Accuracy of C-peptide:insulin molar ratio as a measure of hepatic removal of insulin.

We measured transhepatic C-peptide and insulin concentrations in plasma, and hepatic removal of insulin, to examine whether the practice of reporting the C-peptide:insulin molar ratio as a measure of the hepatic removal of insulin is valid. In anesthetized dogs (n = 6), during electromagnetic hepatic blood flow monitoring, endogenous insulin was suppressed with somatostatin, while equimolar proportions of porcine insulin and simian C-peptide (2.4 and 6.0 pmol/kg.min) were infused during two consecutive 45-min periods. Insulin reached steady state within 20 min (t1/2 = 4.5 min); however, C-peptide concentrations continued to rise (t1/2 V 12.5 min). The ratio decreased when the peptide infusion was changed to the higher rate and increased when it was stopped, reflecting the more rapid removal of insulin than of C-peptide. Hepatic removal of insulin remained constant during the two infusion periods (average 60% extraction) and never correlated with the changing molar ratios. Hepatic net flux of insulin correlated with the ratio (P less than 0.05) only while plasma insulin concentrations were rising during constant-rate infusion. We therefore conclude that the molar ratio is not a reliable measure of the hepatic removal of insulin during non-steady states of insulin or C-peptide.

Pharmacokinetic approach to the estimation of hepatic removal of insulin.

We simultaneously measured hepatic insulin removal invasively and estimated hepatic clearance and extraction of insulin pharmacokinetically from cardiac output and peripheral plasma concentrations (relatively) noninvasively. The invasive methods involved continuous electromagnetic measurements of portal venous and hepatic arterial blood flow and simultaneous intermittent sampling of blood from the portal and hepatic veins and femoral artery for assay of insulin concentrations. The noninvasive method assumed that hepatic plasma flow is proportional to cardiac output and that hepatic clearance is a constant fraction of total body clearance of insulin. In anesthetized dogs (n = 6), endogenous insulin was suppressed with somatostatin (800 ng/kg/min) while biosynthetic human insulin (0.25, 0.50, and 1.00 mU/kg/min) was infused to steady state during three consecutive 90-min periods. Insulin concentrations were directly proportional to the infusion rate (p less than 0.01). Hepatic blood flow accounted for 20 +/- 2% of cardiac output. Measured hepatic clearance accounted for 51 +/- 5% of total body clearance of insulin and correlated with the pharmacokinetic estimates (p less than 0.01); the estimates of hepatic clearance ranged from 91 to 114% of the measured values. We conclude that this pharmacokinetic approach, which requires only samples of peripheral blood and estimates of hepatic blood flow, may be used to study the hepatic removal of insulin relatively noninvasively.

The effect of hepatic insulin influx on insulin retention: comparison of net flux and per cent extraction as indices of hepatic insulin retention.

We studied effects of changes in hepatic insulin influx on hepatic insulin retention. In order to compare insulin net flux (influx - efflux) with percentage (%) hepatic insulin extraction (net flux/influx X 100), as indices of hepatic insulin retention, we examined which index is better predicted by insulin influx to the liver. Electromagnetic hepatic blood flow measurements were made and blood was sampled from portal, hepatic and peripheral veins and femoral artery in anesthetized dogs. Insulin influx was perturbed by sequentially superimposed peripheral venous infusions of somatostatin, glucagon and insulin (which were subsequently discontinued one at a time). Although the somatostatin was biologically effective in inhibiting insulin and glucagon release we found no significant plasma flow changes on starting or stopping the infusion of somatostatin (800 ng X kg-1 X min-1). Net insulin flux was linearly related to influx (n = 56, r = 0.99, p less than 0.001). Hepatic glucose production was better correlated with net insulin flux (r = -0.66; p less than 0.01) than with % extraction (r = 0.08; N.S.), when mean glucagon influx was held constant (partial correlation). Although net insulin flux and % extraction are complementary indices, the former reflects influx changes more faithfully than the latter.

Hepatic insulin retention depends on influx in both diabetic and normal dogs.

Hepatic retention of endogenous and exogenous insulin was investigated in normal and alloxanstreptozotocin diabetic dogs. An hour's peripheral venous infusion of insulin was preceded and followed by saline infusion. Blood samples were drawn simultaneously from the femoral artery and portal, hepatic and peripheral veins. Blood flow was measured electromagnetically in the portal vein and hepatic artery. Hepatic plasma flow was lower in diabetic dogs (p less than 0.001) so that prior to insulin infusion (basal hour) basal mean hepatic venous flux was diminished in them. Hepatic glucose production was higher (p less than 0.05) and arterio-venous glucose difference lower (p less than 0.01) in diabetics basally, but post-insulin infusion, these became similar in diabetics and normals. Although basal hour arterial and peripheral venous insulin concentrations were similar, portal venous insulin was 3.5-fold lower in diabetics. Mean insulin influx (hepatic arterial + portal venous fluxes) was four-fold lower in diabetics. The insulin net flux (influx - hepatic venous flux) was lower in diabetics (p less than 0.05) as was % extraction (p less than 0.001). During the insulin infusion hour the values remained lower for diabetics (p less than 0.05) for influx, net flux and % extraction. During the post-insulin infusion hour the influx, net flux and % extraction became similar. When the basal hour data in normals was restricted to the range of diabetic insulin influx values less than or equal to 10 mU X min-1, the differences in net flux and % extraction between normals and diabetics were no longer present.(ABSTRACT TRUNCATED AT 250 WORDS)