Sema Akcurin

Heart rate variability and circadian variations in type 1 diabetes mellitus

Abstract:  Diabetic autonomic neuropathy (DAN) commonly complicates diabetes and is associated with increased mortality rates over 5 yr. This fact denotes the significance of DAN prevention, mainly with effective glycemic control. However, total prevention of autonomic neuropathy in diabetic patients is not achievable. Thus, the timely detection of DAN and the use of effective means to improve autonomic nervous system function or slow down its progression become of utmost significance. Heart rate variability (HRV) is a technique that measures the beat‐to‐beat variability in RR intervals, which reflects changes in autonomic activity and their impact on cardiovascular function. Circadian variation in time and frequency domains of heart variability has been shown to correlate with circadian rhythm of ambulatory ischemia and suggests that relative changes in vagal and sympathetic tone at different times during the day may have a direct relationship to the severity of clinical events. Forty‐seven (21 boys and 26 girls) type I insulin‐dependent diabetics and 46 control subjects (19 boys and 27 girls) were included in the study. Our investigation demonstrated that overall HRV is markedly depressed in diabetes mellitus (DM). All time domain parameters except standard deviation of all 5‐min mean RR intervals and all frequency domain indices maintain significant circadian variation. These changes in overall HRV and HRV circadian rhythms reflect significant reductions in cardiac parasympathetic activity and, possibly, increased sympathetic tone.

Permanent neonatal diabetes mellitus caused by a novel homozygous (T168A) glucokinase (GCK) mutation: initial response to oral sulphonylurea therapy.

OBJECTIVE To evaluate the clinical response to sulphonylurea treatment in a child with a homozygous T168A GCK (glucokinase) mutation, causing permanent neonatal diabetes mellitus (PNDM). STUDY DESIGN Oral glibenclamide was given for 3 months. Pancreatic beta cell function was assessed by a glucagon stimulation test. Mutant and wild-type (WT) GCK were characterized. RESULTS Sulphonylurea treatment resulted in a 12-fold increase in basal and stimulated C-peptide levels. HbA1c levels were reduced from 9.4% to 8.1% on a reduced insulin dose (0.85 to 0.60 U/kg/day). Mutant T168A-GST-GCK showed reduced kinetic activity (0.02 fold) compared to WT. CONCLUSIONS Sulphonylureas can close the adenosine triphosphate (ATP)-sensitive potassium channel and elicit insulin secretion, but the ATP generated from metabolism is insufficient to fully restore insulin secretory capacity. Nonetheless, sulphonylurea treatment should be tried in patients with GCK-PNDM, particularly those with mutations resulting in less severe kinetic defects, in whom improved glycemic control may be obtained with lower doses of insulin.

Urinary Bisphenol A Levels in Girls with Idiopathic Central Precocious Puberty

Objective: Bisphenol A (BPA) is an industrial chemical, particularly used to harden plastics. BPA is thought to have negative health effects on both laboratory animals and humans. Consider ing the decline in age of onset of puberty noted in recent years, particularly among girls, the importance of BPA as an estrogenic endocrine disruptor has increased. In this study, we aimed to determine urinary BPA levels in girls with idiopathic central precocious puberty (ICPP). Methods: Non-obese girls newly diagnosed with ICPP (n=28, age 4-8 years) constituted the study group. The control group consisted of 25 healthy age-matched girls with no history of ICPP or any other endocrine disorder. Urinary BPA levels were measured by using high-performance liquid chromatography. Results: In the ICPP group, urinary BPA levels were significantly higher compared to the control group [median 8.34 (0.84-67.35) μg/g creatinine and 1.62 (0.3-25.79) μg/g creatinine, respectively (OR=8.68, 95% CI:2.03-32.72, p=0.001)]. There was no marked correlation between urinary BPA levels and body mass index in either group. In the ICPP group, no significant correlations were found between urinary BPA levels and serum luteinizing hormone, follicle-stimulating hormone and estradiol levels. Conclusions: To our knowledge, this is the first study evaluating the urinary BPA levels in Turkish girls with ICPP. Our results indicate that the estrogenic effects of BPA may be an etiologic factor in ICPP.

Clinical and genetic analysis of patients with vitamin D‐dependent rickets type 1A

Vitamin D‐dependent rickets type 1A (VDDR‐IA, OMIM 264700) is a rare autosomal recessive disorder and is caused by mutations in the CYP27B1 gene.

Effects of Vitamin D Receptor Gene Polymorphisms on Susceptibility to Disease and Bone Mineral Density in Turkish Patients with Type 1 Diabetes Mellitus

ABSTRACT Background: Vitamin D receptor (VDR) gene is regarded as one of the candidate genes for type 1 diabetes mellitus (T1D) susceptibility and of some genetic factors involved in the development of osteoporosis in this group. Study design: We characterized the VDR gene polymorphism (BsmI, ApaI, TaqI, FokI and Cdx-2 binding site) in a group of Turkish patients with T1D (n=90) and correlated respective VDR genotypes with the bone mass and some parameters of bone turnover. Results: There were no differences in the genotype frequencies of the BsmI, ApaI, TaqI and Cdx-2 polymorphisms in patients and control subjects. We found a significantly higher prevalence of the F allele/the FF genotype in the patients compared to controls (p=0,0031, odds 1.96 (1,27-3,01)). We observed no difference in markers of bone turnover (Serum levels of osteocalcin, PINP and alkaline phosphatase, urinary levels of calcium/creatinine and N-telopeptid) among different VDR genotypes. No correlation was found between VDR polymorphisms and DEXA measurements of these patients. Conclusions: Although the FF genotype was found to be a risk factor in a Turkish population, elucidation of this result is necessary in other larger study groups drawn from the same ethnic population.

CTLA-4 (+49A/G) Polymorphism and Type-1 Diabetes in Turkish Children

Objective: To evaluate the contribution of cytotoxic T-Iymphocyte antigen-4 (CTLA-4)+49A/G polymorphism to the susceptibility to type-1 diabetes (T1D) in Turkish children. Methods: A case-control study was designed to include 91 Turkish children with T1D and 99 healthy controls. CTLA-4 (+99A/G) gene polymorphism typing was done by PCR amplification followed by restriction fragment length polymorphism method. Results: The genotype and allele frequencies of the CTLA-4 (+99A/G) polymorphism in patients with T1D were not different from those in the controls (p>0.05). The allele frequency of G was 36.2% in patients with T1D, and 31.8% in controls (p>0.05). Additionally, this polymorphism was not associated with the clinical and laboratory characteristics of the patients with T1D (p>0.05). Conclusions: Our case-control study suggests that the CTLA-4 (+99A/G) gene polymorphism is not associated with T1D in the Turkish population. Conflict of interest:None declared.

Intrathyroidal ectopic thymic tissue may mimic thyroid cancer: a case report

Abstract Ectopic intrathyroidal thymus tissue that may be present as a thyroid nodule is rarely reported. We present a case of a 4-year-old boy with a solitary thyroid nodule. Real-time thyroid ultrasound showed a calcified nodule in the right lobe. Complete blood count, serum calcitonin, and thyroglobulin concentration were normal and antithyroid antibodies were negative. Fine-needle aspiration (FNA) biopsy was revealed as inadequate for cytological examination. During his follow-up, nodular enlargement was found, and the patient was subjected to surgical total excision of the right lobe of the thyroid gland. Pathological examination showed an ectopic intrathyroidal thymus tissue. In childhood, ectopic intrathyroidal thymus tissue can present as an enlarging microcalcified thyroid nodule that may mimic thyroid cancer and may grow during follow-up.

A Combination of Nifedipine and Octreotide Treatment in an Hyperinsulinemic Hypoglycemic Infant

Hyperinsulinemic hypoglycemia (HH) is the commonest cause of persistent hypoglycemia in the neonatal and infancy periods. Mutations in the ABCC8 and KCNJ11 genes, which encode subunits of the ATP-sensitive potassium channel in the pancreatic beta cell, are identified in approximately 50% of these patients. The first-line drug in the treatment of HH is diazoxide. Octreotide and glucagon can be used in patients who show no response to diazoxide. Nifedipine, a calcium-channel blocker, has been shown to be an effective treatment in a small number of patients with diazoxide-unresponsive HH. We report a HH patient with a homozygous ABCC8 mutation (p.W1339X) who underwent a near-total pancreatectomy at 2 months of age due to a lack of response to diazoxide and octreotide treatment. Severe hypoglycemic attacks continued following surgery, while the patient was being treated with octreotide. These attacks resolved when nifedipine was introduced. Whilst our patient responded well to nifedipine, the dosage could not be increased to 0.75 mg/kg/day due to development of hypotension, a reported side effect of this drug. Currently, our patient, now aged 4 years, is receiving a combination of nifedipine and octreotide treatment. He is under good control and shows no side effects. In conclusion, nifedipine treatment can be started in patients with HH who show a poor response to diazoxide and octreotide treatment.

Spontaneous Endogenous Hypermelatoninemia: A New Disease?

Melatonin, a major photoperiod-dependent hormone, regulates circadian rhythms and biological rhythms and acts as a prominent sleep promoter. Symptoms related to hypermelatoninemia have been reported in individuals supplemented with melatonin. However, spontaneous endogenous hypermelatoninemia has not been reported previously. A 6-year-old girl previously diagnosed with Shapiro’s syndrome was admitted to our hospital on several occasions during a 1-year period with complaints of altered consciousness, syncope, hypothermia and episodes of sweating. The episodes occurred daily and during sleep and lasted for 1–6 h. During these episodes, she sweated profusely and felt faint and her skin was pale and cool. Other complaints included recurrent abdominal pain, urge incontinence and myopia. She was shown to have hypermelatoninemia (>1,000 pg/ml, normal range 0–150 pg/ml) during these episodes. The duration of her attacks decreased with phototherapy and she was successfully treated with propranolol. To our knowledge, this is the first case of hypermelatoninemia without any detectable organic pathology. We did not determine the exact mechanism of hypermelatoninemia in this patient; however, it might have been related to irregular control of pinealocytes by the suprachiasmatic nucleus or related pathways. Hypermelatoninemia should be considered in patients with spontaneous periodic hypothermia and hyperhidrosis, and also in patients with Shapiro’s syndrome.

Analysis of TPO gene in Turkish children with iodide organification defect: identification of a novel mutation

The objective was to determine molecular genetic analysis of the TPO gene in Turkish children with iodide organification defect (IOD). Patients with a diagnosis of primary hypothyroidism were evaluated. Subjects having a definite diagnosis of autoimmune thyroiditis, thyroid gland dysplasia and, or iodine deficiency were excluded. A total of 10 patients from nine unrelated Turkish families, with an unknown etiology of hypothyroidism, and with a presumptive diagnosis of IOD were included in the study. A perchlorate discharge test (PDT) was performed to all subjects, and sequence analysis of TPO gene was applied in patients with a positive PDT. Five out of 10 patients have a total IOD, while the five remaining patients have a partial IOD according to PDT results. In two sisters, one has a partial and the other one has a total IOD a novel homozygous nonsense p.Q315X mutation was found in exon 8. Additionally, a previously known homozygous missense p.R314W mutation was detected in the same exon in another patient with a total IOD. No TPO gene mutation was detected in any of the seven remaining patients. Two different TPO gene mutations were found to be responsible for IOD in two unrelated Turkish families from the same ethnic background. More subjects should be screened for detecting the prevalence and spectrum profile of TPO mutations in our population that might be helpful for understanding the pathophysiology of congenital hypothyroidism.