The Effects of TZD on Fat Metabolism and Insulin Sensitivity in GH-Replaced GHD Patients

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Brief Title

The Effects of TZD on Fat Metabolism and Insulin Sensitivity in GH-Replaced GHD Patients

Official Title

"Can Growth Hormone's Lipolytic and Insulin-Antagonistic Effects be Modified by Peroxisome Proliferator-Activated Gamma Agonists?"

Brief Summary

      In the present double blind, placebo-controlled, parallel study we evaluated the impact of 12
      weeks thiazolidinedione (TZD) administration on basal and insulin-stimulated substrate
      metabolism in growth hormone-replaced adults with growth hormone deficiency.
    

Detailed Description

      In human subjects GH (Growth Hormone) acutely antagonises the effects of insulin on glucose
      uptake in skeletal muscle and increases the hepatic glucose production of humans. This has
      clinical implications for patients with active acromegaly, in whom the prevalence of glucose
      intolerance and overt diabetes mellitus is increased. It is also of significance in relation
      to GH replacement therapy in GH-deficient adults not least when considering that a
      substantial proportion of these patients are insulin resistant in the GH-untreated state.
      There is evidence to indicate that the acute insulin antagonistic effects may be balanced
      with time by the favourable effects of GH on body composition and physical fitness, but the
      data are ambiguous. The mechanism underlying these effects of GH are not fully characterised,
      but there is experimental evidence of a causal linked to the concomitant stimulation of
      lipolysis, since GH-induced insulin resistance is partly abrogated when lipolysis is
      pharmacologically suppressed. This is noteworthy since elevated levels of free fatty acids
      (FFA) are also implicated in the pathogenesis of insulin resistance in patients with the
      metabolic syndrome and type 2 diabetes mellitus. Thiazolidinediones (TZDs) are insulin
      sensitizers which function as highaffinity agonists for the nuclear
      peroxisome-proliferator-activated receptor (PPAR) gamma, which improve insulin sensitivity in
      T2DM. PPAR gamma is a nuclear receptor expressed mainly in adipocytes, which activates the
      transcription of genes involved in lipid and glucose metabolism. Administration of TZD in
      T2DM enhances insulin-stimulated glucose uptake via mechanisms including a lowering of
      circulating FFA and a redistribution of fat away from hepatocytes and myocytes and into
      peripheral adipocytes. To our knowledge, the impact of TZDs on GH-induced insulin resistance
      has not previously been reported. Experimental data in human subjects on this issue are of
      potential importance not only in relation to patients with abnormal GH status, but also
      regarding our understanding of the pathogenesis of insulin resistance in general and the
      complex actions of PPAR gamma activation in particular.
    


Study Type

Interventional


Primary Outcome

Circulating FFA level


Condition

Growth Hormone Deficiency

Intervention

Pioglitazone


Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

20

Start Date

September 2004

Completion Date

March 2006


Eligibility Criteria

        Inclusion Criteria:

          -  Growth hormone replaced (minimum 6 months) growth hormone deficient men

          -  Age over 18 years

        Exclusion Criteria:

          -  Ischemic coronary disease, defined by EF<0.6, former myocardial infarction, angina
             pectoris or actual treatment of cardiac insufficiency

          -  Actual or former malignancy, except intracranial neoplasia that caused the
             participants pituitary disease, provided that there was clinical evidence for
             permanent remission

          -  Blood donation within 6 months

          -  Excessive alcohol consumption

          -  Known allergic reaction from contents of test drug

          -  Radioactive radiation exposure in terms of treatment or study enrollment within one
             year

          -  Liver insufficiency

          -  Insulin treatment
      

Gender

Male

Ages

19 Years - 71 Years

Accepts Healthy Volunteers

No

Contacts

Jens OL Jorgensen, MD, , 

Location Countries

Denmark

Location Countries

Denmark

Administrative Informations


NCT ID

NCT00459940

Organization ID

20030288



Study Sponsor

University of Aarhus


Study Sponsor

Jens OL Jorgensen, MD, Principal Investigator, University of Aarhus


Verification Date

April 2007