Promyelocytic leukaemia zinc finger (PLZF) is a transcriptional repressor that was originally isolated from a patient with promyelocytic leukaemia. PLZF also affects key elements for cell cycle progression, such as cyclin A, and can affect the tumourigenicity of various cancers. Thus far, the behaviour of PLZF in thyroid carcinoma remains unclear.
We analysed the expression profile of PLZF in different types of benign and malignant thyroid lesions as well as in normal thyroid tissue. Specifically, we examined PLZF expression in normal thyroid (N; n = 4), adenomatous lesion (AL; n = 5), follicular adenoma (FA; n = 2), papillary thyroid carcinoma (PTC; n = 20), and anaplastic thyroid carcinoma (ATC; n = 3) samples. PLZF expression was estimated by western blotting and immunohistochemical (IHC) staining.
PLZF was expressed in all samples of thyroid lesions examined. In N, AL, and FA, PLZF was mainly localized in the nucleus. In contrast, in PTC and ATC, PLZF was mainly expressed in the cytosol with high intensity. In more detail, the cytoplasmic IHC scores in PTC with capsular invasion (CI) and lymph node (LN) metastasis were higher than those in PTC without CI and LN metastasis.
PLZF shows different subcellular localizations among PTC, ATC, and other thyroid lesions. Furthermore, high cytoplasmic expression of PLZF may be correlated with CI and LN metastasis in thyroid carcinoma. The present report is the first to describe the implications of intracellular PLZF expression in thyroid carcinomas.
PLZF; Localization; Thyroid carcinoma; Tumourigenesis; Lymph node metastasis
Cushing’s syndrome results from exposure to excess glucocorticoids. Ectopic Cushings is endogenous ACTH dependant form of Cushing’s associated with markedly raised ACTH and cortisol levels. This leads to an impaired immune response, setting the stage for occurrence of opportunistic infections. Nocardiosis is a gram positive bacterial infection caused by aerobic actinomycetes in genus Nocardia. We report a series of patients diagnosed with ectopic Cushings, having pneumonia with Nocardia spp. In one of these cases, the manifestations of Cushing’s disappeared with treatment for Nocardia.
Two middle aged men of Asian descent presented to the Endocrine clinic: the first with history of exertional shortness of breath, and weight loss for 1 year, the other with facial swelling, disturbed sleep and lethargy for a month. The third case was a young Asian male who presented with progressive weakness & weight loss for 2 months. All three patients had uncontrolled hypertension, high blood sugars & were hypokalemic (K: 2.52, 2.9, 1.5 mmol/l); 24 hour urine cortisol was elevated at 2000, 27216 and 9088 (32-243 ug/24 hours); ACTH 68.5, 159, 255 [0–48 pg/ml), respectively. Their MRI pituitary was normal, inferior petrosal sinus sampling revealed no central peripheral gradient. CT chest of these subjects demonstrated cavitatory lung lesions; microscopic analysis of respiratory samples was suggestive of infection with Nocardia spp. Histopathology of bronchoscopic-guided biopsy revealed no malignancy. Antihypertensives, insulin, potassium replacement, ketoconazole & trimethoprim-sulphamethoxazole (TS) were initiated. The patients’ symptomatology improved & cavitatory lesions resolved with treatment. The primary source for the ectopic cushings remained unknown. The first case required bilateral adrenalectomy. The second case followed a progressively downhill course leading to death. In the third case, we were able to completely taper off ketoconazole, potassium, insulin & antihypertensives, after starting TS.
Opportunistic infections are known to be associated with Cushing’s syndrome, and higher levels of glucocorticoid secretion are found in patients with ectopically produced ACTH. Pulmonary nocardiosis is important differential to consider. This series includes the first case reported in which signs and symptoms of cushings subsided after treatment of Nocardia.
ACTH Adrenocorticotrophin Hormone; TS trimethoprim-sulphamethoxazole; IPSS inferior petrosal sinus sampling
Hypoglycemic episodes are infrequent in individuals without a history of diabetes mellitus or bariatric surgery. When hypoglycemia does occur in such individuals, an uncommon but important diagnosis to consider is non-islet cell tumor hypoglycemia (NICTH). We report a case of NICTH associated with paraneoplastic insulin-like growth factor-2 (IGF-2) production and review current relevant medical literature.
A 60 year old male with no relevant past medical history was referred to the endocrinology clinic with 18 month history of episodic hypoglycemic symptoms and, on one occasion was noted to have a fingerstick glucose of 36 mg/dL while having symptoms of hypoglycemia. Basic laboratory evaluation was unrevealing. Further evaluation however showed an elevated serum IGF-2 level at 2215 ng/mL (reference range 411–1248 ng/mL). Imaging demonstrated a large right suprarenal mass. A right nephrectomy with resection of the mass demonstrated a malignant solitary fibrous tumor. Post resection, the patient’s IGF-2 levels normalized and hypoglycemic symptoms resolved.
Due to the structural and biochemical homology between IGF-2 and insulin, elevated levels of IGF-2 can result in hypoglycemia. A posttranslational precursor to IGF-2 known as “big IGF” also possesses biologic activity. Review of recent reported cases of NICTH identified widespread anatomic locations and varied pathologic diagnoses of tumors associated with paraneoplastic production of IGF-2 causing hypoglycemia. Definitive management of hypoglycemia associated with paraneoplastic production of IGF-2 consists of resection of the tumor responsible for IGF-2 production. Accumulating literature provides a firm basis for routine IGF-2 laboratory evaluation in patients presenting with spontaneous hypoglycemia with no readily apparent cause.
Non islet cell tumor hypoglycemia (NICTH); Insulin like Growth Factor–2 (IGF-2); Big IGF-2; Hypoglycemia; Paraneoplastic production; Insulinoma; Solitary fibrous tumor
Obesity and diabetes mellitus are well-defined risk factors for cardiovascular mortality. The impact of antecedent hyperglycemia and body size on mortality in critical ill patients in intensive care units (ICUs) may vary across their range of values. Therefore, we prospectively analyzed the relationship between in-hospital mortality and preexisting hyperglycemia and body size in critically ill ICU patients to understand how mortality varied among normal, overweight, and obese patients and those with low, intermediate, and high glycated hemoglobin (HbA1c) levels.
Medical history, weight, height, physiologic variables, and HbA1c were obtained during the first 24 h for patients who were consecutively admitted to the high complexity ICU of Hospital de Clínicas de Porto Alegre, Brazil, from April to August 2011. The relationships between mortality and obesity and antecedent hyperglycemia were prospectively analyzed by cubic spline analysis and a Cox proportional hazards model.
The study comprised 199 patients. The overall hospital mortality rate was 43.2% during a median 16 (8–28) days of follow-up. There was a progressive risk of in-hospital mortality with higher HbA1c levels, with the relationship becoming significant at HbA1c >9.3% compared with lower levels (hazard ratio 1.74; 95% confidence interval with Bonferroni correction 1.49–2.80). In contrast, mean body mass index (BMI) was higher in survivors than in nonsurvivors (27.2 kg/m2 ± 7.3 vs. 24.7 kg/m2 ± 5.0 P = 0.031, respectively). Cubic spline analysis showed that these relationships differed nonlinearly through the spectrum of BMI values. In a Cox proportional hazards model adjusted for Acute Physiology and Chronic Health Evaluation II score and HbA1c, the risk of in-hospital mortality progressively decreased with increasing BMI (BMI <20 vs. 20–23.9 kg/m2, P = 0.032; BMI <20 vs. 24–34.9 kg/m2, P = 0.010; BMI <20 vs. ≥35 kg/m2, P = 0.032).
Our findings suggest that significant hyperglycemia prior to ICU admission is a risk factor for in-hospital mortality. Conversely, increasing BMI may confer an advantageous effect against mortality in critical illness independently of previous glycemic control.
Diabetes mellitus; Glycated hemoglobin; Obesity; Intensive care unit; Mortality
Obesity and gestational diabetes (GDM) in pregnancy are recognized risk factors for adverse outcomes, including cesarean section (CS), macrosomia and preeclampsia. The aim of this study was to investigate the independent effect of GDM and obesity on the adverse pregnancy outcomes at term.
A retrospective cohort of postpartum women, in King Khalid University Hospital, were stratified according to body mass index (obese ≥30 kg/m2, non-obese <30 kg/m2) and the results of GDM screening into the following groups, women with no obesity and no GDM (reference group), women with no obesity but with GDM, women with obesity but no GDM and women with both GDM and obesity. Adverse pregnancy outcomes included high birth weight, macrosomia, CS delivery and preeclampsia. Multiple logistic regression used to examine independent associations of GDM and obesity with macrosomia and CS.
2701 women were included, 44% of them were obese and 15% had GDM. 63% of the women with GDM were obese. There was significant increase in the percentage of macrosomia, P < 0.001, high birth weight, P < 0.001, CS, P < 0.001 and preeclampsia, P < 0.001 in women with GDM and obesity compared to the reference group. Obesity increased the estimated risk of CS delivery, odds ratio (OR) 2.16, confidence intervals (CI) 1.74-2.67. The combination of GDM and obesity increased the risk of macrosomia OR 3.45, CI 2.05-5.81 and the risk of CS delivery OR 2.26, CI 1.65-3.11.
Maternal obesity and GDM were independently associated with adverse pregnancy outcomes. The combination of both conditions further increase the risk.
Gestational diabetes; Maternal obesity; Cesarean section; Macrosomia
Mexican Americans are at an increased risk of both thyroid dysfunction and metabolic syndrome (MS). Thus it is conceivable that some components of the MS may be associated with the risk of thyroid dysfunction in these individuals. Our objective was to investigate and replicate the potential association of MS traits with thyroid dysfunction in Mexican Americans.
We conducted association testing for 18 MS traits in two large studies on Mexican Americans – the San Antonio Family Heart Study (SAFHS) and the National Health and Nutrition Examination Survey (NHANES) 2007–10. A total of 907 participants from 42 families in SAFHS and 1633 unrelated participants from NHANES 2007–10 were included in this study. The outcome measures were prevalence of clinical and subclinical hypothyroidism and thyroid function index (TFI) – a measure of thyroid function. For the SAFHS, we used polygenic regression analyses with multiple covariates to test associations in setting of family studies. For the NHANES 2007–10, we corrected for the survey design variables as needed for association analyses in survey data. In both datasets, we corrected for age, sex and their linear and quadratic interactions.
TFI was an accurate indicator of clinical thyroid status (area under the receiver-operating-characteristic curve to detect clinical hypothyroidism, 0.98) in both SAFHS and NHANES 2007–10. Of the 18 MS traits, waist circumference (WC) showed the most consistent association with TFI in both studies independently of age, sex and body mass index (BMI). In the SAFHS and NHANES 2007–10 datasets, each standard deviation increase in WC was associated with 0.13 (p < 0.001) and 0.11 (p < 0.001) unit increase in the TFI, respectively. In a series of polygenic and linear regression models, central obesity (defined as WC ≥ 102 cm in men and ≥88 cm in women) was associated with clinical and subclinical hypothyroidism independent of age, sex, BMI and type 2 diabetes in both datasets. Estimated prevalence of hypothyroidism was consistently high in those with central obesity, especially below 45y of age.
WC independently associates with increased risk of thyroid dysfunction. Use of WC to identify Mexican American subjects at high risk of thyroid dysfunction should be investigated in future studies.
Waist circumference; Central obesity; Thyroid dysfunction; Mexican Americans
11 patients were referred to our Molecular Genetics Department at the Royal Devon and Exeter Hospital between 2000-2012 with a physician’s diagnosis of remitting diabetes. Our aim was to identify patients with remitting diabetes whose clinical presentation is not explained by any known aetiology of diabetes.
We obtained longitudinal clinical data on all 11 patients from the hospital records. All patients were aged between 0.5 and 35 years at diagnosis. We applied clinical criteria derived from the literature to establish 1) definite diabetes, 2) diabetes initially severe-requiring treatment with insulin, 3) remission of diabetes, and 4) exclusion of known causes of remitting diabetes.
10 out of 11 patients had an alternative explanation for their remission or a clear diagnosis was not identified. We identified a single patient with idiopathic remitting diabetes using these criteria. The patient was a white Caucasian female diagnosed aged 15 with symptoms of diabetes, laboratory glucose of 21.2 mmol/L and HbA1c 134 mmol/mol. Her BMI was 23.6 kg/m2. She was treated with basal bolus insulin but discontinued two years after diagnosis due to hypoglycaemia. 13 years post diagnosis, she had a normal oral glucose tolerance test during pregnancy (fasting glucose 4.5 mmol/L, 2 hr glucose 4.8 mmol/L) and an HbA1c of 30 mmol/mol. This patient does not appear to have Type 1 or Type 2 diabetes, and furthermore does not fit into current classifications of diabetes.
Idiopathic remitting diabetes is rare but does exist. Strict clinical criteria are important to ensure patients have a robust clinical diagnosis. Identification of more patients with idiopathic remitting diabetes will enable further study of the clinical course of this syndrome. Applying these strict criteria will allow the identification of patients with remitting diabetes to assess its aetiology.
Diabetes; Remission; Criteria; Diagnosis; Remitting diabetes
Quantifying the burden of diabetes mellitus is fundamental for managing patients in health service delivery systems and improves the understanding of the importance of prevention and early intervention of diabetes. In Switzerland, epidemiological data on diabetes are very scarce. In this study we provide a first national overview of the current situation of diabetes mellitus in Switzerland as well as the development of the prevalence, incidence, mortality and costs between 2006 and 2011.
Using health care claims data of a large health insurance group, current epidemiology and costs were determined from a sample of adult enrollees in 2011. The identification of patients with diabetes was based on prescription data of diabetes related drugs using the Anatomical Therapeutic Chemical Classification as proxy for clinical diagnosis. We further evaluated changes in epidemiology and costs between 2006 and 2011. All results were weighted with census data to achieve an extrapolation to the Swiss general population level.
A total of 920’402 patients were enrolled in 2011 and 49’757 (5.4%) were identified as diabetes cases. The extrapolated overall prevalence of diabetes in Switzerland was 4.9% (2006, 3.9%). The incidence was 0.58% in 2011 (2007, 0.63%). The extrapolated mortality rate was 2.6% with no significant change over time. Annual diabetes costs to the mandatory health insurance increased from EUR 5,036 per patient in 2006 to EUR 5’331 per patient in 2011.
This study shows a high medical and economic burden of diabetes. The prevalence and costs of diabetes in Switzerland increased substantially over time. Findings stress the need for public health strategies to manage patients with chronic conditions and optimize resource allocation in health service delivery systems.
Diabetes; Prevalence; Incidence; Mortality; Costs
Testicular morphology and immunohistochemical studies have never been reported in genetically documented adult patients with 5 alpha-reductase type 2 deficiency (5α-R2 deficiency).
We describe the testicular histopathology of a 17-year-old XY subject with 5α-R2 deficiency caused by the recurrent homozygous Gly115Asp loss of function mutation of the SRD5A2 gene.We also performed an immunohistochemical analysis in order to further study the relationship between seminiferous tubules structure, Sertoli cell differentiation and androgenic signaling impairment in this case. We thus evaluated the testicular expression of the anti-Müllerian hormone (AMH), androgen receptor (AR) and 3β-hydroxysteroid dehydrogenase (3βHSD). Histological analysis revealed a heterogeneous aspect with a majority (92%) of seminiferous tubules (ST) presenting a mature aspect but containing only Sertoli cells and devoid of germ cells and spermatogenesis. Focal areas of immature ST (8%) were also found. Testicular AR and 3βHSD expression were detected in adult male control, 5α-R2 deficiency and CAIS subjects. However, AMH expression was heterogeneous (detectable only in few AR negative prepubertal ST, but otherwise repressed) in the 5α-R2 deficiency, conversely to normal adult testis in which AMH was uniformly repressed and to an adult CAIS testis in which AMH was uniformly and strongly expressed.
Intratesticular testosterone can repress AMH by itself, independently of its metabolism into dihydrotestosterone. We also compare our results to the few post pubertal cases of 5α-R2 deficiency with available histological testicular description, reported in the literature. We will discuss these histological findings, in the more general context of evaluating the fertility potential of these patients if they were raised as males and were azoospermic.
5α-reductase type 2 deficiency; Testicular histology; Sertoli cell; Anti-Müllerian hormone; Androgen receptor
Previously considered as a disease of the affluent, west or urban people and not of public health importance, diabetes mellitus is increasingly becoming a significant cause of morbidity and mortality in sub-Saharan Africa. However, population-based data to inform prevention, treatment and control are lacking.
Using the WHO STEPwise approach to chronic disease risk factor surveillance, a population-based, nationwide cross-sectional survey was conducted between July and September 2009 on participants aged 25–64 years. A multi-stage cluster sample design and weighting were used to produce a national representative data for that age range. Detailed findings on the magnitude of diabetes mellitus and impaired fasting blood glucose are presented in this paper.
Fasting blood glucose measurement was conducted on 3056 participants (70.2% females, 87.9% from rural areas). The age- sex standardised population-based mean fasting blood glucose was 4.3 mmol/L (95% CI 4.1-4.4 mmol/L) with no significant differences by age, sex and location (urban/rural). The overall prevalence of impaired fasting blood glucose was 4.2% (95% CI 3.0%-5.4%). Prevalence of impaired blood glucose was higher in men than in women, 5.7% (95% CI 3.9%-7.5%) vs 2.7% (95% CI 1.6%- 3.8%), p < 0.01. In both men and women, prevalence of raised fasting blood glucose or currently on medication for diabetes was 5.6% (95% CI 2.6%- 8.5%). Although the prevalence of diabetes was higher in men than women, 6.5% (95% CI 2.6%-10.3%) vs 4.7% (95% CI 2.4%-7.0%), in rural than urban, 5.4% (95% CI 2.4%-8.4%) vs 4.4% (95% CI 2.8%-5.9%) and in males in rural than males in urban, 6.9% (95% CI 2.8%-11.0%) vs 3.2% (95% CI 0.1%-6.3%), the differences were not statistically significant, p > 0.05. Compared to previous estimates, prevalence of diabetes increased from <1.0% in 1960s to 5.6% in 2009 (this study).
High prevalence of impaired fasting blood glucose and diabetes mellitus call for the implementation of primary healthcare approaches such as the WHO package for essential non-communicable diseases to promote healthy lifestyles, early detection, treatment and control.
Diabetes; Non-communicable diseases; Sub-Saharan Africa; Malawi
Although chronic adrenocorticotropic hormone (ACTH) and androgen hyperstimulation are assumed to be involved in the pathogenesis of adrenal myelolipomas associated with poor-compliance patients with congenital adrenal hyperplasia (CAH), the expression of their receptors has not yet been demonstrated in these tumors so far.
We analyzed Melanocortin 2 receptor (MC2R), Androgen Receptor (AR), Leptin (LEP), and Steroidogenic factor 1 (SF1) expression using real-time qRT-PCR in two giant bilateral adrenal myelolipomas from two untreated simple virilizing CAH cases and in two sporadic adrenal myelolipomas. In addition, the X-chromosome inactivation pattern and CAG repeat numbers in AR exon 1 gene were evaluated in the 4 cases.
The MC2R gene was overexpressed in myelolipomas from 3 out of 4 patients. AR overexpression was detected in 2 tumors: a giant bilateral myelolipoma in a CAH patient and a sporadic case. Simultaneous overexpression of AR and MC2R genes was found in two of the cases. Interestingly, the bilateral giant myelolipoma associated with CAH that had high androgen and ACTH levels but lacked MC2R and AR overexpression presented a significantly shorter AR allele compared with other tumors. In addition, X-chromosome inactivation pattern analysis showed a polyclonal origin in all tumors, suggesting a stimulatory effect as the trigger for tumor development.
These findings are the first evidence for MC2R or AR overexpression in giant bilateral myelolipomas from poor-compliance CAH patients.
Adrenal myelolipoma; Congenital adrenal hyperplasia; ACTH; MC2R; Androgen receptor; Clonality analysis
Few studies have examined young adults with type 1 diabetes use of health services and the development of vascular complications. As part of the Youth Outreach for Diabetes (YOuR-Diabetes) project, this study identified health service usage, the prevalence and factors predictive of development of vascular complications (hypertension, retinopathy and nephropathy) in a cohort of young adults (aged 16–30 years) with type 1 diabetes in Hunter New England and the Lower Mid-North Coast area of New South Wales, Australia.
A cross-sectional retrospective documentation survey was undertaken of case notes of young adults with type 1 diabetes accessing Hunter New England Local Health District public health services in 2010 and 2011, identified through ambulatory care clinic records, hospital attendances and other clinical records. Details of service usage, complications screening and evidence of vascular complications were extracted. Independent predictors were modelled using linear and logistic regression analyses.
A cohort of 707 patients were reviewed; mean (SD) age was 23.0 (3.7) years, with mean diabetes duration of 10.2 (5.8, range 0.2 - 28.3) years; 42.4% lived/ 23.1% accessed services in non-metropolitan areas.
Routine preventative service usage was low and unplanned contacts high; both deteriorated with increasing age. Low levels of complications screening were found. Where documented, hypertension, particularly, was common, affecting 48.4% across the study period. Diabetes duration was a strong predictor of vascular complications along with glycaemic control; hypertension was linked with renal dysfunction.
Findings indicate a need to better understand young people’s drivers and achievements when accessing services, and how services can be reconfigured or delivered differently to better meet their needs and achieve better outcomes. Regular screening is required using current best practice guidelines as this affords the greatest chance for early complication detection, treatment initiation and secondary prevention.
‘Service usage’; Health services; ‘Vascular complications’; ‘Prevalence’; ‘Prediction’; ‘Retinopathy’; ‘Nephropathy’; ‘Hypertension’; ‘Blood pressure’; ‘Young adults’; ‘Type 1 diabetes’
Increased morbidity and mortality associated with conventional glucocorticoid replacement therapy for primary adrenal insufficiency (primary AI; estimated prevalence 93–140/million), secondary AI (estimated prevalence, 150–280/million, respectively) or congenital adrenal hyperplasia (estimated prevalence, approximately 65/million) may be due to the inability of typical glucocorticoid treatment regimens to reproduce the normal circadian profile of plasma cortisol. A once-daily modified-release formulation of hydrocortisone has been developed to provide a plasma cortisol profile that better mimics the daytime endogenous profile of cortisol. Here, we describe the protocol for the European Adrenal Insufficiency Registry (EU-AIR), an observational study to assess the long-term safety of modified-release hydrocortisone compared with conventional glucocorticoid replacement therapies in routine clinical practice (ClinicalTrials.gov identifier: NCT01661387).
Patients enrolled in EU-AIR have primary or secondary AI and are receiving either modified-release or conventional glucocorticoid replacement therapy. The primary endpoints of EU-AIR are the incidence of intercurrent illness, adrenal crisis and serious adverse events (SAEs), as well as the duration of SAEs and dose changes related to SAEs. Data relating to morbidity, mortality, adverse drug reactions, dosing and concomitant therapies will be collected. Patient diaries will record illness-related dose changes between visits. All decisions concerning medical care are made by the registry physician and patient. Enrolment is targeted at achieving 3600 patient-years of treatment (1800 patient-years per group) for the primary analysis, which is focused on determining the non-inferiority of once-daily modified-release replacement therapy compared with conventional glucocorticoid therapy.
Recruitment began in August 2012 and, as of March 2014, 801 patients have been enrolled. Fifteen centres are participating in Germany, the UK and Sweden, with recruitment soon to be initiated in the Netherlands.
EU-AIR will provide a unique opportunity not only to collect long-term safety data on a modified-release preparation of glucocorticoid but also to evaluate baseline data on conventional glucocorticoid replacement. Such data should help to improve the treatment of AI.
Central precocious puberty (CPP) and phenylketonuria (PKU) are two rare conditions, the latter being the rarer. To date, only one case featuring both these conditions has been reported, and hyperphenylalaninemia was assumed triggering CPP.
We present a 3.2 years old girl referred with a 12 months history of breast and pubic hair development, and vaginal discharge. Hyperphenylalaninemia had been identified by newborn screening and PKU subsequently confirmed by plasma amino acid and genetic analysis. Early dietary control of plasma phenylalanine had been excellent afterwards, resulting in phenylalanine concentrations consistently within the recommended range. Clinical scenario, hormonal assessment and imaging were in keeping with true idiopathic central precocious puberty. Treatment with long lasting gonadotropin-releasing hormone analogue led to regression of secondary sexual characteristics.
We describe for the first time CPP in a girl affected with PKU but with persistently well controlled blood phenylalanine concentrations. This finding is in contrast to a previous report which suggested persistently high phenylalaninemia levels as potential trigger for CPP in PKU patients. Our report, together with the lack of evidence in published cohort studies of children with PKU, strongly suggests this rare association is coincidental and independent of the presence of severe hyperphenylalaninemia.
Precocious puberty; Phenylketonuria; Hyperphenylalaninaemia; Gonadotropin-realising hormone agonist treatment
Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). The efficacy and safety of canagliflozin were evaluated in patients with T2DM <65 and ≥65 years of age.
Pooled data from 4 randomised, placebo-controlled, 26-week, Phase 3 studies (N = 2,313) evaluating canagliflozin 100 and 300 mg were analysed by age: <65 years (n = 1,868; mean age, 52.8 years) or ≥65 years (n = 445; mean age, 69.3 years). Efficacy evaluations included change from baseline in glycaemic parameters and systolic blood pressure (BP), and percent change from baseline in body weight. Assessment of safety/tolerability included adverse event (AE) reports, incidence of documented hypoglycaemia, and percent change from baseline in fasting plasma lipids.
Canagliflozin 100 and 300 mg reduced HbA1c and fasting plasma glucose relative to placebo in patients <65 and ≥65 years of age. Both canagliflozin doses reduced body weight and systolic BP relative to placebo in patients <65 and ≥65 years of age. Incidence of overall AEs was similar across all treatment groups in patients <65 and ≥65 years of age. Incidences of serious AEs and AE-related discontinuations were similar across all treatment groups in patients <65 years of age and higher with canagliflozin 100 mg than other groups in patients ≥65 years of age. As in patients <65 years of age, incidences of genital mycotic infections and osmotic diuresis-related AEs were higher with canagliflozin relative to placebo in those ≥65 years of age. Incidences of urinary tract infections (UTIs), renal-related AEs, AEs related to volume depletion, and documented hypoglycaemia episodes were similar across all treatment groups in patients ≥65 years of age; no notable trends were observed with canagliflozin 100 and 300 mg relative to placebo in these AEs among patients <65 years of age. Changes in lipid parameters with canagliflozin were similar in both age subsets.
Canagliflozin improved glycaemic control, body weight, and systolic BP, and was generally well tolerated in older patients with T2DM.
ClinicalTrials.gov, NCT01081834; NCT01106677; NCT01106625; NCT01106690.
Canagliflozin; Type 2 diabetes mellitus; Sodium glucose co-transporter 2 (SGLT2) inhibitor; Antihyperglycaemic agent; Older patients
Hypoglycemia secondary to ectopic insulin secretion of non-pancreatic tumors is rare.
We describe a middle aged woman with recurrent hypoglycemia. On evaluation, she was detected to have hyperinsulinemic hypoglycemia and right sided renal mass lesion. 68Ga-Dotanoc and 99mTc-HYNICTOC scans confirmed the intrarenal mass to be of neuroendocrine origin. Right nephrectomy was done and it turned out to be an insulin secreting neuroendocrine tumour. Neuroendocrine nature of this tumour was further confirmed by ultra-structural examination. Her hypoglycemia did not recur after resection of this tumour.
Few cases of ectopic insulin secretion have been reported though some are not proven convincingly. This case addresses all the issues raised in previous case reports and proves by clinical, laboratory, functional imaging and immunohistochemical analysis that ectopic origin of insulin by non-pancreatic tumors does occur. To our knowledge, this is the first reported case of ectopic insulinoma arising from the kidney.
Hyperinsulinemic hypoglycemia; Neuroendocrine tumour; Insulinoma; Carcinoid tumor; Renal tumour; 68Ga-Dotanoc scan; 99mTc-HYNICTOC scan
Insulin aspart (IAsp) and its biphasic preparations BIAsp50 and BIAsp70 (containing 50% and 70% IAsp, respectively) have distinct glucose-lowering properties as compared to human insulin (HI). We investigated whether this affected the circulating IGF-system which depends on the hepatic insulin exposure.
In a randomized, four-period crossover study, 19 patients with type 1 diabetes received identical doses (0.2 U/kg sc) of IAsp, BIAsp70, BIAsp50 and HI together with a standardized meal. Serum total IGF-I and IGFBP-1 to -3 were measured by immunoassays for nine hours post-prandially. Bioactive IGF was determined by an in-house, cell-based IGF-I receptor kinase activation (KIRA) assay.
Despite marked differences in peripheral insulin concentrations and plasma glucose, the four insulin preparations resulted in parallel decreases in IGFBP-1 levels during the first 3 hours, and parallel increases during the last part of the study (3–9 hours). Thus, only minor significances were seen. Insulin aspart and human insulin resulted in a lower area under the curve (AUC) during the first 3 hours as compared to BIAsp70 (p = 0.009), and overall, human insulin resulted in a lower IGFBP-1 AUC than BIAsp70 (p = 0.025). Nevertheless, responses and AUCs of bioactive IGF were similar for all four insulin preparations. Changes in levels of bioactive IGF were inversely correlated to those of IGFBP-1, increasing during the first 3 hours, whereafter levels declined (-0.83 ≤ r ≤ -0.30; all p-values <0.05).
Total IGF-I and IGFBP-3 remained stable during the 9 hours, whereas IGFBP-2 changed opposite of IGFBP-1, increasing after 3–4 hours whereafter levels gradually declined. The four insulin preparations resulted in similar profiles and AUCs of total IGF-I, IGFBP-2 and IGFBP-3.
Despite distinct glucose-lowering properties, the tested insulin preparations had similar effects on IGF-I concentration and IGF bioactivity, IGFBP-2 and IGFBP-3 as compared to HI; only small differences in IGFBP-1 were seen and they did not affect bioactive IGF. Thus, insulin aspart containing preparation behaves as HI in regards to the circulating IGF-system. However, bioactive IGF appeared to be more sensitive to insulin exposure than total IGF-I. The physiological significance of this finding remains to be determined.
Insulin; Insulin analogue; IGF; IGFBP
Osmotic demyelination syndrome (ODS) may be observed as a result of a rapid change in serum osmolarity, such as that induced by an overly rapid correction of serum sodium levels in hyponatraemic patients.
We describe the case of a 21-year-old woman who was hospitalized at week 10 of gestation because of severe hyperemesis. At admission the patient appeared restless and confused and severe hyponatraemia (serum sodium 107 mmol/L) and hypokalemia (serum potassium 1.1 mmol/L) were detected. Active and simultaneous correction of these imbalances led to an overly rapid increase of serum sodium levels (17 mmol/L in the first 24 hours). Isotonic saline solution was stopped and replaced by 5% dextrose solution infusion. However, the neurological alterations worsened and the radiological features were consistent with the diagnosis of extra-pontine ODS. Steroids were administered intravenously with progressive improvement of biochemical and clinical abnormalities. At the time of discharge, 20 days later, the patient was able to walk and eat autonomously with only minimal external support.
This report illustrates an unusual case of ODS, occurred after an excessive rate of correction of hyponatraemia obtained with isotonic saline infusion. Hypokaliemia and its active correction very likely played a crucial role in facilitating the onset of ODS. This interesting aspect will be explained in detail in the article. A more cautious and thoughtful correction of electrolyte alterations, would have probably prevented the onset of ODS in this patient. Physicians should be aware of the possibly fatal consequences that an exceedingly rapid change of serum osmolarity may have and should strictly follow the known safety measures in order to prevent it to occur.
Osmotic demyelination syndrome; Hyponatraemia; Pregnancy
Increased risk of osteoporosis and its clinical significance in patients with diabetes is controversial. We analyze osteoporosis prevalence and determinants of bone mineral density (BMD) in patients with type 1 and 2 diabetes.
Three hundred and ninety-eight consecutive diabetic patients from a single outpatient clinic received a standardized questionnaire on osteoporosis risk factors, and were evaluated for diabetes-related complications, HbA1c levels, and lumbar spine (LS) and femoral neck (FN) BMD. Of these, 139 (71 men, 68 women) type 1 and 243 (115 men, 128 women) type 2 diabetes patients were included in the study. BMD (T-scores and values adjusted for age, BMI and duration of disease) was compared between patient groups and between patients with type 2 diabetes and population-based controls (255 men, 249 women).
For both genders, adjusted BMD was not different between the type 1 and type 2 diabetes groups but was higher in the type 2 group compared with controls (p < 0.0001). Osteoporosis prevalence (BMD T-score < −2.5 SD) at FN and LS was equivalent in the type 1 and type 2 diabetes groups, but lower in type 2 patients compared with controls (FN: 13.0% vs 21.2%, LS: 6.1% vs 14.9% men; FN: 21.9% vs 32.1%, LS: 9.4% vs 26.9% women). Osteoporosis prevalence was higher at FN-BMD than at LS-BMD. BMD was positively correlated with BMI and negatively correlated with age, but not correlated with diabetes-specific parameters (therapy, HbBA1c, micro- and macrovascular complications) in all subgroups. Fragility fracture prevalence was low (5.2%) and not different between diabetes groups. Fracture patients had lower BMDs compared with those without fractures; however, BMD T-score was above −2.5 SD in most patients.
Diabetes-specific parameters did not predict BMD. Fracture occurrence was similar in both diabetes groups and related to lower BMD, but seems unrelated to the threshold T-score, <−2.5 SD. These results suggest that osteoporosis, and related fractures, is a clinically significant and commonly underestimated problem in diabetes patients.
Bone mineral density; Diabetes mellitus; Fractures; Osteoporosis; Vascular complications
Seminomas have been rarely associated with malignant hypercalcemia. The responsible mechanism of hypercalcemia in this setting has been described to be secondary to 1,25-dihydroxyvitamin D secretion. The relationship with PTHrP has not been determined or studied.
The aim of this study is to describe and discuss the case and the pathophysiological mechanisms involved in a malignant hypercalcemia mediated by 1,25-dihydroxyvitamin D and PTHrP cosecretion in a patient with seminoma.
A 35-year-old man was consulted for assessment and management of severe hypercalcemia related to an abdominal mass. Nausea, polyuria, polydipsia, lethargy and confusion led him to the emergency department. An abdominal and pelvic enhanced CT confirmed a calcified pelvic mass, along with multiple retroperitoneal lymphadenopathy. Chest x-ray revealed “cannon ball” pulmonary metastases. The histopathology result was consistent with a seminoma. Serum calcium was 14.7 mg/dl, PTH was undetectable, 25-dihydroxyvitamin D was within normal values and PTHrP and 1,25-dihydroxyvitamin were elevated (35.0 pg/ml, and 212 pg/ml, respectively). After the first cycle of chemotherapy with bleomycin, etoposide and cisplatin, normocalcemia was restored. Both PTHrP and 1,25-dihydroxyvitamin D, dropped dramatically to 9.0 pg/ml and 8.0 pg/ml, respectively.
The association of seminoma and malignant hypercalcemia is extremely rare. We describe a case of a patient with a seminoma and malignant hypercalcemia related to paraneoplastic cosecretion of 1,25-dihydroxyvitamin D and PTHrP. After successful chemotherapy, calcium, PTHrP and 1,25-Dihydroxyvitamin D returned to normal values.
1,25-dihydroxyvitamin D; Calcitriol; PTHrP; Malignant hypercalcemia; Seminoma
Diabetes education and self-care remains the cornerstone of diabetes management. There are many structured diabetes modules available in the United Kingdom, Europe and United States of America. Contrastingly, few structured and validated diabetes modules are available in Malaysia. This pilot study aims to develop and validate diabetes education material suitable and tailored for a multicultural society like Malaysia.
The theoretical framework of this module was founded from the Health Belief Model (HBM). The participants were assessed using 6-item pre- and post-test questionnaires that measured some of the known HBM constructs namely cues to action, perceived severity and perceived benefit. Data was analysed using PASW Statistics 18.0.
The pre- and post-test questionnaires were administered to 88 participants (31 males). In general, there was a significant increase in the total score in post-test (97.34 ± 6.13%) compared to pre-test (92.80 ± 12.83%) (p < 0.05) and a significant increase in excellent score (>85%) at post-test (84.1%) compared to pre-test (70.5%) (p < 0.05). There was an improvement in post-test score in 4 of 6 items tested. The remaining 2 items which measured the perceived severity and cues to action had poorer post-test score.
The preliminary results from this pilot study suggest contextualised content material embedded within MY DEMO maybe suitable for integration with the existing diabetes education programmes. This was the first known validated diabetes education programme available in the Malay language.
Self-efficacy; Validation; Education; Module; Knowledge; Health-belief model
Continuous intraperitoneal insulin infusion (CIPII) with an implantable pump is a treatment option for patients with type 1 diabetes mellitus (T1DM). Aim of the present study was to describe the long-term course of glycaemic control, complications, health related quality of life (HRQOL) and treatment satisfaction among T1DM patients treated with CIPII.
Nineteen patients that participated in a randomized cross-over trial comparing CIPII and subcutaneous (SC) therapy in 2006 were followed until 2012. Laboratory, continuous glucose monitoring, HRQOL and treatment satisfaction measurements were performed at the start of the study, the end of the SC-, the end of the CIPII treatment phase in 2006 and during CIPII therapy in 2012. Linear mixed models were used to calculate estimated values and to test differences between the moments in time.
In 2012, more time was spent in hyperglycaemia than after the CIPII treatment phase in 2006: 37% (95% CI 29, 44) vs. 55% (95% CI 48, 63), mean difference 19.8% (95% CI 3.0, 36.6). HbA1c was 65 mmol/mol (95% CI 60, 71) at the end of the SC treatment phase in 2006, 58 mmol/mol (95% CI 53, 64) at the end of the CIPII treatment phase and 65 mmol/mol (95% CI 60, 71) in 2012, respectively (p > 0.05). In 2012, the median number of grade 2 hypoglycaemic events per week (1 (95% CI 0, 2)) was still significantly lower than during prior SC therapy (3 (95% CI 2, 4)): mean change -1.8 (95% CI -3.4, -0.4). Treatment satisfaction with CIPII was better than with SC insulin therapy and HRQOL remained stable. Pump or catheter dysfunction of the necessitated re-operation in 7 patients. No mortality was reported.
After 6 years of CIPII treatment, glycaemic regulation is stable and the number of hypoglycaemic events decreased compared to SC insulin therapy. Treatment satisfaction with CIPII is superior to SC insulin therapy, HRQOL is stable and complications are scarce. CIPII is a safe and effective treatment option for selected patients with T1DM, also on longer term.
Type 1 diabetes mellitus; Intraperitoneal insulin; Insulin infusion devices; Quality of life; Treatment satisfaction; Complications; Subcutaneous insulin
Aldosterone synthase (CYP11B2) deficiency is a rare autosomal recessive disorder, usually presenting with severe salt-wasting in infancy or stress-induced hyperkalaemia and postural hypotension in adulthood. Neonatal screening for congenital adrenal hyperplasia, another cause of salt wasting, using 17-hydroxyprogesterone measurement would fail to detect aldosterone synthase deficiency, a diagnosis which may be missed until the patient presents with salt-wasting crisis. Due to this potential life-threatening risk, comprehensive hormonal investigation followed by genetic confirmation for suspected patients would facilitate clinical management of the patient and assessment of the genetic implication in their offspring.
We describe a 33-year old Chinese man who presented in infancy with life-threatening hyponatraemia and failure to thrive, but remained asymptomatic on fludrocortisone since. Chromosomal analysis confirmed a normal male karyotype of 46, XY. Plasma steroid profile showed high plasma renin activity, low aldosterone level, and elevated 18-hydroxycorticosterone, compatible with type 2 aldosterone synthase deficiency. The patient was heterozygous for a novel CYP11B2 mutation: c.977C > A (p.Thr326Lys) in exon 3. He also carried a heterozygous mutation c.523_525delAAG (p.Lys175del) in exon 6, a known pathogenic mutation causing aldosterone synthase deficiency. Sequencing of CYP11B2 in his parents demonstrated that the mother was heterozygous for c.977C > A, and the father was heterozygous for c.523_525delAAG.
Although a rare cause of hyperreninaemic hypoaldosteronism, aldosterone synthase deficiency should be suspected and the diagnosis sought in patients who present with life-threatening salt-wasting in infancy, as it has a good long-term prognosis when adequate fludrocortisone replacement is instituted. To our knowledge, this is the first Chinese patient in which the molecular basis of aldosterone synthase deficiency has been identified.
Aldosterone synthase deficiency; Salt-wasting; Hypoaldosteronism
Some of the patients with idiopathic hypoparathyroidism (IHP) report symptoms of hypocalcemia during menstruation. There is limited data on this observation.
Twenty six menstruating women with IHP and 26 healthy controls were questioned regarding symptoms suggestive of hypocalcemia during menstruation. Twelve patients and eight controls were asked to prospectively monitor symptoms suggestive of hypocalcemia and premenstrual syndrome (PMS) if any, over two consecutive menstrual cycles. Serum ionized calcium (SiCa++), total and albumin adjusted calcium and intact paratharmone (iPTH) were measured at eight points covering menstrual, immediate post-menstrual, mid-cycle and premenstrual phase.
Twelve of the 26 (46.2%) patients with IHP reported hypocalcemic symptoms during menstruation as compared to none of the controls. During prospective monitoring, there was no specific trend of hypocalcemic symptoms with respect to the phase of menstrual cycle. The mean SiCa++, serum total and albumin-adjusted calcium, iPTH and inorganic-phosphorus measured over two menstrual cycles were not significantly different in either of the two study groups. None of the subjects had PMS.
Women with IHP do not show any trend of hypocalcemic symptoms or fluctuations in serum calcium over different phases of menstrual cycles. Therefore, patients with hypoparathyroidism linking hypocalcemic symptoms with menstruation should be reassured regarding lack of this association.
Hypoparathyroidism; Hypocalcemic symptoms; Ionized calcium; Menstruation
The effects of brain natriuretic peptide (BNP) on the risk of cardiovascular disease and atherosclerosis have been studied. However, little information is available regarding peripheral arterial disease (PAD), particularly among subjects with type-2 diabetes mellitus (T2DM). The aim of our study was to assess the potential relationship between BNP levels and PAD among T2DM patients.
The study cohort was 507 T2DM outpatients in which BNP levels were measured. Cross-sectional associations between BNP levels (in tertiles) and PAD were examined.
Compared withT2DM patients without PAD, BNP levels were markedly higher in patients with PAD (p = 0.001). Correlation analyses showed that the BNP level was negatively correlated with the ankle–brachial index (r = −0.453, p = 0.033). At a cutoff value of 78.2 pg/ml, the BNP level showed a sensitivity of 71.9%, a specificity of 68.1%, and a positive predictive value of 84.3% for a diagnosis of PAD. The area under the receiver-operating characteristic curve increased significantly if BNP levels were incorporated into a predictive model of the potential risk factors for PAD (0.85 vs 0.81, p = 0.029).
BNP is a potential and promising biomarker for PAD screening in T2DM patients.
Brain natriuretic peptide; Peripheral arterial disease; Type-2 diabetes mellitus