Endocytosis of KATP Channels Drives Glucose-Stimulated Excitation of Pancreatic β Cells

Abstract

Insulin secretion from pancreatic β cells in response to high glucose (HG) critically depends on the inhibition of K channel activity in HG. It is generally believed that HG-induced effects are mediated by the increase in intracellular ATP, but here, we showed that, in INS-1 cells, endocytosis of K channel plays a major role. Upon HG stimulation, resting membrane potential depolarized by 30.6 mV (from -69.2 to -38.6 mV) and K conductance decreased by 91% (from 0.243 to 0.022 nS/pF), whereas intracellular ATP was increased by only 47%. HG stimulation induced internalization of K channels, causing a significant decrease in surface channel density, and this decrease was completely abolished by inhibiting endocytosis using dynasore, a dynamin inhibitor, or a PKC inhibitor. These drugs profoundly inhibited HG-induced depolarization. Our results suggest that the control of K channel surface density plays a greater role than ATP-dependent gating in regulating β cell excitability.

High‐fat‐diet‐induced remission of diabetes in a subset of KATP‐GOF insulin‐secretory‐deficient mice

“…An HFD is known to accelerate the onset and severity of diabetes in some spontaneously occurring diabetes models . It has been proposed that glucotoxic conditions promote internalization of K ATP channels, leading to a decrease in the membrane hyperpolarized state, thereby inducing insulin secretion . Pharmacological inhibition of large conductance K + channels leads to higher action potentials in an HFD, increased Ca +2 currents and insulin secretion .…”

“…40 It has been proposed that glucotoxic conditions promote internalization of K ATP channels, leading to a decrease in the membrane hyperpolarized state, thereby inducing insulin secretion. 41 Pharmacological inhibition of large conductance K + channels leads to higher action potentials in an HFD, increased Ca +2 currents and insulin secretion. 42,43 Chow diet-fed K ATP -GOF mice showed loss of β-cell identity and dedifferentiation 7 similar to the dedifferentiation observed in other models 44,45 ;…”

Protein kinase Cε activation induces EHD-dependent degradation and downregulation of KATPchannels: Implications for glucose stimulated insulin secretion

“…These HG effects were prevented by dynasore, an inhibitor of endocytosis, as well as inhibition of protein kinase C (PKC). This has led the authors to conclude that PKC-induced endocytosis of KATP channels drives glucosestimulated β-cell excitation (Han et al, 2018). While the ability of PKC to downregulate KATP channels is consistent with a number of other studies (Bruederle et al, 2011;Hu et al, 2003), including ours (Mankouri et al, 2006;Manna et al, 2010), the mechanism proposed by the authors is inconsistent with our previous studies (Manna et al, 2010).…”

“…This cell line responds to HG and secretes insulin. Furthermore, HG stimulates PKC activity leading to KATP channel downregulation as well as depolarisation and electrical excitation of INS-1 cells (Han et al, 2018). Thus we examined the effect of expression of EHD-1(G428R)-GFP on PKC regulation of KATP currents in this cell line.…”

“…Researchers have long believed that ATP inhibition of KATP channels represents the dominant mechanism linking glucose metabolism to insulin secretion (Ashcroft and Rorsman, 2013;Nichols, 2006;Seino and Miki, 2003). However, a recent study challenged this notion (Han et al, 2018). The authors proposed that downregulation of KATP channels plays a greater role than ATP-dependent gating in β-cell excitability.…”