Leptin and Its Emerging Role in Children and Adolescents

Leptin is an adipocyte-secreted hormone which plays a key role in energy homeostasis. Recent “proof of concept” studies involving leptin administration to humans support its critical role in regulating energy homeostasis, neuroendocrine and immune function as well as insulin resistance in states of energy/ caloric deprivation. Moreover, interventional studies in leptin deficient children and observational studies in normal girls and boys support a role for leptin as a permissive factor for the initiation of puberty in children. The potential clinical usefulness of leptin in several disease states in children and adolescents, including hypothalamic amenorrhea, eating disorders and syndromes of insulin resistance is still under investigation

The Development of INT131 as a Selective PPARγ Modulator: Approach to a Safer Insulin Sensitizer

INT131 (formerly T0903131, T131, AMG131) is a potent non-thiazolidinedione (TZD) selective peroxisome proliferator-activated receptor γ modulator (SPPARM) currently in Phase 2 clinical trials for treatment of type-2 diabetes mellitus (T2DM). This new chemical entity represents a second generation SPPARM approach developed after the first generation PPARγ full agonists to address their inherent limitations. INT131 was specifically and carefully designed using preclinical models to exhibit a biological profile of strong efficacy with de minimis side effects compared to PPARγ full agonists. As a potent PPARγ modulator, INT131 binds to PPARγ with high affinity. In pharmacology models of diabetes and in early clinical studies, it achieved a high level of efficacy in terms of antidiabetic actions such as insulin sensitization and glucose and insulin lowering, but had little activity in terms of other, undesired, effects associated with TZD PPARγ full agonists such as edema and adipogenesis. Ongoing clinical development is directed at translating these findings into establishing a novel and effective treatment for T2DM patients with an improved safety profile in relation to that currently available

Obese individuals with more components of the metabolic syndrome and/or prediabetes demonstrate decreased activation of reward-related brain centers in response to food cues in both the fed and fasting states: A preliminary fMRI study

It remains unknown whether obese individuals with more components of the metabolic syndrome and/or prediabetes demonstrate altered activation of brain centers in response to food cues. We examined obese prediabetics (n=26) vs. obese nondiabetics (n=11) using fMRI. We also performed regression analyses on the basis of the number of MetS components per subject. Obese individuals with prediabetes have decreased activation of the reward-related putamen in the fasting state and decreased activation of the salience- and reward-related insula after eating. Obese individuals with more components of MetS demonstrate decreased activation of the putamen while fasting. All these activations remain significant when corrected for BMI, waist circumference (WC), HbA1c and gender. Decreased activation in reward-related brain areas between obese individuals is more pronounced in subjects with prediabetes and MetS. Prospective studies are needed to quantify their contributions to the development of prediabetes/MetS and to study whether these conditions may predispose to the exacerbation of obesity and the development of comorbidities over time

Circulating Irisin Levels Are Not Affected by Coffee Intake: A Randomized Controlled Trial

Irisin, secreted by skeletal muscle and possibly fat, is hypothesized to play an important role in modulating energy expenditure, obesity and metabolism. Coffee consumption also increases energy expenditure and leads to positive metabolic effects, but whether these effects are mediated by irisin remains unknown. The objective of this study was to determine the association between baseline irisin levels and the metabolic profile in humans and to investigate whether consumption of caffeinated coffee alters irisin levels. To this end, a secondary analysis was performed investigating irisin levels at baseline and after eight weeks in 32 healthy, overweight coffee drinkers who were randomized to consumption of 5 cups per day of instant caffeinated coffee, decaffeinated coffee, or water. Spearman correlation and analysis of covariance analyses were performed to identify possible associations. Irisin levels were positively correlated with waist circumference (r = 0.41, p = 0.02), fat mass (r = 0.44, p = 0.01) and CRP (r = 0.47, p = 0.007). Though there was a trend towards increased levels of irisin over time in the caffeinated coffee group (+1.8%) when compared to the placebo group (−4%) this did not reach statistical significance (p = 0.75 for the trend). This first randomized trial failed to reveal any effects of coffee consumption on irisin levels, but a larger trial, appropriately sized on the basis of data provided by this study, is needed to conclusively investigate such a relationship. Trial Registration Clinicaltrials.gov NCT0030509

Effects of Lipid-Lowering Drugs on Irisin in Human Subjects In Vivo and in Human Skeletal Muscle Cells Ex Vivo

Context and Objective The myokine irisin has been proposed to regulate energy homeostasis. Little is known about its association with metabolic parameters and especially with parameters influencing pathways of lipid metabolism. In the context of a clinical trial, an exploratory post hoc analysis has been performed in healthy subjects to determine whether simvastatin and/or ezetimibe influence serum irisin levels. The direct effects of simvastatin on irisin were also examined in primary human skeletal muscle cells (HSKMCs). Design and Participants A randomized, parallel 3-group study was performed in 72 men with mild hypercholesterolemia and without apparent cardiovascular disease. Each group of 24 subjects received a 14-day treatment with either simvastatin 40 mg, ezetimibe 10 mg, or their combination. Results: Baseline irisin concentrations were not significantly correlated with age, BMI, estimated GFR, thyroid parameters, glucose, insulin, lipoproteins, non-cholesterol sterols, adipokines, inflammation markers and various molecular markers of cholesterol metabolism. Circulating irisin increased significantly in simvastatin-treated but not in ezetimibe-treated subjects. The changes were independent of changes in LDL-cholesterol and were not correlated with changes in creatine kinase levels. In HSKMCs, simvastatin significantly increased irisin secretion as well as mRNA expression of its parent peptide hormone FNDC5. Simvastatin significantly induced cellular reactive oxygen species levels along with expression of pro- and anti-oxidative genes such as Nox2, and MnSOD and catalase, respectively. Markers of cellular stress such as atrogin-1 mRNA and Bax protein expression were also induced by simvastatin. Decreased cell viability and increased irisin secretion by simvastatin was reversed by antioxidant mito-TEMPO, implying in part that irisin is secreted as a result of increased mitochondrial oxidative stress and subsequent myocyte damage. Conclusions: Simvastatin increases irisin concentrations in vivo and in vitro. It remains to be determined whether this increase is a result of muscle damage or a protective mechanism against simvastatin-induced cellular stress. Trial Registration ClinicalTrials.gov NCT00317993 NCT00317993

Glucagon-Like Peptide-1 Receptor Agonists and Dual Glucose-Dependent Insulinotropic Polypeptide/Glucagon-Like Peptide-1 Receptor Agonists in the Treatment of Obesity/Metabolic Syndrome, Prediabetes/Diabetes and Non-Alcoholic Fatty Liver Disease-Current Evidence

The obesity pandemic is accompanied by increased risk of developing metabolic syndrome (MetS) and related conditions: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), type 2 diabetes mellitus (T2DM) and cardiovascular (CV) disease (CVD). Lifestyle, as well as an imbalance of energy intake/expenditure, genetic predisposition, and epigenetics could lead to a dysmetabolic milieu, which is the cornerstone for the development of cardiometabolic complications. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs promote positive effects on most components of the "cardiometabolic continuum " and consequently help reduce the need for polypharmacy. In this review, we highlight the main pathophysiological mechanisms and risk factors (RFs), that could be controlled by GLP-1 and dual GIP/GLP-1 RAs independently or through synergism or differences in their mode of action. We also address the evidence on the use of GLP-1 and dual GIP/GLP-1 RAs in the treatment of obesity, MetS and its related conditions (prediabetes, T2DM and NAFLD/NASH). In conclusion, GLP-1 RAs have already been established for the treatment of T2DM, obesity and cardioprotection in T2DM patients, while dual GIP/GLP-1 RAs appear to have the potential to possibly surpass them for the same indications. However, their use in the prevention of T2DM and the treatment of complex cardiometabolic metabolic diseases, such as NAFLD/NASH or other metabolic disorders, would benefit from more evidence and a thorough clinical patient-centered approach. There is a need to identify those patients in whom the metabolic component predominates, and whether the benefits outweigh any potential harm