Glucose Uptake In Mice Research Articles

Mitochondrial function, but not glucose uptake, is disrupted in skeletal muscle from Bmal1−/− mice

Molecular clocks regulate circadian rhythms including muscle function and metabolism. Mice lacking Bmal1, a circadian clock transcription factor, showed a decreased in mitochondrial density in skeletal muscle. We hypothesize that mitochondrial function and glucose uptake are compromised in skeletal muscle of Bmal1−/− mice. O2 consumption was measured by polarography in mitochondria from 18 week‐old gastrocnemius muscles. Content of respiratory complexes, UCP3 and VDAC1 was measured in isolated mitochondria by western blot. Glucose uptake was measured with [3H] glucose upon insulin stimulation in the soleus muscles of 13 and 36 week‐old mice. Blood glucose was measured using a commercial glucose meter in 7, 13 and 36 week‐old mice. Serum insulin was measured with an Elisa kit in 13 and 36 week‐old mice. Respiration states 3 (ADP‐driven) and 5 (uncoupled) were 47±6% and 50±8% lower in mitochondria isolated from the gastrocnemius muscles of Bmal1−/− vs. control mice. There were no differences in the content of respiratory complexes, UCP3 and VDAC1. Blood glucose was 61% higher in 7 week‐old Bmal1−/− mice but there was no difference at other ages. Serum insulin was significantly lower in 36 week‐old Bmal1−/− mice. Basal and insulin‐stimulated glucose uptake rates were not different in soleus muscles at any age. We suggest that the molecular clock regulates mitochondrial function but not glucose uptake in mice.

SIRT6 Deficiency Results in Severe Hypoglycemia by Enhancing Both Basal and Insulin-stimulated Glucose Uptake in Mice

Glucose homeostasis in mammals is mainly regulated by insulin signaling. It was previously shown that SIRT6 mutant mice die before 4 weeks of age, displaying profound abnormalities, including low insulin, hypoglycemia, and premature aging. To investigate mechanisms underlying the pleiotropic phenotypes associated with SIRT6 deficiency, we generated mice carrying targeted disruption of SIRT6. We found that 60% of SIRT6(-/-) animals had very low levels of blood glucose and died shortly after weaning. The remaining animals, which have relatively higher concentrations of glucose, survived the early post-weaning lethality, but most died within one year of age. Significantly, feeding the mice with glucose-containing water increased blood glucose and rescued 83% of mutant mice, suggesting that the hypoglycemia is a major cause for the lethality. We showed that SIRT6 deficiency results in more abundant membrane association of glucose transporters 1 and 4, which enhances glucose uptake. We further demonstrated that SIRT6 negatively regulates AKT phosphorylation at Ser-473 and Thr-308 through inhibition of multiple upstream molecules, including insulin receptor, IRS1, and IRS2. The absence of SIRT6, consequently, enhances insulin signaling and activation of AKT, leading to hypoglycemia. These data uncover an essential role of SIRT6 in modulating glucose metabolism through mediating insulin sensitivity.

A pilot study on palmyrah pinattu (dried fruit pulp) as an anti-diabetic food component

The fruit pulp of palmyrah (Borassus flabellifer L.) has been shown to inhibit intestinal glucose uptake in mice, the active principle being a steroidal saponin, flabelliferin-II which inhibits intestinal ATPase in mice at 5×10-5M level. Palmyrah fruit pulp (PFP) is widely used to manufacture many food products including dried PFP (pinattu), which has been consumed in North-East Sri Lanka for centuries. The present study was carried out to investigate whether PFP in the form of pinattu could reduce serum glucose levels of mild diabetic (Type-II) patients who were not on a drug regimen with a view to developing pinattu as an anti-diabetic food component. Patients (newly diagnosed, Type-II, mild diabetic patients) attending the diabetic clinic at the Family Practice Centre, University of Sri Jayewardenepura, Sri Lanka, were subjected to a glucose challenge (75g/50kg BW) after a 10 hour overnight fast and the blood glucose levels determined. On subsequent visits of each patient (3 days after the first visit) blood glucose was determined after administration of PFP in the form of pinattu (6g/50kg BW) or fibre (4g/50kg BW) extracted from PFP prior to the glucose challenge. The methodology employed was the cross over method where each patient was its own control. In all mild diabetic patients treated with pinattu, there was a significant reduction (p< 0.01, by 15-48%) in blood glucose concentration after a glucose challenge. Therefore the results of the present study suggest that pinattu (dried PFP) could be used as an anti-hyperglycemic agent. Keywords: Borassus flabellifer, flabelliferin, palmyrah fruit pulp, blood glucose, diabetes. International Journal of Biological and Chemical Sciences Vol. 1 (3) 2007: pp. 250-254

The effect of flabelliferins of palmyrah fruit pulp on intestinal glucose uptake in mice

Keywords: Flabelliferins, glucose uptake, ICR mice, palmyrah fruit pulp. J. Natn.Sci.Foundation Sri Lanka 2006 34 (1) 37-41 doi:10.4038/jnsfsr.v34i1.2074

Transcriptional basis for exercise limitation in male eNOS-knockout mice with age: heart failure and the fetal phenotype

Endothelium-derived nitric oxide (NO) is pivotal in regulating mitochondrial O(2) consumption (Vo(2)) and glucose uptake in mice. The aim of this study was to investigate the mechanism of age- and genotype-related exercise limitation in male endothelial NO synthase (eNOS)-knockout (KO, n = 16) and wild-type (WT, n = 19) mice. Treadmill testing was performed at 12, 14, 16, 18, and 21 mo of age. Vo(2), CO(2) production, respiratory exchange ratio, and maximal running distance were determined during treadmill running. There were good linear correlations for increase of speed with increase of Vo(2). The difference between KO and WT mice was not significant at 12 mo but was significant at 18 mo. Linear regression showed that KO mice consumed more O(2) at the same absolute and relative workloads, suggesting that Vo(2) was not inhibited by NO in KO mice. KO mice performed 30-50% less work than WT mice at each age (work = vertical distance x weight). In contrast to WT mice, the work performed by KO mice significantly decreased from 17 +/- 1.4 m.kg at 12 mo to 9.4 +/- 1.7 m.kg at 21 mo. Running distance was significantly decreased from 334 +/- 27 m at 12 mo to 178 +/- 38 m at 21 mo, and maximal Vo(2), CO(2) production, and respiratory exchange ratio per work unit were significantly higher in KO than in WT mice. Gene arrays showed evidence of a fetal phenotype in KO mice at 21 mo. In conclusion, age- and genotype-related exercise limitations in maximal work performed and maximal running distance in male eNOS-KO mice indicated that fetal phenotype and age were related to onset of heart failure.

Sixteen hours of fasting differentially affects hepatic and muscle insulin sensitivity in mice

Fasting readily induces hepatic steatosis. Hepatic steatosis is associated with hepatic insulin resistance. The purpose of the present study was to document the effects of 16 h of fasting in wild-type mice on insulin sensitivity in liver and skeletal muscle in relation to 1) tissue accumulation of triglycerides (TGs) and 2) changes in mRNA expression of metabolically relevant genes. Sixteen hours of fasting did not show an effect on hepatic insulin sensitivity in terms of glucose production in the presence of increased hepatic TG content. In muscle, however, fasting resulted in increased insulin sensitivity, with increased muscle glucose uptake without changes in muscle TG content. In liver, fasting resulted in increased mRNA expression of genes promoting gluconeogenesis and TG synthesis but in decreased mRNA expression of genes involved in glycogenolysis and fatty acid synthesis. In muscle, increased mRNA expression of genes promoting glucose uptake, as well as lipogenesis and beta-oxidation, was found. In conclusion, 16 h of fasting does not induce hepatic insulin resistance, although it causes liver steatosis, whereas muscle insulin sensitivity increases without changes in muscle TG content. Therefore, fasting induces differential changes in tissue-specific insulin sensitivity, and liver and muscle TG contents are unlikely to be involved in these changes.

Contrasting effects of exercise and NOS inhibition on tissue-specific fatty acid and glucose uptake in mice.

Isotopic techniques were used to test the hypothesis that exercise and nitric oxide synthase (NOS) inhibition have distinct effects on tissue-specific fatty acid and glucose uptakes in a conscious, chronically catheterized mouse model. Uptakes were measured using the radioactive tracers (125)I-labeled beta-methyl-p-iodophenylpentadecanoic acid (BMIPP) and deoxy-[2-(3)H]glucose (DG) during treadmill exercise with and without inhibition of NOS. [(125)I]BMIPP uptake at rest differed substantially among tissues with the highest levels in heart. With exercise, [(125)I]BMIPP uptake increased in both heart and skeletal muscles. In sedentary mice, NOS inhibition induced by nitro-L-arginine methyl ester (L-NAME) feeding increased heart and soleus [(125)I]BMIPP uptake. In contrast, exercise, but not L-NAME feeding, resulted in increased heart and skeletal muscle [2-(3)H]DG uptake. Significant interactions were not observed in the effects of combined exercise and L-NAME feeding on [(125)I]BMIPP and [2-(3)H]DG uptakes. In the conscious mouse, exercise and NOS inhibition produce distinct patterns of tissue-specific fatty acid and glucose uptake; NOS is not required for important components of exercise-associated metabolic signaling, or other mechanisms compensate for the absence of this regulatory mechanism.