betadex and Insulin-Resistance

In patients with non-insulin dependent diabetes mellitus (T2DM) and associated chronic liver disease, plasma levels of glucose, insulin and triglycerides are high, lipid peroxidation is increased and natural antioxidant reserves are reduced. Thus, we hypothesised that the re-balancing of cell redox levels and amelioration of liver function could result in a better glucose and lipid metabolism. To study this, we assessed the effect of a new oral formulation of an antioxidant agent - silybin-beta-cyclodextrin (named IBI/S) - in patients with chronic alcoholic liver disease and concomitant T2DM.. Sixty outpatients were enrolled in a three-centre, double blind, randomised, IBI/S vs placebo study. Forty-two (21 in the group IBI/S - 135 mg/d silybin per os - and 21 in the placebo group) concluded the 6-month treatment period. The efficacy parameters included fasting and mean daily plasma glucose levels, glycosylated hemoglobin (HbA1c), basal, stimulated C-peptide and insulin levels, total-, HDL-cholesterol and triglycerides levels in addition to conventional liver function tests. Insulin sensitivity was estimated by HOMA-IR. Malondialdehyde (MDA) was also measured before and after treatment as an index of oxidative stress.. Fasting blood glucose levels, which were similar at baseline in IBI/S group and in the placebo group (173.9 mg/dl and 177.1 mg/dl, respectively), decreased to 148.4 mg/dl (-14.7% vs baseline; p = 0.03) in the IBI/S group while they were virtually unchanged in the placebo group. The comparison between the groups at mo 6 (T6) also showed a significant reduction of glucose levels in the IBI/S group (p = 0.03). The same trend was observed in mean daily blood glucose levels, HbA1c and HOMA-IR, although differences were not significant. Basal and stimulated C-peptide values showed that only a few changes had occured in both groups. Such results indicate that insulin secretion was virtually unaffected, as confirmed also by the insulinemia data. Plasma triglycerides concentrations dropped from a baseline value of 186 mg/dl to 111 mg/dl (T6) in the IBI/S group, with significant differences at all instances with respect to baseline values. By contrast, triglycerides increased from 159 mg/dl at entry to 185 mg/dl (T6) in the placebo group. The difference between the groups at T6 was highly significant (p < 0.01). Total and HDL cholesterol as well as liver function tests did not change significantly during the study in both groups. MDA decreased significantly only in the group receiving IBI/S. No clinically relevant side effects were observed in either group.. Oral administration silybin-beta-cyclodextrin in patients with T2DM and compensated chronic alcoholic liver disease causes a significant decrease in both glucose and triglyceride plasma levels. These effects may be due to the recovery of energy substrates, consistent with a reduced lipid peroxidation and an improved insulin activity.

Topics: Antioxidants; beta-Cyclodextrins; Blood Glucose; C-Peptide; Cholesterol, HDL; Cyclodextrins; Diabetes Mellitus, Type 2; Double-Blind Method; Female; gamma-Glutamyltransferase; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Liver Diseases, Alcoholic; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Placebos; Silybin; Silymarin; Triglycerides

Skeletal muscle insulin resistance manifests shortly after high-fat feeding, yet mechanisms are not known. Here we set out to determine whether excess skeletal muscle membrane cholesterol and cytoskeletal derangement known to compromise glucose transporter (GLUT)4 regulation occurs early after high-fat feeding. We fed 6-wk-old male C57BL/6NJ mice either a low-fat (LF, 10% kcal) or a high-fat (HF, 45% kcal) diet for 1 wk. This HF feeding challenge was associated with an increase, albeit slight, in body mass, glucose intolerance, and hyperinsulinemia. Liver analyses did not reveal signs of hepatic insulin resistance; however, skeletal muscle immunoblots of triad-enriched regions containing transverse tubule membrane showed a marked loss of stimulated GLUT4 recruitment. An increase in cholesterol was also found in these fractions from HF-fed mice. These derangements were associated with a marked loss of cortical filamentous actin (F-actin) that is essential for GLUT4 regulation and known to be compromised by increases in membrane cholesterol. Both the withdrawal of the HF diet and two subcutaneous injections of the cholesterol-lowering agent methyl-β-cyclodextrin at 3 and 6 days during the 1-wk HF feeding intervention completely mitigated cholesterol accumulation, cortical F-actin loss, and GLUT4 dysregulation. Moreover, these beneficial membrane/cytoskeletal changes occurred concomitant with a full restoration of metabolic responses. These results identify skeletal muscle membrane cholesterol accumulation as an early, reversible, feature of insulin resistance and suggest cortical F-actin loss as an early derangement of skeletal muscle insulin resistance.

Topics: Animals; beta-Cyclodextrins; Cell Membrane; Cholesterol; Diet, High-Fat; Diet, Western; Dietary Fats; Glucose Intolerance; Hyperinsulinism; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal

The present investigation was designed to explore the effectiveness of pterostilbene (PT) on insulin resistance, metabolic syndrome and oxidative stress in fructose-fed insulin resistant rats.. Age-matched, male Sprague-Dawley rats (330±30g body weight) were allocated into five groups (n=10). Control (C) group received 65% cornstarch, and the diabetic (D) group received 65% fructose for eight weeks. The third group (D+PT20) received 65% fructose and PT 20mg/kg/day for eight weeks. The fourth group (D+PT40) received 65% fructose and PT 40mg/kg/day for eight weeks. The fifth group (D+M) received 65% fructose and metformin (M) 100mg/kg/day for eight weeks. PT was dissolved in 10% β-cyclodextrin and given orally to rats. Several biochemical parameters were determined to assess the PT efficacy against insulin resistance, metabolic complications, and hepatic oxidative stress.. Significantly high HOMA-IR (p<0.001) values in D group compared to C group indicate the presence of insulin resistance. Significantly high levels of TBARS (p<0.001) and decreased levels of SOD (p<0.001) and GSH (p<0.001) in hepatic tissues of D group indicate oxidative stress associated with insulin resistance. Pterostilbene treatment to fructose-fed diabetic rats significantly decreased HOMA-IR (p<0.001) values. Furthermore, PT treatment significantly decreased hepatic TBARS (p<0.001) and increased SOD (p<0.001) and GSH (p<0.001) levels in fructose-fed diabetic rats.. Current study reveals that PT is successful in ameliorating glycemic control, insulin sensitivity while diminishing metabolic disturbances and hepatic oxidative stress in a fructose-induced T2DM rat model.

Topics: Animals; beta-Cyclodextrins; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fructose; Insulin Resistance; Male; Metabolic Syndrome; Metformin; Oxidative Stress; Rats; Rats, Sprague-Dawley; Stilbenes; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

Insulin stimulates glucose uptake in adult skeletal muscle by promoting the translocation of GLUT4 glucose transporters to the transverse tubule (T-tubule) membranes, which have particularly high cholesterol levels. We investigated whether T-tubule cholesterol content affects insulin-induced glucose transport. Feeding mice a high-fat diet (HFD) for 8 wk increased by 30% the T-tubule cholesterol content of triad-enriched vesicular fractions from muscle tissue compared with triads from control mice. Additionally, isolated muscle fibers (flexor digitorum brevis) from HFD-fed mice showed a 40% decrease in insulin-stimulated glucose uptake rates compared with fibers from control mice. In HFD-fed mice, four subcutaneous injections of MβCD, an agent reported to extract membrane cholesterol, improved their defective glucose tolerance test and normalized their high fasting glucose levels. The preincubation of isolated muscle fibers with relatively low concentrations of MβCD increased both basal and insulin-induced glucose uptake in fibers from controls or HFD-fed mice and decreased Akt phosphorylation without altering AMPK-mediated signaling. In fibers from HFD-fed mice, MβCD improved insulin sensitivity even after Akt or CaMK II inhibition and increased membrane GLUT4 content. Indinavir, a GLUT4 antagonist, prevented the stimulatory effects of MβCD on glucose uptake. Addition of MβCD elicited ryanodine receptor-mediated calcium signals in isolated fibers, which were essential for glucose uptake. Our findings suggest that T-tubule cholesterol content exerts a critical regulatory role on insulin-stimulated GLUT4 translocation and glucose transport and that partial cholesterol removal from muscle fibers may represent a useful strategy to counteract insulin resistance.

Topics: Animals; Anticholesteremic Agents; beta-Cyclodextrins; Biological Transport; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cells, Cultured; Cholesterol; Glucose; Glucose Transporter Type 4; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Membrane Transport Modulators; Mice, Inbred C57BL; Muscle Fibers, Skeletal; Obesity; Phosphorylation; Protein Kinase Inhibitors; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Ryanodine Receptor Calcium Release Channel

Although estrogen contributes to glucose homeostasis, its mechanisms remain unclear.. To investigate the role of caveolin-3 in estrogen's effects on glucose metabolism.. Ovariectomized (OVX) and sham-operated rats, fed with normal chow diet (NCD) or high-calorie diet (HCD), received 17β-estradiol (E(2)) or placebo. Fasting plasma glucose (FPG) was detected and HOMA-IR was calculated. Primary cultured skeletal muscle cells were treated with E(2), in the presence or absence of β-methyl-cyclodextrin and tamoxifen. Glucose consumption and transportation and expression of caveolin-3 were examined.. In NCD-fed rats, OVX or E(2) had no effects on FPG or HOMA-IR. In HCD-fed rats, OVX led to the increase of FPG and HOMA-IR, which was attenuated by E(2). In cultured cells, E(2) improved glucose consumption and transportation and enhanced caveolin-3 expression, which were blocked by β-methyl-cyclodextrin and tamoxifen.. Caveolin-3 plays an important role in the mechanism by which E(2) attenuates diet-induced glucose intolerance.

Topics: Animals; beta-Cyclodextrins; Blotting, Western; Caveolin 3; Estradiol; Estrogen Antagonists; Female; Homeostasis; Insulin Resistance; Muscle, Skeletal; Rats; Rats, Wistar; Tamoxifen; Up-Regulation