Novel dopaminergic mechanisms of islet hormone secretion and antipsychotic drug-induced metabolic disturbances

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Antipsychotic drugs (APDs) treat several highly prevalent psychiatric illnesses including schizophrenia, bipolar disorder and major depressive disorder, making them among the most widely prescribed medications today. Yet, APDs also cause profound metabolic disturbances including weight gain, glucose intolerance, and insulin resistance, and increase risks of type 2 diabetes (T2D) and cardiovascular disease. Significantly, all APDs cause metabolic side effects to differing degrees, and current treatments to reduce these metabolic symptoms have only limited efficacy. The mechanisms by which APDs produce metabolic disturbances are not well understood. The single unifying property of all APDs is their blockade of dopamine D2-like receptors, including D2 (D2R) and D3 (D3R) receptors, suggesting a role for these receptors in APD-induced metabolic dysfunction. Though D2R and D3R are expressed in the central nervous system in hypothalamic regions that mediate appetite and feeding behavior, interventional studies targeting these centers have not reduced APD-induced metabolic dysfunction. This suggests that APD effects on the hypothalamus do not fully explain the metabolic effects of these drugs. Notably, we and others found D2R and D3R are also expressed in human and rodent insulin-secreting pancreatic β-cells, and dopamine inhibits glucose-stimulated insulin secretion (GSIS). This suggests pancreatic DA signaling modulates GSIS and raises the possibility that APDs also act on pancreatic endocrine cells to drive dysglycemia. Indeed, we recently found: (1) APD blockade of β-cell D2R/D3R disrupts dopamine’s inhibition of GSIS, leading to elevated insulin secretion – a potential driver of insulin resistance in T2D. We similarly found that β-cell-specific D2R knockout mice exhibit hyperinsulinemia in vivo, further supporting a role for D2-like receptors as modulators of insulin release. (2) α-cells also express D2R and D3R, and APD blockade of α-cell D2R/D3R profoundly elevates glucagon secretion. These data are consistent with work showing APD-induced hyperglucagonemia in vivo which drives hyperglycemia. Thus, we hypothesize that pancreatic α- and β-cell D2R/D3R signaling is important for glucose homeostasis and disrupting this signaling leads to dysglycemia. Using new genetic and pharmacologic tools we developed, we propose to establish how D2R and D3R signaling in α- and β-cells regulates islet insulin and glucagon secretion. We also propose to better understand the intracellular mechanisms by which these receptors signal, and by which APDs alter intracellular signaling pathways to induce dysglycemia (Aims 1, 2). In parallel, we will examine the therapeutic potential of peripheral D2R/D3R agonism by determining if pharmacological stimulation of specifically peripheral D2R/D3R can ameliorate or prevent APD-induced dysglycemia in vivo in mice and in human islets (Aim 3). Ultimately, our work may elucidate new pancreatic D2R/D3R signaling mechanisms that APDs disrupt to produce dysglycemia, and lead to novel drugs that prevent or significantly reduce APDs’ metabolic side effects.