Glucose-responsive beta cells in islets isolated from a patient with long-standing type 1 diabetes mellitus

Walker, Jonathan N.; Johnson, Paul; Shigeto, Makoto; Hughes, Stephen J.; Clark, Anne; Rorsman, Patrik

doi:10.1007/s00125-010-1930-6

Cited by 12 publications

(10 citation statements)

References 9 publications

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“…These findings are consistent with our findings in α cells in the STZ-induced diabetes mouse model. Diabetes development in the STZ-treated mouse model (8) or in patients with T1D (36) is associated with similar inflammatory processes in the islets (i.e., insulitis), wherein cytotoxic T cells are recruited and release inflammatory cytokines (26) that can be predicted to perturb ion channels in α cells, perhaps in a manner similarly observed in this study.…”

Section: Discussionsupporting

confidence: 55%

In Situ Electrophysiological Examination of Pancreatic α Cells in the Streptozotocin-Induced Diabetes Model, Revealing the Cellular Basis of Glucagon Hypersecretion

et al. 2013

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Early-stage type 1 diabetes (T1D) exhibits hyperglucagonemia by undefined cellular mechanisms. Here we characterized α-cell voltage-gated ion channels in a streptozotocin (STZ)-induced diabetes model that lead to increased glucagon secretion mimicking T1D. GYY mice expressing enhanced yellow fluorescence protein in α cells were used to identify α cells within pancreas slices. Mice treated with lowdose STZ exhibited hyperglucagonemia, hyperglycemia, and glucose intolerance, with 71% reduction of β-cell mass. Although α-cell mass of STZ-treated mice remained unchanged, total pancreatic glucagon content was elevated, coinciding with increase in size of glucagon granules. Pancreas tissue slices enabled in situ examination of α-cell electrophysiology. α cells of STZ-treated mice exhibited the following: 1) increased exocytosis (serial depolarization-induced capacitance), 2) enhanced voltage-gated Na+ current density, 3) reduced voltage-gated K+ current density, and 4) increased action potential (AP) amplitude and firing frequency. Hyperglucagonemia in STZ-induced diabetes is thus likely due to increased glucagon content arising from enlarged glucagon granules and increased AP firing frequency and amplitude coinciding with enhanced Na+ and reduced K+ currents. These alterations may prime α cells in STZ-treated mice for more glucagon release per cell in response to low glucose stimulation. Thus, our study provides the first insight that STZ treatment sensitizes release mechanisms of α cells.

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Section: Discussionsupporting

confidence: 55%

In Situ Electrophysiological Examination of Pancreatic α Cells in the Streptozotocin-Induced Diabetes Model, Revealing the Cellular Basis of Glucagon Hypersecretion

et al. 2013

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“…Most of the studies show that besides the loss in beta cell mass in type 1 diabetes, both rodent and human/NHP islets display an increase in alpha and delta cell mass and alpha cell proliferation [6,[103][104][105]. Surprisingly, studies have suggested the presence of glucose-responsive beta cells in patients with long standing type 1 diabetes [106,107].…”

Section: Islet Structure-function and Diabetesmentioning

confidence: 99%

New insights into the architecture of the islet of Langerhans: a focused cross-species assessment

et al. 2015

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The human genome project and its search for factors underlying human diseases has fostered a major human research effort. Therefore, unsurprisingly, in recent years we have observed an increasing number of studies on human islet cells, including disease approaches focusing on type 1 and type 2 diabetes. Yet, the field of islet and diabetes research relies on the legacy of rodent-based investigations, which have proven difficult to translate to humans, particularly in type 1 diabetes. Whole islet physiology and pathology may differ between rodents and humans, and thus a comprehensive cross-species as well as species-specific view on islet research is much needed. In this review we summarise the current knowledge of interspecies islet cytoarchitecture, and discuss its potential impact on islet function and future perspectives in islet pathophysiology research.

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“…Currently there are no reliable ways to image the organ such that the cellular and molecular events associated with islet inflammation can be studied in living individuals, although efforts are continuing towards the achievement of this goal . Thus, the limited information which is available has been derived from samples recovered post‐mortem from patients with T1DM , from glands recovered at the time of organ donation or from surgical biopsy samples recovered from living patients . Unfortunately, even among these valuable resources, there are important issues which militate against a full understanding of the disease pathology.…”

Section: Introductionmentioning

confidence: 99%

Islet inflammation in human type 1 diabetes mellitus

2014

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Type 1 diabetes mellitus (T1DM) is caused by the selective deletion of pancreatic b-cells in response to an assault mounted within the pancreas by infiltrating immune cells. However, this apparently clear and focussed annunciation conceals a stark reality in which the cellular and molecular events leading to b-cell loss remain poorly understood in humans. This reflects the difficulty of studying these processes in living individuals and the fact that, using pathological specimens, islet inflammation has been analysed in fewer than 200 recent-onset cases of T1DM worldwide, over the past century. Nevertheless, insights have been gained and the composition of the islet infiltrate is being disclosed. This is shown to be primarily lymphocytic in nature, with populations of both CD81 and CD41 T cells displaying an autoreactivity against specific islet antigenic peptides. The T cells are often accompanied by influent CD201 B cells, although new data imply that the proportions of these individual cell types vary and that patients fall into at least two distinct categories having either a hyper-immune (CD20Hi) or a pauci-immune (CD20Lo) phenotype. The overall rate of b-cell decline appears to correlate with these two phenotypes such that hyperimmune patients lose b-cells more quickly and tend to develop disease at an earlier age than those with the pauciimmune profile. In this article, we review the evidence which underpins our current understanding of the aetiology of T1DM and highlight both the established features as well as areas of on-going ambiguity and debate. V C 2014 IUBMB Life, 66(11):723-734, 2014

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Glucose-responsive beta cells in islets isolated from a patient with long-standing type 1 diabetes mellitus

Cited by 12 publications

References 9 publications

In Situ Electrophysiological Examination of Pancreatic α Cells in the Streptozotocin-Induced Diabetes Model, Revealing the Cellular Basis of Glucagon Hypersecretion

In Situ Electrophysiological Examination of Pancreatic α Cells in the Streptozotocin-Induced Diabetes Model, Revealing the Cellular Basis of Glucagon Hypersecretion

New insights into the architecture of the islet of Langerhans: a focused cross-species assessment

Islet inflammation in human type 1 diabetes mellitus

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