Psychiatric conditions such as schizophrenia have long been linked with an elevated risk of type 2 diabetes. In a new study published in The FASEB Journal, researchers at UMass Medical School led by Rita Bortell, PhD, and Agata Jurczyk, PhD, report evidence that a shared genetic factor may help explain the co-occurrence of these disorders. The team identified the gene Disrupted in Schizophrenia 1 (DISC1) — previously linked to major psychiatric illnesses including schizophrenia — as having an unexpected role in the survival and function of pancreatic beta cells. This work offers the first molecular connection suggesting DISC1 dysregulation could contribute to the higher incidence of type 2 diabetes observed in people with psychiatric disorders.
To investigate the role of DISC1 outside the brain, the researchers engineered mice in which the DISC1 gene was selectively disrupted only in pancreatic beta cells, leaving brain expression intact. Mice with beta cell–specific DISC1 disruption showed higher rates of beta cell death, reduced insulin secretion and poorer glucose regulation than control animals. Complementary experiments in cultured beta cells, where DISC1 expression was suppressed, demonstrated that DISC1 normally restrains the activity of the enzyme glycogen synthase kinase-3β (GSK3β). Since appropriate suppression of GSK3β activity is critical for beta cell health and insulin secretion, loss of DISC1 allowed inappropriate GSK3β activation, impairing beta cell proliferation and survival.
To confirm the role of GSK3β in the observed defects, the team treated the DISC1-deficient mice with a GSK3β inhibitor. Antagonizing GSK3β improved beta cell survival and restored normal glucose tolerance in mice lacking DISC1 in their beta cells. These findings indicate DISC1 performs an essential role in maintaining normal beta cell physiology and that its influence on blood glucose regulation may operate independently of its functions in the brain.
“People with psychiatric disorders are known to face a higher risk of developing type 2 diabetes, a risk shaped by a mix of genetics, lifestyle and medication,” Bortell said. “Our mouse studies suggest that disruption of DISC1 could be one genetic factor that shifts the balance toward metabolic disease, although confirming this in humans remains necessary. We hope establishing this link will guide the development of better strategies that address both psychiatric illness and metabolic complications, conditions that together cause substantial suffering and health burden.”
Bortell noted that the findings highlight the importance of assessing how antipsychotic drugs affect not only brain function but also pancreatic beta cells. Many antipsychotic medications are associated with an increased risk of diabetes, so careful metabolic monitoring of patients receiving these treatments is prudent. She also observed that people with diabetes have higher rates of depression, suggesting there may be additional molecular connections between the brain and pancreatic beta cells yet to be discovered.
Source: Sarah Willey – UMass Medical School
Image Credit: The image is in the public domain
Original Research: Abstract for “Beyond the brain: disrupted in schizophrenia 1 regulates pancreatic β-cell function via glycogen synthase kinase-3β” by Agata Jurczyk, Anetta Nowosielska, Natalia Przewozniak, Ken-Edwin Aryee, Philip DiIorio, David Blodgett, Chaoxing Yang, Martha Campbell-Thompson, Mark Atkinson, Leonard Shultz, Ann Rittenhouse, David Harlan, Dale Greiner, and Rita Bortell in FASEB Journal. Published online November 6 2015. doi:10.1096/fj.15-279810
Abstract
Beyond the brain: disrupted in schizophrenia 1 regulates pancreatic β-cell function via glycogen synthase kinase-3β
People with schizophrenia and their close relatives show substantially higher rates of type 2 diabetes (T2D) than the general population, even when differences in body mass index and antipsychotic treatment are taken into account. This pattern suggests shared genetic contributors might link the two conditions. Mutations in Disrupted in Schizophrenia 1 (DISC1) are strongly associated with increased risk for psychiatric disorders. In this study, DISC1 emerged as a key regulator of pancreatic beta cell proliferation and insulin secretion through its control of glycogen synthase kinase-3β (GSK3β).
DISC1 expression was enriched in the developing mouse and human pancreas and persisted in adult beta and ductal cells. Reducing DISC1 function—either by siRNA-mediated knockdown or by expressing a dominant-negative DISC1 truncation that mimics a human chromosomal translocation associated with schizophrenia—led to decreased beta cell proliferation, increased apoptosis, and glucose intolerance in transgenic mice. Insulin secretion was diminished, and essential beta cell transcription factors such as Pdx1 and Nkx6.1 were reduced. Loss of DISC1 permitted inappropriate activation of GSK3β in beta cells. Pharmacological inhibition of GSK3β with a specific antagonist rescued the observed beta cell defects, supporting a model in which DISC1 maintains beta cell health by limiting GSK3β activity. These results reveal an unanticipated role for DISC1 in pancreatic beta cell physiology and suggest that DISC1 disruption may contribute to risk for type 2 diabetes independently of its neurological effects.