Glucose Uptake

fat where lipolysis is activated, resulting in the release of free fatty acids into the circulation. The increase of free fatty acids may enhance the accumulation of hepatic lipids reducing glucose uptake and activating various serine kinases which results in decreased insulin signaling. Moreover, mice with a liver-specific disruption of the glucocorticoid receptor had diminished hepatic triglycerides levels. In humans, a high prevalence (up to 20%) of hepatic steatosis was also reported in patients with Cushing's syndrome. Genetic variations in the glucocorticoid receptors may also affect the activity of cortisol, lipid metabolism and cardiovascular risk.

Circulating leptin decreases during fasting in rodents and humans; however, the mechanism of the decrease is unknown. The aim of this study was to examine the relationship between decrements of serum leptin concentrations and changes of hormonal (insulin and cortisol) and metabolic (glucose, ketones, and fatty acids) parameters involved in the metabolic adaptation to energy restriction in normal-weight humans. Because there are marked gender differences in circulating leptin, both men and women were studied. The body mass index (BMI), percent body fat (% body fat), and serum leptin, insulin, cortisol, glucose, ~-hydroxybutyrate (BOHB), and nonesterified fatty acids (NEFA) were determined in 11 men and 13 women (age, 20 to 41 years; BMI, 21.2 to 26.8 kg/m 2) before and during 7 days of energy restriction (-68% 4-1% of daily energy requirements). Weight loss averaged about 4% in both men and women. Leptin in men was 3.7 4-0.5 and decreased to 2.1 + 0.4 ng/mL (percent change [%4], -36% -6.0%, P < .0005) during restriction. Concurrently, insulin decreased from 7.2 _+ 0.6 to 1.8 _ 0.3 I~U/mL (%A, -74% ---4%, P < .0001). In contrast, leptin was higher in women before (16.2 _+ 1.9 ng/mL) and after (6.0 -+ 0.8 ng/mL) restriction and decreased more than in men (%A, -61% -+ 4%, P < .02 v men), whereas the decrease of insulin in women was less than in men: 10.1 _+ 1.9 to 6.1 ---1.0 I~U/mL (%A, -31% __. 9%, P < .0025; P < .0005 vmen), perhaps because glucose decreased less in women than in men. Overall, the changes of leptin during fasting were independently correlated with the changes of glucose (r = .53, P < .007), NEFA (r = .53, P < .01), and BOHB (r = .65, P < .001). In addition, the change of leptin correlated with a combined index of the parameters that reflect decreased glucose availability and increased lipolysis ([Aglucose + Ainsulin + ANEFA]/3, r = .73, P < .0001) or a combined index of parameters that would be expected to limit glucose uptake by adipocytes ([Aglucose + Ainsulin + Acortisol]/3, r = .48, P < .02). We conclude that there are significant differences between men and women in the responses of leptin and insulin to energy restriction. Furthermore, decreases of circulating leptin during negative energy balance are related to changes of endocrine and metabolic parameters, suggesting that leptin secretion may be regulated by alterations of adipocyte glucose and lipid metabolism, ie, decreased glucose uptake and metabolism and increased lipolysis.

The adapter protein Grb10 binds to phosphotyrosine residues in insulin receptors via its C-terminal region and regulates insulin signaling. This study investigated Grb10 regulation of glucose uptake and the importance of the Grb10 N-terminal region using 3T3-L1 adipocytes overexpressing full-length (FL-Grb10) or N-terminally truncated Grb10 (BPS-SH2). Overexpression of FL-Grb10 inhibited insulin-stimulated receptor autophosphorylation and glucose uptake. In contrast, the BPS-SH2 fragment of Grb10 had no effect on receptor phosphorylation or glucose uptake. In spite of these differences, both FL-Grb10 and the BPS-SH2 fragment inhibited insulin-stimulated phosphorylation of IRS1, IRS2, Akt/PKB, Shc, ERK1/2, APS, and c-Cbl to a similar extent. Co-precipitation studies demonstrated more sustained binding of the BPS-SH2 fragment than FL-Grb10 to insulin receptors. Although receptor binding domains of Grb10 are sufficient to inhibit insulin effects on proximal post-receptor signaling responses, N-terminal domains of Grb10 are essential for the effects of this adapter protein on receptor phosphorylation and glucose uptake.

The relationship between grape seed-derived procyanidin extract components and their bioactivity was explored. The monomeric and dimeric structures only acted as anti-inflammatory agents. Similarly, pure C1 trimer was highly effective on LPS-activated macrophages. To reproduce all of the bioactivities of the total extract, a fraction enriched with trimeric structures was needed. This trimeric-enriched fraction was divided into subfractions, the most bioactive of which contained two compounds with a molecular weight equal to a trimer (865) and a dimer-gallate (729), according to spectrometric analysis. Thus, it may be concluded that a mixture of both molecules reproduces the bioactivity in glucose metabolism (3T3-L1), lipid metabolism (HepG2) and macrophage functionality (RAW 264.6).

Type 2 diabetes, a chronic disease, affects about 150 million people world wide. It is characterized by insulin resistance of peripheral tissues such as liver, skeletal muscle, and fat. Insulin resistance is associated with elevated levels of tumor necrosis factor alpha (TNF-a), which in turn inhibits insulin receptor tyrosine kinase autophosphorylation. It has been reported that cannabis is used in the treatment of diabetes. A few reports indicate that smoking cannabis can lower blood glucose in diabetics. D 9 -tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis. This study aimed to determine the effect of a lipophilic cannabis extract on adipogenesis, using 3T3-L1 cells, and to measure its effect on insulin sensitivity in insulin resistant adipocytes. Cells were cultured in Dulbecco's modified eagle medium (DMEM) with 10% fetal bovine serum (FBS) and differentiated over a 3 day period for all studies. In the adipogenesis studies, differentiated cells were exposed to the extract in the presence and absence of insulin. Lipid content and glucose uptake was subsequently measured. Insulin-induced glucose uptake increased, while the rate of adipogenesis decreased with increasing THC concentration. Insulin-resistance was induced using TNF-a, exposed to the extract and insulin-induced glucose uptake measured. Insulin-induced glucose was increased in these cells after exposure to the extract. Semiquantitative real time polymerase chain reaction (RT-PCR) was performed after ribonucleic acid (RNA) extraction to evaluate the effects of the extract on glucose transporter isotype 4 (GLUT-4), insulin receptor substrate-1 (IRS-1) and IRS-2 gene expression.