Basal hepatic glucose production is regulated by the portal vein insulin concentration.

Abstract

The ability of portal vein insulin to control hepatic glucose production (HGP) is debated. The aim of the present study was to determine, therefore, if the liver can respond to a selective decrease in portal vein insulin. Isotopic ([3H]glucose) and arteriovenous difference methods were used to measure HGP in conscious overnight fasted dogs. A pancreatic clamp (somatostatin plus basal portal insulin and glucagon) was used to control the endocrine pancreas. A 40-min control period was followed by a 180-min test period. During the latter, the portal vein insulin level was selectively decreased while the arterial insulin level was not changed. This was accomplished by stopping the portal insulin infusion and giving insulin peripherally at half the basal portal rate (PID, n=5). In a control group (n=5), the portal insulin infusion was not changed and glucose was infused to match the hyperglycemia that occurred in the PID group. A selective decrease of 120 pmol/l in portal vein insulin was achieved (basal, 150+/-36 to last 30 min, 30+/-12 pmol/l) in the absence of a change in the arterial insulin level (basal, 30+/-3 to last 30 min, 36+/-4 pmol/l). Neither arterial nor portal insulin levels changed in the control group (30+/-6 and 126+/-30 pmol/l, respectively). In response to the selective decrease in portal vein insulin, net hepatic glucose output (NHGO) increased significantly, from 8+/-1 (basal) to 30+/-6 and 14+/-2 micromol x kg(-1) x min(-1) by 15 min and the last 30 min (P < 0.05) of the experimental period, respectively. Arterial plasma glucose increased from 5.9+/-0.2 (basal) to 10.5+/-0.4 micromol/l (last 30 min). Three-carbon gluconeogenic precursor uptake fell from 11.2+/-2.9 (basal) to 5.9+/-0.7 micromol x kg(-1) x min(-1) (last 30 min), and thus a change in gluconeogenesis could not account for any of the increase in NHGO. With matched hyperglycemia (basal, 5.5+/-0.3 to last 30 min, 10.5+/-0.8 micromol/l) but no change in insulin, NHGO decreased from 12+/-1 (basal) to 0 (-1+/-6 micromol x kg(-1) x min(-1), last 30 min, P < 0.05) and hepatic gluconeogenic precursor uptake did not change (basal, 8.0+/-1.7 to last 30 min, 8.9+/-2.2 micromol x kg[-1] x min[-1]). Thus, the liver responds rapidly to a selective decrease in portal vein insulin by markedly increasing HGP as a result of increased glycogenolysis. These studies indicate that after an overnight fast, basal HGP (glycogenolysis) is highly sensitive to the hepatic sinusoidal insulin level.

Pharmacologic restoration of the early insulin response in pre-diabetic monkeys controls mealtime glucose excursions without peripheral hyperinsulinaemia

“…This could in part reflect the insulin-resistant state of the subjects but it is also possible that the lipolytic rate was low in these animals due to a neurosuppressive effect of the sedative used, thus further insulin-mediated suppression of lipolysis would be difficult to detect. Nevertheless, since the animals were in the fasted state, this finding does indicate that the insulin-mediated glucose lowering observed after treatment with either agent represents a direct effect of insulin to suppress hepatic glucose production and/or to increase peripheral glucose uptake [20] rather than an indirect effect mediated by lowering NEFA [21].…”

“…Available evidence, however, suggests that it is likely due to a direct effect of insulin to switch the liver from a state of production to one of uptake and storage [20]. Such a direct effect is also supported by the observation that NEFA (potential mediator of insulin-induced reduction of hepatic glucose output) were suppressed similarly in the control and nateglinide-treated and repaglinide-treated groups.…”

Different contributions of insulin resistance and beta‐cell dysfunction in overweight Israeli Arabs with IFG and IGT

“…HOMA-IR index was greater in subjects with IFG than in subjects with NGT or IGT. Since HGP is the primary determinant of the fasting plasma glucose concentration [19] and the FPI concentration is the primary regulator of HGP [20], the product of FPG and FPI primarily reflects hepatic insulin resistance. Whole body insulin sensitivity measured with WBISI index was also reduced in subjects with isolated IFG compared to those with NGT.…”

“…The HOMA-IR index was calculated as the product of fasting plasma insulin (FPI) and FPG divided by 22.5 [18]. Since hepatic glucose production (HGP) is the main determinant of FPG concentration [19], and FPI concentration is the main regulator of HGP [20], HOMA-IR index is practically a measure of hepatic insulin resistance. In addition, in order to have an estimate of muscle insulin resistance, we used whole body insulin sensitivity index (WBISI), which was developed by Matsuda & DeFronzo and integrates plasma glucose and insulin concentrations during the OGTT [21].…”

Hyperinsulinaemia during exercise does not suppress hepatic glycogen concentrations in patients with type 1 diabetes: a magnetic resonance spectroscopy study

“…A large body of evidence concerning hepatic glucose metabolism during exercise in diabetes has been derived from animal experiments [18][19][20][21][22] but there is a lack of in vivo human data. Human studies using magnetic resonance spectroscopy (MRS) have reported defects in mobilisation of hepatic glycogen stores in patients with type 1 diabetes [23,24].…”