Halil Kutlu Erol

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

Changes in insulin sensitivity during leptin replacement therapy in leptin-deficient patients

Leptin replacement rescues the phenotype of morbid obesity and hypogonadism in leptin-deficient adults. However, leptins effects on insulin resistance are not well understood. Our objective was to evaluate the effects of leptin on insulin resistance. Three leptin-deficient adults (male, 32 yr old, BMI 23.5 kg/m(2); female, 42 yr old, BMI 25.1 kg/m(2); female, 46 yr old, BMI 31.7 kg/m(2)) with a missense mutation of the leptin gene were evaluated during treatment with recombinant methionyl human leptin (r-metHuLeptin). Insulin resistance was determined by euglycemic hyperinsulinemic clamps and by oral glucose tolerance tests (OGTTs), whereas patients were on r-metHuLeptin and after treatment was interrupted for 2-4 wk in the 4th, 5th, and 6th years of treatment. At baseline, all patients had normal insulin levels, C-peptide, and homeostatic model assessment of insulin resistance index, except for one female diagnosed with type 2 diabetes. The glucose infusion rate was significantly lower with r-metHuLeptin (12.03 +/- 3.27 vs. 8.16 +/- 2.77 mg.kg(-1).min(-1), P = 0.0016) but did not differ in the 4th, 5th, and 6th years of treatment when all results were analyzed by a mixed model [F(1,4) = 0.57 and P = 0.5951]. The female patient with type 2 diabetes became euglycemic after treatment with r-metHuLeptin and subsequent weight loss. The OGTT suggested that two patients showed decreased insulin resistance while off treatment. During an off-leptin OGTT, one of the patients developed a moderate hypoglycemic reaction attributed to increased posthepatic insulin delivery and sensitivity. We conclude that, in leptin-deficient adults, the interruption of r-metHuLeptin decreases insulin resistance in the context of rapid weight gain. Our results suggest that hyperleptinemia may contribute to mediate the increased insulin resistance of obesity.

Congenital leptin deficiency and thyroid function

Thyroid function is closely related to leptins secretion by the adipose tissue. In states of leptin-deficiency, the circadian rhythm of TSH is altered, leading to central hypothyroidism in animal models. In humans, central hypothyroidism has also been described in rare cases of congenital leptin deficiency. However, the thyroid phenotype in these cases is heterogeneous, with the occurrence of central hypothyroidism in a minority of cases. Here we describe thyroid function in four leptin-deficient humans (2 males aged 5 and 27, and 2 females aged 35 and 40), before and during leptin replacement with recombinant human methionyl leptin (r-metHuLeptin). The child was evaluated for four years, and the adults, for eight years. In addition, the adults were submitted to a brief withdrawal of leptin during six weeks in the sixth year. Our results show that, regardless of leptin replacement, our leptin-deficient patients have normal thyroid function. In spite of having an important role in regulating the hypothalamic-pituitary-thyroidal axis, leptin is not required for normal thyroid function.Trial RegistrationClinicalTrials.gov Identifiers: NCT00659828 and NCT00657605

Cellular Immunity Before and After Leptin Replacement Therapy

BACKGROUND The few identified leptin-deficient children have immune deficiency. AIMS To evaluate whether a newly-identified leptin-deficient boy has immune defects; to assess the immune changes during leptin replacement. METHODS A 5 year-old boy with congenital leptin deficiency was evaluated before, 2 weeks and 6 weeks after the initiation of recombinant methionyl human leptin. Thymic volume was measured by computed tomography. Humoral immunity was assessed by measuring levels of several immunoglobulins. Cellular immunity was evaluated by the analysis of lymphocyte proliferation in response to mitogens. Lymphocyte subsets were quantified by flow cytometry. RESULTS At baseline, thymic volume was increased. The lymphocyte subsets count and humoral/cellular immunities were normal. After treatment, proliferative response to mitogens increased by 1.5- to 3-fold, and lymphocyte count decreased by 17%. CONCLUSIONS Immune defects are not an obligatory feature of congenital leptin deficiency. Even in the absence of significant immune defects, leptin replacement therapy enhanced T-cell responsiveness.

Early severe pre-eclamptic findings in a patient with Cushing's syndrome.

Cushings syndrome occurs rarely in pregnancy because of ovulatory disturbances including anovulation which is caused by hypercortisolism, but it can cause maternal complications such as hypertension, gestational diabetes, spontaneous abortion, premature birth, pre-eclampsia and stillbirth. Herein we present the case of a 22-year-old patient in the 11th week of pregnancy who was admitted to our hospital with Cushings syndrome complicated by early pre-eclampsia. Severe pre-eclampsia has high maternal and perinatal morbidities, and therefore the possibility of this complication requires that Cushings syndrome, although rare in pregnancy, be given a high clinical suspicion. Medical therapy and/or surgical therapy should be considered promptly to influence outcome favorably.

Autoimmune thyroid disease in patients with anti-GAD positive type 1 diabetes mellitus

The aim of the study was to determine the frequency and titers of anti-thyroid peroxidase (Anti-TPO), anti-thyroglobulin (Anti-TG), and anti-glutamic acid decarboxylase (Anti-GAD) antibodies in Turkish patients with type 1 diabetes mellitus (DM), and to compare the frequency of anti-TPO and anti-TG titers in the presence or absence of anti-GAD. A total of 104 patients including 56 males and 48 females with type 1 DM and their age-, gender-, and body mass index-matched control group, including 31 males and 27 females, 58 cases in total with an age range of 15-50 years, were recruited into this study. In patients with type 1 DM, positive anti-GAD was detected in 30.8% (n=32). In patients with positive anti-GAD, rate of positive anti-TPO was 37.5%; however, in patients with negative anti-GAD, the rate of positive anti-TPO was 9.7% and the difference was statistically significant (p=0.001). In patients with positive anti-GAD, the rate of positive anti-TG was 18.8%. In patients with negative anti-GAD, the rate of positive anti-TG was 2.8%, and the difference between them was statistically significant (p=0.005). In patients with positive and negative anti-GAD, rates of both positive anti-TPO and anti-TG were 15.6% and 1.4%, respectively, with the difference showing statistical significance (p=0.004). Thyroid autoimmunity in type 1 DM patients with positive anti-GAD was apparently higher; therefore, these patients should be followed more frequently and carefully.