[Show abstract][Hide abstract] ABSTRACT: Background:
Alstrom syndrome and Bardet-Biedl syndrome are autosomal recessively inherited ciliopathies with common characteristics of obesity, diabetes, and blindness. Alstrom syndrome is caused by a mutation in the ALMS1 gene, and Bardet-Biedl syndrome is caused by mutations in BBS1-16 genes. Herein we report genetically confirmed cases of Alstrom syndrome and Bardet-Biedl syndrome in Korea using whole exome sequencing.
Exome capture was done using SureSelect Human All Exon Kit V4+UTRs (Agilent Technologies). HiSeq2000 system (Illumina) was used for massive parallel sequencing. Sanger sequencing was used for genotype confirmation and familial cosegregation analysis.
A 21-year old Korean woman was clinically diagnosed with Alstrom syndrome. She had diabetes, blindness, obesity, severe insulin resistance, and hearing loss. Whole exome sequencing revealed a nonsense mutation in exon 10 of ALMS1 (c.8776C>T, p.R2926X) and a seven base-pair deletion resulting in frameshift mutation in exon 8 (c.6410_6416del, p.2137_2139del). A 24-year-old Korean man had Bardet-Biedl syndrome with diabetes, blindness, obesity, and a history of polydactyly. Whole exome sequencing revealed a nonsynonymous mutation in exon 11 of the BBS1 gene (c.1061A>G, p.E354G) and mutation at the normal splicing recognition site of exon 7 of the BBS1 gene (c.519-1G>T).
We found novel compound heterozygous mutations of Alstrom syndrome and Bardet-Biedl syndrome using whole exome sequencing. The whole exome sequencing successfully identified novel genetic variants of ciliopathy-associated diabetes.
[Show abstract][Hide abstract] ABSTRACT: Mature osteoblasts have three fates: as osteocytes, quiescent lining cells, or osteoblasts that undergo apoptosis. However, whether intermittent parathyroid hormone (PTH) can modulate the fate of mature osteoblasts in vivo is uncertain. We performed a lineage-tracing study using an inducible gene system. Dmp1-CreERt2 mice were crossed with Rosa26R reporter mice to obtain targeted mature osteoblasts and their descendants, lining cells or osteocytes, which were detected using X-gal staining. Rosa26R:Dmp1-CreERt2(+) mice were injected with 0.25 mg 4-OH-tamoxifen (4-OHTam) on postnatal days 5, 7, 9, 16, and 23. In a previous study, at 22 days after the last 4-OHTam, most LacZ+ cells on the periosteal surface were inactive lining cells. On day 25 (D25), the mice were challenged with an injection of human PTH (1-34, 80 μg/kg) or vehicle daily for 10 (D36) or 20 days (D46). We evaluated the number and thickness of LacZ+ osteoblast descendants in the calvaria and tibia. In the vehicle group, the number and thickness of LacZ+ osteoblast descendants at both D36 and D46 significantly decreased compared to D25, which was attenuated in the PTH group. In line with these results, PTH inhibited the decrease in the number of LacZ+/osteocalcin-positive cells compared to vehicle at both D36 and D46. As well, the serum levels of sclerostin decreased, as did the protein expression of sclerostin in the cortical bone. These results suggest that intermittent PTH treatment can increase the number of periosteal osteoblasts by preventing mature osteoblasts from transforming into lining cells in vivo.
Journal of Bone and Mineral Metabolism 08/2015; DOI:10.1007/s00774-015-0707-x · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Measurement of the plasma adrenocorticotropic hormone (ACTH) level has been recommended as the first diagnostic test for differentiating between ACTH-independent Cushing syndrome (CS) and ACTH-dependent CS. When plasma ACTH values are inconclusive, a differential diagnosis of CS can be made based upon measurement of the serum dehydroepiandrosterone sulfate (DHEA-S) level and results of the high-dose dexamethasone suppression test (HDST). The aim of this study was to assess the utility of plasma ACTH to differentiate adrenal CS from Cushing' disease (CD) and compare it with that of the HDST results and serum DHEA-S level.
We performed a retrospective, multicenter study from January 2000 to May 2012 involving 92 patients with endogenous CS. The levels of plasma ACTH, serum cortisol, 24-hour urine free cortisol (UFC) after the HDST, and serum DHEA-S were measured.
Fifty-seven patients had adrenal CS and 35 patients had CD. The area under the curve of plasma ACTH, serum DHEA-S, percentage suppression of serum cortisol, and UFC after HDST were 0.954, 0.841, 0.950, and 0.997, respectively (all P<0.001). The cut-off values for plasma ACTH, percentage suppression of serum cortisol, and UFC after HDST were 5.3 pmol/L, 33.3%, and 61.6%, respectively. The sensitivity and specificity of plasma ACTH measurement were 84.2% and 94.3%, those of serum cortisol were 95.8% and 90.6%, and those of UFC after the HDST were 97.9% and 96.7%, respectively.
Significant overlap in plasma ACTH levels was seen between patients with adrenal CS and those with CD. The HDST may be useful in differentiating between these forms of the disease, especially when the plasma ACTH level alone is not conclusive.
[Show abstract][Hide abstract] ABSTRACT: This study investigated the interaction between polydeoxyribonucleotide (PDRN) and several ionic and nonionic isotonic agents, thickeners and a preservative that were employed as excipients in ophthalmic preparations. Interaction of each individual excipient and PDRN aqueous solution was evaluated by analyzing their rheological properties. Rheological properties of PDRN solutions were evaluated by dynamic oscillatory shear tests and values of elastic modulus (G'), viscous modulus (G″) and loss tangent (tan δ) were used to assess the relative changes in viscoelastic properties. At given concentrations, sodium chloride was found to show alteration in viscoelastic properties of PDRN solution while nonionic isotonic agents like d-glucose and d-sorbitol did not alter them. Similarly, nonionic water soluble polymers like polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) also did not interact with PDRN to alter the viscoelastic properties. However, there were changes observed when carbopol 940 was used as a thickener. Therefore, PDRN was found to interact with ionic excipients and the interactions were negligible when nonionic materials were examined, which suggests that nonionic excipients are suitable to be formulated with PDRN.
Drug Development and Industrial Pharmacy 05/2015; DOI:10.3109/03639045.2015.1040417 · 2.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aims:
Dioxin or dioxin-like compounds are ligands of the aryl hydrocarbon receptor (AhR), which is a ligand-activated nuclear transcription factor. There are limited studies about the association of serum AhR ligand activities and T2DM. Our objective was to investigate the association of serum AhR ligand activities with T2DM and its related metabolic parameters.
This case-control study involved 83 subjects with T2DM as well as age-, sex-, and body mass index (BMI)-matched subjects with impaired glucose tolerance (IGT, n = 130) and normal glucose tolerance (NGT, n = 83). Serum AhR ligand activities were measured using a cell-based AhR ligand assay and standardized as 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TCDDeq, pmol/l).
The T2DM group had the highest AhR ligand activities compared to the IGT and NGT groups [median (interquartile range), 68.1 (53.1, 81.5), 60.2 (45.8, 75.1), and 53.3 (46.1, 63.7) pmol/l, respectively; P = 0.003]. In the multivariate analysis, the log2-transformed TCDDeq levels were significantly associated with the risk of T2DM after adjusting for age, sex, and BMI (odds ratio 2.26, 95 % confidence interval 1.34-3.82; P = 0.002). In nondiabetic subjects, serum AhR ligand activities showed a positive correlation with fasting glucose and insulin concentrations and the homeostasis model assessment of insulin resistance, but showed a negative correlation with adiponectin concentrations.
Serum AhR ligand activities were higher in the T2DM group and were correlated with the parameters of insulin resistance. Further investigation is required to elucidate the causal relationship between AhR ligand activity and T2DM.
[Show abstract][Hide abstract] ABSTRACT: Background
Among the various diagnostic criteria for insulinoma, the ratio criteria have been controversial. However, the amended insulin-glucose ratio exhibited excellent diagnostic performance in a recent retrospective cohort study, although it has not yet been validated in other patient cohorts. We examined the diagnostic performance of the current criteria of the Endocrine Society, insulin-glucose ratio, C-peptide-glucose ratio, and amended ratios in terms of differentiating insulinomas.
We reviewed the medical records of patients who underwent evaluation for hypoglycemia from 2000 to 2013. Fourteen patients with histopathologically confirmed insulinoma and 18 patients without clinical evidence of insulinoma were included. The results of a prolonged fast test were analyzed according to the abovementioned criteria.
Fulfilling all three Endocrine Society criteria-plasma levels of glucose (<3.0 mmol/L), insulin (≥8 pmol/L), and C-peptide (≥0.2 nmol/L)-exhibited 100% sensitivity and 89% specificity. Fulfilling the glucose and C-peptide criteria showed 100% sensitivity and 83% specificity, while fulfilling the glucose and insulin criteria showed 100% sensitivity and 72% specificity. Among the ratio criteria, the insulin-glucose ratio [>24.0 (pmol/L)/(mmol/L)] gave the highest area under the receiver operating characteristic curve, with 93% sensitivity and 94% specificity.
Fulfilling the glucose, insulin, and C-peptide criteria of the Endocrine Society guidelines exhibited the best diagnostic performance for insulinoma. Nonetheless, the insulin-glucose ratio may still have a role in the biochemical diagnosis of insulinoma.
[Show abstract][Hide abstract] ABSTRACT: Growing evidence shows the possibility of role of microRNAs (miRNA) in regulating bone mass. We investigated the change of miRNAs and mRNA expression profiles in bone tissue in ovariectomized mice model and evaluated regulatory mechanism of bone mass mediated by miRNAs in estrogen deficiency state. Eight-week old female C3H/HeJ mice underwent ovariectomy (OVX) or sham operation (Sham-op) and their femur and tibia were harvested to extract total bone RNAs after 4 weeks for microarray analysis. Eight miRNAs (miR-127, -133a, -133a*, -133b, -136 -206, -378, -378*) were identified to be upregulated after OVX while one miRNA (miR-204) was downregulated. Concomitant analysis of mRNA microarray revealed that 658 genes were differentially expressed between OVX and Sham-op mice. Target prediction of differentially expressed miRNAs identified potential targets and integrative analysis using the mRNA microarray results showed that PPARγ and CREB pathways are activated in skeletal tissues after ovariectomy. Among the potential candidates of miRNA, we further studied the role of miR-127 in vitro, which exhibited the greatest changes after OVX. We also studied the effects of miR-136, which has not been studied in the context of bone mass regulation. Transfection of miR-127 inhibitor has enhanced osteoblastic differentiation in UAMS-32 cells as measured by alkaline phosphatase activities and mRNA expression of osteoblast-specific genes while miR-136 precursor has inhibited osteoblastic differentiation. Furthermore, transfection of both miR-127 and miR-136 inhibitors enhanced the osteocyte-like morphological changes and survival in MLO-Y4 cells while precursors of miR-127 and -136 has aggravated dexamethasone-induced cell death. Both of the precursors enhanced osteoclastic differentiation in bone marrow macrophages, indicating that both miR-127 and -136 are negatively regulating bone mass. Taken together, these results suggest a novel insight into the association between distinct miRNAs expression and their possible role through regulatory network with mRNAs in the pathogenesis of estrogen deficiency induced osteoporosis.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 03/2014; 29(3). DOI:10.1002/jbmr.2060 · 6.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The short Synacthen test (SST) is widely used as alternative test to the insulin tolerance test (ITT) to investigate central adrenal insufficiency (CAI), but the methodology and cut-off values of the SST are controversial. Our aim was to evaluate the cut-off value of the ITT in normal subjects and to assess the different cutoff values of the high-dose SST (250 μg, HDT) and the low-dose SST (1 μg, LDT) in subjects with suspected CAI SUBJECTS AND METHODS: We conducted ITTs in 208 normal subjects to establish the cut-off value for the ITT, and 28 of those subjects underwent the HDT and LDT. From 1999 to 2007, 182 patients with suspected CAI were recruited and underwent ITTs, LDTs and HDTs to establish cut-off values and compare the diagnostic accuracy between the LDT and HDT.
The 95(th) percentile of the peak cortisol level during the ITT in the normal control subjects was 14.8 μg/dl. Receiver-operator characteristics (ROC) analysis revealed that the optimal cut-off values of peak cortisol in the LDT and HDT in patients with suspected CAI were 15.8 and 17.4 μg/dl, respectively. However, the cut-off values from normative data (mean-2SD) were 18.3 μg/dl for the LDT and 20.5 μg/dl for the HDT in normal control.
The optimal cut-off values of SSTs needed to be individualized according to the type of SST and tested patient population. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: 17α-hydroxylase/17,20-lyase deficiency is a rare form of congenital adrenal hyperplasia, characterized by hypertension and sexual infantilism and caused by loss-of-function mutations in CYP17A1. This study investigated the clinical and molecular characteristics of six adults with 17α-hydroxylase/17,20-lyase deficiency and the functional consequences of a novel CYP17A1 mutation.
Six phenotypic females, three with 46,XY and three with 46,XX karyotypes, presented with primary amenorrhea and hypertension. All had elevated levels of plasma adrenocorticotropic hormone, serum gonadotropin, progesterone, and 11-deoxycorticosterone, and reduced testosterone and dehydroepiandrosterone sulfate (DHEA-S). All coding exons and flanking intronic sequences of CYP17A1 were directly sequenced using genomic DNA. Wild-type and mutant CYP17A1 cDNAs were inserted into the pcDNA3.1/V5-His-P450c17 vector, and transiently expressed in COS-7 cells. This was followed by an assessment of 17α-hydroxylase and 17,20-lyase activities by measuring the conversions of progesterone to 17-hydroxyprogesterone and 17-hydroxypregnenolone to DHEA.
The mutation analysis identified one patient with compound heterozygosity for p.H373L and p.W406L, one with compound heterozygosity for p.H373L and p.A174E, three with compound heterozygosity for p.Y329fs and p.H373L, and one with homozygosity for p.H373L. An in vitro functional analysis of the novel p.W406L mutation revealed a complete loss of 17α-hydroxylase/17, 20-lyase activities.
p.H373L was the most common mutation among these Korean patients, consistent with the high allele frequency of p.H373L in Chinese and Japanese populations, suggesting possible founder effects in Asian countries. The novel p.W406L mutation caused a complete loss of both catalytic activities, indicating that this amino acid is critical for P450c17 function.
[Show abstract][Hide abstract] ABSTRACT: The aim of our study was to assess the frequency of germline mutations and develop the genetic testing strategy in patients with apparently sporadic pheochromocytoma/paraganglioma (PPGL) in Korea. We included 53 patients diagnosed with nonsyndromic PPGL without a family history of PPGLs in three referral centers from 2004 to 2011. Succinate dehydrogenase complex B (SDHB), succinate dehydrogenase complex D (SDHD), Von Hippel-Lindau (VHL), and RET genes were examined by direct sequencing and multiple ligation-dependent probe amplification. The study patients were composed of 26 men and 27 women, and mean age was 50.1 ± 13.5 years. The frequency of germline mutations was 13.2% (7/53): RET (n =2), VHL (n = 1), SDHB (n = 2), SDHD (n = 2). Six of seven mutation carriers were diagnosed before the age of 50 years. One of two patients harboring an SDHB mutation had malignant PPGLs. One patient with multifocal head and neck PGL and PHEO carried a SDHD mutation. The carriers of germline mutations in patients with apparently sporadic PPGL were 13.2% in our study. We recommend genetic testing in patients under 50 years and SDHD genetic testing in patients with multifocal PPGLs. In malignant PPGLs, SDHB genetic testing may be performed.
[Show abstract][Hide abstract] ABSTRACT: Women with a history of gestational diabetes mellitus (GDM) are at increased risk of future development of type 2 diabetes. Recently, over 65 genetic variants have been confirmed to be associated with diabetes. We investigated whether this genetic information could improve the prediction of future diabetes in women with GDM.
This was a prospective cohort study consisting of 395 women with GDM who were followed annually with an OGTT. A weighted genetic risk score (wGRS), consisting of 48 variants, was assessed for improving discrimination (C statistic) and risk reclassification (continuous net reclassification improvement [NRI] index) when added to clinical risk factors.
Among the 395 women with GDM, 116 (29.4%) developed diabetes during a median follow-up period of 45 months. Women with GDM who went on to develop diabetes had a significantly higher wGRS than those who did not (9.36 ± 0.92 vs 8.78 ± 1.07; p < 1.56 × 10(-7)). In a complex clinical model adjusted for age, prepregnancy BMI, family history of diabetes, blood pressure, fasting glucose and fasting insulin concentration, the C statistic marginally improved from 0.741 without the wGRS to 0.775 with the wGRS (p = 0.015). The addition of the wGRS to the clinical model resulted in a modest improvement in reclassification (continuous NRI 0.430 [95% CI 0.218, 0.642]; p = 7.0 × 10(-5)).
In women with GDM, who are at high risk of diabetes, the wGRS was significantly associated with the future development of diabetes. Furthermore, it improved prediction over clinical risk factors.
[Show abstract][Hide abstract] ABSTRACT: Leptin plays a critical role in the central regulation of bone mass. Ghrelin counteracts leptin. In this study, we investigated the effect of chronic intracerebroventricular administration of ghrelin on bone mass in Sprague-Dawley rats (1.5 μg/day for 21 days). Rats were divided into control, ghrelin ad libitum-fed (ghrelin ad lib-fed), and ghrelin pair-fed groups. Ghrelin intracerebroventricular infusion significantly increased body weight in ghrelin ad lib-fed rats but not in ghrelin pair-fed rats, as compared with control rats. Chronic intracerebroventricular ghrelin infusion significantly increased bone mass in the ghrelin pair-fed group compared with control as indicated by increased bone volume percentage, trabecular thickness, trabecular number and volumetric bone mineral density in tibia trabecular bone. There was no significant difference in trabecular bone mass between the control group and the ghrelin ad-lib fed group. Chronic intracerebroventricular ghrelin infusion significantly increased the mineral apposition rate in the ghrelin pair-fed group as compared with control. In conclusion, chronic central administration of ghrelin increases bone mass through a mechanism that is independent of body weight, suggesting that ghrelin may have a bone anabolic effect through the central nervous system.
PLoS ONE 07/2013; 8(7):e65505. DOI:10.1371/journal.pone.0065505 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Context:The widespread use of thyroid tests in asymptomatic individuals identifies many patients with transient subclinical hypothyroidism.Objective:To determine the effect of seasonal change on serum TSH levels and the transition between subclinical hypothyroid and euthyroid status.Design, Setting, and Subjects:This was a retrospective longitudinal study of 1751 subclinical hypothyroid and 28096 euthyroid subjects aged over 18 years who underwent serial thyroid function tests at a health screening center between October 2003 and May 2011. Main Outcome Measures:Age-adjusted geometric mean values of the TSH level by month were calculated using linear mixed models. Adjusted odds ratios of test season and multiple baseline clinical factors were determined using generalized estimating equations.Results:During median 36 months of follow-up, 57.9% of subclinical hypothyroid subjects reverted to euthyroidism, and 4.3% of euthyroid subjects developed subclinical hypothyroidism. The monthly distribution of follow-up TSH levels indicated a biphasic pattern, i.e., an increase during the winter-spring season and a decrease during the summer-fall season, with a maximal TSH difference of 0.69 mIU/L in subclinical hypothyroid and 0.30 mIU/L in euthyroid subjects. Normalization of subclinical hypothyroidism was increased 1.4-fold in follow-up tests during the summer-fall follow-up, whereas subclinical hypothyroidism increased 1.4-fold in euthyroid subjects during the winter-spring follow-up.Conclusions:The season in which thyroid testing was performed was independently related to the transition between subclinical hypothyroid and euthyroid status. Seasonal variations in TSH concentration should be considered before deciding on treatment of subclinical hypothyroidism, particularly in the areas with a wide annual temperature range.
The Journal of Clinical Endocrinology and Metabolism 06/2013; 98(8). DOI:10.1210/jc.2013-1607 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated characteristics associated with the efficacy of dipeptidyl peptidase-4 inhibitors (DPP4i) in Korean patients with type 2 diabetes. We reviewed medical records of 477 patients who had taken sitagliptin or vildagliptin longer than 40 weeks. Response to DPP4i was evaluated with HbA1c change after therapy (ΔHbA1c). The Student's t-test between good responders (GR: ΔHbA1c > 1.0%) and poor responders (PR: ΔHbA1c < 0.5%), a correlation analysis among clinical parameters, and a linear multivariate regression analysis were performed. The mean age was 60 yr, duration of diabetes 11 yr and HbA1c was 8.1%. Baseline fasting plasma glucose (FPG), HbA1c, C-peptide, and creatinine were significantly higher in the GR compared to the PR. Duration of diabetes, FPG, HbA1c, C-peptide and creatinine were significantly correlated with ΔHbA1c. In the multivariate analysis, age (r(2) = 0.006), duration of diabetes (r(2) = 0.019), HbA1c (r(2) = 0.296), and creatinine levels (r(2) = 0.024) were independent predictors for the response to DPP4i. Body mass index and insulin resistance were not associated with the response to DPP4i. In conclusion, better response to DPP4i would be expected in Korean patients with type 2 diabetes who have higher baseline HbA1c and creatinine levels with shorter duration of diabetes.
Journal of Korean medical science 06/2013; 28(6):881-7. DOI:10.3346/jkms.2013.28.6.881 · 1.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Farnesoid X receptor (FXR) is a nuclear receptor, which functions as a bile acid sensor controlling bile acid homeostasis. We investigated the role of FXR in regulating bone metabolism. We identified the expression of FXR in calvaria and bone marrow cells, which gradually increased during osteoblastic differentiation in vitro. In male mice, deletion of FXR (FXR(-/-) ) in vivo resulted in a significant reduction in bone mineral density by 4.3∼6.6% in mice 8 to 20 weeks of age compared with FXR(+/+) mice. Histological analysis of the lumbar spine showed that FXR deficiency reduced the bone formation rate as well as the trabecular bone volume and thickness. Moreover, TRACP staining of the femurs revealed that both the osteoclast number and osteoclast surface were significantly increased in FXR(-/-) mice compared with FXR(+/+) mice. At the cellular level, induction of alkaline phosphatase (ALP) activities was blunted in primary calvarial cells in FXR(-/-) mice compared with FXR(+/+) mice in concert with a significant reduction in Col1a1, ALP, and Runx2 gene expressions. Cultures of bone marrow derived macrophages from FXR(-/-) mice exhibited an increased number of osteoclast formations and protein expression of NFATc1. In female FXR(-/-) mice, although BMD was not significantly different from that in FXR(+/+) mice, bone loss was accelerated after an ovariectomy compared with FXR(+/+) mice. In vitro, activation of FXR by bile acids (CDCA or 6-ECDCA) or FXR agonists (GW4064 or Fexaramine) significantly enhanced osteoblastic differentiation through the upregulation of Runx2 and enhanced ERK and β-catenin signaling. FXR agonists also suppressed osteoclast differentiation from bone marrow macrophages. Finally, administration of a farnesol diet (1%) marginally prevented OVX-induced bone loss and enhanced bone mass gain in growing C57BL/6J mice. Taken together, these results suggest that FXR positively regulates bone metabolism through both arms of the bone remodeling pathways, i.e. bone formation and resorption.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 05/2013; 28(10). DOI:10.1002/jbmr.1961 · 6.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Context:Women with a history of gestational diabetes mellitus (GDM) are at increased risk of type 2 diabetes (T2DM). However, the time to progression to diabetes differs individually.Objective:We investigated the clinical and genetic risk factors that are associated with T2DM early or late post partum after GDM pregnancy.Design and Setting:This was a hospital-based prospective cohort study that enrolled GDM women.Patients and Outcome Measures:A total of 843 GDM subjects were followed for the development of T2DM. Clinical risk factors were investigated during pregnancy, 2 months post partum, and annually thereafter. GDM subjects were genotyped for 21 known T2DM-associated genetic variants, and their genotype frequencies were compared with elderly nondiabetic controls.Results:At 2 months post partum, 105 (12.5%) subjects had T2DM (early converters). Among the 370 remaining subjects who underwent more than 1 year of follow-up, 88 (23.8%) had newly developed T2DM (late converters). Independent risk factors for early converters were higher prepregnancy body mass index, higher area under the curve of glucose during an antepartum oral glucose tolerance test, lower fasting insulin concentration, and decreased β-cell function. Independent risk factors for late converters were higher prepregnancy body mass index and higher glucose area under the curve. Variants in CDKN2A/2B and HHEX were associated with early conversion, whereas variants in CDKAL1 were associated with late conversion.Conclusions:Obesity was a risk factor for both early and late T2DM converters. However, early converters had more pronounced defects in β-cell function, which might be explained, in part, by differences in genetic predisposition.
The Journal of Clinical Endocrinology and Metabolism 03/2013; 98(4). DOI:10.1210/jc.2012-3324 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report here the cases of two females with Graves' disease who developed insulin autoimmune syndrome after treatment with methimazole. The patients exhibited a sudden altered mental state after treatment with methimazole for approximately 4 weeks. Patients had hypoglycemia with serum glucose below 70 mg/dL, and laboratory findings showed both high levels of serum insulin and high titers of insulin autoantibodies. The two women had never been exposed to insulin or oral antidiabetic agents, and there was no evidence of insulinoma in imaging studies. After glucose loading, serum glucose, and total insulin levels increased abnormally. One of the patient was found to have HLA-DRB1*0406, which is known to be strongly associated with methimazole-induced insulin autoimmune syndrome. After discontinuation of methimazole, hypoglycemic events disappeared within 1 month. Insulin autoantibody titer and insulin levels decreased within 5 months and there was no further development of hypoglycemic events. We present these cases with a review of the relevant literature.
[Show abstract][Hide abstract] ABSTRACT: Osteoblasts are derived from mesenchymal progenitors. Differentiation to osteoblasts and adipocytes is reciprocally regulated. Transcriptional coactivator with a PDZ-binding motif (TAZ) is a transcriptional coactivator that induces differentiation of mesenchymal cells into osteoblasts while blocking differentiation into adipocytes. To investigate the role of TAZ on bone metabolism in vivo, we generated transgenic mice that overexpress TAZ under the control of the procollagen type 1 promoter (Col1-TAZ). Whole body bone mineral density (BMD) of 6- to 19-week-old Col-TAZ mice was 4% to 7% higher than that of their wild-type (WT) littermates, whereas no difference was noticed in Col.1-TAZ female mice. Microcomputed tomography analyses of proximal tibiae at 16 weeks of age demonstrated a significant increase in trabecular bone volume (26.7%) and trabecular number (26.6%) with a reciprocal decrease in trabecular spacing (14.2%) in Col1-TAZ mice compared with their WT littermates. In addition, dynamic histomorphometric analysis of the lumbar spine revealed increased mineral apposition rate (42.8%) and the serum P1NP level was also significantly increased (53%) in Col.1-TAZ mice. When primary calvaria cells were cultured in osteogenic medium, alkaline phosphatase (ALP) activity was significantly increased and adipogenesis was significantly suppressed in Col1-TAZ mice compared with their WT littermates. Quantitative real-time polymerase chain reaction analyses showed that expression of collagen type 1, bone sialoprotein, osteocalcin, ALP, osterix, and Runx2 was significantly increased in calvaria cells from Col1-TAZ mice compared to their WT littermates. In vitro, TAZ enhanced Runx2-mediated transcriptional activity while suppressing the peroxisome proliferator-activated receptor gamma signaling pathway. TAZ also enhanced transcriptional activity from 3TP-Lux, which reflects transforming growth factor-beta (TGF-β)-mediated signaling. In addition, TAZ enhanced TGF-β-dependent nuclear translocation of Smad2/3 and Smad4. Taken together, these results suggest that TAZ positively regulates bone formation in vivo, which seems to be mediated by enhancing both Runx2 and TGF-β signaling.
PLoS ONE 02/2013; 8(2):e56585. DOI:10.1371/journal.pone.0056585 · 3.23 Impact Factor