Release of insulin granules by simultaneous, high-speed correlative SICM-FCM

Exocytosis of peptides and steroids stored in a dense core vesicular (DCV) form is the final step of every secretory pathway, indispensable for the function of nervous, endocrine and immune systems. The lack of live imaging techniques capable of direct, label‐free visualisation of DCV release makes many aspects of the exocytotic process inaccessible to investigation. We describe the application of correlative scanning ion conductance and fluorescence confocal microscopy (SICM‐FCM) to study the exocytosis of individual granules of insulin from the top, nonadherent, surface of pancreatic β‐cells. Using SICM‐FCM, we were first to directly follow the topographical changes associated with physiologically induced release of insulin DCVs. This allowed us to report the kinetics of the full fusion of the insulin vesicle as well as the subsequent solubilisation of the released insulin crystal

Na+ current properties in islet α- and β-cells reflect cell-specific Scn3a and Scn9a expression

Key points α‐ and β‐cells express both Nav1.3 and Nav1.7 Na+ channels but in different relative amounts. The differential expression explains the different properties of Na+ currents in α‐ and β‐cells. Nav1.3 is the functionally important Na+ channel α subunit in both α‐ and β‐cells. Islet Nav1.7 channels are locked in an inactive state due to an islet cell‐specific factor. Mouse pancreatic β‐ and α‐cells are equipped with voltage‐gated Na+ currents that inactivate over widely different membrane potentials (half‐maximal inactivation (V0.5) at −100 mV and −50 mV in β‐ and α‐cells, respectively). Single‐cell PCR analyses show that both α‐ and β‐cells have Nav1.3 (Scn3) and Nav1.7 (Scn9a) α subunits, but their relative proportions differ: β‐cells principally express Nav1.7 and α‐cells Nav1.3. In α‐cells, genetically ablating Scn3a reduces the Na+ current by 80%. In β‐cells, knockout of Scn9a lowers the Na+ current by >85%, unveiling a small Scn3a‐dependent component. Glucagon and insulin secretion are inhibited in Scn3a−/− islets but unaffected in Scn9a‐deficient islets. Thus, Nav1.3 is the functionally important Na+ channel α subunit in both α‐ and β‐cells because Nav1.7 is largely inactive at physiological membrane potentials due to its unusually negative voltage dependence of inactivation. Interestingly, the Nav1.7 sequence in brain and islets is identical and yet the V0.5 for inactivation is >30 mV more negative in β‐cells. This may indicate the presence of an intracellular factor that modulates the voltage dependence of inactivation

Low Al-content n-type AlxGa1-xN layers with a high-electron-mobility grown by hot-wall metalorganic chemical vapor deposition

In this work, we demonstrate the capability of the hot-wall metalorganic\ua0chemical vapor deposition\ua0to deliver high-quality\ua0n-AlxGa1−xN (x\ua0= 0\ua0–\ua00.12, [Si] = 1 71017\ua0cm−3)\ua0epitaxial layers\ua0on 4H-SiC(0001). All layers are crack-free, with a very small root mean square roughness (0.13\ua0–\ua00.25 nm), homogeneous distribution of Al over film thickness and a very low unintentional incorporation of oxygen at the detection limit of 5 71015\ua0cm−3\ua0and carbon of 2 71016\ua0cm−3. Edge type dislocations in the layers gradually increase with increasing Al content while\ua0screw dislocations\ua0only raise for\ua0x\ua0above 0.077. The room temperature\ua0electron mobility\ua0of the\ua0n-AlxGa1−xN remain in the range of 400\ua0–\ua0470 cm2/(V.s) for Al contents between 0.05 and 0.077 resulting in comparable or higher Baliga figure of merit with respect to GaN, and hence demonstrating their suitability for implementation as drift layers in power device applications. Further increase in Al content is found to result in significant deterioration of the electrical properties

Type 2 Diabetes Susceptibility Gene TCF7L2 and Its Role in β-Cell Function

Type 2 diabetes is associated with impaired insu-lin secretion. Both 1st- and 2nd-phase insulinsecretion are reduced, but the effect is particu-larly pronounced for the 1st phase. The pro-cesses culminating in impaired insulin secretion are not fully understood, but both genetic and environmental factors are thought to play a role. Over the past 2 years, genome-wide association scans have transformed the ge-netic landscape of type 2 diabetes susceptibility, with the current gene count close to 20 (1). A couple of common themes have emerged from these studies. First, the major-ity of the genes identified thus far seem to affect diabetes susceptibility through -cell dysfunction (2). Second, the risk alleles tend to be common in the population, but their effect on diabetes risk is relatively small (3,4). TCF7L2, the susceptibility gene with the largest effect on disease susceptibility discovered to date, was iden-tified pre–genome-wide association by Grant et al. i