Glucosamine Increases The Bioactivity of Insulin
Oral administration of Glucosamine Hydrochloride increases the effectiveness of Insulin Therapy.
In a ground breaking new study, it was shown that oral administration of Glucosamine Hydrochloride (GlcN·HCl) increased the effectiveness of Insulin Therapy, in adult male Sprague Dawley rats. The beneficial affect was demonstrated using both insulin as an injection and orally. Apparently, GlcN·HCl an increase in the relative bioavailability of insulin therapy of approximately 23%.
Effect of GlcN·HCl SC administration on insulin BA
The presence of GlcN·HCl prior to SC injection of insulin (1 IU/kg) significantly enhanced the action of insulin by reducing the blood glucose levels of the tested rats (P<0.01). In the post hoc analysis, the reduction in blood glucose levels was confirmed to be significant at GlcN·HCl doses of 50, 100, and 200 mg/kg. Therefore, a dose-dependent effect of GlcN·HCl on enhancing the BA of insulin could be inferred. The maximum glucose reduction was also obtained in rats pretreated with 200 mg GlcN·HCl/kg where the glucose level reached 47%.
As previously stated, in vitro studies by Marshall et al12 showed that exogenous GlcN could increase the activity of HBP, a metabolic process that is believed to function as a nutrient sensor modulating insulin resistance. Increasing tissue levels of GlcN also impair insulin secretion.28 To assess the biological importance of these studies it is important to compare the GlcN concentrations used in vitro with those expected in vivo. Interference with glucose metabolism occurs only at concentrations comparable with those of GlcN≈6.6 mmol; a concentration that is several hundred folds greater than plasma concentrations that occur during oral GlcN therapy in humans.29 At these concentrations (<10 μmol/L) GlcN neither augments the HBP nor does it reduce mediated glucose uptake.30,31
In this study, the SC coadministration of insulin and GlcN yielded different results depending on the ratios of insulin:GLcN used (Figure 1). At ratios of 1:1 and 1:4, the hypoglycemic effect was similar to insulin as no significant difference was obtained. However, at ratios of 1:10 and 1:20, the hypoglycemic effect was higher than insulin alone. GlcN can reduce blood glucose levels;16,17 the mechanism is not well understood. However, it might be related to the role of ATP depletion.32 The effect is only observed at 2 and 3 hours, thus supporting the role of ATP depletion in enhancing the hypoglycemic effect of insulin,2–4 and that GlcN as a COX-2 inhibitor will prevent insulin degradation.7
When GlcN·HCl was administered SC 30 minutes before insulin, the reduction in the level of glucose was greater when compared with insulin alone (Figure 2). The peak level of GlcN·HCl is approximately 2 hours and the maximum hypoglycemic effect occurs between 1 and 2 hours, taking into account that GlcN·HCl was administered 30 minutes before insulin. GlcN·HCl at a dose of 100 mg/kg showed a different hypoglycemic peak effect compared to other (50 and 200 mg/kg) concentrations. The time at minimum glucose level for doses of 50 and 200 mg/kg was at 1 hour, similar to a dose of insulin alone, while for GlcN·HCl at a dose of 100 mg/kg a minimum glucose level was obtained after 1.5 hours as GlcN is rapidly absorbed. After 6 hours, the GlcN·HCl level is minimal as plasma GlcN is eliminated,33 that is, the least effect on insulin activity. The decrease in blood glucose level is most likely due to ATP depletion. Such an effect leads to a decrease in insulin degradation, which explains the lower glucose levels at 1, 2, 3, and 4 hours.
Insulin is metabolized in the liver by the oxidoreductase behavior of a protein–disulfide isomerase, also known as glutathione–insulin transhydrogenase enzyme. This enzyme breaks the disulfide bonds of insulin, thereby causing its degradation.34 As the enzyme is an oxidoreductase and depends on NADH to degrade insulin, it might be inhibited by ATP/NADH depletion state as was noted in cytochrome P450 and GlcN.35
In this study, blood glucose levels tended to decrease compared to the control group in the group fed with 100 mg GlcN·HCl/kg for 5 days. GlcN HCl is usually taken orally and in human (≈90%) is absorbed,36 orally administered GlcN HCl has only 26% of the bioavailability of the intravenously administered form of GlcN HCl in humans37 and as 20% in rats.38 Data on pharmacokinetics, bioavailability, and metabolism of GlcN in rats38 are similar to those reported for human.36 Plasma GlcN is eliminated in approximately 10 hours postdosing. Pharmacokinetic parameters for GlcN, after multiple doses for 7 days, indicated no significant accumulation effects.33 This may be explained by the fact that the absorption of orally administered GlcN is limited, which is due to its dependence on facilitated transport and presystemic loss brought by the gut microbiota and so the liver is not exposed to high concentrations of GlcN in the portal venous blood even when it is consumed at high concentrations. So feeding of GlcN·HCl for 5 days is not increasing plasma GlcN·HCl levels.39,40 Based on such facts, we can explain why the hypoglycemic effect was not more pronounced than that of a single dose of GlcN·HCl. It seems, as anticipated, that GlcN homeostasis is responsible for preventing the accumulation of GlcN.
Encapsulation of GlcN·HCl in nanoparticles using chitosan as a polymer together with insulin for oral delivery was not investigated. We solubilized GlcN·HCl with IC-PEC inside RMs in order to evaluate its effect on insulin administered orally. The use of the micellar delivery system avoids the effects of pepsin and protects insulin from degradation, minimizing the effect of degrading enzymes on insulin. Therefore, part of insulin activity is retained. In the presence of GlcN·HCl, the hypoglycemic effect of insulin encapsulated in the RMs is higher than that obtained using insulin alone. The relative BA was calculated to be 6.7% compared to a value of 5.4% obtained for the group of rats treated with the RMs, which did not contain GlcN·HCl. The BA obtained for insulin delivered through the micellar system reflect that part of insulin activity is retained. Higher value is obtained when GlcN HCl is encapsulated with insulin in RMs, this result may be because when GlcN·HCl is given orally together with insulin it will enter the hepatic portal system and so it is carried through the portal vein into the liver, where most drug metabolism occurs. The biological activity of GlcN HCl on drug metabolism enzymes (DMEs) has been reported.35,41 Total cytochrome P450 content in liver decreased with rats fed with GlcN·HCl. Modulation of DME activity by GlcN may originate from indirect action on the immune system as this alters DME expression.42 However, it must be noted that all in vivo experiments were conducted on STZ diabetic rats and alteration of the metabolism might be expected due to the toxicity of the diabetogenic agent.43
This is not the first study to show that Glucosamine supplementation has benefits that go well beyond expectations.
Article Source: GreenMedInfo