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AIMS: To determine the fetal and maternal outcomes in pregnant women with Glucokinase-Maturity onset diabetes of the young (GCK-MODY). METHODS: We studied the obstetric and perinatal outcomes in 99 pregnancies of 34 women with GCK-MODY. The mutation status of the offspring was known in 29 and presumed in 33. Clinical outcomes were determined and compared between affected (n = 39) and unaffected (n = 23) offspring. RESULTS: 59% of pregnancies were treated with diet alone and 41% received insulin. Birthweight, percentage of large for gestational age (LGA) and caesarean section (CS) in GCK-unaffected offspring was significantly higher than in GCK-affected offspring (4.0 ± 0.7 vs. 3.4 ± 0.4 kg, p = 0.001), 15 (65%) vs. 5(13%) (p = 0.00006) and 17 (74%) vs. 11 (28%) (p = 0.001), respectively. We observed an earlier gestational age at delivery on insulin in unaffected offspring (38.3 ± 1.0 vs. 39.5 ± 1.5 weeks, p = 0.03) with no significant change in LGA (9 (82%) vs. 6 (50%); p = 0.12), and a higher rate of CS (8 [73%] vs. 3 [11%]; p < 0.001), and no change in small for gestational age (0 [0%] vs. 4 [14%]; p = 0.30) in affected offspring. CONCLUSION: Insulin therapy in unaffected offspring did not reduce LGA and was associated with earlier gestational age at delivery. Insulin treatment in GCK-affected offspring was associated with an increased incidence of CS, but did not adversely affect fetal outcome. Fetal genotype determines birthweight rather than treatment. Pre-pregnancy diagnosis of GCK-MODY, use of continuous glucose monitoring and non-invasive fetal genotyping may enable further investigation of targeted therapy in this condition.
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DNA/genética , Diabetes Mellitus Tipo 2/genética , Glucoquinase/genética , Mutação , Gravidez em Diabéticas/genética , Adulto , Peso ao Nascer , Glicemia/metabolismo , Automonitorização da Glicemia , Análise Mutacional de DNA , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Seguimentos , Idade Gestacional , Glucoquinase/metabolismo , Humanos , Incidência , Linhagem , Gravidez , Resultado da Gravidez , Gravidez em Diabéticas/sangue , Gravidez em Diabéticas/epidemiologia , Estudos Retrospectivos , Espanha/epidemiologiaRESUMO
OBJECTIVE: Women with maturity-onset diabetes of the young (MODY) are often first identified and diagnosed with diabetes during pregnancy. Genetics and hyperglycemia play an important role in determining fetal size in MODY pregnancies. The principal objective of the current study is to determine the outcomes and clinical management of hyperglycemia in pregnancies complicated by glucokinase gene (GCK) and hepatocyte nuclear factor (HNF)-1α MODY mutations. STUDY DESIGN: A retrospective chart review of 37 women with a GCK/HNF-1α mutation was conducted. Data on variables such as birthweight, mode of delivery, and the treatment of hyperglycemia were available on 89 pregnancies. RESULTS: The birthweight in unaffected GCK offspring was significantly higher than in the affected GCK offspring (4.8 [4.1-5.2] kg vs 3.2 [3.1-3.7] kg; P = .01). Seven-point home blood glucose monitoring over a 7-day period in each trimester demonstrated higher fasting and postprandial glycemic excursions in the first trimester of GCK pregnancies when compared to HNF-1α pregnancies (fasting 104 [90-115] mg/dL vs 84 [77-88] mg/dL; P = .01 and postprandial 154 [135-196] mg/dL vs 111 [100-131] mg/dL; P = .04) despite insulin treatment. There was a higher percentage of miscarriages in the GCK group when compared to the HNF-1α MODY group (33.3% vs 14%; P = .07), which was similar to the background population. Insulin initiated at an early gestation appeared to lower the incidence of macrosomia in GCK unaffected offspring. CONCLUSION: Hyperglycemia in HNF-1α pregnancies is easily managed with current insulin protocols; in contrast, glycemic excursions are difficult to manage in GCK pregnancies. There was an increased percentage of miscarriages in GCK pregnancies highlighting the importance of a diagnosis of GCK-MODY in women prior to conception and the necessity for preconception care.
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucoquinase/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Gravidez em Diabéticas , Aborto Espontâneo/epidemiologia , Adolescente , Automonitorização da Glicemia , Estudos de Coortes , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Gravidez , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Heterozygous insulin receptor mutations (INSR) are associated with insulin resistance, hyperglycaemia and hyperinsulinaemic hypoglycaemia in addition to hyperandrogenism and oligomenorrhoea in women. Numerous autosomal dominant heterozygous mutations involving the INSR ß-subunit tyrosine kinase domain resulting in type A insulin resistance have been previously described. We describe the phenotype, obstetric management and neonatal outcomes in a woman with type A insulin resistance caused by a mutation in the ß-subunit of the INSR. CASE PRESENTATION: We describe a woman with a p.Met1180Lys mutation who presents with hirsutism, oligomenorrhoea and diabetes at age 20. She has autoimmune thyroid disease, Coeliac disease and positive GAD antibodies. She is overweight with no features of acanthosis nigricans and is treated with metformin. She had 11 pregnancies treated with insulin monotherapy (n = 2) or combined metformin and insulin therapy (n = 9). The maximum insulin dose requirement was 134 units/day or 1.68 units/kg/day late in the second pregnancy. Mean birthweight was on the 37th centile in INSR positive offspring (n = 3) and the 94th centile in INSR negative offspring (n = 1). CONCLUSION: The p.Met1180Lys mutation results in a phenotype of diabetes, hirsutism and oligomenorrhoea. This woman had co-existent autoimmune disease. Her insulin dose requirements during pregnancy were similar to doses observed in women with type 2 diabetes. Metformin may be used to improve insulin sensitivity in women with this mutation. Offspring inheriting the mutation tended to be smaller for gestational age.
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BACKGROUND: There is a significant clinical overlap between patients with hepatocyte nuclear factor (HNF)-1A and HNF4A maturity-onset diabetes of the young (MODY), two forms of monogenic diabetes. HNF1A and HNF4A are transcription factors that control common and partly overlapping sets of target genes. We have previously shown that elevated serum pancreatic stone protein / regenerating protein A (PSP/reg1A) levels can be detected in subjects with HNF1A-MODY. In this study, we investigated whether PSP/reg is differentially regulated by HNF1A and HNF4A. METHODS: Quantitative real-time PCR (qPCR) and Western blotting were used to validate gene and protein expression in cellular models of HNF1A- and HNF4A-MODY. Serum PSP/reg1A levels and high-sensitivity C-reactive protein (hsCRP) were measured by ELISA in 31 HNF1A- and 9 HNF4A-MODY subjects. The two groups were matched for age, body mass index, diabetes duration, blood pressure, lipid profile and aspirin and statin use. RESULTS: Inducible repression of HNF1A and HNF4A function in INS-1 cells suggested that PSP/reg induction required HNF4A, but not HNF1A. In contrast, crp gene expression was significantly reduced by repression of HNF1A, but not HNF4A function. PSP/reg levels were significantly lower in HNF4A subjects when compared to HNF1A subjects [9.25 (7.85-12.85) ng/ml vs. 12.5 (10.61-17.87) ng/ml, U-test P = 0.025]. hsCRP levels were significantly lower in HNF1A-MODY [0.22 (0.17-0.35) mg/L] compared to HNF4A-MODY group [0.81 (0.38-1.41) mg/L, U-test P = 0.002], Parallel measurements of serum PSP/reg1A and hsCRP levels were able to discriminate HNF1A- and HNF4A-MODY subjects. CONCLUSION: Our study demonstrates that two distinct target genes, PSP/reg and crp, are differentially regulated by HNF1A and HNF4A, and provides clinical proof-of-concept that serum PSP/reg1A and hsCRP levels may distinguish HNF1A-MODY from HNF4A-MODY subjects.
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Proteína C-Reativa/metabolismo , Diabetes Mellitus Tipo 2/terapia , Regulação da Expressão Gênica , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Fator 4 Nuclear de Hepatócito/metabolismo , Litostatina/sangue , Adulto , Animais , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Adulto JovemRESUMO
We describe the clinical and genetic findings in pedigree with a novel mutation in the calcium sensing receptor (CaSR) gene and the unusual coexistence of primary hyperparathyroidism (HPT) and familial hypocalciuric hypercalcaemia (FHH) and its clinical management. The occurrence of both FHH and primary HPT in the same patient has been described rarely. Our pedigree has a novel mutation in the CaSR gene. Parathyroidectomy led to a reduction, but not normalization of the calcium levels in the patient identified as having HPT. The coexistence of HPT and FHH was considered in this patient as her calcium and PTH levels were rising with time. Surgical resection of her parathyroid adenoma resulted in reduction of her calcium levels to above normal and significant reduction in her symptoms of fatigue and low mood.
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Hipercalcemia/congênito , Hiperparatireoidismo Primário/complicações , Hiperparatireoidismo Primário/genética , Mutação/genética , Receptores de Detecção de Cálcio/genética , Feminino , Humanos , Hipercalcemia/complicações , Hipercalcemia/genética , Masculino , Glândulas Paratireoides/patologia , LinhagemRESUMO
Inactivating mutations in the transcription factor hepatocyte nuclear factor (HNF) 1A cause HNF1A-maturity-onset diabetes of the young (HNF1A-MODY), the most common monogenic form of diabetes. To examine HNF1A-MODY-induced defects in gene expression, we performed a microarray analysis of the transcriptome of rat INS-1 cells inducibly expressing the common hot spot HNF1A frameshift mutation, Pro291fsinsC-HNF1A. Real-time quantitative PCR (qPCR), Western blotting, immunohistochemistry, reporter assays, and chromatin immunoprecipitation (ChIP) were used to validate alterations in gene expression and to explore biological activities of target genes. Twenty-four hours after induction of the mutant HNF1A protein, we identified a prominent down-regulation of the bone morphogenetic protein 3 gene (Bmp-3) mRNA expression. Reporter assays, qPCR, and Western blot analysis validated these results. In contrast, inducible expression of wild-type HNF1A led to a time-dependent increase in Bmp-3 mRNA and protein levels. Moreover, reduced protein levels of BMP-3 and insulin were detected in islets of transgenic HNF1A-MODY mice. Interestingly, treatment of naïve INS-1 cells or murine organotypic islet cultures with recombinant human BMP-3 potently increased their insulin levels and restored the decrease in SMAD2 phosphorylation and insulin gene expression induced by the HNF1A frameshift mutation. Our study suggests a critical link between HNF1A-MODY-induced alterations in Bmp-3 expression and insulin gene levels in INS-1 cells and indicates that the reduced expression of growth factors involved in tissue differentiation may play an important role in the pathophysiology of HNF1A-MODY.
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Proteína Morfogenética Óssea 3/farmacologia , Regulação para Baixo/efeitos dos fármacos , Mutação da Fase de Leitura/efeitos dos fármacos , Fator 1-alfa Nuclear de Hepatócito/genética , Insulina/genética , Animais , Linhagem Celular Tumoral , Regulação para Baixo/genética , Perfilação da Expressão Gênica , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas/genética , RatosRESUMO
BACKGROUND: Mutations in the transcription factor hepatocyte nuclear factor-1-alpha (HNF1A) result in the commonest type of maturity onset diabetes of the young (MODY). HNF1A-MODY carriers have reduced pancreatic beta cell mass, partially due to an increased rate of apoptosis. To date, it has not been possible to determine when apoptosis is occurring in HNF1A-MODY.We have recently demonstrated that beta cell apoptosis stimulates the expression of the pancreatic stone protein/regenerating (PSP/reg) gene in surviving neighbour cells, and that PSP/reg1A protein is subsequently secreted from these cells. The objective of this study was to determine whether serum levels of PSP/reg1A are elevated during disease progression in HNF1A-MODY carriers, and whether it may provide information regarding the onset of beta-cell apoptosis. METHODS: We analysed serum PSP/reg1A levels and correlated with clinical and biochemical parameters in subjects with HNF1A-MODY, glucokinase (GCK-MODY), and type 1 diabetes mellitus. A control group of normoglycaemic subjects was also analysed. RESULTS: PSP/reg1A serum levels were significantly elevated in HNF1A-MODY (n = 37) subjects compared to controls (n = 60) (median = 12.50 ng/ml, IQR = 10.61-17.87 ng/ml versus median = 10.72 ng/ml, IQR = 8.94-12.54 ng/ml, p = 0.0008). PSP/reg1A correlated negatively with insulin levels during OGTT, (rho = -0.40, p = 0.02). Interestingly we noted a significant positive correlation of PSP/reg1A with age of the HNF1A-MODY carriers (rho = 0.40 p = 0.02) with an age of 25 years separating carriers with low and high PSP/reg1A levels. Patients with type 1 diabetes mellitus also had elevated serum levels of PSP/reg1A compared to controls, however this was independent of the duration of diabetes. CONCLUSION: Our data suggest that beta cell apoptosis contributes increasingly to the pathophysiology of HNF1A-MODY in patients 25 years and over. PSP/reg1A may be developed as a serum marker to detect increased beta-cell apoptosis, or its therapeutic response.
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Heterozygous loss-of-function mutations in the hepatocyte nuclear factor 1A (HNF1A) gene result in the pathogenesis of maturity-onset diabetes-of-the-young type 3, (HNF1A-MODY). This disorder is characterized by a primary defect in metabolism-secretion coupling and decreased beta cell mass, attributed to excessive beta cell apoptosis. Here, we investigated the link between energy stress and apoptosis activation following HNF1A inactivation. This study employed single cell fluorescent microscopy, flow cytometry, gene expression analysis, and gene silencing to study the effects of overexpression of dominant-negative (DN)-HNF1A expression on cellular bioenergetics and apoptosis in INS-1 cells. Induction of DN-HNF1A expression led to reduced ATP levels and diminished the bioenergetic response to glucose. This was coupled with activation of the bioenergetic stress sensor AMP-activated protein kinase (AMPK), which preceded the onset of apoptosis. Pharmacological activation of AMPK using aminoimidazole carboxamide ribonucleotide (AICAR) was sufficient to induce apoptosis in naive cells. Conversely, inhibition of AMPK with compound C or AMPKα gene silencing protected against DN-HNF1A-induced apoptosis. Interestingly, AMPK mediated the induction of the pro-apoptotic Bcl-2 homology domain-3-only protein Bmf (Bcl-2-modifying factor). Bmf expression was also elevated in islets of DN-HNF1A transgenic mice. Furthermore, knockdown of Bmf expression in INS-1 cells using siRNA was sufficient to protect against DN-HNF1A-induced apoptosis. Our study suggests that overexpression of DN-HNF1A induces bioenergetic stress and activation of AMPK. This in turn mediates the transcriptional activation of the pro-apoptotic Bcl-2-homology protein BMF, coupling prolonged energy stress to apoptosis activation.
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Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/fisiologia , Metabolismo Energético/fisiologia , Proteínas Quinases Ativadas por AMP/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Trifosfato de Adenosina/metabolismo , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacologia , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Linhagem Celular Tumoral , Doxiciclina/farmacologia , Metabolismo Energético/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Hipoglicemiantes/farmacologia , Insulinoma/genética , Insulinoma/metabolismo , Insulinoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Interferência de RNA , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ribonucleotídeos/farmacologiaRESUMO
HNF1A-maturity onset diabetes of the young (HNF1A-MODY) is caused by mutations in Hnf1a gene encoding the transcription factor hepatocyte nuclear factor 1alpha (HNF1A). An increased rate of apoptosis has been associated with the decrease in beta-cell mass that is a hallmark of HNF1A-MODY and other forms of diabetes. In a cellular model of HNF1A-MODY, we have recently shown that signalling through mammalian target of rapamycin (mTOR) is decreased by the overexpression of a dominant-negative mutant of HNF1A (DN-HNF1A). mTOR is a protein kinase which has important roles in cell metabolism and growth, but also in cell survival, where it has been shown to be both protective and detrimental. Here, we show that pharmacological inhibition of mTOR activity with rapamycin protected INS-1 cells against DN-HNF1A-induced apoptosis. Rapamycin also prevented DN-HNF1A-induced activation of AMP-activated protein kinase (AMPK), an intracellular energy sensor which we have previously shown to mediate DN-HNF1A-induced apoptosis. Conversely, activation of mTOR with leucine potentiated DN-HNF1A-induced apoptosis. Gene silencing of raptor (regulatory associated protein of mTOR), a subunit of mTOR complex 1 (mTORC1), also conferred protection on INS-1 cells against DN-HNF1A-induced apoptosis, confirming that mTORC1 mediates the protective effect. The potential relevance of this effect with regards to the clinical use of rapamycin as an immunosuppressant in diabetics post-transplantation is discussed.
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Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Diabetes Mellitus Tipo 1/metabolismo , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Insulinoma/metabolismo , Neoplasias Pancreáticas/metabolismo , Transdução de Sinais , Sirolimo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Genes Dominantes , Fator 1-alfa Nuclear de Hepatócito/genética , Células Secretoras de Insulina/citologia , Insulinoma/genética , Insulinoma/patologia , Leucina/farmacologia , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
SUMMARY: A 41-year-old male presented to the Emergency Department with a 6-month history of back and hip pain. Skeletal survey revealed bilateral pubic rami fractures and MRI of the spine demonstrated multiple thoracic and lumbar fractures. Secondary work up for osteoporosis was undertaken. There was no evidence of hyperparathyroidism and the patient was vitamin D replete. Testosterone (T) was low at 1.7 nmol/L (8.6-29.0) and gonadotrophins were undetectable. The patient failed a 1 mg dexamethasone suppression test (DST) with a morning cortisol of 570 nmol/L (<50) and subsequently a low dose DST with a cortisol post 48 h of dexamethasone of 773 nmol/L (<50) and an elevated ACTH 98 ng/L. A corticotropin-releasing factor (CRF) test suggested ectopic ACTH secretion. The patient was commenced on teriparatide for osteoporosis and metyrapone to control the hypercortisolaemia. A positron emission tomography (PET) scan to look for the source of ACTH secretion demonstrated right neck adenopathy. Biopsy and subsequent lymph node dissection were performed and histology revealed a metastatic neuroendocrine tumour. Immunostaining was positive for calcitonin and thyroid transcription factor 1 (TTF1). Serum calcitonin was also significantly elevated at 45 264 ng/L (<10). The patient proceeded to a total thyroidectomy and left neck dissection. Histology confirmed a 7 mm medullary thyroid carcinoma (MTC). Post-operatively, the patient commenced vandetanib therapy and achieved a clinical and biochemical response. After approximately 18 months of vandetanib therapy, the patient developed recurrent disease in his neck. He is currently on LOXO-292 and is doing well 36 months post-diagnosis. LEARNING POINTS: Unexplained osteoporosis requires thorough investigation and the workup for secondary causes is not complete without excluding glucocorticoid excess. MTC should be considered when searching for sources of ectopic ACTH secretion. Resistance to tyrosine kinase inhibitors is well described with MTC and clinicians should have a low threshold for screening for recurrent disease.
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Younger maternal age at delivery has been linked to adverse reproductive outcomes. Pregnancy complicated by type 1 diabetes mellitus (T1DM) is also associated with adverse pregnancy outcomes. Optimising diabetic glycaemic control prior to pregnancy is known to reduce the rate of congenital abnormalities and improve pregnancy outcomes. Teenage pregnancies are not usually planned and little data exist on teenage pregnancy complicated by T1DM. We sought to identify the glycemic control achieved in teenage pregnancy with T1DM and to clarify if there is an associated increase in adverse pregnancy outcomes compared to those seen in older women with T1DM. We compared outcomes in 18 teenagers (TG) with 582 older women with T1DM (CON) from 1995-2007. TG booked to the combined diabetes-obstetrical service at a median gestational age of 11 weeks (range 6-22) compared to 7 weeks in CON (range 4-40, p < 0.02). Glycaemic was worse in TG compared to CON at 13, 26 and 35 weeks gestation, despite higher insulin doses. First trimester miscarriage rate did not differ between groups. Major congenital anomaly rate was 6.2% (1/16) compared to 3.2% in CON. This preliminary study has demonstrated that pregnant teenage women with T1DM book later to specialised care and have worse glycaemic control in pregnancy compared to older women with T1DM. This group also appear to be more insulin resistant than older women in early pregnancy. Our data would suggest that teenagers with type 1 diabetes mellitus may constitute a high-risk group for adverse pregnancy outcomes.
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Resultado da Gravidez , Gravidez na Adolescência , Gravidez de Alto Risco , Aborto Espontâneo/epidemiologia , Adolescente , Glicemia/metabolismo , Anormalidades Congênitas/epidemiologia , Diabetes Mellitus Tipo 1 , Feminino , Hemoglobinas Glicadas , Humanos , Resistência à Insulina , Gravidez , Gravidez em Diabéticas , Cuidado Pré-NatalRESUMO
Gestational Diabetes Mellitus (GDM) is characterised by insulin resistance accompanied by reduced beta-cell compensation to increased insulin demand, typically observed in the second and third trimester and associated with adverse pregnancy outcomes. There is a need for a biomarker that can accurately monitor status and predict outcome in GDM, reducing foetal-maternal morbidity and mortality risks. To this end, circulating microRNAs (miRNAs) present themselves as promising candidates, stably expressed in serum and known to play crucial roles in regulation of glucose metabolism. We analysed circulating miRNA profiles in a cohort of GDM patients (n = 31) and nondiabetic controls (n = 29) during the third trimester for miRNA associated with insulin-secretory defects and glucose homeostasis. We identified miR-330-3p as being significantly upregulated in lean women with GDM compared to nondiabetic controls. Furthermore, increased levels of miR-330-3p were associated with better response to treatment (diet vs. insulin), with lower levels associated with exogenous insulin requirement. We observed miR-330-3p to be significantly related to the percentage of caesarean deliveries, with miR-330-3p expression significantly higher in spontaneously delivered GDM patients. We report this strong novel association of circulating miR-330-3p with risk of primary caesarean delivery as a pregnancy outcome linked with poor maternal glycaemic control, strengthening the growing body of evidence for roles of diabetes-associated miRNAs in glucose homeostasis and adaptation to the complex changes related to pregnancy.
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Diabetes Gestacional/diagnóstico , Estudos de Associação Genética , MicroRNAs/sangue , Monitorização Fisiológica/métodos , Resultado da Gravidez , Magreza , Adulto , Biomarcadores/sangue , Cesárea , Feminino , Glucose/metabolismo , Homeostase/genética , Humanos , Resistência à Insulina/genética , MicroRNAs/fisiologia , Valor Preditivo dos Testes , Gravidez , Risco , Adulto JovemRESUMO
Coexistence of autoimmune diabetes and maturity-onset diabetes of the young (MODY) is rare. We report the first case of coexisting latent autoimmune diabetes of adulthood (LADA) and glucokinase (GCK) MODY. A 32-year-old woman was treated with insulin for gestational diabetes at age 32 years; post-partum, her fasting blood glucose was 6.0 mmol/L and 2-h glucose was 11.8 mmol/L following an oral glucose tolerance test, and she was maintained on diet alone. Five years later, a diagnosis of LADA was made when she presented with fasting blood glucose of 20.3 mmol/L and HbA1C 125 mmol/mol (13.6%). GCK-MODY was identified 14 years later when genetic testing was prompted by identification of a mutation in her cousin. Despite multiple daily insulin injections her glycaemic control remained above target and her clinical course has been complicated by multiple episodes of hypoglycaemia with unawareness. Although rare, coexistence of latent autoimmune diabetes of adulthood and monogenic diabetes should be considered if there is a strong clinical suspicion, for example, family history. Hypoglycaemic unawareness developed secondary to frequent episodes of hypoglycaemia using standard glycaemic targets for LADA. This case highlights the importance of setting fasting glucose targets within the expected range for GCK-MODY in subjects with coexisting LADA. Learning points: We report the first case of coexisting latent autoimmune diabetes of adulthood (LADA) and GCK-MODY. It has been suggested that mutations in GCK may lead to altered counter-regulation and recognition of hypoglycaemia at higher blood glucose levels than patients without such mutation. However, in our case, hypoglycaemic unawareness developed secondary to frequent episodes of hypoglycaemia using standard glycaemic targets for LADA. This case highlights the importance of setting fasting glucose targets within the expected range for GCK-MODY in subjects with coexisting LADA to avoid hypoglycaemia.
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BACKGROUND: We report the case of a giant intrathyroidal parathyroid adenoma weighing 59 g in a young woman presenting acutely with severe hypercalcemia requiring correction and adequate preoperative management prior to surgery. Parathyroid adenomas account for 85 % of cases of primary hyperparathyroidism. Those weighing more than 3.5g are classified as giant parathyroid adenomas. There are only 25 cases of parathyroid adenomas weighing over 30g reported in the literature. With the wide availability of biochemical screening tests in Western countries, mildly elevated calcium levels are often discovered incidentally. Our case is unusual for the extreme level of hypercalcemia, the patient's young age, and the weight of the adenoma, particularly in a developed country. CASE PRESENTATION: A 21-year-old Irish woman presented with a 3-week history of an enlarging right-sided neck mass. There was no dysphagia, stridor, or symptoms of hyperthyroidism or hypercalcemia. On examination, there was a firm painless swelling in the right lobe of her thyroid. Her thyroid function tests were normal. Corrected serum calcium was markedly elevated at 3.96 mmol/L with hypophosphatemia of 0.35 mmol/L. She was treated with bisphosphonates and fluids administered intravenously. Her parathyroid hormone level was over 20 times the upper limit of normal. Ultrasound revealed a solid and cystic nodule in the lower pole of the right lobe of her thyroid. Parathyroid scintigraphy demonstrated a 5×4 cm lesion which concentrated tracer. A right-sided parathyroidectomy, right thyroid lobectomy, and level VI neck dissection were performed. An encapsulated multiloculated solid cystic mass weighing 59 g was removed. There was no definite infiltration of the capsule and MIB1 count was low at 1 % thus the specimen lacked the diagnostic features of carcinoma. On the third postoperative day, hungry bone syndrome developed and calcium replacement administered intravenously was required. At 1-year postoperative, she was weaned off calcium and alfacalcidol. A follow-up ultrasound showed unremarkable residual thyroid. CONCLUSIONS: Any patient with an isolated hypercalcemia warrants a thorough work-up. Hungry bone syndrome is a potentially avoidable condition; thus the clinician should be highly attuned to the risk of hungry bone syndrome post-parathyroidectomy, which correlates with the weight of the adenoma resected.
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Adenoma/patologia , Neoplasias das Paratireoides/patologia , Glândula Tireoide/patologia , Doença Aguda , Adenoma/complicações , Adenoma/diagnóstico por imagem , Adenoma/cirurgia , Conservadores da Densidade Óssea/administração & dosagem , Feminino , Humanos , Hidroxicolecalciferóis/administração & dosagem , Hipercalcemia/diagnóstico , Hipercalcemia/tratamento farmacológico , Hipercalcemia/etiologia , Hiperparatireoidismo/diagnóstico , Hipofosfatemia/diagnóstico , Hipofosfatemia/etiologia , Esvaziamento Cervical , Hormônio Paratireóideo/sangue , Neoplasias das Paratireoides/complicações , Neoplasias das Paratireoides/diagnóstico por imagem , Neoplasias das Paratireoides/cirurgia , Paratireoidectomia , Carga Tumoral , Adulto JovemRESUMO
MicroRNA (miRNA) are a class of non-coding, 19-25 nucleotide RNA critical for network-level regulation of gene expression. miRNA serve as paracrine signaling molecules. Using an unbiased array approach, we previously identified elevated levels of miR-224 and miR-103 to be associated with a monogenic form of diabetes; HNF1A-MODY. miR-224 is a novel miRNA in the field of diabetes. We sought to explore the role of miR-224 as a potential biomarker in diabetes, and whether such diabetes-associated-miRNA can also be detected in the urine of patients. Absolute levels of miR-224 and miR-103 were determined in the urine of n = 144 individuals including carriers of a HNF1A mutation, participants with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM) and normal controls. Expression levels were correlated with clinical and biochemical parameters. miR-224 was significantly elevated in the urine of carriers of a HNF1A mutation and participants with T1DM. miR-103 was highly expressed in urine across all diabetes cohorts when compared to controls. For both miR-224 and-103, we found a significant correlation between serum and urine levels (p < 0.01). We demonstrate that miRNA can be readily detected in the urine independent of clinical indices of renal dysfunction. We surmise that the differential expression levels of miR-224 in both HNF1A-MODY mutation carriers and T1DM may be an attempt to compensate for beta-cell demise.
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INTRODUCTION: Premature atherosclerosis is a significant cause of morbidity and mortality in type 2 diabetes mellitus. Maturity onset diabetes of the young (MODY) accounts for approximately 2% of all diabetes, with mutations in the transcription factor; hepatocyte nuclear factor 1 alpha (HNF1A) accounting for the majority of MODY cases. There is somewhat limited data available on the prevalence of macrovascular disease in HNF1A-MODY carriers with diabetes. Marked insulin resistance and the associated dyslipidaemia are not clinical features of HNF1A-MODY carriers. The scavenger protein CD36 has been shown to play a substantial role in the pathogenesis of atherosclerosis, largely through its interaction with oxidised LDL. Higher levels of monocyte CD36 and plasma CD36(sCD36) are seen to cluster with insulin resistance and diabetes. The aim of this study was to determine levels of sCD36 in participants with HNF1A-MODY diabetes and to compare them with unaffected normoglycaemic family members and participants with type 2 diabetes mellitus. METHODS: We recruited 37 participants with HNF1A-MODY diabetes and compared levels of sCD36 with BMI-matched participants with type 2 diabetes mellitus and normoglycaemic HNF1A-MODY negative family controls. Levels of sCD36 were correlated with phenotypic and biochemical parameters. RESULTS: HNF1A-MODY participants were lean, normotensive, with higher HDL and lower triglyceride levels when compared to controls and participants with type 2 diabetes mellitus. sCD36 was also significantly lower in HNF1A-MODY participants when compared to both the normoglycaemic family controls and to lean participants with type 2 diabetes mellitus. CONCLUSION: In conclusion, sCD36 is significantly lower in lean participants with HNF1A-MODY diabetes when compared to weight-matched normoglycaemic familial HNF1A-MODY negative controls and to lean participants with type 2 diabetes mellitus. Lower levels of this pro-atherogenic marker may result from the higher HDL component in the lipid profile of HNF1A-MODY participants.
Assuntos
Antígenos CD36/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Heterozigoto , Adolescente , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVE: In diabetes, ß-cell mass is not static but in a constant process of cell death and renewal. Inactivating mutations in transcription factor 1 (tcf-1)/hepatocyte nuclear factor1a (hnf1a) result in decreased ß-cell mass and HNF1A-maturity onset diabetes of the young (HNF1A-MODY). Here, we investigated the effect of a dominant-negative HNF1A mutant (DN-HNF1A) induced apoptosis on the regenerative capacity of INS-1 cells. RESEARCH DESIGN AND METHODS: DN-HNF1A was expressed in INS-1 cells using a reverse tetracycline-dependent transactivator system. Gene(s)/protein(s) involved in ß-cell regeneration were investigated by real-time quantitative RT-PCR, Western blotting, and immunohistochemistry. Pancreatic stone protein/regenerating protein (PSP/reg) serum levels in human subjects were detected by enzyme-linked immunosorbent assay. RESULTS: We detected a prominent induction of PSP/reg at the gene and protein level during DN-HNF1A-induced apoptosis. Elevated PSP/reg levels were also detected in islets of transgenic HNF1A-MODY mice and in the serum of HNF1A-MODY patients. The induction of PSP/reg was glucose dependent and mediated by caspase activation during apoptosis. Interestingly, the supernatant from DN-HNF1A-expressing cells, but not DN-HNF1A-expressing cells treated with zVAD.fmk, was sufficient to induce PSP/reg gene expression and increase cell proliferation in naïve, untreated INS-1 cells. Further experiments demonstrated that annexin-V-positive microparticles originating from apoptosing INS-1 cells mediated the induction of PSP/reg. Treatment with recombinant PSP/reg reversed the phenotype of DN-HNF1A-induced cells by stimulating cell proliferation and increasing insulin gene expression. CONCLUSIONS: Our results suggest that apoptosing INS-1 cells shed microparticles that may stimulate PSP/reg induction in neighboring cells, a mechanism that may facilitate the recovery of ß-cell mass in HNF1A-MODY.
Assuntos
Caspases/genética , Diabetes Mellitus Tipo 2/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Células Secretoras de Insulina/fisiologia , Animais , Apoptose , Caspase 3/metabolismo , Caspases/farmacologia , Morte Celular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/fisiopatologia , Ensaio de Imunoadsorção Enzimática , Fator 1-alfa Nuclear de Hepatócito/farmacologia , Humanos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Insulinoma/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Regiões Promotoras Genéticas , Ratos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: ICSI into the oocyte is the only treatment currently available for most male patients with severe oligozoospermia who wish to father children. In order to perform ICSI, motile sperm need to be recovered from the ejaculate and, if no sperm or not enough motile sperm are recovered on the day of ICSI, testicular sperm extraction (TESE) must be performed. Oxytocin stimulates epididymal contractility and may be important for the release of stored sperm. The aim of this randomized single-blind cross-over study was to establish the effects of oxytocin on sperm output in severely oligozoospermic men. METHODS: Forty-nine infertile men with sperm concentrations <0.2 x 10(6)/ml were studied on two occasions after 3-4 days of sexual abstinence. They received an i.v. injection of saline or oxytocin 0.75 IU in random order, and commenced masturbation within 5 min. Ejaculate analysis was performed according to the WHO 1999 guidelines. RESULTS: A single i.v. dose of oxytocin resulted in no change in ejaculate volume (P = 0.4), total sperm count (P = 0.14) or sperm motility (P = 0.9). There was no significant correlation between the change in total sperm count and FSH levels (r = -0.32, P = 0.2), or the change in total sperm count and estradiol levels (r = -0.02, P = 0.9). Similar results were found in a subgroup of men with total sperm counts of <100. CONCLUSIONS: Our data indicate that a single-dose of i.v. oxytocin has no detectable effect on seminal parameters in men with severe oligozoospermia.
Assuntos
Oligospermia/tratamento farmacológico , Oligospermia/fisiopatologia , Ocitocina/administração & dosagem , Espermatogênese/efeitos dos fármacos , Adulto , Estudos Cross-Over , Ejaculação , Estradiol/sangue , Hormônio Foliculoestimulante/sangue , Humanos , Injeções Intravenosas , Masculino , Oligospermia/sangue , Oligospermia/patologia , Sêmen/efeitos dos fármacos , Índice de Gravidade de Doença , Método Simples-Cego , Contagem de Espermatozoides , Motilidade dos Espermatozoides/efeitos dos fármacosRESUMO
Impaired glucose tolerance (IGT) and non-insulin-dependent diabetes mellitus (NIDDM) are associated with an impaired ability of the beta-cell to sense and respond to small changes in plasma glucose. The aim of this study was to establish whether acute hyperglycemia per se plays a role in inducing this defect in beta-cell response. Seven healthy volunteers with no family history of NIDDM were studied on two occasions during a 12-h oscillatory glucose infusion with a periodicity of 144 min. Once, low-dose glucose was infused at a mean rate of 6 mg x kg(-1) x min(-1) and amplitude 33% above and below the mean rate, and, once, high-dose glucose was infused at 12 mg x kg(-1) x min(-1) and amplitude 16% above and below the mean rate. Mean glucose levels were significantly higher during the high-dose compared with the low-dose glucose infusion [9.5 +/- 0.8 vs. 6.8 +/- 0.2 mM (P < 0.01)], resulting in increased mean insulin secretion rates [ISRs; 469.1 +/- 43.8 vs. 268.4 +/- 29 pmol/min (P < 0.001)] and mean insulin levels [213.6 +/- 46 vs. 67.9 +/- 10.9 pmol/l (P < 0.008)]. Spectral analysis evaluates the regularity of oscillations in glucose, insulin secretion, and insulin at a predetermined frequency. Spectral power for glucose, ISR, and insulin was reduced during the high-dose glucose infusion [11.8 +/- 1.4 to 7.0 +/- 1.6 (P < 0.02), 7.6 +/- 1.5 to 3.2 +/- 0.5 (P < 0.04), and 10.5 +/- 1.6 to 4.6 +/- 0.7 (P < 0.01), respectively]. In conclusion, short-term infusion of high-dose glucose to obtain glucose levels similar to those previously seen in IGT subjects results in reduced spectral power for glucose, ISR, and insulin. The reduction in spectral power previously observed for ISR in IGT or NIDDM subjects may be due partly to hyperglycemia.