title: Insulin action and hepatic glucose cycling in Cushing's syndrome.
abstract: OBJECTIVE
  Although it is well established that hypercortisolism causes insulin resistance, the mechanisms responsible for impaired insulin action in Cushing's syndrome are unclear. This study investigated the contribution of the glucose/glucose-6-phosphate substrate cycle (G/G6P).
  
  
  METHODS
  Eight patients with Cushing's syndrome and seven control subjects were studied. All had normal fasting plasma glucose.
  
  
  METHODS
  Insulin action was assessed using the euglycaemic glucose clamp at insulin infusion 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 activity was calculated as the difference in glucose turnover rates determined separately for [2(3)H]- and [6(3)H]-glucose by selective enzymatic detritiation.
  
  
  RESULTS
  Exogenous glucose infusion rates required to maintain euglycaemia were significantly lower in Cushing's patients compared to controls, during the 0.4 mU/kg/min (7.8 +/- 1.2 vs 15.7 +/- 0.5 mumol/kg/min, P < 0.001) and the 2.0 mU/ kg/min insulin infusions (26.2 +/- 2.8 vs 51.5 +/- 3.5 mumol/ kg/min, P < 0.001). Endogenous glucose production was similar in both groups in the postabsorptive state (10.2 +/- 0.3 vs 10.8 +/- 0.4 mumol/kg/min, P = 0.50) and suppressed to a similar degree during hyperinsulinaemia. G/G6P cycle activity was markedly increased in the Cushing's group in the postabsorptive state (5.4 +/- 1.1 vs 2.0 +/- 0.5 mumol/kg/min, P = 0.028) and during the 0.4 mU/kg/min (3.2 +/- 0.6 vs 1.2 +/- 0.4 mumol/kg/min, P = 0.014) and 2.0 mU/kg/min insulin infusions (3.3 +/- 0.8 vs 1.1 +/- 0.5 mumol/kg/min, P = 0.049).
  
  
  CONCLUSIONS
  Patients with Cushing's syndrome show marked peripheral insulin resistance and enhanced hepatic G/G6P cycle activity. In the fasting state increased glucose/glucose-6-phosphate cycle activity may be a protective mechanism limiting hyperglycaemia. During hyperinsulinaemia G/G6P cycle activity was increased but insulin resistance was predominantly due to reduced peripheral glucose uptake.
authors.affiliation: Sir George E. Clark Metabolic Unit, Royal Victoria Hospital, Belfast, Northern Ireland, UK.
authors.forename: A P
authors.initials: AP
authors.lastname: Heaney
authors.forename: R
authors.initials: R
authors.lastname: Harper
authors.forename: C
authors.initials: C
authors.lastname: Ennis
authors.forename: D P
authors.initials: DP
authors.lastname: Rooney
authors.forename: B
authors.initials: B
authors.lastname: Sheridan
authors.forename: A B
authors.initials: AB
authors.lastname: Atkinson
authors.forename: P M
authors.initials: PM
authors.lastname: Bell
mesh_terms: D020155:3-Hydroxybutyric Acid; D000328:Adult; D000368:Aged; D003480:Cushing Syndrome / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D005952:Glucose-6-Phosphatase / Q000378:metabolism*; D005990:Glycerol / Q000097:blood; D006801:Humans; D006885:Hydroxybutyrates / Q000097:blood; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged
chemical_list: D005230:Fatty Acids, Nonesterified; D006885:Hydroxybutyrates; D007328:Insulin; D005952:Glucose-6-Phosphatase; D005947:Glucose; D005990:Glycerol; D020155:3-Hydroxybutyric Acid