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Nina Clausen, Per-Eric Lins, Ulf Adamson, Bertil Hamberger and Suad Efendić

Abstract. Hypothyroidism has been alleged to modulate insulin action and influence the secretion of growth hormone and catecholamines. We recently investigated the influence of hypothyroidism on glucose counterregulatory capacity and the hormonal responses to insulin-induced hypoglycaemia in 6 patients with primary hypothyroidism (age 32–52 years, TSH-values 66–200 mU/l). Hypoglycaemia was induced in the hypothyroid state and again when the subjects were euthyroid. After an overnight fast a constant rate infusion of insulin (2.4 U/h) was given for 4 h. Glucose was measured every 15 min and insulin, C-peptide, glucagon, epinephrine, norepinephrine, growth hormone and cortisol every 30 min for 5 h.

During insulin infusion somewhat higher concentrations of the hormone were obtained in the hypothyroid state and simultaneously glucose levels were 0.5 mmol/l lower. As expected, basal norepinephrine levels were higher in hypothyroidism. However, no increase in circulating norepinephrine during hypoglycaemia was registered in the two experiments. The responses of counterregulatory hormones showed an enhanced response of cortisol, similar responses of growth hormone and epinephrine while the glucagon response was paradoxically impaired. Our findings suggest that hypothyroidism alters insulin metabolism, and that the glucagon response to hypoglycaemia is impaired in this condition.

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Johannes Järhult, Lars-Ove Farnebo, Bertil Hamberger, Jens Holst and Thue W. Schwartz

Abstract.

The effects of insulin hypoglycaemia (0.15 IU/kg) on plasma adrenaline, noradrenaline, dopamine, glucagon and pancreatic polypeptide (PP) concentrations were investigated in 6 adrenalectomized subjects and 6 healthy controls. Both the rise in mean plasma insulin and the fall in mean blood glucose concentration were closely similar in the two groups. Mean plasma adrenaline concentration rose by about 3 nmol/l in the normal subjects, but remained unchanged in adrenalectomized subjects. Mean plasma noradrenaline concentration increased by about 2 nmol/l in both groups. Despite the large difference in adrenaline concentrations during hypoglycaemia, there was no significant difference between the responses of the endocrine pancreas of the normal and adrenalectomized subjects. Thus, mean plasma glucagon concentration rose by about 30 pmol/l and mean plasma PP concentration by about 150 pmol/l in each group. We conclude that the release of glucagon and PP during hypoglycaemia does not depend upon changes in plasma adrenaline concentration in man.

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Cecilia Laurell, David Velázquez-Fernández, Kristina Lindsten, Christofer Juhlin, Ulla Enberg, Janos Geli, Anders Höög, Magnus Kjellman, Joakim Lundeberg, Bertil Hamberger, Catharina Larsson, Peter Nilsson and Martin Bäckdahl

Objective

Tumours in the adrenocortex are common human tumours. Malignancy is however, rare, the yearly incidence being 0.5–2 per million inhabitants, but associated with a very aggressive behaviour. Adrenocortical tumours are often associated with altered hormone production with a variety of clinical symptoms. The aggressiveness of carcinomas together with the high frequency of adenomas calls for a deeper understanding of the underlying biological mechanisms and an improvement of the diagnostic possibilities.

Methods

Microarray gene expression analysis was performed in tumours of adrenocortex with emphasis on malignancy as well as hormonal activity. The sample set consisted of 17 adenomas, 11 carcinomas and 4 histological normal adrenocortexes. RNA from these was hybridised according to a reference design on microarrays harbouring 29 760 human cDNA clones. Confirmation was performed with quantitative real time-PCR and western blot analysis.

Results

Unsupervised clustering to reveal relationships between samples based on the entire gene expression profile resulted in two subclusters; carcinomas and non-cancer specimens. A large number of genes were accordingly found to be differentially expressed comparing carcinomas to adenomas. Among these were IGF2, FGFR1 and FGFR4 in growth factor signalling the most predominant and also the USP4, UBE2C and UFD1L in the ubiquitin-proteasome pathway. Moreover, two subgroups of carcinomas were identified with different survival outcome, suggesting that survival prediction can be made on the basis of gene expression profiles. Regarding adenomas with aldosterone overproduction, OSBP and VEGFB were among the most up-regulated genes compared with the other samples.

Conclusions

Adrenocortical carcinomas are associated with a distinct molecular signature apparent in their gene expression profiles. Differentially expressed genes were identified associated with malignancy, survival as well as hormonal activity providing a resource of candidate genes for an exploration of possible drug targets and diagnostic and prognostic markers.