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  • Author: Ulf Elbelt x
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Altered insulin requirement in patients with type 1 diabetes and primary adrenal insufficiency receiving standard glucocorticoid replacement therapy

Ulf Elbelt, Stefanie Hahner, and Bruno Allolio

Objective

Current glucocorticoid replacement regimens fail to fully mimic physiologic cortisol secretion in patients with primary adrenal insufficiency. This may lead to changes in insulin requirement in patients with primary adrenal insufficiency and type 1 diabetes. Therefore, we assessed insulin requirement in patients with autoimmune polyendocrine syndrome type 2 (APS-2).

Design and subjects

Ten females with primary adrenal insufficiency and type 1 diabetes (mean duration of type 1 diabetes 13±11 years and of primary adrenal insufficiency 11±9 years) were retrospectively assessed regarding insulin regimen and insulin dose adjustment. Data were compared with control patients matched for age, sex and duration of diabetes drawn from all patients with type 1 diabetes attending the diabetes outpatient clinics at the University Hospital Wuerzburg for a scheduled consultation.

Results

Glycaemia was well controlled in both groups (mean HbA1c 6.99±0.81% in APS-2 patients versus 6.69±1.03% in control patients). The mean weight-adjusted daily dose of insulin was non-significantly higher in patients with APS-2 compared with control patients (0.69±0.35 IU/kg body weight versus 0.51±0.17 respectively). The mean insulin (IU)/carbohydrate-ratio for 10 g of carbohydrate in the morning was 1.9±1.0 and 1.4±0.5 respectively. However, the insulin/carbohydrate-ratios were significantly higher in the APS-2 patients both at noon (mean ratio 2.0±0.9 vs 1.1±0.5 in control patients) and in the evening (mean ratio 2.1±1.1 vs 1.3±0.5 respectively; P<0.05).

Conclusions

Glucocorticoid replacement therapy in patients with primary adrenal insufficiency and type 1 diabetes leads to significant changes in insulin requirement compared with patients with type 1 diabetes only.

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Heterozygous inactivating CaSR mutations causing neonatal hyperparathyroidism: function, inheritance and phenotype

Markus Glaudo, Saskia Letz, Marcus Quinkler, Ulrich Bogner, Ulf Elbelt, Christian J Strasburger, Dirk Schnabel, Erwin Lankes, Sandra Scheel, Joachim Feldkamp, Christine Haag, Egbert Schulze, Karin Frank-Raue, Friedhelm Raue, Bernhard Mayr, and Christof Schöfl

Background

Homozygous inactivating mutations of the calcium-sensing receptor (CaSR) lead to neonatal severe hyperparathyroidism (NSHPT), whereas heterozygous inactivating mutations result in familial hypocalciuric hypercalcemia (FHH). It is unknown why in some cases heterozygous CaSR mutations cause neonatal hyperparathyroidism (NHPT) clinically similar to NSHPT but with only moderately elevated serum calcium.

Methods

A literature survey was conducted to identify patients with heterozygous CaSR mutations and NHPT. The common NHPT CaSR mutants R185Q and R227L were compared with 15 mutants causing only FHH in the heterozygous state. We studied in vitro calcium signaling including the functional consequences of co-expression of mutant and wild-type (wt) CaSR, patients’ phenotype, age of disease manifestation and mode of inheritance.

Results

All inactivating CaSR mutants impaired calcium signaling of wt-CaSR regardless of the patients’ clinical phenotype. The absolute intracellular calcium signaling response to physiologic extracellular calcium concentrations in vitro showed a high correlation with patients’ serum calcium concentrations in vivo, which is similar in NHPT and FHH patients with the same genotype. Pedigrees of FHH families revealed that paternal inheritance per se does not necessarily lead to NHPT but may only cause FHH.

Conclusions

There is a significant correlation between in vitro functional impairment of the CaSR at physiologic calcium concentrations and the severity of alterations in calcium homeostasis in patients. Whether a particular genotype leads to NHPT or FHH appears to depend on additional predisposing genetic or environmental factors. An individual therapeutic approach appears to be warranted for NHPT patients.