Splanchnic and renal metabolism of insulin in human subjects: a dose-response study

Abstract

Kinetic analyses of insulin metabolism were performed in 32 healthy subjects with hepatic-venous or renal-venous catheters, in whom steady-state conditions of hyperinsulinemia or hyperglycemia were achieved with the use of the glucose-insulin clamp technique. In the basal state, the splanchnic bed removed 42 +/- 2% of the insulin influx. After graded insulin infusions with maintenance of euglycemia, stable arterial insulin levels of 35-1,430 microU/ml were attained. Splanchnic insulin extraction was constant (approximately 60%) at physiological insulin levels but fell (to 29 +/- 1%, P less than 0.02) at supraphysiological (greater than 500 microU/ml) concentrations. The metabolic clearance rate of infused insulin was essentially constant within the physiological concentration range. Hyperglycemia (+125 mg/100 ml) did not alter splanchnic insulin extraction. Basally, the kidneys extracted 0.04 +/- 0.01 mU X min-1 X kg-1 or 25 +/- 5% of arterial insulin. Renal insulin clearance (3.9 +/- 0.4 ml X min-1 X kg-1) represented over 80% of the extrasplanchnic insulin clearance. Hyperglycemia (+125 mg/100 ml) had no effect on renal insulin extraction. In conclusion, a) both splanchnic and renal insulin removal are independent of glycemia and increase in proportion to plasma insulin concentration within the physiological range; b) splanchnic uptake is the dominant mechanism of removal of insulin from the circulation whether the route of delivery is portal or peripheral; and c) the kidneys account for the greater part of extrasplanchnic insulin metabolism.

Effect of increased plasma non-esterified fatty acids (NEFAs) on arginine-stimulated insulin secretion in obese humans

“…The most likely explanation for this finding is a NEFA-mediated reduction of insulin extraction by the liver [28]. Although insulin extraction by the liver seems to be constant throughout the physiological range of insulin concentration at steady state insulin concentrations [29,30], it declines during dynamic (non steady state) conditions and in the presence of very high insulin concentrations, similar to those seen in our study during the second bolus infusion of arginine [31±33].…”

Acute blockade by endothelin-1 of haemodynamic insulin action in rats

“…Of these tissues, liver and kidney have been identified as the main sites of insulin clearance (approximately 40 and 23%, respectively) [34], although Mondon et al [27] have shown that in spontaneously hypertensive rats skeletal muscle plays a significant role. In the present study endothelin-1 blocked the increase in FBF and capillary recruitment seen during insulin infusion.…”

Racial differences in glucagon-like peptide-1 (GLP-1) concentrations and insulin dynamics during oral glucose tolerance test in obese subjects

“…Brandt et al, 13 although not finding a direct effect of GLP-1 on the hepatic insulin clearance, suggested that the increased insulin secretion in response to GLP-1 itself may drive the reduction of hepatic insulin extraction. 11 The reduced insulin clearance is presumably due to alterations in insulin receptor number and/or affinity, in view of the importance of the insulin receptor in mediating insulin clearance. 36 The effect of higher GLP-1 concentration may also be a potential factor to explain the higher prevalence of obesity and type 2 diabetes in AAs by fostering a hyperinsulinemic state.…”

“…10 GLP-1's action is mediated by its binding to cell surface receptors (GLP-1R) that are highly expressed on the cell membranes of pancreatic b-cells. 10,11 In addition to stimulating insulin secretion, GLP-1 has been shown to have other profound biological effects on b-cells. 12 GLP-1 regulates b-cell function by maintaining a portion of the b-cell population in a glucose-competent state by making resistant islets glucose sensitive.…”