Regulation of Insulin Secretion in Human Pancreatic Islets
Abstract
Pancreatic β cells secrete insulin, the body's only hormone capable of lowering plasma glucose levels. Impaired or insufficient insulin secretion results in diabetes mellitus. The β cell is electrically excitable; in response to an elevation of glucose, it depolarizes and starts generating action potentials. The electrophysiology of mouse β cells and the cell's role in insulin secretion have been extensively investigated. More recently, similar studies have been performed on human β cells. These studies have revealed numerous and important differences between human and rodent β cells. Here we discuss the properties of human pancreatic β cells: their glucose sensing, the ion channel complement underlying glucose-induced electrical activity that culminates in exocytotic release of insulin, the cellular control of exocytosis, and the modulation of insulin secretion by circulating hormones and locally released neurotransmitters. Finally, we consider the pathophysiology of insulin secretion and the interactions between genetics and environmental factors that may explain the current diabetes epidemic.
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The primary secretory pathway of glucose-stimulated insulin secretion is associated with complex patterns of electrical activity across the plasma membrane, which allow Ca2+ ions to enter the cell and trigger the secretory machinery.
“The primary secretory pathway of glucose-stimulated insulin secretion is associated with complex patterns of electrical activity across the plasma membrane, which allow Ca2+ ions to enter the cell and trigger the secretory machinery.”
From Mathematical Modelling of Endocrine Systems (2019) · cites this paper as [11]
Electrical activity in beta cells is coupled to cell metabolism, which acts as a glucose sensor by raising the intracellular ATP:ADP ratio, causing KATP channels to close, depolarising the membrane and driving it towards its threshold for action potential initiation.
“This electrical activity is coupled to cell metabolism, which acts as a glucose sensor by raising the intracellular ATP:ADP ratio, causing KATP channels to close, depolarising the membrane and driving it towards its threshold for action potential initiation [11].”
From Mathematical Modelling of Endocrine Systems (2019) · cites this paper as [11]
Adrenaline and somatostatin lead to transient repolarization and suppression of glucose-induced electrical activity in human β-cells.
“Adrenaline and somatostatin lead to transient repolarization and suppression of glucose-induced electrical activity (327, 568).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [568]
Human β-cell action potentials are triggered from a more negative membrane potential than mouse β-cells (-60 mV rather than -50 to -40 mV) and often overshoot, peaking above zero mV.
“The action potentials of human β-cells are also triggered from a more negative membrane potential in human than in mouse β-cells (-60 mV rather than -50 to -40 mV) and often overshoot, peaking at potentials above zero mV (568).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [568]
The action potentials of both mouse and human β-cells are short, ranging between 5 ms (human) and 30-40 ms (mouse).
“The action potentials of both mouse and human β-cells are short, ranging between 5 ms (human) and 30-40 ms (mouse) (568, 570).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [568]
Delayed rectifying K+ channels may not activate much during the human β-cell action potential, which lasts only about 5 ms.
“Thus, delayed rectifying K+ channels may not activate much during the human β-cell action potential, which lasts only ~5 ms (568).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [568]
Blocking SK channels with apamin, or the non-selective antagonist NS8593, results in membrane depolarization and action potential firing in human β-cells and stimulates insulin secretion.
“Blocking SK channels with apamin, or the non-selective antagonist NS8593, results in membrane depolarization and action potential firing in human β-cells (311) and stimulates insulin secretion (568).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [568]
Inhibition of inward rectifiers with Ba2+ (0.1 mM) or Cs+ (1 mM) in human β-cells exposed to glucose (6 mM) and tolbutamide (0.1 mM) results in membrane depolarization and stimulation of action potential firing.
“Inhibition of inward rectifiers with Ba2+ (0.1 mM) or Cs+ (1 mM) in human β-cells exposed to glucose (6 mM) and tolbutamide (0.1 mM) resulted in membrane depolarization and stimulation of action potential firing (568).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [568]
These tolbutamide-resistant inward currents are blocked by low concentrations of Ba2+ (100 μM) and Cs+ (1 mM).
“These currents were blocked by low concentrations of Ba2+ (100 μM) and Cs+ (1 mM).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [568]
The Ba2+-sensitive current in human β-cells displays strongly inward rectification and reverses at approximately -85 mV, close to EK.
“The Ba2+-sensitive current displayed strongly inward rectification and reversed at ~-85 mV, which is close to EK.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [568]
In human β-cells, hyperpolarizing voltage steps from a holding potential of -70 mV evoke progressively larger tolbutamide-resistant inward currents.
“In human β-cells, hyperpolarizing voltage steps from a holding potential of -70 mV evoked progressively larger tolbutamide-resistant inward currents (553, 568).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [568]
In human β-cells exposed to 6 mM glucose, carbachol evokes membrane depolarization (~5 mV) and increased action potential firing.
“Similarly, in human β-cells exposed to 6 mM glucose, carbachol evoked membrane depolarization (~5 mV) and increased action potential firing (568).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [568]
The smallest cell aggregates reported by the authors were ca. 200 microns in diameter; the typical human islet has a diameter of ca. 130 microns.
“The smallest cell aggregates reported by the authors were ca. 200 microns in diameter; the typical human islet has a diameter of ca. 130 microns176.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [176]
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- Authors
- Rorsman, P., & Braun, M.
- Affiliations
- University of Oxford (GB)
- University of Alberta (CA)
- Venue
- Annual Review of Physiology
- Publisher
- Annual Reviews
- Published
- 2013-02-10
- Volume
- 75
- Issue
- 1
- Pages
- 155-179
- ISSN
- 0066-4278 (ISSN-L)
- 1545-1585
- OpenAlex
- W2140402299
- Cited by
- 599
- References
- 134
- Citations by year
- 2026: 15 · 2025: 21 · 2024: 26 · 2023: 44 · 2022: 60 · 2021: 57 · 2020: 42 · 2019: 41 · 2018: 59 · 2017: 47 · 2016: 50 · 2015: 51 · 2014: 54 · 2013: 28 · 2012: 2
- FWCI
- 8.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annual Review of Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (095531/Z/11/Z, 095531)
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- insulin secretion, pancreatic beta cells, human beta cells, glucose detection, action potential, ion channels, exocytosis, neurotransmitters, circulating hormones, diabetes mellitus, genetic and environmental risk factors
- MeSH terms
- Insulin Secretion, Action Potentials, Diabetes Mellitus, Type 2, Glucose, Humans, Insulin, Ion Channels, Islets of Langerhans, Insulin-Secreting Cells
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