Insulin secretion from pancreatic islet β‐cells is stimulated by glucose. Glucose‐induced insulin release is potentiated or suppressed by hormones and neural substances. Ghrelin, an acylated 28‐amino ...acid peptide, was isolated from the stomach in 1999 as the endogenous ligand for the growth hormone (GH) secretagogue‐receptor (GHS‐R). Circulating ghrelin is produced predominantly in the stomach and to a lesser extent in the intestine, pancreas and brain. Ghrelin, initially identified as a potent stimulator of GH release and feeding, has been shown to suppress glucose‐induced insulin release. This insulinostatic action is mediated by Gαi2 subtype of GTP‐binding proteins and delayed outward K+ (Kv) channels. Interestingly, ghrelin is produced in pancreatic islets. The ghrelin originating from islets restricts insulin release and thereby upwardly regulates the systemic glucose level. Furthermore, blockade or elimination of ghrelin enhances insulin release, which can ameliorate glucose intolerance in high‐fat diet fed mice and ob/ob mice. This review focuses on the insulinostatic action of ghrelin, its signal transduction mechanisms in islet β‐cells, ghrelin's status as an islet hormone, physiological roles of ghrelin in regulating systemic insulin levels and glycaemia, and therapeutic potential of the ghrelin‐GHS‐R system as the target to treat type 2 diabetes.
Abstract
Ghrelin is a peptide hormone that is produced mainly from the stomach. Ghrelin is reported to have many biological functions, such as modulating feeding behavior, energy balance, and glucose ...homeostasis. This study aimed to examine whether YIL, a ghrelin receptor antagonist, could counteract the effect of ghrelin-inhibited insulin release in the pancreatic islet of Langerhans. This study is experimental research using wild-type C57BL/6J mice 8-10 weeks old. Islet of Langerhans was isolated by collagenase digestion and the insulin release ng/islet/h from the islet is examined by the ELISA method. Data represent means ± SEM and is analyzed by one-way ANOVA. The result showed that 8.3 mM glucose concentration increase insulin release compared to 2.8 mM glucose, respectively 0,393 ± 0,025 vs 0,219 ± 0,022 ng/islet/h. In the presence of 8.3 mM glucose, ghrelin 1 nM showed a decrease in insulin release significantly compared to 8.3 mM glucose only 0,283 ± 0,001 vs 0,393 ± 0,025, p < 0,01. In contrast, in the presence of 8.3 mM glucose and ghrelin 1 nM, YIL 1 μM induced insulin secretion 0,386 ± 0,012 vs 0,283 ± 0,001, p < 0,01. In conclusion, YIL is significantly counteracted ghrelin-inhibited insulin release in pancreatic islets of Langerhans. Furthermore, YIL is one of the candidates for the treatment of type 2 diabetes.
Hyperphagia triggers and accelerates diabetes, and prevents proper dietary control of glycemia. Inversely, the impact of hyperglycemia on hyperphagia and possible mechanistic cause common for these ...two metabolic disorders in type 2 diabetes are less defined. The present study examined the precise developmental process of hyperglycemia and hyperphagia and explored the alterations in the hypothalamic arcuate nucleus (ARC), the primary feeding and metabolic center, in Goto-Kakizaki (GK) rats with type 2 diabetes and nearly normal body weight. At mid 3 to 4 weeks of age, GK rats first exhibited hyperglycemia, and then hyperphagia and reduced mRNA expressions for anorexigenic pro-opiomelanocortin (POMC) and glucokinase in ARC. Furthermore, Ca2+i responses to high glucose in ARC POMC neurons were impaired in GK rats at 4 weeks. Treating GK rats from early 3 to mid 6 weeks of age with an anti-diabetic medicine miglitol not only suppressed hyperglycemia but ameliorated hyperphagia and restored POMC mRNA expression in ARC. These results suggest that the early hyperglycemia occurring in weaning period may lead to impaired glucose sensing and neuronal activity of POMC neurons, and thereby induce hyperphagia in GK rats. Correction of hyperglycemia in the early period may prevent and/or ameliorate the progression of hyperphagia in type 2 diabetes.
•Goto-Kakizaki (GK) rats at weaning 4 weeks develop hyperglycemia and hyperphagia.•Reduced POMC, glucokinase and glucose-induced Ca2+i rises in arcuate neurons.•Anti-diabetic miglitol ameliorates hyperglycemia and hyperphagia and restores POMC.•Early hyperglycemia induces POMC neuron dysfunction and hyperphagia in GK rats.•Correcting hyperglycemia early may decelerate POMC reduction/hyperphagia in T2DM.
To date, 11 thermosensitive transient receptor potential (thermo-TRP) channels have been identified. Recent studies have characterized the mechanism of thermosensing by thermo-TRPs and the ...physiological role of thermo-TRPs in energy metabolism. In this review, we highlight the role of various thermo-TRPs in energy metabolism and hormone secretion. In the pancreas, TRPM2 and other TRPs regulate insulin secretion. TRPV2 expressed in brown adipocytes contributes to differentiation and/or thermogenesis. Sensory nerves that express TRPV1 promote increased energy expenditure by activating sympathetic nerves and adrenaline secretion. Here, we first show that capsaicin-induced adrenaline secretion is completely impaired in TRPV1 knockout mice. The thermogenic effects of TRPV1 agonists are attributable to brown adipose tissue (BAT) activation in mice and humans. Moreover, TRPA1- and TRPM8-expressing sensory nerves also contribute to potentiation of BAT thermogenesis and energy expenditure in mice. Together, thermo-TRPs are promising targets for combating obesity and metabolic disorders.
Ghrelin, isolated from the human and rat stomach, is the endogenous ligand for the growth hormone (GH) secretagogue receptor, which is expressed in a variety of tissues, including the pancreatic ...islets. It has been shown that low plasma ghrelin levels correlates with elevated fasting insulin levels and type 2 diabetes. Here we show a physiological role of endogenous ghrelin in the regulation of insulin release and blood glucose in rodents. Acylated ghrelin, the active form of the peptide, was detected in the pancreatic islets. Counteraction of endogenous ghrelin by intraperitoneal injection of specific GH secretagogue receptor antagonists markedly lowered fasting glucose concentrations, attenuated plasma glucose elevation, and enhanced insulin responses during the glucose tolerance test (GTT). Conversely, intraperitoneal exogenous ghrelin GH-independently elevated fasting glucose concentrations, enhanced plasma glucose elevation, and attenuated insulin responses during GTT. Neither GH secretagogue receptor antagonist nor ghrelin affected the profiles of the insulin tolerance test. In isolated islets, GH secretagogue receptor blockade and antiserum against acylated ghrelin markedly enhanced glucose-induced increases in insulin release and intracellular Ca2+ concentration (Ca2+i), whereas ghrelin at a relatively high concentration (10 nmol/l) suppressed insulin release. In single beta-cells, ghrelin attenuated glucose-induced first-phase and oscillatory Ca2+i increases via the GH secretagogue receptor and in a pertussis toxin-sensitive manner. Ghrelin also increased tetraethylammonium-sensitive delayed outward K+ currents in single beta-cells. These findings reveal that endogenous ghrelin in islets acts on beta-cells to restrict glucose-induced insulin release at least partly via attenuation of Ca2+ signaling, and that this insulinostatic action may be implicated in the upward control of blood glucose. This function of ghrelin, together with inducing GH release and feeding, suggests that ghrelin underlies the integrative regulation of energy homeostasis.
A fundamental property of animal cells is the ability to regulate their own cell volume. Even under hypotonic stress imposed
by either decreased extracellular or increased intracellular osmolarity, ...the cells can re-adjust their volume after transient
osmotic swelling by a mechanism known as regulatory volume decrease (RVD). In most cell types, RVD is accomplished mainly
by KCl efflux induced by parallel activation of K + and Cl â channels. We have studied the molecular mechanism of RVD in a human epithelial cell line (Intestine 407). Osmotic swelling
results in a significant increase in the cytosolic Ca 2+ concentration and thereby activates intermediate-conductance Ca 2+ -dependent K + (IK) channels. Osmotic swelling also induces ATP release from the cells to the extracellular compartment. Released ATP stimulates
purinergic ATP (P2Y 2 ) receptors, thereby inducing phospholipase C-mediated Ca 2+ mobilization. Thus, RVD is facilitated by stimulation of P2Y 2 receptors due to augmentation of IK channels. In contrast, stimulation of another G protein-coupled Ca 2+ -sensing receptor (CaR) enhances the activity of volume-sensitive outwardly rectifying Cl â channels, thereby facilitating RVD. Therefore, it is possible that Ca 2+ efflux stimulated by swelling-induced and P2Y 2 receptor-mediated intracellular Ca 2+ mobilization activates the CaR, thereby secondarily upregulating the volume-regulatory Cl â conductance. On the other hand, the initial process towards apoptotic cell death is coupled to normotonic cell shrinkage,
called apoptotic volume decrease (AVD). Stimulation of death receptors, such as TNFα receptor and Fas, induces AVD and thereafter
biochemical apoptotic events in human lymphoid (U937), human epithelial (HeLa), mouse neuroblastoma à rat glioma hybrid (NG108-15)
and rat phaeochromocytoma (PC12) cells. In those cells exhibiting AVD, facilitation of RVD is always observed. Both AVD induction
and RVD facilitation as well as succeeding apoptotic events can be abolished by prior treatment with a blocker of volume-regulatory
K + or Cl â channels, suggesting that AVD is caused by normotonic activation of ion channels that are normally involved in RVD under
hypotonic conditions. Therefore, it is likely that G protein-coupled receptors involved in RVD regulation and death receptors
triggering AVD may share common downstream signals which should give us key clues to the detailed mechanisms of volume regulation
and survival of animal cells. In this Topical Review, we look at the physiological ionic mechanisms of cell volume regulation
and cell death-associated volume changes from the facet of receptor-mediated cellular processes.
Ghrelin, a novel growth hormone-releasing peptide isolated from human and rat stomach, is a 28-amino acid peptide with a posttranslational acylation modification that is indispensable for stimulating ...growth hormone secretion by increasing intracellular Ca(2+) concentration. It also functions in the regulation of feeding behavior, energy metabolism, and gastric acid secretion and motility. Using two different antibodies against the NH(2)- and COOH-terminal regions of ghrelin, we studied its localization in human and rat pancreas by immunohistochemistry. Ghrelin-immunoreactive cells were identified at the periphery of pancreatic islets in both species. Ghrelin co-localized exclusively with glucagon in rat islets, indicating that it is produced in alpha-cells. We identified ghrelin and des-acyl ghrelin in the rat pancreas using reverse-phase high-performance liquid chromatography combined with two radioimmunoassays. We also detected mRNA encoding ghrelin and its receptor in the rat pancreatic islets. Ghrelin increased the cytosolic free Ca(2+) concentration in beta-cells and stimulated insulin secretion when it was added to isolated rat pancreatic islets. These findings indicate that ghrelin may regulate islet function in an endocrine and/or paracrine manner.
1
Diabetic modifications of nicotinic receptor‐operated noncontractile Ca2+ mobilization observed in the presence of anticholinesterase were investigated by measuring Ca2+‐aequorin luminescence in ...diaphragm muscles of mice with diabetes induced by injections of streptozotocin (150 mg kg−1, bolus i.v.) and alloxan (85 mg kg−1, bolus i.v.).
2
The diabetic state accelerated the decline of noncontractile Ca2+ transients without affecting their peak amplitude. Insulin treatment reversed this alteration.
3
The increase in contractile Ca2+ transients by cholinesterase inhibition was attenuated 0.6 fold and became resistant to changes in Ca2+o in the diabetic state.
4
Changes in extracellular pH from 7.6 to 5.6 depressed the peak amplitude of noncontractile Ca2+ transients without affecting their duration, and enhanced the peak amplitude of contractile Ca2+ transients.
5
These results suggest that the inactivation process of noncontractile Ca2+ mobilization is promoted in diabetic muscles, presumably by desensitization of the nicotinic acetylcholine receptor.
1
Nicotinic acetylcholine receptor (AChR)‐operated non‐contractile Ca2+ mobilization (unaccompanied by muscle contraction) depressed contractile Ca2+ mobilization (accompanied by muscle contraction) ...in mouse diaphragm muscles. In the process of nicotinic AChR desensitization, the enhancing role of calcitonin gene‐related peptide (CGRP) on the non‐contractile Ca2+‐induced depression of contractile Ca2+ mobilization was investigated by measurement of Ca2+‐aequorin luminescence in the presence of neostigmine (0.1 μm).
2
When the phrenic nerve was stimulated with paired pulses at intervals of 150, 300, 600, 1000 and 2000 ms, contractile Ca2+ transients were elicited during the generation of non‐contractile Ca2+ mobilization. The amplitude of the contractile Ca2+ transients elicited by the second pulse (S2) was depressed at the shorter pulse intervals, but not at the longer pulse intervals.
3
The extent of depression of S2 was enhanced when the duration of non‐contractile Ca2+ mobilization was prolonged by CGRP (10 nM). However, CGRP failed to enhance the depression of S2 when non‐contractile Ca2+ mobilization was not observed at the low external Ca2+ concentration (1.3 mM).
4
The enhancing effect by CGRP on the depression of S2 was counteracted by staurosporine (3 nM), a protein kinase‐C inhibitor, despite prolongation of the duration of non‐contractile Ca2+ mobilization.
5
When H‐89 (1 μm), a protein kinase‐A inhibitor, completely blocked non‐contractile Ca2+ mobilization, the depression of S2 was diminished. The prolongation of the duration of non‐contractile Ca2+ mobilization by AA373 (300 μm), a protein kinase‐A activator, enhanced the depression of S2. The enhancing effect was observed neither with CGRP nor with AA373, in the presence of H‐89 (0.1 μm).
6
These findings suggest that the CGRP mobilizes non‐contractile Ca2+ through activation of protein kinase‐A, which in turn may activate protein kinase‐C, then enhance the desensitization of postsynaptic nicotinic AChRs at the neuromuscular junction.
Neuronal-type nicotinic acetylcholine receptors (N-nAChR) are co-localized with muscle-type (M-)nAChR in the postjunctional endplate membrane of adult skeletal muscle fibers. The postsynaptic ...desensitizing functions of the N-nAChR at the neuromuscular junction and at single skeletal muscle cells have been investigated using aequorin luminescence and fluorescence confocal imaging. A biphasic elevation of local intracellular Ca2+ is elicited by prolonged nicotinic action at the mouse muscle endplates. The contractile fast and noncontractile slow Ca2+ components are operated by postsynaptic M- and colocalized N-type nAChR, respectively. We have named the latter slow one RAMIC (receptor-activity modulating intracellular Ca2+). The N-nAChR are activated by nicotine and choline, and RAMIC are antagonized by methyllycaconitine and dihydro-β-erythroidine. Neuromuscular functions may be regulated by a dual nAChR system to maintain the normal postsynaptic excitability. Certain N-nAChR may be also endowed with the same functional role in the central nervous system.
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