The Effects of Leptin Replacement on Neural Plasticity.

Leptin, an adipokine synthesized and secreted mainly by the adipose tissue, has multiple effects on the regulation of food intake, energy expenditure, and metabolism. Its recently-approved analogue, metreleptin, has been evaluated in clinical trials for the treatment of patients with leptin deficiency due to mutations in the leptin gene, lipodystrophy syndromes, and hypothalamic amenorrhea. In such patients, leptin replacement therapy has led to changes in brain structure and function in intra- and extrahypothalamic areas, including the hippocampus. Furthermore, in one of those patients, improvements in neurocognitive development have been observed. In addition to this evidence linking leptin to neural plasticity and function, observational studies evaluating leptin-sufficient humans have also demonstrated direct correlation between blood leptin levels and brain volume and inverse associations between circulating leptin and risk for the development of dementia. This review summarizes the evidence in the literature on the role of leptin in neural plasticity (in leptin-deficient and in leptin-sufficient individuals) and its effects on synaptic activity, glutamate receptor trafficking, neuronal morphology, neuronal development and survival, and microglial function.

Association between circulating adipocytokine concentrations and microvascular complications in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of controlled cross-sectional studies.

BACKGROUND: The adipocytokines leptin and adiponectin have been variously associated with diabetic microvascular complications. No comprehensive clinical data exist examining the association between adipocytokines and the presence of these complications. METHODS: This is a systematic review of cross-sectional studies comparing circulating adipocytokines in patients with type 2 diabetes mellitus (T2DM), with and without microvascular complications. Studies were retrieved from MEDLINE, EMBASE, Scopus and Cochrane databases. Study quality was evaluated using a modified Newcastle-Ottawa Scale. Meta-analysis was performed using an inverse-variance model, providing standardised mean differences (SMD) and 95% confidence intervals (CI). Heterogeneity was determined by I(2) statistic. RESULTS: Amongst 554 identified studies, 28 were included in the review. Study quality range was 3.5-9 (maximum 11). Higher leptin levels were associated with microalbuminuria (SMD=0.41; 95% CI=0.14-0.67; n=901; p=0.0003), macroalbuminuria (SMD=0.68; 95% CI=0.30-1.06; n=406; p=0.0004), and neuropathy (SMD=0.26; 95% CI=0.07-0.44; n=609; p=0.008). Higher adiponectin levels were associated with microalbuminuria (SMD=0.55; 95% CI=0.29-0.81, n=274; p<0.001), macroalbuminuria (SMD=1.37; 95% CI=0.78-1.97, n=246; p<0.00001), neuropathy (SMD=0.25; 95% CI=0.14-0.36; n=1516; p<0.00001), and retinopathy (SMD=0.38; 95% CI=0.25-0.51; n=1306; p<0.00001). Meta-regression suggested no influence of body mass index and duration of diabetes on effect size, and a weak trend in terms of age on effect size. DISCUSSION: Our meta-analysis suggests leptin and adiponectin levels are higher in T2DM patients with microvascular complications. Studies were limited by cross-sectional design. Large prospective analyses are required to validate these findings.

New advances in the treatment of generalized lipodystrophy: role of metreleptin.

Recombinant methionyl human leptin or metreleptin is a synthetic leptin analog that has been trialed in patients with leptin-deficient conditions, such as leptin deficiency due to mutations in the leptin gene, hypothalamic amenorrhea, and lipodystrophy syndromes. These syndromes are characterized by partial or complete absence of adipose tissue and hormones derived from adipose tissue, most importantly leptin. Patients deficient in leptin exhibit a number of severe metabolic abnormalities such as hyperglycemia, hypertriglyceridemia, and hepatic steatosis, which can progress to diabetes mellitus, acute pancreatitis, and hepatic cirrhosis, respectively. For the management of these abnormalities, multiple therapies are usually required, and advanced stages may be progressively difficult to treat. Following many successful trials, the US Food and Drug Administration approved metreleptin for the treatment of non-HIV-related forms of generalized lipodystrophy. Leptin replacement therapy with metreleptin has, in many cases, reversed these metabolic complications, with improvements in glucose-insulin-lipid homeostasis, and regression of fatty liver disease. Besides being effective, a daily subcutaneous administration of metreleptin is generally safe, but the causal association between metreleptin and immune complications (such as lymphoma) is still unclear. Moreover, further investigation is needed to elucidate mechanisms by which metreleptin leads to the development of anti-leptin antibodies. Herein, we review clinical aspects of generalized lipodystrophy and the pharmacological profile of metreleptin. Further, we examine studies that assessed the safety and efficacy of metreleptin, and outline some clinical perspectives on the drug.

Thiamazole as an adjuvant to radioiodine for volume reduction of multinodular goiter.

BACKGROUND: Radioiodine ((131)I) is an alternative to surgery for the treatment of multinodular goiter (MNG). Frequently, high activities of (131)I are required for effective thyroid volume reduction (TV), due to the low and heterogeneous radioactive iodine uptake (RAIU). Thiamazole (MTZ) may be used as an adjuvant to (131)I, by increasing RAIU. OBJECTIVE: To evaluate the effects of MTZ in the treatment of MNG with (131)I, in terms of TV reduction. DESIGN/METHODS: Nine female patients (aged 73.8 +/- 7.4 years) with MNG (eight with subclinical hyperthyroidism) were treated with MTZ. Doses started at 10 - 20 mg, and were adjusted monthly based on thyroid hormone levels. RAIU and TV were measured at baseline, and repeated when TSH levels > 6 mU/l were achieved. At that time, 1.11 GBq of (131)I were administered. RESULTS: Patients were treated with MTZ for 2.8 +/- 0.8 months. When a tracer activity of (131)I was administered, the mean serum TSH was elevated to 11.7 +/- 5.4 mU/l. MTZ led to significant increases in 24-h RAIU, from 21.3 +/- 8.1% to 78.3 +/- 15.3% (p < 0.001). One year after (131)I, median TV decreased from 97 ml (range 47 - 555 ml) to 56 ml (range 13 - 350 ml), a mean reduction of 46.2 +/- 17.8% (p = 0.012). Eight patients (89%) had subclinical hyperthyroidism, which was reversed in all patients after 1 year. Five patients (56%) developed overt hypothyroidism, and no clinical adverse events were observed. CONCLUSION: Pretreatment with MTZ targeting against an increased serum TSH did not impair the effects of (131)I. In our patients with MNG, MTZ increased RAIU and possibly enhanced (131)I efficacy, leading to significant TV reduction and reversion of hyperthyroidism in all patients.

Recombinant human thyrotropin in the management of thyroid disorders.

BACKGROUND: Recombinant human thyroid stimulating hormone (rhTSH) is a valuable tool in the management of thyroid diseases. It is useful for radioiodine ablation in patients with differentiated thyroid carcinoma (DTC), for their follow-up, and for treatment of selected patients with metastatic or recurrent DTC. More recently, it has been suggested that rhTSH is useful for treatment of multinodular goiter and amiodarone-induced thyrotoxicosis, as well as for diagnosis of congenital hypothyroidism. OBJECTIVE: To provide an outline of literature regarding the uses of rhTSH in thyroid diseases. METHODS: We performed a literature search for relevant articles in the PubMed database. CONCLUSION: rhTSH has important roles in management of thyroid diseases, and some are still controversial. For patients with DTC, it avoids the need for thyroid hormone withdrawal, without being detrimental to short-term outcomes. Further studies are warranted to assess its effects on long-term outcomes.

Leptin replacement improves cognitive development.

BACKGROUND: Leptin changes brain structure, neuron excitability and synaptic plasticity. It also regulates the development and function of feeding circuits. However, the effects of leptin on neurocognitive development are unknown. OBJECTIVE: To evaluate the effect of leptin on neurocognitive development. METHODOLOGY: A 5-year-old boy with a nonconservative missense leptin gene mutation (Cys-to-Thr in codon 105) was treated with recombinant methionyl human leptin (r-metHuLeptin) at physiologic replacement doses of 0.03 mg/kg/day. Cognitive development was assessed using the Differential Ability Scales (DAS), a measure of general verbal and nonverbal functioning; and selected subtests from the NEPSY, a measure of neuropsychological functioning in children. PRINCIPAL FINDINGS: Prior to treatment, the patient was morbidly obese, hypertensive, dyslipidemic, and hyperinsulinemic. Baseline neurocognitive tests revealed slower than expected rates of development (developmental age lower than chronological age) in a majority of the areas assessed. After two years, substantial increases in the rates of development in most neurocognitive domains were apparent, with some skills at or exceeding expectations based on chronological age. We also observed marked weight loss and resolution of hypertension, dyslipidemia and hyperinsulinemia. CONCLUSIONS: We concluded that replacement with r-metHuLeptin is associated with weight loss and changes in rates of development in many neurocognitive domains, which lends support to the hypothesis that, in addition to its role in metabolism, leptin may have a cognitive enhancing role in the developing central nervous system. TRIAL REGISTRATION: ClinicalTrials.gov NCT00659828.