Numerous studies have suggested that ovarian hormones are able to modulate insulin sensitivity, but their exact role remains unclear. We have investigated whether different doses of 17beta-oestradiol mediate changes in insulin sensitivity and if these changes could be related to modifications of insulin receptor substrate-1 (IRS-1). Female rats were ovariectomized and later separated into three groups: untreated; treated with a dose of 17beta-oestradiol sufficient to reproduce gestational plasma concentrations of 17beta-oestradiol (group E); and treated with a dose 100 times greater than that given to group E (group E2). A euglycaemic-hyperinsulinaemic clamp was used to measure insulin sensitivity. Changes in IRS-1 were analysed by Western blotting and RT-PCR assays. In group E we found a decrease in insulin sensitivity between days 11 and 16 of treatment as in late gestation, whereas in the untreated group and group E2, development of insulin resistance was observed throughout the treatment. In contrast, whereas in group E2 insulin resistance throughout the hormonal treatment was related to diminished expression and phosphorylation of IRS-1, in group E the decrease in insulin sensitivity between days 11 and 16 of treatment was not related to a decrease in IRS-1 expression. Our results suggest that the effects of oestradiol on insulin sensitivity were dose-dependent and that the insulin resistance associated with a high dose of 17beta-oestradiol was related to downregulation of IRS-1 expression.
C Gonzalez, A Alonso, F Diaz, and AM Patterson
M Furuhashi, N Ura, H Murakami, M Hyakukoku, K Yamaguchi, K Higashiura, and K Shimamoto
We investigated the effect of fenofibrate, a peroxisome proliferator-activated receptor-alpha agonist, on insulin sensitivity including lipid metabolism in skeletal muscle. Six-week-old male Sprague-Dawley rats were divided into two groups: those fed a standard chow (control) or a fructose-rich chow (fructose-fed rats (FFRs)) for 6 weeks. FFRs were treated either with a vehicle or with 30 mg/kg per day of fenofibrate for the last 2 weeks. Insulin sensitivity (M-value) was estimated by the euglycemic hyperinsulinemic glucose clamp method. Fatty acid-binding protein (FABP) in skeletal muscle was measured by ELISA, and the expression of FABP mRNA was analyzed by semi-quantitative RT-PCR. The serum and muscle triglyceride (sTG and mTG) levels and the activity of 3-hydroxyacyl-CoA dehydrogenase (HADH), a beta-oxidation enzyme, in muscle were also determined. FFRs showed a lower M-value and higher blood pressure, sTG and mTG than did the control group. The mTG was correlated positively with sTG and negatively with the M-value. Fenofibrate treatment for 2 weeks did not change blood pressure but significantly improved the M-value, sTG and mTG. FABP content and mRNA in the soleus muscle were significantly elevated in FFRs compared with those in the control group. Fenofibrate treatment further increased FABP. The HADH activity was comparable between the control group and FFRs, but significantly increased by fenofibrate treatment. These results suggest that fenofibrate improves insulin sensitivity not only by lowering serum lipids and subsequent influx of fatty acids into muscles but also by reducing intramuscular lipid content via further induction of FABP and stimulation of beta-oxidation in muscles.
L M McShane, N Irwin, D O’Flynn, Z J Franklin, C M Hewage, and F P M O’Harte
end of the treatment period, oral and i.p. (18mmol/kg bw) glucose tolerance tests were performed in overnight-fasted mice. In addition, an insulin sensitivity (10U/kgbw) test was also performed in non-fasted mice. At termination, pancreatic tissue was
Li Feng, Ling Gao, Qingbo Guan, Xiaolei Hou, Qiang Wan, Xiangdong Wang, and Jiajun Zhao
Introduction The high-fat (HF) diet with a high ratio of saturated fatty acid is considered as a risk factor for insulin resistance, while moderate ethanol drinking was reported to have beneficial effect on insulin sensitivity ( Kiechl et al . 1996
Tetsuya Kouno, Nobuteru Akiyama, Takahito Ito, Tomohiko Okuda, Isamu Nanchi, Mitsuru Notoya, Shogo Oka, and Hideo Yukioka
concentration during the OGTT was dramatically decreased ( Fig. 5 F and H), indicating that GOAT KO mice showed increased insulin sensitivity. Moreover, ITT revealed that GOAT KO mice exhibited improved insulin response ( Fig. 6 C and D). Importantly, KO mice
K. Holemans, L. Aerts, and F. A. Van Assche
We have previously demonstrated insulin resistance in the liver and peripheral tissues of the adult offspring of rats made diabetic with streptozotocin (SDF rats). In this study, a euglycaemic hyperinsulinaemic clamp was used to test the hypothesis that insulin resistance is further aggravated during pregnancy in SDF rats. Normal pregnancy was accompanied by a decrease in the sensitivity of the liver and peripheral tissues to insulin, with a normal responsiveness to insulin. In SDF rats no further decrease in the sensitivity of peripheral tissues to insulin occurred during pregnancy when compared with non-pregnant rats, and the dose–response curves of the glucose metabolic clearance rate during hyperinsulinaemia were similar in pregnant control and pregnant SDF rats. There was, however, a modest decrease in the sensitivity of the liver to insulin during pregnancy in SDF rats.
The normal increase in plasma insulin levels during pregnancy was blunted in SDF rats: this resulted in increased glucose levels in maternal and fetal rats and increased fetal insulin concentrations, features compatible with mild 'gestational diabetes'.
In conclusion, gestational diabetes develops in pregnant SDF rats, although there is no further deterioration in peripheral insulin resistance.
Journal of Endocrinology (1991) 131, 387–393
E. BLÁZQUEZ and C. LOPEZ QUIJADA
The influence of the diet on the levels of insulin was studied in rats on a high-fat diet. Plasma and glucose insulin concentrations of a control group and of rats on a high-fat diet were compared, and so was the insulin concentration in the pancreas of the two groups.
The mean plasma insulin concentration in the control group was 40 μ-u./ml. and that of insulin extracted from the pancreas was 2·5 μg./100 mg. tissue; plasma glucose was 156 mg./100 ml.
The animals fed on a high-fat diet showed diabetic features. The mean plasma insulin level was 9 μ-u./ml., and plasma glucose increased to 210 mg./100 ml. The insulin concentration in the pancreas was not significantly different from that in the controls. In vitro the epididymal fat and the diaphragm of the high-fat-diet group were less sensitive to insulin than the same tissues in the control group.
E. BLÁZQUEZ and CLEMENTE LOPEZ QUIJADA
When groups of rats were kept on control and high-carbohydrate diets from the end of lactation until their body weight reached 150 g. it was found that the animals fed on the high-carbohydrate diet gained weight more rapidly, with an increase in fat deposits.
Glucose and plasma insulin in both groups were compared with the amounts of hormone extracted from their pancreases. When the rats on the control diet were killed the insulin and glucose plasma levels were 40 ± 3 μu./ml. and 156·69 ± 13 mg./100 ml. respectively. After 17–20 hr. fasting these values decreased significantly (P < 0·01) to 18 ± 1·5 μu./ml. and 116 ± 13 mg./ml. The amount of insulin in the pancreas was not modified by fasting. In the rats fed on the high-carbohydrate diet the plasma insulin and glucose values were higher than those in the control rats (50 ± 3·8 μu./ml. and 187 ± 19 mg./100 ml.); after 17–20 hr. starvation the glucose levels were reduced and the plasma insulin concentration remained higher (44 ± 2·9 μu./ml.); the insulin content of the pancreas was higher than in the control rats. In vitro the epididymal fat and the diaphragm of the rats on the high-carbohydrate diet were less sensitive to insulin than the same tissues in the controls.
R H Rao
The metabolic effects of angiotensin II (AII) were studied under steady-state conditions of euglycaemic hyperinsulinaemia in anaesthetized rats. Pressor doses of AII (50 and 400 ng/kg per min) had dose-dependent hypertensive and hyperglycaemic effects during glucose clamp studies. Glucose turnover measurements showed that hepatic glucose output (HGO) increased equally at both pressor doses compared with either saline infusion or AII infusion at a dose without a pressor effect (20 ng/kg per min); however, glucose disposal increased significantly only at 50 ng/kg per min. Infusion of the AII receptor antagonist, saralasin, did not itself alter glucose output or disposal significantly, but it abolished the effects of a simultaneous infusion of All. It is concluded that pressor doses of AII increase HGO by a receptor-mediated mechanism that is not related to the pressor response to the hormone. The hyperglycaemic reaction to this metabolic effect of AII is partially offset by increased glucose disposal at lower doses. The physiological significance of these metabolic actions of AII remains to be established, but they raise the possibility that AII could potentially play a role in glucose homeostasis in vivo.
Journal of Endocrinology (1996) 148, 311–318
Alex Rafacho, Henrik Ortsäter, Angel Nadal, and Ivan Quesada
first-degree relatives of diabetic patients ( Van Raalte et al . 2009 ). The ability of GCs to produce peripheral IR is central to explain their impact on glucose homeostasis. It is well known that any reduction in peripheral insulin sensitivity, e