Upregulation of Kv2.1 in human T2D β-cells improves exocytotic function. Upregulation of Kv2.1 in human T2D β-cells improves exocytotic function. Knockdown.

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Upregulation of Kv2.1 in human T2D β-cells improves exocytotic function. Upregulation of Kv2.1 in human T2D β-cells improves exocytotic function. Knockdown of Kv2.1 (A; KCNB1; n = 13 and 13 cells from 2 donors) or Kv2.2 (B; KCNB2; n = 19 and 23 cells from 3 donors) expression failed to reduce voltage-dependent K+ currents in β-cells from donors with T2D. C: Expression of Kv2.1 (KCNB1) mRNA in islets from ND donors or donors with T2D (n = 11 and 5 donors, respectively). Representative capacitance responses at 10 mmol/L glucose from untransfected (D) β-cells of ND donors and donors with T2D and of transfected β-cells (E) of donors with T2D expressing GFP alone or together with Kv2.1-WT. F: The cumulative exocytotic responses from D and E (n = 30 cells from 3 ND donors and n = 30, 32 and 34 cells from 3–5 donors with T2D). G: Images from live-cell TIRF of ND and T2D β-cells expressing mCherry, mCherry-Kv2.1-WT, or mCherry-Kv2.1-ΔC318 and the granule marker NPY-EGFP (greyscale). Red dots indicate exocytotic events occurring over 2 min upon increasing glucose from 2.8 to 5 mmol/L. Scale bars, 5 μm. Average frequency of exocytotic events in ND (H; n = 17, 20, and 21 cells from 2 donors) and T2D (I; n = 24, 34, and 30 cells from 2 donors with T2D) β-cells. J and K: Insulin secretory profiles of islets from a donor with T2D transduced with control adenovirus (Ad-GFP; circles) or an electrically silent full-length Kv2.1 (Ad-Kv2.1W365C/Y380T; squares). The first phase secretory response is shown on expanded time scale (K) (one donor; experiment run in duplicate). L: Averaged and individual (circles) area under the curve (AUC) values for baseline, first-phase, and second-phase responses of islets from donors with T2D transduced as in J and K (n = 3 donors in duplicate). *P < 0.05 versus ND or as indicated; **P < 0.01 versus mCherry; ***P < 0.001 as indicated. Jianyang Fu et al. Diabetes 2017;66:1890-1900 ©2017 by American Diabetes Association