Socioeconomic deprivation, technology use, C-peptide, smoking and other predictors of glycaemic control in adults with type 1 diabetes.

AIMS: Intensive glycaemic control is associated with substantial health benefits in people with type 1 diabetes. We sought to examine clinical and demographic factors associated with meeting glycaemic targets in type 1 diabetes. METHODS: We conducted a cross-sectional analysis of 4594 individuals with type 1 diabetes. The primary outcome of the study was assessing factors associated with meeting HbA1c targets. Secondary endpoints included factors associated with continuous subcutaneous insulin infusion (CSII) use and persistent C-peptide secretion. RESULTS: Socioeconomic deprivation was strongly associated with a lower likelihood of achieving an HbA1c <58 mmol/mol (7.5%) (20% in the most deprived quintile vs. 40% in the least deprived, p < 0.001). In multivariate analysis, absence of smoking history (OR 3.06, p < 0.001), flash monitoring (OR 1.49, p < 0.001), CSII (1.43, p = 0.022) and longer diabetes duration (OR 1.02 per year, p = 0.004) were independently associated with achieving HbA1c <58 mmol/mol (7.5%), whereas increasing age (OR 0.99 per year, p = 0.004) and C-peptide <50 pM (OR 0.58, p < 0.001) were associated with a lower likelihood of meeting this target. Low C-peptide (<50 pM) was less likely in men (OR 0.55, p < 0.001) and never smokers (0.44, p < 0.001) in multivariate analysis. CONCLUSIONS: Lower levels of deprivation, non-smoking, higher C-peptide, technology use, lower BMI and male gender were all associated with a higher likelihood of meeting HbA1c targets. Access to proven diabetes treatments is lower in the most deprived individuals. Urgent efforts are required to provide treatments which are effective across the socioeconomic gradient.

GDF15 Is Elevated in Conditions of Glucocorticoid Deficiency and Is Modulated by Glucocorticoid Replacement.

CONTEXT: GDF15 is a stress-induced hormone acting in the hindbrain that activates neural circuitry involved in establishing aversive responses and reducing food intake and body weight in animal models. Anorexia, weight loss, nausea and vomiting are common manifestations of glucocorticoid deficiency, and we hypothesized that glucocorticoid deficiency may be associated with elevated levels of GDF15. OBJECTIVE: To determine the impact of primary adrenal insufficiency (PAI) and glucocorticoid replacement on circulating GDF15 levels. METHODS AND RESULTS: We measured circulating concentrations of GDF15 in a cohort of healthy volunteers and Addison's disease patients following steroid withdrawal. Significantly higher GDF15 (mean ± standard deviation [SD]) was observed in the Addison's cohort, 739.1 ± 225.8 pg/mL compared to healthy controls, 497.9 ± 167.7 pg/mL (P = 0.01). The effect of hydrocortisone replacement on GDF15 was assessed in 3 independent PAI cohorts with classical congenital adrenal hyperplasia or Addison's disease; intravenous hydrocortisone replacement reduced GDF15 in all groups. We examined the response of GDF15 to increasing doses of glucocorticoid replacement in healthy volunteers with pharmacologically mediated cortisol deficiency. A dose-dependent difference in GDF15 (mean ± SD) was observed between the groups with values of 491.0 ± 157.7 pg/mL, 427.0 ± 152.1 pg/mL and 360 ± 143.1 pg/mL, in the low, medium and high glucocorticoid replacement groups, respectively, P < .0001. CONCLUSIONS: GDF15 is increased in states of glucocorticoid deficiency and restored by glucocorticoid replacement. Given the site of action of GDF15 in the hindbrain and its effects on appetite, further study is required to determine the effect of GDF15 in mediating the anorexia and nausea that is a common feature of glucocorticoid deficiency.

Validated criteria for the interpretation of a single measurement of serum cortisol in the investigation of suspected adrenal insufficiency.

OBJECTIVE: The diagnostic value of a single measurement of serum cortisol as a first step in the investigation of suspected adrenal insufficiency remains unclear. Previously proposed criteria have not been validated, and little is known regarding the performance of the test outwith morning samples in outpatients. We aimed to identify and validate criteria for morning and afternoon serum cortisol which could be used to determine which individuals require dynamic testing, in both outpatient and medical inpatient settings. METHODS: We performed a retrospective analysis of 2768 patients attending endocrinology clinics and patients admitted to general medical units in two hospitals in Edinburgh, UK. In baseline samples from the short synacthen test, thresholds which identified a subnormal-stimulated serum cortisol (<430 nmol/L using the Abbott Architect assay) with 95% sensitivity were identified. Criteria drawn from data in patients attending outpatient clinics in one hospital were tested in additional outpatient and inpatient validation cohorts. RESULTS: A morning (8 am-12 pm) serum cortisol of <275 nmol/L identified subnormal-stimulated cortisol with 96.2% sensitivity. For afternoon (12 pm-6 pm) samples, a cut-off of <250 nmol/L achieved 96.1% sensitivity. Sensitivity was maintained when the criteria were applied to outpatients in the validation cohort for both morning and afternoon samples. For inpatients, the test was sufficiently sensitive in morning samples only. CONCLUSIONS: A single measurement of serum cortisol carries the potential to significantly reduce the need for dynamic testing in the investigation of adrenal insufficiency, whether this is taken in morning or afternoon outpatient clinics, or in morning samples from medical inpatients.

ABCC1 confers tissue-specific sensitivity to cortisol versus corticosterone: A rationale for safer glucocorticoid replacement therapy.

The aim of treatment in congenital adrenal hyperplasia is to suppress excess adrenal androgens while achieving physiological glucocorticoid replacement. However, current glucocorticoid replacement regimes are inadequate because doses sufficient to suppress excess androgens almost invariably induce adverse metabolic effects. Although both cortisol and corticosterone are glucocorticoids that circulate in human plasma, any physiological role for corticosterone has been neglected. In the brain, the adenosine 5'-triphosphate-binding cassette transporter ABCB1 exports cortisol but not corticosterone. Conversely, ABCC1 exports corticosterone but not cortisol. We show that ABCC1, but not ABCB1, is expressed in human adipose and that ABCC1 inhibition increases intracellular corticosterone, but not cortisol, and induces glucocorticoid-responsive gene transcription in human adipocytes. Both C57Bl/6 mice treated with the ABCC1 inhibitor probenecid and FVB mice with deletion of Abcc1 accumulated more corticosterone than cortisol in adipose after adrenalectomy and corticosteroid infusion. This accumulation was sufficient to increase glucocorticoid-responsive adipose transcript expression. In human adipose tissue, tissue corticosterone concentrations were consistently low, and ABCC1 mRNA was up-regulated in obesity. To test the hypothesis that corticosterone effectively suppresses adrenocorticotropic hormone (ACTH) without the metabolic adverse effects of cortisol, we infused cortisol or corticosterone in patients with Addison's disease. ACTH suppression was similar, but subcutaneous adipose transcripts of glucocorticoid-responsive genes were higher after infusion with cortisol rather than with corticosterone. These data indicate that corticosterone may be a metabolically favorable alternative to cortisol for glucocorticoid replacement therapy when ACTH suppression is desirable, as in congenital adrenal hyperplasia, and justify development of a pharmaceutical preparation.

Presence and hazards of nutrients and emerging organic micropollutants from sewage lagoon discharges into Dead Horse Creek, Manitoba, Canada.

Nutrient enrichment and loadings of pharmaceuticals and agrochemicals into freshwater systems are common concerns, especially for water bodies receiving wastewater inputs. In the rural communities of Morden and Winkler of Manitoba, Canada, sewage lagoons discharge their wastewater directly into Dead Horse Creek, a small tributary of the Red River that empties into Lake Winnipeg. This lagoon approach to managing rural wastewaters is common across the North American Prairies. Therefore, this study aimed to assess the hazards of lagoon treatment releases at this model site. This was done by characterizing the nutrients, organic micropollutants (i.e., pesticides, pharmaceuticals) and standard water quality parameters in the creek prior to and following lagoon discharge events over a number of years (2009-2011). Measured concentrations of nutrients were compared to regulatory expectations and micropollutants were assessed using hazard quotients. As expected, concentrations of nitrogen and phosphorus species were greatest in sites downstream of the sewage outfall immediately following discharge events. Pharmaceutical and agricultural chemicals were detected at concentrations between 0.5 and 90 ng/L. Detection frequencies and concentrations matched typical use patterns. Those compounds used predominately for human medicine were detected at downstream sites following discharge events, while those used in an agricultural setting were detected at relatively consistent levels over time at sites both upstream and downstream of the outfall location. Hazard quotients calculated for micropollutants of interest indicated minimal toxicological risk to aquatic biota in the creek, with only erythromycin and diazinon presenting a potential concern to aquatic algae and invertebrates. Concentrations of nutrients exceeded Canadian guideline thresholds during release, but returned to background levels once discharges ceased. Therefore, it is advisable that wastewater treatment and management strategies such as constructed wetlands and/or staggered releases be used in order to minimize the hazard posed by nutrient pulses in Dead Horse Creek and other similar systems.