The role of nesfatin‐1 in the regulation of food intake and body weight: recent developments and future endeavors

Nesfatin‐1 was discovered in 2006 and introduced as a potential novel anorexigenic modulator of food intake and body weight. The past years have witnessed increasing evidence establishing nesfatin‐1 as a potent physiological inhibitor of food intake and body weight and unravelled nesfatin‐1's interaction with other brain transmitters to exert its food consumption inhibitory effect. As observed for other anorexigenic brain neuropeptides, nesfatin‐1 is also likely to exert additional, if not pleiotropic, actions in the brain and periphery. Recent studies established the prominent expression of the nesfatin‐1 precursor, nucleobindin2 (NUCB2), in the stomach and pancreas, where nesfatin‐1 influences endocrine secretion. This review will highlight the current experimental state‐of‐knowledge on the effects of NUCB2/nesfatin‐1 on food intake, body weight and glucose homeostasis. Potential implications in human obesity will be discussed in relation to the evidence of changes in circulating levels of NUCB2/nesfatin‐1 in disease states, the occurrence of genetic NUCB2 polymorphisms and – in contrast to several other hormones – the independence of leptin signalling known to be blunted under conditions of chronically increased body weight.     

Glucagon-like peptide-1: a potent regulator of food intake in humans

Background/Aims—Studiesin animals suggest a physiological role for glucagon-likepeptide-1-(7-36)-amide (GLP-1) in regulating satiety. The role ofGLP-1 in regulating food intake in man has, however, not been investigated.
Subjects—Sixteen healthy male subjects were examined in adouble blind placebo controlled fashion.
Methods—The effect ofgraded intravenous doses (0,0.375, 0.75, and 1.5 pmol/kg/min) ofsynthetic human GLP-1 on food intake and feelings of hunger and satietywas tested in healthy volunteers.
Results—Graded GLP-1infusions resulted in a dose dependent reduction in food intake(maximal inhibition 35%, p<0.001 vcontrol) and a similar reduction in calorie intake (32%; p<0.001). Fluid ingestion was also reduced by GLP-1 (18% reduction, p<0.01). Noovert side effects were produced by GLP-1, but subjects experienced less hunger and early fullness in the period before a meal during GLP-1infusion at the highest dose (p<0.05).
Conclusions—Intravenousinfusions of GLP-1 decrease spontaneous food intake even atphysiological plasma concentrations, implying an important role forGLP-1 in the regulation of the early satiety response in humans.

Keywords:glucagon-like peptide-1; satiety; food intake; hunger and fullness score

     

Review and meta‐analysis of the short‐term effects of a vegetable oil emulsion on food intake

Several short‐term studies have investigated the effects of a vegetable oil emulsion on subsequent food intake, although findings have been inconsistent. This work aimed to review all studies, and investigate differences in study outcomes based on methodology. All known studies were identified. Data were abstracted from published studies (n = 7). Details of unpublished studies were gained from investigators/sponsors (n = 5), or were unavailable for reasons of confidentiality (n = 4). Available data were combined using meta‐analyses. A combined appetite suppressant effect of the emulsion compared with control was found for test meal intake at approximately 4, 12 and 36 h post‐treatment: smallest combined mean difference (random effects model) = 0.53 MJ (95% confidence interval 0.20, 0.86), P < 0.01. However, considerable heterogeneity (variability) between study results was also found (smallest I² = 94%, P < 0.01), questioning the predictive validity of the above findings. Meta‐regression suggested this heterogeneity to be related to differences in the processed nature of the product, treatment dose and in particular year of study (smallest B = 0.54, 95% confidence interval 0.06, 1.03, P = 0.04), although again heterogeneity was found. The only consistent finding was a lack of effect on food intake 4 h post‐preload in studies conducted after 2003. These results suggest a small but inconsistent appetite suppressant effect of the vegetable oil emulsion. However, due to the large heterogeneity, no definitive conclusions can be drawn.     

Sodium tungstate regulates food intake and body weight through activation of the hypothalamic leptin pathway

Aims: Sodium tungstate is an anti‐obesity drug targeting peripheral tissues. In vivo, sodium tungstate reduces body weight gain and food intake through increasing energy expenditure and lipid oxidation, but it also modulates hypothalamic gene expression when orally administered, raising the possibility of a direct effect of sodium tungstate on the central nervous system. Methods: Sodium tungstate was administered intraperitoneally (ip) to Wistar rats, and its levels were measured in cerebrospinal fluid through mass spectrometry. Body weight gain and food intake were monitored for 24 h after its administration in the third ventricle. Hypothalamic protein was obtained and subjected to western blot. In vitro, hypothalamic N29/4 cells were treated with 100 µM sodium tungstate or 1 nM leptin, and protein and neural gene expression were analysed. Results: Sodium tungstate crossed the blood–brain barrier, reaching a concentration of 1.31 ± 0.07 mg/l in cerebrospinal fluid 30 min after ip injection. When centrally administered, sodium tungstate decreased body weight gain and food intake and increased the phosphorylation state of the main kinases and proteins involved in leptin signalling. In vitro, sodium tungstate increased the phosphorylation of janus kinase‐2 (JAK2) and extracellular signal‐regulated kinase‐1/2 (ERK1/2), but the activation of each kinase did not depend on each other. It regulated c‐myc gene expression through the JAK2/STAT system and c‐fos and AgRP (agouti‐related peptide) gene expression through the ERK1/2 pathway simultaneously and independently. Conclusions: Sodium tungstate increased the activity of several kinases involved in the leptin signalling system in an independent way, making it a suitable and promising candidate as a leptin‐mimetic compound in order to manage obesity.     

The effect of glucagon‐like peptide‐1 and glucagon‐like peptide‐2 on microcirculation: A systematic review

GLP‐1 and GLP‐2 are gut‐derived hormones used in the treatment of diabetes type‐2 and short bowel syndrome, respectively. GLP‐1 attenuates insulin resistance and GLP‐2 reduces enterocyte apoptosis and enhances crypt cell proliferation in the small intestine. In addition, both hormones have vasoactive effects and may be useful in situations with impaired microcirculation. The aim of this systematic review was to provide an overview of the potential effects of GLP‐1 and GLP‐2 on microcirculation. A systematic search was performed independently by two authors in the following databases: PubMed, EMBASE, Cochrane library, Scopus, and Web of Science. Of 1111 screened papers, 20 studies were included in this review: 16 studies in animals, three in humans, and one in humans and rats. The studies were few and heterogeneous and had a high risk of bias. However, it seems that GLP‐1 regulates the pancreatic, skeletal, and cardiac muscle flow, indicating a role in the glucose homeostasis, while GLP‐2 acts primarily in the regulation of the microcirculation of the mid‐intestine. These findings may be useful in gastrointestinal surgery and in situations with impaired microcirculation of the gut.     

Investigation of doublecortin and calcium/calmodulin‐dependent protein kinase‐like‐1‐expressing cells in the mouse stomach

Background and Aims: For lack of a definite stem cell marker, there is limited knowledge of the precise location and fate of stem cells after injury. Doublecortin and calcium/calmodulin‐dependent protein kinase‐like‐1 (DCAMKL‐1) is a putative intestinal and colon stem cell marker. Our aim was to identify DCAMKL‐1‐expressing cells in the gastric epithelium and to analyze the fate of DCAMKL‐1‐expressing cells during gastric mucosal injury and repair. Methods: Acidified ethanol was administered to wild‐type mice. DCAMKL‐1 expression were detected by immunohistochemistry and western blotting. Results: There were some DCAMKL‐1‐expressing cells in normal mouse stomachs. All the cells were located in the gastric isthmus region. All DCAMKL‐1‐expressing cells were double stained with Dolichos biflorus lectin‐expressing parietal cells and Musashi‐1‐expressing cells. The DCAMKL‐1 antigen expression decreased 12 h after injury and gradually increased to normal 4 d after injury. Conclusion: Using DCAMKL‐1 as a marker for stomach stem cells, we could describe the expression pattern of stomach stem cells during mucosal injury.     

Improved glycaemic control with minimal hypoglycaemia and no weight change with the once‐daily human glucagon‐like peptide‐1 analogue liraglutide as add‐on to sulphonylurea in Japanese patients with type 2 diabetes

Aim: Sulphonylureas (SUs) are often used as first‐line treatments for type 2 diabetes in Japan, hence it is important to study new antidiabetic drugs in combination with SUs in Japanese patients. Methods: The efficacy and safety of the once‐daily human glucagon‐like peptide‐1 (GLP‐1) analogue liraglutide were compared in 264 Japanese subjects [mean body mass index (BMI) 24.9 kg/m²; mean glycated haemoglobin (HBA1c) 8.4%] randomized and exposed to receive liraglutide 0.6 mg/day (n = 88), 0.9 mg/day (n = 88) or placebo (n = 88) each added to SU monotherapy (glibenclamide, glicazide or glimeprimide) in a 24‐week, double‐blind, parallel‐group trial. Results: The mean change in HBA1c from baseline to week 24 (LOCF) was ?1.56 (s.d. 0.84) and ?1.46 (s.d. 0.95) with liraglutide 0.9 and 0.6 mg respectively, and ?0.40 (s.d. 0.93) with placebo. HBA1c decreased in the placebo group from 8.45 to 8.06%, while liraglutide reduced HBA1c from 8.60 to 7.14%, and from 8.23 to 6.67% at the 0.6 and 0.9 mg doses respectively. Mean HBA1c at week 24 of the two liraglutide groups were significantly lower than the placebo group (p < 0.0001 for both). More subjects reached HBA1c < 7.0% with liraglutide (0.6 mg: 46.5%; 0.9 mg: 71.3%) vs. placebo (14.8%). Fasting plasma glucose (FPG) levels were significantly improved with liraglutide (difference ?1.47 mmol/l and ?1.80 mmol/l with 0.6 and 0.9 mg vs. placebo; p < 0.0001). Overall safety was similar between treatments: no major hypoglycaemic episodes were reported, while 84/77/38 minor hypoglycaemic episodes occurred in the 0.6 mg/0.9 mg and placebo treatment groups (all in combination with SU), reflecting lower ambient glucose levels. No relevant change in mean body weight occurred in subjects receiving liraglutide (0.6 mg: 0.06 kg; 0.9 mg: ?0.37 kg), while mean body weight decreased in subjects receiving placebo (?1.12 kg). Conclusions: The addition of liraglutide to SU treatment for 24 weeks dose‐dependently improved glycaemic control vs. SU monotherapy, without causing major hypoglycaemia or weight gain or loss.     

Glucagon‐like peptide‐1 receptor agonists for type 2 diabetes: A rational drug development

Today, glucagon‐like peptide‐1 (GLP‐1) receptor agonists are established glucose‐lowering drugs used in the management of type 2 diabetes. Their development emerged from the understanding that a combined islet dysfunction comprising of impaired insulin secretion and exaggerated glucagon secretion is the key defect of hyperglycemia. GLP‐1 was shown to target these defects, and after the discovery that dipeptidyl peptidase‐4 inactivates native GLP‐1, several different dipeptidyl peptidase‐4‐resistant GLP‐1 receptor agonists have been developed. They are administered subcutaneously, but show differences in molecular structure, molecular size and pharmacokinetics, the latter allowing twice‐daily, once‐daily or once‐weekly administration. They have been shown to be efficient in reducing both glycated hemoglobin and bodyweight, and to be safe and highly tolerable. Cardiovascular outcomes trials have shown them to be neutral or beneficial. GLP‐1 receptor agonists are positioned as add‐ons to metformin alone or in combination with oral agents in the clinical paradigm. They are also efficient when combined with insulin, and fixed dose combinations with long‐acting insulin have been developed. Recent development includes a very long administration schedule and oral availability. The research from the first demonstration of the antidiabetic action of GLP‐1 in the early 1990s to the enormously accumulated data today represents a successful and rational development, which has been characterized by focused perseverance to establish this therapy in the management of type 2 diabetes.     

Plasma gastric inhibitory polypeptide and glucagon‐like peptide‐1 levels after glucose loading are associated with different factors in Japanese subjects

Aims/Introduction: Gastric inhibitory polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are major incretins that potentiate insulin secretion from pancreatic β‐cells. The factors responsible for incretin secretion have been reported in Caucasian subjects, but have not been thoroughly evaluated in Japanese subjects. We evaluated the factors associated with incretin secretion during oral glucose tolerance test (OGTT) in Japanese subjects with normal glucose tolerance (NGT). Materials and Methods: We measured plasma GIP and GLP‐1 levels during OGTT in 17 Japanese NGT subjects and evaluated the factors associated with GIP and GLP‐1 secretion using simple and multiple regression analyses. Results: GIP secretion (AUC‐GIP) was positively associated with body mass index (P < 0.05), and area under the curve (AUC) of C‐peptide (P < 0.05) and glucagon (P < 0.01), whereas GLP‐1 secretion (AUC‐GLP‐1) was negatively associated with AUC of plasma glucose (P < 0.05). The insulinogenic index was most strongly associated with GIP secretion (P < 0.05); homeostasis model assessment β‐cell was the most the strongly associated factor in GLP‐1 secretion (P < 0.05) among the four indices of insulin secretion and insulin sensitivity. Conclusions: Several distinct factors might be associated with GIP and GLP‐1 secretion during OGTT in Japanese subjects. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00078.x, 2011)     

Nutritional status and food intake of children with cow's milk allergy

Introduction and objectivesCow's milk allergy (CMA) is common, especially in children. The treatment is based on the exclusion of milk and dairy products and guidance regarding the exclusion diet. This study aimed to compare the anthropometric measurements and food intake of children with CMA with those of healthy controls, and to evaluate the serum concentrations of Vitamin A and 25(OH)D in children with CMA.MethodsThis is a cross-sectional study with 27 children in the CMA group and 30 in the control group. z-Scores of body mass index and height, skinfolds, food intake and serum concentrations of retinol, beta-carotene, lycopene, 25(OH)D, parathyroid hormone and high sensitivity C-reactive protein were evaluated.ResultsMean age was four years (±1.9). The CMA group evidenced a lower height compared to those from the control group (p = 0.0043). The CMA group showed a lower intake of calcium (p = 0.0033) and lipids (p = 0.0123). Low serum concentrations of retinol, beta-carotene, lycopene, 25(OH)D were found in 25.9%, 59.3%, 48.1% and 70.3% of the CMA group, respectively.ConclusionsChildren with CMA consume smaller amounts of calcium and lipids and have shorter height compared to healthy controls. Insufficient levels of vitamins A and D were frequent in the CMA group, emphasizing the need for nutritional guidance and monitoring.     

Safety and efficacy of the combination of the glucagon‐like peptide‐1 receptor agonist liraglutide with an oral antidiabetic drug in Japanese patients with type 2 diabetes: Post‐hoc analysis of a randomized, 52‐week,open‐label,parallel‐group trial

Aims/Introduction

The aim of the present post‐hoc analysis was to investigate the safety and efficacy of liraglutide in combination with one oral antidiabetic drug (OAD) across different OAD classes.

Materials and Methods

This was a post‐hoc analysis using data from a 52‐week, open‐label, parallel‐group trial, in which patients with type 2 diabetes inadequately controlled with a single OAD (α‐glucosidase inhibitor, glinide, metformin or thiazolidinedione) were randomized to either pretrial OAD in combination with liraglutide 0.9 mg/day (liraglutide group) or pretrial OAD in combination with an additional OAD (additional OAD group). The primary outcome investigated in this post‐hoc analysis was the incidence of adverse events.

Results

The proportions of patients experiencing adverse events across the different groups of pretrial OADs were comparable between liraglutide and additional OAD (α‐glucosidase inhibitor 74.6 vs 70.0%; glinide 93.1 vs 87.1%; metformin 91.8 vs 87.1%; thiazolidinedione 86.2 vs 96.4%, respectively). Minor hypoglycemia was infrequent (seven episodes in two patients randomized to liraglutide, and two episodes in two patients randomized to additional OAD). The mean reduction in glycated hemoglobin appeared greater with liraglutide therapy, with the estimated mean treatment difference (95% confidence interval [CI]) for liraglutide vs additional OAD ranging from ?0.14%, 95% CI: ?0.48 to 0.21 (?1.5 mmol/mol, 95 CI: ?5.2 to 2.3) to ?0.44%, 95% CI:?0.79 to ?0.09 (?4.8 mmol/mol, 95% CI: ?8.6 to ?1.0).

Conclusions

The present analysis suggests that Japanese patients on OAD monotherapy might benefit from a greater improvement in glycemic control, without impacting tolerability, by combining their OAD with liraglutide rather than another OAD, regardless of which OAD monotherapy they are receiving.

     

Interactions of amylinergic and melanocortinergic systems in the control of food intake and body weight in rodents

Aims: Amylinergic and melanocortinergic systems have each been implicated in energy balance regulation. We examined the interactive effects of both systems using gene knockout and pharmacological approaches. Methods: Acute food consumption was measured in overnight fasted male wild‐type (WT) and melanocortin‐4 receptor (MC‐4R) deficient rats and in male and female WT and amylin knockout mice (AmyKO). Changes in food intake, body weight and composition in male WT and MC‐4R deficient rats and in male diet‐induced obese (DIO) rats. Pharmacological treatments included either rat amylin, murine leptin and/or the MC‐4R agonist, Ac‐R[CEH‐dF‐RWC]‐amide. Results: Amylin (10 µg/kg, IP) decreased food intake in WT but not in MC‐4R deficient rats (30 and 60 min post‐injection). Ac‐R[CEH‐dF‐RWC]‐amide (100 µg/kg, IP) suppressed food intake similarly in male WT and AmyKO, but was ineffective in female AmyKO. Amylin (50 µg/kg/day for 28 days) and leptin (125 µg/kg/day) synergistically reduced food intake and body weight in WT and MC‐4R deficient rats to a similar extent. Amylin (100 µg/kg) combined with Ac‐R[CEH‐dF‐RWC]‐amide (100 µg/kg, IP) decreased acute food intake over 3 h to a greater extent than either agent alone in fasted mice. In DIO rats, additive anorexigenic, weight‐ and fat‐lowering effects were observed over 12 days with the combination of rat amylin (50 µg/kg/day) and Ac‐R[CEH‐dF‐RWC]‐amide (2.3 mg/kg, SC injected daily). Conclusions: Although amylin's acute anorexigenic effects are somewhat blunted in MC‐4R deficiency and those of MC‐4R agonism in amylin deficiency, these effects are surmountable with pharmacological administration lending therapeutic potential to combined amylin/melanocortin agonism for obesity.     

Combining GLP‐1 receptor agonists with insulin: therapeutic rationales and clinical findings

Due to the increasing prevalence of type 2 diabetes mellitus (T2DM), the emergent trend towards diagnosis in younger patients and the progressive nature of this disease, many more patients than before now require insulin to maintain glycaemic control. However, there is a degree of inertia among physicians and patients regarding the initiation and intensification of insulin therapy, in part due to concerns about the associated weight gain and increased risk of hypoglycaemia. Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) increase insulin release and suppress glucagon secretion in a glucose‐dependent manner, thus conferring glycaemic control with a low incidence of hypoglycaemia. GLP‐1RAs also promote weight loss, and have beneficial effects on markers of β cell function, lipid levels, blood pressure and cardiovascular risk markers. However, the durability of their effectiveness is unknown and, compared with insulin, the antihyperglycaemic efficacy of GLP‐1RAs is limited. The combination of a GLP‐1RA and insulin might thus be highly effective for optimal glucose control, ameliorating the adverse effects typically associated with insulin. Data from clinical studies support the therapeutic potential of GLP‐1RA–insulin combination therapy, typically showing beneficial effects on glycaemic control and body weight, with a low incidence of hypoglycaemia and, in established insulin therapy, facilitating reductions in insulin dose. In this review, the physiological and pharmacological rationale for using GLP‐1RA and insulin therapies in combination is discussed, and data from clinical studies that have assessed the efficacy and safety of this treatment strategy are outlined.