Search

Aims: To examine the psychometric properties of the Diabetes Management Experiences Questionnaire (DME-Q). Adapted from the validated Glucose Monitoring Experiences Questionnaire, the DME-Q captures satisfaction with diabetes management irrespective of treatment modalities., Methods: The DME-Q was completed by adults with type 1 diabetes as part of a randomized controlled trial comparing hybrid closed loop (HCL) to standard therapy. Most psychometric properties were examined with pre-randomization data (n = 149); responsiveness was examined using baseline and 26-week follow-up data (n = 120)., Results: Pre-randomization, participants' mean age was 44 ± 12 years, 52% were women. HbA1c was 61 ± 11 mmol/mol (7.8 ± 1.0%), diabetes duration was 24 ± 12 years and 47% used an insulin pump prior to the trial. A forced three-factor analysis revealed three expected domains, that is, 'Convenience', 'Effectiveness' and 'Intrusiveness', and a forced one-factor solution was also satisfactory. Internal consistency reliability was strong for the three subscales ( α range = 0.74-0.84) and 'Total satisfaction' ( α  = 0.85). Convergent validity was demonstrated with moderate correlations between DME-Q 'Total satisfaction' and diabetes distress (PAID: r s  = -0.57) and treatment satisfaction (DTSQ; r s  = 0.58). Divergent validity was demonstrated with a weak correlation with prospective/retrospective memory (PRMQ: r s  = -0.16 and - 0.13 respectively). Responsiveness was demonstrated, as participants randomized to HCL had higher 'Effectiveness' and 'Total satisfaction' scores than those randomized to standard therapy., Conclusions: The 22-item DME-Q is a brief, acceptable, reliable measure with satisfactory structural and construct validity, which is responsive to intervention. The DME-Q is likely to be useful for evaluation of new pharmaceutical agents and technologies in research and clinical settings., (© 2023 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Context: Many adrenal adenomas exhibit mild autonomous cortisol secretion (MACS). Although MACS is associated with increased cardiovascular mortality, the underlying mechanisms are not fully defined., Objective: To investigate mechanisms that may link MACS and cardiovascular mortality in adults with adrenal adenoma., Design: Cross-sectional study., Patients: Twenty adults with adrenal adenoma and MACS and 20 controls with nonfunctioning adrenal adenoma., Methods: Reactive hyperemia index (RHI) was measured by peripheral artery tonometry and 24-hour ambulatory blood pressure monitoring (24h AMBP) was performed. Indices of insulin secretion and sensitivity were estimated by measuring glucose and insulin fasting and following a mixed meal., Main Outcome Measure: The primary outcome was the difference in RHI between participants with MACS vs nonfunctioning adrenal adenoma., Results: The average cortisol after 1-mg dexamethasone and urinary free cortisol were higher in patients with MACS. There was no significant difference in fasting RHI (2.0 [interquartile range (IQR) 1.6-2.4] vs 2.0 [IQR 1.7-2.2, P = .72), but postprandial RHI was higher in patients with MACS (2.2 [1.8-2.7] vs 1.8 [1.5-2.2], P = .04). 24-hour ambulatory blood pressure monitoring and Matsuda index were not significantly different in the groups. Fasting glucose and glucose area under the curve after the mixed meal were higher and insulinogenic index was lower in participants with MACS., Conclusion: Adults with adrenal adenoma and MACS do not have fasting endothelial dysfunction and postprandial endothelial function may be better. These patients have fasting and postprandial hyperglycemia with lower insulin secretion, which may underlie the association between MACS and increased cardiovascular mortality., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Few studies have evaluated the performance of flash glucose monitoring in hospitalized patients requiring intravenous insulin therapy. In this prospective study, an intravenous insulin infusion was adjusted hourly using flash glucose monitoring in hospitalized adults with prednisolone-associated hyperglycemia. The difference in paired point of care (POC) and flash glucose measurements and risk of severe hyper- or hypoglycemia (assessed by Clarke error grid analysis) were assessed. Glucose concentration measured by flash glucose monitoring was lower than POC glucose (mean difference 1.5 mmol/L [27 mg/dL], p < 0.001); however, mean POC glucose was within the target range (9.1 ± 4.1 mmol/L [164 ± 72 mg/dL]) and 97.8% of glucose measurements were within Zone A and B on error grid analysis. Flash glucose monitoring could be used in combination with POC glucose monitoring to minimize the frequency of finger prick blood glucose levels in hospitalized patients prescribed an intravenous insulin infusion.

Background: Changes in the arginine metabolites asymmetric dimethyl-L-arginine (ADMA) and L-homoarginine and acute blood glucose concentrations have been shown to cause endothelial dysfunction and be independently associated with mortality in Intensive Care Unit (ICU) patients. The aim of this study was to investigate whether hyperglycemia potentially modulates these arginine metabolite concentrations to provide a mechanism that may link hyperglycemia and mortality in this patient group., Methods: A clinical and in vitro study were undertaken. Glucose, glycosylated hemoglobin-A1c (HbA1c) and the stress hyperglycemia ratio (SHR) (to quantify absolute, chronic and relative hyperglycemia respectively) were measured in 1155 acutely unwell adult patients admitted to a mixed medical-surgical ICU. SHR was calculated by dividing the admission glucose by the estimated average glucose over the last 3 months, which was derived from HbA1c. ADMA and L-homoarginine were measured in a plasma sample collected at admission to ICU by liquid chromatography tandem mass spectrometry. The activity of dimethylarginine-dimethylaminohydrolase 1 (DDAH1), the main enzyme regulating ADMA concentrations, was assessed at varying glucose concentrations in vitro by quantifying the conversion of ADMA to citrulline in HEK293 cells that overexpress DDAH1., Results: In the clinical study, plasma ADMA was not significantly associated with any measure of hyperglycemia. L-homoarginine was positively associated with glucose (β = 0.067, p = 0.018) and SHR (β = 0.107, p < 0.001) after correction for glomerular filtration rate. However, as L-homoarginine is a negative predictor of mortality, the direction of these associations are the opposite of those expected if hyperglycemia was affecting mortality via changes in L-homoarginine. In vitro DDAH1 activity was not significantly influenced by glucose concentrations (p = 0.506)., Conclusion: In critically ill patients the association between relative hyperglycemia and mortality is not mediated by changes in ADMA or L-homoarginine. Trial registration ANZCTR Trial ID ACTRN12615001164583., (© 2023. The Author(s).)

The fact that growth hormone (GH) plays an important role in health after the cessation of growth requiring replacement therapy in adult life has only been recognised in the last three decades. This has only been made possible by recombinant technology providing GH supplies required to undertake investigations in the physiology of GH action and the benefits of replacement therapy in patients identified by rigorously validated diagnostic tests for GH deficiency (GHD). Human studies have revealed important regulatory roles in substrate metabolism, sodium homeostasis, body composition, and physical function. GH-induced anabolism is achieved by stimulating amino acid incorporation into protein while reducing oxidative loss simultaneously enhancing lipid utilisation by stimulating fatty acid oxidation and reducing lipid storage. Sodium and fluid retention are enhanced by activating the renin-angiotensin system and distal renal tubular reabsorption. GH stimulates the aerobic and anaerobic energy systems that underpin muscle and cardiovascular function. These pleiotropic actions explain the clinical picture of increased adiposity, reduced lean mass, and impaired physical and psychological function in the GHD adult, all of which are reversed when GH is replaced. Women require a greater replacement dose of GH than men. This is because androgens enhance while oestrogens attenuate GH action. The oestrogen effect is route-dependent, occurring with oral delivery blunting the liver-mediated actions of GH by directly inhibiting GH receptor signalling, global experience spanning over 30 years has attested to the safety, efficacy, and benefits of replacement therapy for adults with GHD.

Aims: The optimal treatment of prednisolone-associated hyperglycaemia is unclear, but guidelines recommend using a body weight-based daily insulin dose. This study evaluated how clinical variables were associated with insulin requirements in hospitalised patients with prednisolone-associated hyperglycaemia., Methods: In this prospective study, fifty adult inpatients who were taking prednisolone ≥20 mg/day and experienced hyperglycaemia were prescribed a 24-h intravenous insulin infusion. The daily insulin dose required to attain a mean glucose of 8 mmol/L was calculated. The associations between daily insulin dose and clinical variables were assessed., Results: The participants age was 69 ± 10 years, daily prednisolone dose was 34 ± 10 mg, HbA1c was 7.7 ± 2.0 % (61 ± 10 mmol/mol), 77 % had known type 2 diabetes and 30 % were female. In univariate analysis, weight was associated with daily insulin dose (r 2  = 0.11, p = 0.024). A multivariate model comprising sex, HbA1c, a prior diagnosis of diabetes, diabetes treatment and weight explained nearly-two thirds of the variability in daily insulin dose (r 2  = 0.65, p < 0.001)., Conclusions: In patients with prednisolone-associated hyperglycaemia, calculating insulin doses based on sex, HbA1c, diabetes status and regular diabetes treatment and weight may improve glycaemic control compared to weight-based dosing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Adrenal adenomas are incidentally identified in up to 5% of computer tomography scans performed for unrelated indications. A proportion of these adrenal incidentalomas are found to autonomously secrete cortisol based on definitions in current guidelines. Epidemiological studies suggest that chronic exposure to mild glucocorticoid excess from adrenal incidentalomas is associated with significantly increased cardiometabolic risk. However, current management guidelines adopt a conservative approach as no large prospective randomized studies have demonstrated that these patients benefit from surgery. This narrative review examines the epidemiological and mechanistic studies related to three common clinical settings of mild glucocorticoid excess to gain further insight into the potential benefits of treating patients with adrenal incidentaloma and possible autonomous cortisol secretion., (© 2022 John Wiley & Sons Ltd.)

Background: Cardiovascular disease is a leading cause of death in breast cancer survivors, but the underlying cause is not fully characterised., Aims: To determine whether insulin sensitivity, cardiovascular risk markers and body composition were perturbed in women treated with chemotherapy for early stage breast cancer and whether perturbations occurred before or after cancer treatment., Methods: Sixteen women with breast cancer and 17 control subjects were studied. Twelve breast cancer patients returned for a second visit following cancer treatment comprising chemotherapy (n = 2), or chemotherapy and radiotherapy (n = 10). The Matsuda index to estimate insulin sensitivity, fasting lipids, pulse wave velocity (PWV), reactive hyperaemia index (RHI) and body composition by dual energy X-ray absorptiometry were measured., Results: There were no significant differences in age (53 ± 9 vs 54 ± 11 years; P = 0.82) or body mass index (28 ± 7 vs 28 ± 6; P = 0.97) between patients with breast cancer and controls. Patients with breast cancer had higher triglycerides than controls (1.2 ± 0.1 vs 0.8 ± 0.1 mmol/L; P = 0.03), but there were no significant differences in the Matsuda index, PWV and RHI. Following cancer treatment, there was a lower Matsuda index (6.3 ± 1.2 vs 5.2 ± 1.0; P = 0.01), but this was not associated with a significant change in vascular function. Bone mass fell by 3% from 2.27 ± 0.11 to 2.20 ± 0.10 kg after cancer treatment (P = 0.03)., Conclusions: Patients with breast cancer had higher triglycerides before treatment and a reduction in insulin sensitivity and bone mass following cancer treatment. Future larger and longer-term studies should characterise the effect of reduced insulin sensitivity on rates of diabetes, cardiovascular disease, cancer outcomes and fracture., Trial Registration: ACTRN12614001055695., (© 2021 Royal Australasian College of Physicians.)

Objective: The objective of this study is to assess the relationship between hypothalamic-pituitary-adrenal (HPA) axis activity, vascular function and insulin sensitivity in healthy adults., Design: Open observational study., Patients: Thirty healthy adults were studied at the Endocrine Research Unit, Repatriation General Hospital, Adelaide, SA, Australia., Measurements: HPA activity was assessed from the serum cortisol 30 min after 1 µg ACTH 1-24 (Novartis Pharmaceuticals). Subjects with a cortisol below (n = 15) and above (n = 15) the median were categorized as low and high responders, respectively. Reactive hyperaemia index (RHI) was measured fasting to estimate endothelial function. Matsuda index was calculated from glucose and insulin concentrations collected fasting and 30 minutely for 2 h after a mixed meal (10 kcal/kg, 45% carbohydrate, 15% protein, 40% fat). The primary endpoint was the difference in RHI between low and high responders., Results: There were no significant differences in age (61 ± 9 vs. 64 ± 7 years, p = .19), body mass index (BMI; 26 ± 3 vs. 24 ± 4 kg/m 2 , p = .25) and sex (p = .71) between low and high responders. High responders had a lower RHI (2.1 ± 0.2 vs. 2.6 ± 0.2, p = .04) than low responders and there was a negative association between RHI and peak cortisol post ACTH 1-24 (β = -.56, p < .01). There were no significant differences in Matsuda index (15.0 ± 2.4 vs. 22.7 ± 5.2, p = .19) between high and low responders., Conclusion: In healthy adults, endothelial dysfunction is likely to contribute to the association between HPA hyperactivity and increased cardiovascular risk. As insulin sensitivity was not different in high and low responders, endothelial dysfunction is not primarily secondary to insulin resistance., (© 2022 John Wiley & Sons Ltd.)

There is limited evidence supporting the recommendation that drivers with insulin-treated diabetes need to start journeys with glucose >90 mg/dL. Glucose levels of drivers with type 1 diabetes were monitored for 3 weeks using masked continuous glucose monitoring (CGM). Eighteen drivers (median [IQR] age 40 [35, 51] years; 11 men) undertook 475 trips (duration 15 [13, 21] min). Hypoglycemia did not occur in any trip starting with glucose >90 mg/dL (92%; n  = 436). Thirteen drivers recorded at least one trip (total n  = 39) starting with glucose <90 mg/dL. Among these, driving glucose was <70 mg/dL in five drivers (38%) during 10 trips (26%). Among five drivers (28%), a ≥ 36 mg/dL drop was observed within 20 min of starting their journey. Journey duration was positively associated with maximum glucose change. These findings support current guidelines to start driving with glucose >90 mg/dL, and to be aware that glucose levels may change significantly within 20 min. A CGM-based, in-vehicle display could provide glucose information and alerts that are compatible with safe driving. Clinical Trial Registration number: ACTRN12617000520336.

Background: Arginine metabolites are associated with cardiovascular and all-cause mortality in several patient groups. We investigated whether arginine metabolites are associated with mortality in patients with critical illness and whether associations are independent of other factors affecting prognosis in an Intensive Care Unit (ICU)., Methods: 1155 acutely unwell adult patients admitted to a mixed medical-surgical ICU were studied. Arginine, asymmetric dimethyl-l-arginine (ADMA), monomethyl-l-arginine (MMA), symmetric dimethyl-l-arginine (SDMA) and l-homoarginine were measured in a plasma sample collected at admission to ICU by liquid chromatography tandem mass spectrometry. Risk of death score was calculated using data submitted to the Australia and New Zealand Intensive Care Society., Results: In this cohort, 163 patients (14.1%) died. ADMA (odds ratio = 1.159 (1.033-1.300) per 0.1 μmol/L increment, p = 0.012), homoarginine (odds ratio = 0.963 (0.934-0.992), p = 0.013) and risk of death score (odds ratio = 1.045 (1.037-1.053) per 1% increment, p < 0.001) were independently associated with mortality in ICU patients. The area under the receiver operator characteristic curve for risk of death score, ADMA and homoarginine combined for mortality was greater than for risk of death score alone (0.815 (95% CI 0.790-0.837) vs 0.796 (95% CI 0.781-0.820), p = 0.019). Other arginine metabolites were not independently associated with mortality., Conclusions: ADMA is positively and homoarginine negatively associated with mortality in ICU patients, independent of other clinical factors. Measuring ADMA and homoarginine may refine models to predict ICU mortality. Reducing ADMA and increasing homoarginine are potential therapeutic targets to reduce mortality in critically ill patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: To compare meal-time glycaemia in adults with type 1 diabetes mellitus (T1D) managed with multiple daily injections (MDI) vs. insulin pump therapy (IPT), using self-monitoring blood glucose (SMBG), following diabetes education., Methods: Adults with T1D received carbohydrate-counting education and a bolus calculator: MDI (Roche Aviva Expert) and IPT (pump bolus calculator). All then wore 3-weeks of masked-CGM (Enlite, Medtronic). Meal-times were assessed by two approaches: 1) Set time-blocks (breakfast 06:00-10:00hrs; lunch 11:00-15:00hrs; dinner 17:00-21:00hrs) and 2) Bolus-calculator carbohydrate entries signalling meal commencement. Post-meal masked-CGM time-in-range (TIR) 3.9-10.0 mmol/L was the primary outcome., Results: MDI(n = 61) and IPT (n = 59) participants were equivalent in age, sex, diabetes duration and HbA1c. Median (IQR) education time provided did not differ (MDI: 1.1 h (0.75, 1.5) vs. IPT: 1.1 h (1.0, 2.0); p = 0.86). Overall, daytime (06:00-24:00hrs), lunch and dinner TIR did not differ for MDI vs. IPT participants but was greater for breakfast with IPT in both analyses with a mean difference of 12.8%, (95 CI 4.8, 20.9); p = 0.002 (time-block analysis)., Conclusion: After diabetes education, MDI and IPT use were associated with similar day-time glycemia, though IPT users had significantly greater TIR during the breakfast period. With education, meal-time glucose levels are comparable with use of MDI vs. pumps., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Conflicts of Interest JCL reports no potential conflicts of interest relevant to this article. SV reports no potential conflicts of interest relevant to this article. SAM reports speaker honoraria from Roche and that her institution has received research support from Medtronic. BP reports speaker honoraria fees from Medtronic. MBA reports no potential conflicts of interest relevant to this article. MIdB reports no potential conflicts of interest relevant to this article. LAB reports grant funding from AstraZeneca. MGB reports no potential conflicts of interest relevant to this article. NDC reports personal fees from Medtronic and Abbott, grant funds from Ypsomed. PGC reports no potential conflicts of interest relevant to this article. EAD reports no potential conflicts of interest relevant to this article. DJHW reports no potential conflicts of interest relevant to this article. JK reports speaker fees from Novo Nordisk and AstraZeneca, advisory board fees from Abbott Diabetes. RJM reports research grants from Novo Nordisk, Servier, Medtronic, The Rebecca Cooper Medical Research Foundation, St Vincent's Research Foundation, JDRF, Grey Innovations, The Diabetes Australia Research Trust/Program, and The National Health and Medical Research Council of Australia; honoraria for lectures from Eli Lilly, Novo Nordisk, Sanofi Aventis, Astra Zeneca, Merck Sharp & Dohme, Norvartis, and Boehringer Ingelheim; travel support from Novo Nordisk, Sanofi, and Boehringer Ingelheim; is on the advisory boards for Novo Nordisk, Sanofi Aventis, Boehringer Ingelheim-Eli Lilly Diabetes Alliance, and Astra Zeneca, and has been a principal investigator for industry sponsored clinical trials run by Novo Nordisk, Bayer, Johnson-Cilag, and Abbive. ACK reports no potential conflicts of interest relevant to this article. KK reports no potential conflicts of interest relevant to this article. RJM reports no potential conflicts of interest relevant to this article. WMC reports no potential conflicts of interest relevant to this article. CMS reports no potential conflicts of interest relevant to this article. KR reports no potential conflicts of interest relevant to this article. VJS reports no potential conflicts of interest relevant to this article. ST reports non-financial support from Abbott Diabetes. GMW reports no potential conflicts of interest relevant to this article. AJJ has received research support from Medtronic, the National Health and Medical Research Council, JDRF Australia and International, Sanofi-Aventis, Abbott, and Mylan and has served on advisory boards for Medtronic, Sanofi, and Abbott (Diabetes). TWJ reports no potential conflicts of interest relevant to this article. DNO has served on advisory boards for Abbott, Medtronic, MSD, Novo, Roche, and Sanofi; received research support from Medtronic, Novo, Roche, Lilly, and Sanofi; and travel support from Novo and MSD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: This prerandomization analysis from the Australian HCL-Adult trial (registration number: ACTRN12617000520336) compared masked continuous glucose monitoring (CGM) metrics among adults using insulin pumps versus multiple daily injections (MDIs), who were all self-monitoring blood glucose (SMBG). Methods: Adults with type 1 diabetes, using an insulin pump or MDIs without real-time CGM (and entering a trial of closed-loop technology), were eligible. MDI users were given an insulin dosage calculator. All participants received diabetes and carbohydrate-counting education, then wore masked CGM sensors for 3 weeks. Ethics Approval: HREC-D 088/16 Results: Adults using MDIs ( n  = 61) versus pump ( n  = 59) did not differ by age, sex, diabetes duration, insulin total daily dose, or HbA 1c at baseline. After education, median (interquartile range) CGM time in range (TIR) 70-180 mg/dL (3.9-10.0 mmol/L) was 54% (47, 62) for those using MDIs and 56% (48, 66) for those using pump ( P  = 0.40). All CGM metrics were equivalent for 24 h/day for MDI and pump users. Overnight, those using MDIs (vs. pump) spent more time with glucose <54 mg/dL (<3.0 mmol/L): 1.4% (0.1, 5.1) versus 0.5% (0.0, 2.0), respectively ( P  = 0.012). They also had more CGM hypoglycemia episodes (121 vs. 54, respectively; incidence rate ratio [95% confidence interval] 2.48 [1.51, 4.06]; P  < 0.001). Conclusions: Adults with type 1 diabetes using pumps versus MDIs in conjunction with SMBG experienced less nocturnal hypoglycemia, measured by masked CGM, after equivalent diabetes and dietary education in conjunction with insulin dosage calculator provision to all. However, both groups had equivalent TIR. This observation may reflect advantages afforded by flexibility in basal insulin delivery provided by pumps.

Objective: To investigate glycemic and psychosocial outcomes with hybrid closed-loop (HCL) versus user-determined insulin dosing with multiple daily injections (MDI) or insulin pump (i.e., standard therapy for most adults with type 1 diabetes)., Research Design and Methods: Adults with type 1 diabetes using MDI or insulin pump without continuous glucose monitoring (CGM) were randomized to 26 weeks of HCL (Medtronic 670G) or continuation of current therapy. The primary outcome was masked CGM time in range (TIR; 70-180 mg/dL) during the final 3 weeks., Results: Participants were randomized to HCL ( n = 61) or control ( n = 59). Baseline mean (SD) age was 44.2 (11.7) years, HbA 1c was 7.4% (0.9%) (57 [10] mmol/mol), 53% were women, and 51% used MDI. HCL TIR increased from (baseline) 55% (13%) to (26 weeks) 70% (10%) with the control group unchanged: (baseline) 55% (12%) and (26 weeks) 55% (13%) (difference 15% [95% CI 11, 19]; P < 0.0001). For HCL, HbA 1c was lower (median [95% CI] difference -0.4% [-0.6, -0.2]; -4 mmol/mol [-7, -2]; P < 0.0001) and diabetes-specific positive well-being was higher (difference 1.2 [95% CI 0.4, 1.9]; P < 0.0048) without a deterioration in diabetes distress, perceived sleep quality, or cognition. Seventeen (9 device-related) versus 13 serious adverse events occurred in the HCL and control groups, respectively., Conclusions: In adults with type 1 diabetes, 26 weeks of HCL improved TIR, HbA 1c , and their sense of satisfaction from managing their diabetes compared with those continuing with user-determined insulin dosing and self-monitoring of blood glucose. For most people living with type 1 diabetes globally, this trial demonstrates that HCL is feasible, acceptable, and advantageous., (© 2020 by the American Diabetes Association.)

Objectives: To determine whether relative hyperglycemia was associated with in-hospital mortality in critically ill patients independent of other prognostic variables and whether this association is affected by background glycemia., Design: Prospective observational study., Setting: Mixed medical-surgical ICU in a metropolitan teaching hospital., Patients: From 2,617 admissions to ICU between January 27, 2016, and March 30, 2017, 1,262 consecutive patients who met inclusion and exclusion criteria were studied., Interventions: Glycosylated hemoglobin was used to estimate average glucose concentration over the prior 3 months. Glucose concentration on ICU admission was divided by estimated average glucose concentration to calculate the stress hyperglycemia ratio, an index of relative glycemia. Risk of death score was calculated using data submitted to the Australia and New Zealand Intensive Care Society., Measurements and Main Results: In this study, there were 186 deaths (14.7%). Admission glucose was significantly associated with mortality in univariate analysis (odds ratio = 1.08 per mmol/L glucose increment; p < 0.001) but not after adjustment for risk of death score (odds ratio = 1.01; p = 0.338). In contrast, stress hyperglycemia ratio was significantly associated with mortality both in univariate analysis (odds ratio = 1.09 per 0.1 stress hyperglycemia ratio increment; p < 0.001) and after adjustment for risk of death score (odds ratio = 1.03; p = 0.014). Unlike admission glucose concentration, stress hyperglycemia ratio was significantly associated with mortality in patients with glycosylated hemoglobin less than 6.5% (odds ratio = 1.08 per 0.1 stress hyperglycemia ratio increment; p < 0.001) and glycosylated hemoglobin greater than or equal to 6.5% (48 mmol/mol) (odds ratio = 1.08 per 0.1 stress hyperglycemia ratio increment; p = 0.005)., Conclusions: Unlike absolute hyperglycemia, relative hyperglycemia, as assessed by the stress hyperglycemia ratio, independently predicts in-hospital mortality in critically ill patients across the glycemic spectrum. Future studies should investigate whether using measures of relative hyperglycemia to determine individualized glycemic treatment targets improves outcomes in ICU.

This international randomised controlled trial evaluated whether COPD patients with comorbidities, trained in using patient-tailored multidisease exacerbation action plans, had fewer COPD exacerbation days than usual care (UC).COPD patients (Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification II-IV) with ≥1 comorbidity (ischaemic heart disease, heart failure, diabetes, anxiety, depression) were randomised to a patient-tailored self-management intervention (n=102) or UC (n=99). Daily symptom diaries were completed for 12 months. The primary outcome "COPD exacerbation days per patient per year" was assessed using intention-to-treat analyses.No significant difference was observed in the number of COPD exacerbation days per patient per year (self-management: median 9.6 (interquartile range (IQR) 0.7-31.1); UC: median 15.6 (IQR 3.0-40.3); incidence rate ratio (IRR) 0.87 (95% CI 0.54; 1.39); p=0.546). There was a significantly shorter duration per COPD exacerbation for self-management (self-management: median 8.1 (IQR 4.8-10.1) days; UC: median 9.5 (IQR 7.0-15.1) days; p=0.021), with no between-group differences in the total number of respiratory hospitalisations (IRR 0.76 (95% CI 0.42; 1.35); p=0.348), but a lower probability of ≥1 for respiratory-related hospitalisation compared to UC (relative risk 0.55 (95% CI 0.35; 0.87); p=0.008). No between-group differences were observed in all-cause hospitalisations (IRR 1.07 (95% CI 0.66; 1.72)) or mortality (self-management: n=4 (3.9%); UC: n=7 (7.1%); relative risk 0.55 (95% CI 0.17; 1.84)).Patient-tailored exacerbation action plans for COPD patients with comorbidities did not significantly reduce exacerbation days, but reduced the duration per COPD exacerbation and the risk of having at least one respiratory-related hospitalisation during follow-up, without excess all-cause mortality., Competing Interests: Conflict of interest: A. Lenferink reports grants from Stichting Astmabestrijding (SAB) and GlaxoSmithKline (unrestricted grant), during the conduct of the study. Conflict of interest: J. van der Palen reports grants from Netherlands Lung Foundation, during the conduct of the study. Conflict of interest: P.D.L.P.M. van der Valk has nothing to disclose. Conflict of interest: P. Cafarella has nothing to disclose. Conflict of interest: A. van Veen has nothing to disclose. Conflict of interest: S. Quinn has nothing to disclose. Conflict of interest: C.G.M. Groothuis-Oudshoorn has nothing to disclose. Conflict of interest: M.G. Burt has nothing to disclose. Conflict of interest: M. Young has nothing to disclose. Conflict of interest: P.A. Frith has nothing to disclose. Conflict of interest: T.W. Effing reports grants from The Repat Foundation, Australian Lung Foundation and Dutch Asthma Foundation, during the conduct of the study., (Copyright ©ERS 2019.)

Glucocorticoids are frequently prescribed to patients with a wide range of inflammatory and autoimmune diseases. The semi-synthetic glucocorticoid prednisolone is most commonly prescribed and in two main patterns. Prednisolone is prescribed short term at medium-high doses to treat an acute inflammatory illness or long term at lower doses to attenuate chronic inflammatory disease progression. In hospitalized patients with acute prednisolone-induced hyperglycaemia, there is a distinct circadian pattern of glucose elevation, which occurs predominantly in the afternoon and evening. As a morning dose of isophane insulin has a pharmacokinetic pattern that matches this pattern of glucose elevation, treatment comprising a basal dose of morning isophane insulin in combination with short-acting insulin boluses is generally recommended. However, evidence is lacking that isophane-based basal bolus insulin is more efficacious than other insulin regimens. In outpatients, low-dose prednisolone causes a small increase in post glucose-load glucose concentration but no change in overall glycaemic control as measured by glycosylated haemoglobin. If treatment is indicated, metformin has been shown to be effective and may attenuate other adverse effects of long-term prednisolone therapy. Further studies are necessary in order to identify factors underlying the variability in response to insulin therapy and clinical benefits of treatment in hospitalized patients with prednisolone-induced hyperglycaemia. In outpatients prescribed low-dose prednisolone, the cardiovascular risk associated with postprandial hyperglycaemia and efficacy of hypoglycaemic therapies should be evaluated in future randomized clinical trials., (© 2018 European Society of Endocrinology)

Growth hormone (GH) replacement therapy was recently recommended by the Pharmaceutical Benefits Advisory Committee (PBAC) for listing on the Pharmaceutical Benefits Scheme for adults with severe GH deficiency and impaired quality of life. This approval was significant for two reasons. First, the application was initiated and coordinated by a health professional working group, who prepared a 'public interest' submission to PBAC. Second, it resulted in a recommendation to subsidise therapy for a rare disease after two prior rejections on the basis of uncertainty about efficacy and cost effectiveness. There are important lessons to learn about the power of professional groups to drive health policy and attain funding for rare diseases., (© 2018 Royal Australasian College of Physicians.)

Introduction: Manual determination of insulin dosing largely fails to optimise glucose control in type 1 diabetes. Automated insulin delivery via closed-loop systems has improved glucose control in short-term studies. The objective of the present study is to determine the effectiveness of 6 months' closed-loop compared with manually determined insulin dosing on time-in-target glucose range in adults with type 1 diabetes., Methods and Analysis: This open-label, seven-centre, randomised controlled parallel group clinical trial will compare home-based hybrid closed-loop versus standard diabetes therapy in Australia. Adults aged ≥25 years with type 1 diabetes using intensive insulin therapy (via multiple daily injections or insulin pump, total enrolment target n=120) will undertake a run-in period including diabetes and carbohydrate-counting education, clinical optimisation and baseline data collection. Participants will then be randomised 1:1 either to 26 weeks of MiniMed 670G hybrid closed-loop system therapy (Medtronic, Northridge, CA, USA) or continuation of their current diabetes therapy. The hybrid closed-loop system delivers insulin automatically to address basal requirements and correct to target glucose level, while bolus doses for meals require user initiation and carbohydrate estimation. Analysis will be intention to treat, with the primary outcome time in continuous glucose monitoring (CGM) target range (3.9-10.0 mmol/L) during the final 3 weeks of intervention. Secondary outcomes include: other CGM parameters, HbA 1c , severe hypoglycaemia, psychosocial well-being, sleep, cognition, electrocardiography, costs, quality of life, biomarkers of vascular health and hybrid closed-loop system performance. Semistructured interviews will assess the expectations and experiences of a subgroup of hybrid closed-loop users., Ethics and Dissemination: The study has Human Research Ethics Committee approval. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Results will be disseminated at scientific conferences and via peer-reviewed publications., Trial Registration Number: ACTRN12617000520336; Pre-results., Competing Interests: Competing interests: MIdB and NDC report receiving speaker honoraria from Medtronic. DJHW reports receiving speaker and advisory board honoraria from Medtronic. RWM reports receiving conference travel and accommodation support from Medtronic. JS reports that the ACBRD has received honoraria from Medtronic in relation to her speaking engagements and role in advisory boards. DNON reports receiving speaker honoraria and research grants from Medtronic., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Hyperglycemia is associated with increased morbidity and mortality in patients with an acute myocardial infarction (AMI). We evaluated whether complications after AMI are associated with absolute or relative glycemia., Methods: A total of 192 patients with AMI were randomized to intensive or conventional insulin therapy. Absolute glycemia was defined as mean blood glucose level (BGL) during the first 24 h following randomization. Relative glycemia was defined by the stress hyperglycaemia ratio (SHR), calculated as mean BGL divided by average glucose concentration over the prior 3 months estimated from glycosylated haemoglobin. The primary endpoint was a "complicated AMI", defined as an AMI complicated by death, congestive cardiac failure, arrhythmia, cardiac arrest, reinfarction, cardiogenic shock, inotrope use or emergency revascularization., Results: There was not a significant association between mean BGL and complicated AMI (odds ratio (OR) 1.05 per mmol/L glucose increment, 95% confidence intervals (CI) 0.93-1.19). In contrast, SHR was positively associated with a complicated myocardial infarction (OR 1.22 per 0.1 SHR increment, 95% CI 1.06-1.42), and individual complications of death (OR 1.55, 95% CI 1.14-2.11), congestive cardiac failure (OR 1.27, 95% CI 1.05-1.54), arrhythmia (OR 1.31, 95% CI 1.12-1.54) and cardiogenic shock (OR 1.42, 95% CI 1.03-1.97). The relationship between SHR and a complicated AMI was independent of diabetic status, intensive insulin therapy, sex and hypoglycemia., Conclusions: Relative, but not absolute, glycemia during insulin treatment is independently associated with complications after an AMI. Future studies should investigate whether basing therapeutic glycaemic targets on relative glycemia improves patient outcomes.

Competing Interests: Conflict of interest: Morton Burt was previously awarded a competitive Pfizer cardiovascular lipid research grant.

Purpose: Internal carotid artery (ICA) aneurysms have rarely been found in association with marked hyperprolactinemia in the absence of prolactinoma; the cause of hyperprolactinemia has never been investigated. We aimed to determine if the observed hyperprolactinemia is due to a vascular-derived or known prolactin secretagogue from the injured ICA, analogous to pregnancy-associated hyperprolactinemia putatively due to placental factors., Methods: We conducted a case series and literature review of individuals with severe hyperprolactinemia in association with ICA aneurysms. In two affected patients at our institutions, we performed RT-PCR and ELISA of prolactin secretagogues that are produced by vascular tissue and/or upregulated in pregnancy: AGT (encoding angiotensinogen), TAC1 (encoding substance P), HDC (encoding the enzyme responsible for conversion of histidine to histamine), and prolactin-releasing hormone (PRLH). Patient blood samples were compared to pregnancy blood samples (positive controls) and middle-aged male blood samples (negative controls)., Results: Two men presented with serum prolactin >100-fold normal associated with cavernous ICA aneurysms and no pituitary adenoma. Aneurysm stenting in one man more than halved his serum prolactin. In both men, dopamine agonist therapy markedly reduced serum prolactin. RT-PCR and ELISA showed no differences between patients and controls in AGT, TAC1 or HDC expression or PRLH titre, respectively. Literature review revealed 11 similar cases., Conclusions: We propose the term 'vasculogenic hyperprolactinemia' to encompass the hyperprolactinemia associated with ICA aneurysms. This may be mediated by an endothelial factor capable of paracrine stimulation of lactotrophs; however, angiotensin II, substance P, histamine and PRLH appear unlikely to be causative.

We report two cases of hypoglycaemia; one with apparently spontaneous hypoglycaemia and one with presumed insulin overdose. In both cases insulin concentration was normal when measured with the Roche immunoassay, but elevated when remeasured with the Advia Centaur immunoassay and a diagnosis of hypoglycaemia secondary to insulin analogue administration was made. These cases highlight that physicians need to understand the binding characteristics of the insulin immunoassay they use., (© 2017 Royal Australasian College of Physicians.)

Background and Aims: The effects of low dose prednisolone on circulating markers of endothelial function, the arginine metabolites asymmetric dimethyl arginine (ADMA), mono methyl arginine (MMA), and homoarginine, are uncertain. We assessed whether patients with rheumatoid arthritis have perturbations in arginine metabolite concentrations that are reversed by low dose prednisolone., Methods: Eighteen rheumatoid arthritis patients who had not taken prednisolone for >6 months (non-glucocorticoid (GC) users), 18 rheumatoid arthritis patients taking continuous oral prednisolone (6.5 ± 1.8 mg/day) for >6 months (GC users) and 20 healthy controls were studied. Fasting plasma concentrations of ADMA, MMA, and homoarginine were measured by ultra-performance liquid-chromatography. Baseline data from non-GC users were compared with healthy controls to assess the effect of rheumatoid arthritis. The change in arginine metabolites in non-GC users after 7 days of prednisolone (6 mg/day) was used to assess the acute effects of prednisolone. Baseline data from non-GC users were compared with GC users to assess the chronic effects of prednisolone., Results: Non-GC users had higher ADMA (0.59 ± 0.03 vs. 0.47 ± 0.01 μM, p = 0.004) and MMA concentrations (0.10 ± 0.01 vs. 0.05 ± 0.00 μM, p < 0.001) than controls. The only change with acute prednisolone was a reduction in homoarginine (1.23 ± 0.06 vs. 1.08 ± 0.06 μM, p = 0.04) versus baseline. GC users had lower concentrations of ADMA (0.51 ± 0.02 vs. 0.59 ± 0.03 μM, p = 0.03) than non-GC users., Conclusions: Rheumatoid arthritis patients have higher concentrations of ADMA and MMA, inhibitors of endothelial function. Chronic, but not acute, prednisolone therapy is associated with a lower ADMA concentration, suggesting a salutary effect of long-term glucocorticoid treatment on endothelial function., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: Prednisolone causes hyperglycaemia predominantly between midday and midnight. Consequently, glargine-based basal-bolus insulin regimens may under treat daytime hyperglycaemia and cause nocturnal hypoglycaemia. We investigated whether an isophane-based insulin regimen is safer and more effective than a glargine-based regimen in hospitalized patients., Materials and Methods: Fifty inpatients prescribed ≥20 mg/day prednisolone acutely with (1) finger prick blood glucose level (BGL) ≥15 mmol/L or (2) BGLs ≥10 mmol/L within the previous 24 hours were randomized to either insulin isophane or glargine before breakfast and insulin aspart before meals. The initial daily insulin dose was 0.5 U/kg bodyweight or 130% of the current daily insulin dose. Glycaemic control was assessed using a continuous glucose monitoring system., Results: On Day 1, there were no significant differences in percentage of time outside a target glucose range of 4 to 10 mmol/L (41.3% ± 5.5% vs 50.0% ± 5.7%, P  = .28), mean daily glucose (10.2 ± 0.7 vs 10.8 ± 0.8 mmol/L, P  = .57) or glucose <4 mmol/L (2.2% ± 1.1% vs 2.0% ± 1.3%, P  = .92) in patients randomized to isophane and glargine. In patients treated for 3 days, the prednisolone dose was reduced ( P  = .02) and the insulin dose was increased over time ( P  = .02), but the percentage of time outside the 4 to 10 mmol/L glucose range did not differ over time ( P  = .45) or between groups ( P  = .24)., Conclusions: There were no differences in the efficacy or safety of the isophane and glargine-based insulin regimens. We recommend an initial daily insulin dose of 0.5 units/kg bodyweight if not on insulin, a greater than 30% increase in pre-prednisolone insulin dose and larger insulin dose adjustments in patients with prednisolone-induced hyperglycaemia., (© 2016 John Wiley & Sons Ltd.)

Background and Aims: Glucocorticoids could impair vascular function directly, or indirectly by reducing insulin sensitivity. The aim of this study was to determine the direct and indirect effects of acute and chronic low dose prednisolone on arterial stiffness and endothelial function., Methods: Twelve subjects with inflammatory arthritis, who had not taken oral glucocorticoids for ≥6 months, and 12 subjects with inflammatory arthritis, taking chronic (>6 months) low dose (6.3 ± 2.2 mg/day) prednisolone, were studied. Patients not on glucocorticoids underwent measurement of arterial stiffness (pulse wave velocity (PWV)) and endothelial function (reactive hyperaemia index (RHI)) before and after 7-10 days of prednisolone (6 mg/day), to assess the acute effects of prednisolone. Baseline data from patients not on glucocorticoids were compared with patients on long-term prednisolone to assess the chronic effects of prednisolone. Hepatic insulin sensitivity was estimated from percentage suppression of endogenous glucose production and peripheral insulin sensitivity as glucose infusion rate (M/I) during a hyperinsulinaemic-euglycaemic clamp., Results: There were no significant changes in PWV with acute (9.2 ± 0.8 vs. 8.9 ± 0.8 m/sec, p = 0.33) or chronic (8.9 ± 0.8 vs. 9.0 ± 0.7 m/sec, p = 0.69) prednisolone. In multiple regression analysis, PWV was negatively associated with M/I during hyperinsulinemic-euglycemic clamp (p = 0.02), but not with suppression of endogenous glucose production (p = 0.15) or glucocorticoid use (p = 0.70). Chronic (2.4 ± 0.2 vs. 1.9 ± 0.1, p = 0.02), but not acute (1.8 ± 0.2 vs. 1.9 ± 0.1, p = 0.24), prednisolone resulted in a higher RHI., Conclusions: Arterial stiffness is not affected by low dose prednisolone per se, but is negatively associated with peripheral insulin sensitivity. Patients with rheumatoid arthritis taking long-term prednisolone had better endothelial function., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Glucocorticoids can cause postprandial hyperglycaemia, but the effects on postprandial energy and fat metabolism are uncertain. We investigated the effects of acute and chronic low-dose prednisolone on fasting and postprandial energy expenditure and substrate metabolism., Design: An open interventional and cross-sectional study was undertaken., Patients and Measurements: Eighteen patients who had not taken oral glucocorticoids for ≥6 months were studied before and after 7 days prednisolone (6 mg/day) to assess the acute effects of prednisolone. Baseline data from patients, not on glucocorticoids, were compared with 18 patients on long-term prednisolone (6·5 ± 1·8 mg/day for >6 months) to assess the chronic effects. Energy expenditure and substrate oxidation were measured using indirect calorimetry before and after a mixed meal. Adipocyte insulin resistance index and insulin-mediated suppression of NEFA were calculated from fasting and postprandial insulin and NEFA concentrations., Results: There were no significant differences in resting energy expenditure or diet-induced thermogenesis with prednisolone. Acute (-2·1 ± 6·2 vs -16·3 ± 4·8 mg/min, P = 0·01) and chronic (-1·4 ± 2·8 vs -16·3 ± 4·8 mg/min, P = 0·01) prednisolone attenuated postprandial suppression of fat oxidation. Chronic (31·6 ± 3·8 vs 17·0 ± 3·3, P = 0·007), but not acute, prednisolone increased adipocyte insulin resistance index. However, insulin-mediated suppression of NEFA was not significantly different after acute or chronic prednisolone., Conclusions: Prednisolone does not alter energy expenditure. However, even at low doses, prednisolone exerts adverse effects on fat metabolism, which could exacerbate insulin resistance and increase cardiovascular risk. Attenuated postprandial suppression of fat oxidation, but not lipolysis, suggests that prednisolone causes greater insulin resistance in skeletal muscle than in adipocytes., (© 2016 John Wiley & Sons Ltd.)

Vitamin D deficiency is associated with increased arterial stiffness. However, the mechanisms underlying this association have not been clarified. The aim was to investigate whether changes in autonomic nervous system activity could underlie an association between 25 hydroxy vitamin D and arterial stiffness. A total of 49 subjects (age = 60 ± 8 years, body mass index = 26.7 ± 4.6 kg/m², 25 hydroxy vitamin D = 69 ± 22 nmol/L) underwent measurements of pulse wave velocity (PWV) and augmentation index (AIx), spontaneous baroreflex sensitivity, plasma metanephrines and 25 hydroxy vitamin D. Subjects with 25 hydroxy vitamin D ≤ 50 nmol/L were restudied after 200,000 International Units 25 hydroxy vitamin D. Plasma metanephrine was positively associated with AIx (p = 0.02) independent of age, sex, smoking and cholesterol and negatively associated with 25 hydroxy vitamin D (p = 0.002) independent of age, sex and season. In contrast, there was no association between baroreflex sensitivity and 25 hydroxy vitamin D (p = 0.54). Treatment with vitamin D increased 25 hydroxy vitamin D from 43 ± 5 to 96 ± 24 nmol/L (p < 0.0001) but there was no significant change in plasma metanephrine (115 ± 25 vs. 99 ± 39 pmol/L, p = 0.12). We conclude that as plasma metanephrine was negatively associated with 25 hydroxy vitamin D and positively with AIx, it could mediate an association between these two variables. This hypothesis should be tested in larger interventional studies., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Objective: Postprandial hyperglycaemia is associated with increased arterial stiffness and cardiovascular events. Low-dose prednisolone causes insulin resistance that typically manifests as postprandial hyperglycaemia. We investigated whether prednisolone causes postprandial vascular dysfunction in a cohort of patients with rheumatoid arthritis., Design: An open interventional and cross-sectional study was undertaken., Patients and Measurements: Eighteen subjects with rheumatoid arthritis who had not taken oral glucocorticoids for ≥6 months were studied before and after prednisolone 6 mg/day for 7 days to determine the acute effects of prednisolone. Pre-prednisolone data were compared to 18 subjects with rheumatoid arthritis taking long-term (>6 months) prednisolone (6·5 ± 1·8 mg/day) to assess the chronic effects of prednisolone. Augmentation index (by applanation tonometry) and reactive hyperaemia index (by peripheral artery tonometry) were measured before and after a mixed-meal (10 kcal/kg, 45% carbohydrate, 15% protein, 40% fat). Insulin sensitivity was estimated by the Matsuda index and sympathetic nervous system activity from urinary noradrenaline excretion., Results: Matsuda index was lower after acute (2·0 ± 1·0 vs 3·6 ± 1·1, P = 0·01) and chronic (1·9 ± 1·0 vs 3·6 ± 1·1, P = 0·04) prednisolone. Postprandial augmentation index was lower after acute prednisolone (2551 ± 197 vs 2690 ± 272%*min, P ≤ 0·001), but not chronic prednisolone. There were no significant differences in reactive hyperaemia index with acute or chronic prednisolone. Noradrenaline excretion was lower after acute (54 ± 8 vs 93 ± 23 nmol/6 h, P = 0·02), but not chronic, prednisolone., Conclusions: Prednisolone-induced insulin resistance is not associated with postprandial vascular dysfunction in patients with rheumatoid arthritis. Reduced sympathetic activity may contribute to the reduction in postprandial arterial stiffness with acute prednisolone., (© 2015 John Wiley & Sons Ltd.)

Objective: Thrombospondin-1 (TSP1) is a matricellular protein whose gene expression has previously been shown to increase acutely after exposure to dexamethasone in vitro. The aim of this study was to determine if TSP1 is altered by acute and chronic states of glucocorticoid excess in human subjects., Design and Methods: Three studies have been undertaken to assess the difference or change in TSP1 in response to altered glucocorticoid activity: i) an acute interventional study assessed the effects of a single 4 mg dose of dexamethasone in 20 healthy volunteers; ii) a cross-sectional study compared plasma TSP1 in 20 healthy volunteers and eight patients with Cushing's syndrome; iii) an interventional study assessed the effect on plasma TSP1 of an increase in hydrocortisone dose from ≤20 mg/day to 30 mg/day for 7 days in 16 patients with secondary adrenal insufficiency., Results: In healthy volunteers, 4 mg dexamethasone significantly increased peripheral blood mononuclear cell (PBMC) TSP1 mRNA levels (P<0.0001) and plasma TSP1 concentrations (P<0.0001), peaking at 12 h. Median (interquartile range) plasma TSP1 was higher in Cushing's, 638 (535-756) ng/ml, than in healthy volunteers, 272 (237-336) ng/ml (P<0.0001). Plasma TSP1 >400 ng/ml diagnosed Cushing's syndrome with sensitivity of 100% and specificity of 85%. The higher hydrocortisone dose increased plasma TSP1 from 139 (86-199) to 256 (133-516) ng/ml, (P<0.01) in patients with secondary adrenal insufficiency., Conclusions: TSP1 is a glucocorticoid responsive protein in humans. Further research is required to determine if plasma TSP1 has a role as a glucocorticoid biomarker., (© 2016 European Society of Endocrinology.)

Context: Hyperglycemia in hospitalized patients is associated with increased morbidity and mortality., Objective: We examined whether critical illness is more strongly associated with relative or absolute hyperglycemia., Design: The study was an observational cohort study., Patients and Setting: A total of 2290 patients acutely admitted to a tertiary hospital., Main Outcome Measure: The relative hyperglycemia (stress hyperglycemia ratio [SHR]) was defined as admission glucose divided by estimated average glucose derived from glycosylated hemoglobin. The relationships between glucose and SHR with critical illness (in-hospital death or critical care) were examined., Results: In univariable analyses, SHR (odds ratio, 1.23 per 0.1 increment [95% confidence interval, 1.18-1.28]; P < .001) and glucose (odds ratio, 1.18 per mmol/L [1.13-1.23]; P < .001) were associated with critical illness. In multivariable analysis, the association was maintained for SHR (odds ratio, 1.20 per 0.1 increment [1.13-1.28]; P < .001), but not glucose (odds ratio, 1.03 per mmol/L [0.97-1.11]; P = .31). Background hyperglycemia affected the relationship between glucose (P = .002) and critical illness, but not SHR (P = .35) and critical illness. In patients with admission glucose ≤ 10 mmol/L, the odds ratio for critical illness was higher in the fourth (2.4 [1.4-4.2]; P = .001) and fifth (3.9 [2.3-6.8]; P < .001) SHR quintiles than in the lowest SHR quintile., Conclusions: SHR controls for background glycemia and is a better biomarker of critical illness than absolute hyperglycemia. SHR identifies patients with relative hyperglycemia at risk of critical illness. Future studies should explore whether basing glucose-lowering therapy on relative, rather than absolute, hyperglycemia improves outcomes in hospitalized patients.

Background/aim: Few studies have specifically investigated treatment of prednisolone-induced hyperglycaemia., Aim: To determine if a basal bolus insulin (BBI) protocol for inpatient hyperglycaemia is effective in patients prescribed acute prednisolone for an inflammatory disease., Methods: In a cross-sectional study, 66 patients with type 2 diabetes admitted to a general medical ward and treated with BBI for up to 5 days were studied. Twenty-four patients were taking prednisolone ≥10 mg/day to treat an acute inflammatory disease. The remaining 42 patients were a control group. The primary outcome was mean daily blood glucose level., Results: There were no significant differences in glycosylated haemoglobin (8.1 ± 1.0 vs 8.1 ± 1.6%, P = 0.88), age (77 ± 11 vs 75 ± 14 years, P = 0.57), male sex (63 vs 60%, P = 0.81) or body mass index (30.0 ± 5.3 vs 30.2 ± 11.5 kg/m(2) , P = 0.90) between patients taking prednisolone and controls. Mean daily glucose concentration was higher in patients taking prednisolone than in controls (12.2 ± 0.3 vs 10.0 ± 0.1 mmol/L, P < 0.001). Blood glucose level was higher in patients on prednisolone at 1700 h (14.6 ± 0.6 vs 10.3 ± 0.3 mmol/L, P < 0.001) and 2100 h (14.5 ± 0.6 vs 10.5 ± 0.3 mmol/L, P < 0.001), with no significant differences at 0700 h and 1200 h. These findings occurred despite patients taking prednisolone receiving a higher daily insulin dose than controls (0.67-0.70 vs 0.61-0.65 U/kg, P = 0.001) because of higher doses of ultra-rapid-acting insulin at 1200 h and 1700 h., Conclusions: Hospitalised patients taking prednisolone had substantial afternoon and evening hyperglycaemia despite receiving BBI via a protocol for inpatient hyperglycaemia. Specific insulin regimens for prednisolone-induced hyperglycaemia are needed that recommend more insulin during this time period., (© 2015 Royal Australasian College of Physicians.)

Aims: To determine if diabetic lipaemia is caused by loss of function mutations in the lipoprotein lipase gene, LPL., Methods: We conducted a case-control study over 2 years in two tertiary care hospitals in South Australia. Six patients with a history of diabetic lipaemia and 12 control subjects, with previous diabetic ketoacidosis and peak triglyceride concentrations < 2.4 mmol/l were included. Participants were well at the time of study investigations., Results: Only one patient with lipaemia had a loss of function mutation in LPL and no functional mutations in APOC2 or GPIHBP1 were identified. The mean lipoprotein lipase concentration was lower in patients with diabetic lipaemia than in control subjects (306 vs. 484 μg/l, P = 0.04). The mean fasting C-peptide concentration was higher in patients with diabetic lipaemia than in control subjects (771 vs. 50 pmol/l; P = 0.001)., Conclusions: Lipoprotein lipase deficiency in patients with a history of diabetic lipaemia was predominantly quantitative, rather than secondary to mutations in LPL, APOC2 or GPIHBP1. The majority of patients with severe hypertriglyceridaemia in diabetic ketoacidosis may have ketosis-prone Type 2, rather than Type 1, diabetes., (© 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.)

Background: Patient-initiated action plans are an important component of COPD self-management (SM) interventions. When integrated into SM interventions, these action plans have proven to be effective in reducing exacerbation severity, hospitalisations, and costs and in improving health status in patients with COPD without severe comorbidities. Because of overlap in symptoms, a self-treatment (ST) approach that focuses solely on traditional symptoms of COPD is inadequate for patients with COPD and comorbidities. The COPE-III SM intervention combines (I) patient-initiated action plans that are tailored to the individual's co-morbid disease(s), and (II) ongoing nurse support. In this paper we provide information regarding the integration of information from two previous COPD SM studies (COPE I and II) in the development of the current COPE-III ST approach., Materials and Methods: COPE-III ST materials include daily symptom diaries and action plans that take patient's common comorbidities [chronic heart failure (CHF), anxiety, depression, ischaemic heart disease (IHD), and diabetes] into account. The comorbid diary and action plans components were developed in collaboration with multiple disease-experts., Results: Previous SM studies have highlighted some essential topics that need to be considered when developing a SM or ST approach: 'when to initiate ST', 'how to optimize materials and safety', and 'how to achieve behavioural change'. In the COPE-III study, ST is initiated after a significant change in symptoms. This is consistent with the COPE-II approach and was implemented because disease symptoms are often present even when patients are stable. We have tried to ensure patient safety by providing an easily accessible case-manager to patients throughout their involvement in the study. Furthermore, a psychologist has ensured the use of behavioural change techniques throughout the intervention., Conclusions: We should continue to learn from our experiences with SM interventions to further optimize future SM and ST interventions. The use of materials that are suitable for different levels of patient literacy and the training of health care providers are other points of improvement.

Context: Higher hydrocortisone doses are associated with increased overall and cardiovascular mortality in ACTH-deficient patients. The mechanisms underlying this association have not been fully defined., Objective: The aim of the study was to determine whether increasing hydrocortisone (or equivalent) to 30 mg/d in ACTH-deficient patients increased cardiovascular risk and whether a reduction in insulin sensitivity and attenuation of insulin's hemodynamic effects was responsible for this effect., Design: We conducted an open interventional study between 2011 and 2013., Setting: The study was performed in the Endocrine Research Unit, Repatriation General Hospital, Adelaide, Australia., Patients: Seventeen ACTH-deficient subjects taking hydrocortisone (≤20 mg/d) for at least 6 months were studied., Intervention: Subjects were studied before and after a 7-day increase in hydrocortisone to 30 mg/d., Main Outcome Measure: The primary outcome was the change in pulse wave velocity, both fasting and after a 75-g oral glucose load., Results: Fasting and post-glucose load pulse wave velocities were not significantly different on the higher glucocorticoid dose. Fasting augmentation index (24.9 ± 2.7 vs 22.6 ± 2.6%; P = .04) and reactive hyperemia index (2.3 ± 0.2 vs 2.0 ± 0.2; P = 0.04) were lower on the higher glucocorticoid dose, with no significant difference in the post-glucose load changes in these variables. There were no significant changes in insulin sensitivity or secretion on the higher glucocorticoid dose., Conclusions: Endothelial dysfunction may contribute to the increased cardiovascular mortality associated with higher glucocorticoid doses. This may be a direct glucocorticoid effect, not mediated by insulin resistance. ACTH-deficient patients should thus be prescribed the lowest safe glucocorticoid replacement dose.

Context: Factitious Cushing's syndrome is extremely rare. The diagnosis is challenging as cross-reactivity of synthetic corticosteroids or their metabolites in immunoassay measurements of plasma or urinary cortisol can make distinguishing between true and factitious Cushing's syndrome difficult. Adrenocorticotropin (ACTH) is usually suppressed in factitious Cushing's syndrome., Patient: A 54-year-old woman presented with clinical and biochemical features of Cushing's syndrome and an unsuppressed ACTH concentration. She denied recent exogenous corticosteroid use., Investigations and Results: Initial investigations revealed a markedly elevated urinary free cortisol, mildly elevated midnight salivary cortisol and normal morning cortisol concentration. Plasma ACTH was not suppressed at 13 ng/l (RR 10-60 ng/l). A pituitary MRI was normal, but inferior petrosal sinus sampling (IPSS) revealed a post corticotrophin releasing hormone ACTH ratio >20:1 in the left petrosal sinus. Ketoconazole therapy amplified discordance between the urinary free and morning plasma cortisol concentrations. Further investigation of this discordance using high-pressure liquid chromatography tandem mass spectrometry (HPLC-MS/MS) revealed a urinary free cortisol excretion of only 20 nmol/24 h, but prednisolone excretion of 16,200 nmol/24 h., Conclusions: Factitious Cushing's syndrome can mimic endogenous ACTH-dependent hypercortisolism during initial investigations and IPSS. This case highlights the importance of (i) recognizing the significance of discordant results; (ii) using an ACTH assay capable of reliably differentiating ACTH-dependent from ACTH-independent Cushing's syndrome; and (iii) appreciating that IPSS is only useful to localize the source of ACTH in confirmed ACTH-dependent Cushing's syndrome. In this case, measurement of corticosteroids by HPLC-MS/MS was essential in reaching the correct diagnosis., (© 2013 John Wiley & Sons Ltd.)

Objective: The metabolic effects of low-dose prednisolone and optimal management of glucocorticoid-induced diabetes are poorly characterized. The aims were to investigate the acute effects of low-dose prednisolone on carbohydrate metabolism and whether long-term low-dose prednisolone administration increases visceral adiposity, amplifying metabolic perturbations., Research Design and Methods: Subjects with inflammatory rheumatologic disease without diabetes mellitus were recruited. Nine subjects (age, 59 ± 11 years) not using oral glucocorticoids were studied before and after a 7- to 10-day course of oral prednisolone 6 mg daily. Baseline data were compared with 12 subjects (age, 61 ± 8 years) using continuous long-term prednisolone (6.3 ± 2.2 mg/day). Basal endogenous glucose production (EGP) was estimated by 6,6-(2)H2 glucose infusion, insulin sensitivity was estimated by two-step hyperinsulinemic-euglycemic clamp, insulin secretion was estimated by intravenous glucose tolerance test, and adipose tissue areas were estimated by computed tomography., Results: Prednisolone acutely increased basal EGP (2.44 ± 0.46 to 2.65 ± 0.35 mg/min/kg; P = 0.05) and reduced insulin suppression of EGP (79 ± 7 to 67 ± 14%; P = 0.03), peripheral glucose disposal (8.2 ± 2.4 to 7.0 ± 1.6 mg/kg/min; P = 0.01), and first-phase (5.9 ± 2.0 to 3.9 ± 1.6 mU/mmol; P = 0.01) and second-phase (4.6 ± 1.7 to 3.6 ± 1.4 mU/mmol; P = 0.02) insulin secretion. Long-term prednisolone users had attenuated insulin suppression of EGP (66 ± 14 vs. 79 ± 7%; P = 0.03) and nonoxidative glucose disposal (44 ± 24 vs. 62 ± 8%; P = 0.02) compared with nonglucocorticoid users, whereas basal EGP, insulin secretion, and adipose tissue areas were not significantly different., Conclusions: Low-dose prednisolone acutely perturbs all aspects of carbohydrate metabolism. Long-term low-dose prednisolone induces hepatic insulin resistance and reduces peripheral nonoxidative glucose disposal. We conclude that hepatic and peripheral insulin sensitivity should be targeted by glucose-lowering therapy for glucocorticoid-induced diabetes.

We have assessed whether glucose concentration and patient outcome are related in hospitalised patients when glycaemia is quantified in detail. Continuous glucose monitoring was performed on 47 consecutive subjects with an acute exacerbation of chronic obstructive pulmonary disease. Length of hospital stay increased by 10% for each mmol/L increase in mean glucose (P = 0.01). In a multivariable analysis, mean glucose was independently associated with length of hospital stay (P = 0.02). These data add weight to evidence that hyperglycaemia may adversely affect patient outcomes in hospitalised patients., (© 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.)