The coexistence of autoimmune diabetes and maturity-onset diabetes of the young (MODY): a case series.

Summary: The coexistence of autoimmune diabetes and maturity-onset diabetes (MODY) is rare. The absence of pancreatic autoantibodies is a key factor prompting MODY genetic testing. In this study, we report three cases of young-onset diabetes with progressive beta-cell dysfunction, strongly positive glutamic acid decarboxylase (GAD) antibodies, and genetic confirmation of pathogenic gene variants of HNF-1A, HNF-4A, and ABCC8-MODY.

Genotype-phenotype correlations and response to glucose lowering therapy in subjects with HNF1β associated diabetes.

Aims: Molecular defects of hepatic nuclear factor 1β (HNF1β) are associated with multiorgan disease (renal disease, pancreatic hypoplasia, and genital tract anomalies) in addition to diabetes. We examined the phenotypic features, insulin secretory response to glucose, and response to treatment in subjects with HNF1β-MODY (MODY 5).

Methods: Twelve subjects with HNF1β-MODY were phenotyped in detail.

Metastatic medullary thyroid carcinoma presenting as ectopic Cushing's syndrome.

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.

Evaluation of pregnancy outcomes in women with GCK-MODY.

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.

Circulating miR-330-3p in Late Pregnancy is Associated with Pregnancy Outcomes Among Lean Women with GDM.

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.

An evolving spectrum of diabetes in a woman with GCK-MODY.

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.

Acute presentation of a giant intrathyroidal parathyroid adenoma: a case report.

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.

MicroRNA-224 is Readily Detectable in Urine of Individuals with Diabetes Mellitus and is a Potential Indicator of Beta-Cell Demise.

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.

The clinical management of hyperglycemia in pregnancy complicated by maturity-onset diabetes of the young.

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.

Circulating CD36 is reduced in HNF1A-MODY carriers.

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.

Effects of hepatocyte nuclear factor-1A and -4A on pancreatic stone protein/regenerating protein and C-reactive protein gene expression: implications for maturity-onset diabetes of the young.

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.

Primary hyperparathyroidism in a patient with familial hypocalciuric hypercalcaemia due to a novel mutation in the calcium-sensing receptor gene.

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.

Serum levels of pancreatic stone protein (PSP)/reg1A as an indicator of beta-cell apoptosis suggest an increased apoptosis rate in hepatocyte nuclear factor 1 alpha (HNF1A-MODY) carriers from the third decade of life onward.

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.

Rapamycin protects against dominant negative-HNF1A-induced apoptosis in INS-1 cells.

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).

Bone morphogenetic protein 3 controls insulin gene expression and is down-regulated in INS-1 cells inducibly expressing a hepatocyte nuclear factor 1A-maturity-onset diabetes of the young mutation.

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.

AMP-activated protein kinase mediates apoptosis in response to bioenergetic stress through activation of the pro-apoptotic Bcl-2 homology domain-3-only protein BMF.

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.

INS-1 cells undergoing caspase-dependent apoptosis enhance the regenerative capacity of neighboring cells.

Objective: In diabetes, β-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 β-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.

Teenage pregnancy in type 1 diabetes mellitus.

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.

Lack of effect of a single i.v. dose of oxytocin on sperm output in severely oligozoospermic men.

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.

Acute hyperglycemia alters the ability of the normal beta-cell to sense and respond to glucose.

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.

Dominant-negative suppression of HNF-1 alpha results in mitochondrial dysfunction, INS-1 cell apoptosis, and increased sensitivity to ceramide-, but not to high glucose-induced cell death.

Maturity onset diabetes of the young (MODY) 3 is a monogenic form of diabetes caused by mutations in the transcription factor hepatocyte nuclear factor (HNF)-1 alpha. We investigated the involvement of apoptotic events in INS-1 insulinoma cells overexpressing wild-type HNF-1 alpha (WT-HNF-1 alpha) or a dominant-negative mutant (DN-HNF-1 alpha) under control of a doxycycline-dependent transcriptional activator. Forty-eight h after induction of DN-HNF-1 alpha, INS-1 cells activated caspase-3 and underwent apoptotic cell death, while cells overexpressing WT-HNF-1 alpha remained viable.