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Ion Channels of the Islets in Type 2 Diabetes.

ABSTRACT: Ca²⁺ is an essential signal for pancreatic ?-cell function. Ca²⁺ plays critical roles in numerous ?-cell pathways such as insulin secretion, transcription, metabolism, endoplasmic reticulum function, and the stress response. Therefore, ?-cell Ca²⁺ handling is tightly controlled. At the plasma membrane, Ca²⁺ entry primarily occurs through voltage-dependent Ca²⁺ channels. Voltage-dependent Ca²⁺ channel activity is dependent on orchestrated fluctuations in the plasma membrane potential or voltage, which are mediated via the activity of many ion channels. During the pathogenesis of type 2 diabetes the ?-cell is exposed to stressful conditions, which result in alterations of Ca²⁺ handling. Some of the changes in ?-cell Ca²⁺ handling that occur under stress result from perturbations in ion channel activity, expression or localization. Defective Ca²⁺ signaling in the diabetic ?-cell alters function, limits insulin secretion and exacerbates hyperglycemia. In this review, we focus on the ?-cell ion channels that control Ca²⁺ handling and how they impact ?-cell dysfunction in type 2 diabetes.

SUBMITTER: Jacobson DA

PROVIDER: S-EPMC7720859 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Ion Channels of the Islets in Type 2 Diabetes.

Jacobson David A DA Shyng Show-Ling SL

Journal of molecular biology 20190830 5

Ca2+ is an essential signal for pancreatic β-cell function. Ca2+ plays critical roles in numerous β-cell pathways such as insulin secretion, transcription, metabolism, endoplasmic reticulum function, and the stress response. Therefore, β-cell Ca2+ handling is tightly controlled. At the plasma membrane, Ca2+ entry primarily occurs through voltage-dependent Ca2+ channels. Voltage-dependent Ca2+ channel activity is dependent on orche ...[more]

PMID: 31473158

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Project description:ObjectiveTo document the properties of the voltage-gated ion channels in human pancreatic alpha-cells and their role in glucagon release.Research design and methodsGlucagon release was measured from intact islets. [Ca(2+)](i) was recorded in cells showing spontaneous activity at 1 mmol/l glucose. Membrane currents and potential were measured by whole-cell patch-clamping in isolated alpha-cells identified by immunocytochemistry.ResultGlucose inhibited glucagon secretion from human islets; maximal inhibition was observed at 6 mmol/l glucose. Glucagon secretion at 1 mmol/l glucose was inhibited by insulin but not by ZnCl(2). Glucose remained inhibitory in the presence of ZnCl(2) and after blockade of type-2 somatostatin receptors. Human alpha-cells are electrically active at 1 mmol/l glucose. Inhibition of K(ATP)-channels with tolbutamide depolarized alpha-cells by 10 mV and reduced the action potential amplitude. Human alpha-cells contain heteropodatoxin-sensitive A-type K(+)-channels, stromatoxin-sensitive delayed rectifying K(+)-channels, tetrodotoxin-sensitive Na(+)-currents, and low-threshold T-type, isradipine-sensitive L-type, and omega-agatoxin-sensitive P/Q-type Ca(2+)-channels. Glucagon secretion at 1 mmol/l glucose was inhibited by 40-70% by tetrodotoxin, heteropodatoxin-2, stromatoxin, omega-agatoxin, and isradipine. The [Ca(2+)](i) oscillations depend principally on Ca(2+)-influx via L-type Ca(2+)-channels. Capacitance measurements revealed a rapid (<50 ms) component of exocytosis. Exocytosis was negligible at voltages below -20 mV and peaked at 0 mV. Blocking P/Q-type Ca(2+)-currents abolished depolarization-evoked exocytosis.ConclusionsHuman alpha-cells are electrically excitable, and blockade of any ion channel involved in action potential depolarization or repolarization results in inhibition of glucagon secretion. We propose that voltage-dependent inactivation of these channels underlies the inhibition of glucagon secretion by tolbutamide and glucose.

Project description:AimsThe transcriptome of different dissociated pancreatic islet cells has been described in enzymatically isolated islets in both health and disease. However, the isolation, culturing, and dissociation procedures likely affect the transcriptome profiles, distorting the biological conclusions. The aim of the current study was to characterize the cells of the islets of Langerhans from subjects with and without type 1 diabetes in a way that reflects the in vivo situation to the highest possible extent.MethodsIslets were excised using laser capture microdissection directly from frozen pancreatic tissue sections obtained from organ donors with (n = 7) and without (n = 8) type 1 diabetes. Transcriptome analysis of excised samples was performed using AmpliSeq. Consecutive pancreatic sections were used to estimate the proportion of beta-, alpha-, and delta cells using immunofluorescence and to examine the presence of CD31 positive endothelial regions using immunohistochemistry.ResultsThe proportion of beta cells in islets from subjects with type 1 diabetes was reduced to 0% according to both the histological and transcriptome data, and several alterations in the transcriptome were derived from the loss of beta cells. In total, 473 differentially expressed genes were found in the islets from subjects with type 1 diabetes. Functional enrichment analysis showed that several of the most upregulated gene sets were related to vasculature and angiogenesis, and histologically, vascular density was increased in subjects with type 1 diabetes. Downregulated in type 1 diabetes islets was the gene set epithelial mesenchymal transition.ConclusionA number of transcriptional alterations are present in islets from subjects with type 1 diabetes. In particular, several gene sets related to vasculature and angiogenesis are upregulated and there is an increased vascular density, suggesting an altered microvasculature in islets from subjects with type 1 diabetes. By studying pancreatic islets extracted directly from snap-frozen pancreatic tissue, this study reflects the in vivo situation to a high degree and gives important insights into islet pathophysiology in type 1 diabetes.

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Ion Channels of the Islets in Type 2 Diabetes.

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Ion Channels of the Islets in Type 2 Diabetes.

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