Metabolic effects of overnight continuous infusion of unacylated ghrelin in humans

Objective: To clarify the metabolic effects of an overnight i.v. infusion of unacylated ghrelin (UAG) in humans. UAG exerts relevant metabolic actions, likely mediated by a still unknown ghrelin receptor subtype, including effects on β-cell viability and function, insulin secretion and sensitivity, and glucose and lipid metabolism. Design: We studied the effects of a 16-h infusion (from 2100 to 1300 h) of UAG (1.0 μg/kg per h) or saline in eight normal subjects (age (mean±S.E.M.), 29.6±2.4 years; body mass index (BMI), 22.4±1.7 kg/m2), who were served, at 2100 and 0800 h respectively, with isocaloric balanced dinner and breakfast. Glucose, insulin, and free fatty acid (FFA) levels were measured every 20 min. Results: In comparison with saline, UAG induced significant (P<0.05) changes in glucose, insulin, and FFA profiles. UAG infusion decreased glucose area under the curve (AUC) values by 10% (UAG0-960 min: 79.0±1.7×10 3 mg/dl per min vs saline0-960 min: 87.5±3. 8×103 mg/dl per min) and the AUC at night by 14% (UAG 180-660 min: 28.4±0.5×103 mg/dl per min vs saline180-660 min: 33.2±1.1×103 mg/dl per min). The overall insulin AUC was not significantly modified by UAG infusion; however, insulin AUC observed after meals was significantly increased under the exposure to UAG with respect to saline at either dinner or breakfast. The FFA AUC values were decreased by 52% under the exposure to UAG in comparison with saline (UAG0-960 min: 0.3±0.02×103 mEq/l per min vs saline0-960 min: 0.6±0.05×103 mEq/l per min). Conclusions: Exposure to the i.v. administration of UAG improves glucose metabolism and inhibits lipolysis in healthy volunteers. Thus, in contrast to the diabetogenic action of AG, UAG displays hypoglycemic properties

Cortistatin-17 and -14 exert the same endocrine activities as somatostatin in humans

Cortistatin (CST) is a neuropeptide, which binds with high affinity all somatostatin (SS) receptor subtypes and shows high structural homology with SS itself. A receptor specific for CST only, i.e., not recognized by SS, has been recently described in agreement with data reporting that not all CST actions are shared by SS. Interestingly, CST but not SS also binds ghrelin receptor (GHS-R1a) in vitro, suggesting a potential interplay between CST and ghrelin system. The aim of this study was to investigate in humans the endocrine and metabolic activities of human CST-17 in comparison with rat CST-14 that has previously been shown to exert the same endocrine actions of SS in healthy volunteers. To this aim, in six healthy male volunteers (age [median, 3rd-97th centiles]: 28.5; 23.6-34.3 years; Body Mass Index: 23.5; 21.0-25.1 kg/m2), we studied the effects of human CST-17 (2.0 μg/kg/h iv over 120 min), rat CST-14 (2.0 μg/kg/h iv over 120 min) and SS-14 (2.0 μg/kg/h iv over 120 min) on: (a) spontaneous GH, ACTH, PRL, cortisol, insulin and glucose levels; (b) the GH responses to GHRH (1.0 μg/kg iv at 0 min); (c) the GH, PRL, ACTH, cortisol, insulin and glucose responses to ghrelin (1.0 μg/kg iv at 0 min). CST-17 inhibited (p<0.01) basal GH secretion to the same extent of CST-14 and SS-14. Spontaneous PRL, ACTH and cortisol secretion were not significantly modified by CST-17, CST-14 or SS-14. CST-17 as well as CST-14 and SS-14 also inhibited (p<0.05) spontaneous insulin secretion to a similar extent. None of these peptides modified glucose levels. The GH response to GHRH was inhibited to the same extent by CST-17 (p<0.01), CST-14 (p<0.01) and SS-14 (p<0.05). The ghrelin-induced GH response was higher than that elicited by GHRH (p<0.01) and inhibited by CST-17 (p<0.05) as well as by CST-14 (p<0.05) and SS-14 (p<0.01). The PRL, ACTH and cortisol responses to ghrelin were unaffected by CST-17, CST-14 or SS-14. On the other hand, the inhibitory effect of ghrelin on insulin levels was abolished by CST-17, CST-14 or SS-14 (p<0.05) that, in turn, did not modify the ghrelin-induced increase in glucose levels. In conclusion, this study demonstrates that human CST-17 and rat CST-14 exert the same endocrine activities of SS in humans. The endocrine actions of human and rat CST therefore are likely to reflect activation of classical SS receptors

METABOLIC ACTIONS OF GHRELIN.

Ghrelin, a peptide predominantly produced by the stomach, has been discovered as natural ligand of the GH Secretagogue (GHS) receptor type 1a and supposed to play a major role in the control of somatotroph function. Instead ghrelin turned out to exert pleiotropic actions on several endocrine and non-endocrine target tissues consistently with its widespread expression distribution and that of its receptors. Among its actions, particular attention has been focused on its central orexigenic effect, and more recently on its peripheral metabolic influence on glucose and lipid metabolism. Interestingly, some metabolic ghrelin actions are independent of its acylation supporting the hypothesis of the existence of ghrelin receptors subtypes, distinct from the GHS-R1a. Consistently with its remarkable metabolic impact, ghrelin secretion itself (70% in its non-acylated form) is mostly under metabolic control being modulated by glucose, insulin and feeding. Recent studies suggest the hypothesis that ghrelin system would play a role in type 2 diabetes, metabolic syndrome and atherogenesis

Vitamin D status and type 1 diabetes in children: evaluation according to latitude and skin color

We aim to investigate vitamin D (25OHD) levels in children with or without type 1 diabetes (T1D) according to latitude and skin color

Obestatin levels are associated with C-peptide and anti-insulin antibodies at the onset whereas unacylated and acylated ghrelin levels are not predictive of long-term metabolic control in children with type 1 diabetes.

Context and objective: Ghrelin secretion is altered at the onset and after the start of insulin therapy in children with type 1 diabetes. Contemporary regulation of acylated (AG), unacylated ghrelin (UAG) and obestatin (OBST) remains undefined in this disease. It is unknown as to whether they could be good predictors of changes in glucose and metabolic control. Design, setting and subjects: A longitudinal study in a tertiary care center. AG, UAG and OBST were measured at baseline and after 2 years of follow-up in 51 children and adolescents with a history of type 1 diabetes extending beyond 1 year. A total of 33 healthy matched subjects were used as controls. Results: Age, puberty and BMI adjusted UAG levels were lower (p<0.005) and OBST levels were higher (p<0.009) in children with type 1 diabetes, with respect to controls. AG levels were similar to controls, but all ratios of three peptides are altered in diabetic patients. OBST (p<0.05) was negatively correlated with C-peptide (p<0.05) and IAA (p<0.008) at the onset of diabetes. In diabetic patients, baseline AG and UAG levels were negatively correlated with insulin dosage in the short- and long-term (p<0.001). AG, but not OBST, was positively correlated with C-peptide levels 2 years after diagnosis (p<0.05). Overall, the peptides were not predictive of glucose and metabolic control. Conclusions: UAG, AG, OBST and their ratios are differently regulated in children with type 1 diabetes suggesting a role in the metabolic balance of the disease, with insulin a likely regulator of AG and UAG. The peptides do not appear to be good long-term predictors of glucose control, with further investigations needed to explain if OBST could be a precocious predictor of islet dysfunction

Functional pharmacology of GABAA receptors containing the chicken brain ?4 subunit

The functional pharmacology of receptors composed of the chicken brain {GABAA} receptor γ4 subunit and the mammalian {GABAA} receptor α3 and β2 subunits was studied by heterologous expression in Xenopus laevis oocytes using the two electrode voltage-clamp technique. GABA-evoked currents had an {EC50} of 180±30 μM. Responses were blocked by the competitive and non-competitive {GABAA} receptor antagonists, bicuculline methochloride and picrotoxin. Sodium pentobarbital reversibly potentiated the current several-fold, and Zn2+ ions blocked the current with high potency (IC50=20 μM). GABA-evoked currents were potentiated by the benzodiazepine site full agonists flunitrazepam and triazolam and less by the partial agonists abecarnil and bretazenil. The inverse agonists methyl-β-carboline-3-carboxylate (β-CCM) and methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM) reduced the current. However, the imidazobenzodiazepine Ro 15-4513, which acts as an inverse agonist at mammalian αxβyγ2 {GABAA} receptors (where x=1, 2, 3 or 5, and y=1, 2 or 3), acted as a positive agonist at the γ4 subunit-containing receptors

Ghrelin as a New Factor in the Central Network Controlling Appetite and Food Intake.

Ghrelin is a 28 amino acid peptide predominantly produced by the stomach, although it is also expressed in many other central and peripheral endocrine and non-endocrine tissues [1], [3]. Ghrelin displays strong growth hormone (GH)releasing activity mediated by the activation of the GH secretagogue receptor type 1a (GHS-R 1a) [1], [3]. Prior to the discovery of ghrelin, this orphan receptor had been shown to be specific for a family of synthetic peptidyl and non-peptidyl molecules known as GH secretagogues (GHS) [1], [3], [4]. GHS-R are concentrated in the hypothalamic -pituitary unit but are also distributed in other central and peripheral tissues [1] [4]. Apart from the potent GH-releasing effect, ghrelin exhibits additional actions including stimulation of prolactin and ACTH secretion, negative influence on gonadal axis, stimulation of appetite and positive influence on energy balance, endocrine and nonendocrine gastro-entero-pancreatic functions, cardiovascular actions and modulation of cell viability [3], [5], [6]