Type I insulin-like growth factor receptor (IGF-IR) is widely expressed across many cell types in fetal and postnatal tissues. The activation of this receptor after the binding of secreted IGF-I and IGF-II promotes cell differentiation and proliferation. IGF-IR has an important role in normal fetal and postnatal growth and development. IGF-IR gene anomalies presenting with intrauterine and postnatal growth retardation have recently been reported in some families. Familial short stature with IGF-IR gene anomaly is considered rare, and the clinical condition and features remain unknown. IGF-IR gene anomaly such as heterozygous IGF-IR mutation or haploinsufficiency of the IGF-IR gene should be investigated in those patients presenting with 1) low birth weight and birth height (< -1.5 SD), 2) a familial history of low birth weight, 3) a normal or increased IGF-I level, 4) a normal or increased GH response to the GH stimulation test, and/or 5) less response to GH treatment than common small for gestational age (SGA) short-stature patients. In this review, we provide an overview of current knowledge of familial short stature with IGF-IR gene anomaly.
It has been reported that beta cell function progressively declines in patients with type 2 diabetes. The objective of this study was to assess the effect of obesity on declining beta cell function after diagnosis of type 2 diabetes. We conducted a cross-sectional study of 689 consecutive subjects with type 2 diabetes who were admitted to our hospital from 2000 to 2007. Fasting and postprandial serum C-peptide immunoreactivity (CPR) and urinary CPR levels had been measured during admission. The subjects were stratified according to BMI and time since diagnosis. CPR index was calculated as CPR (ng/mL) / plasma glucose (mg/dL) x 100. All CPR measurements were significantly higher in the 263 obese (BMI ≥25) subjects compared to the 426 lean subjects (BMI <25). There was a significant negative correlation between CPR indices and duration of diabetes, suggesting a progressive decline in beta cell function after diagnosis of type 2 diabetes. However, this decline was more apparent in obese subjects (postprandial CPR index 0.059/year) compared to lean subjects (0.025/year). The significant difference in serum CPR indices between the lean and obese subjects was lost in subjects more than 10 years after diagnosis. In conclusion, our observations suggest that beta cell function shows a greater progressive decline in obese subjects than in lean subjects with type 2 diabetes. Treatment of obesity may be an important strategy to preserve beta cell function in patients with type 2 diabetes.
We studied the efficacy of sitagliptin in type 2 diabetic patients of our outpatient clinics. Since December in 2009, 164 patients have been treated by sitagliptin for their management of diabetes. HbA1c decreased by 0.8% in all patients without any change in mean body weight after 3 months. However, actually HbA1c did not decrease in 30 patients, and more than half of patients showed weight gain to some extent. Patients were classified according to the reduction of HbA1c and analyzed based on this category. Baseline characters such as age, gender, duration of diabetes, BMI, concomitantly used oral hypoglycemic agents and the score for life-style assessment were not related to glucose-lowering effect of sitagliptin. Ninety eight patients whose HbA1c had decreased after 3 months were further followed-up for another 3 months. Among them 45 patients showed some relapsing of HbA1c after 6 months, and they were compared with 53 patients without relapsing. More cases had been switched from α-glucosidase inhibitor (α-GI) and the score for life-style assessment was lower in relapsing patients compared to those in patients without relapsing. In conclusion, clinicians should keep the fact in mind that the individual variation of glucose-lowering effects and the possibility of relapsing exist during sitagliptin treatment, and that concern about life-style is still a quite important issue to prevent weight gain and the relapsing of blood glucose control.
The present study was designed to determine the impact of secondary review of thyroid fine-needle aspiration (FNA) biopsy on surgical management. A retrospective review of patients referred to our institution with a thyroid FNA biopsy was conducted. Cytologic diagnoses from the report at our center and the referring institution were re-categorized by the Bethesda System for Reporting Thyroid Cytopathology. The rate of diagnostic disagreement was evaluated between Primary Diagnosis (PD) and Second Opinion Diagnosis (SOD), and the clinicopathologic correlations and the number of cases that prompted changes in treatment as a result of diagnostic disagreement were analyzed. 1499 patients meeting our study criteria were enrolled in this study. Diagnostic disagreement comprised 394 cases (26.3%). In the case of diagnostic disagreement, SOD was supported on clinicopathologic follow-up in 271 cases (68.8%), of which a change in management was made in 54 (13.7%) cases, and PD was supported in 93 (23.6%) cases, of which a change in management was made in 13 (3.3%) cases. By the second opinion, 65 (4.5%) patients received proper management, and 14 (1.0%) patients received superfluous management. Wide use of secondary cytopathologic review of thyroid FNA specimens from referring institutions was recommended.
Thyroid hormones stimulate directly or indirectly growth of erythroid colonies through erythropoietin. Anemia is often the first sign of hypothyroidism. Hypothyroidism can cause a wide variety of anemic disorders. Numerous mechanisms are involved in the pathogenesis of these anemias that can be microcytic, macrocytic and normocytic. We designed this study to investigate the anemia frequency and if present, etiology of anemia in hypothyroid patients. 100 patients with overt hypothyroid, 100 patients with subclinical hypothyroid, and 200 healthy controls were enrolled in this study. Overt hypothyroidism diagnosis is done when elevated TSH and low levels of free T4 and/or free T3 have been observed. Subclinical hypothyroidism is defined as elevated serum TSH with normal free T4 and free T3 levels. Peripheral smears of the anemic patients were examined. Anemia prevalence was 43% in the overt hypothyroid group, 39% in the subclinical hypothyroid group, and 26% in the control group (p=0.0003 and p=0.021 respectively related to controls). Thus, the frequency of anemia in subclinical hypothyroidism is as high as that in overt hypothyroidism. There was no difference between the hypothyroid groups in terms of anemia. Vitamin B12, Fe, and folic acid were similar between these groups. According to our findings, anemia of chronic disease is the most common type of anemia in hypothyroid patients. Suspicion of hypothyroidism should be considered in anemias with uncertain etiology.
There are two main subtypes of GH-producing pituitary adenoma: densely granulated (DG-type) and sparsely granulated (SG-type). Despite the difference in drug responsiveness between the two subtypes, their molecular mechanisms remain unknown. The aim of this study is to evaluate the differential expression of genes related to drug responsiveness between the two subtypes of somatotroph adenoma, and their relationship to the clinical characteristics. Eighty-two acromegaly patients (44 DG-type, 38 SG-type) were studied retrospectively. Clinical characteristics were compared between the two subtypes. Among them, 36 tumor tissue specimens (19 DG-type, 17 SG-type) were available for investigation of the expression of SSTR2, SSTR5 and D2R that are reported to be involved in drug responsiveness by realtime RT-PCR. Protein level was evaluated by immunohistochemical study. Patients with SG-type adenomas were younger in age and showed greater GH suppression by octreotide, but not by bromocriptin, and bigger in size and more invasiveness than DG-type adenomas. The mRNA expression of SSTR2 in DG-type adenomas were greater than those in SG-type adenomas and showed significantly positive correlation with GH suppression by octreotide. There was positive correlation between mRNA and protein levels of SSTR2. These data suggested that the differences of responsiveness to octreotide between DG- and SG-type adenomas are based on the expression levels of SSTR2.
We aimed to explore whether common allelic variations in the SIRT1 gene were associated with excess body weight in a Chinese cohort. Using standard molecular techniques 820 non-diabetic individuals, some of who were classified as overweight (> 23 Kg/m2), were genotyped for four haplotype-tagged single nucleotide polymorphisms. The rs10509291AA and rs10823116GG genotypes were associated with high body mass index (BMI) > 23 Kg/m2, and the rs7894483TT genotype was associated with lower BMI (< 23 Kg/m2). The rs10509291AT genotype was associated with a modestly higher risk of being overweight, consistent with the presence of an rs10509291A being a dominant or semi-dominant allele. The ATAA (rs7894483/rs10823116) and ATAG haplotypes were associated with a higher risk of being overweight (OR: 17.11 and 5.12) compared with the AAAG haplotype (P <0.01). Thus, the rs10509291, rs7894483, and rs10823116 alleles were associated with a high BMI (> 23 Kg/m2) and with overweight in this non-diabetic Chinese population.
Recent studies have shown colestimide, a bile acid-binding resin, to also exert a glucose-lowering effect via amelioration of insulin resistance. To evaluate the effects of colestimide on glucose metabolism and to elucidate the underlying mechanism, we conducted a 6-month, open-label pilot study on 43 type 2 diabetic patients with obesity (BMI ≥ 25). The subjects were randomized to either treatment with colestimide 4g/day (T group, n=23) or continuation of their current therapy (C group, n=20). In the T group patients, mean HbA1c and fasting glucose improved markedly (from 7.71 ± 0.32% to 6.97 ± 0.20%; from 147.4 ± 7.3mg/dL to 127.0 ± 5.0mg/dL, respectively), while obesity-related parameters, i.e. body weight, waist circumference, and visceral fat and subcutaneous fat as determined by umbilical slice abdominal CT, showed no significant changes. Fractionation analyses of serum bile acids revealed significantly increased cholic acids (CA) and decreased chenodeoxycholic acids (CDCA) in the T group patients. However, no correlation was observed between these changes and ΔHbA1c. According to logistic regression analysis, baseline HbA1c was the only variable predicting the decrease of HbA1c (>0.5%) among sex, age, BMI, total cholesterol, ΔCA and ΔCDCA. The index of insulin resistance, i.e. HOMA-R, did not improve, and the index of β cell function, i.e. HOMA-β, actually increased significantly. These results suggests that, in obese patients with type 2 diabetes, the mechanism underlying improved glycemic control with colestimide treatment involves enhanced β cell activity rather than improved insulin resistance.
The recurrent laryngeal nerve (RN) is one of the most common organs to which papillary thyroid carcinoma (PTC) extends. However, the prognosis and prognostic factors for patients with PTC extending to the RN remain unclear. In this study, we investigated this issue in 298 patients who underwent initial and locally curative surgery for PTC requiring RN resection due to carcinoma extension. Preoperative vocal cord paralysis was detected in 179 patients (60.1%), and directly linked to significant extension to other organs, large tumor size, and advanced age. However, it did not have a significant prognostic impact on uni- or multivariate analyses. On multivariate analysis, independent prognostic factors were large node metastasis and advanced age for lymph node recurrence, significant extension to other organs for distant recurrence, and significant extension to other organs, large node metastasis, extranodal tumor extension, and advanced age for carcinoma death, respectively. Most prognostic factors identified in the entire series of patients also had a strong prognostic impact on the subset of patients requiring RN resection, together with significant extension to other organs. Preoperative vocal cord paralysis reflected the aggressive characteristic of PTC to some extent, but did not have a significant prognostic value.
Genetics plays a crucial role in the development of metabolic syndrome (MetS). Here we examined the association between endothelial nitric oxide synthase (eNOS) gene polymorphisms and MetS in a Saudi Arabian cohort to extend the understanding of the genetic basis of MetS in diverse ethnic populations. Anthropometric, clinical and biochemical parameters as well as genotyping for 894G>T, -786T>C variants of eNOS gene by PCR-RFLP and 4a/b by direct PCR were performed in 886 Saudi Arabians (477 MetS and 409 Non-MetS). The genotype distribution (TT, p=0.001; TC, p=0.001; TC+CC, p=0.001) and allele (T, p=0.007; C, p=0.007) frequency of the -786T>C SNP were significantly different between Non-MetS and MetS subjects which remained significant after Bonferroni correction. Moreover: 1) the GT and GT+TT genotypes of the 894G>T SNP were associated with elevated blood pressure (p=0.017, and p=0.022, respectively); 2) the ab variant of 4a/b polymorphism was associated with decreased HDL levels (p= 0.044); and 3) the TC+CC genotype and C allele of the -786T>C SNP were associated with increased fasting glucose levels (p=0.039, and p=0.028, respectively). Also, G-a-C was identified as the risk haplotype for MetS susceptibility (p=0.034). The results suggest a significant association of 894G>T, 4a/b and -786T>C polymorphisms with MetS and its components is present in an Arab population. A genetic predisposition to develop abnormal metabolic phenotypes, consistent with an increased prevalence of metabolic phenotypes can be detected in this ethnic group.
It is not clear what dietary intake standards should be used for children with abnormal body size. To investigate the energy requirements of short-stature children with no underlying diseases, their resting energy requirements (REE) were measured by indirect calorimetry. The short-stature group consisted of 30 prepubertal children with short stature and with no underlying diseases (age 6y±2) and the control group consisted of 13 age-matched children with standard stature. Fasting REE and the respiration quotient (RQ) with subjects in the supine position were measured by canopy indirect calorimetry. Actual measurements and body-size-adjusted REEs were compared between the groups. Also, REE measurements were compared with the basal metabolic rate (BMR) calculated using the Dietary Reference Intakes for Japanese (Dietary Reference Intakes). REE in the control group was significantly higher than that in the short-stature group. However, body-size-adjusted REEs were significantly higher for the short-stature group. When the actual REE was compared with the calculated BMR within both the control group and the short-stature group, which was acquired using the Dietary Reference Intakes, there was no difference within the control group but the actual REE measurements were significantly higher than the calculated BMR in the short-stature group. The same pattern was seen within the short-stature group when subjects were matched for height. There were no significant differences in RQ between the two groups.