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A biophysical model of electrical activity in human β-cells.

ABSTRACT: Electrical activity in pancreatic β-cells plays a pivotal role in glucose-stimulated insulin secretion by coupling metabolism to calcium-triggered exocytosis. Mathematical models based on rodent data have helped in understanding the mechanisms underlying the electrophysiological patterns observed in laboratory animals. However, human β-cells differ in several aspects, and in particular in their electrophysiological characteristics, from rodent β-cells. Hence, from a clinical perspective and to obtain insight into the defects in insulin secretion relevant for diabetes mellitus, it is important to study human β-cells. This work presents the first mathematical model of electrical activity based entirely on published ion channel characteristics of human β-cells. The model reproduces satisfactorily a series of experimentally observed patterns in human β-cells, such as spiking and rapid bursting electrical activity, and their response to a range of ion channel antagonists. The possibility of Human Ether-a-Go-Go-related- and leak channels as drug targets for diabetes treatment is discussed based on model results.

SUBMITTER: Pedersen MG

PROVIDER: S-EPMC2980734 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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A biophysical model of electrical activity in human β-cells.

Pedersen Morten Gram MG

Biophysical journal 20101101 10

Electrical activity in pancreatic β-cells plays a pivotal role in glucose-stimulated insulin secretion by coupling metabolism to calcium-triggered exocytosis. Mathematical models based on rodent data have helped in understanding the mechanisms underlying the electrophysiological patterns observed in laboratory animals. However, human β-cells differ in several aspects, and in particular in their electrophysiological characteristics, from rodent β-cells. Hence, from a clinical perspective and to o ...[more]

PMID: 21081067

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Project description:State of the art mathematical models are currently used to bridge the gap between basic research conducted in the laboratory and preclinical research conducted on large animals, which ultimately paves the way for clinical translation. In this regard, there is a great need for models that can be used alongside experiments for in-depth investigation and validation. One such experimental model is the porcine atrium, which is commonly used to study the mechanisms of onset and control of atrial fibrillation in the context of its surgical management. However, a mathematical model of pig atria is lacking. In this paper, we present the first ionically detailed mathematical model of porcine atrial electrophysiology, at body temperature. The model includes 12 ionic currents, 4 of which were designed based on experimental patch-clamp data directly obtained from literature. The formulations for the other currents are adopted from the human atrial model, and modified for porcine specificity based on our measured restitution data for different action potential characteristics: resting membrane potential, action potential amplitude, maximum upstroke velocity and action potential duration and different levels of membrane voltage repolarization. The intracellular Ca 2+ dynamics follows the Luo-Rudy formulation for guinea pig ventricular cardiomyocytes. The resulting model represents "normal" cells which are formulated as a system of ordinary differential equations. We extend our model to two dimensions to obtain plane wave propagation in tissue with a velocity of 0.58 m/s and a wavelength of 8 cm. The wavelength reduces to 5 cm when the tissue is paced at 200 ms. Using S1-S2 cross-field protocol, we demonstrate in an 11.26 cm square simulation domain, the ability to initiate single spiral waves (rotation period ≃ 180 ms) that remain stable for more than 40 s. The spiral tip exhibits hypermeander. In agreement with previous experimental results using pig atria, our model shows that early repolarization is primarily driven by a calcium-mediated chloride current, I ClCa , which is completely inactivated at high pacing frequencies. This is a condition that occurs only in porcine atria. Furthermore, the model shows spatiotemporal chaos with reduced repolarization.

Project description:Background Previous studies have shown that patients with hypercholesterolemia experience elevated levels of oxidized LDL (oxLDL), a molecule which triggers inflammation and collagenase activity. In this study we discovered novel mechanistic effects of oxLDL on tendon cells and the mediators regulating matrix remodeling by analyzing the expression and activity of related proteins and enzymes. These effects may contribute to tendon damage in patients with high cholesterol. Methods Isolated human tendon cells (male and female donors age 28 ± 1.4 age 37 ± 5.7, respectively) were incubated in the presence or absence of oxLDL. The influence of oxLDL on the expression level of key mRNA and proteins was examined using real time quantitative PCR, ELISA and Western blots. The activities of enzymes relevant to collagen synthesis and breakdown (lysyl oxidase and matrix metalloproteinases) were quantified using fluorometry. Finally, the isolated human tendon cells in a 3D construct were exposed to combinations of oxLDL and TGF-β to examine their interacting effects on collagen matrix remodeling. Results The one-way ANOVA of gene expression indicates that key mRNAs including TGFB, COL1A1, DCN, and LOX were significantly reduced in human tendon cells by oxLDL while MMPs were increased. The oxLDL reduced the activity of LOX at 50 µg/ml, whereas conversely MMP activities were induced at 25 µg/ml (P ≤ 0.01). COL1A1 synthesis and TGF-β secretion were also inhibited (P ≤ 0.05). Adding recombinant TGF-β reversed the effects of oxLDL on the expression of collagens and LOX. OxLDL also impaired collagen matrix remodeling (P ≤ 0.01), and adding TGF-β restored the native phenotype. Conclusion Exposure to oxLDL in patients with hypercholesterolemia may adversely affect the mechanical and structural properties of tendon tissue through a direct action of oxLDL on tendon cells, including impairment of TGF-β expression. This impairment leads to disturbed matrix remodeling and synthesis, thereby potentially leading to increased risk of acute or chronic tendon injury. Our discovery may provide an opportunity for developing effective treatments for tendon injury in hypercholesterolemia patients by targeting the TGF-β pathway. Supplementary Information The online version contains supplementary material available at 10.1186/s12891-023-06308-x.

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A biophysical model of electrical activity in human β-cells.

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A biophysical model of electrical activity in human β-cells.

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