betadex and Diabetes-Mellitus--Type-2

In 1983 it was shown that glucagon administered intranasally (IN) was absorbed through the nasal mucosa and increased blood glucose in healthy subjects. Shortly thereafter, it was shown that IN glucagon counteracts with hypoglycaemia in insulin-treated diabetic patients. In spite of this evidence, IN glucagon was not developed by any pharmaceutical company before 2010, when renewed interest led to intensive evaluation of a possible remedy for hypoglycaemia in insulin-treated diabetic adults and children. IN glucagon is now being developed as a needle-free device that delivers glucagon powder for treatment of severe hypoglycaemia; the ease of using this device stands in stark contrast to the difficulties encountered in use of the current intramuscular glucagon emergency kits. Studies have demonstrated the efficacy, safety and ease-of-use of this IN glucagon preparation, and suggest IN glucagon as a promising alternative to injectable glucagon for treating severe hypoglycaemia in children and adults who use insulin. This would meet the unmet medical need for an easily administered glucagon preparation.

Topics: Adjuvants, Pharmaceutic; Administration, Intranasal; beta-Cyclodextrins; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Compounding; Emergency Treatment; Glucagon; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Phosphorylcholine; Powders; Severity of Illness Index

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

Green coffee is one of health-promoting supplements of the diet, applied in the form of either preparations or enriched food products. Its positive impact is manifested by mitigation of the development of certain tumors, e.g., in the colon and liver, and type 2 diabetes. Many studies proved that chlorogenic acids are the main active substances in green coffee. The bioavailability of these compounds depends among others on their interactions with other components of the diet, mainly proteins. When they are used as food ingredients, their bioavailability is additionally decreased because of the decomposition or interactions with other ingredients during food processing. The undesirable changes may be limited among others by microencapsulation, for example with β-cyclodextrin. In this study, rats were fed the pro-oxidative high fat diet, which was supplemented with chlorogenic acids from green coffee that were used in four forms such as: a purified extract, complexes of chlorogenic acids and β-cyclodextrin, and bread supplemented with either the extract or the β-cyclodextrin inclusion complex. Chlorogenic acids added to bread because of the reduced absorption from the crumb in the small intestine and increased passage to the colon, contributed to the beneficial modification of enzymatic activities of intestinal microbiota. When added directly to the diet, they contributed to the improved antioxidant status in the liver and kidneys, lowered glucose level and increased HDL level. A high ratio of reduced to oxidized glutathione in the liver and a high concentration of antioxidants in the blood serum were observed after administration of chlorogenic acids in the form of inclusion complexes with β-cyclodextrin, indicating that microencapsulation increased their bioaccessibility due to the limited interactions with other components of the diet.

Topics: Animals; Antioxidants; beta-Cyclodextrins; Biological Availability; Bread; Chlorogenic Acid; Coffee; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Drug Compounding; Food, Fortified; Male; Oxidative Stress; Rats

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

The impact of cyclodextrins (CDs) on postprandial glycemic response employing the real-time continuous glucose monitoring system (RT-CGMS) was investigated. For this purpose, α-CD, β-CD, γ-CD, HP-β-CD, curdlan, and dextrin at doses of 10 and 100 mg/kg were orally administered in rats. The RT-CGMS was efficient to evaluate the impact of CDs on postprandial glycemia. The results showed that α-CD, β-CD, dextrin, and curdlan did not reduce the glycemic response after the administration of starch. In contrast, the HP-β-CD (100 mg/kg) attenuated the rise in glycemia. Moreover, the γ-CD blunts the postprandial glycemic excursion at doses of 10 and 100 mg/kg. Therefore, γ-CD could attenuate the rise in glycemia promoted by oral administration of starch. Considering that the treatment of postprandial hyperglycemia is necessary to prevent type 2 diabetes, this study opens the perspective of better control of postprandial glycemia by the addition of γ-CD in food.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins; Blood Glucose; Cyclodextrins; Diabetes Mellitus, Type 2; gamma-Cyclodextrins; Hyperglycemia; Hypoglycemic Agents; Male; Models, Animal; Monitoring, Physiologic; Postprandial Period; Rats, Wistar; Starch

Type 2 diabetes is often associated with high blood cholesterol. Here, we investigated the effect of cholesterol loading on MIN6 cells derived from pancreatic β cells. Exposure of MIN6 cells to cholesterol-induced apoptosis in time- and dose-dependent manner. Treatment with methyl-β-cyclodextrin that removes cholesterol from plasma membrane prevented the cells from cholesterol-induced apoptosis. Western blot analysis revealed that the levels of phosphorylated-p38 mitogen-activated protein kinase (P-p38 MAPK) and c-Jun N-terminal kinases (P-JNK) were significantly increased after the cholesterol loading, suggesting that the stress-activated protein kinase signaling was stimulated. A specific p38 inhibitor rescued MIN6 cells from cholesterol-induced apoptosis, while JNK inhibitor failed, suggesting the importance of activation of p38 MAPK signaling in response to cholesterol. The expression of Bip and CHOP, the endoplasmic reticulum (ER) stress markers, remained unaffected, indicating that the ER stress may not be involved in the cytotoxicity of cholesterol on the ΜΙΝ6 cells. The intracellular concentration of reactive oxygen species measured by use of 2',7'-dichlorofluorescin diacetate was significantly increased after cholesterol loading, demonstrating the induced apoptosis was mediated through oxidative stress. Addition of reduced form of glutathione in the medium rescued MIN6 cells from apoptosis induced by cholesterol loading. Taken together, these results demonstrate that the free cholesterol loading can induce apoptosis of MIN6 cells mediated by oxidative stress and the activation of p38 MAPK signaling.

Topics: Animals; Apoptosis; beta-Cyclodextrins; Cell Line; Cholesterol; Diabetes Mellitus, Type 2; Glutathione; Insulin-Secreting Cells; Mice; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Reactive Oxygen Species; Signal Transduction