Intensification patterns and the probability of HbA1c goal attainment in Type 2 diabetes mellitus: real-world evidence for the concept of 'intensification inertia'.

AIMS: To assess the effects of 'clinical' and 'intensification inertia' by evaluating the impact of different intensification interventions on the probability of HbA1c goal attainment using real-world data. METHODS: Electronic health records (Cleveland Clinic, 2005-2016) were used to identify 7389 people with Type 2 diabetes mellitus and HbA1c ≥53 mmol/mol (≥7.0%), despite a stable regimen of two oral antihyperglycaemic drugs for ≥6 months. The participants were stratified by index HbA1c and analysed over a 6-month period for pharmacological intensification, and then for 12 additional months for HbA1c goal attainment (<53 mmol/mol). RESULTS: The probability of HbA1c goal attainment (Kaplan-Meier analysis) in the group with index HbA1c 53-63 mmol/mol (7.0-7.9%) was highest with the addition of oral antidiabetic drugs [57.3% (95% CI 52.1, 62.0)] or glucagon-like peptide-1 receptor agonists [56.7% (95% CI 40.4, 68.6)], in the 64-74 mmol/mol (8.0-8.9%) group with the addition of oral antidiabetic drugs [31.9% (95% CI 25.1, 38.1)] or insulin [30.6% (95% CI 18.3, 41.0)], and in the ≥75 mmol/mol (≥9.0%) group with the addition of glucagon-like peptide-1 receptor agonists [53.0% (95% CI 31.8, 67.6)] or insulin [43.5% (95% CI 36.4, 49.8)]. CONCLUSIONS: Numerical, but not statistically significant, differences in HbA1c goal attainment probability by type of intensification were most marked in people with the highest index HbA1c [≥75 mmol/mol (≥9.0%)]; in this group, injectable therapy showed trends toward greater glycaemic control benefits. Additional research into the phenomenon of intensification inertia is warranted.

Short-term safety, tolerability and efficacy of a very low-calorie-ketogenic diet interventional weight loss program versus hypocaloric diet in patients with type 2 diabetes mellitus.

UNLABELLED: Brackground:The safety and tolerability of very low-calorie-ketogenic (VLCK) diets are a current concern in the treatment of obese type 2 diabetes mellitus (T2DM) patients. OBJECTIVE: Evaluating the short-term safety and tolerability of a VLCK diet (<50 g of carbohydrate daily) in an interventional weight loss program including lifestyle and behavioral modification support (Diaprokal Method) in subjects with T2DM. METHODS: Eighty-nine men and women, aged between 30 and 65 years, with T2DM and body mass index between 30 and 35 kg m(-)(2) participated in this prospective, open-label, multi-centric randomized clinical trial with a duration of 4 months. Forty-five subjects were randomly assigned to the interventional weight loss (VLCK diet), and 44 to the standard low-calorie diet. RESULTS: No significant differences in the laboratory safety parameters were found between the two study groups. Changes in the urine albumin-to-creatinine ratio in VLCK diet were not significant and were comparable to control group. Creatinine and blood urea nitrogen did not change significantly relative to baseline nor between groups. Weight loss and reduction in waist circumference in the VLCK diet group were significantly larger than in control subjects (both P<0.001). The decline in HbA1c and glycemic control was larger in the VLCK diet group (P<0.05). No serious adverse events were reported and mild AE in the VLCK diet group declined at last follow-up. CONCLUSIONS: The interventional weight loss program based on a VLCK diet is most effective in reducing body weight and improvement of glycemic control than a standard hypocaloric diet with safety and good tolerance for T2DM patients.

How safe is metabolic/diabetes surgery?

Although recent studies have shown the impressive antidiabetic effects of laparoscopic Roux-en-Y gastric bypass (LRYGB), the safety profile of metabolic/diabetes surgery has been a matter of concern among patients and physicians. Data on patients with type 2 diabetes who underwent LRYGB or one of seven other procedures between January 2007 and December 2012 were retrieved from the American College of Surgeons National Surgical Quality Improvement Program database and compared. Of the 66 678 patients included, 16 509 underwent LRYGB. The composite complication rate of 3.4% after LRYGB was similar to those of laparoscopic cholecystectomy and hysterectomy. The mortality rate for LRYGB (0.3%) was similar to that of knee arthroplasty. Patients who underwent LRYGB had significantly better short-term outcomes in all examined variables than patients who underwent coronary bypass, infra-inguinal revascularization and laparoscopic colectomy. In conclusion, LRYGB can be considered a safe procedure in people with diabetes, with similar short-term morbidity to that of common procedures such as cholecystectomy and appendectomy and a mortality rate similar to that of knee arthroplasty. The mortality risk for LRYGB is one-tenth that of cardiovascular surgery and earlier intervention with metabolic surgery to treat diabetes may eliminate the need for some later higher-risk procedures to treat diabetes complications.

White fish reduces cardiovascular risk factors in patients with metabolic syndrome: the WISH-CARE study, a multicenter randomized clinical trial.

BACKGROUND AND AIMS: Reduction of cardiovascular risk with high consumption of fish in diet is still a matter of debate, and concerns about heavy metal contamination have limited consumption of oily fish. We aimed to evaluate the effect of regular ingestion of white fish on cardiovascular risk factors in patients with metabolic syndrome. METHODS AND RESULTS: Multicenter randomized crossover clinical trial including 273 individuals with metabolic syndrome. An 8-week only-one dietary intervention: 100 g/d of white fish (Namibia hake) with advice on a healthy diet, compared with no fish or seafood with advice on a healthy diet. Outcomes were lipid profile, individual components of the metabolic syndrome, serum insulin concentrations, homeostasis model of insulin resistance, serum C-reactive protein and serum fatty acid levels. We found a significant lowering effect of the intervention with white fish on waist circumference (P < 0.001) and diastolic blood pressure (P = 0.014). A significant lowering effect was also shown after the dietary intervention with fish on serum LDL concentrations (P = 0.048), whereas no significant effects were found on serum HDL or triglyceride concentrations. A significant rise (P < 0.001) in serum EPA and DHA fatty acids was observed following white fish consumption. Overall adherence to the intervention was good and no adverse events were found. CONCLUSION: In individuals with metabolic syndrome, regular consumption of hake reduces LDL cholesterol concentrations, waist circumference and blood pressure components of the metabolic syndrome. CLINICAL TRIAL REGISTRY: White Fish for Cardiovascular Risk Factors in Patients with Metabolic Syndrome Study, Registered under ClinicalTrials.gov Identifier: NCT01758601.

Stress hyperglycaemia in critically ill patients: potential role of incretin hormones; a preliminary study.

BACKGROUND: Stress hyperglycaemia is common in the intensive care unit (ICU) setting and has been related to a worst outcome. OBJECTIVE: The objective was to characterize the association of glucoregulatory hormones, mainly incretins, with the levels of glycaemia, and its relationship with outcome in ICU patients. METHODS: We prospectively studied 60 patients. Stress hyperglycaemia was diagnosed when glycaemia was < 115 mg/dL. At ICU admission we determined glycaemia, insulin, glucagon, cortisol, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) plasma levels. Groups were compared using Kruskal-Wallis test. The association between glycaemia levels and glucoregulatory hormones was evaluated using linear regression. RESULTS: Forty-five patients (75%) had hyperglycaemia. We observed no differences in glucoregulatory hormones levels between normo- and hyper- glycaemia groups. Glycaemia levels were not significantly correlated with insulin, glucagon, cortisol or GIP levels, but were correlated with GLP-1 (p = 0.04). GLP-1 was also correlated with cortisol (p = 0.01), but failed to show a significant correlation with insulin, glucagon or GIP levels. Lower levels of plasma GLP-1 were found in patients with stress hyperglycaemia requiring vasoactive support (p = 0.02). CONCLUSIONS: Glycaemia levels were correlated with GLP-1 levels in ICU patients. GLP-1 levels were also associated with cortisol. Patients with stress hyperglycaemia who required vasoactive support had lower incretin levels compared with those patients with stress hyperglycaemia who were hemodynamically stables. (ClinicalTrials.gov Identifier: NCT01087372).

Stress hyperglycaemia in critically ill patients; Potential role of incretinhormones; a preliminary study / Hiperglucemia de estrés en el paciente crítico; papel potencial de las incretinas; estudio preliminar

Background: Stress hyperglycaemia is common in the intensive care unit (ICU) setting and has been related to a worst outcome. Objective: The objective was to characterize the association of glucoregulatory hormones, mainly incretins, with the levels of glycaemia, and its relationship with outcome in ICU patients. Methods: We prospectively studied 60 patients. Stress hyperglycaemia was diagnosed when glycaemia was > 115 mg/dL. At ICU admission we determined glycaemia, insulin, glucagon, cortisol, glucose-dependent insulino -tropic polypeptide (GIP) and glucagon-like peptide-1(GLP-1) plasma levels. Groups were compared using Kruskal-Wallis test. The association between glycaemia levels and glucoregulatory hormones was evaluated using linear regression. Results: Forty-five patients (75%) had hyperglycaemia.We observed no differences in glucoregulatory hormones levels between normo- and hyper- glycaemia groups. Glycaemia levels were not significantly correlated with insulin, glucagon, cortisol or GIP levels, but were correlated withGLP-1 (p = 0.04). GLP-1 was also correlated with cortisol (p = 0.01), but failed to show a significant correlation withinsulin, glucagon or GIP levels. Lower levels of plasmaGLP-1 were found in patients with stress hyperglycaemia requiring vasoactive support (p = 0.02).Conclusions: Glycaemia levels were correlated withGLP-1 levels in ICU patients. GLP-1 levels were also associated with cortisol. Patients with stress hyperglycaemia who required vasoactive support had lower incretin levels compared with those patients with stress hyperglycaemia who were hemodynamically stables.(ClinicalTrials.gov Identifier: NCT01087372) (AU)

Antecedentes: La hiperglucemia de estrés es habitual en el contexto de la Unidad de cuidados intensivos (UCI) y se ha relacionado con un peor pronóstico. Objetivo: el objetivo fue caracterizar la asociación de hormonas glucorreguladoras, principalmente las incretinas, con las glucemias y su relación con el pronóstico de los pacientes de UCI. Métodos: Estudiamos de forma prospectiva a 60pacientes. La hiperglucemia de estrés se diagnosticaba cuando la glucemia era > 115 mg/dl. En el ingreso en la UCI, determinamos la glucemia y las concentraciones plasmáticas de insulina, glucagón, cortisol, polipéptidoinsulinotropo dependiente de glucosa (GIP) y péptido-1de tipo glucagón (GLP-1). Se compararon los grupos mediante la prueba de Kruskal-Wallis. La asociación entre las glucemias y las hormonas contrarreguladoras se evaluó mediante regresión linear. Resultados: 45 pacientes (75%) tenían hiperglucemia.No observamos diferencias en las concentraciones de hormonas glucorreguladoras entre los grupos de normo ehiperglucemia. Las glucemias no se correlacionaron de forma significativa con las concentraciones de insulina,glucagón, cortisol o GIP, pero sí con el GLP-1 (p = 0,04).El GLP-1 también se correlacionó con el cortisol (p =0,01), pero no consiguió mostrar una correlación significativa con las concentraciones de insulina, glucagón o GIP. Se encontraron menores concentraciones plasmáticas de GLP-1 en los pacientes con hiperglucemia de estrés que requerían soporte vasoactivo (p = 0,02). Conclusiones: las glucemias se correlacionaron con las concentraciones de GLP-1 en los pacientes en UCI . Las concentraciones de GLP-1 también se asociaron con el cortisol. Los pacientes con hiperglucemia de estrés que necesitaron soporte vasoactivo tenían menores concentraciones de incretina en comparación con aquellos con hiperglucemia de estrés con estabilidad hemodinámica(ClinicalTrials.gov Identifier: NCT01087372) (AU)

Correlation between brain interstitial and total serum cortisol levels in traumatic brain injury. A preliminary study.

INTRODUCTION: Brain cortisol availability has never been evaluated in patients with traumatic brain injury (TBI). Cerebral microdialysis is a well-established technique for monitoring brain metabolism in neurocritically ill patients, which may be used to measure interstitial cortisol. The objective of this preliminary study was to measure brain interstitial cortisol and its correlation with total serum cortisol in patients with TBI. METHODS: We prospectively studied 6 patients with severe TBI admitted to the Intensive Care Unit of our tertiary University Hospital in which multimodal neuromonitoring including cerebral microdialysis with a high cut-off of 100 k-Da and 20-mm long membrane was used. Serum and brain interstitial cortisol microdialysis samples were obtained every 8 h and analyzed afterwards. RESULTS: Linear regression analysis of total serum cortisol and brain interstitial cortisol in the whole population showed a moderate correlation (R2=0.538, p<0.001, no.=118). However, intra-individual correlation showed a great variability, with correlation coefficients ranging from a R2=0.091 to R2=0.680. CONCLUSION: Our prospective and preliminary study showed a moderate correlation of brain interstitial cortisol and total serum cortisol values in patients with diffuse TBI. However, intra-individual analysis showed a great variability. These results suggest that total serum cortisol may not reflect brain cortisol availability in half of TBI patients.

Utilidad de los fármacos antiobesidad en la diabetes mellitus tipo 2 / Anti-obesity drugs in the treatment of type 2 diabetes mellitus

Tanto la obesidad como la diabetes mellitus tipo 2 son dos problemas de saludcrecientes en nuestra sociedad que muchas veces van unidos, siendo elsegundo consecuencia del primero en muchos casos. La terapia farmacológicade la obesidad puede ser de utilidad en pacientes con diabetes, ya quereducciones importantes en el peso se asocian a una mejoría significativa delcontrol glucémico y otros parámetros metabólicos. El objetivo de esta revisiónes ofrecer un análisis de los fármacos que se utilizan en el tratamiento de laobesidad y que pueden ser de utilidad en pacientes obesos con diabetes tipo 2.Para ello, analizaremos las diferentes perspectivas terapéuticas que ofrecen yrevisaremos el limitado arsenal terapéutico disponible actualmente para abordarel grave problema de la obesidad en el contexto del paciente diabético.Además, se presentan los fármacos antiobesidad que actualmente se encuentranen fase III de desarrollo, como posibles candidatos para el tratamiento dela obesidad y la diabetes(AU)

Both obesity and diabetes mellitus type 2 are major health problems in oursociety that often go together, being in most cases the second consequenceof the first. Obesity drugs may be useful in diabetic patients, since importantweight loss is associated with a significant improvement of glycemic control,as well as other metabolic parameters. The objective of this manuscript is tooffer an analysis of the drugs currently used for the treatment of obesity andthat may be useful for obese patients with type 2 diabetes. We will analyze differenttherapeutic perspectives and review the limited armamentarium currentlyavailable to approach the serious problem of the obesity in the contextof the diabetic patient. Furthermore, anti-obesity drugs currently in phase III ofdevelopment will be presented as possible candidates for treatment of obesityand diabetes(AU)

Novedades en terapia hipoglucemiante. Fármacos con acción incretina / Advances in glucose-lowering therapy. Drugs that enhance incretin action

Las hormonas incretinas son péptidos liberados en el tracto gastrointestinal en respuesta a la ingesta de nutrientes, que potencianl a liberación de insulina y ayudan en el mantenimiento homeostático de la glucemia. El concepto de esta acción incretina se basó en la observación de quela respuesta secretora de insulina a la administración oral de glucosa era superior a la respuesta a cantidades equivalentes de glucosa administrada intravenosa. El efecto incretina se estima que es responsable de hasta el 70% de la secreción de insulina en respuesta a la glucosa oral y es causado principalmente por 2 hormonas intestinales: glucagon-like peptide (GLP-1) y glucose-dependent insulinotropic peptide (GIP).En la diabetes tipo 2, además del efecto deficiente de las incretinas, también se ha encontrado una alteración en la secreción de GLP-1.La administración exógena de GLP-1 ayuda a la normalización de la glucemia tanto basal como posprandial; sin embargo, el GLP-1 es rápidamente degradado por la enzima dipeptidil peptidasa (DPP-IV).Esta circunstancia ha llevado al desarrollo de fármacos análogos deGLP-1, con mayor resistencia a la degradación enzimática o a fármacos inhibidores de DPP-IV. El mecanismo por el cual las incretinas causan su efecto regulador sobre la homeostasis energética es en parte todavía desconocido y es actualmente un área de intensa investigación (AU)

The incretin hormones are peptides released in the gastrointestinal tract in response to nutrient ingestion. These hormones enhance insulin release and help to maintainglycemic homeostasis. The concept of incretin action was based on the observation that the secretory response of insulin to oral glucose administration is greater than that to equivalent quantities of intravenous glucose. The incret in effect is estimated to be responsible for up to 70% of insulin secretion in response to oral glucose and is mainly caused by two gastrointestinal hormones: glucagon-like peptide (GLP-1) y glucose-dependent insulinotropic peptide(GIP). In type 2 diabetes, in addition to a deficiency in incretin-mediated insulinsecretion, alterations in GLP-1 secretion have also been found. Exogenous GLP-1secretion helps to restore normal levels of both basal and postprandial blood glucose. However, GLP-1 is rapidly degraded by the dipeptidyl peptidase enzyme (DPP-IV). This phenomenon has led to the development ofGLP-1 analogs, which are more resistant to enzyme degradation or DPP-IV inhibitors. The mechanism through which the incretin hormones exert their regulatory effect onenergy homeostasis remains unknown and is currently the subject of intense research (AU)

Critical assessment of the current guidelines for the management and treatment of morbidly obese patients.

An interdisciplinary panel of specialists met in Mallorca in the first European Symposium on Morbid Obesity entitled; "Morbid Obesity, an Interdisciplinary Approach". During the two and half days of the meeting, the participants discussed several aspects related to pathogenesis, evaluation, and treatment of morbid obesity. The expert panel included basic research scientists, dietitians and nutritionists, exercise physiologists, endocrinologists, psychiatrists, cardiologists, pneumonologists, anesthesiologists, and bariatric surgeons with expertise in the different weight loss surgeries. The symposium was sponsored by the Balearic Islands Health Department; however, this statement is an independent report of the panel and is not a policy statement of any of the sponsors or endorsers of the Symposium. The prevalence of morbid obesity, the most severe state of the disease, has become epidemic. The current recommendations for the therapy of the morbidly obese comes as a result of a National Institutes of Health (NIH) Consensus Conference held in 1991 and subsequently reviewed in 2004 by the American Society for Bariatric Surgery. This document reviews the work-up evaluation of the morbidly obese patient, the current status of the indications for bariatric surgery and which type of procedure should be recommended; it also brings up for discussion some important real-life clinical practice issues, which should be taken into consideration when evaluating and treating morbidly obese patients. Finally, it also goes through current scientific evidence supporting the potential effectiveness of medical therapy as treatment of patients with morbid obesity.

Effect of barbiturate coma on adrenal response in patients with traumatic brain injury.

INTRODUCTION: Barbiturate coma is the second tier measure recommended by guidelines to treat post-traumatic refractory intracranial pressure. Systemic hypotension is its most important side effect. Recent evidence suggests that low-dose corticosteroid therapy may be used in a subset of patients with traumatic brain injury (TBI) to avoid hypotension. We evaluated adrenal function in TBI patients undergoing barbiturate coma, as treatment of their refractory intracranial hypertension. MATERIALS AND METHODS: We prospectively studied 40 patients with moderate to severe TBI. Group A (17 patients) were treated with barbiturate coma. Group B (23 patients) presented intracranial hypertension controlled with first tier measures, and acted as a control. Adrenal function was evaluated by using the high-dose corticotropin stimulation test within 24 h after brain injury and after barbiturate coma induction. RESULTS: Within 24 h after TBI, adrenal function was similar in both groups. Once barbiturate coma was induced, patients in group A treated with barbiturate coma presented a higher incidence of adrenal insufficiency compared with the control group B (53% vs 22%, p=0.03). Patients treated with barbiturates, who developed adrenal impairment, required higher doses of norepinephrine to maintain cerebral perfusion pressure than patients treated with barbiturates without adrenal impairment (1.07+/-1.04 microg/kg/min vs 0.31+/-0.32 mug/kg/min, p=0.03). CONCLUSIONS: Patients with TBI treated with barbiturate coma are at higher risk of developing adrenal insufficiency. This subset of patients presented higher requirements of vasoactive support to avoid hypotension. In these patients corticosteroid therapy may have potential therapeutic implications to treat hemodynamic instability.

Potential role of hypothalamic ghrelin in the pathogenesis of human obesity.

Ghrelin is a potent appetite stimulator, mainly synthesized in the stomach but also made in the brain. Paradoxically, obese subjects have lower plasma ghrelin than lean subjects and increase their weight in spite of low ghrelin levels. We hypothesize that central, and not peripheral ghrelin, is primarily responsible for overeating in humans. The aim of this study was to determine hypothalamic ghrelin levels in lean vs obese subjects. We collected anterior hypothalamus from lean and obese patients at the time of autopsy, and Western blots and semiquantitative RT-PCR for ghrelin and neuropeptide Y (NPY) were carried out. Our results showed that ghrelin expression was significantly higher in the hypothalamus of obese subjects compared to lean ones. This finding correlates with similar increases in NPY in the obese group. Ghrelin and NPY mRNA levels followed the same trend and were significantly higher in the hypothalamus in obese compared to lean subjects, suggesting a central origin for the increased protein content in the obese subjects. In conclusion, obesity in humans is associated with elevated central ghrelin. This data questions the significance of the role of peripheral ghrelin in the regulation of appetite in humans and suggests an important role for central ghrelin in the pathogenesis of obesity in humans.

Role of serum leptin, insulin, and estrogen levels as potential mediators of the relationship between fat mass and bone mineral density in men versus women.

Although fat mass is related to bone mineral density (BMD), the potential mechanism(s) of this effect remain to be defined. Thus, we assessed the role of the candidate hormones, leptin, insulin, and estrogen in mediating fat mass effects on the skeleton. Specifically, we related these hormones and fat mass to BMD at the total hip, mid-lateral spine, and mid-distal radius in a sample of 137 premenopausal women (age range 21-54 years), 165 postmenopausal women (34-93 years), and 343 men (23-90 years) recruited from the general population. Fat mass and BMD were significantly related in pre- and postmenopausal women at multiple sites, whereas this relationship was only weakly present in men at the total hip. Serum leptin levels were also significantly related to BMD in the women, but not in the men. Insulin was associated with hip BMD in the women, and bioavailable estradiol (E2) was correlated with BMD at all sites in men and in postmenopausal women. In the women, adjusting for leptin reduced the strength of the association between fat mass and BMD, with further adjustments for insulin or bioavailable E2 having no additional effects. Adjusting for leptin in the men had no consistent effect on the relationship between fat mass and BMD. Collectively, these data suggest that there is a sexual dimorphism in the relationship of fat mass and leptin to BMD, with both being positively associated with BMD in women but not in men. In women, leptin may also mediate at least part of the protective effect of fat mass on the skeleton.

Leptin reduces ovariectomy-induced bone loss in rats.

Bone mineral density increases with fat body mass, and obesity has a protective effect against osteoporosis. However, the relationship between fat body mass and bone mineral density is only partially explained by a combination of hormonal and mechanical factors. Serum leptin levels are strongly and directly related to fat body mass. We report here the effects of leptin administration compared with estrogen therapy on ovariectomy-induced bone loss in rats. Leptin was effective at reducing trabecular bone loss, trabecular architectural changes, and periosteal bone formation. Interestingly, the combination of estrogen and leptin further decreased bone turnover compared with that in estrogen-treated ovariectomized rats. Leptin also significantly increased osteoprotegerin mRNA steady state levels and protein secretion and decreased RANK ligand mRNA levels in human marrow stromal cells in vitro. Our findings suggest that leptin could modulate bone remodeling in favor of a better bone balance in rats. This study is the first evidence that leptin therapy has a significant effect in preventing ovariectomy-induced bone loss, and this effect may at least in part be mediated by the osteoprotegerin/RANK ligand pathway.

Leptin access into the brain: a saturated transport mechanism in obesity.

In spite of extensive research in the last few years, we still do not have a clear understanding of how does leptin access its targets in the brain, and whether there is postreceptor defect in the brain of obese individuals. Recent data have shown that leptin is produced in the pituitary, where its receptor is also present. A better understanding of how leptin reaches the brain and how it modulates the release of hypothalamic neuropeptides and pituitary hormones is needed. This information is crucial in order to better understand the role that leptin may play in the pathophysiology of diseases, such as obesity, delayed puberty, or growth defects.

Limited brain access for leptin in obesity.

Obesity is a major health problem that contributes to the development of type 2 diabetes, hypertension, dyslipidemia, and cardiovascular disease. The current pharmacological therapies for obesity are limited and may have significant side effects. Leptin therapy was shown to effectively cause weight loss in obese rats, however its effectiveness in humans is still under investigation. Obese humans have significantly elevated plasma leptin concentrations compared with lean individuals. Plasma leptin concentrations strongly correlated with percentage of body fat. Leptin concentration in the cerebrospinal fluid (CSF) is correlated, in a nonlinear manner, with plasma leptin levels and body mass index (BMI). The ratio of CSF leptin levels to serum leptin levels was 4 times greater in lean individuals than in obese individuals. One interpretation of this finding is that human obesity could be secondary to a central resistance to leptin action, causing a relative leptin deficiency in the CNS. Six years after the discovery of leptin we still do not have a clear understanding of how leptin accesses its targets in the brain, or whether there is defect in this process in the brain of obese individuals. In this manuscript we will review the different leptin gateways to the brain and the potential sites where a defect in leptin action may be present, as well as some potential clinical implications of leptin. A better understanding of how leptin reaches the brain and how it modulates the release of hypothalamic neuropeptides will be important in understanding the role that leptin plays in the pathophysiology of obesity.

Leptin and leptin receptor in anterior pituitary function.

Leptin is a 16 kDa protein that exerts important effects on the regulation of food intake and energy expenditure by interacting with the leptin receptor in the brain and in many other tissues. Although leptin is produced mainly by white adipose tissue, several laboratories have shown low levels of leptin production by a growing number of tissues including the anterior pituitary gland. Many studies have implicated leptin in anterior pituitary function including the observation that homozygous mutations of the leptin receptor gene led to morbid obesity, lack of pubertal development and decreased GH and TSH secretion. In addition, leptin functions as a neuroendocrine hormone and regulates many metabolic activities. Leptin also interacts with and regulates the hypothalamic-pituitary-adrenal, the hypothalamic-pituitary-thyroid and the hypothalamic-pituitary-gonadal axes. All of the anterior pituitary cell types express the leptin receptor. However, leptin has been localized in specific subtypes of anterior pituitary cells indicating cell type-specific production of leptin in the anterior pituitary. Subcellular localization of leptin indicates co-storage with secretory granules and implicates hypothalamic releasing hormones in leptin secretion from anterior pituitary hormone cells. Leptin signal transduction in the anterior pituitary has been shown to involve the janus protein-tyrosine kinase (JAK)/signal transducer and activation of transcription (STAT) as well as suppressor of cytokine signalling (SOCS). These proteins are activated by tyrosine-phosphorylation in anterior pituitary cells. The various steps in pituitary leptin signal transduction remain to be elucidated.

Relationship of serum leptin levels with body composition and sex steroid and insulin levels in men and women.

Whether the higher serum leptin levels in women are due to gender differences in fat mass or to other factors such as sex steroids remains unclear. In addition to sex steroids, serum insulin levels also appear to be related to leptin levels, although whether this effect is independent of the effects of body composition is unclear. The purpose of this study was to identify the major determinants of circulating serum leptin levels. We studied a large, population-based cohort of 345 men (23 to 90 years), 137 premenopausal women (21 to 54 years), and 212 postmenopausal women (34 to 94 years), including 47 women on hormone replacement therapy (HRT). Serum leptin levels were related to body composition as assessed by dual-energy x-ray absorptiometry (DEXA) and to circulating sex steroid and insulin levels. Serum leptin levels remained significantly higher in women versus men even after adjustment for fat mass, and leptin levels were significantly correlated with fat mass independently of age. By univariate analyses, logarithmically transformed serum leptin levels correlated positively with bioavailable estrogen ([E] estradiol plus estrone) in postmenopausal women not on HRT, and negatively with total and bioavailable testosterone (T) levels in men. Serum insulin levels were directly related to leptin levels regardless of gender and age. By multivariate analyses, fat mass, lean mass, and insulin levels were the strongest predictors of leptin levels in all groups. In addition, bioavailable E entered the model in the postmenopausal women not on HRT. These studies indicate that the fat mass, lean mass, and insulin level are the major determinants of the serum leptin level in adults. Moreover, after adjusting for these variables, bioavailable E also explains a significant proportion of the variance in leptin levels among postmenopausal women not on HRT.

Body composition and resting energy expenditure in humans: role of fat, fat-free mass and extracellular fluid.

OBJECTIVE: The objective of this study was to determine whether there are independent effects of extracellular fluid volume (ECF) and fat mass (FM) on resting energy expenditure (REE) relative to fat-free mass (FFM) in adult men and women. METHODS: Multiple linear regression analysis was used to relate REE, as determined by indirect calorimetry, to FFM and FM (measured using dual energy X-ray absorptiometry) and ECF (measured using bromide space and/or the radiosulfate washout space) in 153 women and 100 men with varying amounts of body fat. RESULTS: REE correlated significantly with FFM and FM in women (r=0.65 and r=0.63, both P<0.001) and men (r=0.62 and r=0.48, both P<0.001, FFM and FM, respectively). In a multiple linear regression analysis FFM, FM and age significantly contributed to the ability to predict REE in both genders. The models that were derived were not significantly different between women and men. In women the contribution to REE from FM was easier to detect when FM was greater. Adjustment of FFM for ECF did not improve the relationship between FFM and REE. CONCLUSIONS: FFM, FM and age are significant, independent predictors of REE in both men and women. Adjustment of FFM for ECF does not improve the ability of FFM to predict REE, which suggests that ECF is a highly integrated component of FFM in healthy adults. Expressing REE relative to FFM alone will introduce errors when lean and obese populations are compared.

Kinetics of intramuscular triglyceride fatty acids in exercising humans.

UNLABELLED: A pulse ([(14)C]palmitate)-chase ([(3)H]palmitate) approach was used to study intramuscular triglyceride (imTG) fatty acid and plasma free fatty acid (FFA) kinetics during exercise at approximately 45% peak O(2) consumption in 12 adults. Vastus lateralis muscle was biopsied before and after 90 min of bicycle exercise; (3)H(2)O production, breath (14)CO(2) excretion and lipid oxidation (indirect calorimetry) rates were measured during exercise. RESULTS: during exercise, 8.2+/-1.2 and 8.4+/-0.7 micromol x kg(-1) x min(-1) of imTG fatty acids and plasma FFA, respectively, were oxidized according to isotopic measurements. The sum of these two values was not different (P = 0.6) from lipid oxidation by indirect calorimetry (15.4 +/-1.6 micromol x kg(-1) x min(-1)); the isotopic and indirect calorimetry values were correlated (r = 0.79, P<0.005). During exercise, imTG turnover rate was 0.32+/-0.07%/min (6.0+/-2.0 micromol of imTG x kg wet muscle(-1) x min(-1)) and plasma FFA were incorporated into imTG at a rate of 0.7+/-0.1 micromol x kg wet muscle(-1) x min(-1). The imTG pool size did not change during exercise. This pulse-chase, dual tracer appears to be a reasonable approach to measure oxidation and synthesis kinetics of imTG.