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1.  Transient hypercortisolism and symptomatic hyperthyroidism associated to primary hyperparathyroidism in an elderly patient: case report and literature review 
Background
Primary hyperparathyroidism (PHPT) is often found on routine blood tests, at a relatively asymptomatic stage. However many studies suggest different systemic effects related to PHPT, which could be enhanced by an abnormal cortisol release due to chronic stress of hyperparathyroidism. Being PHPT frequently found in the 6th to 7th decade of life, a careful and multifaceted approach should be taken.
Case presentation
We report the case of an elderly patient with symptomatic PHPT and incidental pulmonary embolism. He was treated with hydration, zoledronic acid, cinacalcet and high-dose unfractionated heparin. Parathyroid surgery was successfully performed, but patient’s conditions suddenly worsened because of a transient thyrotoxicosis, probably induced by a previous exposure to iodine load and/or thyroid surgical manipulation. A short-term treatment with beta-blockers was introduced for symptomatic relief. The patient also presented a transient hypercortisolism with elevated ACTH, likely due to stress related not only to aging and hospitalization but also to PHPT, resolved only four months after parathyroid surgery.
Conclusion
Chronic hyperparathyroidism has been linked with increased all-cause mortality. A functional chronic hypercortisolism could be established, enhancing PHPT related disorders. Only parathyroid surgery has been demonstrated to cure PHPT and complications related, showing similar outcome between older and younger patients. However, the management of post-operative period should be more careful in fragile patients. In particular, the early diagnosis and treatment of a transient post-operative thyrotoxicosis could improve recovery. Due to the increase in prevalence and the evidence of many related complications even in asymptomatic PHPT, expert opinion-based guidelines for surgical treatment of PHPT should be developed especially for elderly patients.
doi:10.1186/1472-6823-15-4
PMCID: PMC4417273  PMID: 25631825
Primary hyperparathyroidism; Elderly; Transient hyperthyroidism; Iodinated-contrast induced thyrotoxicosis; Functional hypercortisolism
2.  Muscle ring finger-3 protects against diabetic cardiomyopathy induced by a high fat diet 
Background
The pathogenesis of diabetic cardiomyopathy (DCM) involves the enhanced activation of peroxisome proliferator activating receptor (PPAR) transcription factors, including the most prominent isoform in the heart, PPARα. In cancer cells and adipocytes, post-translational modification of PPARs have been identified, including ligand-dependent degradation of PPARs by specific ubiquitin ligases. However, the regulation of PPARs in cardiomyocytes and heart have not previously been identified. We recently identified that muscle ring finger-1 (MuRF1) and MuRF2 differentially inhibit PPAR activities by mono-ubiquitination, leading to the hypothesis that MuRF3 may regulate PPAR activity in vivo to regulate DCM.
Methods
MuRF3−/− mice were challenged with 26 weeks 60 % high fat diet to induce insulin resistance and DCM. Conscious echocardiography, blood glucose, tissue triglyceride, glycogen levels, immunoblot analysis of intracellular signaling, heart and skeletal muscle morphometrics, and PPARα, PPARβ, and PPARγ1 activities were assayed.
Results
MuRF3−/− mice exhibited a premature systolic heart failure by 6 weeks high fat diet (vs. 12 weeks in MuRF3+/+). MuRF3−/− mice weighed significantly less than sibling-matched wildtype mice after 26 weeks HFD. These differences may be largely due to resistance to fat accumulation, as MRI analysis revealed MuRF3−/− mice had significantly less fat mass, but not lean body mass. In vitro ubiquitination assays identified MuRF3 mono-ubiquitinated PPARα and PPARγ1, but not PPARβ.
Conclusions
These findings suggest that MuRF3 helps stabilize cardiac PPARα and PPARγ1 in vivo to support resistance to the development of DCM.
MuRF3 also plays an unexpected role in regulating fat storage despite being found only in striated muscle.
Electronic supplementary material
The online version of this article (doi:10.1186/s12902-015-0028-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12902-015-0028-z
PMCID: PMC4515942  PMID: 26215257
MuRF3; Diabetic cardiomyopathy; Post-translational modification; Multi-ubiquitin; PPAR; Ubiquitin ligase
3.  Low concentrations of serum testosterone predict acute myocardial infarction in men with type 2 diabetes mellitus 
Background
The aim of the present study was to investigate the associations between endogenous testosterone concentrations and the incidence of acute myocardial infarction (AMI) in men and women with and without type 2 diabetes.
Methods
The study comprised 1109 subjects ≥40 years of age (mean age 62 ± 12 years) participating in a baseline survey in Sweden in 1993–94. Information about smoking habits and physical activity was obtained using validated questionnaires. Serum concentrations of testosterone and sex hormone-binding globulin (SHBG) were obtained using radioimmunoassay. Diagnosis of type 2 diabetes was based on WHO’s 1985 criteria. Individual patient information on incident AMI was ascertained by record linkage with national inpatient and mortality registers from baseline through 2011.
Results
The prevalence of type 2 diabetes at baseline was 10.0 % in men and 7.5 % in women. During a mean follow-up of 14.1 years (±5.3), there were 74 events of AMI in men and 58 in women. In age-adjusted Cox models, a significant inverse association between concentrations of testosterone and AMI-morbidity was found in men with type 2 diabetes (HR = 0.86 CI (0.75–0.98)). In a final model also including waist-to-hip ratio, systolic blood pressure, total cholesterol and active smoking, the association still remained statistically significant (HR = 0.754 CI (0.61–0.92)).
Conclusion
Low concentrations of testosterone predicted AMI in men with type 2 diabetes independent of other risk factors. Trials with testosterone investigating the effect regarding cardiovascular outcome are still lacking. Future trials in this field should take into account a modification effect of diabetes.
doi:10.1186/s12902-015-0034-1
PMCID: PMC4514972  PMID: 26209521
4.  Two-year assessment of the efficacy and safety of sitagliptin in elderly patients with type 2 diabetes: Post hoc analysis of the ASSET-K study 
Background
There have only been a few reports about use of dipeptidyl peptidase 4 (DPP-4) inhibitors in elderly patients with type 2 diabetes mellitus (T2DM), suggesting that the safety of these agents has not been sufficiently demonstrated. We performed a comparative review of the efficacy and safety of sitagliptin for Japanese patients with T2DM managed in the real-world clinical setting.
Methods
An age-stratified analysis was performed of 831 patients who were treated with sitagliptin for 2 years. Parameters assessed included the hemoglobin A1c (HbA1c), body weight, serum creatinine, and adverse events. HbA1c and the incidence of hypoglycemia were also evaluated in patients treated with sitagliptin and a sulfonylurea (SU), who were divided into three age groups (<65 years, 65–74 years, and ≥75 years).
Results
Comparison of glycemic control parameters, laboratory values, and adverse events revealed significant improvement of HbA1c, casual postprandial plasma glucose, and fasting plasma glucose in each age group with no change in body weight. Serum creatinine increased significantly in all age groups. Hypoglycemia only occurred in patients who received combined treatment with an SU and sitagliptin, and there was no age-related difference in its incidence.
Conclusions
HbA1c was improved by 2 years of sitagliptin therapy in all three age groups, and age did not seem to influence the incidence of hypoglycemic events. These results confirm the efficacy and safety of sitagliptin in patients ≥ 75 years old, suggesting that it is also useful for treating elderly patients with T2DM.
doi:10.1186/s12902-015-0033-2
PMCID: PMC4490678  PMID: 26137940
Type 2 diabetes; Sitagliptin; Elderly patients; Dipeptidyl peptidase 4 inhibitor; Sulfonylurea; Hypoglycemia
5.  The relationship between microvascular complications and vitamin D deficiency in type 2 diabetes mellitus 
Background
Vitamin D deficiency is reported as a possible risk factor for the development of diabetes in several epidemiologic studies. In this study, we investigated the frequency of 25-OH vitamin D deficiency in type 2 diabetes mellitus and the relationship between 25-OH vitamin D deficiency and the prevalence of microvascular complications.
Methods
In this retrospective study, we evaluated the medical records of 557 patients with type 2 diabetes admitted to the Endocrinology Outpatient Clinic from January to March 2010 and 112 healthy controls randomly selected from individuals admitted to the hospital for a check-up and who had a laboratory result for serum 25-OH vitamin D concentrations at screening. The levels of 25-OH vitamin D in patients with type 2 diabetes and the relationship between 25-OH vitamin D deficiency and microvascular complications were investigated.
Results
No significant difference in serum 25-OH vitamin D concentrations was observed between the diabetic and control groups. No correlation was observed between HbA1C and serum 25-OH vitamin D levels. Serum 25-OH vitamin D levels were lower in diabetic patients with nephropathy, and patients not using any medication, i.e., those treated with dietary changes alone, had a higher prevalence of nephropathy.
Conclusion
Vitamin D deficiency is more common in diabetic patients with nephropathy. When microvascular complications were evaluated, vitamin D levels were found to be lower in patients in whom these complications were more severe. Vitamin D deficiency is therefore associated with microvascular complications in diabetic patients.
doi:10.1186/s12902-015-0029-y
PMCID: PMC4480442  PMID: 26109389
Type 2 diabetes mellitus; 25-hydroxyvitamin D; Microvascular complications
6.  Improvement of blood inflammatory marker levels in patients with hypothyroidism under levothyroxine treatment 
Background
There are several specific inflammatory and oxidative correlates among patients with hypothyroidism, but most studies are cross-sectional and do not evaluate the change in parameters during the treatment. The aim of this study was to investigate the effect of levothyroxine replacement therapy on biomarkers of oxidative stress (OS) and systemic inflammation in patients with hypothyroidism.
Methods
In this prospective open-label study, 17 patients with recently diagnosed primary hypothyroidism due to Hashimoto’s thyroiditis who were not taking levothyroxine were included. The following parameters were measured before and at 6 and 12 months of levothyroxine treatment with an average dose of 1.5 to 1.7 μg/kg/day: thyroid-stimulating hormone (TSH), free thyroxine (FT4), high-sensitivity C-reactive protein (hs-CRP), interleukin 1 (IL-1), IL-6, IL-10, interferon gamma (INF-γ), tumor necrosis factor alpha (TNF-α), thiobarbituric acid-reactive substances (TBARS), activity of aminolevulinic acid dehydratase (δ-ALA-D), nonprotein and total thiol (NP-SH and T-SH) groups, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). Generalized estimating equation (GEE) modeling was used to analyze the effects of LRT (at pre-treatment, 6 months and 12 months) on those variables. The hypothyroidism status (i.e., overt or subclinical hypothyroidism) was included as a confounder in all analyses. An additional GEE post hoc analysis was made to compare time points.
Results
There was a significant decrease in TSH over time (P < 0.0001), (initial levels were on average 32.4 μIU/mL and 10.5 μIU/mL at 12 months). There was a significant increase in FT4 (P < 0.0001) (initial levels were on average 0,8 ng/dL and 2.7 ng/dL at 12 months). There were significant changes in interleukin levels over time, with a significant increase in IL-10 (P < 0.0001) and significant decreases in IL-1 (P < 0.0001), IL-6 (P < 0.0001), INF-γ (P < 0.0001) and TNF-α (P < 0.0001). No significant difference in hs-CRP over time was observed (P < 0.284). There was a significant reduction in NP-SH (P < 0.0001).
Conclusions
This study observed significant changes in the inflammatory profile in hypothyroid patients under treatment, with reduction of pro-inflammatory cytokines and elevation of anti-inflammatory cytokine. In these patients, a decrease in low-grade chronic inflammation may have clinical relevance due to the known connection between chronic inflammation, atherosclerosis and cardiovascular events.
doi:10.1186/s12902-015-0032-3
PMCID: PMC4476077  PMID: 26100072
Inflammation; Oxidative stress; Overt hypothyroidism; Subclinical hypothyroidism; Hashimoto’s thyroiditis; Levothyroxine; Atherosclerosis
7.  Serum macroprolactin levels in pregnancy and association with thyroid autoimmunity 
Bacground
To assess the contribution of macroprolactin to high serum prolactin levels and their association with thyroid status and thyroid autoimmunity during pregnancy.
Methods
138 pregnant women who suspected of having thyroid dysfunction were studied and divided into three groups according to the thyroid status; group 1; euthyroidism (n 40), group 2; hypothyroidism (n 54), and group 3; hyperthyroid (n 44). Polyethylene glycol (PEG) precipitation method was used for detection of macroprolactin. A percentage recovery of 40 % or less is considered as macroprolactinemia. If macroprolactin was negative, the percentage of monomeric prolactin recovery (monoPRL %) after PEG precipitation was used for comparison between the groups.
Results
Macroprolactinemia was found in two patients (1.4 %) one from hypothyroid and other from euthyroid group. Basal prolactin levels in these patients were 400 and 403 ng/mL respectively. Referring to all patients, there was no correlation between PRL, macroPRL or monoPRL % with thyroid hormone status and also with the serum levels of thyroid antibodies (p > 0.05). A positive correlation was observed between the serum levels of PRL with TSH (p = 0.014 and r = 0.219), while a negative correlation was found with FT4 (p = 0.011 and r = −0.227).
Conclusions
Despite the fact that serum prolactin levels were found to be high during pregnancy, the contribution of macroprolactin was found to be insignificant in our study. Unlike other auto immune diseases, we could not find any relationship between thyroid autoimmunity and PRL, macroPRL or monoPRL %. These results confirmed that measured prolactin was quite homogeneous during pregnancy.
doi:10.1186/s12902-015-0025-2
PMCID: PMC4475296  PMID: 26091810
Pregnancy; Prolactin; Macroprolactin; Thyroid dysfunction; Thyroid autoimmunity
8.  A rare case of juvenile hypertension: coexistence of type 2 multiple endocrine neoplasia -related bilateral pheochromocytoma and reninoma in a young patient with ACE gene polymorphism 
Background
Pheochromocytoma and reninoma represent two rare diseases causing hypertension. We here reported a rare case of association between type 2 multiple endocrine neoplasia related bilateral pheochromocytoma and reninoma. Moreover, polymorphism of ACE gene, which is known to be related to an increase of cardiovascular risk, has been found in the same patient.
Case presentation
A 24 year old Caucasian man came to our attention for severe hypertension, resistant to anti-hypertensive polytherapy. At the age of twenty he had undergone total thyroidectomy with lymphadenectomy for medullary carcinoma. Genetic testing showed a RET mutation of codon 918 (exon 16) not documented in other family members. During the follow-up, a progressive increase of urinary metanephrines and catecholamines was recorded. Our evaluation confirmed the presence of severe hypertension (220/140 mmHg) and a severe increase of urinary catecholamines and metanephrines. Due to the presence of hypokalemia, other causes of hypertension were researched leading to the discovery of hyperreninemia (236 μUI/ml) with mild hyperaldosteronism, and a mild increase of the renal artery resistance at ultrasound. An abdominal MRI showed multiple adrenal masses and a right kidney nodular lesion of about 2 cm.
The patient underwent bilateral adrenalectomy and right nephrectomy, and histology confirmed the presence of bilateral pheochromocytoma and right reninoma. The post-surgery laboratory evaluation showed a rapid reduction of the urinary metanephrines while plasma renin level remained low in spite of the bilateral adrenalectomy without any mineralocorticoid supplementation. To further investigate these unusual feature, we performed genetic testing for the ACE gene, which revealed the presence of ACE I/D polymorphism.
Conclusion
This unique report describes the association between two rare causes of hypertension in the same patient. Furthermore, the absence of requirement of mineralocorticoid supplementation in spite of bilateral adrenalectomy, represent an uncommon and interest finding.
doi:10.1186/s12902-015-0022-5
PMCID: PMC4472263  PMID: 26084817
Pheochromocytoma; Reninoma; MEN2B; ACE polymorphism; Hypertension
9.  Poor sleep quality is associated with increased arterial stiffness in Japanese patients with type 2 diabetes mellitus 
Background
While poor sleep quality can worsen cardiovascular risk factors such as glucose and lipid profiles in patients with type 2 diabetes mellitus (T2DM), the relationship between sleep quality and atherosclerosis remains largely unknown. The aim of this study was to examine this relationship.
Methods
The study participants comprised 724 Japanese T2DM outpatients free of history of cardiovascular diseases. The relationships between sleep quality (assessed by the Pittsburgh Sleep Quality Index (PSQI)) and various clinical and laboratory parameters were investigated.
Results
The mean PSQI was 5.1 ± 3.0 (±SD). Patients were divided into three groups based on the total PSQI score; subjects with good sleep quality (n = 462), average sleep quality (n = 185), and poor sleep quality (n = 77). In the age/gender-adjusted model, patients with poor sleep quality tended to be obese, evening type and depressed. However, other lifestyles showed no significant trends. Alanine aminotransferase, fasting blood glucose, HbA1c, systolic blood pressure, urinary albumin excretion, and brachial-ankle pulse wave velocity (baPWV) tended to be higher in patients with poor sleep quality. High baPWV was the only parameter that correlated with poor sleep in a model adjusted for several other lifestyle factors.
Conclusions
Our study indicates that poor sleep quality in T2DM patients correlates with increased arterial wall stiffness, a marker of atherosclerosis and a risk factor for cardiovascular diseases.
doi:10.1186/s12902-015-0026-1
PMCID: PMC4472398  PMID: 26084960
Sleep quality; Arterial stiffness; Type 2 diabetes mellitus; Japanese
10.  Paediatric cyclical Cushing’s disease due to corticotroph cell hyperplasia 
Background
Cushing’s disease is very rare in the paediatric population. Although uncommon, corticotroph hyperplasia causing Cushing’s syndrome has been described in the adult population, but appears to be extremely rare in children. Likewise, cyclical cortisol hypersecretion, while accounting for 15 % of adult cases of Cushing’s disease, has only rarely been described in the paediatric population. Here, we describe a very rare case of a 13-year old boy with cyclical cortisol hypersecretion secondary to corticotroph cell hyperplasia.
Case presentation
The case is that of a 13-year old boy, presenting with a long history of symptoms and signs suggestive of hypercortisolism, who was found to have cyclical ACTH-dependent hypercortisolism following dynamic pituitary testing and serial late-night salivary cortisol measurements. The patient underwent endoscopic transsphenoidal resection of the pituitary. Early surgical remission was confirmed by undetectable post-operative morning plasma cortisol levels. Histology and immunocytochemistry of the resected pituitary tissue showed extensive corticotroph cell hyperplasia.
Conclusion
This report describes a rare case of cyclical Cushing’s disease secondary to corticotroph hyperplasia in a paediatric patient. This highlights the challenging and varied nature of Cushing’s disease and its diagnosis, and the need to keep a differential diagnosis in mind during the diagnostic process.
doi:10.1186/s12902-015-0024-3
PMCID: PMC4464624  PMID: 26063496
Corticotroph hyperplasia; Cyclical hypercortisolism; Paediatric Cushing’s
11.  Charcot osteoarthropathy in type 2 diabetes persons presenting to specialist diabetes clinic at a tertiary care hospital 
Background
Charcot osteoarthropathy or charcot foot is a rare, chronic, non-communicable condition of bones and joints which may results into severe deformity and more prone to develop ulcers possibly leading to amputation. The purpose of this study was to determine the prevalence of Charcot osteoarthropathy and its association with age, BMI, gender, duration of diabetes, HBA1c and peripheral neuropathy.
Methods
A total of 1931 subjects with type 2 diabetes having mean age 50.72 ± 10.66 years presenting in a specialist diabetes clinic at shalamar hospital, Lahore, Pakistan were enrolled. The diagnosis of Charcot osteoarthropathy was made by examination of both dorsal and plantar surfaces of foot for swelling, erythema, increase in temperature and any musculoskeletal deformity which was later confirmed by radiographs. Assessment of neuropathy was carried out by checking the sense of pressure, joint position and vibration. BMI (Body Mass Index), fasting blood glucose (FBG) and HbA1C were determined.
Results
In all subjects including male 704 (36.45 %) and female 1227 (63.55 %), 0.4 % subjects had charcot deformity, while 0.2 %, 0.15 % and 0.05 % subjects having right, left and bilateral deformity respectively. Bilaterally symmetrical neuropathy was diagnosed in 25.4 % in subjects. There was a significant association (p < 0.05) of deformity with duration of diabetes, HbA1C and neuropathy, however no significant association (p > 0.05) was found with age, BMI, weight, height and gender.
Conclusion
There is a need to have a special care of persons with diabetes regarding blood glucose control and development of peripheral neuropathy. Early identification and management of risk factors may prevent the occurrence of charcot deformity. Patients must be educated about the foot care.
doi:10.1186/s12902-015-0023-4
PMCID: PMC4465003  PMID: 26065885
Charcot foot; Diabetes; Deformity; Neuropathy; Foot care
12.  Baseline of visceral fat area and decreased body weight correlate with improved pulmonary function after Roux-en-Y Gastric Bypass in Chinese obese patients with BMI 28–35 kg/m2 and Type 2 diabetes: a 6-month follow-up 
Background
Associations between demographic data and pulmonary function have not been adequately examined in patients that underwent Roux-en-Y Gastric Bypass (RYGB). This study was designed to examine changes in body fat distribution and metabolic parameters after RYGB and whether these changes correlated with improved lung function.
Methods
A retrospective review of 32 ethnic Chinese with obesity with body mass index (BMI) 28–35 kg/m2 and type 2 diabetes (T2DM) was conducted, focusing on metabolic outcomes and pulmonary function 6 months after RYGB.
Results
Forced expiratory volume during first second (FEV1), percentage of forced expiratory volume during first second (FEV1 [%pred]), forced vital capacity (FVC), and percentage of forced vital capacity (FVC [%pred]) all improved significantly after RYGB. These increases all were negatively correlated with decreases in body weight and visceral fat area (VFA). The improvements of FEV1, FEV1 [%pred] and FVC were also negatively correlated with baseline of body weight and VFA. Furthermore, increases in FEV1 and FVC were independently associated with baseline of VFA (β = −0.003, P = 0.000; β = −0.004, P = 0.002, respectively).
Conclusions
The baseline of VFA and weight loss induced by RYGB independently correlated with improved pulmonary function in Chinese patients.
doi:10.1186/s12902-015-0027-0
PMCID: PMC4460885  PMID: 26054757
Body weight; Obesity; Abdominal; Visceral fat; Diabetes; Type 2; Pulmonary function test
13.  Diabetes related health knowledge, attitude and practice among diabetic patients in Nepal 
Background
Globally, diabetes is the top priority chronic disease. Health literary would be cost effective for prevention and control of diabetes and its consequences. This study was conducted to determine the level of diabetes related health knowledge, attitude and practice (KAP) among diabetic patient and factors associated with KAP.
Methods
An institutional based cross-sectional study was conducted using a non-probability sampling technique to select the diabetic patients. A total of 244 diabetic patients were interviewed from July to November 2014. Data was collected by face to face interview using structured interviewer rater questionnaires. Relative risk ratio (RRR) and 95 % confidence interval (CI) of associated factors were estimated by a stepwise likelihood ratio method with multinomial logistic regression.
Results
More than half (52.5 %) of all patients were female, 18 % were illiterate, and 24.6 % were from rural residence. The diabetes related risk factors were common among diabetic patients; 9.8 % smoker, 16 % alcohol drinking, and 17.6 % reported low or no physical activity. Median score for knowledge, attitude, and practice were 81, 40 and 14 respectively. Among all patients, 12.3 %, 12.7 % and 16 % had highly satisfactory knowledge, attitude and practice respectively. Using highly insufficient knowledge as the baseline, the likelihood of having a level of highly sufficient knowledge was 17 times higher among patients who have graduated and above level of education compared to those who were illiterate. Albeit this value was comparatively lower than insufficient level of knowledge. The probability of having a sufficient level of practice among diabetic patient with a history of smoking was 0.10 times lower than in patient with no history of smoking.
Conclusions
Our study reveals a variation between diabetes related health knowledge, attitude and practice in Nepal among those who are affected by diabetes. Our results show the potential diabetes health literacy needs to be improved or developed for better health promotion.
doi:10.1186/s12902-015-0021-6
PMCID: PMC4456997  PMID: 26045031
Diabetes; Knowledge; Attitude; Practice; Nepal
14.  Effects of hypoxia inducible factor-1α on apoptotic inhibition and glucocorticoid receptor downregulation by dexamethasone in AtT-20 cells 
Background
Hypoxia inducible factor-1α (HIF-1α) is the central transcriptional regulator of hypoxic responses during the progression of pituitary adenomas. Although previous immunohistochemical studies revealed that HIF-1α is expressed in adreno-cortico-tropic-hormone (ACTH) pituitary adenomas, the role of HIF-1α remains unclear.
Methods
AtT-20 cells were incubated under hypoxic conditions (1 % O2) for 12 h. HIF-1α mRNA and protein expression levels were measured by real-time PCR and western blotting, respectively. BrdU was used to determine the effects of hypoxia on cell viability. AtT-20 cells were transfected with siRNA targeting HIF-1α, followed by hypoxia (1 % O2) for 12 h. Apoptosis was determined by annexin V-FITC flow cytometry and Tdt-mediated dUTP nick end-labelling (TUNEL) assay. In addition, we examined interactions between HIF-1α, glucocorticoid receptor (GR), and dexamethasone under both normoxic and hypoxic conditions.
Results
Hypoxia triggered the time-dependent proliferation of AtT-20 cells in association with increased HIF-1α mRNA and protein levels. However, the viability of AtT-20 cells decreased greatly when they were first transfected with HIF-1α-siRNA and then exposed to hypoxia. According to flow cytometry (annexin V-FITC and PI staining) and TUNEL analyses, a greater percentage of cells were apoptotic when transfected with HIF-1α siRNA and subsequently cultured under hypoxic conditions compared to those in the normoxia and mock groups. After AtT-20 cells were cultured in 1 % O2 and then treated with dexamethasone, HIF-1α levels significantly increased or decreased in normoxic or hypoxic conditions, respectively. Dexamethasone suppressed GR expression to a higher degree in hypoxic than normoxic conditions. Downregulation of GR by dexamethasone was greatly prevented in cells that were transfected with HIF-1α siRNA.
Conclusions
These findings strongly suggest that HIF-1α exerts an antiapoptotic role and participates in the downregulation of GR by dexamethasone in hypoxic AtT-20 cells.
doi:10.1186/s12902-015-0017-2
PMCID: PMC4464719  PMID: 26002039
Hypoxia inducible factor–1α; Glucocorticoid receptor; Apoptosis; Dexamethasone; ACTH pituitary adenomas
15.  Achievement of individualized treatment targets in patients with comorbid type-2 diabetes and hypertension: 6 months results of the DIALOGUE registry 
Background
Patients with type-2 diabetes mellitus (T2DM) and hypertension have increased risk of cardiovascular disease (CVD). We studied individualized treatment targets and their achievement in clinical practice.
Methods
DIALOGUE is a prospective, multi-center registry in patients with both T2DM and hypertension.
Results
Patients (n = 6,586) had a baseline fasting glucose (8.5 ± 2.8 mmol/l), postprandial glucose (10.9 ± 3.4 mmol/l), and HbA1c (7.8 ± 2.1%) levels indicated poor glycemic control. Baseline systolic and diastolic BP were 140.3 ± 15.7 and 82.6 ± 9.5, respectively. Patients were categorized by HbA1c treatment goals: ≤6.5% (strict), >6.5 to ≤7.0% (medium), and >7.0 to ≤7.5% (loose). When considering systolic BP (SBP) targets (≤130 mmHg [strict], >130 to ≤135 mmHg [medium], and >135 to ≤140 mmHg [loose]), patients with strict SBP treatment goals displayed similar characteristics to those with strict HbA1c targets. Although approximately 70% of patients received both strict HbA1c and SBP targeting, overall treatment goals remained unmet in all HbA1c target groups at the 6-month follow-up. SBP targets were not reached in the strict and medium groups, but were achieved in the loose treatment group. Specific predictors for choosing loose SBP or HbA1c treatment goals were identified, including SBP/HbA1c levels and various comorbidities.
Conclusions
Individualized glucose and BP targets were selected by treating physicians based on patient characteristics and overall comorbidity. While treatment goals were not consistently met using various antidiabetic and antihypertensive therapies, our analyses indicated that the strictly targeted patient populations maintained lower overall HbA1c and SBP levels at 6 months.
doi:10.1186/s12902-015-0020-7
PMCID: PMC4426603  PMID: 25934177
16.  Q-Score: development of a new metric for continuous glucose monitoring that enables stratification of antihyperglycaemic therapies 
Background
Continuous glucose monitoring (CGM) has revolutionised diabetes management. CGM enables complete visualisation of the glucose profile, and the uncovering of metabolic ‘weak points’. A standardised procedure to evaluate the complex data acquired by CGM, and to create patient-tailored recommendations has not yet been developed. We aimed to develop a new patient-tailored approach for the routine clinical evaluation of CGM profiles. We developed a metric allowing screening for profiles that require therapeutic action and a method to identify the individual CGM parameters with improvement potential.
Methods
Fifteen parameters frequently used to assess CGM profiles were calculated for 1,562 historic CGM profiles from subjects with type 1 or type 2 diabetes. Factor analysis and varimax rotation was performed to identify factors that accounted for the quality of the profiles.
Results
We identified five primary factors that determined CGM profiles (central tendency, hyperglycaemia, hypoglycaemia, intra- and inter-daily variations). One parameter from each factor was selected for constructing the formula for the screening metric, (the ‘Q-Score’). To derive Q-Score classifications, three diabetes specialists independently categorised 766 CGM profiles into groups of ‘very good’, ‘good’, ‘satisfactory’, ‘fair’, and ‘poor’ metabolic control. The Q-Score was then calculated for all profiles, and limits were defined based on the categorised groups (<4.0, very good; 4.0–5.9, good; 6.0–8.4, satisfactory; 8.5–11.9, fair; and ≥12.0, poor). Q-Scores increased significantly (P <0.01) with increasing antihyperglycaemic therapy complexity. Accordingly, the percentage of fair and poor profiles was higher in insulin-treated compared with diet-treated subjects (58.4% vs. 9.3%). In total, 90% of profiles categorised as fair or poor had at least three parameters that could potentially be optimised. The improvement potential of those parameters can be categorised as ‘low’, ‘moderate’ and ‘high’.
Conclusions
The Q-Score is a new metric suitable to screen for CGM profiles that require therapeutic action. Moreover, because single components of the Q-Score formula respond to individual weak points in glycaemic control, parameters with improvement potential can be identified and used as targets for optimising patient-tailored therapies.
Electronic supplementary material
The online version of this article (doi:10.1186/s12902-015-0019-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12902-015-0019-0
PMCID: PMC4447008  PMID: 25929322
Diabetes mellitus; Continuous glucose monitoring; Patient-tailored therapy; Individualised diabetes management; Metric; Glycemic control
17.  Clinical characteristics and beta cell function in Chinese patients with newly diagnosed type 2 diabetes mellitus with different levels of serum triglyceride 
Background
To explore clinical characteristics and beta cell function in Chinese patients with newly diagnosed drug naive type 2 diabetes mellitus (T2DM) with different levels of serum triglyceride (TG).
Methods
Patients with newly diagnosed T2DM (n = 624) were enrolled and divided into different groups according to levels of serum TG. All patients underwent oral glucose tolerance tests and insulin releasing tests. Demographic data, lipid profiles, glucose levels, and insulin profiles were compared between different groups. Basic insulin secretion function index (homeostasis model assessment for beta cell function index, HOMA-β), modified beta cell function index (MBCI), glucose disposition indices (DI), and early insulin secretion function index (insulinogenic index, IGI) were used to evaluate the beta cell function.
Results
Patients of newly diagnosed T2DM with hypertriglyceridemia were younger, fatter and had worse lipid profiles, glucose profiles, and high insulin levels than those with normal TG. There is no difference in early phase insulin secretion among groups of newly diagnosed T2DM patients with different TG levels. The basal beta cell function (HOMA-β and MBCI) initially increased along rising TG levels and then decreased as the TG levels rose further. The insulin sensitivity was relatively high in patients with a low level of TG and low with a high level of TG.
Conclusions
Hypertriglyceridemia influences clinical characteristics and β cell function of Chinese patients with newly diagnosed T2DM. A better management of dyslipidemia may, to some extent, reduce the effect of lipotoxicity, thereby improving glucose homeostasis in patients with newly diagnosed T2DM.
Electronic supplementary material
The online version of this article (doi:10.1186/s12902-015-0018-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12902-015-0018-1
PMCID: PMC4423127  PMID: 25924608
Newly diagnosed type 2 diabetes; Beta cell function; Insulin resistance; Triglyceride
18.  Living with type 1 diabetes is challenging for Zambian adolescents: qualitative data on stress, coping with stress and quality of care and life 
Background
Psychosocial problems are common in patients with diabetes. However, data on psychosocial issues affecting patients with diabetes in Zambia are scarce. The present study explored sources of stress, stress coping strategies, stigma and perceived quality of life and care as experienced by adolescents living with Type 1 Diabetes in Zambia.
Methods
Semi-structured interviews were carried out. Three groups of participants involving adolescents with Type 1 Diabetes (n = 10), caregivers (n = 8) and health practitioners (n = 4) were interviewed. Transcripts were analyzed using a thematic approach.
Results
Stress was commonly reported by adolescents mainly stemming from social, psychological and physical sources. To deal with stress, adolescents often employed different coping strategies such as adapting, accepting and avoiding among others. Both internal factors (those relating to the patients themselves) and external factors (those related to the context of the patients’) influenced the patients’ quality of health care. In addition, low quality of life was an issue among adolescents and their families. Poor diet, low socioeconomic status and lack of medicine were factors affecting quality of health care.
Conclusion
Stress was an issue affecting adolescents; the coping strategies employed were sometimes maladaptive such as avoiding injecting themselves to escape stress. Several aspects of quality of life were suboptimal in both adolescents and their families, such as stigmatization, short life expectancy, low socioeconomic status and poor social participation. Findings show that there is an urgent need for a strong response from all stakeholders (governments, patients, organizations and companies) to improve diabetes care and living conditions for young people with type 1 diabetes living in Zambia.
doi:10.1186/s12902-015-0013-6
PMCID: PMC4411790  PMID: 25928592
Diabetes; Adolescents; Stress; Quality of life; Zambia
19.  The relationship between N-terminal prosomatostatin, all-cause and cardiovascular mortality in patients with type 2 diabetes mellitus (ZODIAC-35) 
Background
The hormone somatostatin inhibits growth hormone release from the pituitary gland and is theoretically linked to diabetes and diabetes related complications. This study aimed to investigate the relationship between levels of the stable somatostatin precursor, N-terminal prosomatostatin (NT-proSST), with mortality in type 2 diabetes (T2DM) patients.
Methods
In 1,326 T2DM outpatients, participating in this ZODIAC prospective cohort study, Cox proportional hazards models were used to investigate the independent relationship between plasma NT-proSST concentrations with all-cause and cardiovascular mortality.
Results
Median concentration of NT-proSST was 592 [IQR 450–783] pmol/L. During follow-up for 6 [3–10] years, 413 (31%) patients died, of which 176 deaths (43%) were attributable to cardiovascular causes. The age and sex adjusted hazard ratios (HRs) for all-cause and cardiovascular mortality were 1.48 (95%CI 1.14 - 1.93) and 2.21 (95%CI 1.49 - 3.28). However, after further adjustment for cardiovascular risk factors there was no independent association of log NT-proSST with mortality, which was almost entirely attributable to adjustment for serum creatinine. There were no significant differences in Harrell’s C statistics to predict mortality for the models with and without NT-proSST: both 0.79 (95%CI 0.77 – 0.82) and 0.81 (95%CI 0.77 – 0.84).
Conclusions
NT-proSST is unsuitable as a biomarker for cardiovascular and all-cause mortality in stable outpatients with T2DM.
doi:10.1186/s12902-015-0009-2
PMCID: PMC4404603  PMID: 25880900
Type 2 diabetes mellitus; Somatostatin; N-terminal prosomatostatin; Mortality
20.  Primary care physicians’ practice regarding diabetes mellitus diagnosis, evaluation and management in the West region of Cameroon 
Background
Primary care physicians (PCPs) are the main providers of diabetes care especially in resource-limited countries which experience extreme shortage of specialists. The present study aimed to evaluate PCPs’ approach towards diabetes mellitus (DM) diagnosis, evaluation and management in Cameroon.
Methods
We carried-out a cross-sectional survey in February 2012 in the West Region of Cameroon. Using a structured pretested questionnaire, we interviewed all PCPs working in the region who were present at their working place when the investigators visited, and volunteered to be enrolled in the study.
Results
Sixty-six PCPs were interviewed. Their ages ranged from 24 to 56 years (mean 38.3, standard deviation 9.2 years). The levels of knowledge of PCPs regarding DM diagnosis were: 72.7%, 37.9%, 19.7% and 32.8% respectively obtained when using fasting plasma glucose, post-prandial glycemia, random glycemia and glycated hemoglobin as diagnostic tools. Only 6 PCPs (9.9%) prescribed the correct minimal work-up to evaluate diabetes patients at diagnosis. PCPs advised lifestyle modifications in 92.4% of cases, and thirty nine (53.1%) PCP’s used to prescribe both generic and specialty oral anti-diabetic drugs in case of uncomplicated type 2 DM management. The two main classes of anti-diabetic drugs prescribed were biguanides (77.3%) and sulfonamides (60.6%). Nearly all PCPs (97%) used to give frequent follow-up appointments to their patients. Ninety eight point five percent of participants were willing to receive any further continuous training on DM management.
Conclusion
PCPs knowledge and practices towards diabetes mellitus diagnosis, evaluation and management were not optimal, stressing the need to improve their capacities regarding diabetes care. As such, more educational initiatives should be taken on, alongside regular upgrade and dissemination of clinical guidelines.
doi:10.1186/s12902-015-0016-3
PMCID: PMC4403824  PMID: 25881080
Primary care physicians; Diabetes mellitus; Sub-Saharan Africa; Cameroon
21.  Altered Platelets’ morphological parameters in children with type 1 diabetes – a case-control study 
Background
Platelet hyperreactivity is a factor which contributes towards increased risk of cardiovascular events in adults with type 2 diabetes (T2DM). However, little is known about platelets’ disturbances among children with type 1 diabetes (T1DM). The aim of the study was to investigate whether platelets’ morphology or function are altered in children with type 1 diabetes, potentially predisposing them to cardiovascular events in the future.
Methods
The study group consisted of 389 children with T1DM during the 2008–2010 period. Patients with acute diabetes complications and ongoing infections were excluded from the study. An equinumerous (N = 389), age and sex-matched control group was assembled from children undergoing routine, minor surgical procedures in the same hospital. Platelet: count (PLT), mean volume (MPV), distribution width (PDW) and platelet large cell ratio (P-LCR) as well as HbA1c levels were measured. For statistical analysis we used Chi-square tests, the student’s t-test, one-way analysis of variance (ANOVA), the Pearson’s correlation coefficient and linear regression models in order to adjust for covariates.
Results
MPV, PDW and P-LCR were significantly higher among children with diabetes in comparison with the control group (MPV 10.47+/−0.85 fL vs 10.23+/−0.94 fL, p = 0.0007; PDW 12.09+/−1.80% vs 11.66+/−1.90%, p = 0.0032; P-LCR 28.21+/−6.15% vs 26.29+/−6.38%, p < 0.0001). PLT however, were shown to be similar (263.55+/−60.04 vs 268.77+/−65.78 103/μl; p = 0.5637). In both cases and controls age was inversely correlated with platelet count (for study group: r = −0.30, p < 0.0001; for control group: r = −0.34, p < 0.0001), positively correlated with MPVs (r = 0.20, p < 0.0001; r = 0.26, p < 0.0001), PDW (r = 0.25, p < 0.0001 and r = 0.24, p < 0.0001) and P-LCR (r = 0.26, p < 0.0001; r = 0.26, p < 0.0001). After adjustment for confounding factors, higher platelet counts were associated with poorer metabolic control (beta = 0.20; 0.0001).
Conclusions
Platelets of paediatric patients with T1DM show morphological evidence of hyperreactivity (higher MPV, PDW and P-LCR), while poorer metabolic control increases their number potentially predisposing the patients to future cardiovascular events.
doi:10.1186/s12902-015-0011-8
PMCID: PMC4391729  PMID: 25886514
Platelets; Mean platelet volume; Type 1 diabetes; Children
22.  High prevalence of metabolic syndrome in a mestizo group of adult patients with primary hyperparathyroidism (PHPT) 
Background
Primary hyperparathyroidism (PHPT) and metabolic syndrome (MS) have been independently related to cardiovascular morbidities, however this association is still controversial. Mexican population has a high prevalence of metabolic syndrome, however its frequency seems to be even higher than expected in patients with PHPT.
Methods
We retrospectively reviewed the charts of patients that underwent parathyroidectomy for PHPT in a referral center and used the criteria from the National Cholesterol Educational Program (NCEP)/Adult Treatment Panel III (ATP III) to define MS before surgery. We compared the characteristics between the patients with and without MS.
Results
60 patients were analyzed, 77% were female and 72% had a single parathyroid adenoma. MS was present in 59% of the patients, this group was significantly older (57 vs. 48 years, p = 0.01) and they had lower iPTH (115 vs. 161 ng/ml, p = 0.017). Other parameters did not show differences.
Conclusions
MS is frequent in our population diagnosed with primary hyperparathyroidism, adverse cardiovascular parameters are common and significant differences in calcium metabolism compared to the non-MS group are present.
doi:10.1186/s12902-015-0014-5
PMCID: PMC4415358  PMID: 25886602
Primary hyperparathyroidism; Metabolic syndrome; Central obesity; Parathyroid hormone
23.  Low-dose combined oral contraceptive use is associated with lower bone mineral content variation in adolescents over a 1-year period 
Background
Low-dose combined oral contraceptives (COCs) can interfere with bone mass acquisition during adolescence. This study aimed to evaluate bone mineral density (BMD) and bone mineral content (BMC) in female adolescents taking a standard low-dose COC (ethinylestradiol 20 μg/desogestrel 150 μg) over a 1-year period and to compare their data with those of healthy adolescents from the same age group not taking COCs.
Methods
This was a non-randomized parallel-control study with a 1-year follow-up. Sixty-seven adolescents aged from 12 to 19 years, divided into COC users (n = 41) taking 20 μg ethinylestradiol/150 μg desogestrel and COC non-user controls (n = 26), were evaluated by bone densitometry examinations at baseline and after 12 months. Comparisons between the groups at the study onset were performed using the Mann–Whitney test with the significance level fixed at 5% or p < 0.05. Comparisons between the groups at the study onset and after 12 months were based on variations in the median percentages for bone mass variables.
Results
The COC users presented with low bone mass acquisition in the lumbar spine, and had BMD and BMC median variations of 2.07% and +1.57%, respectively, between the measurements at baseline and 12 months. The control group had median variations of +12.16% and +16.84% for BMD and BMC, respectively, over the same period. The total body BMD and BMC showed similar evolutions during the study in both groups. Statistical significance (p < 0.05) was seen for the BMC percentage variation between COC users and non-users.
Conclusions
Use of a low-dose COC (ethinylestradiol 20 μg/desogestrel 150 μg) was associated with lower bone mass acquisition in adolescents during the study period.
Trial registration
Registry Number, RBR-5h9b3c.
doi:10.1186/s12902-015-0012-7
PMCID: PMC4443632  PMID: 25990414
Adolescent; Bone density; Bone mineral content; Contraceptives; Osteoporosis
24.  Influence of phthalates on glucose homeostasis and atherosclerosis in hyperlipidemic mice 
Background
Phthalates are widely used as plasticizer and are considered as a typical endocrine-disrupting chemical. Epidemiological studies have associated serum or urinary phthalate metabolites with the prevalence of type 2 diabetes or related phenotypes. However, direct evidence supporting a causal role for exposure to phthalates in type 2 diabetes is lacking.
Methods
To determine the potential influence of phthalates on glucose homeostasis and atherosclerosis, female apolipoprotein E-deficient (Apoe−/−) mice were started at 6 weeks of age on a Western diet together with or without Bis-(2-ethylhexyl) phthalate. Phthalate was administered in drinking water at a daily dosage of 100 mg/kg. We examined glucose and insulin tolerance, plasma glucose and triglyceride levels, body weight, and atherosclerotic lesions in the aortic root.
Results
Two weeks after treatment, phthalate-exposed mice had significantly higher fasting blood glucose level (97.9 ± 2.1 vs. 84.3 ± 5.3 mg/dl, P = 0.034) and exhibited a trend of increased glucose intolerance compared to control mice. Insulin tolerance test on non-fasted mice 3 weeks after treatment revealed that phthalate had little influence on insulin sensitivity though phthalate-treated mice had a higher glucose concentration (159.2 ± 6.0 vs. 145.2 ± 3.6 mg/dl; P = 0.086). On the Western diet, Apoe−/− mice showed a time-dependent rise in fasting plasma glucose and triglyceride levels. However, no significant differences were observed between phthalate-treated and control mice in either phenotype after 4, 8, and 12 weeks of phthalate exposure. Neither body weight nor atherosclerotic lesions of Apoe−/− mice was affected.
Conclusion
This study indicates that exposure to phthalates gives rise to a brief interference of glucose homeostasis but has little impact on the development of type 2 diabetes and atherosclerosis in Apoe−/− mice.
doi:10.1186/s12902-015-0015-4
PMCID: PMC4382848  PMID: 25881014
Phthalates; Type 2 diabetes; Atherosclerosis; Dyslipidemia; Mice
25.  The effects of treatment with liraglutide on atherothrombotic risk in obese young women with polycystic ovary syndrome and controls 
Background
Polycystic ovary syndrome (PCOS) is associated with obesity and increased cardiovascular (CV) risk markers. In this study our aim was to assess the effects of six months treatment with liraglutide 1.8 mg od on obesity, and CV risk markers, particularly platelet function, in young obese women with PCOS compared to controls of similar age and weight.
Methods
Carotid intima-media wall thickness (cIMT) was measured by B-mode ultrasonography, platelet function by flow cytometry, clot structure/lysis by turbidimetric assays and endothelial function by ELISA and post-ischaemic reactive hyperemia (RHI). Data presented as mean change (6-month – baseline) ± standard deviation.
Results
Nineteen obese women with PCOS and 17 controls, of similar age and weight, were recruited; baseline atherothrombotic risk markers did not differ between the two groups. Twenty five (69.4%) participants completed the study (13 PCOS, 12 controls). At six months, weight was significantly reduced by 3.0 ± 4.2 and 3.8 ± 3.4 kg in the PCOS and control groups, respectively; with no significant difference between the two groups, P = 0.56. Similarly, HOMA-IR, triglyceride, hsCRP, urinary isoprostanes, serum endothelial adhesion markers (sP-selectin, sICAM and sVCAM), and clot lysis area were equally significantly reduced in both groups compared to baseline. Basal platelet P-selectin expression was significantly reduced at six months in controls −0.17 ± 0.26 but not PCOS −0.12 ± 0.28; between groups difference, 95% confidence interval = −0.14 – 0.26, P = 0.41. No significant changes were noted in cIMT or RHI.
Conclusions
Six months treatment with liraglutide (1.8 mg od) equally affected young obese women with PCOS and controls. In both groups, liraglutide treatment was associated with 3–4% weight loss and significant reduction in atherothrombosis markers including inflammation, endothelial function and clotting. Our data support the use of liraglutide as weight loss medication in simple obesity and suggest a potential beneficial effect on platelet function and atherothrombotic risk at 6 months of treatment.
Trial registration
Clinical trial reg. no. ISRCTN48560305. Date of registration 22/05/2012.
doi:10.1186/s12902-015-0005-6
PMCID: PMC4389314  PMID: 25880805
PCOS; Liraglutide; Platelet function; cIMT; Obesity

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