Electrical activity plays a pivotal role in glucose-stimulated insulin secretion from pancreatic -cells. Recent findings have shown that the electrophysiological characteristics of human -cells differ from their rodent counterparts. We show that the electrophysiological responses in human -cells to a range of ion channels antagonists are heterogeneous. In some cells, inhibition of small-conductance potassium currents has no effect on action potential firing, while it increases the firing frequency dramatically in other cells. Sodium channel block can sometimes reduce action potential amplitude, sometimes abolish electrical activity, and in some cells even change spiking electrical activity to rapid bursting. We show that, in contrast to L-type -channels, P/Q-type -currents are not necessary for action potential generation, and, surprisingly, a P/Q-type -channel antagonist even accelerates action potential firing. By including SK-channels and dynamics in a previous mathematical model of electrical activity in human -cells, we investigate the heterogeneous and nonintuitive electrophysiological responses to ion channel antagonists, and use our findings to obtain insight in previously published insulin secretion measurements. Using our model we also study paracrine signals, and simulate slow oscillations by adding a glycolytic oscillatory component to the electrophysiological model. The heterogenous electrophysiological responses in human -cells must be taken into account for a deeper understanding of the mechanisms underlying insulin secretion in health and disease, and as shown here, the interdisciplinary combination of experiments and modeling increases our understanding of human -cell physiology.

Loss of first-phase insulin secretion is an early sign of developing type 2 diabetes (T2D). Ca2+ entry through voltage-gated L-type Ca2+ channels triggers exocytosis of insulin-containing granules in pancreatic β cells and is required for the postprandial spike in insulin secretion. Using high-resolution microscopy, we have identified a subset of docked insulin granules in human β cells and rat-derived clonal insulin 1 (INS1) cells for which localized Ca2+ influx triggers exocytosis with high probability and minimal latency. This immediately releasable pool (IRP) of granules, identified both structurally and functionally, was absent in β cells from human T2D donors and in INS1 cells cultured in fatty acids that mimic the diabetic state. Upon arrival at the plasma membrane, IRP granules slowly associated with 15 to 20 L-type channels. We determined that recruitment depended on a direct interaction with the synaptic protein Munc13, because expression of the II–III loop of the channel, the C2 domain of Munc13-1, or of Munc13-1 with a mutated C2 domain all disrupted L-type channel clustering at granules and ablated fast exocytosis. Thus, rapid insulin secretion requires Munc13-mediated recruitment of L-type Ca2+ channels in close proximity to insulin granules. Loss of this organization underlies disturbed insulin secretion kinetics in T2D.

Non-invasive continuous glucose monitoring (NI-CGM) sensors are still at an early stage of development, but, in the near future, they could become particularly appealing in diabetes management. Solianis Monitoring AG (Zurich, Switzerland) has proposed an approach for NI-CGM based on a multi-sensor concept, embedding primarily dielectric spectroscopy and optical sensors. This concept requires a mathematical model able to estimate glucose levels from the 150 channels directly measured through the Multisensor. A static multivariate linear regression model (with order and parameters common to the entire population of subjects) was proposed for such a scope (Caduff et al., Biosens Bioelectron 26:3794-3800, 2011). The aim of this work is to evaluate the accuracy in the estimation of glucose levels and trends that the NI-CGM Multisensor platform can achieve by exploiting different techniques for model identification, namely, ordinary least squares, subset variable selection, partial least squares and least absolute shrinkage and selection operator (LASSO). Data collected in human beings monitored for a total of 45 study days were used for model identification and model test. Several metrics of standard use in the diabetes scientific community to measure point and clinical accuracy of glucose sensors were used to assess the models. Results indicate that the LASSO technique is superior to the others shrinking many channel weights to zero thus leading to smoother glucose profiles and resulting in a more robust model to possible artifacts in the Multisensor data. Although, as expected, the performance of the NI-CGM system with the LASSO model is not yet comparable with that of enzyme-based needle glucose sensors, glucose trends are satisfactorily estimated. Considering the non-invasive nature of the multi-sensor platform, this result can have an immediate impact in the current clinical practice, e.g., to integrate sparse self-monitoring of blood glucose data with an indication of the glucose trend to aid the diabetic patient in dealing with, or even preventing in the short time scale, the threats of critical events such as hypoglycaemia.

Aim To evaluate the change in insulin sensitivity, β‐cell function and glucose absorption after 28 days of treatment with high and low doses of SAR425899, a novel dual glucagon‐like peptide‐1 receptor/glucagon receptor agonist, versus placebo. Materials and Methods Thirty‐six overweight to obese subjects with type 2 diabetes were randomized to receive daily subcutaneous administrations of low‐dose SAR425899 (0.03, 0.06 and 0.09 mg) and high‐dose SAR425899 (0.06, 0.12 and 0.18 mg) or placebo for 28 days; dose escalation occurred after days 7 and 14. Mixed meal tolerance tests were conducted before treatment (day −1) and on days 1 and 28. Oral glucose and C‐peptide minimal models were used to quantify metabolic indices of insulin sensitivity, β‐cell responsiveness and glucose absorption. Results With low‐dose SAR425899, high‐dose SAR425899 and placebo, β‐cell function from day −1 to day 28 increased by 163%, 95% and 23%, respectively. The change in area under the curve for the rate of meal glucose appearance between 0 and 120 minutes was −32%, −20% and 8%, respectively. Conclusions After 28 days of treatment, SAR425899 improved postprandial glucose control by significantly enhancing β‐cell function and slowing glucose absorption rate.

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