Recombinant human leptin treatment in genetic lipodystrophic syndromes: the long-term Spanish experience.

Lipodystrophies are a group of diseases mainly characterized by a loss of adipose tissue and frequently associated with insulin resistance, hypertriglyceridemia, and hepatic steatosis. In uncommon lipodystrophies, these complications frequently are difficult to control with conventional therapeutic approaches. This retrospective study addressed the effectiveness of recombinant methionyl leptin (metreleptin) for improving glucose metabolism, lipid profile, and hepatic steatosis in patients with genetic lipodystrophic syndromes. We studied nine patients (five females and four males) with genetic lipodystrophies [seven with Berardinelli-Seip syndrome, one with atypical progeroid syndrome, and one with type 2 familial partial lipodystrophy (FPLD)]. Six patients were children under age 9 years, and all patients had baseline triglycerides levels >2.26 mmol/L and hepatic steatosis; six had poorly controlled diabetes mellitus. Metreleptin was self-administered subcutaneously daily at a final dose that ranged between 0.05 and 0.24 mg/(kg day) [median: 0.08 mg/(kg day)] according to the body weight. The duration of treatment ranged from 9 months to 5 years, 9 months (median: 3 years). Plasma glucose, hemoglobin A1c (Hb A1c), lipid profile, plasma insulin and leptin, and hepatic enzymes were evaluated at baseline and at least every 6 months. Except for the patient with FPLD, metreleptin replacement significantly improved metabolic control (Hb A1c: from 10.4 to 7.1 %, p < 0.05). Plasma triglycerides were reduced 76 % on average, and hepatic enzymes decreased more than 65 %. This study extends knowledge about metreleptin replacement in genetic lipodystrophies, bearing out its effectiveness for long periods of time.

Intestinal absorption and pancreatic function are preserved in anorexia nervosa patients in both a severely malnourished state and after recovery.

INTRODUCTION: Anorexia nervosa (AN) is characterised by a refusal to normal body weight accompanied by a marked restriction of food intake, frequently leading to severe malnutrition. In severe malnutrition and wasting syndromes, mucosal atrophy, altered gastrointestinal motility and pancreatic atrophy, which alter digestive function and can exacerbate malnutrition, have been described. The objective of this work was to determine intestinal absorption and pancreatic function in severely malnourished AN patients before and after recovery. METHODS: Ten severely malnourished AN women were studied at hospital admittance (body mass index = 11.44-16.16 kg/m(2)) and after weight recovery with artificial nutrition (body mass index ≥ 20 kg/m(2)). A (13)C-labelled triglycerides digestion test, faecal elastase test and d-xylose absorption test were performed. RESULTS: In nine patients, (13)C-labelled triglycerides digestion tests and the faecal elastase and d-xylose tests were normal both before and after weight recovery. In one patient, the results were abnormal, and they led to the detection of a previously undiagnosed celiac disease in addition to her AN. CONCLUSION: In this series, there was neither intestinal absorption nor pancreatic function disturbances in severely malnourished AN patients either before or after weight recovery. The usefulness of these tests in the differentiation of functional versus structural changes needs further studies.

Weight regain after a diet-induced loss is predicted by higher baseline leptin and lower ghrelin plasma levels.

CONTEXT: Appetite-related hormones may play an important role in weight regain after obesity therapy. OBJECTIVE: Our objective was to investigate the potential involvement of ghrelin, leptin, and insulin plasma levels in weight regain after a therapeutic hypocaloric diet. DESIGN: A group of obese/overweight volunteers (49 women and 55 men; 35 ± 7 yr; 30.7 ± 2.4 kg/m(2)) followed an 8-wk hypocaloric diet (-30% energy expenditure) and were evaluated again 32 wk after treatment. Body weight as well as plasma fasting ghrelin, leptin, and insulin concentrations were measured at three points (wk 0, 8, and 32). RESULTS: After the 8-wk hypocaloric diet, the average weight loss was -5.0 ± 2.2% (P < 0.001). Plasma leptin and insulin concentrations decreased significantly, whereas ghrelin levels did not markedly change. In the group regaining more than 10% of the weight loss, leptin levels were higher (P < 0.01), whereas ghrelin levels were lower (P < 0.05). No differences were observed in insulin levels. Weight regain at wk 32 was negatively correlated with ghrelin and positively associated with leptin levels at baseline (wk 0) and endpoint (wk 8). These outcomes showed a gender-specific influence, being statistically significant among men for ghrelin and between women for leptin. Moreover, a decrease in ghrelin after an 8-wk hypocaloric diet was related to an increased risk for weight regain (odds ratio = 3.109; P = 0.008) whereas a greater reduction in leptin (odds ratio = 0.141; P = 0.001) was related to weight-loss maintenance. CONCLUSIONS: Subjects with higher plasma leptin and lower ghrelin levels at baseline could be more prone to regain lost weight, and hormones levels could be proposed as biomarkers for predicting obesity-treatment outcomes.

Testing growth hormone deficiency in adults.

Growth hormone deficiency (GHD) in adults is a recognized syndrome which is defined biochemically within an appropriate clinical context. Clinically, patients investigated for GHD should include those with signs and symptoms of hypothalamic-pituitary disease, those who have received cranial irradiation or tumor treatment and those with traumatic brain injury or subarachnoid hemorrhage. Patients with three or more pituitary hormone deficiencies and an IGF-I below the reference range do not require provocative testing. The other patients need a provocative test of GH secretory reserve for the diagnosis of GHD. Insulin tolerance test is considered the diagnostic test of choice, however, the GH-releasing hormone (GHRH)+arginine, the GHRH+growth hormone-releasing peptide and the glucagon stimulation tests are well validated alternative tests in adults. Cutoffs differ across tests and results may be influenced by gender, age, body mass index, and the assay reference preparation.

Ghrelin levels are suppressed and show a blunted response to oral glucose in women with polycystic ovary syndrome.

OBJECTIVE: Abnormal ghrelin regulation may influence the development of obesity-associated conditions including polycystic ovary syndrome (PCOS). Our aim was to compare ghrelin regulation between PCOS cases and controls. DESIGN: We compared serum ghrelin (total) levels, fasting and 30-min post-oral (75 g) glucose load, between 50 PCOS cases and 28 female controls, including 22 body mass index (BMI)/fat mass-matched pairs. All subjects were of UK British/Irish origin. METHODS: Measurements included serum ghrelin (RIA technique (LINCO Research, St Charles MO, USA)), fat mass, serum testosterone, fasting serum insulin and plasma glucose levels. Insulin sensitivity was calculated as the homeostasis model assessment of insulin resistance (HOMA2 IR). RESULTS: Fasting serum ghrelin levels were significantly lower in PCOS cases versus BMI/fat mass-matched controls (geometric mean (s.d. range), 1104 pg/ml (764-1595) vs 1756 pg/ml (1314-2347) respectively; P=2.3 x 10(-4)). Ghrelin suppression following oral glucose load was significantly blunted in PCOS cases versus BMI/fat mass-matched controls (geometric mean ghrelin suppression (s.d. range), 160 pg/ml (88-289) vs 424 pg/ml (220-818) respectively; P=2.0 x 10(-4)). Whole-group comparisons (50 PCOS cases versus 28 controls) adjusted for fat mass and age revealed similar results. In PCOS cases, there was a significant negative correlation between fasting serum ghrelin and HOMA2 IR (r(2)=-0.40, P=5.7 x 10(-3)). Following adjustment for HOMA2 IR, fat mass and age, comparisons between the whole groups of PCOS cases and controls revealed attenuated but significant differences in fasting serum ghrelin (P=1.3 x 10(-3)) and ghrelin suppression (P=1.8 x 10(-3)). CONCLUSIONS: In women with PCOS, serum ghrelin levels are suppressed, showing a negative relationship with HOMA2 IR and a blunted response to oral glucose.

Hypopituitarism and growth hormone deficiency in adult subjects after traumatic brain injury: who and when to test.

Traumatic brain injury (TBI) was traditionally considered an infrequent cause of hypopituitarism. However recent reports strongly suggest that TBI-mediated pituitary hormones deficiency may well be more frequent than previously thought. As the prevalence of hypopituitarism is not dependent on the severity of the trauma and considering the high number of TBI events in all industrialized countries a screening procedure for detecting hormone deficiencies in all TBI patients is not possible. In the present work a suggestion for screening a subgroup of TBI patients is discussed in order to increase the effectiveness of the whole procedure.

Ghrelin: from a GH-secretagogue to the regulation of food intake, sleep and anxiety.

Grhelin is an endogenous ligand for the growth hormone secretagogue receptor from the stomach. It is a 28-aminoacid peptide of which the serine 3 residue is n-octanoylated. Ghrelin strongly stimulates GH secretion in vivo as well as in vitro. This endogenous ligand promotes the production of orexigenic neuropeptides (NPY and AgRP) in the hypothalamic arcuate nuclei and activates the neurons that produce these orexigenic peptides, resulting in an increase in feeding and body weight. Ghrelin has other significant actions, including control of acid secretion, influences on sleep and on the regulation of anxiety.

Evidence of free leptin in human seminal plasma.

Leptin is an adipose tissue-secreted hormone that actively participates in the regulation of energy homeostasis. Besides this principal role, leptin has been implicated in a large variety of neuroendocrine, paracrine, and autocrine actions involved in the regulation of reproductive function in both experimental animals and humans. Although the participation of leptin in female reproduction is well established, any role in male reproductive function is at best tenuous. The aim of this study was to ascertain whether true leptin is present in human seminal fluid and the tissue of its production. Pooled human seminal plasma obtained from healthy donors showed by direct radioimmunoassay (RIA) the presence of radioimmunoassayable leptin. Serial dilutions of unextracted semen paralleled the RIA standard curve, also devoid of interference in the assay. To prove that this activity was true leptin, seminal plasma was subjected to size-exclusion chromatography, which showed that leptin immunoreactivity eluted with the same partition coefficient as cold leptin, 125I-leptin, and 125I-leptin preincubated with seminal plasma. The results demonstrate that true leptin was present in semen in a free form, i.e., without binding proteins. The presence of leptin charge variants in seminal plasma was assessed by anion-exchange chromatography, which showed two peaks of leptin inmunoreactivity, while 125I-leptin eluted as a single peak. Preincubation of 125I-leptin with seminal fluid converted the single peak into a double peak, indicating that components of the seminal fluid introduce a charge variation in leptin. Leptin levels in seminal plasma of 40 healthy men were 0.95+/-0.19 ng/mL while in 5 vasectomized men the levels were 0.92+/-0.25 ng/mL, suggesting that testicular tissues were not the source of seminal leptin. No correlation was observed between leptin concentrations in semen and the physical characteristics of semen samples or physical characteristics of spermatozoids, such as concentration, motility, vitality, or morphology. In conclusion it was unambiguously demonstrated that human leptin is present in seminal fluid, with at least two charge variants and no binding proteins, the most likely source being either seminal vesicles or prostate tissue. The role of seminal fluid leptin in the male reproductive function or sperm capacitation is at present unknown.