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


CONCLUSIONS
Short-term administration of pegvisomant leads to a reduction in overnight endogenous glucose production, and this may be related to reduced levels of FFA.
Department of Endocrinology, Christie Hospital, Manchester M20 4BX, United Kingdom.
C E
CE
Higham
S
S
Rowles
D
D
Russell-Jones
A M
AM
Umpleby
P J
PJ
Trainer
D000172:Acromegaly / Q000097:blood* / Q000188:drug therapy* / Q000378:metabolism; D000328:Adult; D002940:Circadian Rhythm / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D019382:Human Growth Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D050356:Lipid Metabolism / Q000187:drug effects; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009994:Osmolar Concentration
D005230:Fatty Acids, Nonesterified; D006727:Hormone Antagonists; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D005947:Glucose; C406545:pegvisomant