OBJECTIVE Although it is well established hypercortisolism causes insu
lin resistance, mechanisms responsible for impaired insulin action in
Gushing's syndrome are unclear, This study investigated the contributi
on of the glucose/glucose-6-phosphate substrate cycle (G/G6P). PATIENT
S Eight patients with Gushing's syndrome and seven control subjects we
re studied, All had normal fasting plasma glucose, DESIGN Insulin acti
on was assessed using the euglycaemic glucose clamp at insulin infusio
n rates of 0.4 and 2.0 mU/kg/min combined with a simultaneous infusion
of [2(3)H]- and [6(3)-H]-glucose, Glucose/glucose-6-phosphate cycle a
ctivity was calculated as the difference in glucose turnover rates det
ermined separately for [2(3)H]- and [6(3)H]-glucose by selective enzym
atic detritiation. MEASUREMENTS AND RESULTS Exogenous glucose infusion
rates required to maintain euglycaemia were significantly lower in Gu
shing's patients compared to controls, during the 0.4 mU/kg/min (7.8 /- 1.2 vs 15.7 +/- 0.5 mu mol/kg/min, P<0.001) and the 2.0 mU/kg/min i
nsulin infusions (26.2 +/- 2.8 vs 51.5 +/- 3.5 mu mol/kg/min, P<0.001)
. Endogenous glucose production was similar in both groups in the post
absorptive state (10.2 +/- 0.3 vs 10.8 +/- 0.4 mu mol/kg/min, P = 0.50
) and suppressed to a similar degree during hyperinsulinaemia. G/G6P c
ycle activity was markedly increased in the Gushing's group in the pos
tabsorptive state (5.4 +/- 1.1 vs 2.0 +/- 0.5 mu mol/kg/min, P = 0.028
) and during the 0.4 mU/kg/min (3.2 +/- 0 6 vs 1.2 +/- 0.4 mu mol/kg/m
in, P = 0.014) and 2.0 mU/kg/min insulin infusions (3.3 +/- 0.8 vs 1.1
+/- 0.5 mu mol/kg/min, P = 0.049), CONCLUSIONS Patients with Gushing'
s syndrome show marked peripheral insulin resistance and enhanced hepa
tic G/G6P cycle activity, In the fasting state increased glucose/gluco
se-6-phosphate cycle activity may be a protective mechanism limiting h
yperglycaemia, During hyperinsulinaemia G/G6P cycle activity was incre
ased but insulin resistance was predominantly due to reduced periphera
l glucose uptake.