Catecholamine neurotransmitters dopamine (DA) and norepinephrine (NE) are essential for a myriad of functions throughout the central nervous system, including metabolic regulation. These molecules are also present in the pancreas, and their study may shed light on the effects of peripheral neurotransmission on glycemic control. Though sympathetic innervation to islets provides NE that signals at local α-cell and β-cell adrenergic receptors to modify hormone secretion, α-cells and β-cells also synthesize catecholamines locally. We propose a model where α-cells and β-cells take up catecholamine precursors in response to postprandial availability, preferentially synthesizing DA. The newly synthesized DA signals in an autocrine/paracrine manner to regulate insulin and glucagon secretion and maintain glycemic control. This enables islets to couple local catecholamine signaling to changes in nutritional state. We also contend that the DA receptors expressed by α-cells and β-cells are targeted by antipsychotic drugs (APDs)—some of the most widely prescribed medications today. Blockade of local DA signaling contributes significantly to APD-induced dysglycemia, a major contributor to treatment discontinuation and development of diabetes. Thus, elucidating the peripheral actions of catecholamines will provide new insights into the regulation of metabolic pathways and may lead to novel, more effective strategies to tune metabolism and treat diabetes.

Nervous system function and glycemic control are both important in metabolic regulation. Neurons and pancreatic islet cells share many vital features. Foremost, these cells are professional secretors that release vesicular content in response to stimulation. Like neurons, islet cells are excitable with distinct electrical thresholds for depolarization to trigger exocytic vesicle release (1). In neurons, peptide-derived signaling molecules are loaded into large dense-core vesicles, while nonpeptidergic content including neurotransmitters is loaded into smaller synaptic vesicles. Similarly, islet cells contain large dense-core vesicles loaded with peptide hormones. Islets also contain small synaptic-like microvesicles, analogous to neuronal synaptic vesicles (2). Just as importantly, islets express the machinery of neurotransmitter biosynthesis, catabolism, and vesicle packaging (37). For example, α-cells and β-cells express catecholamine biosynthetic enzymes such as tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC) for dopamine (DA) biosynthesis as well as dopamine β-hydroxylase (DBH) for the conversion of DA to norepinephrine (NE) (35). These cells also express catabolic enzymes including monoamine oxidases (MAOs) and catechol-O-methyltransferase (COMT), which degrade catecholamines (4,79). Finally, α-cells and β-cells also express plasma membrane and vesicular neurotransmitter transporters including the dopamine transporter (DAT) and the vesicular monoamine transporter 2 (VMAT2). These transporters take up neurotransmitters from the extracellular space into the cytoplasm, followed by their packaging into vesicles for subsequent exocytic release (5,1013).

Given the parallels between neurons and islet cells, it was originally assumed that both share a common developmental origin from the ectodermal neural crest (2,14). However, neural and endocrine cells possess different developmental origins. Pancreatic islets are derived from endoderm, while neurons are derived from ectoderm, including enteric neurons, which are derived from the neural crest (15,16). Nevertheless, these different cell types appear to have functionally converged, though the mechanisms are not well understood. In beginning to disentangle the shared biology between neurons and islet cells, concepts from neuroscience may be relevant to the cell biology and physiology of endocrine cells including α-cells and β-cells.

Neurotransmitters are some of the most well-studied molecules in the central nervous system (CNS), given their essential roles as mediators of synaptic communication between neurons. Except for acetylcholine (ACh), most neurotransmitters are derived from amino acids and are categorized into several classes: 1) catecholamines, DA, NE, and epinephrine (Epi); 2) indolamines, serotonin (5-HT); 3) imidazoleamines, histamine; and 4) glutamate and γ-aminobutyric acid. Importantly, these neurotransmitters are also found outside the CNS in the periphery. Indeed, the 5-HT synthesized in the CNS accounts for only ∼5% of total body 5-HT. Instead, ∼95% of the body’s total 5-HT is primarily produced in the gut (17,18). Yet, the anatomic localization and functional relevance of peripheral neurotransmitters remain poorly understood.

Peripheral neurotransmission has primarily been studied in the context of the autonomic nervous system, which is comprised of sympathetic and parasympathetic divisions. NE is released locally from sympathetic nerve terminals innervating organs, but circulating catecholamines, NE and Epi, are also released from the adrenal medulla in response to stress. Within the human pancreas, most axons innervating islets are sympathetic and express TH, the rate-limiting enzyme for DA, NE, and Epi synthesis. In contrast, direct parasympathetic innervation of human islets is cholinergic and more sparsely distributed (19).

The contributions of extrinsic innervation to endocrine pancreatic function are not well characterized. Though ACh released by parasympathetic nerves stimulates insulin and glucagon secretion during vagal stimulation (20), and sympathetic release of NE modulates the contractility of local vascular cells (19), other work suggests that this autonomic modulation is nonessential. Indeed, denervation of islets after vagotomy or sympathectomy does not significantly disturb glycemic control (2123). Furthermore, the degree of autonomic innervation varies between rodents and humans, where human pancreatic islets are more sparsely innervated compared with mouse islets (19). The lack of well-defined nerve terminals at release sites alongside islet cells has made it challenging to determine the exact extent of autonomic innervation and which cells receive neuronal inputs (19,24). Consequently, the sparseness of innervation suggests that a key source of neurotransmitters within islets may come from the islets themselves, which can produce these molecules for local signaling.

Catecholamines DA and NE are amino acid derivatives, resulting from modification of tyrosine. Tyrosine is hydroxylated by TH to generate L-3,4-dihydroxyphenylalanine (L-DOPA), the biosynthetic precursor of DA. L-DOPA is then decarboxylated by AADC to form DA. This newly synthesized DA is subsequently packaged into hormone-containing vesicles via VMAT2 (25,26). Once packaged, a fraction of the vesicular DA may undergo an additional step where its catechol ring is further hydroxylated by DBH to generate NE (27,28) (Fig. 1).

Importantly, while human and rodent α-cells and β-cells express AADC and DBH (35,10,29,30), there are species-specific differences in β-cell TH expression. Notably, human β-cells express considerably less TH compared with rodents (4,2931). Mice also exhibit marked variations in β-cell DA synthesis and secretion across different strains (31). Unlike widely used B6 mice, the CAST/EiJ founder mouse strain expresses higher levels of TH, resulting in more de novo DA synthesis. Nevertheless, despite these differences in TH expression, mouse and human β-cells clearly secrete DA (35,10,31), suggesting that β-cells can use precursors other than tyrosine, such as L-DOPA, to produce DA. This also points to the importance of substrate availability in DA biosynthesis either separate from, or complementary to, de novo biosynthesis. Consistent with this DA production, α-cells and β-cells express L-type amino acid transporters (LATs) LAT1 and LAT2, which are responsible for cellular uptake of L-DOPA, stimulating intracellular DA production (3,32,33). Though both LAT1 and LAT2 take up L-DOPA into cells (3,3436), these transporters possess similar but nonidentical specificities for additional substrates. LAT1 is the major transporter of tyrosine, with higher affinity and greater tyrosine uptake versus LAT2 (34,37).

Interestingly, α-cells are capable of de novo catecholamine biosynthesis, including production and secretion of L-DOPA and DA (4). Presently, whether the heterogeneity in β-cell DA biosynthesis is also evident in α-cells remains unclear. In contrast to β-cells, α-cells also secrete NE. However, following L-DOPA supplementation, α-cells raise DA production 60-fold, while NE is only increased 3-fold, suggesting a clear preference toward DA synthesis and secretion (4).

TH

As the rate-limiting enzyme for all catecholamines, TH is a key control point for catecholamine biosynthesis (3840). TH’s cytoplasmic localization renders it sensitive to changes in intracellular substrate availability. Indeed, depletion of cytoplasmic pools of tyrosine significantly boosts TH’s reaction rate as a compensatory response (41). Conversely, TH activity is negatively regulated via feedback inhibition by pathway end products (4244). This feedback inhibition is reversible and concentration-dependent where catecholamines competitively inhibit TH (45,46). Such inhibition prevents accumulation of catecholamines, which can be converted into quinones that lead to formation of toxic reactive oxygen species (42,47,48).

TH activity is positively regulated by phosphorylation via kinases, including protein kinase A (PKA) and protein kinase C (PKC). Phosphorylation increases TH enzymatic activity by diminishing feedback inhibition and enhances TH’s affinity for its cofactor, tetrahydrobiopterin (4953). Longer-term regulation of TH activity occurs via control of TH gene expression and mRNA stability (42,54). The TH promoter contains response elements sensitive to calcium and to the second messenger cAMP (55,56). Interestingly, the human TH gene is part of a larger gene cluster that includes INS, the gene encoding insulin (57). Consequently, TH and INS genes are within the same open chromatin domain and coordinate their transcription in human islets (57). This points to coordinated regulation between catecholamine biosynthesis and islet cell function.

AADC

Though not considered a rate-limiting enzyme in catecholamine biosynthesis, AADC is nevertheless regulated by pre- and posttranslational mechanisms (58). Like TH, AADC is localized to the cytoplasm, and its activity is similarly increased via phosphorylation by PKA and PKC (38,5861). Additionally, AADC’s activity is enhanced on binding its cofactor, pyridoxal phosphate (vitamin B6) (62). AADC activity is sensitive to DA levels where 1) DA depletion raises AADC activity, while 2) raising DA levels diminishes AADC activity (63,64). Finally, AADC is regulated transcriptionally by alternative splicing and differential expression via alternative promoter usage (58,65).

Circadian regulation of pancreatic islet function is an important mechanism of metabolic control (66,67). Rodent and human islets exhibit circadian oscillations to temporally coordinate insulin and glucagon secretion (66,68,69). Using INS-1E cells, a rat β-cell line, we discovered that Ddc (which encodes AADC) gene expression exhibits clear diurnal rhythms and is coordinated with the β-cell circadian clock (70); in contrast, TH gene expression shows no diurnal variation. Further work is needed to ascertain whether circadian regulation of these enzymes differs between islet cell types or whether this regulation is altered by diabetes. Indeed, type 2 diabetes (T2D) islets have disrupted regulation of α-cell and β-cell circadian clocks, altering temporal coordination between insulin and glucagon secretion (71).

In islets, both α-cells and β-cells express DAT (4,5). DAT-mediated reuptake of DA terminates DA receptor signaling and facilitates the replenishment of intracellular DA stores (4,5,10). Thus, maintaining a balance between DAT-mediated DA reuptake versus activation of cognate receptors by extracellular DA offers islet cells a mechanism for temporal and spatial control over the duration of DA signaling (4,5,10,11). Disrupting the balance between DA reuptake and receptor signaling via DAT inhibition leads to changes in DA-mediated modulation of islet hormone secretion. While acute DAT reuptake inhibition transiently increases local extracellular DA levels (72), extended DAT inhibition depletes islet DA stores and permits remaining extracellular DA to diffuse away (5). This ultimately diminishes dopaminergic inhibition of insulin secretion via reduced DA receptor signaling (5).

The evidence demonstrating that local islet catecholamine biosynthesis is sensitive to precursor availability raises the question, what are the sources of the L-DOPA taken up by α-cells and β-cells and their physiological relevance? The GI tract and foregut are key sources of circulating peripheral L-DOPA and DA, with gastric enterochromaffin-like cells expressing the DA biosynthetic machinery (7375). Dietary protein content also significantly contributes to DA precursor availability. Indeed, plasma tyrosine concentrations vary directly with dietary protein intake (76). Moreover, we showed that an α-cell line synthesizes L-DOPA de novo, suggesting that α-cells may provide other local islet cell types with precursors for DA biosynthesis (4). This also suggests that local DA production may be part of the paracrine signaling between α-cells and β-cells, as well as potentially other islet cell types, to coordinate islet hormone release. Finally, pancreatic acinar cells express TH and use circulating tyrosine to synthesize L-DOPA, accounting for high L-DOPA content in the pancreatic exocrine secretion into the ducts (7779).

Newly synthesized L-DOPA contributes significantly to local DA synthesis by nonneuronal cell types in the periphery (80,81). Importantly, availability of peripheral L-DOPA and DA is coupled to feeding. Following meals, blood L-DOPA levels rise >50-fold in humans and rodents (8184). Moreover, we discovered that glucose stimulation boosts β-cell L-DOPA uptake via LAT1 and LAT2 (3). This provides a mechanism by which islet cells can control DA biosynthesis via precursor availability in proportion to meal size and the resulting elevations in blood glucose levels. Because pancreatic DA functions as an autocrine/paracrine negative regulator of insulin and glucagon secretion, coupling the regulation of hormone secretion to meal size offers an additional layer of protection against inappropriately high or low levels of hormone secretion.

The coupling of local DA versus NE production to feeding and meal size effectively creates a separate mechanism by which the pancreas relies on catecholamine signaling that is independent of the NE and Epi released during states of stress. Therefore, we propose a model where peripheral glycemic control via catecholamines varies according to the specific metabolic needs associated with either stress, which works primarily through NE and Epi, or normal diurnal cycles of feeding, where there is a preference for signaling through DA. Specifically, during periods of stress, activation of the sympathetic nervous system leads to rapid release of NE through local sympathetic innervation. In parallel, stress states raise levels of circulating NE and Epi via release from the adrenal medulla (85). In islets, the combined rise in NE and Epi stimulates local adrenergic receptors to increase α-cell glucagon release and decrease β-cell insulin secretion. This results in rapid mobilization of blood glucose to fuel energetically expensive processes required for either a transient or prolonged stress response (86) (Fig. 2A). On the other hand, diurnal rises and falls of circulating L-DOPA and DA in response to feeding are meant to evoke transient changes in local islet DA that are proportional in magnitude to meal size. This enables fine-tuning of postprandial glycemic control through coupling the magnitude of dopaminergic inhibition of glucose-stimulated insulin secretion (GSIS) to meal-dependent substrate availability (Fig. 2B).

Our understanding of the relationships between postprandial, meal-derived DA and local islet cell–derived DA remains limited. Some insights come from studies of the dynamics by which nutritional tyrosine is converted to L-DOPA and DA in the gut and later taken up by pancreatic islets (80). These studies show similar timing for meal-derived DA synthesis and local islet DA synthesis (3,5,80). Yet, this work was limited by the relative paucity of time points. Improved temporal resolution is therefore needed to better discern potential temporal differences between local versus meal-derived DA and their impacts on islet function. In the interim, we hypothesize the following: 1) In islets, postprandial elevations in blood glucose trigger an initial wave of exocytic vesicle fusion, releasing hormones and previously synthesized DA. 2) This premade vesicular DA acts rapidly to locally modulate hormone secretion during the first phase of release. 3) Concurrently, postprandial elevations of meal-derived L-DOPA and DA permit further islet DA synthesis for subsequent waves of vesicle release.

DA receptor signaling is an important modulator of metabolism (87,88). In vivo human and rodent studies showed that treatment with the DA precursor L-DOPA caused hyperglycemia due to decreased GSIS (8992). Indeed, up to 80% of patients with Parkinson disease on L-DOPA therapy exhibit hyperglycemia, suggesting that systemic DA signaling has profound effects on metabolic regulation (93). Consistent with this, dopamine D2 receptor (D2R) polymorphisms are associated with insulin resistance and T2D (94). In addition to brain DA receptors’ established roles in mediating the circuitry of appetite and feeding (95,96), DA receptors are also expressed in the periphery including in the endocrine pancreas.

Human and rodent β-cells express all five DA receptors including stimulatory D1-like (D1, D5) and inhibitory D2-like (D2, D3, D4) receptors (5,10,25), unlike neurons, which typically express a limited repertoire of DA receptors, restricted by brain region and/or cell type. Functionally, we and others demonstrated that D2R and D3 receptor (D3R) are negative regulators of insulin secretion (3,5,10,25,97). Agonist stimulation of β-cell D2R and D3R inhibits GSIS in both human and mouse pancreatic islets (3,5,97). These findings suggest that β-cell D2R/D3R signaling is an important component of an autocrine/paracrine negative feedback circuit that regulates GSIS (5,10,25,97). Conversely, blockade of β-cell D2R/D3R significantly increases GSIS (3,5). Moreover, β-cell-specific D2R knockout (KO) mice show higher serum insulin compared with littermate controls in vivo (3). Chronically, increases in circulating insulin due to disrupted D2R/D3R signaling may desensitize insulin-sensitive peripheral targets (e.g., liver, skeletal muscle, adipose tissue), resulting in insulin resistance (88,98,99). Overall, these in vivo and islet data suggest that β-cell D2R and D3R are key downregulators of insulin secretion. While these receptors act similarly, they are likely nonredundant, since KO of either D2R or D3R impacts insulin secretion (3).

D2-like receptors are also expressed by rodent and human α-cells (4,100,101). As in β-cells, D2R/D3R signaling inhibits glucagon secretion, especially at very low DA concentrations (4). These findings suggest that local islet DA produced by α-cells and β-cells acts via autocrine and paracrine signaling to limit insulin and glucagon release. Disrupting these dopaminergic paracrine communications may contribute to dysglycemia and diabetes (102106). Finally, δ-cells also express D2R and earlier work in rat islets showed that DA diminishes somatostatin (SST) secretion via inhibitory D2-like receptors (107,108). It is therefore likely that paracrine DA signaling extends to δ-cells where DA produced by α-cells and β-cells activates δ-cell D2R to inhibit SST release, adding an additional layer of paracrine cross talk to regulate hormone secretion within islets.

The signaling mechanisms used by β-cell D2R and D3R to modulate insulin secretion remain poorly understood. D2R and D3R are G protein-coupled receptors (GPCRs) that signal via inhibitory Gαi/o/z (109114). Receptor stimulation recruits these inhibitory G proteins to diminish the activity of adenylate cyclase, the enzyme responsible for biosynthesis of cAMP, which amplifies GSIS (115). This D2R/D3R-mediated drop in cAMP may explain how DA dose-dependently decreases GSIS. D2R and D3R also recruit β-arrestin-2 (116), which mediates receptor desensitization and internalization to control duration and magnitude of DA signaling (111,117). Additionally, DA-mediated signaling via β-cell D3R modulates the frequency of intracellular Ca2+ oscillations that is correlated to the inhibition of GSIS (10). Because Ca2+ is a necessary trigger for exocytic fusion of insulin-containing secretory granules, D3R-mediated gating of Ca2+ availability tightly regulates hormone release. This raises the possibility that DA-mediated mechanisms contribute to the dysregulated release of insulin and glucagon in diabetes.

The roles of D1-like DA receptors are less well characterized in islets. D1-like receptors are stimulatory, since they recruit Gαs proteins that stimulate cAMP synthesis and promote increased hormone release in neurons (116,118,119). Yet, despite islet expression of D1-like receptors, the net effect of DA treatment is inhibition of hormone release (35,10,25). This suggests that the inhibitory tone of islet D2-like receptors overrides any stimulatory effect of D1-like receptors. Moreover, since D2-like receptors possess a 10- to 100-fold higher affinity for DA compared with D1-like receptors(120), at higher DA concentrations, increasing coactivation of D1-like receptors may start to offset D2-like receptor-mediated inhibition, enabling finer modulation of hormone secretion. Finally, recent work suggests that the D1 receptor (D1R) can modulate β-cell D2R signaling by forming a heteromeric D1R-D2R complex capable of mediating glucose-stimulated calcium flux (121). While D1R-D2R heteromeric complexes and their functional implications remain controversial in the CNS (122,123), such complexes may offer novel insights into the role of D1R/D2R coexpression in islet cells.

α-Cells and β-cells express adrenergic receptors alongside DA receptors. In β-cells, inhibitory α2A-adrenergic receptors are the predominant adrenergic receptors, while stimulatory β1-adrenergic receptors are the main adrenergic receptors in α-cells. Consequently, agonism of α2A-adrenergic receptors diminishes GSIS, while β1-adrenergic receptor stimulation enhances glucagon secretion (4). Because DA and NE are structurally nearly identical, differing only by NE’s extra hydroxyl group on the catechol ring, we recently showed that DA signals at both dopaminergic and adrenergic receptors in islets (4,114). DA activates islet α2A- and β1-adrenergic receptors, albeit as a lower-affinity ligand versus NE, consistent with CNS studies (124126).

Analogous to DA’s actions at adrenergic receptors, NE signals via D2R as a lower-affinity ligand compared with DA (4,114). Epi also activates D2-like receptors, binding the receptors with 2- to 20-fold higher affinity than NE (124,127,128). Importantly, the potency of NE and Epi in cross-activating dopaminergic receptors falls within the physiological range (124,127,128), making this a potentially relevant mechanism for regulating islet function. Since Epi is the predominant catecholamine secreted by the adrenal medulla (129,130), during stress, Epi-induced activation of islet DA receptors may predominate over NE, but further work is needed to test this possibility.

We propose a model where DA’s ability to signal through both dopaminergic and adrenergic receptors translates to distinct modulation of hormone release according to substrate availability (Fig. 3). In β-cells, when DA availability is low, inhibitory D2R and D3R first bind DA with high affinity. As DA levels rise, lower-affinity inhibitory α2A-adrenergic receptors then bind DA. Because these β-cell dopaminergic and adrenergic receptors are inhibitory, the result is a net monophasic pattern of diminished GSIS as a function of DA concentration (4). In contrast, human α-cells exhibit a bimodal pattern of glucagon secretion in response to DA. Low DA concentrations elicit reductions in glucagon secretion, while higher concentrations raise glucagon secretion. Dissection of the mechanisms for this bimodal pattern revealed that when DA levels are low, DA is more likely to successfully activate inhibitory D2R and D3R receptors, which bind DA at high affinity. However, as local DA concentrations rise, the levels of local DA become sufficient to trigger the activation of stimulatory α-cell β1-adrenergic receptors, which enhances glucagon secretion (4).

Consistent with amino acids as modulators of hormone release, the amino acid constituents of a mixed meal contribute to transient elevations in glucagon secretion (131). Indeed, alanine, glutamine, and arginine are potent α-cell secretagogues (131133). Postprandial elevations of tyrosine may similarly raise glucagon through tyrosine’s role as a DA precursor where conversion of dietary tyrosine to DA following the mixed meal leads to subsequent DA-induced activation of α-cell β1-adrenergic receptors to increase glucagon release.

Surprisingly, DA signals differently at DA receptors versus adrenergic receptors. When DA activates D2R, both G proteins and β-arrestin-2 are recruited to the receptor, modifying cAMP production and triggering receptor internalization, respectively. On the other hand, DA’s stimulation of the α2A-adrenergic receptor triggers only G-protein recruitment and not β-arrestin-2. This discrepancy suggests that DA is a G protein-biased ligand at adrenergic receptors and provides a functional rationale for α-cell and β-cell catecholamine receptor preferences for signaling via DA versus NE/Epi. DA’s inability to effectively recruit β-arrestin-2 to adrenergic receptors may limit receptor desensitization, which can lead to sustained receptor signaling at the cell surface (134). Overall, we posit that substrate-specific signaling differences at adrenergic receptors may be used by islets as an efficient strategy to control signaling according to either substrate availability, which depends on the rise and fall of blood DA and its precursors, or stress states, which elicit NE/Epi signaling from the sympathetic axis.

Catecholamines have increasingly been implicated in pancreatic development. TH-deficient pancreata during development subsequently demonstrate decreased numbers of insulin-expressing β-cells. Moreover, DA treatment of pancreatic explants selectively increases total insulin content and β-cell number, while α-cells remain unaffected (135). Consistent with this, the absence of pancreatic D2R produces decreases in β-cell mass as well as diminished β-cell replication in 2-month-old mice. This suggests that the absence of inhibitory tone by islet D2R during development leads to detrimental effects on β-cell proliferation, which results in longer-term effects on insulin homeostasis and glycemic control (89,136). Together, these findings suggest that TH activity and DA are critical for β-cell differentiation as well as for maintenance of β-cell number postdevelopment. It is also possible that disruptions to catecholamine biosynthesis, metabolism, and/or receptor signaling may have profound impacts on pancreatic islet homeostasis and glycemic control.

There is growing evidence that diabetes alters both CNS and peripheral catecholamine signaling. In brain, preclinical rodent models and clinical data show diabetes-induced alterations in catecholamine content, biosynthesis, vesicular packaging, and turnover (137141). Rat diabetes models also demonstrate decreased Th mRNA expression in noradrenergic and dopaminergic neurons with accompanying decreases in Th activity (142144). In the periphery, islets of db/db mice similarly exhibit diminished Th gene expression, though both AADC and VMAT expression is elevated. These findings suggest that homeostatic changes are occurring to boost islet catecholamine synthesis and packaging in response to diabetes (7).

Antipsychotic drugs (APDs) treat highly prevalent psychiatric illnesses including schizophrenia, major depression, and bipolar disorder, making these drugs some of the most widely prescribed medications today (145,146). Yet, APDs also cause differing degrees of weight gain and dysglycemia (88,99,147) and substantially increase T2D risk (88,99,148,149). These metabolic side effects are common reasons for poor drug compliance and treatment discontinuation that ultimately result in life-shortening morbidities, affecting millions worldwide (88). Yet, the mechanisms for metabolic side effects of APDs remain poorly understood.

Although multiple cellular targets for APDs have been identified (88,99,147,150,151), the main unifying property of all APDs is their blockade of D2R and D3R, implicating the receptors both in these drugs’ therapeutic actions and in their metabolic side effects. Though D2R and D3R are expressed in brain regions that mediate appetite and feeding behavior (95,96), interventional studies targeting these centers have not substantially reduced APD-induced metabolic dysfunction (88). This indicates that actions of APDs in the CNS do not fully explain the metabolic effects of these drugs (88,152). Indeed, APD-induced changes in glucose homeostasis occur in the absence of increased food intake or psychiatric disease (153,154). Moreover, psychotic illnesses like schizophrenia carry intrinsic metabolic risk independently of APDs; to control for this, studies in drug-naïve human subjects show that as little as a single administration of APDs is sufficient to alter glucose homeostasis (87,88,154).

The above findings suggest that APDs act directly on metabolically relevant targets in the periphery to cause dysglycemia. Consistent with this, we found that APDs act directly on mouse and human β-cells to significantly raise GSIS (35). APDs also raise blood glucagon in humans and rodents (155158) despite concurrent increases in blood insulin and glucose—conditions that ordinarily decrease glucagon (155,158). APD-elevated glucagon may drive hyperglycemia, since glucagon receptor KO mice are protected against APD-induced hyperglycemia independent of changes in insulin levels (158). Because rodent and human α-cells express DA D2-like receptors including D2R and D3R (100,101), APDs may directly target α-cells to raise glucagon and drive hyperglycemia, further contributing to insulin resistance. Indeed, in human islets, the APDs associated with the greatest metabolic liability, clozapine and olanzapine, substantially increase glucagon secretion; haloperidol, which has lower metabolic risk, also raises glucagon secretion, albeit less so (88,99). These data lead us to propose the following: 1) In β-cells, APDs block inhibitory D2R/D3R receptors, which increases GSIS. This disinhibition inappropriately elevates secreted insulin that, over time, desensitizes insulin-sensitive peripheral targets, leading to insulin resistance. 2) APDs also act directly on α-cells, disrupting inhibitory D2R/D3R signaling to boost glucagon secretion. The resulting hyperglycemia exacerbates insulin resistance. 3) APDs also interfere with paracrine communication between α-cells and β-cells, further worsening dysglycemia (Fig. 4).

APDs may also block activation of D2-like receptors by NE. We therefore speculate that APDs may diminish NE’s inhibitory tone in α-cells and β-cells, especially during periods of stress when circulating NE is elevated, further exacerbating APD-induced dysglycemia.

Besides actions of APDs on DA receptors, these drugs act at additional targets including the 5-HT system. In the CNS, APD blockade of hypothalamic 5HT2a and 5HT2c receptors has been implicated in drug-induced weight gain (99). However, APDs may concurrently disrupt islet 5-HT signaling. Indeed, human and rodent β-cells produce, package, and store 5-HT, which is coreleased with insulin (7,159161), and express most 5-HT receptors, albeit with species- and cell type–specific differences (159,162,163). Moreover, 5-HT produced by β-cells stimulates inhibitory α-cell 5-HT1F receptors to decrease glucagon secretion, producing hypoglycemia (159). These results highlight the importance of paracrine signaling between α-cells and β-cells for glycemic control and suggest that APDs similarly interfere with α-cell and β-cell 5-HT signaling to potentiate their dysglycemic effects.

Amino acids are ubiquitous given their roles as building blocks of protein synthesis. However, these molecules have been repurposed in virtually all organ systems for cell signaling. While largely associated with brain functions, these molecules play substantial roles in pancreatic α-cells and β-cells to modulate hormone secretion. Context matters; where these molecules signal plays a critical role in what they do and explains why these amino acid derivatives possess one set of functions in the CNS as neurotransmitters while, in the pancreas, they serve as modulators of hormone secretion. For DA and NE, an important advantage of amino acid–derived signaling is that this permits the pancreas to couple local signaling to changes in the nutritional state, since the precursors of these molecules rise and fall according to states of feeding versus fasting. Furthermore, the capability of catecholamines to signal interchangeably at dopaminergic versus adrenergic receptors, but trigger distinct intracellular signaling cascades, enables the pancreas to further distinguish between NE/Epi-driven states of stress versus states of feeding in which local DA biosynthesis predominates. Lastly, psychiatric medications designed to target the brain are just as likely to act in the periphery. Consequently, APDs disrupt local pancreatic receptor signaling responsible for modulation of hormone release, leading to dysglycemia. Better understanding of how neurotransmitters signal in the periphery provides new opportunities to design novel, more effective strategies to tune metabolism and treat diabetes.

Acknowledgments. Figures were created with BioRender (BioRender.com).

Funding. This work was supported by National Institutes of Health grants R01 DK124219, R21 AG068607, R21 DA052419, and R21 AA028800 (to Z.F.) and R01 DK112836, R01 DK120377, and 1R01DK120698-01 (to G.K.G.) as well as by U.S. Department of Defense grant PR210207 (Z.F.).

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. Z.F. and G.K.G. conceived, designed, wrote, edited, and revised the manuscript and associated figures.

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