In addition to cognitive impairment, schizophrenics often suffer from non-obese T2D. Here, we examined whether similar cellular changes occur in pancreatic beta-cells as found in neurons from a genetic model of schizophrenia. Specifically we tested whether beta-cells exhibit disrupted excitation-secretion coupling when a truncated human DISC1 (thDISC1) gene, originally discovered in a Scottish family having high penetrance for schizophrenia, is expressed selectively in mouse beta-cells upon ingesting doxycycline (+DOX). Expression of thDISC1 significantly decreases blood insulin levels and GSIS from isolated mouse islets, revealing an independent role for DISC1 in beta-cells. In central neurons, DISC1 regulates Ca2+ CaV2 channel expression, Ca2+ influx and transmitter release. To determine whether DISC1 similarly regulates Ca2+ physiology in beta-cells, we tested thDISC1 DOX+ vs. DOX- beta-cells for changes in: i) intracellular Ca2+signaling using Fluo 3-AM; ii) CaV1 channel expression, the dominant channel class controlling GSIS; iii) and CaV1 channel activity using whole-cell recording methods. We found increases in [Ca2+]i following 20 mM glucose were delayed >2 min and diminished ∼50% in dissociated beta-cells expressing thDISC1. When sections of pancreas were stained with an anti-CaV1.2/1.3 antibody, thDISC1 DOX+ vs. DOX- insulin-positive cells exhibited decreased staining. Lastly, both peak inward Ba2+ current and FPL 64176 induced long-lasting L-type tail current decreased significantly in thDISC1 DOX+ vs. DOX- beta-cells. No obvious change in activation kinetics was observed. These changes in excitation-secretion coupling parallel those in neurons expressing truncated DISC1. Thus at the cellular level, truncated DISC1 precipitates disorders of secretion such as schizophrenia and T2D.

Disclosure

P. Lu: None. R.B. Sharma: None. L.C. Alonso: None. R. Zhuge: None. A.R. Rittenhouse: None. A. Jurczyk: None.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.