Permanent neonatal diabetes: combining sulfonylureas with insulin may be an effective treatment.

BACKGROUND: Permanent neonatal diabetes caused by mutations in the KCNJ11 gene may be managed with high-dose sulfonylureas. Complete transfer to sulfonylureas is not successful in all cases and can result in insulin monotherapy. In such cases, the outcomes of combining sulfonylureas with insulin have not been fully explored. We present the case of a woman with diabetes due to a KCNJ11 mutation, in whom combination therapy led to clinically meaningful improvements. CASE: A 22-year-old woman was found to have a KCNJ11 mutation (G334V) following diagnosis with diabetes at 3 weeks. She was treated with insulin-pump therapy, had hypoglycaemia unawareness and suboptimal glycaemic control. We assessed the in vitro response of the mutant channel to tolbutamide in Xenopus oocytes and undertook sulfonylurea dose-titration with C-peptide assessment and continuous glucose monitoring. In vitro studies predicted the G334V mutation would be sensitive to sulfonylurea therapy [91 ± 2% block (n = 6) with 0.5 mM tolbutamide]. C-peptide increased following a glibenclamide test dose (from 5 to 410 pmol/l). Glibenclamide dose-titration was undertaken: a lower glibenclamide dose did not reduce blood glucose levels, but at 1.2 mg/kg/day insulin delivery was reduced to 0.1 units/h. However, when insulin was stopped, hyperglycaemia ensued. Glibenclamide was further increased (2 mg/kg/day), but once-daily long-acting insulin was still required to maintain glycaemia. This resulted in improved HbA1c of 52 mmol/mol (6.9%), restoration of hypoglycaemia awareness and reduced glycaemic variability. CONCLUSION: In people with KCNJ11 mutations causing permanent neonatal diabetes, and where complete transfer is not possible, consideration should be given to dual insulin and sulfonylurea therapy. This article is protected by copyright. All rights reserved.

Utility of ketone measurement in the prevention, diagnosis and management of diabetic ketoacidosis.

Ketone measurement is advocated for the diagnosis of diabetic ketoacidosis and assessment of its severity. Assessing the evidence base for ketone measurement in clinical practice is challenging because multiple methods are available but there is a lack of consensus about which is preferable. Evaluating the utility of ketone measurement is additionally problematic because of variability in the biochemical definition of ketoacidosis internationally and in the proposed thresholds for ketone measures. This has led to conflicting guidance from expert bodies on how ketone measurement should be used in the management of ketoacidosis. The development of point-of-care devices that can reliably measure the capillary blood ketone ß-hydroxybutyrate (BOHB) has widened the spectrum of applications of ketone measurement, but whether the evidence base supporting these applications is robust enough to warrant their incorporation into routine clinical practice remains unclear. The imprecision of capillary blood ketone measures at higher values, the lack of availability of routine laboratory-based assays for BOHB and the continued cost-effectiveness of urine ketone assessment prompt further discussion on the role of capillary blood ketone assessment in ketoacidosis. In the present article, we review the various existing methods of ketone measurement, the precision of capillary blood ketone as compared with other measures, its diagnostic accuracy in predicting ketoacidosis and other clinical applications including prevention, assessment of severity and resolution of ketoacidosis.

Glucose sensors: a review of current and emerging technology.

Glucose monitoring technology has been used in the management of diabetes for three decades. Traditional devices use enzymatic methods to measure glucose concentration and provide point sample information. More recently continuous glucose monitoring devices have become available providing more detailed data on glucose excursions. In future applications the continuous glucose sensor may become a critical component of the closed loop insulin delivery system and, as such, must be selective, rapid, predictable and acceptable for continuous patient use. Many potential sensing modalities are being pursued including optical and transdermal techniques. This review aims to summarize existing technology, the methods for assessing glucose sensing devices and provide an overview of emergent sensing modalities.

The role of the biochemistry department in the diagnosis of pituitary apoplexy.

A 47-year-old man presented with severe clinical hypoglycaemia. He had long-standing insulin-dependent diabetes with previously good glycaemic control. Intense headaches and vomiting initiated hospitalization. A brain computed tomography (CT) scan was normal, and a lumbar puncture showed elevated cerebrospinal fluid (CSF) protein [0.67 g/L; normal range (NR) 0.15-0.45 g/L], suggesting resolving viral meningitis. Routine thyroid function tests were abnormal (free thyroxine 10.6 pmol/L, NR 9-22.5 pmol/L; thyroid-stimulating hormone 0.16 mU/L, NR 0.35-5 mU/L). In the absence of evident thyroid therapy, the laboratory policy required an urgent cortisol assay to be added; this was very abnormal (42 nmol/L), suggesting hypopituitarism. Later analysis showed that concentrations of gonadotrophins and adrenocorticotrophin were low. An urgent pituitary magnetic resonance imaging scan revealed an unsuspected pituitary tumour with recent haemorrhage (pituitary apoplexy). The patient was given intravenous hydrocortisone and then stabilized on oral hydrocortisone, thyroxine and mesterolone. He made a full recovery and the hypoglycaemia resolved. The normal brain CT scan was falsely reassuring and the CSF protein was not due to viral meningitis but to haemorrhage into the pituitary tumour. If laboratory policy had not required the urgent cortisol assay be added, the diagnosis of hypopituitarism would have been delayed or even missed altogether. This could have led to the death of the patient.