24 HOUR C-PEPTIDE AND INSULIN-SECRETION RATES AND DIURNAL PROFILES OF GLUCOSE, LIPIDS AND INTERMEDIARY METABOLITES IN CIRRHOSIS

1. To examine the contributions of hypersecretion and decreased insulin clearance to the hyperinsulinaemia of cirrhosis, insulin secretion was calculated over the day from serum C-peptide concentrations and C-peptide metabolic clearance rate. The latter was measured during infusions of recombinant human C-peptide. In cirrhotic patients (n=9) insulin secretion rate was twice that of normal control subjects (n= 10), both in the basal state [02.00-07.00 hours, 15.7 +/- 2.1 (mean +/- SEM) nmol/h (2.6 +/- 0.4 units/h) versus 7.0 +/- 0.9 nmol/h (1.2 +/- 0.2 units/h), P<0.002] and over 24h [787 +/- 93 nmol (132 +/- 16 units) versus 346 +/- 34 nmol (58 +/- 6 units), P<0.001]. However, the area under the serum insulin concentration curve was approximately six times greater in the cirrhotic patients (24 h basal, 6.3 +/- 1.0 versus 1.1 +/- 0.3 nmol l-1 h, P<0.001; 24 h total, 21.7 +/- 3.2 versus 3.7 +/- 0.7 nmol l-1 h, P<0.001). Thus, despite impairment of insulin clearance there is continuing hypersection of insulin in cirrhosis. 2. The relationship of carbohydrate and lipid metabolism with insulin secretion was assessed. In cirrhotic patients, 24h blood glucose profiles showed a worsening of glucose tolerance over breakfast, despite greater insulin secretion compared with other meals, suggesting that the insulin insensitivity of cirrhosis is worse at this time. 3. Cirrhotic patients showed impaired suppression of blood glycerol levels after meals but normal suppression of serum non-esterified fatty acid concentrations. The greatest differences in the profiles of serum lipids and lipid-related metabolites in cirrhotic patients and control subjects occurred at night. Whereas in control subjects, serum non-esterified fatty acid, blood glycerol and blood 3-hydroxybutyrate concentrations peaked between 01.00 and 03.00 hours, falling gradually thereafter until 08.00 hours, in cirrhotic patients serum non-esterified fatty acid and blood glycerol levels showed a gradual increase during the night to reach maximal levels at 08.00 hours when they were twice those of control subjects (P<0.001). 4. The blood 3-hydroxybutyrate and serum triacylglycerol profiles suggested that in cirrhotic patients there was preferential utilization of non-esterified fatty acids for ketogenesis and reduced reesterification to triacylglycerol.