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Title: Manipulation of the growth hormone IGF-I axis in type one diabetes : insight into physiological mechanisms and potential strategies for therapeutic intervention
Author: Williams, Rachel Mair
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2008
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Methods: 1) In a crossover study, 2 doses (5 and 10mg) of a specific GH antagonist (B2036-PEG, Somavert) were each administered for 3 weeks to 7 subjects, in random order with a 3 week washout period. Euglycaemic clamp techniques incorporating cold isotopes were used to quantify carbohydrate and fat metabolism at baseline and following GH blockade. 2) In a double blind controlled crossover study, rhIGF-I/rhIGFBP-3 complex (0.4mg/kg/day) was administered to 6 subjects for 7 days. Overnight GH secretion, insulin requirements, glomerular filtration rate and urinary albumin excretion rate were determined at the end of each treatment period. Results: 1) Selective GH blockade using B2036-PEG led to reductions in IGF-I concentrations, reductions in insulin requirement and suppression of lipolysis overnight. During a hyperinsulinaemic euglycaemic clamp, there was no effect on glucose or glycerol turnover. 2) Administration of rhIGF/I/rhIGFBP-3 complex led to increases in IGF-I concentrations and suppression of endogenous GH secretion. Overnight insulin requirements were reduced and there was no effect either on glomerular filtration rate or urinary albumin excretion rate. Following rhIGF-I/rhIGFBP-3 complex administration there appeared to be an induction of the proteolysis of IGFBP-3 within 7 hours, with subsequent excretion of proteolysed fragments in the urine. Conclusion: Blockade of the action of excessive GH or suppression of endogenous secretion of GH using novel compounds in T1D leads to reductions in overnight insulin requirements. Failure to observe effects on other parameters may reflect opposing actions of IGF-I and GH on insulin sensitivity and GFR or the limitations of hyperinsulinaemic clamp methodology.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available