OBJECTIVE: To study plasma concentrations of insulin-like growth factor-I (IGF-I) in adults with type 1 diabetes (IDDM) in comparison with a reference population, and the influence of glycaemic control, dose of insulin, and sex on the concentration of circulating IGF-I in IDDM. DESIGN AND METHODS: Patients with type 1 diabetes were recruited consecutively from our outpatient diabetes unit. In all, 79 men and 55 women aged 20-60 years with a disease duration >/=6 years (range 6-51 years) took part in the study. A reference population of 80 men and 83 women aged 20-60 years was randomly obtained from the population registry. IGF-I was measured with radioimmunoassay after acid-ethanol extraction. RESULTS: Mean +/- s. d. values of IGF-I were lower in patients with diabetes (146+/-66 microg/l) than in controls (238+/-83 microg/l, P<0.001). Those with diabetes had lower IGF-I concentrations in all age groups and the differences were highly significant in all decades except in women aged 50-59 years. IGF-I was negatively correlated with age in patients and controls. No correlation was found between IGF-I and glycaemic control measured as haemoglobin A(1c) (HbA(1c)) in the patients. IGF-I was positively associated with the dose of insulin/kg body weight in male patients independently of age, HbA(1c) and body mass index (P<0.03), but not in female patients (P=0.14). CONCLUSIONS: Our data show that IGF-I concentrations are low in adult patients with type 1 diabetes with a disease duration >/=6 years, independently of glycaemic control. This suggests that subcutaneous insulin substitution is inadequate to normalize circulating IGF-I concentrations in patients without endogenous insulin secretion.
B Ekman, F Nystrom and HJ Arnqvist
B Ekman, T Lindstrom, F Nystrom, AG Olsson, G Toss and HJ Arnqvist
OBJECTIVE: To evaluate a dose titration model for recombinant human GH substitution in adult patients with GH deficiency, aiming at normal plasma levels of IGF-I. DESIGN AND METHODS: Eighteen patients participated and a start dose of 0.17 mg GH/day was used except by two men who started with 0.33 mg/day. To demonstrate a clear GH effect the patients were first titrated, with steps of 0.17 mg GH/day every 6-8 weeks, to IGF-I levels in the upper range of age-adjusted reference values. The GH dose was then reduced 1 dose step and kept for a further 6 months. For comparison we investigated 17 healthy control subjects. RESULTS: Plasma IGF-I was increased after 2 weeks on the start dose and did not increase further for up to 8 weeks. Women had significantly lower GH sensitivity than men measured as net increment of IGF-I on the start dose of GH. GH sensitivity was not changed by age. The plasma IGF-I levels increased from 76.3+/-47.0 (s.d.) to 237+/-97 microg/l at the end of the study (P<0.001), and similar IGF-I levels were obtained in both sexes. The maintenance median GH dose was 0.33 mg/day in males and 0.83 mg/day in females (P=0.017). The GH dose correlated negatively with age in both sexes. Body weight, very low density triglycerides, lipoprotein(a) (Lp(a)), and fasting insulin increased, whereas insulin sensitivity index (QUICKI) decreased significantly. In comparison with the controls, the patients had lower fasting blood glucose, fasting insulin and Lp(a) levels at baseline, but these differences disappeared after GH substitution. The two groups had equal insulin sensitivity (QUICKI), but 2 h oral glucose tolerance test values of blood glucose and insulin were significantly higher in the patients at the end of the study. CONCLUSIONS: In conclusion our data suggest that the starting dose of GH substitution and the dose titration steps should be individualised according to GH sensitivity (gender) and the IGF-I level aimed for (age). The reduced insulin sensitivity induced by GH substitution could be viewed as a normalisation if compared with control subjects.
A G Nilsson, C Marelli, D Fitts, R Bergthorsdottir, P Burman, P Dahlqvist, B Ekman, B Edén Engström, T Olsson, O Ragnarsson, M Ryberg, J Wahlberg, H Lennernäs, S Skrtic and G Johannsson
The objective was to assess the long-term safety profile of dual-release hydrocortisone (DR-HC) in patients with adrenal insufficiency (AI).
Randomised, open-label, crossover trial of DR-HC or thrice-daily hydrocortisone for 3 months each (stage 1) followed by two consecutive, prospective, open-label studies of DR-HC for 6 months (stage 2) and 18 months (stage 3) at five university clinics in Sweden.
Sixty-four adults with primary AI started stage 1, and an additional 16 entered stage 3. Patients received DR-HC 20–40 mg once daily and hydrocortisone 20–40 mg divided into three daily doses (stage 1 only). Main outcome measures were adverse events (AEs) and intercurrent illness (self-reported hydrocortisone use during illness).
In stage 1, patients had a median 1.5 (range, 1–9) intercurrent illness events with DR-HC and 1.0 (1–8) with thrice-daily hydrocortisone. AEs during stage 1 were not related to the cortisol exposure-time profile. The percentage of patients with one or more AEs during stage 1 (73.4% with DR-HC; 65.6% with thrice-daily hydrocortisone) decreased during stage 2, when all patients received DR-HC (51% in the first 3 months; 54% in the second 3 months). In stages 1–3 combined, 19 patients experienced 27 serious AEs, equating to 18.6 serious AEs/100 patient-years of DR-HC exposure.
This long-term prospective trial is the first to document the safety of DR-HC in patients with primary AI and demonstrates that such treatment is well tolerated during 24 consecutive months of therapy.
S Fjalldal, C Follin, D Svärd, L Rylander, S Gabery, Å Petersén, D van Westen, P C Sundgren, I M Björkman-Burtscher, J Lätt, B Ekman, A Johanson and E M Erfurth
Patients with craniopharyngioma (CP) and hypothalamic lesions (HL) have cognitive deficits. Which neural pathways are affected is unknown.
To determine whether there is a relationship between microstructural white matter (WM) alterations detected with diffusion tensor imaging (DTI) and cognition in adults with childhood-onset CP.
A cross-sectional study with a median follow-up time of 22 (6–49) years after operation.
The South Medical Region of Sweden (2.5 million inhabitants).
Included were 41 patients (24 women, ≥17 years) surgically treated for childhood-onset CP between 1958–2010 and 32 controls with similar age and gender distributions. HL was found in 23 patients.
Main outcome measures
Subjects performed cognitive tests and magnetic resonance imaging, and images were analyzed using DTI of uncinate fasciculus, fornix, cingulum, hippocampus and hypothalamus as well as hippocampal volumetry.
Right uncinate fasciculus was significantly altered (P ≤ 0.01). Microstructural WM alterations in left ventral cingulum were significantly associated with worse performance in visual episodic memory, explaining approximately 50% of the variation. Alterations in dorsal cingulum were associated with worse performance in immediate, delayed recall and recognition, explaining 26–38% of the variation, and with visuospatial ability and executive function, explaining 19–29%. Patients who had smaller hippocampal volume had worse general knowledge (P = 0.028), and microstructural WM alterations in hippocampus were associated with a decline in general knowledge and episodic visual memory.
A structure to function relationship is suggested between microstructural WM alterations in cingulum and in hippocampus with cognitive deficits in CP.