A randomised controlled trial of additional bolus insulin using an insulin-to-protein ratio compared with insulin-to-carbohdrate ratio alone in people with type 1 diabetes following a carbohydrate-restricted diet.

AIMS: Postprandial hyperglycemia can be problematic for people with type 1 diabetes (T1DM) following carbohydrate-restricted diets. Bolus insulin calculated for meal protein plus carbohydrate may help. This study evaluated the effect of additional bolus insulin using an insulin-to-protein ratio (IPR) on glycaemic control. MATERIALS AND METHODS: Participants with T1DM aged ≥18-years were randomly allocated (1:1) to either carbohydrate and protein-based, or carbohydrate-based insulin dosing alone for 12 weeks while following a carbohydrate-restricted diet (50-100 g/day). Measurement of HbA1c and continuous glucose monitoring occurred at baseline and 12 weeks, with assessment of participant experience at 12 weeks. RESULTS: Thirty-four participants were randomised, 22 female, mean(SD): age 39.2 years (12.6) years; diabetes duration 20.6 years (12.9); HbA1c 7.3 % (0.8), 56.7 mmol/mol (9.2). Seven in each group used insulin pump therapy. HbA1c reduced at 12 weeks with no difference between treatments: mean (SD) control 7.2 % (1.0), 55.7 mmol/mol (10.6); intervention 6.9 % (0.7), 52.3 mmol/mol (7.2) (p = 0.65). Using additional protein-based insulin dosing compared with carbohydrate alone, there was no difference in glycaemic variability, time spent in euglycemic range (TIR), or below range. Participants using IPR reported more control of their diabetes, but varying levels of distress. CONCLUSIONS: Additional bolus insulin using an IPR did not improve glycaemic control or TIR in patients with well controlled T1DM following a carbohydrate-restricted diet. Importantly, the use of the IPR does not increase the risk of hypoglycemia and may be preferred.

The value of plasma metanephrine measurements during adrenal vein sampling.

Objective: The assessment of primary aldosteronism incorporates adrenal vein sampling (AVS) to lateralize aldosterone excess. Current adrenal vein sampling protocols rely on concurrent cortisol measurements to assess successful cannulation and lateralization and may be inaccurate in the setting of autonomous cortisol secretion. We aimed to compare the measurement of plasma cortisol and metanephrine concentrations to assess cannulation and lateralization during AVS. Design: This is a diagnostic accuracy study in a tertiary referral endocrinology department. Methods: Forty-one consecutive patients with confirmed primary aldosteronism undergoing AVS (49 procedures) were included. None had cortisol autonomy. The use of plasma metanephrine-based ratios were compared with standard cortisol-based ratios to assess cannulation and lateralization during ACTH-stimulated AVS. Results: There was strong agreement between a cortisol selectivity index (SI) ≥5.0 and an adrenal vein (AV) to peripheral vein (PV) plasma metanephrine ratio (AVmet-PVmet) of ≥12.0 to indicate successful cannulation of the AV (n = 117, sensitivity 98%, specificity 89%, positive predictive value (PPV) 95%, negative predictive value (NPV) 94%). There was strong agreement between the standard cortisol-based SI and an AV plasma metanephrine-to-normetanephrine ratio (AVmet-AVnormet) of ≥2.0 to indicate successful cannulation (n = 117, sensitivity 93%, specificity 86%, PPV 94%, NPV 84%). There was strong agreement between the cortisol- or metanephrine-derived lateralization index (LI) > 4.0 for determining lateralization (n = 26, sensitivity 100%, specificity 94.1%, PPV 91.6%, NPV 100%). Conclusions: Ratios incorporating plasma metanephrines provide comparable outcomes to standard cortisol-based measurements for interpretation of AVS. Further studies are required to assess the use of metanephrine-derived ratios in the context of confirmed cortisol autonomy. Significance statement: Primary aldosteronism is a common cause of secondary hypertension, and adrenal vein sampling remains the gold standard test to assess lateralization. Cortisol-derived ratios to assess cannulation and lateralization may be affected by concurrent cortisol dysfunction, which is not uncommon in the context of primary aldosteronism. Our study showed comparable outcomes when using accepted cortisol-derived or metanephrine-derived ratios to determine cannulation and lateralization during adrenal vein sampling. Further research is required to validate these findings and to assess the use of metanephrine-derived ratios in the context of confirmed concurrent cortisol dysfunction.

Increasing rates of referrals for investigation of primary aldosteronism at a tertiary centre.

AIM: To describe the frequency and characteristics of patients referred for specialist investigation of primary aldosteronism (PA) in the lower North Island over a 5-year period, and the outcomes of those who received treatment. METHODS: Patients who underwent confirmatory testing or treatment for PA at Wellington Regional Hospital were retrospectively identified and data were collected from electronic clinical records. RESULTS: There has been a five-fold increase in both referrals and confirmatory testing for PA in 2021 compared to 2015. Compared to patients without PA, those eventually diagnosed with PA had a higher ARR, serum sodium, antihypertensive requirement and cardiovascular disease prevalence, as well as lower serum renin, potassium and GFR (all p <0.05), but similar blood pressure. Complete or partial clinical success was achieved in 96% of surgically treated patients compared with 70% of medically treated patients. Thirty-nine percent of patients experienced minor adverse effects with spironolactone and only one significant adverse event was experienced perioperatively. CONCLUSIONS: The rate of referrals and confirmatory testing for PA are increasing in our region. Adrenalectomy and mineralocorticoid antagonist therapy are both safe and effective treatments, although minor adverse effects were common with spironolactone.

Where can you wear your Libre? Using the FreeStyle Libre continuous glucose monitor on alternative sites.

AIM: To investigate the accuracy and acceptability of the FreeStyle Libre Flash continuous glucose monitoring system (FSL-CGM) at alternative sites during free living and under experimental conditions. MATERIALS AND METHODS: Participants with type 1 diabetes were provided with three FSL-CGM sensors applied to the upper arm, the lower back, and the anterior chest. On day 2 or 3, FSL-CGM sensor glucose was compared with venous glucose following a standard meal, during and after an exercise test, and after skin cooling. Participants completed 14-day use of the sensors with concomitant sensor scanning at all sites and capillary glucose tests. The primary outcome was accuracy between sensor sites of 14-day mean glucose. Clarke's error grids, precision absolute relative deviation, and mean absolute relative deviation were calculated. RESULTS: In the 20 participants, compared with the arm sensor, the accuracy of the back sensor and the chest sensor was 97.9% and 98%, respectively. Under experimental conditions, the arm sensor was more accurate than that of the back and chest. All the sensors recorded higher glucose concentration than venous samples during exercise. The arm and chest sites were most preferred, with the greatest sensor failures from the back. CONCLUSIONS: The FSL-CGM is clinically accurate when the sensors are applied to alternate chest or back sites. Greater variability occurs during rapid changes in glucose concentration with all sensor sites compared with venous glucose. Understanding these variabilities allows appropriate use of an economically viable continuous glucose monitor.

Optimizing the management of hypoglycaemia in individuals with type 2 diabetes: A randomized crossover comparison of a weight-based protocol compared with two fixed-dose glucose regimens.

AIMS: To determine whether an individualized body weight-based glucose treatment in adults with type 2 diabetes (T2DM) is more likely to resolve hypoglycaemia with a single treatment without excessive rebound hyperglycaemia compared to fixed doses of 12 or 30 g of glucose. METHODS: Adults with T2DM were enrolled in a cross-over study. Each episode of hypoglycaemia (capillary glucose <4.0 mmol/L) was randomly assigned to 1 of 3 treatment protocols: 0.3 g glucose/kg body-weight or a fixed dose of either 12 or 30 g glucose, independent of weight. All participants received each treatment in random order for up to 15 hypoglycaemic episodes. Glucose was re-tested 10 minutes after treatment, with a repeat dose if still <4 mmol/L. RESULTS: Mean (SD) age of the 30 participants was 68 (8.1) years, mean weight was 91.5 (16.8) kg and mean HbA1c was 58.7 (9.2) mmol/mol. Among a total of 244 episodes of hypoglycaemia, 10 participants had 15 treatment episodes and 18 participants had fewer than 10 treatment episodes. The odds ratio, adjusted for multiple comparisons, for resolution of hypoglycaemia at 10 minutes, comparing weight-based treatment and 12 g treatment was 3.2 (95% CI, 1.1-9.0), P = .009, comparing 30 g treatment and 12 g treatment was 8.9 (95% CI, 2.2-36.6), P < .001, and comparing weight-based treatment and 30 g treatment was 0.36 (95% CI, 0.08-1.67) P = .10. CONCLUSION: In T2DM, both a weight-based 0.3 g/kg treatment and a fixed 30 g glucose treatment result in higher blood glucose than a 12 g treatment, along with increased probability of resolution of hypoglycaemia after 10 minutes. Both treatments result in an excess of mild rebound hyperglycaemia (>8 mmol/L) at 30 minutes.

Identifying coronary artery disease in men with type 2 diabetes: osteoprotegerin, pulse wave velocity, and other biomarkers of cardiovascular risk.

OBJECTIVES: In patients with type 2 diabetes, high serum levels of osteoprotegerin (OPG) have been associated with a greater risk of cardiovascular events. However, it remains unclear how well OPG performs when compared with traditional biomarkers of cardiovascular risk such as high-sensitivity C-reactive protein (hsCRP). Furthermore, OPG levels are also high in the presence of diabetes-related microvascular disease, and it is unclear whether OPG can distinguish microvascular disease from large-vessel atherosclerosis. The first aim of this study was to compare OPG levels against other biomarkers of cardiovascular risk in the identification of patients with documented multivessel coronary artery disease (CAD). The second aim was to compare OPG levels in patients with microvascular complications (microalbuminuria) against those with established CAD. METHODS: Three groups of male patients with type 2 diabetes were recruited: patients without microvascular complications or large-vessel atherosclerosis (n = 24), patients with microalbuminuria only (n = 23), and patients with microalbuminuria and documented multivessel CAD (n = 25). OPG, hsCRP, interleukin 6, urate, and pulse wave velocity were measured. RESULTS: Serum OPG levels were significantly higher in patients with a combination of microalbuminuria and CAD than in those with microalbuminuria alone. There were no significant differences in any of the other biomarkers between the groups. CONCLUSION: OPG was found to be superior to the other biomarkers studied in identifying patients with documented CAD. The presence of CAD was a greater determinant of serum OPG levels than microalbuminuria in our population. These findings support the use of OPG as a biomarker of cardiovascular risk.

The amyloid precursor protein intracellular domain(AICD) disrupts actin dynamics and mitochondrial bioenergetics.

The amyloid precursor protein (APP) is critically involved in the pathogenesis of Alzheimer's disease, and is strongly up-regulated in response to traumatic, metabolic, or toxic insults to the nervous system. The processing of APP by gamma/epsilon-secretase activity results in the generation of the APP intracellular domain (AICD). Previously, we have shown that AICD induces the expression of genes (transgelin, alpha2-actin) with functional roles in actin organization and dynamics and demonstrated that the induction of AICD and its co-activator Fe65 (AICD/Fe65) resulted in a loss of organized filamentous actin structures within the cell. As mitochondrial function is thought to be reliant on ordered actin dynamics, we examined mitochondrial function in human SHEP neuroblastoma cells inducibly expressing AICD/Fe65. Confocal analysis of the mitochondrial membrane potential (DeltaPsim) identified a significant decrease in the DeltaPsim in the AICD50/Fe65 over-expressing cells. This was paralleled by significantly reduced ATP levels and decreased basal superoxide production. Overexpression of the proposed AICD target gene transgelin in SHEP-SF parental cells and primary neurons was sufficient to destabilize actin filaments, depolarize DeltaPsim, and significantly alter mitochondrial distribution and morphology. Our data demonstrate that the induction of AICD/Fe65 or transgelin significantly alters actin dynamics and mitochondrial function in neuronal cells.