Xiaohui Pan1,2†
Shibing Tao
Nanwei Tong- 1Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
- 2Laboratory of Diabetes and Islet Transplantation, Center for Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu, China
- 3Department of Endocrinology, Ziyang First People’s Hospital, Ziyang, China
Neurotransmitters are signaling molecules secreted by neurons to coordinate communication and proper function among different sections in the central neural system (CNS) by binding with different receptors. Some neurotransmitters as well as their receptors are found in pancreatic islets and are involved in the regulation of glucose homeostasis. Neurotransmitters can act with their receptors in pancreatic islets to stimulate or inhibit the secretion of insulin (β cell), glucagon (α cell) or somatostatin (δ cell). Neurotransmitter receptors are either G-protein coupled receptors or ligand-gated channels, their effects on blood glucose are mainly decided by the number and location of them in islets. Dysfunction of neurotransmitters receptors in islets is involved in the development of β cell dysfunction and type 2 diabetes (T2D).Therapies targeting different transmitter systems have great potential in the prevention and treatment of T2D and other metabolic diseases.
Introduction
Glucose homeostasis is critical for life maintenance, and the normal glucose ranges for the body are set by the biological defended level of glycemia (BDGL) in the central nervous system (CNS). The neuronal populations in the arcuate nucleus of the hypothalamus are crucial for the regulation of energy balance, primarily in the control of food intake (i.e., appetite), which makes the CNS an indispensable part of metabolism (1). The pancreatic islets are key parts of glucose homeostasis. Pancreatic β cells are the only source of the glucose-lowering hormone insulin in the body. Dysfunction of β cells leads to impaired or insufficient insulin secretion, which results in hyperglycemia and diabetes. Nutrients in circulation, such as glucose, fatty acids and amino acids, can act on islets directly or indirectly to modulate the secretion of hormones from islets to regulate blood glucose.
Glucose is the most important insulin secretagogue. When blood glucose is higher than the Km of glucose transporters on the β cell membrane, they work to take up glucose into cells. The metabolism of glucose generates adenosine triphosphate (ATP), resulting in closure of ATP-sensitive K+ channels (KATP) to trigger membrane depolarization, electrical activity and opening of voltage-dependent Ca2+ channels (VDCCs), increasing the intracellular Ca2+concentration ([Ca2+]i) and initiating exocytosis of insulin granules (2, 3). The other cells in the islets share a similar secretion pattern and play roles in the maintenance of glucose homeostasis. The α cells of the pancreatic islets secrete glucagon to raise blood glucose in response to hypoglycemia, and the δ cells secrete somatostatin to inhibit the secretion of both insulin and glucagon. Appropriate communication within the islets as well as between islets and other organs is needed to maintain glucose homeostasis under different situations (4).
Neurotransmitters are a group of signaling molecules secreted by neurons that modulate the function of the nervous system, including amino acids, monoamines, peptides, and purines (5). The blood–brain barrier (BBB) restricts the communication of neurotransmitters between the CNS and periphery to keep the brain functioning correctly. The islet is a mini-organ vascularized and innervated substantially, and CNS-derived neurotransmitters can function on islets through sympathetic and parasympathetic nerves (6, 7). Moreover, neurotransmitters in the CNS can also be synthesized in the periphery, including islets, and regulate insulin secretion in a glucose-dependent or glucose-independent manner to maintain glucose homeostasis. Upon binding with corresponding receptors on the membrane, the signaling molecules exert stimulatory or inhibitory effects on hormones secretion. There are two major types of neurotransmitter receptors: inotropic receptors and metabotropic receptors (8). Ionotropic receptors provide ligand-gated channels for ions and alter the membrane potential to excite or inhibit cell activity. Most metabotropic receptors are G protein-coupled receptors (GPCRs), which rely on second messengers inside the cell to modulate ion channels or trigger signaling cascades to release calcium from cells (9).
Functional GPCRs can be divided into four families depending on the α subunit type: the Gαs family, Gαi/Gαo family, Gαq/11 family, and Gα12/Gα13 family. The Gαs and Gαi/o pathways target the cyclic adenosine monophosphate (cAMP)-generating enzyme adenylyl cyclase (AC) to stimulate or inhibit the conversion of cytosolic ATP to cAMP. Cytosolic cAMP determines the activities of ion channels and is considered a second messenger of GPCRs. The effector of the Gq/11 pathway is phospholipase C-β, which produces the second messengers inositol (1,4,5) trisphosphate (IP3) and diacylglycerol (DAG) to increase cytosolic Ca2+ levels.
The pancreatic islets are key parts of glucose homeostasis. Appropriate communication between islets and other organs is needed to maintain glucose homeostasis under different situations (4).
The neuronal populations in the arcuate nucleus of the hypothalamus are crucial for the regulation of energy balance, primarily in the control of food intake. In addition, the normal glucose ranges are set by the biological defended level of glycemia (BDLG) in the central nervous system (CNS) (1). Nutrients in circulation, such as glucose, fatty acids and amino acids, can act on islets directly or indirectly to modulate the secretion of hormones from islets to regulate glucose levels. The endocrine cells in islets (α, β and δ cells) share the same vesicular formation and secretion mechanisms as those in the CNS.
In this paper, we will review the function of neurotransmitters and their related receptors in islets and their roles in the development of type 2 diabetes (T2D), and discuss their potential in the treatment of T2D and other metabolic diseases.
Amino Acids
Glutamate
Glutamate is a nonessential amino acid in the body and a primary excitatory neurotransmitter in the CNS (10). Glutamate is synthesized in most tissues and is contained in many foods. Intracellular glutamate is formed in mitochondria by glutamate dehydrogenase (GDH) or in the cytosol with the malate-aspartate shuttle (MA). In islets, glutamate mainly comes from α cells, and glutamate infiltration from blood through vessels is insignificant (11). Once formed, intracellular glutamate can be loaded into secretory granules by vesicular glutamate transporter 2 (VGLUT2) and released with glucagon under low-glucose conditions (12).
The glutamate receptors include ionotropic receptors N-methyl-D-aspartate (NMDA) receptors and non-NMDA receptors and metabotropic receptors named mGluR1-8. NMDA receptors can be activated by glycine and glutamate, regulating intracellular sodium and calcium balance. Non-NMDA receptors, including α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors and kainate receptors, mediate fast excitatory synaptic transmission. In islets, NMDA receptors are expressed on β cells, and non-NMDA or AMPA/kainate receptors are expressed on α and δ cells. The activation of NMDA receptors on β cells facilitates calcium influx and induces transient insulin secretion. However, the net effect of NMDA receptor activation is inhibiting repolarization after depolarization, resulting in inhibited glucose-stimulated insulin secretion (GSIS). Continuous NMDA receptor activation causes excitotoxicity and death of neurons in the CNS, so does β cells in islets (13). Inhibition of NMDA receptors can enhance GSIS and increase insulin content in islets to improve glucose tolerance in mice (14, 15). AMPA/kainate receptors have less affinity for glutamate than NMDA receptors, and they mediate the excitatory effect of glutamate on neurons in the CNS and α cells in islets. Glutamine is an amino acid with known glucagonotropic effects. Activation of AMPA/kainite receptors on α cells induces influxes of sodium and calcium, leading to depolarization and secretion of glucagon along with intracellular glutamate. The released glutamate can bind with AMPA/kainate receptors again to form a positive feedback loop for glucagon secretion (15, 16). Rat δ cells express the AMPA receptor, and glutamate induces somatostatin release from δ cells under low-glucose conditions, inhibits the secretion of glutamate and glucagon from α cells and forms negative feedback in islets (17).
The mGluRs and related GPCRs have also been shown to regulate islet function, in addition to their roles in the CNS and diabetic neuropathy (18). Group I mGluRs (mGluR1,5) belong to the Gq/11 family, and group II mGluRs (mGluR2,3) and group III mGluRs (mGluR4,6,7,8) belong to the Gi/o and Gs families, respectively. The mGluR4 was identified in rat islets and plays a role in PP cells as well as α cells (19, 20). The mGluR8 was detected in male Wistar rat islets, rodent insulin-secreted cell lines RINm5F and MIN6 cells (20), in which the specific agonist of group III receptors inhibited insulin release. However, mGluR8 is also present in α cells of female Sprague–Dawley rats, and the mGluR8 agonist inhibited glucagon release; the group III receptor antagonist reduced this effect (21). The mGluR3 and mGluR5 were detected in rat and human islets (20), and agonists specific to group I or group II increased the release of insulin. The mGluR5 was shown to functionally interact with NMDARs and is needed for optimal insulin secretion (22). The expression of mGluRs in other cells of islets and their function needs further research.
Plasma glutamate levels are elevated in many chronic oxidative stress conditions, such as obesity, insulin resistance, diabetes and cancer (23), and in acute injuries, such as head trauma or cerebral ischemia, creating excitotoxicity and facilitating inflammation (24). Prolonged high glutamate levels accelerate the onset of T2D and increase the risks of cardiovascular diseases in obesity and T2D patients (25, 26). Type 1 diabetes (T1D) patients have higher glutamate levels in their brains, which can be used as an early marker of diabetes-related neurodegenerative diseases (27). Recently, therapies targeting glutamate receptors have been developed to treat T2D. NMDAR antagonists, such as dextromethorphan (DXM), amantadine and memantine, have been successfully used in the treatment of many diseases for decades, including nonproductive cough, nonketotic hyperglycemia, Parkinson’s disease, and Alzheimer’s disease (28). DXM was proven to improve insulin secretion and glycemic control in T2D patients (14, 29). The DXM derivative Lam39M increased the duration and frequency of Ca2+ oscillations, extended the time of insulin secretion, and protected mouse and human pancreatic islets from cell death. Lam39M also has lower penetration to the BBB, minimizing the NMDA inhibition effects on the CNS (30). Hence, developing NMDA receptor antagonists with higher specificity to β cells or islets can be a promising road for the treatment of T2D.
Gamma-Aminobutyric Acid
Gamma-aminobutyric acid (GABA) is synthesized by glutamate and glutamate decarboxylase (GAD) in GABAergic neurons and is the most important inhibitory neurotransmitter in the mammalian CNS. Bacteroidetes in the gut are the main source of GABA in the periphery (31). Although the BBB separates peripheral GABA from the CNS, supplemental GABA or precursors of GABA can orally feedback to the CNS through the enteric nervous system (ENS) (32) and GABA receptors on adrenergic and cholinergic nerves (33, 34).
The islet has a density of GABA and GABA receptors comparable to that of the CNS (35). The receptors of GABA include the ligand-gated ion channel GABAA and the GPCR member GABAB. GABAA activation induces chloride influx, inhibiting depolarization and reducing excitability of target cells. GABAB couples with the Gi/o protein and inhibits cAMP production to exert an inhibitory effect.
The GABA in islets is supplied by β cells by the time of insulin secretion (36). The simultaneously released GABA can bind with GABAA receptors on β cells to inhibit insulin secretion as an autocrine signal. Activation of GABAA receptors also enhanced proliferation of β cells (37). Meanwhile, GABA from β cells can inhibit glucagon secretion and cell proliferation by binding with GABAA receptors on α cells as a paracrine signal (38).When the glucose level is not high enough to evoke action potentials on membranes of β cells, the chloride potential made by the GABAA receptor can moderately depolarize β cells to induce insulin and GABA release (39), but when the glucose level is higher than BDLG, GABA will inhibit excessive release of insulin (40). It has been reported that human δ cells express GABAA receptors and that the GABAA antagonist SR95531 reduces the secretion of somatostatin at different glucose concentrations (39).
The mRNAs of GABAB receptors 1 and 2 were identified in islets of rats and human and MIN6 cells, and the GABAB receptor agonist inhibited the release of insulin in the presence of 25 mmol/l glucose (20, 41). Knockout of the GABAB receptor improved glucose tolerance and increased insulin content in the islets of mice, but constitutive absence of the GABAB receptor induced insulin resistance in mice (42).
The GABA content in islets of T2D patients and animals is lower than normal, accompanied by β cell dysfunction and lower insulin content (43). The presence of GAD autoantibodies is important for the diagnosis of autoimmune diabetes (44). In addition to endocrine cells in islets, GABA also works on innate immune cells such as T cells, inhibiting NF-κB signaling and protecting β cells from inflammation, especially in conditions such as T1D and islet transplantations (45).
Glycine
Glycine is the simplest stable amino acid acting as an inhibitory neurotransmitter in the CNS (46). The glycine level in human cerebrospinal fluid is 5 µM but increases to 150-400 µM in blood. Extracellular glycine can bind with glycine receptors (GlyRs) or be transported into cells by glycine transporters (GlyTs). GlyR is an ionotropic receptor that mediates the transport of chloride. Both GlyR and GlyT are expressed on α cells and β cells of human islets but are barely detected in rodents (47, 48). Although glycine inhibits the activity of neurons in the CNS, it actually excites β cells in islets due to different intracellular chloride concentrations (7 mM in neurons and 32 mM in β cells). Glycine induced depolarization and increased intracellular calcium in β cells (47). Glycine can be coreleased with insulin, and insulin can enhance the effect of glycine-activated current (47, 49). In α cells of islets, glycine can induce glucagon secretion in vitro and in vivo without a significant change in insulin levels (48, 50). Moreover, glycine can bind with and saturate NMDA receptors as an endogenous antagonist (51), block the excitotoxic effect of glutamate and help maintain normal GSIS (14, 15).
The lower glycine levels in circulation are related to obesity, diabetes and nonalcoholic fatty liver disease (NAFLD), and GlyR expression and glycine-induced currents on β cells of T2D patients is also reduced (52, 53). Supplementation with glycine can alleviate oxidative stress, lower blood pressure, and reduce risks for T2D (54). The elevation of glycine might be protective for people with higher metabolic risks.
D-Amino Acids
Natural amino acids can be divided into L-type and D-type based on their chirality (except glycine). D-amino acids can be derived from L-amino acids by racemases or under oxidative stress, and some of them also come from food and gut microbiota (55). D-aspartate (D-Asp) and D-serine (D-Ser) are major D-amino acids in mammals.
D-Asp is a racemase product of L-aspartate and a precursor of NMDA and is located at the pineal gland and pituitary in the CNS and adrenal gland (56). D-Asp can stimulate hormone secretion from pituitary glands and the hypothalamus (57). Hyperglycemia can induce the release of D-Asp from the retina of diabetic rats and is related to diabetic retinopathy (58). Although D-Asp is found in α cells and can be released from the rat insulinoma cell line INS-1 along with insulin (59, 60), the function of D-Asp in islets is unclear.
D-Ser is a neuromodulator derived from serine under serine racemase (SRR) in the CNS. D-Ser can inhibit high-fat diet consumption and reduce body weight in mice (61). The content of D-Ser is highest in the CNS, others are also present in the liver, kidney and pancreas (62).The key enzyme of D-Ser synthesis, SRR, is expressed in β cells of human and mouse (63). SRR-knockout mice (Srr-KO) have similar D-Ser content but less insulin content in the pancreas than wild-type (WT) mice (64). Srr-KO mice have lower blood glucose and fasting insulin levels and better glucose tolerance and insulin sensitivity (65). D-Ser acts as a coactivator of NMDA receptors in the CNS, and deletion of SRR in the brain impairs the function of NMDA receptors. Not surprisingly, Srr-KO mice have fewer NMDA receptors on islets, and the NMDA receptor antagonist MK-801 failed to suppress insulin secretion in the islets of Srr-KO mice (65).
A high D-Ser diet increases D-Ser levels in blood and leads to hyperglycemia and impaired glucose tolerance in mice, which can be blocked by α2-adrenergic receptor antagonists (61). Therefore, the adrenergic system might participate in the effect of D-Ser in islets. Polymorphisms of the SRR gene are associated with T2D susceptibility (66) and metformin efficiency (67). Thus researches on the metabolism and effects of D-amino acids are worthwhile in the treatment of T2D.
Monoamine
Monoamine neurotransmitters (MNTs), including serotonin, norepinephrine, dopamine and histamine, exist broadly in the central and peripheral neural system (68). MNTs are degraded by monoamine oxidase (MAO) or reuptake by monoamine transporters (vesicular monoamine transporters, dopamine transporters, norepinephrine transporters) to halt the effects (69). Dysregulation of MNTs is a primary cause of mental diseases.
Serotonin
Tryptophan is processed by tryptophan hydroxylase (TPH) and aromatic-L-amino acid decarboxylase (AADC) to form 5-hydroxy tryptamine (5-HT, serotonin) in the CNS and intestines. Entrochromaffin cells (ECCs) contribute approximately 90% of 5-HT in the body, and the others function separately due to the existence of the BBB (70). The receptors of 5-HT belong to GPCRs except 5-HT receptor 3 (5-HT3R), which is a ligand-gated ion channel.
β cells have the key enzymes TPH and ADCC to synthesize 5-HT (71) and vesicular monoamine transporters (VMATs) to load 5-HT on vesicles, so the 5-HT can be released with insulin, GABA and glycine from β cells (72). 5-HT has multiple effects on β cells. Action through 5-HT2BR increases β cell proliferation, and activation of 5-HT3R increases insulin secretion and improves glucose sensitivity. The add-on effects of receptors are critical for compensatory insulin secretion during metabolic stress conditions such as pregnancy and a high-fat diet, by which the expression of TPH also increases. After the physical stresses finish, 5-HT1DR can help to recover β cell mass back to normal (73, 74). In addition to receptor-mediated effects, 5-HT can regulate insulin secretion by serotonylation of GTPase in β cells and facilitate the secretion of insulin (75).
Some 5-HTRs couple with Gi/o to reduce cAMP levels and inhibit depolarization. In islets, the inhibitory receptors 5-HT1FR and 5-HT5AR are expressed on α cells, and 5-HT1DR is expressed on δ cells. Therefore, 5-HT inhibits the release of glucagon and SS (76, 77). Although δ cells can also synthesize and release 5-HT, the major source of 5-HT in islets is still β cells, and the inhibition of glucagon by 5-HT also comes from paracrine signals of β cells (78).
5-HT is necessary to maintain glucose homeostasis in humans and mice. The 5-HT1FR on α cells is lower in T2D patients, which might contribute to hyperglycemia (78, 79). Obesity and hyperglycemia are common side effects of the antipsychotic drugs 5-HT receptor antagonists and MAO antagonists, which can be relieved after drug withdrawal (80).
Catecholamine
Catecholamine (CA) is a group of chemicals synthesized from phenylalanine or tyrosine in the central and peripheral nervous systems, including dopamine, epinephrine and norepinephrine.
Dopamine comes mainly from dopaminergic neurons in the substantia nigra and ventral tegmental area in the CNS and peripheral nerves, the adrenal medulla and some neuroendocrine cells are the main sources of dopamine in the periphery (81). Norepinephrine is synthesized and released by the locus coeruleus in the CNS and sympathetic nerves in the periphery. Epinephrine is released from the adrenal gland and some neurons in the brain stem. Both α and β cells in islets of humans and rodents possess enzymes of CA synthesis and specific transporters for CAs, which means they could be possible sources of CAs in islets (82).
The receptors of CAs are GPCRs. The CAs couple with Gs or Gi/o subunits to induce excitation and inhibition, respectively. The excitatory receptors increasing cAMP concentration include the D1 and D5 dopamine receptors and the α1, β1, β2 and β3 adrenergic receptors. The inhibitory receptors D2, D3 and D4 dopamine receptors, the α2 adrenergic receptors, reduce the cAMP level in cells (83).
The dopamine receptors D1, D5 (82, 84) and the adrenergic receptor α2 are expressed on β cells (85), while the dopamine receptors D2 and D3 (82) and the adrenergic receptors α1, β1, and β2 are expressed on α cells (86, 87). The effects of dopamine and norepinephrine on islets are inhibiting insulin secretion and promoting glucagon secretion (87, 88). The activation of α2 adrenergic receptors on β cells can suppress insulin secretion, insulin gene expression and insulin synthesis (89, 90). There is clear evidence that overexpression of α2 adrenergic receptors in rodent β cells causes impaired insulin secretion and is associated with spontaneous onset of T2D in GK rats and increased risk of T2D in human (91, 92). Knockout of the α2 adrenergic receptor in mice showed lower blood glucose levels and higher plasma insulin levels, as well as improved glucose tolerance, than the wild type (93). A high level of dopamine inhibits β cell proliferation and induces apoptosis of β cells (94). However, dopamine is necessary for the survival and development of islets, and mice lacking synthesis enzymes or receptors of dopamine develop glucose intolerance and impaired GSIS early in their life (95). β3 adrenergic receptors exist on adipose tissue and induce lipolysis and fatty acid production upon activation (96).
The dopamine transporter (DAT) is located on the surface of β cells. DAT can take up dopamine and store them in vesicles together with intracellularly synthesized dopamine with the help of VMAT2. When β cells depolarize and secrete insulin, dopamine will act on dopamine receptors and adrenergic receptors to inhibit insulin release as an autocrine signal in negative feedback (97).
Bromocriptine is a dopamine D2 receptor agonist used in the treatment of Parkinson’s disease and hyperprolactinemia. Additionally, it has been used as a central antidiabetic drug for years and is still recommended by the American Diabetes Association (ADA) in the latest guidelines (98). Bromocriptine can cause metabolic alterations in patients with insulin resistance and obesity by resetting the hypothalamic circadian rhythm of monoamine neuronal activities. The agonistic action of dopamine may reduce the hypothalamus drive for increased lipid and hepatic glucose production and insulin resistance (99). Elevated prolactin levels are frequently associated with weight gain and obesity, which are common in hyperprolactinemia patients (100). Bromocriptine has the ability to suppress prolactin levels, thereby augmenting glucose tolerance and regulating GSIS (99).
The adrenergic nerve system is activated under stresses such as cold, nervousness and hypoglycemia, promoting heat generation, glucose supplementation, lipolysis and glycolysis. The α cell is able to synthesize and release dopamine and norepinephrine and stimulate glucagon secretion by binding with the adrenergic β1 receptors themselves (82). The autocrine, paracrine and nerve-derived signals in islets can partly explain the higher risk of T2D under prolonged stresses.
T2D patients have higher norepinephrine levels in blood, which inhibits the secretion of insulin (101) and impairs the responsiveness of β cells to adrenergic signals (102). Insulin resistance is characterized by a higher insulin level in the periphery, which will inhibit the reuptake of CAs and activate adrenergic receptors on α and β cells constantly, resulting in damage to glucose homeostasis and accelerating the progression to T2D (79, 103).
Pheochromocytoma is a rare neuroendocrine tumor capable of producing CAs. Hyperglycemia is a common metabolic dysfunction of Pheochromocytoma patients, mostly because of impaired insulin secretion and insulin sensitivity. Epinephrine and norepinephrine disturb glucose homeostasis in different ways. Epinephrin tends to impair insulin secretion, while norepinephrine tends to promote insulin resistance (104). The metabolic mechanism of hyperglycemia in Pheochromocytoma patients depends on the dominant CAs released by Pheochromocytoma and the distribution of adrenergic receptors (105). In addition, it has been reported that the Pheochromocytoma cell line PC12 is rich in D-Asp (62), which can inhibit GSIS by acting on NMDA receptors on β cells (14, 15).
Histamine
Histamine is synthesized from histidine by histidine decarboxylase (HDC) and stored in mast cells and basophils in an inactive form. The tuberomammillary nucleus (TMN) neurons expressing HDC are the primary source of histamine in the CNS, and the parietal cells in the stomach also express HDC and secrete histamine. mast cell-derived histamine is scarce in the CNS and periphery under normal conditions (106).
Histamine receptors (HRs), including H1-4, are GPCRs with potential ion ligand-gated channel activity. H1R couples with the Gq/11 subunit to induce calcium current and cell excitation. H2R and H3R are inhibitory receptors that bind the Gs and Gi/o subunits, respectively. HDC is expressed in α and β cells in islets, but is more highly expressed in tumors (107). The main sources of histamine in islets are mast cells and basophils.
H1R, H2R and H3R are expressed in islet β cells of human and rodents (88, 108). The general effect of histamine on β cells is inhibition of insulin secretion and cell proliferation (109). Agonists of H1R can facilitate insulin secretion and partially counteract cytokine-induced β cell destruction (108, 110). The first generation of the antihistamine drug trimeprazine can incompletely activate H1R and increase β cell proliferation in mice (111). The H1R antagonist cetirizine did not affect diabetes development in NOD mice but did improve the glucose tolerance of high-fat diet-fed mice (112). A selective H3R inverse agonist (antagonist), JNJ-5207852, facilitates insulin secretion and possibly promotes β cell proliferation, while a selective H3R agonist inhibits insulin secretion and cell proliferation of MIN6 cells (108). Both agonists and antagonists of H2R can inhibit insulin secretion, possibly due to species variation and different receptor distributions (88, 108). H3R is expressed on α cells in islets and can inhibit glucagon release (113). Although direct evidence of H4R expression in islets is lacking, blocking H4R with its selective antagonist JNJ-39758979 was efficient in the prevention of diabetic nephropathy progression (114), possibly by inhibiting inflammatory activities in tissues.
Chronic H3R agonist treatment shows multiple metabolic benefits in mice with diet-induced obesity (DIO), such as reducing food intake and body weight and alleviating hyperleptinemia and hyperinsulinemia (115). Proxyfan is an H3R protean agonist that can be used as an agonist, inverse agonist and antagonist of H3R. In T2D mice, oral administration of Proxyfan can lower blood glucose and glycosylated hemoglobin A1c (HbA1c), and intracerebroventricular administration of Proxyfan can increase plasma insulin levels via a glucose-independent mechanism (116).
Systemic histaminergic activity is elevated in T2D patients and animals (117). Reactive oxygen species (ROS) are necessary for histamine release, and hyperglycemia can increase ROS and might contribute to the higher histamine levels in T2D patients (118). Higher histamine levels in the plasma of T2D patients also accelerate vascular injury, especially in the aorta, increasing the risk of cardiovascular diseases (119). The islets of T1D patients and streptozotocin-induced diabetic animals have significant mast cell infiltration, and the histamine released by mast cells can aggravate immune injury and lead to cell death through the caspase pathway (120). H2R antagonists are widely used as antacid agents to treat peptic ulcers, and H2R antagonist treatment is associated with a lower prevalence of NAFLD in men (121). It is possible that they have antioxidant properties and direct effects on inflammatory cells, including monocytes, which might prevent inflammation. However, prolonged treatment with H2R antagonists increases the risk of T2D in peptic ulcer patients (122, 123).
Acetylcholine
Acetylcholine (ACh) is a product of choline and acetyl-coenzyme A (CoA), synthesized by choline acetyltransferase (ChAT) and stored by vesicular acetylcholine transporter (vAChT) in the CNS cholinergic neurons and peripheral autonomic nervous system (sympathetic and parasympathetic nerves). The ACh in islets mainly comes from cholinergic nerve terminals in rodents but comes from both nerves and α cells in humans. The ACh in α cells is loaded into different vesicles from glucagon by vAChT so that they can be released separately (124, 125). The α cells are scattered in human islets but are located on the boundary of islets in rodents, which facilitates paracrine ACh signals from α cells passing to neighboring cells easily in human islets.
Cholinergic receptors can be divided into muscarinic (M) and nicotine (N) receptors. M-type receptors (mAChRs) are GPCRs that couple with the Gq/11 (M1, M3, M5) or Gi/o (M2, M4) subunits to induce excitatory or inhibitory effects on cells. The N-type receptors (nAChRs) are a ligand-gated ion channel consisting of subunits.
The M3 and M5 receptors are present on β cells and can increase insulin release upon activation (124). M3 receptor-deficient mice displayed lower glucagon and insulin levels and impaired postprandial insulin release (126). Decreased expression of M3 receptors in islets was observed under hyperglycemic conditions both in vivo and in vitro (127). These results suggest the therapeutic potential of the M3 receptor. In addition, ACh can also be involved in paracrine regulation within islets indirectly, which increases or reduces the secretion of somatostatin by binding with M1 receptors on δ cells of human or (128) with M3 and M4 receptors on δ cells of mice (129).The effects mediated by nAChRs are much more complex than those mediated by nAChRs. Isoforms of nAChRs, including α2, α3, α4, α5, α7, β2, and β4 subunits, assemble to form functional nAChRs. The predominant subunits expressed in islets are α5 and β2 in human, α7 and β2 in rodents (130, 131). Nicotine is a natural agonist of nAChRs. Smoking is one of the most famous risk factors for T2D (132). However, chronically treating db/db mice with a small amount of nicotine could improve glucose metabolism and insulin sensitivity (133). The activation of nAChRs can increase β cell mass and enhance insulin secretion (134, 135), as well as protect β cells against cytokine toxicity (130). Loss of α5nAChR in mice was related to increased nicotine intake, of which the impact on glucose homeostasis remains unclear (136). Deletion of α7-nAChR in mice impairs glucose tolerance and causes insulin resistance (133). PUN-282987 is a selective α7-nAChR agonist capable of enhancing insulin sensitivity in muscle, liver and adipose tissue in mice and reducing inflammation via the STAT3 pathway (137). Recently, nicotine was found to act on TCF7L2 in the pineal gland and transmit nicotine signals to islets, leading to dysregulation of insulin and glucagon (138).
Peptides
Peptide signals play a role in both endocrine and neural systems. The term “neuropeptide” is defined by small proteinaceous substances produced and released by neurons through the regulated secretory route and acting on neural substrates. Neuropeptides may act as neurotransmitters or neuromodulators and commonly bind to GPCRs to affect the activities of neurons and other tissues, including pancreatic islets (139, 140). With the help of genetics and multiomics techniques, the family of neuropeptides has expanded quickly during decades. We only discussed several members of the large family and their roles in pancreatic islets due to limited space, including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin, oxytocin and vasopressin. Other neuropeptides present in islets, such as peptide tyrosine-tyrosine (PYY) (141), neuropeptide Y (142) and somatostatin (129, 143), have been extensively reviewed elsewhere.
Incretin
Incretins are a group of metabolic hormones released after eating that augment the secretion of insulin by a blood glucose-dependent mechanism. GLP-1 and GIP are two main candidate molecules that fulfill the criteria for incretin (144). Both GLP-1 and GIP are rapidly inactivated by dipeptideyl peptidase-4 (DPP-4).
GLP-1 is secreted by preproglucagon neurons in the solitary nucleus in the CNS, regulating the activities of the hypothalamus and brain areas (145). GLP-1 in the periphery mostly comes from enteroendocrine L cells (146). The α cells in islets also express the preproglucagon gene and synthesize and secrete propglucagon-derived peptides, including glucagon and GLP-1 (147). The receptors of glucagon and GLP-1 share significant homology and both belong to the Gs family of GPCRs and are expressed on β cells in islets, which contribute to the cross-reactivity of glucagon and GLP-1 and induce insulin secretion (148, 149). GLP-1 promotes insulin synthesis and secretion upon stimulation (150) and acts synergistically with glucose to promote insulin gene transcription, mRNA stability, facilitate insulin biosynthesis to replenish insulin stores and prevent exhaustion and apoptosis of β cells (151). GLP-1R agonists enhance β cell proliferation and expand β cell mass even in normoglycemic rodents (152). Some researchers also found GLP-1 receptors on δ cells to control the release of somatostatin (153).
GIP is synthesized by K cells of the duodenum and small intestine. The GIP receptor is a Gs family member of GPCRs widely expressed within the CNS (154), α cells and β cells in islets (155) and white adipose tissues (156). The GIP receptor (GIPR) is expressed in similar amounts in α and β cells. GIP stimulates glucagon secretion directly through GIPRs on β cells, while GIP can potentiate the release of glucagon by activating GIPRs on α cells. Glucagon then binds with GLP-1R or the glucagon receptor and stimulates insulin secretion (155, 157). In addition to stimulating the secretion of insulin, such as GLP-1, GIP promotes triglyceride storage by directly activating GIP receptors on adipocytes and indirectly through the lipogenic actions of insulin (158) and enhances glucose uptake and insulin sensitivity of adipocytes, therefore improving the long-term storage of lipids by facilitating the healthy expansion of white adipose tissues (159). Our previous work found that GLP-1 levels in the plasma of T2D and prediabetes patients were lower than those in healthy people but did not differ between T2D and prediabetes patients (160). The genes encoding the human GLP-1 or GIP receptors have not been linked to enhanced genetic susceptibility to diabetes (63). GLP-1-targeted treatments can reduce body weight and risks of cardiovascular events, which are independent of glucose-lowering effects (161, 162). The new generation of anti-diabetic drugs GLP-1 receptor agonists (GLP-1RAs) have shown promising benefits on T2D treatment, as well as the DPP-4 inhibitors, which raises levels of GLP-1 and GIP to augment insulin release after a meal. Central and peripheral administration of GIP receptor agonists lowers body weight by reducing caloric intake (163, 164).
Clinical trials employing liraglutide (human GLP-1 analogue) or exenatide (exendin-4 derivates, animal GLP-1) in addition to intensified insulin regimes in T1D patients did not demonstrate convincing hypoglycemic benefits or describe potential adverse outcomes such as a higher risk of ketoacidosis. Only body weight and insulin doses were consistently reduced (165, 166). Some GLP-1RAs can improve the metabolism and function of the CNS when administered in the periphery they are strongly recommended by ADA for the treatment of T2D and might play positive roles in the treatment of neurodegenerative diseases (167).
Cholecystokinin
Cholecystokinin (CCK) is secreted by specialized neurons in the CNS and ENS and by enteroendocrine I cells in the intestine (168). The receptors of CCK belong to GPCRs, including CCK1 (CCKA) receptor and CCK2 (CCKB) receptor. CCK plays roles in inducing anxiety and satiety in the CNS, regulating gastric emptying and distension and gallbladder contraction in the gastrointestinal system. It is also a potent stimulator of pancreatic acinar cells that release digestive enzymes after meals (168).
The CCK1 receptor is colocalized with insulin and glucagon in the islets of pigs, rodents and human (169). Activation of CCK1 receptors initiates the Gs and Gq/11 signaling pathways in islet β cells under high- and low-glucose conditions, respectively (170). The biologically active fragment CCK-8 and agonists of the CCK1 receptor can induce insulin secretion and protect β cells against apoptosis (170, 171). CCK2 receptors were found in α cells and δ cells of islets. The CCK2 receptor is also called the gastrin receptor because another gastrointestinal peptide, gastrin, secreted by G cells in the gastric antrum shares a similar sequence with CCK and can bind to the CCK2 receptor with almost the same affinity and potency (172). Gastrin and CCK induced glucagon secretion from purified human islets, which was blocked by an antagonist of CCK2 (173).
Recently, the gene encoding cholecystokinin (Cck) was found to be expressed and upregulated in islets of obese and insulin-resistant mice. CCK was detected in both α and β cells (174). Overexpression of CCK was able to protect β cells from apoptosis, while loss of CCK resulted in reduced islet size and β cell mass and induced a diabetogenic phenotype in mice (174, 175).
The insulinotropic and protective role of CCK in islets makes it a promising therapeutic target for T2D and obesity. Structural modified CCK analogs (such as glycated CCK8 and (pGlu-Gln)-CCK8) have been proven to suppress appetite and improve glucose tolerance and plasma lipids and reduce lipid accumulation in the pancreas and body weight in obese and diabetic rodents (176). CCK has been thought to be an incretin candidate because it originates from guts and responses to nutrients, but CCK receptor blockade failed to affect postprandial insulin secretion, like GLP-1 and GIP (177). However, CCK has the potential to reduce weight and blood glucose and could be an effective adjunct therapy for T2D (178).
Oxytocin and Vasopressin
Oxytocin and vasopressin have similar structures and are synthesized in the supraoptic nucleus and paraventricular nucleus of the hypothalamus, respectively. They are stored in the neurohypophysis and released upon stimulation, such as labor and hypertonicity. Peripheral OT also comes from the uterus, placenta, amnion and heart.
The receptors of VP (V1a, V1b, V2) and oxytocin are GPCRs expressed broadly in the CNS and periphery (179). The V1a, V1b and oxytocin receptors belong to the Gq/11 family and induce excitatory effects. The V1a receptor is expressed on vessels to regulate vasoconstriction, and the V1b receptor in the CNS assist the release of andrenocorticotropic hormone (ACTH). Oxytocin plays an anorexigenic role in the CNS and primarily stimulates uterine contraction and lactation in peripheral. The V2 receptor couples with the Gs subunits to control water absorption in the kidney (180).
The pancreas is unable to generate oxytocin or vasopressin but has receptors for them on α and β cells (181, 182). The vasopressin receptor V1b is expressed both on α and β cells and can regulate glucose homeostasis in a glucose-dependent way, which increases insulin during hyperglycemia and increases glucagon during hypoglycemia (183, 184). The structure of oxytocin is similar to vasopressin, oxytocin can also bind with V1b on α cells to d induce glucagon secretion (182). V1b knockout mice present reduced fasting insulin, glucagon and blood glucose along with enhanced insulin sensitivity (185).
Oxytocin can protect β cells from metabolic stress and cytokines, promoting insulin secretion and cell proliferation (186, 187). Infusion of oxytocin can improve GSIS in healthy unpregnant humans (188), induce insulin secretion and improve glucose tolerance in DIO mice (189). In pregnant mice, oxytocin can not only initiate parturition but also increase β cell proliferation and mass (189). Gestational diabetes mellitus (GDM) patients have lower plasma oxytocin levels than healthy pregnant women, and oxytocin antagonists can impair insulin secretion and lead to the development of GDM symptoms in pregnant mice (190). Intracerebroventricular application of nanogram amounts of oxytocin causes a rise in insulin levels but can be blocked by atropine, indicating that cholinergic neurons are involved in the CNS regulation of oxytocin on glucose homeostasis (191).
T2D patients have higher vasopressin but lower oxytocin levels in plasma (185). Chronic vasopressin infusion impairs fasting glucose and glucose tolerance in lean rats, which can be observed earlier in the obese rats (184). Treatment with oxytocin can reduce food intake and body weight in human and alleviate metabolic syndromes by improve insulin resistance (192, 193). However, therapies targeting receptors of vasopressin and oxytocin or themselves for diabetes treatment might be difficult due to safety concerns, especially chronic effects on the function of neurohypophysis.
Purines
Purines are basic components synthesized biologically as nucleosides in cells, functioning as energy molecules and mediating the purinergic signaling cascade by acting on purinergic receptors in the CNS and periphery (194). Adenosine, ATP and other nucleotides, such as uridine triphosphate (UDP), are ligands of purinergic receptors P1 (adenosine receptor), P2Y and P2X receptors. P1 and P2Y receptors are GPCRs, P2X receptors are ligand-gated ion channels.
The P1 receptors A1, A2A, A2B and A3 are all found in islets. A1 receptor is a Gi/o member expressed in α and β cells, inhibiting secretion of glucagon and insulin upon activation (195–197). Knockout of A1 receptor mice had no significant effect on the first phase of insulin secretion, but prolonged and amplified the second phase of insulin, glucagon and somatostatin secretion (195). It is also reported that the expression of A1 receptor in α cells declined during the progression of autoimmune diabetes and contributed to the hyperglucagonemia in prediabetic NOD mice (198). The role of another Gi/o member A3 receptor in islets is unclear, possibly involved in the survival of β cells (197). A2A receptor and A2B receptor belong to Gs family. Activation of A2B induce insulin release in islets of rodents (199). However, the effect of A2A receptor showed species heterogeneity, which is increasing insulin secretion in mice but suppressing insulin secretion in rat β cell lines upon activation (200, 201). While in the islets of zebrafish, the nonselective adenosine receptor agonist 5’-N-ethylcarboxamidoadenosinne (NECA) was found to increase the proliferation of β cells (202).
The P2Y receptors are highly conserved across species, eight P2Y receptors have been discovered in human and six of them are expressed in the islets of either human or rodents, which are P2Y1, P2Y4, P2Y6, P2Y11, P2Y13 and P2Y14 (196, 203–208). Nucleotides including purines and pyrimidines are ligands of P2Y receptors (209). Activation of P2Y1 and P2Y6 receptors increased insulin secretion in MIN6 cells (203), P2Y6 agonist MRS 2957 induced insulin secretion at high glucose concentrations (16.7mM) (206). P2Y13 antagonist MRS2211 increased the secretion of both insulin and glucagon independent of glucose concentrations (204).
All of the known subunits of P2X receptors (P2X1-7) have been found in islets β cell of human and/or rodent (207, 210–214), the P2X7 was also found in α cells of human and mice (207, 210, 215). Activation of P2X receptors induces insulin secretion from β cells. ATP is the ligand of P2X receptors, which is generated during glucose metabolism within cells and is co-released with insulin from β cells (2). Therefore ATP plays an autocrine or paracrine role via P2X receptors in the islets (216). The expression of P2X receptors can be various in different developmental and functional state of the islets. The P2X1 and P2X4 receptors in islets of mice only emerged after birth and progressively upregulated with age (210). The P2X7 receptors in β cells of islets were upregulated in non-diabetic obese human compared with the leans possibly as a compensation, but undetectable in T2D patients (215). It is reasonable to consider P2X7 receptor a promising target for treatment of obesity and T2D (217).
Summary and Discussion
Signals from the central and peripheral nervous systems act on islets collaboratively to maintain glucose homeostasis, which is critical for life. The isolated islets are unable to survive for a long time without the regulation of transmitters and fail to proliferate and secrete insulin, which is also an obstacle for islet transplantation therapies (218, 219). The dysregulation of signals in the CNS can impair BDLG and push the onset of T2D (4). Obesity and glucose dysregulation are common side effects of antipsychotic drugs, which bring a higher risk of developing T2D (80).
Here, we review the evidence of the neurotransmitters presented out of the CNS and their roles in the glucose homeostasis, especially the transmitters that can be synthesized in the islets and their corresponding receptors expressed on cells in islets (Supplementary Table 1). With developments in imaging skills and multiomics methods, our understanding of transmitters in organisms has been expanded largely during the past decades (220, 221). As a matter of course, the transmitters synthesized by islets also function on the CNS as feedback signals, such as 5-HT and insulin (222, 223), but the specific mechanism needs further study.
Signal molecules in the CNS and periphery are promising treatment targets for many diseases. It is known that T2D is a metabolic disease caused by multiple risk factors. Hyperglycemia, which is a marker of T2D, can be found in various physiological and pathological conditions. Islet dysfunction in diabetes also promotes the progression of neurodegeneration (224). The success of GLP-1RAs is a good example of transmitter-targeted therapy (161, 162).
The gut-brain axis is a hot section of researches on glucose homeostasis, especially for a great variety of peripheral transmitters are derived from the intestines, not only endocrine cells but also bacteria capable of producing multiple neurotransmitters in the gut, such as dopamine, norepinephrine and GABA (225), which can act on both the central and peripheral regions (225). It is not surprising that some medicines for the digestive system also influence the metabolic system (122). The germ-free mice display increased turnover rates of dopamine, norepinephrine and serotonin in the brain, which could generally reduce pools in systemic circulation independent of microbial production (although factors influencing that increased turnover rate remain to be determined) (226). It is not surprising that some medicines for the digestive system also influence the metabolic system (122). Supplementation with GABA or glycine or the consumption of natural products such as resveratrol, which can influence GLP-1 and 5-HT levels in the peripheral and brain-gut axes, are beneficial to glucose homeostasis and could lower oxidative stress (32, 54, 227). Except for GLP-1, GABA and 5-HT, the intestine secretes dozens of other hormones that probably interact with the CNS to regulate glucose homeostasis, such as GIP, CCK, ghrelin, and peptide YY. The relationship between intestine-derived hormones and metabolic conditions deserves more attention and should be a promising therapeutic target for the treatment of both metabolic diseases and neural diseases.
Therapies targeting on more than one signaling molecules may bring more benefits. For example, LY3298176, a novel dual GIP and GLP-1 receptor agonist developed for the treatment of T2D, has been proven to improve glucose control and reduce body weight in T2D mice and humans (228) Another dual agonist is GEP44, a weight-loss drug acting on both receptors of GLP-1 and peptide YY, which performs better than each single drug and has less unfavorable gastrointestinal reactions (229). Direct supplementation of GABA with sitagliptin (a DPP-4 inhibitor) in T2D patients can promote β cell proliferation and protect cells against apoptosis (230). Recently, the GLP-1/GIP/Glucagon receptor triagonist SAR441255 has been proven effective in glycemic control and weight loss in humans (231). These findings show great potentials of multitarget therapies in the treatment of T2D and obesity and encourage the development of more multitarget therapies in the future. Remarkably, there is interaction among different neurotransmitters and their receptors, for example, L-cells cosecrete ATP together with GLP-1 and PYY, and ATP acts as an additional signal triggering vagal activation and potentially synergizes with the actions of locally elevated peptide hormone concentrations (232). The cross reactivities among neurotransmitter signals expand their effects, clarifying the detail procedures of their interaction can promote the development of new therapies with higher efficiency and less side effects. In addition to drugs, implanted devices directly acting on nerves also find their way in the field. Implantable vagal nerve stimulators (IVNSs) have been approved by the Food and Drug Administration (FDA) to treat epilepsy and depression, which can manipulate target tissues more precisely than planted in the CNS (233, 234). In obesity and T2D patients, the application of IVNSs has also improve glucose homeostasis (235).
Research on transmitters in the central and peripheral nervous systems can extend our understanding of neurodegenerative diseases, mental diseases and metabolic diseases, assisting in disease prevention and the development of new antipsychotic drugs with higher selectivity and fewer side metabolic effects. New therapies based on the function of neural transmitters and corresponding receptors targeting pancreatic islets or beyond are also promising for the treatment of T2D and other metabolic diseases.
Author Contributions
XP and ST reviewed the literature and wrote the manuscript. NT guided critical discussion of the topic and reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
NT has worked on clinical trials funded by Huadong Medicine Group Company Limited, and received lecture fees from Novo Nosdik. However, theses interests will not impair justice and scientific nature of this study.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Acknowledgments
This work is supported by grants from the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (No. ZYGD 18017). We sincerely thank Shishi Xu for help in discussion of the manuscript.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fendo.2022.884549/full#supplementary-material
References
1. Grayson BE, Seeley RJ, Sandoval DA. Wired on Sugar: The Role of the CNS in the Regulation of Glucose Homeostasis. Nat Rev Neurosci (2013) 14(1):24–37. doi: 10.1038/nrn3409
2. Ashcroft FM, Harrison DE, Ashcroft SJ. Glucose Induces Closure of Single Potassium Channels in Isolated Rat Pancreatic Beta-Cells. Nature (1984) 312(5993):446–8. doi: 10.1038/312446a0
3. Rorsman P, Braun M. Regulation of Insulin Secretion in Human Pancreatic Islets. Annu Rev Physiol (2013) 75:155–79. doi: 10.1146/annurev-physiol-030212-183754
4. Schwartz MW, Seeley RJ, Tschöp MH, Woods SC, Morton GJ, Myers MG, et al. Cooperation Between Brain and Islet in Glucose Homeostasis and Diabetes. Nature (2013) 503(7474):59–66. doi: 10.1038/nature12709
6. Tang S-C, Baeyens L, Shen C-N, Peng S-J, Chien H-J, Scheel DW, et al. Human Pancreatic Neuro-Insular Network in Health and Fatty Infiltration. Diabetologia (2018) 61(1):168–81. doi: 10.1007/s00125-017-4409-x
7. Sandoval D, Cota D, Seeley RJ. The Integrative Role of CNS Fuel-Sensing Mechanisms in Energy Balance and Glucose Regulation. Annu Rev Physiol (2008) 70:513–35. doi: 10.1146/annurev.physiol.70.120806.095256
8. Ferré S, Ciruela F, Woods AS, Lluis C, Franco R. Functional Relevance of Neurotransmitter Receptor Heteromers in the Central Nervous System. Trends Neurosci (2007) 30(9):440–6. doi: 10.1016/j.tins.2007.07.001
9. Hauser AS, Attwood MM, Rask-Andersen M, Schiöth HB, Gloriam DE. Trends in GPCR Drug Discovery: New Agents, Targets and Indications. Nat Rev Drug Discov (2017) 16(12):829–42. doi: 10.1038/nrd.2017.178
10. Meldrum BS. Glutamate as a Neurotransmitter in the Brain: Review of Physiology and Pathology. J Nutr (2000) 130(4S Suppl):1007S–15S. doi: 10.1093/jn/130.4.1007S
11. Zhou Y, Waanders LF, Holmseth S, Guo C, Berger UV, Li Y, et al. Proteome Analysis and Conditional Deletion of the EAAT2 Glutamate Transporter Provide Evidence Against a Role of EAAT2 in Pancreatic Insulin Secretion in Mice. J Biol Chem (2014) 289(3):1329–44. doi: 10.1074/jbc.M113.529065
12. Tapiero H, Mathé G, Couvreur P, Tew KD. II. Glutamine and Glutamate. BioMed Pharmacother (2002) 56(9):446–57. doi: 10.1016/S0753-3322(02)00285-8
13. Huang X-T, Li C, Peng X-P, Guo J, Yue S-J, Liu W, et al. An Excessive Increase in Glutamate Contributes to Glucose-Toxicity in β-Cells via Activation of Pancreatic NMDA Receptors in Rodent Diabetes. Sci Rep (2017) 7:44120. doi: 10.1038/srep44120
14. Marquard J, Otter S, Welters A, Stirban A, Fischer A, Eglinger J, et al. Characterization of Pancreatic NMDA Receptors as Possible Drug Targets for Diabetes Treatment. Nat Med (2015) 21(4):363–72. doi: 10.1038/nm.3822
15. Otter S, Lammert E. Exciting Times for Pancreatic Islets: Glutamate Signaling in Endocrine Cells. Trends Endocrinol Metab (2016) 27(3):177–88. doi: 10.1016/j.tem.2015.12.004
16. Cabrera O, Jacques-Silva MC, Speier S, Yang S-N, Köhler M, Fachado A, et al. Glutamate Is a Positive Autocrine Signal for Glucagon Release. Cell Metab (2008) 7(6):545–54. doi: 10.1016/j.cmet.2008.03.004
17. Muroyama A, Uehara S, Yatsushiro S, Echigo N, Morimoto R, Morita M, et al. A Novel Variant of Ionotropic Glutamate Receptor Regulates Somatostatin Secretion From Delta-Cells of Islets of Langerhans. Diabetes (2004) 53(7):1743–53. doi: 10.2337/diabetes.53.7.1743
18. Anjaneyulu M, Berent-Spillson A, Russell JW. Metabotropic Glutamate Receptors (Mglurs) and Diabetic Neuropathy. Curr Drug Targets (2008) 9(1):85–93. doi: 10.2174/138945008783431772
19. Uehara S, Muroyama A, Echigo N, Morimoto R, Otsuka M, Yatsushiro S, et al. Metabotropic Glutamate Receptor Type 4 Is Involved in Autoinhibitory Cascade for Glucagon Secretion by Alpha-Cells of Islet of Langerhans. Diabetes (2004) 53(4):998–1006. doi: 10.2337/diabetes.53.4.998
20. Brice NL, Varadi A, Ashcroft SJH, Molnar E. Metabotropic Glutamate and GABA(B) Receptors Contribute to the Modulation of Glucose-Stimulated Insulin Secretion in Pancreatic Beta Cells. Diabetologia (2002) 45(2):242–52. doi: 10.1007/s00125-001-0750-0
21. Tong Q, Ouedraogo R, Kirchgessner AL. Localization and Function of Group III Metabotropic Glutamate Receptors in Rat Pancreatic Islets. Am J Physiol Endocrinol Metab (2002) 282(6):E1324–33. doi: 10.1152/ajpendo.00460.2001
22. Storto M, Capobianco L, Battaglia G, Molinaro G, Gradini R, Riozzi B, et al. Insulin Secretion Is Controlled by Mglu5 Metabotropic Glutamate Receptors. Mol Pharmacol (2006) 69(4):1234–41. doi: 10.1124/mol.105.018390
23. Gaggini M, Carli F, Rosso C, Buzzigoli E, Marietti M, Della Latta V, et al. Altered Amino Acid Concentrations in NAFLD: Impact of Obesity and Insulin Resistance. Hepatology (2018) 67(1):145–58. doi: 10.1002/hep.29465
24. Hossmann KA. Glutamate-Mediated Injury in Focal Cerebral Ischemia: The Excitotoxin Hypothesis Revised. Brain Pathol (1994) 4(1):23–36. doi: 10.1111/j.1750-3639.1994.tb00808.x
25. Liu X, Zheng Y, Guasch-Ferré M, Ruiz-Canela M, Toledo E, Clish C, et al. High Plasma Glutamate and Low Glutamine-to-Glutamate Ratio Are Associated With Type 2 Diabetes: Case-Cohort Study Within the PREDIMED Trial. Nutr Metab Cardiovasc Dis (2019) 29(10):1040–9. doi: 10.1016/j.numecd.2019.06.005
26. Palmer ND, Stevens RD, Antinozzi PA, Anderson A, Bergman RN, Wagenknecht LE, et al. Metabolomic Profile Associated With Insulin Resistance and Conversion to Diabetes in the Insulin Resistance Atherosclerosis Study. J Clin Endocrinol Metab (2015) 100(3):E463–E8. doi: 10.1210/jc.2014-2357
27. Wiegers EC, Rooijackers HM, van Asten JJA, Tack CJ, Heerschap A, de Galan BE, et al. Elevated Brain Glutamate Levels in Type 1 Diabetes: Correlations With Glycaemic Control and Age of Disease Onset But Not With Hypoglycaemia Awareness Status. Diabetologia (2019) 62(6):1065–73. doi: 10.1007/s00125-019-4862-9
28. Kalia LV, Kalia SK, Salter MW. NMDA Receptors in Clinical Neurology: Excitatory Times Ahead. Lancet Neurol (2008) 7(8):742–55. doi: 10.1016/S1474-4422(08)70165-0
29. Welters A, Klüppel C, Mrugala J, Wörmeyer L, Meissner T, Mayatepek E, et al. NMDAR Antagonists for the Treatment of Diabetes Mellitus-Current Status and Future Directions. Diabetes Obes Metab (2017) 19(Suppl 1):95–106. doi: 10.1111/dom.13017
30. Scholz O, Otter S, Welters A, Wörmeyer L, Dolenšek J, Klemen MS, et al. Peripherally Active Dextromethorphan Derivatives Lower Blood Glucose Levels by Targeting Pancreatic Islets. Cell Chem Biol (2021) 28(10):1484–8.e7. doi: 10.1016/j.chembiol.2021.05.011
31. Strandwitz P, Kim KH, Terekhova D, Liu JK, Sharma A, Levering J, et al. GABA-Modulating Bacteria of the Human Gut Microbiota. Nat Microbiol (2019) 4(3):396–403. doi: 10.1038/s41564-018-0307-3
32. Boonstra E, de Kleijn R, Colzato LS, Alkemade A, Forstmann BU, Nieuwenhuis S. Neurotransmitters as Food Supplements: The Effects of GABA on Brain and Behavior. Front Psychol (2015) 6:1520. doi: 10.3389/fpsyg.2015.01520
33. Shi Y, Li Y, Yin J, Hu H, Xue M, Li X, et al. A Novel Sympathetic Neuronal GABAergic Signalling System Regulates NE Release to Prevent Ventricular Arrhythmias After Acute Myocardial Infarction. Acta Physiol (Oxf) (2019) 227(2):e13315. doi: 10.1111/apha.13315
34. Malomouzh A, Ilyin V, Nikolsky E. Components of the GABAergic Signaling in the Peripheral Cholinergic Synapses of Vertebrates: A Review. Amino Acids (2019) 51(8):1093–102. doi: 10.1007/s00726-019-02754-x
35. Okada Y, Taniguchi H, Schimada C. High Concentration of GABA and High Glutamate Decarboxylase Activity in Rat Pancreatic Islets and Human Insulinoma. Science (1976) 194(4265):620–2. doi: 10.1126/science.185693
36. Reetz A, Solimena M, Matteoli M, Folli F, Takei K, De Camilli P. GABA and Pancreatic Beta-Cells: Colocalization of Glutamic Acid Decarboxylase (GAD) and GABA With Synaptic-Like Microvesicles Suggests Their Role in GABA Storage and Secretion. EMBO J (1991) 10(5):1275–84. doi: 10.1002/j.1460-2075.1991.tb08069.x
37. Untereiner A, Xu J, Bhattacharjee A, Cabrera O, Hu C, Dai FF, et al. γ-Aminobutyric Acid Stimulates β-Cell Proliferation Through the Mtorc1/P70s6k Pathway, an Effect Amplified by Ly49, a Novel γ-Aminobutyric Acid Type A Receptor Positive Allosteric Modulator. Diabetes Obes Metab (2020) 22(11):2021–31. doi: 10.1111/dom.14118
38. Feng AL, Xiang Y-Y, Gui L, Kaltsidis G, Feng Q, Lu W-Y. Paracrine GABA and Insulin Regulate Pancreatic Alpha Cell Proliferation in a Mouse Model of Type 1 Diabetes. Diabetologia (2017) 60(6):1033–42. doi: 10.1007/s00125-017-4239-x
39. Braun M, Ramracheya R, Bengtsson M, Clark A, Walker JN, Johnson PR, et al. Gamma-Aminobutyric Acid (GABA) Is an Autocrine Excitatory Transmitter in Human Pancreatic Beta-Cells. Diabetes (2010) 59(7):1694–701. doi: 10.2337/db09-0797
40. Dong H, Kumar M, Zhang Y, Gyulkhandanyan A, Xiang YY, Ye B, et al. Gamma-Aminobutyric Acid Up- and Downregulates Insulin Secretion From Beta Cells in Concert With Changes in Glucose Concentration. Diabetologia (2006) 49(4):697–705. doi: 10.1007/s00125-005-0123-1
41. Rachdi L, Maugein A, Pechberty S, Armanet M, Hamroune J, Ravassard P, et al. Regulated Expression and Function of the GABA Receptor in Human Pancreatic Beta Cell Line and Islets. Sci Rep (2020) 10(1):13469. doi: 10.1038/s41598-020-69758-6
42. Bonaventura MM, Catalano PN, Chamson-Reig A, Arany E, Hill D, Bettler B, et al. GABAB Receptors and Glucose Homeostasis: Evaluation in GABAB Receptor Knockout Mice. Am J Physiol Endocrinol Metab (2008) 294(1):E157–67. doi: 10.1152/ajpendo.00615.2006
43. Menegaz D, Hagan DW, Almaça J, Cianciaruso C, Rodriguez-Diaz R, Molina J, et al. Mechanism and Effects of Pulsatile GABA Secretion From Cytosolic Pools in the Human Beta Cell. Nat Metab (2019) 1(11):1110–26. doi: 10.1038/s42255-019-0135-7
44. Regnell SE, Lernmark Å. Early Prediction of Autoimmune (Type 1) Diabetes. Diabetologia (2017) 60(8):1370–81. doi: 10.1007/s00125-017-4308-1
45. Prud'homme GJ, Glinka Y, Hasilo C, Paraskevas S, Li X, Wang Q. GABA Protects Human Islet Cells Against the Deleterious Effects of Immunosuppressive Drugs and Exerts Immunoinhibitory Effects Alone. Transplantation (2013) 96(7):616–23. doi: 10.1097/TP.0b013e31829c24be
46. Betz H, Laube B. Glycine Receptors: Recent Insights Into Their Structural Organization and Functional Diversity. J Neurochem (2006) 97(6):1600–10. doi: 10.1111/j.1471-4159.2006.03908.x
47. Yan-Do R, Duong E, Manning Fox JE, Dai X, Suzuki K, Khan S, et al. A Glycine-Insulin Autocrine Feedback Loop Enhances Insulin Secretion From Human β-Cells and Is Impaired in Type 2 Diabetes. Diabetes (2016) 65(8):2311–21. doi: 10.2337/db15-1272
48. Li C, Liu C, Nissim I, Chen J, Chen P, Doliba N, et al. Regulation of Glucagon Secretion in Normal and Diabetic Human Islets by γ-Hydroxybutyrate and Glycine. J Biol Chem (2013) 288(6):3938–51. doi: 10.1074/jbc.M112.385682
49. Caraiscos VB, Bonin RP, Newell JG, Czerwinska E, Macdonald JF, Orser BA. Insulin Increases the Potency of Glycine at Ionotropic Glycine Receptors. Mol Pharmacol (2007) 71(5):1277–87. doi: 10.1124/mol.106.033563
50. Gannon MC, Nuttall JA, Nuttall FQ. The Metabolic Response to Ingested Glycine. Am J Clin Nutr (2002) 76(6):1302–7. doi: 10.1093/ajcn/76.6.1302
51. Johnson JW, Ascher P. Glycine Potentiates the NMDA Response in Cultured Mouse Brain Neurons. Nature (1987) 325(6104):529–31. doi: 10.1038/325529a0
52. Alves A, Bassot A, Bulteau A-L, Pirola L, Morio B. Glycine Metabolism and Its Alterations in Obesity and Metabolic Diseases. Nutrients (2019) 11(6):1356. doi: 10.3390/nu11061356
53. Adeva-Andany M, Souto-Adeva G, Ameneiros-Rodríguez E, Fernández-Fernández C, Donapetry-García C, Domínguez-Montero A. Insulin Resistance and Glycine Metabolism in Humans. Amino Acids (2018) 50(1):11–27. doi: 10.1007/s00726-017-2508-0
54. Díaz-Flores M, Cruz M, Duran-Reyes G, Munguia-Miranda C, Loza-Rodríguez H, Pulido-Casas E, et al. Oral Supplementation With Glycine Reduces Oxidative Stress in Patients With Metabolic Syndrome, Improving Their Systolic Blood Pressure. Can J Physiol Pharmacol (2013) 91(10):855–60. doi: 10.1139/cjpp-2012-0341
55. Abdulbagi M, Wang L, Siddig O, Di B, Li B. D-Amino Acids and D-Amino Acid-Containing Peptides: Potential Disease Biomarkers and Therapeutic Targets? Biomolecules (2021) 11(11):1716. doi: 10.3390/biom11111716
56. Wolosker H, D'Aniello A, Snyder SH. D-Aspartate Disposition in Neuronal and Endocrine Tissues: Ontogeny, Biosynthesis and Release. Neuroscience (2000) 100(1):183–9. doi: 10.1016/S0306-4522(00)00321-3
57. D'Aniello G, Tolino A, D'Aniello A, Errico F, Fisher GH, Di Fiore MM. The Role of D-Aspartic Acid and N-Methyl-D-Aspartic Acid in the Regulation of Prolactin Release. Endocrinology (2000) 141(10):3862–70. doi: 10.1210/endo.141.10.7706
58. Santiago AR, Pereira TS, Garrido MJ, Cristóvão AJ, Santos PF, Ambrósio AF. High Glucose and Diabetes Increase the Release of [3H]-D-Aspartate in Retinal Cell Cultures and in Rat Retinas. Neurochem Int (2006) 48(6-7):453–8. doi: 10.1016/j.neuint.2005.10.013
59. Hiasa M, Moriyama Y. Immunohistochemical Localization of D-Aspartate in Islets of Langerhans. Biol Pharm Bull (2006) 29(6):1251–3. doi: 10.1248/bpb.29.1251
60. Iharada M, Hiasa M, Kobara A, Moriyama Y. Exocytosis of D-Aspartate From INS-1E Clonal Beta Cells. Biol Pharm Bull (2007) 30(7):1329–31. doi: 10.1248/bpb.30.1329
61. Suwandhi L, Hausmann S, Braun A, Gruber T, Heinzmann SS, Gálvez EJC, et al. Chronic D-Serine Supplementation Impairs Insulin Secretion. Mol Metab (2018) 16:191–202. doi: 10.1016/j.molmet.2018.07.002
62. Ito T, Hayashida M, Kobayashi S, Muto N, Hayashi A, Yoshimura T, et al. Serine Racemase Is Involved in D-Aspartate Biosynthesis. J Biochem (2016) 160(6):345–53. doi: 10.1093/jb/mvw043
63. Benner C, van der Meulen T, Cacéres E, Tigyi K, Donaldson CJ, Huising MO. The Transcriptional Landscape of Mouse Beta Cells Compared to Human Beta Cells Reveals Notable Species Differences in Long Non-Coding RNA and Protein-Coding Gene Expression. BMC Genomics (2014) 15:620. doi: 10.1186/1471-2164-15-620
64. Horio M, Kohno M, Fujita Y, Ishima T, Inoue R, Mori H, et al. Levels of D-Serine in the Brain and Peripheral Organs of Serine Racemase (Srr) Knock-Out Mice. Neurochem Int (2011) 59(6):853–9. doi: 10.1016/j.neuint.2011.08.017
65. Lockridge AD, Baumann DC, Akhaphong B, Abrenica A, Miller RF, Alejandro EU. Serine Racemase Is Expressed in Islets and Contributes to the Regulation of Glucose Homeostasis. Islets (2016) 8(6):195–206. doi: 10.1080/19382014.2016.1260797
66. Tsai F-J, Yang C-F, Chen C-C, Chuang L-M, Lu C-H, Chang C-T, et al. A Genome-Wide Association Study Identifies Susceptibility Variants for Type 2 Diabetes in Han Chinese. PloS Genet (2010) 6(2):e1000847. doi: 10.1371/journal.pgen.1000847
67. Dong M, Gong Z-C, Dai X-P, Lei G-H, Lu H-B, Fan L, et al. Serine Racemase Rs391300 G/A Polymorphism Influences the Therapeutic Efficacy of Metformin in Chinese Patients With Diabetes Mellitus Type 2. Clin Exp Pharmacol Physiol (2011) 38(12):824–9. doi: 10.1111/j.1440-1681.2011.05610.x
68. Walther DJ, Stahlberg S, Vowinckel J. Novel Roles for Biogenic Monoamines: From Monoamines in Transglutaminase-Mediated Post-Translational Protein Modification to Monoaminylation Deregulation Diseases. FEBS J (2011) 278(24):4740–55. doi: 10.1111/j.1742-4658.2011.08347.x
69. Ng J, Papandreou A, Heales SJ, Kurian MA. Monoamine Neurotransmitter Disorders–Clinical Advances and Future Perspectives. Nat Rev Neurol (2015) 11(10):567–84. doi: 10.1038/nrneurol.2015.172
70. Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, et al. Indigenous Bacteria From the Gut Microbiota Regulate Host Serotonin Biosynthesis. Cell (2015) 161(2):264–76. doi: 10.1016/j.cell.2015.02.047
71. Bird JL, Wright EE, Feldman JM. Pancreatic Islets: A Tissue Rich in Serotonin. Diabetes (1980) 29(4):304–8. doi: 10.2337/diab.29.4.304
72. Freeby M, Ichise M, Harris PE. Vesicular Monoamine Transporter, Type 2 (VMAT2) Expression as It Compares to Insulin and Pancreatic Polypeptide in the Head, Body and Tail of the Human Pancreas. Islets (2012) 4(6):393–7. doi: 10.4161/isl.22995
73. Ohara-Imaizumi M, Kim H, Yoshida M, Fujiwara T, Aoyagi K, Toyofuku Y, et al. Serotonin Regulates Glucose-Stimulated Insulin Secretion From Pancreatic β Cells During Pregnancy. Proc Natl Acad Sci USA (2013) 110(48):19420–5. doi: 10.1073/pnas.1310953110
74. Kim H, Toyofuku Y, Lynn FC, Chak E, Uchida T, Mizukami H, et al. Serotonin Regulates Pancreatic Beta Cell Mass During Pregnancy. Nat Med (2010) 16(7):804–8. doi: 10.1038/nm.2173
75. Paulmann N, Grohmann M, Voigt J-P, Bert B, Vowinckel J, Bader M, et al. Intracellular Serotonin Modulates Insulin Secretion From Pancreatic Beta-Cells by Protein Serotonylation. PloS Biol (2009) 7(10):e1000229. doi: 10.1371/journal.pbio.1000229
76. Bennet H, Balhuizen A, Medina A, Dekker Nitert M, Ottosson Laakso E, Essén S, et al. Altered Serotonin (5-HT) 1D and 2A Receptor Expression may Contribute to Defective Insulin and Glucagon Secretion in Human Type 2 Diabetes. Peptides (2015) 71:113–20. doi: 10.1016/j.peptides.2015.07.008
77. Uvnäs-Moberg K, Ahlenius S, Alster P, Hillegaart V. Effects of Selective Serotonin and Dopamine Agonists on Plasma Levels of Glucose, Insulin and Glucagon in the Rat. Neuroendocrinology (1996) 63(3):269–74. doi: 10.1159/000126970
78. Almaça J, Molina J, Menegaz D, Pronin AN, Tamayo A, Slepak V, et al. Human Beta Cells Produce and Release Serotonin to Inhibit Glucagon Secretion From Alpha Cells. Cell Rep (2016) 17(12):3281–91. doi: 10.1016/j.celrep.2016.11.072
79. Gromada J, Chabosseau P, Rutter GA. The α-Cell in Diabetes Mellitus. Nat Rev Endocrinol (2018) 14(12):694–704. doi: 10.1038/s41574-018-0097-y
80. De Hert M, Detraux J, van Winkel R, Yu W, Correll CU. Metabolic and Cardiovascular Adverse Effects Associated With Antipsychotic Drugs. Nat Rev Endocrinol (2011) 8(2):114–26. doi: 10.1038/nrendo.2011.156
81. Rubí B, Maechler P. Minireview: New Roles for Peripheral Dopamine on Metabolic Control and Tumor Growth: Let's Seek the Balance. Endocrinology (2010) 151(12):5570–81. doi: 10.1210/en.2010-0745
82. Aslanoglou D, Bertera S, Sánchez-Soto M, Benjamin Free R, Lee J, Zong W, et al. Dopamine Regulates Pancreatic Glucagon and Insulin Secretion via Adrenergic and Dopaminergic Receptors. Transl Psychiatry (2021) 11(1):59. doi: 10.1038/s41398-020-01171-z
83. Beaulieu J-M, Gainetdinov RR. The Physiology, Signaling, and Pharmacology of Dopamine Receptors. Pharmacol Rev (2011) 63(1):182–217. doi: 10.1124/pr.110.002642
84. Chen Y, Hong F, Chen H, Fan R-F, Zhang X-L, Zhang Y, et al. Distinctive Expression and Cellular Distribution of Dopamine Receptors in the Pancreatic Islets of Rats. Cell Tissue Res (2014) 357(3):597–606. doi: 10.1007/s00441-014-1894-9
85. Fagerholm V, Grönroos T, Marjamäki P, Viljanen T, Scheinin M, Haaparanta M. Altered Glucose Homeostasis in Alpha2a-Adrenoceptor Knockout Mice. Eur J Pharmacol (2004) 505(1-3):243–52. doi: 10.1016/j.ejphar.2004.10.023
86. Vieira E, Liu Y-J, Gylfe E. Involvement of Alpha1 and Beta-Adrenoceptors in Adrenaline Stimulation of the Glucagon-Secreting Mouse Alpha-Cell. Naunyn Schmiedebergs Arch Pharmacol (2004) 369(2):179–83. doi: 10.1007/s00210-003-0858-5
87. Zhang Y, Zheng R, Meng X, Wang L, Liu L, Gao Y. Pancreatic Endocrine Effects of Dopamine Receptors in Human Islet Cells. Pancreas (2015) 44(6):925–9. doi: 10.1097/MPA.0000000000000357
88. Nagata M, Yokooji T, Nakai T, Miura Y, Tomita T, Taogoshi T, et al. Blockade of Multiple Monoamines Receptors Reduce Insulin Secretion From Pancreatic β-Cells. Sci Rep (2019) 9(1):16438. doi: 10.1038/s41598-019-52590-y
89. Filipponi P, Gregorio F, Ferrandina C, Nicoletti I, Mannarelli C, Pippi R, et al. Alpha-Adrenergic System in the Modulation of Pancreatic A and B Cell Function in Normal Rats. Diabetes Res Clin Pract (1986) 2(6):325–36. doi: 10.1016/S0168-8227(86)80069-9
90. Redmon JB, Towle HC, Robertson RP. Regulation of Human Insulin Gene Transcription by Glucose, Epinephrine, and Somatostatin. Diabetes (1994) 43(4):546–51. doi: 10.2337/diabetes.43.4.546
91. Rosengren AH, Jokubka R, Tojjar D, Granhall C, Hansson O, Li D-Q, et al. Overexpression of Alpha2a-Adrenergic Receptors Contributes to Type 2 Diabetes. Science (2010) 327(5962):217–20. doi: 10.1126/science.1176827
92. Rodriguez-Pena MS, Collins R, Woodard C, Spiegel AM. Decreased Insulin Content and Secretion in RIN 1046-38 Cells Overexpressing Alpha 2-Adrenergic Receptors. Endocrine (1997) 7(2):255–60. doi: 10.1007/BF02778148
93. Savontaus E, Fagerholm V, Rahkonen O, Scheinin M. Reduced Blood Glucose Levels, Increased Insulin Levels and Improved Glucose Tolerance in Alpha2a-Adrenoceptor Knockout Mice. Eur J Pharmacol (2008) 578(2-3):359–64. doi: 10.1016/j.ejphar.2007.09.015
94. Garcia Barrado MJ, Iglesias Osma MC, Blanco EJ, Carretero Hernández M, Sánchez Robledo V, Catalano Iniesta L, et al. Dopamine Modulates Insulin Release and Is Involved in the Survival of Rat Pancreatic Beta Cells. PloS One (2015) 10(4):e0123197. doi: 10.1371/journal.pone.0123197
95. Vázquez P, Robles AM, de Pablo F, Hernández-Sánchez C. Non-Neural Tyrosine Hydroxylase, via Modulation of Endocrine Pancreatic Precursors, Is Required for Normal Development of Beta Cells in the Mouse Pancreas. Diabetologia (2014) 57(11):2339–47. doi: 10.1007/s00125-014-3341-6
96. de Souza CJ, Burkey BF. Beta 3-Adrenoceptor Agonists as Anti-Diabetic and Anti-Obesity Drugs in Humans. Curr Pharm Des (2001) 7(14):1433–49. doi: 10.2174/1381612013397339
97. Rubí B, Ljubicic S, Pournourmohammadi S, Carobbio S, Armanet M, Bartley C, et al. Dopamine D2-Like Receptors Are Expressed in Pancreatic Beta Cells and Mediate Inhibition of Insulin Secretion. J Biol Chem (2005) 280(44):36824–32. doi: 10.1074/jbc.M505560200
98. Draznin B, Aroda VR, Bakris G, Benson G, Brown FM, Freeman R, et al. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care (2022) 45(Supplement_1):S125–43. doi: 10.2337/dc22-S009
99. Kerr JL, Timpe EM, Petkewicz KA. Bromocriptine Mesylate for Glycemic Management in Type 2 Diabetes Mellitus. Ann Pharmacother (2010) 44(11):1777–85. doi: 10.1345/aph.1P271
100. Macotela Y, Triebel J, Clapp C. Time for a New Perspective on Prolactin in Metabolism. Trends Endocrinol Metab (2020) 31(4):276–86. doi: 10.1016/j.tem.2020.01.004
101. Walters JM, Ward GM, Barton J, Arackal R, Boston RC, Best JD, et al. The Effect of Norepinephrine on Insulin Secretion and Glucose Effectiveness in Non-Insulin-Dependent Diabetes. Metabolism (1997) 46(12):1448–53. doi: 10.1016/S0026-0495(97)90146-3
102. Ortiz-Alonso FJ, Herman WH, Zobel DL, Perry TJ, Smith MJ, Halter JB. Effect of Epinephrine on Pancreatic Beta-Cell and Alpha-Cell Function in Patients With NIDDM. Diabetes (1991) 40(9):1194–202. doi: 10.2337/diabetes.40.9.1194
103. Figlewicz DP, Bentson K, Ocrant I. The Effect of Insulin on Norepinephrine Uptake by PC12 Cells. Brain Res Bull (1993) 32(4):425–31. doi: 10.1016/0361-9230(93)90210-3
104. Abe I, Fujii H, Ohishi H, Sugimoto K, Minezaki M, Nakagawa M, et al. Differences in the Actions of Adrenaline and Noradrenaline With Regard to Glucose Intolerance in Patients With Pheochromocytoma. Endocr J (2019) 66(2):187–92. doi: 10.1507/endocrj.EJ18-0407
105. Abe I, Islam F, Lam AK-Y. Glucose Intolerance on Phaeochromocytoma and Paraganglioma-The Current Understanding and Clinical Perspectives. Front Endocrinol (Lausanne) (2020) 11:593780. doi: 10.3389/fendo.2020.593780
106. Panula P, Nuutinen S. The Histaminergic Network in the Brain: Basic Organization and Role in Disease. Nat Rev Neurosci (2013) 14(7):472–87. doi: 10.1038/nrn3526
107. Tanimoto A, Matsuki Y, Tomita T, Sasaguri T, Shimajiri S, Sasaguri Y. Histidine Decarboxylase Expression in Pancreatic Endocrine Cells and Related Tumors. Pathol Int (2004) 54(6):408–12. doi: 10.1111/j.1440-1827.2004.01641.x
108. Nakamura T, Yoshikawa T, Noguchi N, Sugawara A, Kasajima A, Sasano H, et al. The Expression and Function of Histamine H3 Receptors in Pancreatic Beta Cells. Br J Pharmacol (2014) 171(1):171–85. doi: 10.1111/bph.12429
109. Sjöholm A. Histaminergic Regulation of Pancreatic Beta-Cell Replication and Insulin Secretion. Biochem Biophys Res Commun (1995) 214(1):224–9. doi: 10.1006/bbrc.1995.2278
110. Anvari E, Fred RG, Welsh N. The H1-Receptor Antagonist Cetirizine Protects Partially Against Cytokine- and Hydrogen Peroxide-Induced β-TC6 Cell Death In Vitro. Pancreas (2014) 43(4):624–9. doi: 10.1097/MPA.0000000000000076
111. Kuznetsova A, Yu Y, Hollister-Lock J, Opare-Addo L, Rozzo A, Sadagurski M, et al. Trimeprazine Increases IRS2 in Human Islets and Promotes Pancreatic β Cell Growth and Function in Mice. JCI Insight (2016) 1(3):e80749. doi: 10.1172/jci.insight.80749
112. Anvari E, Wang X, Sandler S, Welsh N. The H1-Receptor Antagonist Cetirizine Ameliorates High-Fat Diet-Induced Glucose Intolerance in Male C57BL/6 Mice, But Not Diabetes Outcome in Female Non-Obese Diabetic (NOD) Mice. Ups J Med Sci (2015) 120(1):40–6. doi: 10.3109/03009734.2014.967422
113. Nakamura T, Yoshikawa T, Naganuma F, Mohsen A, Iida T, Miura Y, et al. Role of Histamine H3 Receptor in Glucagon-Secreting αtc1.6 Cells. FEBS Open Bio (2015) 5:36–41. doi: 10.1016/j.fob.2014.12.001
114. Pini A, Grange C, Veglia E, Argenziano M, Cavalli R, Guasti D, et al. Histamine H Receptor Antagonism Prevents the Progression of Diabetic Nephropathy in Male DBA2/J Mice. Pharmacol Res (2018) 128:18–28. doi: 10.1016/j.phrs.2018.01.002
115. Yoshimoto R, Miyamoto Y, Shimamura K, Ishihara A, Takahashi K, Kotani H, et al. Therapeutic Potential of Histamine H3 Receptor Agonist for the Treatment of Obesity and Diabetes Mellitus. Proc Natl Acad Sci USA (2006) 103(37):13866–71. doi: 10.1073/pnas.0506104103
116. Henry MB, Zheng S, Duan C, Patel B, Vassileva G, Sondey C, et al. Antidiabetic Properties of the Histamine H3 Receptor Protean Agonist Proxyfan. Endocrinology (2011) 152(3):828–35. doi: 10.1210/en.2010-0757
117. Pini A, Obara I, Battell E, Chazot PL, Rosa AC. Histamine in Diabetes: Is It Time to Reconsider? Pharmacol Res (2016) 111:316–24. doi: 10.1016/j.phrs.2016.06.021
118. Mannaioni PF, Masini E. The Release of Histamine by Free Radicals. Free Radic Biol Med (1988) 5(3):177–97. doi: 10.1016/0891-5849(88)90080-9
119. Gill DS, Thompson CS, Dandona P. Histamine Synthesis and Catabolism in Various Tissues in Diabetic Rats. Metabolism (1990) 39(8):815–8. doi: 10.1016/0026-0495(90)90124-U
120. Martino L, Masini M, Bugliani M, Marselli L, Suleiman M, Boggi U, et al. Mast Cells Infiltrate Pancreatic Islets in Human Type 1 Diabetes. Diabetologia (2015) 58(11):2554–62. doi: 10.1007/s00125-015-3734-1
121. Shen H, Liangpunsakul S. Histamine H2-Receptor Antagonist Use Is Associated With Lower Prevalence of Nonalcoholic Fatty Liver Disease: A Population-Based Study From the National Health and Nutrition Examination Survey, 2001-2006. J Clin Gastroenterol (2016) 50(7):596–601. doi: 10.1097/MCG.0000000000000503
122. Yuan J, He Q, Nguyen LH, Wong MCS, Huang J, Yu Y, et al. Regular Use of Proton Pump Inhibitors and Risk of Type 2 Diabetes: Results From Three Prospective Cohort Studies. Gut (2021) 70(6):1070–7. doi: 10.1136/gutjnl-2020-322557
123. Grund VR, Martino R, Hunninghake DB. Cimetidine Blockade of Histamine-Induced Insulin Secretion. Clin Pharmacol Ther (1980) 28(3):392–7. doi: 10.1038/clpt.1980.178
124. Rodriguez-Diaz R, Dando R, Jacques-Silva MC, Fachado A, Molina J, Abdulreda MH, et al. Alpha Cells Secrete Acetylcholine as a Non-Neuronal Paracrine Signal Priming Beta Cell Function in Humans. Nat Med (2011) 17(7):888–92. doi: 10.1038/nm.2371
125. Rodriguez-Diaz R, Abdulreda MH, Formoso AL, Gans I, Ricordi C, Berggren P-O, et al. Innervation Patterns of Autonomic Axons in the Human Endocrine Pancreas. Cell Metab (2011) 14(1):45–54. doi: 10.1016/j.cmet.2011.05.008
126. Duttaroy A, Zimliki CL, Gautam D, Cui Y, Mears D, Wess J. Muscarinic Stimulation of Pancreatic Insulin and Glucagon Release Is Abolished in M3 Muscarinic Acetylcholine Receptor-Deficient Mice. Diabetes (2004) 53(7):1714–20. doi: 10.2337/diabetes.53.7.1714
127. Hauge-Evans AC, Reers C, Kerby A, Franklin Z, Amisten S, King AJ, et al. Effect of Hyperglycaemia on Muscarinic M3 Receptor Expression and Secretory Sensitivity to Cholinergic Receptor Activation in Islets. Diabetes Obes Metab (2014) 16(10):947–56. doi: 10.1111/dom.12301
128. Molina J, Rodriguez-Diaz R, Fachado A, Jacques-Silva MC, Berggren P-O, Caicedo A. Control of Insulin Secretion by Cholinergic Signaling in the Human Pancreatic Islet. Diabetes (2014) 63(8):2714–26. doi: 10.2337/db13-1371
129. Rorsman P, Huising MO. The Somatostatin-Secreting Pancreatic δ-Cell in Health and Disease. Nat Rev Endocrinol (2018) 14(7):404–14. doi: 10.1038/s41574-018-0020-6
130. Klee P, Bosco D, Guérardel A, Somm E, Toulotte A, Maechler P, et al. Activation of Nicotinic Acetylcholine Receptors Decreases Apoptosis in Human and Female Murine Pancreatic Islets. Endocrinology (2016) 157(10):3800–8. doi: 10.1210/en.2015-2057
131. Somm E, Guérardel A, Maouche K, Toulotte A, Veyrat-Durebex C, Rohner-Jeanrenaud F, et al. Concomitant Alpha7 and Beta2 Nicotinic AChR Subunit Deficiency Leads to Impaired Energy Homeostasis and Increased Physical Activity in Mice. Mol Genet Metab (2014) 112(1):64–72. doi: 10.1016/j.ymgme.2014.03.003
132. Pan A, Wang Y, Talaei M, Hu FB, Wu T. Relation of Active, Passive, and Quitting Smoking With Incident Type 2 Diabetes: A Systematic Review and Meta-Analysis. Lancet Diabetes Endocrinol (2015) 3(12):958–67. doi: 10.1016/S2213-8587(15)00316-2
133. Wang X, Yang Z, Xue B, Shi H. Activation of the Cholinergic Antiinflammatory Pathway Ameliorates Obesity-Induced Inflammation and Insulin Resistance. Endocrinology (2011) 152(3):836–46. doi: 10.1210/en.2010-0855
134. Gupta D, Lacayo AA, Greene SM, Leahy JL, Jetton TL. β-Cell Mass Restoration by α7 Nicotinic Acetylcholine Receptor Activation. J Biol Chem (2018) 293(52):20295–306. doi: 10.1074/jbc.RA118.004617
135. Stagner JI, Samols E. Modulation of Insulin Secretion by Pancreatic Ganglionic Nicotinic Receptors. Diabetes (1986) 35(8):849–54. doi: 10.2337/diabetes.35.8.849
136. Fowler CD, Lu Q, Johnson PM, Marks MJ, Kenny PJ. Habenular α5 Nicotinic Receptor Subunit Signalling Controls Nicotine Intake. Nature (2011) 471(7340):597–601. doi: 10.1038/nature09797
137. Xu T-Y, Guo L-L, Wang P, Song J, Le Y-Y, Viollet B, et al. Chronic Exposure to Nicotine Enhances Insulin Sensitivity Through α7 Nicotinic Acetylcholine Receptor-STAT3 Pathway. PloS One (2012) 7(12):e51217. doi: 10.1371/journal.pone.0051217
138. Duncan A, Heyer MP, Ishikawa M, Caligiuri SPB, Liu X-A, Chen Z, et al. Habenular TCF7L2 Links Nicotine Addiction to Diabetes. Nature (2019) 574(7778):372–7. doi: 10.1038/s41586-019-1653-x
139. de Wied D. The Neuropeptide Story. Geoffrey Harris Lecture, Budapest, Hungary, July 1994. Front Neuroendocrinol (1997) 18(1):101–13. doi: 10.1006/frne.1996.0148
140. Snyder SH, Innis RB. Peptide Neurotransmitters. Annu Rev Biochem (1979) 48:755–82. doi: 10.1146/annurev.bi.48.070179.003543
141. Manning S, Batterham RL. The Role of Gut Hormone Peptide YY in Energy and Glucose Homeostasis: Twelve Years on. Annu Rev Physiol (2014) 76:585–608. doi: 10.1146/annurev-physiol-021113-170404
142. Herzog H. Neuropeptide Y and Energy Homeostasis: Insights From Y Receptor Knockout Models. Eur J Pharmacol (2003) 480(1-3):21–9. doi: 10.1016/j.ejphar.2003.08.089
143. Gao R, Yang T, Zhang Q. δ-Cells: The Neighborhood Watch in the Islet Community. Biol (Basel) (2021) 10(2):74. doi: 10.3390/biology10020074
144. Rehfeld JF. The Origin and Understanding of the Incretin Concept. Front Endocrinol (Lausanne) (2018) 9:387. doi: 10.3389/fendo.2018.00387
145. Sarkar S, Fekete C, Légrádi G, Lechan RM. Glucagon Like Peptide-1 (7-36) Amide (GLP-1) Nerve Terminals Densely Innervate Corticotropin-Releasing Hormone Neurons in the Hypothalamic Paraventricular Nucleus. Brain Res (2003) 985(2):163–8. doi: 10.1016/S0006-8993(03)03117-2
146. Lewis JE, Miedzybrodzka EL, Foreman RE, Woodward ORM, Kay RG, Goldspink DA, et al. Selective Stimulation of Colonic L Cells Improves Metabolic Outcomes in Mice. Diabetologia (2020) 63(7):1396–407. doi: 10.1007/s00125-020-05149-w
147. Tornehave D, Kristensen P, Rømer J, Knudsen LB, Heller RS. Expression of the GLP-1 Receptor in Mouse, Rat, and Human Pancreas. J Histochem Cytochem (2008) 56(9):841–51. doi: 10.1369/jhc.2008.951319
148. Capozzi ME, Svendsen B, Encisco SE, Lewandowski SL, Martin MD, Lin H, et al. β Cell Tone Is Defined by Proglucagon Peptides Through cAMP Signaling. JCI Insight (2019) 4(5):e126742. doi: 10.1172/jci.insight.126742
149. Larraufie P, Roberts GP, McGavigan AK, Kay RG, Li J, Leiter A, et al. Important Role of the GLP-1 Axis for Glucose Homeostasis After Bariatric Surgery. Cell Rep (2019) 26(6):1399–408.e6. doi: 10.1016/j.celrep.2019.01.047
150. Gromada J, Holst JJ, Rorsman P. Cellular Regulation of Islet Hormone Secretion by the Incretin Hormone Glucagon-Like Peptide 1. Pflugers Arch (1998) 435(5):583–94. doi: 10.1007/s004240050558
151. Li Y, Cao X, Li L-X, Brubaker PL, Edlund H, Drucker DJ. Beta-Cell Pdx1 Expression Is Essential for the Glucoregulatory, Proliferative, and Cytoprotective Actions of Glucagon-Like Peptide-1. Diabetes (2005) 54(2):482–91. doi: 10.2337/diabetes.54.2.482
152. Edvell A, Lindström P. Initiation of Increased Pancreatic Islet Growth in Young Normoglycemic Mice (Umeå +/?). Endocrinology (1999) 140(2):778–83. doi: 10.1210/endo.140.2.6514
153. de Heer J, Rasmussen C, Coy DH, Holst JJ. Glucagon-Like Peptide-1, But Not Glucose-Dependent Insulinotropic Peptide, Inhibits Glucagon Secretion via Somatostatin (Receptor Subtype 2) in the Perfused Rat Pancreas. Diabetologia (2008) 51(12):2263–70. doi: 10.1007/s00125-008-1149-y
154. Kaplan AM, Vigna SR. Gastric Inhibitory Polypeptide (GIP) Binding Sites in Rat Brain. Peptides (1994) 15(2):297–302. doi: 10.1016/0196-9781(94)90016-7
155. El K, Gray SM, Capozzi ME, Knuth ER, Jin E, Svendsen B, et al. GIP Mediates the Incretin Effect and Glucose Tolerance by Dual Actions on α Cells and β Cells. Sci Adv (2021) 7(11):eadf1948. doi: 10.1126/sciadv.abf1948
156. Rudovich N, Kaiser S, Engeli S, Osterhoff M, Gögebakan O, Bluher M, et al. GIP Receptor mRNA Expression in Different Fat Tissue Depots in Postmenopausal Non-Diabetic Women. Regul Pept (2007) 142(3):138–45. doi: 10.1016/j.regpep.2007.02.006
157. Christensen M, Vedtofte L, Holst JJ, Vilsbøll T, Knop FK. Glucose-Dependent Insulinotropic Polypeptide: A Bifunctional Glucose-Dependent Regulator of Glucagon and Insulin Secretion in Humans. Diabetes (2011) 60(12):3103–9. doi: 10.2337/db11-0979
158. Campbell JE, Ussher JR, Mulvihill EE, Kolic J, Baggio LL, Cao X, et al. TCF1 Links GIPR Signaling to the Control of Beta Cell Function and Survival. Nat Med (2016) 22(1):84–90. doi: 10.1038/nm.3997
159. Mohammad S, Ramos LS, Buck J, Levin LR, Rubino F, McGraw TE. Gastric Inhibitory Peptide Controls Adipose Insulin Sensitivity via Activation of cAMP-Response Element-Binding Protein and P110β Isoform of Phosphatidylinositol 3-Kinase. J Biol Chem (2011) 286(50):43062–70. doi: 10.1074/jbc.M111.289009
160. Zhang F, Tang X, Cao H, Lü Q, Li N, Liu Y, et al. Impaired Secretion of Total Glucagon-Like Peptide-1 in People With Impaired Fasting Glucose Combined Impaired Glucose Tolerance. Int J Med Sci (2012) 9(7):574–81. doi: 10.7150/ijms.4128
161. Honigberg MC, Chang L-S, McGuire DK, Plutzky J, Aroda VR, Vaduganathan M. Use of Glucagon-Like Peptide-1 Receptor Agonists in Patients With Type 2 Diabetes and Cardiovascular Disease: A Review. JAMA Cardiol (2020) 5(10):1182–90. doi: 10.1001/jamacardio.2020.1966
162. Pan X, Xu S, Li J, Tong N. The Effects of DPP-4 Inhibitors, GLP-1ras, and SGLT-2/1 Inhibitors on Heart Failure Outcomes in Diabetic Patients With and Without Heart Failure History: Insights From CVOTs and Drug Mechanism. Front Endocrinol (Lausanne) (2020) 11:599355. doi: 10.3389/fendo.2020.599355
163. NamKoong C, Kim MS, Jang B-T, Lee YH, Cho Y-M, Choi HJ. Central Administration of GLP-1 and GIP Decreases Feeding in Mice. Biochem Biophys Res Commun (2017) 490(2):247–52. doi: 10.1016/j.bbrc.2017.06.031
164. Mroz PA, Finan B, Gelfanov V, Yang B, Tschöp MH, DiMarchi RD, et al. Optimized GIP Analogs Promote Body Weight Lowering in Mice Through GIPR Agonism Not Antagonism. Mol Metab (2019) 20:51–62. doi: 10.1016/j.molmet.2018.12.001
165. Dejgaard TF, Frandsen CS, Hansen TS, Almdal T, Urhammer S, Pedersen-Bjergaard U, et al. Efficacy and Safety of Liraglutide for Overweight Adult Patients With Type 1 Diabetes and Insufficient Glycaemic Control (Lira-1): A Randomised, Double-Blind, Placebo-Controlled Trial. Lancet Diabetes Endocrinol (2016) 4(3):221–32. doi: 10.1016/S2213-8587(15)00436-2
166. Johansen NJ, Dejgaard TF, Lund A, Schlüntz C, Frandsen CS, Forman JL, et al. Efficacy and Safety of Meal-Time Administration of Short-Acting Exenatide for Glycaemic Control in Type 1 Diabetes (MAG1C): A Randomised, Double-Blind, Placebo-Controlled Trial. Lancet Diabetes Endocrinol (2020) 8(4):313–24. doi: 10.1016/S2213-8587(20)30030-9
167. Hunter K, Hölscher C. Drugs Developed to Treat Diabetes, Liraglutide and Lixisenatide, Cross the Blood Brain Barrier and Enhance Neurogenesis. BMC Neurosci (2012) 13:33. doi: 10.1186/1471-2202-13-33
168. Chandra R, Liddle RA. Cholecystokinin. Curr Opin Endocrinol Diabetes Obes (2007) 14(1):63–7. doi: 10.1097/MED.0b013e3280122850
169. Morisset J, Julien S, Lainé J. Localization of Cholecystokinin Receptor Subtypes in the Endocine Pancreas. J Histochem Cytochem (2003) 51(11):1501–13. doi: 10.1177/002215540305101110
170. Ning S-l, Zheng W-s, Su J, Liang N, Li H, Zhang D-l, et al. Different Downstream Signalling of CCK1 Receptors Regulates Distinct Functions of CCK in Pancreatic Beta Cells. Br J Pharmacol (2015) 172(21):5050–67. doi: 10.1111/bph.13271
171. Karlsson S, Ahrén B. CCK-8-Stimulated Insulin Secretion In Vivo Is Mediated by CCKA Receptors. Eur J Pharmacol (1992) 213(1):145–6. doi: 10.1016/0014-2999(92)90245-Y
172. Dufresne M, Seva C, Fourmy D. Cholecystokinin and Gastrin Receptors. Physiol Rev (2006) 86(3):805–47. doi: 10.1152/physrev.00014.2005
173. Saillan-Barreau C, Dufresne M, Clerc P, Sanchez D, Corominola H, Moriscot C, et al. Evidence for a Functional Role of the Cholecystokinin-B/gastrin Receptor in the Human Fetal and Adult Pancreas. Diabetes (1999) 48(10):2015–21. doi: 10.2337/diabetes.48.10.2015
174. Lavine JA, Raess PW, Stapleton DS, Rabaglia ME, Suhonen JI, Schueler KL, et al. Cholecystokinin Is Up-Regulated in Obese Mouse Islets and Expands Beta-Cell Mass by Increasing Beta-Cell Survival. Endocrinology (2010) 151(8):3577–88. doi: 10.1210/en.2010-0233
175. Lavine JA, Kibbe CR, Baan M, Sirinvaravong S, Umhoefer HM, Engler KA, et al. Cholecystokinin Expression in the β-Cell Leads to Increased β-Cell Area in Aged Mice and Protects From Streptozotocin-Induced Diabetes and Apoptosis. Am J Physiol Endocrinol Metab (2015) 309(10):E819–28. doi: 10.1152/ajpendo.00159.2015
176. Irwin N, Frizelle P, Montgomery IA, Moffett RC, O'Harte FPM, Flatt PR. Beneficial Effects of the Novel Cholecystokinin Agonist (Pglu-Gln)-CCK-8 in Mouse Models of Obesity/Diabetes. Diabetologia (2012) 55(10):2747–58. doi: 10.1007/s00125-012-2654-6
177. Hildebrand P, Ensinck JW, Ketterer S, Delco F, Mossi S, Bangerter U, et al. Effect of a Cholecystokinin Antagonist on Meal-Stimulated Insulin and Pancreatic Polypeptide Release in Humans. J Clin Endocrinol Metab (1991) 72(5):1123–9. doi: 10.1210/jcem-72-5-1123
178. Pathak V, Flatt PR, Irwin N. Cholecystokinin (CCK) and Related Adjunct Peptide Therapies for the Treatment of Obesity and Type 2 Diabetes. Peptides (2018) 100:229–35. doi: 10.1016/j.peptides.2017.09.007
179. Gimpl G, Fahrenholz F. The Oxytocin Receptor System: Structure, Function, and Regulation. Physiol Rev (2001) 81(2):629–83. doi: 10.1152/physrev.2001.81.2.629
180. Koshimizu T-a, Nakamura K, Egashira N, Hiroyama M, Nonoguchi H, Tanoue A. Vasopressin V1a and V1b Receptors: From Molecules to Physiological Systems. Physiol Rev (2012) 92(4):1813–64. doi: 10.1152/physrev.00035.2011
181. Suzuki M, Honda Y, Li M-Z, Masuko S, Murata Y. The Localization of Oxytocin Receptors in the Islets of Langerhans in the Rat Pancreas. Regul Pept (2013) 183:42–5. doi: 10.1016/j.regpep.2013.03.019
182. Yibchok-anun S, Hsu WH. Effects of Arginine Vasopressin and Oxytocin on Glucagon Release From Clonal Alpha-Cell Line In-R1-G9: Involvement of V1b Receptors. Life Sci (1998) 63(21):1871–8. doi: 10.1016/S0024-3205(98)00463-9
183. Mohan S, Moffett RC, Thomas KG, Irwin N, Flatt PR. Vasopressin Receptors in Islets Enhance Glucose Tolerance, Pancreatic Beta-Cell Secretory Function, Proliferation and Survival. Biochimie (2019) 158:191–8. doi: 10.1016/j.biochi.2019.01.008
184. Abu-Basha EA, Yibchok-Anun S, Hsu WH. Glucose Dependency of Arginine Vasopressin-Induced Insulin and Glucagon Release From the Perfused Rat Pancreas. Metabolism (2002) 51(9):1184–90. doi: 10.1053/meta.2002.34052
185. Ding C, Magkos F. Oxytocin and Vasopressin Systems in Obesity and Metabolic Health: Mechanisms and Perspectives. Curr Obes Rep (2019) 8(3):301–16. doi: 10.1007/s13679-019-00355-z
186. Mohan S, Khan D, Moffett RC, Irwin N, Flatt PR. Oxytocin Is Present in Islets and Plays a Role in Beta-Cell Function and Survival. Peptides (2018) 100:260–8. doi: 10.1016/j.peptides.2017.12.019
187. Watanabe S, Wei F-Y, Matsunaga T, Matsunaga N, Kaitsuka T, Tomizawa K. Oxytocin Protects Against Stress-Induced Cell Death in Murine Pancreatic β-Cells. Sci Rep (2016) 6:25185. doi: 10.1038/srep25185
188. Klement J, Ott V, Rapp K, Brede S, Piccinini F, Cobelli C, et al. Oxytocin Improves β-Cell Responsivity and Glucose Tolerance in Healthy Men. Diabetes (2017) 66(2):264–71. doi: 10.2337/db16-0569
189. Mohan S, McCloskey AG, McKillop AM, Flatt PR, Irwin N, Moffett RC. Development and Characterisation of Novel, Enzymatically Stable Oxytocin Analogues With Beneficial Antidiabetic Effects in High Fat Fed Mice. Biochim Biophys Acta Gen Subj (2021) 1865(3):129811. doi: 10.1016/j.bbagen.2020.129811
190. Gu P, Lin Y, Wan Q, Su D, Shu Q. Oxytocin Signal Contributes to the Adaptative Growth of Islets During Gestation. Endocr Connect (2021) 10(7):694–706. doi: 10.1530/EC-21-0043
191. Björkstrand E, Eriksson M, Uvnäs-Moberg K. Evidence of a Peripheral and a Central Effect of Oxytocin on Pancreatic Hormone Release in Rats. Neuroendocrinology (1996) 63(4):377–83. doi: 10.1159/000126978
192. Lawson EA. The Effects of Oxytocin on Eating Behaviour and Metabolism in Humans. Nat Rev Endocrinol (2017) 13(12):700–9. doi: 10.1038/nrendo.2017.115
193. Ding C, Leow MKS, Magkos F. Oxytocin in Metabolic Homeostasis: Implications for Obesity and Diabetes Management. Obes Rev (2019) 20(1):22–40. doi: 10.1111/obr.12757
194. Burnstock G, Novak I. Purinergic Signalling and Diabetes. Purinergic Signal (2013) 9(3):307–24. doi: 10.1007/s11302-013-9359-2
195. Salehi A, Parandeh F, Fredholm BB, Grapengiesser E, Hellman B. Absence of Adenosine A1 Receptors Unmasks Pulses of Insulin Release and Prolongs Those of Glucagon and Somatostatin. Life Sci (2009) 85(11-12):470–6. doi: 10.1016/j.lfs.2009.08.001
196. Tudurí E, Filiputti E, Carneiro EM, Quesada I. Inhibition of Ca2+ Signaling and Glucagon Secretion in Mouse Pancreatic Alpha-Cells by Extracellular ATP and Purinergic Receptors. Am J Physiol Endocrinol Metab (2008) 294(5):E952–E60. doi: 10.1152/ajpendo.00641.2007
197. Ohtani M, Oka T, Ohura K. Possible Involvement of a2A and A3 Receptors in Modulation of Insulin Secretion and β-Cell Survival in Mouse Pancreatic Islets. Gen Comp Endocrinol (2013) 187:86–94. doi: 10.1016/j.ygcen.2013.02.011
198. Yip L, Taylor C, Whiting CC, Fathman CG. Diminished Adenosine A1 Receptor Expression in Pancreatic α-Cells may Contribute to the Pathology of Type 1 Diabetes. Diabetes (2013) 62(12):4208–19. doi: 10.2337/db13-0614
199. Hayashi M. Expression of Adenosine Receptors in Rodent Pancreas. Int J Mol Sci (2019) 20(21):5329. doi: 10.3390/ijms20215329
200. Rüsing D, Müller CE, Verspohl EJ. The Impact of Adenosine and A(2B) Receptors on Glucose Homoeostasis. J Pharm Pharmacol (2006) 58(12):1639–45. doi: 10.1211/jpp.58.12.0011
201. Németh ZH, Bleich D, Csóka B, Pacher P, Mabley JG, Himer L, et al. Adenosine Receptor Activation Ameliorates Type 1 Diabetes. FASEB J (2007) 21(10):2379–88. doi: 10.1096/fj.07-8213com
202. Andersson O, Adams BA, Yoo D, Ellis GC, Gut P, Anderson RM, et al. Adenosine Signaling Promotes Regeneration of Pancreatic β Cells In Vivo. Cell Metab (2012) 15(6):885–94. doi: 10.1016/j.cmet.2012.04.018
203. Balasubramanian R, Ruiz de Azua I, Wess J, Jacobson KA. Activation of Distinct P2Y Receptor Subtypes Stimulates Insulin Secretion in MIN6 Mouse Pancreatic Beta Cells. Biochem Pharmacol (2010) 79(9):1317–26. doi: 10.1016/j.bcp.2009.12.026
204. Amisten S, Meidute-Abaraviciene S, Tan C, Olde B, Lundquist I, Salehi A, et al. ADP Mediates Inhibition of Insulin Secretion by Activation of P2Y13 Receptors in Mice. Diabetologia (2010) 53(9):1927–34. doi: 10.1007/s00125-010-1807-8
205. Coutinho-Silva R, Parsons M, Robson T, Lincoln J, Burnstock G. P2X and P2Y Purinoceptor Expression in Pancreas From Streptozotocin-Diabetic Rats. Mol Cell Endocrinol (2003) 204(1-2):141–54. doi: 10.1016/S0303-7207(03)00003-0
206. Balasubramanian R, Maruoka H, Jayasekara PS, Gao Z-G, Jacobson KA. AMP-Activated Protein Kinase as Regulator of P2Y(6) Receptor-Induced Insulin Secretion in Mouse Pancreatic β-Cells. Biochem Pharmacol (2013) 85(7):991–8. doi: 10.1016/j.bcp.2012.11.029
207. Lee DH, Park K-S, Kim D-R, Lee J-W, Kong ID. Dual Effect of ATP on Glucose-Induced Insulin Secretion in HIT-T15 Cells. Pancreas (2008) 37(3):302–8. doi: 10.1097/MPA.0b013e318168daaa
208. Parandeh F, Amisten S, Verma G, Mohammed Al-Amily I, Dunér P, Salehi A. Inhibitory Effect of UDP-Glucose on cAMP Generation and Insulin Secretion. J Biol Chem (2020) 295(45):15245–52. doi: 10.1074/jbc.RA120.012929
209. Jacobson KA, Delicado EG, Gachet C, Kennedy C, von Kügelgen I, Li B, et al. Update of P2Y Receptor Pharmacology: IUPHAR Review 27. Br J Pharmacol (2020) 177(11):2413–33. doi: 10.1111/bph.15005
210. Coutinho-Silva R, Parsons M, Robson T, Burnstock G. Changes in Expression of P2 Receptors in Rat and Mouse Pancreas During Development and Ageing. Cell Tissue Res (2001) 306(3):373–83. doi: 10.1007/s004410100458
211. Silva AM, Rodrigues RJ, Tomé AR, Cunha RA, Misler S, Rosário LM, et al. Electrophysiological and Immunocytochemical Evidence for P2X Purinergic Receptors in Pancreatic Beta Cells. Pancreas (2008) 36(3):279–83. doi: 10.1097/MPA.0b013e31815a8473
212. Ohtani M, Ohura K, Oka T. Involvement of P2X Receptors in the Regulation of Insulin Secretion, Proliferation and Survival in Mouse Pancreatic β-Cells. Cell Physiol Biochem (2011) 28(2):355–66. doi: 10.1159/000331752
213. Richards-Williams C, Contreras JL, Berecek KH, Schwiebert EM. Extracellular ATP and Zinc Are Co-Secreted With Insulin and Activate Multiple P2X Purinergic Receptor Channels Expressed by Islet Beta-Cells to Potentiate Insulin Secretion. Purinergic Signal (2008) 4(4):393–405. doi: 10.1007/s11302-008-9126-y
214. Jacques-Silva MC, Correa-Medina M, Cabrera O, Rodriguez-Diaz R, Makeeva N, Fachado A, et al. ATP-Gated P2X3 Receptors Constitute a Positive Autocrine Signal for Insulin Release in the Human Pancreatic Beta Cell. Proc Natl Acad Sci USA (2010) 107(14):6465–70. doi: 10.1073/pnas.0908935107
215. Glas R, Sauter NS, Schulthess FT, Shu L, Oberholzer J, Maedler K. Purinergic P2X7 Receptors Regulate Secretion of Interleukin-1 Receptor Antagonist and Beta Cell Function and Survival. Diabetologia (2009) 52(8):1579–88. doi: 10.1007/s00125-009-1349-0
216. North RA. Molecular Physiology of P2X Receptors. Physiol Rev (2002) 82(4):1013–67. doi: 10.1152/physrev.00015.2002
217. Coccurello R, Volonté C. P2X7 Receptor in the Management of Energy Homeostasis: Implications for Obesity, Dyslipidemia, and Insulin Resistance. Front Endocrinol (Lausanne) (2020) 11:199. doi: 10.3389/fendo.2020.00199
218. Rickels MR, Robertson RP. Pancreatic Islet Transplantation in Humans: Recent Progress and Future Directions. Endocr Rev (2019) 40(2):631–68. doi: 10.1210/er.2018-00154
219. Alonge KM, D'Alessio DA, Schwartz MW. Brain Control of Blood Glucose Levels: Implications for the Pathogenesis of Type 2 Diabetes. Diabetologia (2021) 64(1):5–14. doi: 10.1007/s00125-020-05293-3
220. Makhmutova M, Caicedo A. Optical Imaging of Pancreatic Innervation. Front Endocrinol (Lausanne) (2021) 12:663022. doi: 10.3389/fendo.2021.663022
221. Li Z, Xing Y, Guo X, Cui Y. Development of an UPLC-MS/MS Method for Simultaneous Quantitation of 11 D-Amino Acids in Different Regions of Rat Brain: Application to a Study on the Associations of D-Amino Acid Concentration Changes and Alzheimer's Disease. J Chromatogr B Analyt Technol BioMed Life Sci (2017) 1058:40–6. doi: 10.1016/j.jchromb.2017.05.011
222. Makhmutova M, Weitz J, Tamayo A, Pereira E, Boulina M, Almaça J, et al. Pancreatic β-Cells Communicate With Vagal Sensory Neurons. Gastroenterology (2021) 160(3):875–88.e11. doi: 10.1053/j.gastro.2020.10.034
223. Banks WA, Owen JB, Erickson MA. Insulin in the Brain: There and Back Again. Pharmacol Ther (2012) 136(1):82–93. doi: 10.1016/j.pharmthera.2012.07.006
224. Cukierman-Yaffe T, Gerstein HC, Williamson JD, Lazar RM, Lovato L, Miller ME, et al. Relationship Between Baseline Glycemic Control and Cognitive Function in Individuals With Type 2 Diabetes and Other Cardiovascular Risk Factors: The Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) Trial. Diabetes Care (2009) 32(2):221–6. doi: 10.2337/dc08-1153
225. Strandwitz P. Neurotransmitter Modulation by the Gut Microbiota. Brain Res (2018) 1693(Pt B):128–33. doi: 10.1016/j.brainres.2018.03.015
226. Diaz Heijtz R, Wang S, Anuar F, Qian Y, Björkholm B, Samuelsson A, et al. Normal Gut Microbiota Modulates Brain Development and Behavior. Proc Natl Acad Sci USA (2011) 108(7):3047–52. doi: 10.1073/pnas.1010529108
227. Chung JY, Jeong J-H, Song J. Resveratrol Modulates the Gut-Brain Axis: Focus on Glucagon-Like Peptide-1, 5-HT, and Gut Microbiota. Front Aging Neurosci (2020) 12:588044. doi: 10.3389/fnagi.2020.588044
228. Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, et al. LY3298176, a Novel Dual GIP and GLP-1 Receptor Agonist for the Treatment of Type 2 Diabetes Mellitus: From Discovery to Clinical Proof of Concept. Mol Metab (2018) 18:3–14. doi: 10.1016/j.molmet.2018.09.009
229. Milliken BT, Elfers C, Chepurny OG, Chichura KS, Sweet IR, Borner T, et al. Design and Evaluation of Peptide Dual-Agonists of GLP-1 and NPY2 Receptors for Glucoregulation and Weight Loss With Mitigated Nausea and Emesis. J Med Chem (2021) 64(2):1127–38. doi: 10.1021/acs.jmedchem.0c01783
230. Liu W, Lau HK, Son DO, Jin T, Yang Y, Zhang Z, et al. Combined Use of GABA and Sitagliptin Promotes Human β-Cell Proliferation and Reduces Apoptosis. J Endocrinol (2021) 248(2):133–43. doi: 10.1530/JOE-20-0315
231. Bossart M, Wagner M, Elvert R, Evers A, Hübschle T, Kloeckener T, et al. Effects on Weight Loss and Glycemic Control With SAR441255, a Potent Unimolecular Peptide GLP-1/GIP/GCG Receptor Triagonist. Cell Metab (2022) 34(1):59–74. doi: 10.1016/j.cmet.2021.12.005
232. Lu VB, Rievaj J, O'Flaherty EA, Smith CA, Pais R, Pattison LA, et al. Adenosine Triphosphate Is Co-Secreted With Glucagon-Like Peptide-1 to Modulate Intestinal Enterocytes and Afferent Neurons. Nat Commun (2019) 10(1):1029. doi: 10.1038/s41467-019-09045-9
233. Payne SC, Ward G, MacIsaac RJ, Hyakumura T, Fallon JB, Villalobos J. Differential Effects of Vagus Nerve Stimulation Strategies on Glycemia and Pancreatic Secretions. Physiol Rep (2020) 8(11):e14479. doi: 10.14814/phy2.14479
234. Yin J, Ji F, Gharibani P, Chen JD. Vagal Nerve Stimulation for Glycemic Control in a Rodent Model of Type 2 Diabetes. Obes Surg (2019) 29(9):2869–77. doi: 10.1007/s11695-019-03901-9
235. Shikora SA, Toouli J, Herrera MF, Kulseng B, Brancatisano R, Kow L, et al. Intermittent Vagal Nerve Block for Improvements in Obesity, Cardiovascular Risk Factors, and Glycemic Control in Patients With Type 2 Diabetes Mellitus: 2-Year Results of the VBLOC DM2 Study. Obes Surg (2016) 26(5):1021–8. doi: 10.1007/s11695-015-1914-1
Keywords: glucose homeostasis, neurotransmitters, neurotransmitter receptor, pancreatic islets, type 2 diabetes
Citation: Pan X, Tao S and Tong N (2022) Potential Therapeutic Targeting Neurotransmitter Receptors in Diabetes. Front. Endocrinol. 13:884549. doi: 10.3389/fendo.2022.884549
Received: 26 February 2022; Accepted: 19 April 2022;
Published: 20 May 2022.
Edited by:
Åke Sjöholm, Gävle Hospital, SwedenReviewed by:
Ravinder Abrol, California State University, United StatesMichael A. Kalwat, Indiana Biosciences Research Institute, United States
Copyright © 2022 Pan, Tao and Tong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Nanwei Tong, tongnw@scu.edu.cn
†These authors have contributed equally to this work