Über den Einfluß von Insulin auf die Alaningluconeogenese in der isoliert perfundierten Leber von New Zealand Obese Mice

Abstract

The influence of insulin and fat-rich diet on the alanine gluconeogenesis was investigated on isolated perfused livers of 3l/,-4 month-old male New Zealand obese mice (NZO-mice). White mice were taken as controls for an insulin effect. Glucose tolerances of NZO-mice were distinctly changed compared with those of white mice. Insulin inhibited gluconeogenesis in the livers of white mice in the same way as in the livers of rats. No insulin effect could be demonstrated out in livers of NZO-mice, however. This result shows that not only the periphery but also the livers of these animals are insusceptible to insulin. Fat-rich diet over 6 weeks had no influence on gluconeogenesis. Under the influence of this diet the production of ketone bodies was distinctly increased, the ,&hydroxybutyrate/acetoacetate ratio was unchanged, however. Fat-rich diet increased body weight significantly, but the liver contents of total lipids and esterified fatty acids was clearly decreased as well as 14C-incorporation from [U-14C]alanine in total lipids. This suggests that fat is broken down in the liver a t a higher rate to meet the energy requirement.

Evolution of Insulin Resistance in New Zealand Obese Mice

“…During the clamp, the NZC mice suppressed completely, whereas the NZO mice continued to produce glucose, consistent with hepatic insulin resistance. This confirms the previous finding of Rudorff et al (25), who showed that, when livers from adult mice were perfused in situ, hepatic glucose release could be modestly reduced by insulin in the control mice, but there was no decrease in NZO mice. They concluded that adult NZO mice have hepatic insulin resistance.…”

Differential hepatic gene expression in a polygenic mouse model with insulin resistance and hyperglycemia: evidence for a combined transcriptional dysregulation of gluconeogenesis and fatty acid synthesis

“…Most importantly, the data reveal that marked changes in the hepatic gene expression take place in insulin-resistant mice, in particular an induction of genes involved in lipid synthesis in the insulin-resistant population. This profound dysregulation appears to reflect the biochemical basis of the previously described (Subrahmanyam 1960, Rudorff et al 1970, Veroni et al 1991 severe hepatic insulin resistance of the NZO mouse.…”

“…NZO mice exhibit a markedly increased gluconeogenesis which is resistant to insulin (Rudorff et al 1970). Accordingly, transcript levels of PEPCK and G6 Pase were found upregulated in the diabetic and, to a lesser extent, also in the insulin-resistant cluster of backcross mice (Fig.…”

“…These data have convincingly demonstrated that the effect of insulin on glucose metabolism is dissociated from that on lipogenesis in the NZO mouse. Glucose is converted to fat, but not to glycogen (Subrahmanyam 1960, Rudorff et al 1970. In contrast, alanine-dependent gluconeogenesis in the perfused liver is not inhibitable by insulin (Subrahmanyam 1960).…”

“…In the course of this syndrome, a large proportion of male mice develop hyperglycemia due to islet cell failure (Leiter et al 1998). Hepatic glucose overproduction, which is resistant to insulin, has been shown to be a critical, early abnormality that precedes the overt fasting hyperglycemia of the NZO mouse (Rudorff et al 1970, Veroni et al 1991. Furthermore, NZO mice exhibit a reduced hepatic storage of glycogen, but an enhanced conversion of a glucose load to fat (Subrahmanyam 1960).…”