHODS-A total of 16 single nucleotide polymorphisms (SNPs) associated with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9-16 years. We performed meta-analyses to test associations of individual SNPs and a weighted risk score of the 16 loci with fasting glucose. RESULTS-Nine loci were associated with glucose levels in healthy children and adolescents, with four of these associations reported in previous studies and five reported here for the first time (GLIS3, PROX1, SLC2A2, ADCY5, and CRY2). Effect sizes were similar to those in adults, suggesting age-independent effects of these fasting glucose loci. Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced p-cell function, as indicated by homeostasis model assessment of beta-cell function. Analysis using a weighted risk score showed an increase [beta (95% CI)] in fasting glucose level of 0.026 mrnol/L (0.021-0.031) for each unit increase in the score. CONCLUSIONS-Novel fasting glucose loci identified in genome-wide association studies of adults are associated with altered fasting glucose levels in healthy children and adolescents with effect sizes comparable to adults. In nondiabetic adults, fasting glucose changes little over time, and our results suggest that age-independent effects of fasting glucose loci contribute to long-term interindividual differences in glucose levels from childhood onwards. Diabetes 60:1805-1812, 2011
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13.
  • Benedict, Christian, et al. (författare)
  • Intranasal Insulin Enhances Postprandial Thermogenesis and Lowers Postprandial Serum Insulin Levels in Healthy Men
  • 2011
  • Ingår i: Diabetes. - 0012-1797 .- 1939-327X. ; 60:1, s. 114-118
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE Animal studies indicate a prominent role of brain insulin signaling in the regulation of peripheral energy metabolism. We determined the effect of intranasal insulin, which directly targets the brain, on glucose metabolism and energy expenditure in humans.RESEARCH DESIGN AND METHODSIn a double-blind, placebo-controlled, balanced within-subject comparison, 19 healthy normal-weight men (18-26 years old) were intranasally administered 160 IU human insulin after an overnight fast. Energy expenditure assessed via indirect calorimetry and blood concentrations of glucose, insulin, C-peptide, and free fatty acids (FFAs) were measured before and after insulin administration and the subsequent consumption of a high-calorie liquid meal of 900 kcal.RESULTSIntranasal insulin, compared with placebo, increased postprandial energy expenditure, i.e., diet-induced thermogenesis, and decreased postprandial concentrations of circulating insulin and C-peptide, whereas postprandial plasma glucose concentrations did not differ from placebo values. Intranasal insulin also induced a transient decrease in prandial serum FFA levels.CONCLUSIONSEnhancing brain insulin signaling by means of intranasal insulin administration enhances the acute thermoregulatory and glucoregulatory response to food intake, suggesting that central nervous insulin contributes to the control of whole-body energy homeostasis in humans.
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14.
  • Benedict, Christian, et al. (författare)
  • The fat mass and obesity-associated gene (FTO) is linked to higher plasma levels of the hunger hormone ghrelin and lower serum levels of the satiety hormone leptin in older adults
  • 2014
  • Ingår i: Diabetes. - 0012-1797 .- 1939-327X. ; 63:11, s. 3955-3959
  • Tidskriftsartikel (refereegranskat)abstract
    • The mechanisms through which common polymorphisms in the fat mass and obesity-associated gene (FTO) drive the development of obesity in humans are poorly understood. By using C: ross-sectional data from 985 elderly (50% females) who participated at age 70 years in the Prospective Investigation of the Vasculature in Uppsala Seniors, circulating levels of ghrelin and leptin were measured after an overnight fast. In addition, subjects were genotyped for FTO rs17817449 (AA, n=345 (35%); AC/CA, n=481 (48.8%); CC, n=159 (16.1%). Linear regression analyses controlling for sex, self-reported physical activity level, fasting plasma glucose, and body mass index were utilized. A positive relationship between the number of FTO C risk alleles and plasma ghrelin levels was found (P=0.005; relative plasma ghrelin difference between CC and AA carriers = ∼9%). In contrast, serum levels of the satiety enhancing hormone leptin were inversely linked to the number of FTO C risk alleles (P=0.001; relative serum leptin difference between CC and AA carriers = ∼11%). These associations were also found when controlling for waist circumference. The present findings suggest that FTO may facilitate weight gain in humans by shifting the endocrine balance from the satiety hormone leptin toward the hunger promoting hormone ghrelin.
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15.
  • Bergman, Marie-Louise, et al. (författare)
  • Diabetes protection and restoration of thymocyte apoptosis in NOD Idd6 congenic strains
  • 2003
  • Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 52:7, s. 1677-1682
  • Tidskriftsartikel (refereegranskat)abstract
    • Type 1 diabetes in the nonobese diabetic (NOD) mouse is a multifactorial and polygenic disease. The NOD-derived genetic factors that contribute to type 1 diabetes are named Idd (insulin-dependent diabetes) loci. To date, the biological functions of the majority of the Idd loci remain unknown. We have previously reported that resistance of NOD immature thymocytes to depletion by dexamethazone (Dxm) maps to the Idd6 locus. Herein, we refine this phenotype using a time-course experiment of apoptosis induction upon Dxm treatment. We confirm that the Idd6 region controls apoptosis resistance in immature thymocytes. Moreover, we establish reciprocal Idd6 congenic NOD and B6 strains to formally demonstrate that the Idd6 congenic region mediates restoration of the apoptosis resistance phenotype. Analysis of the Idd6 congenic strains indicates that a 3-cM chromosomal region located within the distal part of the Idd6 region controls apoptosis resistance in NOD immature thymocytes. Together, these data support the hypothesis that resistance to Dxm-induced apoptosis in NOD immature thymocytes is controlled by a genetic factor within the region that also contributes to type 1 diabetes pathogenesis. We propose that the diabetogenic effect of the Idd6 locus is exerted at the level of the thymic selection process.
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16.
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17.
  • Bjorklund, A., et al. (författare)
  • Glucose-induced Ca2+ (i) abnormalities in human pancreatic islets - Important role of overstimulation
  • 2000
  • Ingår i: Diabetes. - 0012-1797 .- 1939-327X. ; 49:11, s. 1840-1848
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic hyperglycemia desensitizes beta -cells to glucose. To further define the mechanisms behind desensitization and the role of overstimulation, we tested human pancreatic islets for the effects of long-term elevated glucose levels on cytoplasmic free Ca2+ concentration ([Ca2+](i)) and its relationship to overstimulation. Islets were cultured for 48 h with 5.5 or 27 mmol/l glucose. Culture with 27 mmol/l glucose obliterated postculture insulin responses to 27 mmol/l glucose. This desensitization was specific for glucose versus arginine, Desensitization was accompanied by three major [Ca2+](i) abnormalities: 1) elevated basal [Ca2+](i),) loss of a glucose-induced rise in [Ca2+](i) and 3) perturbations of oscillatory activity with a decrease in glucose-induced slow oscillations (0.2-0.5 min(-1)). Coculture with 0.3 mmol/l diazoxide was performed to probe the role of overstimulation. Neither glucose nor diazoxide affected islet glucose utilization or oxidation, Coculture with diazoxide and 27 mmol/l glucose significantly (P < 0.05) restored postculture insulin responses to glucose and lowered basal [Ca2+](i) and normalized glucose-induced oscillatory activity. However, diazoxide completely failed to revive an increase in [Ca2+](i) during postculture glucose stimulation. In conclusion, desensitization of glucose-induced insulin secretion in human pancreatic islets is induced in parallel with major glucose-specific [Ca2+](i) abnormalities. Overstimulation is an important but not exclusive factor behind [Ca2+](i) abnormalities.
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18.
  • Bohlooly-Yeganeh, Mohammad, 1966, et al. (författare)
  • Growth hormone overexpression in the central nervous system results in hyperphagia-induced obesity associated with insulin resistance and dyslipidemia.
  • 2005
  • Ingår i: Diabetes. - : American Diabetes Association Inc.. - 0012-1797 .- 1939-327X. ; 54:1, s. 51-62
  • Tidskriftsartikel (refereegranskat)abstract
    • It is well known that peripherally administered growth hormone (GH) results in decreased body fat mass. However, GH-deficient patients increase their food intake when substituted with GH, suggesting that GH also has an appetite stimulating effect. Transgenic mice with an overexpression of bovine GH in the central nervous system (CNS) were created to investigate the role of GH in CNS. This study shows that overexpression of GH in the CNS differentiates the effect of GH on body fat mass from that on appetite. The transgenic mice were not GH-deficient but were obese and showed increased food intake as well as increased hypothalamic expression of agouti-related protein and neuropeptide Y. GH also had an acute effect on food intake following intracerebroventricular injection of C57BL/6 mice. The transgenic mice were severely hyperinsulinemic and showed a marked hyperplasia of the islets of Langerhans. In addition, the transgenic mice displayed alterations in serum lipid and lipoprotein levels and hepatic gene expression. In conclusion, GH overexpression in the CNS results in hyperphagia-induced obesity indicating a dual effect of GH with a central stimulation of appetite and a peripheral lipolytic effect.
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19.
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20.
  • Cabric, Sanja, et al. (författare)
  • Islet Surface Heparinization Prevents the Instant-Blood Mediated Inflammatory Reaction in Islet Transplantation
  • 2007
  • Ingår i: Diabetes. - : American Diabetes Association Inc.. - 0012-1797 .- 1939-327X. ; 56:8, s. 2008-2015
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE—In clinical islet transplantation, the instant blood-mediated inflammatory reaction (IBMIR) is a major factor contributing to the poor initial engraftment of the islets. This reaction is triggered by tissue factor and monocyte chemoattractant protein (MCP)-1, expressed by the transplanted pancreatic islets when the islets come in contact with blood in the portal vein. All currently identified systemic inhibitors of the IBMIR are associated with a significantly increased risk of bleeding or other side effects. To avoid systemic treatment, the aim of the present study was to render the islet graft blood biocompatible by applying a continuous heparin coating to the islet surface.RESEARCH DESIGN AND METHODS—A biotin/avidin technique was used to conjugate preformed heparin complexes to the surface of pancreatic islets. This endothelial-like coating was achieved by conjugating barely 40 IU heparin per full-size clinical islet transplant.RESULTS—Both in an in vitro loop model and in an allogeneic porcine model of clinical islet transplantation, this heparin coating provided protection against the IBMIR. Culturing heparinized islets for 24 h did not affect insulin release after glucose challenge, and heparin-coated islets cured diabetic mice in a manner similar to untreated islets.CONCLUSIONS—This novel pretreatment procedure prevents intraportal thrombosis and efficiently inhibits the IBMIR without increasing the bleeding risk and, unlike other pretreatment procedures (e.g., gene therapy), without inducing acute or chronic toxicity in the islets.
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