Endocrine Abstracts

Introduction: The prevalence of non-alcoholic fatty liver disease (NAFLD) is greatly increased in patients with lipodystrophy and some other forms of severe insulin resistance. Liver biopsy remains the definitive technique for diagnosis and staging of NAFLD. However, non-invasive techniques, such as magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) are increasingly used to assess response to therapeutic interventions. The National Severe Insulin Resist...

Selective transsphenoidal adenomectomy remains the accepted first line treatment for Cushing’s disease (CD), until recently by microscopic (sublabial) transsphenoidal pituitary surgery. Endonasal transsphenoidal endoscopic surgery is emerging as a novel, less invasive treatment for pituitary adenomas with lower postoperative complications and morbidity. The safety of endoscopic surgery has been extensively reviewed in adult patients and is now considered best practice for...

Expression of the ACTH receptor (MC2R), a 7 transmembrane GPCR, has been difficult to achieve in cell lines that are not of adrenal origin. Heterologous expression of this gene in many cell lines (CHO, Hela, H295R, HEK293) produces a protein that is trapped in the ER, suggesting that an accessory factor(s) might be necessary to traffic MC2R through the cell. We recently identified such an accessory factor, MRAP that rescues MC2R expression in some, but not all, cell lines. Mut...

A number of single nucleotide polymorphisms (SNPs) have been identified in the GHRH receptor gene. Two of these SNPs, A57T and V225I, have been found to cause an increased cAMP response to GHRH stimulation in vitro, and it has been suggested that they may be associated with the abnormal biochemistry in patients with somatotroph adenomas. The objective of this study was to clarify the frequencies of these SNPs in the normal population and in subjects with short stature. The sub...

Previously we reported two loss-of-function dominant negative mutations (P467L, V290M) in human peroxisome proliferator-activated receptor gamma (PPARg) in three individuals with severe insulin resistance, early onset type 2 diabetes mellitus (T2DM) and hypertension. Subsequent detailed clinical and radiological evaluation of these subjects has revealed that each exhibits a stereotyped pattern of partial lipodystrophy affecting the limbs and buttocks. Recently a female with pa...

Background: The majority of patients with GH insensitivity have defects in the extracellular domain of the GHR. We have identified a 47yr old woman homozygous for a 22bp deletion in the cytoplasmic domain of the GHR. The patient had high GH levels, and low IGF-1 of 8 ug/L (normal 54-389 ug/L), IGFBP-3 16nmol/L (normal 61-254 nmol/L) and GHBP 6.8 percent (normal greater than 10 percent) levels. We report functional studies for this mutation (GHR1-449) which results in premature...

Continuation of GH at final height in hypopituitary adolescents with severe GH-deficiency results in accrual of bone mass over 12 months. We report body composition and BMD in 7 of these patients who discontinued GH but continued to have observations over 24 months. Five males and 2 females were included (17.4plus/minus0.3, years, meanplus/minusSE), in this Ethics Commitee approved study. All had severe GH-deficiency with multiple pituitary hormone deficits on appropriate repl...

We have previously reported dominant negative missense mutations (P467L, V290M) in human PPAR gamma (peroxisome proliferator-activated receptor gamma) in association with severe insulin resistance, early onset type 2 diabetes and hypertension. In a large UK kindred, where the proband presented at age 15 years with severe insulin resistance (acanthosis nigricans, hyperinsulinaemia, PCOS), we have identified a novel heterozygous frameshift premature stop mutation in the PPAR gam...

Background: Mutations in the GHR result in extreme short stature (Laron's syndrome). We have studied mutations from two patients with Laron's syndrome. Patient 1 (GHRextra) has a mutation in the GHR extracellullar domain due to a 108bp inframe pseudoexon between exons 6 and 7. Patient 2 (GHRintra) has a 22bp deletion in exon 10 of the GHR leading to premature termination of the GHR upstream of the intracellular STAT5 binding site.Aim: To compare GHR str...

Objectives: Patients with homozygous 6Ψ mutations have GH insensitivity (GHI). We previously described spectrum of clinical and biochemical phenotypes of 11 6Ψ patients (David et al. JCEM 2007;92:655) and now report 9 additional patients. Response to rhIGF-I therapy has not previously been assessed.Methods: 20 6Ψ patients (12 M, 11 families, mean age 4.0±2.2 year) were diagnosed genetically in our centre. Continuous ...