Steroid Metabolism and Metabolic Disease Research Group

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Group leader: Dr Jeremy Tomlinson

Overview

The research focus of the group is to identify the impact of glucocorticoids and androgens and their metabolism upon carbohydrate and lipid homeostasis and insulin action in a tissue specific manner focussing on key metabolic target tissues including adipose (subcutaneous and omental), liver and muscle. There is a fundamental translational component whereby all the in vitro observations are endorsed in rodent and human clinical studies.

Our research group

Regulation of androgen synthesis and action

Current projects:

Glucocorticoid and androgen regulation of insulin signalling and lipid homeostasis

  • Utilizing in vitro models including primary cultures of human adipocytes and hepatocytes and using a variety of techniques including dynamic radioactive tracer studies and ell as gene and protein expression to determine the tissue specific effects of glucocorticoids and androgens
  • Rodent models of glucocorticoid excess and the tissue specific contribution of 11β-HSD1 to the development of the Cushing’s phenotype.

5 alpha reductase as a regulator of glucocorticoid and androgen action and metabolic phenotype

  • In vitro studies transfecting 5 alpha reductase isoforms into liver cell models to determine the impact upon insulin action and lipid metabolism.
  • Generation of liver specific transgenic over expression of 5 alpha reductase type 2 mouse model
  • Identification and characterization of a novel mutation in SRD5A1 in a patient with urinary stoerid metabolite ratios consistent with decreased 5-alpha reductase activity.
  • Clinical studies investigating the metabolic phenotype in healthy volunteers given Finasteride or Dutasteride as well as patients with proven 5 alpha reductase type 2 or androgen receptor mutations (Finasteride, Dutasteride and Insulin action – FIND IT study)

5 beta reductase as a regulator of glucocorticoid action and metabolic phenotype

  • Generation and characterization of 5-beta reductase (AKR1D1) knock-out mouse

Birmingham Prospective Obesity Diabetes and Steroid metabolism study (BPODS)

  • Ongoing prospective analysis of metabolic and steroid profiling in approximately 100 obese individuals (annually for 5 years)

GLP-1 analogues, NAFLD and glucocorticoid metabolism

  • LEAN study – randomised double blind placebo controlled study to determine the efficacy of GLP-1 analogues as a treatment modality for NAFLD – incorporating 2-step clamps and adipose tissue microdialysis.
  • In vitro studies examining the effect of GLP-1 analogues on lipid flux and GC metabolism in human subcutaneous and omental adipose tissue

Glucocorticoid metabolism and neonatal growth, feeding and development

  • 24h urine collections across the first year of life in 80 children - study now extended to collect samples into the 2nd and 3rd year of life (in collaboration with Jackie Blissett, School of Psychology)

Hepatitis C, glucocorticoid action, hepatic steatosis and insulin sensitivity

  • Clinical study investigating metabolic phenotype in Hepatitis C patients before and after anti-viral therapy
  • In vitro studies investigating the impact of HCV infection upon lipid flux and GC action in human hepatoma cell lines.

Hypoxia and glucocorticoid receptor activation in metabolic target tissues

  • In vitro studies in rodent and human cell lines as well as primary cultures investigating the impact of hypoxia to drive ligand independent GR activation and metabolic phenotype in adipose tissue (and muscle) (in collaboration with Jane McKeating, School of Immunity and Infection)

Insulin sensitization and ovarian cancer

  • In vitro experiments determining the impact of metformin upon ovarian cancer cell line insulin signaling and proliferative phenotype  (in collaboration with Sudha Sunda, School of Cancer Sciences)

Current Projects

  • Assessing the therapeutic efficacy of an 11β-hydroxysteroid dehydrogenase type 1 inhibitor (AZD4017) in idiopathic intracranial hypertension (IIH)
  • Hepatic steatosis and hepatitis C infection
  • Unravelling the link between insulin resistance and androgen excess
  • Top Jabs – Improving vaccination responses in older adults
  • The effect of GLP-1 agonist, Liraglutide on non-alcoholic steatohepatitis in patients with and without type 2 diabetes mellitus
  • Translational steroid physiology
  • Glucocorticoid metabolism and the control of metabolic phenotype

Recent Publications

Staff

Principal Investigator
Dr Jeremy Tomlinson - School of Clinical and Experimental Medicine

Postdoctoral Researchers
Laura L Gathercole - Postdoctoral Fellow, School of Clinical and Experimental Medicine
Maryam Nasiri - Research Technician, School of Clinical and Experimental Medicine

PhD Students
Matthew Armstrong
Maryam Nasiri
Michael O’Reilly
Reina Lim
Emma McCabe
David Hughes

Internal Collaborators
Dr Gareth Lavery - School of Clinical and Experimental Medicine
Professor Wiebke Arlt - School of Clinical and Experimental Medicine
Professor Janet Lord - School of Immunity and Infection
Dr Warwick Dunn - School of Biosciences
Dr Jackie Blissett - School of Psychology
Dr Suzanne Higgs - School of Psychology
Dr Kai-Michael Toellner - School of Immunity and Infection
Professor Phil Newsome - School of Immunity and Infection
Professor Jane McKeating - School of Immunity and Infection

External Collaborators
Professor Paul Stewart - University of Leeds