• Pegvisomant improves insulin sensitivity and reduces overnight free fatty acid concentrations in patients with acromegaly.

      Higham, Claire E; Rowles, Susannah V; Russell-Jones, D; Umpleby, A M; Trainer, Peter J; Department of Endocrinology, Christie Hospital, Manchester M20 4BX, United Kingdom. (2009-07)
      INTRODUCTION: Acromegaly is complicated by an increased incidence of diabetes mellitus caused by impaired insulin sensitivity and reduced beta-cell function. Pegvisomant blocks activity at GH receptors, normalizing IGF-I in over 90% of patients and improving insulin sensitivity. The mechanisms for this increase in insulin sensitivity are not fully determined. We used stable isotope techniques to investigate the effects of pegvisomant on glucose and lipid metabolism in acromegaly. METHODS: Five patients (age, 43 yr +/- sd) with active acromegaly were studied on two occasions: before pegvisomant and after 4 wk of pegvisomant (20 mg daily sc). (2)H(5)-glycerol was infused overnight to measure overnight and early morning (basal) glycerol production rate (Ra). The next morning (2)H(2)-glucose was infused for 2 h before and throughout a hyperinsulinemic euglycemic (1.5 mU/kg x min insulin) clamp to measure basal glucose Ra and insulin-stimulated peripheral glucose disposal (Rd). RESULTS: Mean IGF-I was significantly reduced after pegvisomant treatment (mean, 539 +/- 176 vs. 198 +/- 168 microg/ml; P = 0.001). The insulin sensitivity of endogenous glucose production was significantly increased after pegvisomant [mean glucose Ra *insulin, 118.5 +/- 28 vs. 69.2 +/- 22 micromol/kg x min *(mU/liter); P = 0.04]. No differences in glucose Rd were seen after pegvisomant. All patients showed a reduction in glycerol Ra adjusted for insulin [mean, 18.12 +/- 1.75 vs. 14.4 +/- 4.75 micromol/kg x min *(mU/liter); P = 0.08] and overnight FFA concentrations (mean area under the curve, 278 +/- 84 vs. 203 +/- 71; P < 0.05) after pegvisomant. CONCLUSION: Short-term administration of pegvisomant leads to a reduction in overnight endogenous glucose production, and this may be related to reduced levels of FFA.
    • A subnormal peak cortisol response to stimulation testing does not predict a subnormal cortisol production rate.

      Paisley, Angela N; Rowles, Susannah V; Brandon, D; Trainer, Peter J; Department of Endocrinology, Christie Hospital, Manchester M20 4BX, United Kingdom. (2009-05)
      INTRODUCTION: The decision to commence lifelong glucocorticoid replacement therapy is often based on a cortisol stimulation test. We investigated the relationship between the peak cortisol response to insulin-induced hypoglycemia and daily cortisol production rate (CPR) to ascertain whether provocative tests are accurate in indicating the need to initiate lifelong glucocorticoid replacement. PATIENTS AND METHODS: Ten patients (five male; mean age, 44 +/- 13 yr) with pituitary disease and with demonstrably suboptimal peak cortisol response (350-500 nmol/liter) to insulin-induced hypoglycemia, underwent CPR measurement by isotope dilution using gas chromatography-mass spectrometry and 24-h urinary free cortisol (UFC). RESULTS: The median baseline and peak cortisol attained with hypoglycemia were 284 (164-323) and 473.5 (366-494) nmol/liter, respectively. A strong positive correlation was seen between peak stimulated cortisol and CPR (adjusted for body surface area) (r = 0.75; P = 0.02), and in all patients CPR [4.6 (2.9-15.1) mg/d x m(2)] was within the reference range (2.1-12 mg/d x m(2)) or elevated (one patient). A wide range was found for 24-h UFC [116.5 (20.5-265.9) nmol/liter] in this group of patients, and this parameter lacked significant correlation with either serum cortisol concentration or CPR. CONCLUSION: This is the first study to demonstrate a significant correlation between CPR and peak cortisol values during hypoglycemic challenge. An inadequate cortisol response to hypoglycemia suggests the need for glucocorticoid cover at times of stress, but these data indicate that a suboptimal peak cortisol does not equate to a low CPR and should not be an automatic indication for lifelong glucocorticoid replacement therapy. UFC bears no relation to serum cortisol or CPR and is therefore unhelpful in assessment of such patients.