Cortisol is produced by the adrenal cortex and by local regeneration via the enzyme 11-beta
HSD1, eg in adipose tissue. Th is glucocorticoid hormone has strong insulin-antagonistic
eff ects and it is suggested to play a role in the development of the metabolic syndrome, visceral
obesity and type 2 diabetes. We studied the eff ect of the synthetic glucocorticoid, dexamethasone
(Dex), on gene expression and glucose uptake capacity in human subcutaneous and omental
adipose tissue aiming to identify new mechanisms and biomarkers for glucocorticoid-induced
insulin resistance as well as for 11-beta HSD1 inhibitor treatment aiming for a reduction in local
cortisol action. Moreover, phase I studies were done to characterize a novel selective 11-beta
HSD1 inhibitor in healthy lean or obese male subjects, and subcutaneous adipose biopsies were
performed . We assessed 11-beta HSD1 activity, genome-wide mRNA expression (microarray
analysis) as well as circulating markers (novel markers based on gene expression data as well as
established markers related to the cortisol axis).
Dex changed the expression of more than 500 genes in both subcutaneous and omental
adipose tissue and pathway analysis of Dex-regulated genes showed a clear over-representation of
functions and pathways related to infl ammation. Single genes aff ecting lipolysis, glucose uptake
and oxidation or adipocyte diff erentiation were changed aft er Dex incubation. Th e expression
of the secreted peptides leptin and TIMP4 (metallopeptidase inhibitor 4) were increased by Dex
in both depots. Dex dose-dependently impaired basal and insulin-stimulated glucose uptake in
omental, and to a lesser degree in subcutaneous, adipocytes.
Repeated dosing of the novel 11-beta HSD1 inhibitor (AZD4017) in healthy subjects
markedly reduced 11-beta HSD1 activity in the liver assessed by a prednisone challenge
test and by the ratio of urinary cortisol:cortisone metabolites. 11-beta HSD1 inhibition was
demonstrated also in adipose tissue aft er a single dose, but this eff ect seemed not to be sustained
following repeated dosing for 9 days. Eff ects on circulating markers are being analysed and will
A proposed strategy for use of translational and early clinical biomarkers in the development
of novel diabetes treatments, as exemplifi ed above, will be described.
MD, PhD, Full Professor in Internal Medicine. Board-certifi ed specialist in Internal Medicine and Endocrinology.
Currently part-time position as Professor, Dept of Molecular and Clinical Medicine, Sahlgrenska University
Hospital, Gothenburg, Sweden.Medical Science Director, Diabetes Disease Area, Cardiovascular/
Gastrointestinal Clinical Development, AstraZeneca R&D. M?lndal, Sweden.
During more than 20 years several positions as senior consultant physician, mainly in diabetology and
endocrinology at University Hospitals in G?teborg, Lund, Ume? in Sweden. These include senior leadership
roles such as Head of Department and Head of Research Units. In the same time period leader of research
projects in experimental and clinical diabetology and metabolism. Focus on mechanisms of insulin resistance,
in particular translational aspects. Author of approx. 150 scientifi c papers.
Since 2007 Medical Science Director in Clinical Development, Diabetes (and Obesity) at AstraZeneca R&D.
Leader of a large group of MDs, PhDs and other scientists that is responsible for translational and early clinical
research in numerous drug projects. PI or co-PI for several internal and external scientifi c networks and
collaborations, for example focusing on mechanisms and markers of insulin resistance and on markers of beta
cell function and mass in diabetes
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