Antipsychotics Stimulate Pancreas to Make More Hormones

During his psychiatry residency, Zachary Freyberg, M.D., Ph.D., saw firsthand the profound benefits and costs of antipsychotic medications for patients with schizophrenia—as patients’ hallucinations subsided, they would experience significant weight gain in a short amount of time.

“Psychiatrists were asking patients to make this serious choice about their health [whether or not to take antipsychotics], yet they knew so little about what these medicines did and how they did it,” Freyberg, now an assistant professor of psychiatry and cell biology at the University of Pittsburgh, told Psychiatric News. The one thing the field could agree on was that dopamine receptors were involved, so once Freyberg completed his residency, he set out to study the mysteries of dopamine signaling.

Earlier this year, he and colleagues added a major piece to the puzzle of why antipsychotics and metabolic problems, including weight gain and diabetes, are inextricably linked.

They found that antipsychotics directly inhibit dopamine signaling in the pancreas, which leads to uncontrolled production of two hormones that regulate blood sugar: glucagon, which is produced by pancreatic alpha cells and increases blood glucose, and insulin, which is produced by pancreatic beta cells and lowers blood sugar. Their analysis also suggested that glucagon is as important as insulin, or maybe even more critical, in causing antipsychotic-induced metabolic problems.

Though dopamine is primarily known as a neurotransmitter, dopamine receptors are present in multiple cell types in the body, including pancreatic alpha and beta cells. Freyberg and others have shown that the dopamine D2 and D3 receptors (the primary targets of all antipsychotics) are important in regulating insulin production by beta cells. Alpha cells have been less studied, Freyberg noted, in large part because glucagon degrades more rapidly than insulin.

But once Despoina Aslanoglou, Ph.D., a postdoctoral researcher in Freyberg’s lab, designed a fluorescence-based assay to rapidly measure glucagon in cultured pancreatic islets, the researchers could start to peek inside these cellular black boxes.

“What we found was that at low concentrations, dopamine bound to alpha cell D2 and D3 receptors and triggered a reduction in glucagon production,” Aslanoglou said. “At higher concentrations, all the dopamine receptors were occupied, and dopamine started binding to norepinephrine receptors. And that led to elevated glucagon production.”

Freyberg and his team next exposed pancreas tissue to one of three antipsychotics (clozapine, haloperidol, or olanzapine) or an inert control molecule. They found that compared with the control molecule, clozapine increased glucagon production by 200%, olanzapine increased glucagon production by 106%, and haloperidol increased glucagon production by 67%. The antipsychotics also triggered increased insulin production, but at lower levels (20% for clozapine, 44% for olanzapine, and 24% for haloperidol).

Glucagon increases of the magnitude seen in this study can quickly trigger hyperglycemia, which can eventually lead to diabetes, Freyberg noted. At the same time, the lower but still relevant increases in insulin can gradually lead to insulin resistance, thus providing a second avenue for diabetes.

“We also discovered that pancreatic alpha cells have the full set of molecular machinery needed to make dopamine from scratch,” Aslanoglou said. (Beta cells can also synthesize dopamine, but require the precursor molecule L-DOPA as a starting point.) Though alpha and beta cells normally secrete their hormones in response to changes in external dopamine levels during fasting and eating states, these new data suggest that alpha cells may use their in-house production capabilities to fine-tune dopamine concentrations as needed.

“This illustrates how little we know about the fundamentals of dopamine signaling, above the neck or below it,” Freyberg explained. He said that he is hopeful that additional studies of the role of dopamine in the pancreas might reveal some drug development targets, as well as provide clues about dopamine’s activity in the brain.

This study was published in Translational Psychiatry and supported by grants from the Department of Defense, National Institute of Neurological Disorders and Stroke, and U.S. Department of Veterans Affairs, with additional support from the John F. and Nancy A. Emmerling Fund of The Pittsburgh Foundation. ■