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Träfflista för sökning "L773:0012 1797 OR L773:1939 327X srt2:(2000-2004)"

Sökning: L773:0012 1797 OR L773:1939 327X > (2000-2004)

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1.
  • Barg, Sebastian, et al. (författare)
  • A subset of 50 secretory granules in close contact with L-type Ca2+ channels accounts for first-phase insulin secretion in mouse beta-cells.
  • 2002
  • Ingår i: Diabetes. - 0012-1797 .- 1939-327X. ; 51 Suppl 1, s. S74-82
  • Tidskriftsartikel (refereegranskat)abstract
    • Capacitance measurements were applied to mouse pancreatic beta-cells to elucidate the cellular mechanisms underlying biphasic insulin secretion. We report here that only <50 of the beta-cell's >10,000 granules are immediately available for release. The releasable granules tightly associate with the voltage-gated alpha(1C) Ca(2+) channels, and it is proposed that the release of these granules accounts for first-phase insulin secretion. Subsequent replenishment of the releasable pool by priming of previously nonreleasable granules is required for second-phase insulin secretion. The latter reaction depends on intragranular acidification due to the concerted action of granular bafilomycin-sensitive v-type H(+)-ATPase and 4,4-diisothiocyanostilbene-2,2-disulfonate--blockable ClC-3 Cl(-) channels. Lowering the cytoplasmic ATP/ADP ratio prevents granule acidification, granule priming, and refilling of the releasable pool. The latter finding provides an explanation to the transient nature of insulin secretion elicited by, for example, high extracellular K(+) in the absence of metabolizable fuels.
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2.
  • 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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3.
  • 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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4.
  • 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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5.
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6.
  • Ek, I, et al. (författare)
  • A unique defect in the regulation of visceral fat cell lipolysis in the polycystic ovary syndrome as an early link to insulin resistance
  • 2002
  • Ingår i: Diabetes. - : American Diabetes Association Inc.. - 1939-327X .- 0012-1797. ; 51:2, s. 484-492
  • Tidskriftsartikel (refereegranskat)abstract
    • The etiology of polycystic ovary syndrome (PCOS) is unknown. However, PCOS has a strong resemblance to the insulin resistance (metabolic) syndrome, where an increased rate of visceral fat cell lipolysis is believed to play a pathophysiological role. We hypothesized that primary defects in visceral lipolysis might also exist in PCOS. Ten young, nonobese, and otherwise healthy PCOS women were compared with 13 matched control women. In vitro lipolysis regulation and stoichiometric properties of the final step in lipolysis activation, namely the protein kinase A (PKA)-hormone sensitive lipase (HSL) complex, were investigated in isolated visceral (i.e., omental) fat cells. Body fat distribution and circulating levels of insulin, glucose, and lipids were normal in PCOS women. However, in vivo insulin sensitivity was slightly decreased (P = 0.03). Catecholamine-induced adipocyte lipolysis was markedly (i.e., about twofold) increased in PCOS women due to changes at the postreceptor level, although there was no change in the antilipolytic properties of visceral fat cells. Western blot analyses of visceral adipose tissue showed twofold increased levels of the catalytic and the regulatory la components of PKA. In contrast, the regulatory RIIbeta component of PKA was almost 50% decreased in visceral adipose tissue in PCOS women. Recent studies on genetically modified mice have shown that a similar transition in the regulatory PKA units induces an increased lipolytic response to catecholamines. Further analysis showed that the level of HSL-short, an enzymatically inactive splice form of HSL, was decreased in PCOS (P < 0.01). The altered lipolysis in PCOS is different from that observed in visceral fat cells in the insulin resistance syndrome that occurs at the level of adrenergic receptors. We concluded that increased catecholamine-induced lipolysis in visceral fat cells may be due to unique alterations in the stoichiometric properties of the adipose PKA-HSL holoenzymes. This could be an early and possibly primary lipolysis defect in PCOS.
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7.
  • Graham, J, et al. (författare)
  • Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes.
  • 2002
  • Ingår i: Diabetes. - : American Diabetes Association Inc.. - 1939-327X .- 0012-1797. ; 51:5, s. 1346-1355
  • Tidskriftsartikel (refereegranskat)abstract
    • Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0-34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P = 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P = 0.03) and with INS VNTR (P = 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P = 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P = 0.04), and all four autoantibody markers (P = 0.004). The CTLA-4 3' end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development.
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8.
  • Holm, P, et al. (författare)
  • Interaction and association analysis of a type 1 diabetes susceptibility locus on chromosome 5q11-q13 and the 7q32 chromosomal region in Scandinavian families
  • 2004
  • Ingår i: Diabetes. - : American Diabetes Association Inc.. - 1939-327X .- 0012-1797. ; 53:6, s. 1584-1591
  • Tidskriftsartikel (refereegranskat)abstract
    • We have previously reported suggestive linkage to chromosome 5p13-q13 in type 1 diabetic families. ISL1, a transcription factor involved in pancreas development, maps to this region. Sequencing of the ISL1 gene in patients and control subjects identified seven single nucleotide polymorphisms (SNPs) and one microsatellite in noncoding regions. Four haplotypes formed by six of these SNPs and one microsatellite were associated with type 1 diabetes in Swedish families (P < 0.04). To identify possible interactions with the 5q11-q13 region, we applied pathway-restricted linkage analysis by analyzing for effects from regions encoding other transcription factors that are active during pancreas development and maintenance of insulin production. Linkage analysis allowing for interaction between 5q11q13 and 7q32 resulted in an increase of logarithm of odds from 2.2 to 5.3. This increase was estimated to correspond to a P value < 0.0016 using permutation. The transcription factor PAX4 is located at 7q32 and participates downstream of ISL1 in the transcription factor cascade critical to P-cell development. Association with type 1 diabetes was also observed using the transmission disequilibrium test for two haplotypes at the PAX4 locus (P < 0.05). We conclude that pathway-restricted linkage analysis assists in the identification of possible gene-gene interactions and that 5q11-q13 and 7q32 together constitute a significant susceptibility factor for type 1 diabetes.
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9.
  • Islam, M. Shahidul, et al. (författare)
  • The ryanodine receptor calcium channel of beta-cells : molecular regulation and physiological significance
  • 2002
  • Ingår i: Diabetes. - 0012-1797 .- 1939-327X. ; 51:5, s. 1299-1309
  • Tidskriftsartikel (refereegranskat)abstract
    • The list of Ca(2+) channels involved in stimulus-secretion coupling in beta-cells is increasing. In this respect the roles of the voltage-gated Ca(2+) channels and IP(3) receptors are well accepted. There is a lack of consensus about the significance of a third group of Ca(2+) channels called ryanodine (RY) receptors. These are large conduits located on Ca(2+) storage organelle. Ca(2+) gates these channels in a concentration- and time-dependent manner. Activation of these channels by Ca(2+) leads to fast release of Ca(2+) from the stores, a process called Ca(2+)-induced Ca(2+) release (CICR). A substantial body of evidence confirms that beta-cells have RY receptors. CICR by RY receptors amplifies Ca(2+) signals. Some properties of RY receptors ensure that this amplification process is engaged in a context-dependent manner. Several endogenous molecules and processes that modulate RY receptors determine the appropriate context. Among these are several glycolytic intermediates, long-chain acyl CoA, ATP, cAMP, cADPR, NO, and high luminal Ca(2+) concentration, and all of these have been shown to sensitize RY receptors to the trigger action of Ca(2+). RY receptors, thus, detect co-incident signals and integrate them. These Ca(2+) channels are targets for the action of cAMP-linked incretin hormones that stimulate glucose-dependent insulin secretion. In beta-cells some RY receptors are located on the secretory vesicles. Thus, despite their low abundance, RY receptors are emerging as distinct players in beta-cell function by virtue of their large conductance, strategic locations, and their ability to amplify Ca(2+) signals in a context-dependent manner.
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10.
  • Krook, Henrik, et al. (författare)
  • A distinct Th1 immune response precedes the described Th2 response in Islet xenograft rejection
  • 2002
  • Ingår i: Diabetes. - 0012-1797 .- 1939-327X. ; 51:1, s. 79-86
  • Tidskriftsartikel (refereegranskat)abstract
    • Previous studies using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) have demonstrated that islet xenograft rejection in mice is dominated by Th2-associated cytokines, i.e., interleukin (IL)-4 and IL-10. However, immunohistochemical stainings show that the morphological pattern in this model is more reminiscent of a delayed-type hypersensitivity (DTH) reaction, which is associated with a Th1 response. This study was designed to resolve the mechanisms of acute cellular xenograft rejection in rats transplanted with fetal porcine islet-like cell clusters (ICCs). Real-time quantitative RT-PCR was used to quantify the mRNA expression of cytokines in the grafts and lymph nodes, and the findings were related to the immunopathology of the rejecting grafts. By day 1, mRNA expression levels of IL-1 beta, IL-2, IL-12p40, interferon-gamma, and tumor necrosis factor-alpha were already induced in the lymph nodes. From days 3 to 12, an increasing amount of activated macrophages was seen in the grafts, whereas T- and NK-cells were fewer and mainly accumulated in the periphery of the grafts. Most of the ICCs were rejected by day 5. Transcripts of Th1-associated cytokines were dominant in both regional lymph nodes and in the grafts, with peak levels on days 3 and 5, respectively. The mRNA expression of IL-4 was increased on day 12, and it correlated with the infiltration of eosinophils and an increased level of xenoreactive IgG. The data presented indicate that an islet xenograft triggers a sequential activation of 1) a Th1-associated response characterized by graft destruction in a DTH-like reaction and then 2) a subsequent Th2-associated response characterized by increased levels of xenoreactive antibodies.
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