Associations between glycaemic control and activation of the renin-angiotensin-aldosterone system in participants with type 2 diabetes mellitus and hypertension.

Introduction Hyperglycaemia increases succinate concentrations and succinate receptor activation in the kidney resulting in renin release. The aim of our study was to determine if there is an association between glycaemic control as evidenced by glycated haemoglobin values and activation of the renin-angiotensin-aldosterone system in patients with type 2 diabetes mellitus and hypertension. Methods A cross-sectional study was conducted at Galway University Hospitals between December 2014 and March 2015. Participants ( n = 66) were identified following interrogation of the electronic database for patients with type 2 diabetes mellitus. Baseline clinical demographics, aldosterone, plasma renin activity, direct renin concentration, urea and electrolytes, glycated haemoglobin, cholesterol, urine sodium and albumin creatinine ratio were recorded. Results There was a significant positive linear correlation between glycated haemoglobin and renin (both plasma renin activity [ P = 0.002] and direct renin concentration [ P = 0.008]) and between serum creatinine and aldosterone measured using both radioimmunoassay ( P = 0.008) and immunochemiluminometric assay ( P = 0.008). A significant negative linear correlation was demonstrated between serum sodium and plasma renin activity ( P = 0.005) and direct renin concentration ( P = 0.015) and between estimated glomerular filtration rate and aldosterone measured using radioimmunoassay ( P = 0.02) and immunochemiluminometric assay ( P = 0.016). A significant negative linear correlation existed between urine sodium and plasma renin activity ( P = 0.04) and aldosterone measured using radioimmunoassay ( P = 0.045). Conclusions There is a direct positive association between glycaemic control and renin. We advocate for renin measurement to be part of the diabetologist's armamentarium to assess, guide and optimize therapeutic strategies in patients with diabetes.

Screening for primary aldosteronism using the newly developed IDS-iSYS® automated assay system.

BACKGROUND: The recommended approach to screening for primary aldosteronism (PA) in at-risk populations is to determine the ratio of aldosterone concentration (serum (SAC)/plasma (PAC)) to renin measured in plasma as activity (PRA) or concentration (DRC). However, lack of assay standardisation mandates the need for method-specific decision thresholds and clinical validation in the local population. AIM: The study objective was to establish method-specific aldosterone: renin ratio (ARR) cut-offs for PA in men and women using the IDS-iSYS® assay system (IDS plc). METHODS: A prospective cohort study design was used. PAC and DRC were measured immunochemically in ethylenediamine-tetraacetic acid (EDTA) plasma on the IDS-iSYS® instrument. RESULTS: A total of 437 subjects (218 men, 219 women) were recruited including: healthy normotensive volunteers (n=266) and women taking the oral contraceptive pill (OCP; n=15); patients with essential hypertension (EH; n=128); confirmed PA (n=16); adrenal cortical carcinoma (ACC; n=3); Addison's disease (AD; n=4) and phaeochromocytoma/paraganglioma (PPGL; n=5). In this population, an ARR cut-off at >37.4 pmol/mIU provided 100% diagnostic sensitivity, 96% specificity and positive likelihood ratio for PA of 23:1. When the ARR decision threshold was stratified according to gender, a cut-off of >26.1 pmol/mIU in men and >113.6 pmol/mIU in women resulted in diagnostic sensitivity and specificity of 100%. CONCLUSION: This study demonstrates that decision thresholds for PA should not only be method-specific but also gender-specific. However, given the small number of PA patients (n=16), particularly women (n=4), further validation through a prospective study with a larger PA cohort is required before the thresholds presented here could be recommended for routine clinical use.

Screening for phaeochromocytoma and paraganglioma: impact of using supine reference intervals for plasma metanephrines with samples collected from fasted/seated patients.

Background The Endocrine Society Clinical Practice Guideline on Phaeochomocytoma and Paraganglioma recommends phlebotomy for plasma-free metanephrines with patients fasted and supine using appropriately defined reference intervals. Studies have shown higher diagnostic sensitivities using these criteria. Further, with seated-sampling protocols, for result interpretation, reference intervals that do not compromise diagnostic sensitivity should be employed. Objective To determine the impact on diagnostic performance and financial cost of using supine reference intervals for result interpretation with our current plasma-free metanephrines fasted/seated-sampling protocol. Methods We conducted a retrospective cohort study of patients who underwent screening for PPGL using plasma-free metanephrines from 2009 to 2014 at Galway University Hospitals. Plasma-free metanephrines were measured using liquid chromatography-tandem mass spectrometry. Supine thresholds for plasma normetanephrine and metanephrine set at 610 pmol/L and 310 pmol/L, respectively, were used. Results A total of 183 patients were evaluated. Mean age of participants was 53.4 (±16.3) years. Five of 183 (2.7%) patients had histologically confirmed PPGL (males, n=4). Using seated reference intervals for plasma-free metanephrines, diagnostic sensitivity and specificity were 100% and 98.9%, respectively, with two false-positive cases. Application of reference intervals established in subjects supine and fasted to this cohort gave diagnostic sensitivity of 100% with specificity of 74.7%. Financial analysis of each pretesting strategy demonstrated cost-equivalence (€147.27/patient). Conclusion Our cost analysis, together with the evidence that fasted/supine-sampling for plasma-free metanephrines, offers more reliable exclusion of PPGL mandates changing our current practice. This study highlights the important advantages of standardized diagnostic protocols for plasma-free metanephrines to ensure the highest diagnostic accuracy for investigation of PPGL.

Radiological remission and recovery of thirst appreciation after infliximab therapy in adipsic diabetes insipidus secondary to neurosarcoidosis.

BACKGROUND: Neurosarcoidosis is a rare and aggressive variant of systemic sarcoidosis which may result in hypothalamic-pituitary dysfunction. We report a case of hypothalamic hypopituitarism secondary to neurosarcoidosis complicated by adipsic diabetes insipidus (ADI). Initiation of anti-tumour necrosis factor-α (TNF-α) therapy resulted in both radiological disease remission and recovery of osmoregulated thirst appreciation after 3 months. CASE SUMMARY: A 22-year-old man was referred to the endocrinology service with profound weight gain, polyuria and lethargy. Biochemical testing confirmed anterior hypopituitarism while posterior pituitary failure was confirmed by hypotonic polyuria responding to desmopressin. Magnetic resonance imaging (MRI) demonstrated extensive hypothalamic infiltration; neurosarcoidosis was confirmed histologically after excisional cervical lymph node biopsy. Osmoregulated thirst appreciation was normal early in the disease course despite severe hypotonic polyuria. However, subsequent subjective loss of thirst appreciation and development of severe hypernatraemia in the setting of normal cognitive function indicated onset of ADI. MANAGEMENT: Clinical management involved daily weighing, regular plasma sodium measurement, fixed daily fluid intake and oral desmopressin. We initiated immunosuppressive therapy with pulsed intravenous anti-TNF-α therapy (infliximab) after multidisciplinary team consultation. OUTCOME: Infliximab therapy resulted in successful radiological disease remission and complete recovery of osmoregulated thirst appreciation. This was confirmed by subjective return of thirst response and maintenance of plasma sodium in the normal range in the absence of close biochemical monitoring.

The prevalence of diabetes, pre-diabetes and the metabolic syndrome in an Irish regional homeless population.

BACKGROUND: Diabetes is a major chronic health condition. Prevalence is rising, superseding public health estimates. Chronic diseases are more common among lower socioeconomic groups, for example, the homeless population. There is paucity of data on the health status of the homeless population in Ireland, and the prevalence of diabetes and associated cardiovascular risk factors is unknown. AIM: We aimed to assess the prevalence of diabetes, pre-diabetes and the metabolic syndrome (MetS) in an Irish regional homeless population. DESIGN: This study is a cross-sectional study of the homeless population living in a regional university city of Ireland. METHODS: After informed consent and following an overnight fast, blood was drawn for fasting plasma glucose, total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein and glycosylated haemoglobin (HbA1c). A 75 g glucose load was given orally and an oral glucose tolerance test completed. Anthropometric measurements and blood pressure were recorded. Smoking, alcohol and drug status were noted. RESULTS: Of the 252 participants, 8% (n = 20), 10% (n = 24) and 21% (n = 54) were diagnosed with type 2 diabetes, pre-diabetes and MetS, respectively. Obesity (body mass index >30) was present in 22%, while 90% displayed abdominal obesity. Participants who screened positive for diabetes, pre-diabetes and MetS demonstrated an inferior cardiovascular risk profile. CONCLUSION: The prevalence of diabetes, pre-diabetes and MetS in this homeless population is in keeping with national estimates. As this cohort is less likely to seek health care, this may result in later diagnosis and a greater risk of diabetic complications at presentation.

Atlantic DIP: the prevalence and consequences of gestational diabetes in Ireland.

ATLANTIC DIP carried out a universal screening programme for gestational diabetes mellitus (GDM) along the Irish Atlantic seaboard. Using a 75g OGTT and new International Association of Diabetes in Pregnancy Study Groups (IADPSG) cut off points for diagnosis we found the prevalence of GDM to be 12.4%. Pregnancies complicated by GDM displayed increased morbidities for mother and infant when compared to women who had normal glucose tolerance. With rising obesity levels and older age of mothers, both risk factors for GDM, these results would support a national universal screening programme.

The impact of maternal obesity on gestational outcomes.

To investigate the effects of raised maternal BMI on pregnancy outcome in glucose tolerant women, using the IADPSG criteria. Prospective observational study of fetal and maternal outcome in a cohort of pregnant women recruited to a universal screening programme for gestational diabetes under the ATLANTIC-DIP partnership. Maternal outcomes included glucose, delivery mode, pregnancy induced hypertension (PIH), preeclampsia (PET), antepartum hemorrhage (APH) and postpartum hemorrhage (PPH). Fetal outcomes included birthweight, congenital malformation, fetal death, neonatal jaundice, hypoglycemia and respiratory distress. Increasing maternal BMI was associated with adverse pregnancy outcomes: higher cesarean section rates, pre-eclamptic toxemia, pregnancy induced hypertension, increased birth weight and congenital malformation. There was also an association between normal range glucose and emergency cesarean section, hypertension of pregnancy and birthweight. In spite of tightening criteria for hyperglycemia during pregnancy, raised BMI is associated with adverse pregnancy outcome.

Breast-feeding is associated with reduced postpartum maternal glucose intolerance after gestational diabetes.

Gestational diabetes mellitus (GDM) is associated with adverse foetal and maternal outcomes, and identifies women at risk of future Type 2 Diabetes Mellitus (T2DM). Breast-feeding may improve postpartum maternal glucose tolerance. We prospectively examined the prevalence of postpartum dysglycaemia after GDM and examined the effect of lactation on postpartum glucose tolerance. We compared postpartum 75g oral glucose tolerance test (OGTT) results from 300 women with GDM and 220 controls with normal gestational glucose tolerance (NGT). Breast-feeding data was collected at time of OGTT. Postpartum OGTT results were classified as normal [fasting plasma glucose (FPG) < 5.6mmol/l, 2-h < 7.8 mmol/l] and abnormal [impaired fasting glucose (IFG), FPG 5.6-6.9 mmol/l; impaired glucose tolerance (IGT), 2-h glucose 7.8-11 mmol/l; IFG+IGT; T2DM, FPG > or = 7 mmol/l +/- 2h glucose > or = 11.1 mmol/l]. 6 (2.7%) with NGT in pregnancy had postpartum dysglycaemia compared to 57 (19%) with GDM in index pregnancy (p < 0.001). Non-European ethnicity (OR 3.40, 95% CI 1.45-8.02, p = 0.005), family history of T2DM (OR 2.14, 95% CI 1.06-4.32, p = 0.034) and gestational insulin use (OR 2.62, 95% CI 1.17-5.87 p = 0.019) were associated with persistent dysglycaemia. The prevalence of persistent hyperglycaemia was significantly lower in women who breast-fed versus bottle-fed postpartum (8.2% v 18.4%, p < 0.001). Breast-feeding may confer beneficial metabolic effects after GDM and should be encouraged.

Atlantic Diabetes in Pregnancy (DIP): the prevalence and outcomes of gestational diabetes mellitus using new diagnostic criteria.

AIMS/HYPOTHESIS: New diagnostic criteria for gestational diabetes mellitus (GDM) have recently been published. We wished to evaluate what impact these new criteria would have on GDM prevalence and outcomes in a predominantly European population. METHODS: The Atlantic Diabetes In Pregnancy (DIP) programme performed screening for GDM in 5,500 women with an oral glucose tolerance test at 24-28 weeks. GDM was defined according to the new International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria and compared with previous WHO criteria; maternal and neonatal adverse outcomes were prospectively recorded. RESULTS: Of the participants, 12.4% and 9.4% were diagnosed with GDM using IADPSG and WHO criteria, respectively. IADPSG GDM pregnancies were associated with a statistically significant increased incidence of adverse maternal outcomes (gestational hypertension, polyhydramnios and Caesarean section) and neonatal outcomes (prematurity, large for gestational age, neonatal unit admission, neonatal hypoglycaemia and respiratory distress). The odds ratio for the development of these adverse outcomes remained significant after adjustment for maternal age, body mass index and non-European ethnicity. Those women who were classified as having normal glucose tolerance by WHO criteria but as having GDM by IADPSG criteria also had significant adverse pregnancy outcomes. CONCLUSIONS/INTERPRETATION: GDM prevalence is higher when using newer IADPSG, compared with WHO, criteria, and these women and their offspring experience significant adverse pregnancy outcomes. Higher rates of GDM pose a challenge to healthcare systems, but improved screening provides an opportunity to attempt to reduce the associated morbidity for mother and child.

Corticosteroids and fetal vasculature: effects of hydrocortisone, dexamethasone and betamethasone on human umbilical artery.

OBJECTIVE: To investigate the direct effects of corticosteroids on human umbilical artery resistance, in vitro. DESIGN: Prospective laboratory study. SETTING: University teaching hospital. SAMPLES AND METHODS: Umbilical artery samples were obtained following normal, term deliveries (n = 50) and dissected rings were suspended for isometric recording under physiological conditions. The effects of hydrocortisone (10(-9) - 10(-4) M), dexamethasone (10(-9) - 10(-4) M) and betamethasone (10(-9) - 10(-4) M) on umbilical artery resistance were measured in vitro. MAIN OUTCOME MEASURES: Changes in umbilical artery resistance, in vitro. RESULTS: Hydrocortisone (n = 12) exerted a vasodilatory effect on human umbilical artery at all concentrations studied compared with vehicle control experiments (n = 12) (P < 0.0001). The mean net relaxant effect of hydrocortisone ranged from 11.77% (10(-9) M) to 57.01% (10(-4)). Both exogenous compounds, dexamethasone (n = 12) and betamethasone (n = 12), similarly exerted a significant relaxant effect on human umbilical artery tone (P < 0.05-0.01), compared with vehicle control experiments (n = 12). The mean net relaxant effect of dexamethasone ranged from 14.43% (10(-9) M) to 38.12% (10(-4)) and that of betamethasone ranged from 6.02% (10(-9) M) to 42.30% (10(-4)), in a cumulatively increasing fashion. There was a non-significant trend towards a greater vasodilatory effect of dexamethasone than betamethasone at lower bath concentrations studied. CONCLUSION: Corticosteroids exert a direct and potent vasodilatory effect on human umbilical artery resistance in vitro, thus providing an explanation for the previously unexplained vascular effects associated with antenatal administration of corticosteroids.

Beta-3 versus beta-2 adrenergic agonists and preterm labour: in vitro uterine relaxation effects.

OBJECTIVE: 1. To investigate the effects of the selective beta-3 adrenoreceptor agonist, BRL 37344, on human pregnant myometrial contractility in vitro. 2. to compare these effects with those of the beta-2 adrenoreceptor agonist, ritodrine. METHODS: Isometric tension recording was performed under physiological conditions in isolated myometrial strips from biopsies obtained at elective caesarean section. Following pre-incubation with oxytocin (10(-9) M), the effects of cumulative additions of BRL 37344 or ritodrine (10(-8)-10(-3.5) M) on myometrial contractility were investigated. Results were expressed as -log EC50 (pD2) and mean maximal inhibition achieved for both drug compounds. RESULTS: BRL 37344 exerted a concentration dependant relaxant effect on myometrial contractions in all strips exposed [pD2, 7.26 (0.48) (SEM); mean maximal inhibition 61.98 (4.89%); n = 6]. Similarly, ritodrine exerted a concentration dependant inhibition of myometrial contractility in all strips exposed [pD2 = 7.40 (0.28); mean maximal inhibition 59.49 (3.97%); n = 6]. There was no significant difference between calculated pD2 values (P = 0.65) or mean maximal inhibition achieved (P = 0.79). CONCLUSIONS: The beta-3 adrenoreceptor agonist BRL 37344 induced relaxation of human myometrial contractions with similar potency to that of the most commonly used tocolytic agent ritodrine. This raises the possibility that the novel beta-3 adrenoreceptor agonists may have potential as therapeutic agents for human preterm labour. In view of their reported reduced cardiovascular side effects their potential clinical use requires further evaluation.

Methylenedioxymethamphetamine-induced suppression of interleukin-1beta and tumour necrosis factor-alpha is not mediated by serotonin.

The purpose of the present study was to examine the role of serotonin release in methylenedioxymethamphetamine (MDMA)-induced immunosuppression in rats. We examined the effect of pretreatment with the selective serotonin reuptake inhibitor paroxetine, and the tryptophan hydroxylase inhibitor para-chlorophenylalanine on MDMA-induced suppression of interleukin-1beta and tumour necrosis factor (TNF)-alpha secretion following an in vivo lipopolysaccharide challenge. Although paroxetine blocked MDMA-induced serotonin depletion in the cortex and hypothalamus, it failed to alter the suppressive effect of MDMA on lipopolysaccharide-induced TNF-alpha secretion. Similarly, although para-chlorophenylalanine caused a 90% depletion in cortical and hypothalamic serotonin content, it failed to alter the suppressive effect of MDMA on lipopolysaccharide-induced interleukin-1beta or TNF-alpha secretion. In conclusion, although MDMA is a potent releaser of serotonin, the suppressive effects of MDMA on lipopolysaccharide-induced proinflammatory cytokine secretion cannot be attributed to its serotonin-releasing properties.