Beta-cell Activity and Destruction in Type 1 Diabetes

Karlsson, F. Anders; Berne, Christian; Björk, Erik; Kullin, M; Li, Z; Y, J; Schölin, Anna; Zhao, Liling

doi:10.1517/03009734000000056

Cited by 16 publications

(8 citation statements)

References 56 publications

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“…It is tempting to speculate that the selective destruction of the ␤-cells in type 1 diabetes, although the autoantigen GAD65 is expressed in several other cells (Tillakaratne et al, 1995), is a consequence of the functional significance of GABAergic processes within the islet and the high rate of SLMV exocytosis. Intriguingly, pharmacological procedures that hyperpolarize the ␤-cell and thus can be expected to inhibit exocytosis of the SLMVs have been reported to reduce GAD65 presentation and exert a ␤-cell protective action in type 1 diabetes (Karlsson et al, 2000). In addition, altered paracrine signaling in the islet may be a causative factor for the increase in glucagon secretion that contributes to the metabolic disturbances in both type 1 and type 2 diabetes (Krentz and Nattrass, 1997;Shah et al, 2000).…”

Section: Significance To Diabetesmentioning

confidence: 99%

Regulated Exocytosis of GABA-containing Synaptic-like Microvesicles in Pancreatic β-cells

Braun

Wendt

Birnir

et al. 2004

The Journal of General Physiology

121

149

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We have explored whether γ-aminobutyric acid (GABA) is released by regulated exocytosis of GABA-containing synaptic-like microvesicles (SLMVs) in insulin-releasing rat pancreatic β-cells. To this end, β-cells were engineered to express GABAA-receptor Cl−-channels at high density using adenoviral infection. Electron microscopy indicated that the average diameter of the SLMVs is 90 nm, that every β-cell contains ∼3,500 such vesicles, and that insulin-containing large dense core vesicles exclude GABA. Quantal release of GABA, seen as rapidly activating and deactivating Cl−-currents, was observed during membrane depolarizations from −70 mV to voltages beyond −40 mV or when Ca2+ was dialysed into the cell interior. Depolarization-evoked GABA release was suppressed when Ca2+ entry was inhibited using Cd2+. Analysis of the kinetics of GABA release revealed that GABA-containing vesicles can be divided into a readily releasable pool and a reserve pool. Simultaneous measurements of GABA release and cell capacitance indicated that exocytosis of SLMVs contributes ∼1% of the capacitance signal. Mathematical analysis of the release events suggests that every SLMV contains 0.36 amol of GABA. We conclude that there are two parallel pathways of exocytosis in pancreatic β-cells and that release of GABA may accordingly be temporally and spatially separated from insulin secretion. This provides a basis for paracrine GABAergic signaling within the islet.

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Section: Significance To Diabetesmentioning

confidence: 99%

Regulated Exocytosis of GABA-containing Synaptic-like Microvesicles in Pancreatic β-cells

Braun

Wendt

Birnir

et al. 2004

The Journal of General Physiology

121

149

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“…Typically, it is thought that as few as 15–20% of β cells remain at the time of the first clinical symptoms of T1D [1,2]. Left unchecked, this residual islet cell function/mass is generally short‐lived due to continued immune‐mediated β cell death [3].…”

Section: Introductionmentioning

confidence: 99%

Developing combination immunotherapies for type 1 diabetes: recommendations from the ITN–JDRF Type 1 Diabetes Combination Therapy Assessment Group

Matthews

Staeva

Bernstein

et al. 2010

Clinical and Experimental Immunology

108

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SummaryLike many other complex human disorders of unknown aetiology, autoimmune-mediated type 1 diabetes may ultimately be controlled via a therapeutic approach that combines multiple agents, each with differing modes of action. The numerous advantages of such a strategy include the ability to minimize toxicities and realize synergies to enhance and prolong efficacy. The recognition that combinations might offer far-reaching benefits, at a time when few single agents have yet proved themselves in well-powered trials, represents a significant challenge to our ability to conceive and implement rational treatment designs. As a first step in this process, the Immune Tolerance Network, in collaboration with the Juvenile Diabetes Research Foundation, convened a Type 1 Diabetes Combination Therapy Assessment Group, the recommendations of which are discussed in this Perspective paper.

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“…Development of an autoimmune disease such as IDDM requires expression of a number of immune-related genes such as those which encode cytokines (tumour necrosis factor alpha (TNF ) and interleukin (IL)-1; Rabinovitch & Suarez-Pinzon 1998), chemokines (Bradley et al 1999), adhesion molecules (vascular cell adhesion molecule-1 and intercellular cell adhesion molecule (ICAM; Bradley et al 1999), costimulatory molecules (Karlsson et al 2000) and cytotoxic enzymes (inducible nitric oxide synthase (iNOS) and cyclo-oxygenase (COX)-2; Eizirik et al 1996). These proteins have crucial roles in the activation, migration and effector functions of inflammatory cells.…”

Section: Introductionmentioning

confidence: 99%

NFkappaB1 (p50)-deficient mice are not susceptible to multiple low-dose streptozotocin-induced diabetes

Mabley¹,

Haskó²,

Liaudet³

et al. 2002

Journal of Endocrinology

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Insulin-dependent diabetes mellitus (IDDM) is a disease characterized by the autoimmune destruction of the pancreatic -cells, which requires the expression of a number of immune-related genes including major histocompatibility complex proteins, cytokines, chemokines, and cytotoxic enzymes, many of which are regulated by the transcription factor, NF B. Inhibition of the entire NF B family of transcription factors may be harmful, as these factors are involved in many normal physiological processes. However, identifying and targeting specific NF B subunits critical for the pathogenesis of disease may prove to be valuable in designing new therapeutic strategies. To assess the potential role of the NF B subunit, p50, in the development of IDDM, mice with gene disruption for NF B (p50) were investigated for susceptibility to IDDM. We found that p50-deficient mice were fully resistant against multiple low-dose streptozotocin-induced diabetes, a model of diabetes with a strong autoimmune component. The site of involvement of NF B (p50) lies at an early, critical juncture of immune activation and proinflammatory mediator production, because: (1) isolated islets of Langerhans from NF B (p50)-deficient mice were not protected from the islet dysfunction induced by in vitro application of proinflammatory cytokines; (2) p50-deficient mice were not resistant to diabetes induced by a single high dose of streptozotocin, a model with a large oxidant component and no autoimmune involvement; and (3) diabetes induced up-regulation of nitric oxide and interleukin-12 was blocked in the p50-deficient mice. Our data suggest that NF B (p50) has an essential role in the development of autoimmune diabetes. Selective therapeutic blockade of this subunit may be beneficial in preventing IDDM.

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Beta-cell Activity and Destruction in Type 1 Diabetes

Cited by 16 publications

References 56 publications

Regulated Exocytosis of GABA-containing Synaptic-like Microvesicles in Pancreatic β-cells

Regulated Exocytosis of GABA-containing Synaptic-like Microvesicles in Pancreatic β-cells

Developing combination immunotherapies for type 1 diabetes: recommendations from the ITN–JDRF Type 1 Diabetes Combination Therapy Assessment Group

NFkappaB1 (p50)-deficient mice are not susceptible to multiple low-dose streptozotocin-induced diabetes

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