Greater Hypoglycemic Effect Research Articles

Evaluation of Biological Activity of Two Steroid Derivatives on Glucose Levels Using a Diabetic Model

In this study, three steroid derivatives (compounds 2-4) were prepared from an estrone derivative (compound 1) to evaluate their biological activity on glucose concentration using a diabetic model. Besides, the compounds 1 and 4 were bound to technetium-99m (Tc-99m) via a radioimmunoassay method to evaluate the biodistribution of either compounds 1 and 4 in different organs over time (15, 30, 45, and 60 min). The results showed that both compounds 1 and 4 increase glucose levels compared with either compounds 2 and 3. In addition, other data showed that the biodistribution of the Tc-99m-compound 4 conjugate in all organs was higher compared with Tc-99m- compound 1 complex. In conclusion, compound 4 had greater hypoglycemic effects, and its biodistribution was wider than 1. The data suggest that amino groups may be important to the hypoglycemic activity of compound 4, and this could be related to their higher lipophilicity degree compared with compound 1.

Glibenclamide-pregnenolone derivative has greater hypoglycemic effects and biodistribution than glibenclamide-OH in alloxan-rats

The present study was designed to investigate the activity of two glibenclamide derivatives on glucose concentration. An additional aim was to identify the biodistribution of glibenclamide derivatives in different organs in a diabetic animal model. The effects of two glibenclamide derivatives on glucose concentration were evaluated in a diabetic animal model. In addition, glibenclamide derivatives were bound to Tc-99m using radioimmunoassay methods. To evaluate the pharmacokinetics of the glibenclamide derivatives over time (15, 30, 45 and 60 min) the Tc-99m-glibenclamide conjugates were used. The results showed that glibenclamide-pregnenolone had greater hypoglycemic activity than glibenclamide or glibenclamide-OH. The data also showed that the biodistribution of Tc-99m-glibenclamide-OH in all organs was less than that of the Tc-99m-glibenclamide-pregnenolone derivative. The glibenclamide-pregnenolone derivative had greater hypoglycemic effects and its biodistribution was wider than glibenclamide-OH. The data suggest that the steroid nucleus may be important to the hypoglycemic activity of the glibenclamide-pregnenolone derivative and this could be related to the degree of lipophilicity induced by the steroid nucleus in the chemical structure of glibenclamide-pregnenolone.

Increased action of pulsatile compared to non-pulsatile insulin delivery during a meal-like glucose exposure simulated by computerized infusion in healthy humans

It has previously been demonstrated that pulsatile insulin has a greater hypoglycemic effect than non-pulsatile insulin during euglycemic conditions. The aim of the present study was to examine the effect of pulsatile versus non-pulsatile insulin delivery during a meal-like iv-glucose challenge. Ten healthy young subjects were examined on two occasions. A pancreatic–pituitary clamp was maintained with somatostatin infusion and replacement of glucagon and growth hormone at baseline levels. During the first three hours on both study days, insulin was infused in a pulsatile manner. Hereafter glucose and insulin were infused by computer-controlled pumps for four hours in a pattern mimicking the postprandial glucose and insulin profiles. At one study day, insulin infusion was done in a continuous manner, while at the other study day this profile was done in a pulsatile pattern. The hypoglycemic effect of insulin was measured as the integrated area under the curve of glucose during the four-hour infusion period. The mean insulin concentration measured as the integrated area under the curve was identical (P > .9). The hypoglycemic effect of insulin was significantly augmented by 13% during pulsatile delivery as compared to continuous delivery (P = .015). Likewise was the maximal glucose concentration significantly lower at the day of the pulsatile profile (9.9 ± 1.0 vs. 11.4 ± 2.3mmol/l, P = .036). Pulsatile insulin release plays an important role in the postprandial glucose homeostasis. The disturbed insulin pulsatility in type 2 diabetes mellitus may contribute to the postprandial hyperglycemia.

Pharmacodynamics of Cibenzoline-Induced Hypoglycemia in Rats

Hypoglycemia is one of the serious adverse effects induced by cibenzoline (CBZ), an antiarrhythmic agent. In order to clarify the pharmacodynamics of CBZ-induced hypoglycemia, CBZ was administered intravenously to conscious rats at a dose of 5, 10 or 20 mg/kg and serum samples were collected periodically to determine the concentrations of CBZ, insulin and glucose. The pharmacokinetics of CBZ showed nonlinear characteristics and could be described by a two-compartment model with Michaelis-Menten elimination kinetics. CBZ induced a rapid increase in the serum concentration of insulin. As the CBZ dose was increased, a greater hypoglycemic effect occurred. The indirect response model was applied to account for the CBZ-induced increase in insulin secretion and the subsequent decrease in serum glucose. A linear relationship was assumed between the serum concentration of CBZ and its stimulating effect on insulin secretion. A nonlinear relationship was assumed between the serum concentration of insulin and its stimulating effect on the elimination of serum glucose. The time courses of serum concentrations of CBZ, insulin and glucose after intravenous injection of CBZ could be described by the pharmacokinetic and pharmacodynamic model developed. This approach will be useful for the identification of variable factors related to CBZ-induced hypoglycemia.

Hypoglycemic effects of black glutinous corn polysaccharides on alloxan-induced diabetic mice

To investigate substances from corn with the potential to affect blood sugar levels, black glutinous corn polysaccharides (BGCP) were isolated and evaluated for hypoglycemic activity in alloxan-induced diabetic mice. Mice were administered daily doses of 800, 500 or 200 mg/kg BGCP for 4 weeks. Blood glucose, serum insulin levels, body weight and the organ weight of liver, kidney, spleen and thymus were measured. All three BGCP-treated groups showed reduced blood glucose levels, and treatment with 800 mg/kg resulted in greater hypoglycemic effects than treatment with lower doses. At week 4 of the trial, mice receiving 800 or 500 mg/kg BGCP showed blood glucose levels that were significantly lower (P < 0.05) than untreated diabetic control mice. Administration of alloxan led to significant loss of body weight after 2, 3 and 4 weeks. BGCP treatment did not affect the weight of the thymus and spleen compared to untreated diabetic control mice. The weight of the liver decreased and the weight of kidney increased in alloxan-treated diabetic mice, but kidney weight did not increase in diabetic mice treated with 800 mg/kg BGCP.

Optimization and In Vivo Evaluation of an Oral Dual Controlled-Release Tablet Dosage Form of Insulin and Duck Ovomucoid

The objectives of the present study were to (1) optimizethe release rate of insulin from compressed microparticulatesand (2) compare the in vivo hypoglycemic effect of optimizedinsulin microparticulates with compressed enzyme inhibitor(duck ovomucoid) and without inhibitor. A 3-factor, 15-runBox Behnken design was used to construct polynomial modelscorrelating the dependent and independent variables. Independentprocessing variables were rate of addition of the alcoholicEudragit© L100 dispersion, volume of the antisolvent, andcompression pressure. Responses were cumulative percent ofinsulin released from 1–6 hours. Insulin and ovomucoid releasewas simultaneously analyzed by high-performance liquidchromatography. They demonstrated variable release rates,which were optimized to the Higuchi's square root of timemodel to release the insulin and the inhibitor over 6 hours. Therelationship between dissolution profiles and process parameterswere demonstrated by contour and response surface plots.In vivo hypoglycemic effect was evaluated in rabbits in a 3-waycrossover design. Cocompressed microparticulates of insulinand duck ovomucoid displayed a 3.2-fold greater hypoglycemiceffect when compared with a similar preparation without ovomucoid.This study demonstrated the potential benefits of dosageforms with dual controlled-release mechanisms for both theprotein and enzyme inhibitor.

Sustained-release self-dissolving micropiles for percutaneous absorption of insulin in mice

Microparticles-adsorbed insulin and zinc insulin (Penfil®N) were molded to self-dissolving micropiles (SDMPs) with chondroitin sulfate as the base for the percutaneous administration of insulin. Porous silicon dioxide (Sylysia® 320, 440 and 730) and porous calcium silicate (Florite®RE) were used as microparticles. As a reference, insulin loaded SDMPs were prepared. SDMPs were percutaneously administered to mice at the insulin dose level of 2.5 IU/kg. After the insertion of SDMPs to mouse skin, blood samples were collected for 8 h and plasma glucose levels were measured. There were not significant differences on minimum plasma glucose levels between the test preparations. However, Tmins, the time when the minimum glucose level appeared were 1.5 ± 0.2 h (Sylysia 320), 1.3 ± 0.2 h (Sylysia 440), 1.6 ± 0.4 h (Sylysia 730), 2.1 ± 0.3 h (Florite) and 1.7 ± 0.3 h (zinc insulin) which were greater than insulin SDMP, 0.8 ± 0.1 h. In addition, greater hypoglycemic effects were observed with SDMPs containing adsorbent-insulin and/or zinc insulin than insulin SDMP. The mean AACs (area above the plasma glucose level vs. time curve) of SDMPs containing adsorbent-insulin and zinc insulin were 357.8% h for Florite®RE, 333.1% h for Sylysia 320, 308.1% h for Sylysia 440, 328.1% h for Sylysia 730, and 374.7% h for zinc insulin, respectively, which were about two folds higher than that of insulin SDMN, 161.2% h. Those results suggest the usefulness of SDMPs composed of adsorbent-insulin as a long-acting percutaneous insulin preparation.

Mucosal insulin delivery systems based on complexation polymer hydrogels: effect of particle size on insulin enteral absorption

Insulin-loaded polymer (ILP) microparticles composed of poly(methacrylic acid) and poly(ethylene glycol), which have pH-dependent complexation and mucoadhesive properties have been thought to be potential carriers for insulin via an oral route. Nevertheless, further optimization of the polymer delivery system is required to improve clinical application. Therefore, the effect of particle size of the ILP (L-ILP: 180–230 μm, S-ILP: 43–89 μm, SS-ILP: <43 μm) on insulin absorption was studied in the in situ loop system, hypothesizing smaller particle sizes of ILP could induce bigger hypoglycemic effects due to increase mucoadhesive capacity. To verify the hypothesis, the adhesive capacities of differently sized ILPs to the mucosal tissues were evaluated. Additionally, the intestinal site-specificity of ILP for insulin absorption was investigated. Intra- and inter-cellular integrity and/or damage were also examined by lactate dehydrogenase leakage and membrane electrical resistance change to ensure the safety of ILP as a carrier for oral route. As hypothesized, the smaller sized microparticles (SS-ILP) showed a rapid burst-type insulin release and higher insulin absorption compared with the microparticles having larger sizes, resulting in greater hypoglycemic effects without detectable mucosal damage. In fact, SS-ILP demonstrated higher mucoadhesive capacity to the jejunum and the ileum than those of L-ILP. Moreover, SS-ILP's enhancement effect of insulin mucosal absorption showed a site-specificity, demonstrating maximum effect at the ileal segment. These results imply that the particle size and delivery site are very important factors for ILP with respect to increasing the bioavailability of insulin following oral administration.

Mucosal insulin delivery systems based on complexation polymer hydrogels: effect of particle size on insulin enteral absorption

Insulin-loaded polymer (ILP) microparticles composed of poly(methacrylic acid) and poly(ethylene glycol), which have pH-dependent complexation and mucoadhesive properties have been thought to be potential carriers for insulin via an oral route. Nevertheless, further optimization of the polymer delivery system is required to improve clinical application. Therefore, the effect of particle size of the ILP (L-ILP: 180–230 μm, S-ILP: 43–89 μm, SS-ILP: <43 μm) on insulin absorption was studied in the in situ loop system, hypothesizing smaller particle sizes of ILP could induce bigger hypoglycemic effects due to increase mucoadhesive capacity. To verify the hypothesis, the adhesive capacities of differently sized ILPs to the mucosal tissues were evaluated. Additionally, the intestinal site-specificity of ILP for insulin absorption was investigated. Intra- and inter-cellular integrity and/or damage were also examined by lactate dehydrogenase leakage and membrane electrical resistance change to ensure the safety of ILP as a carrier for oral route. As hypothesized, the smaller sized microparticles (SS-ILP) showed a rapid burst-type insulin release and higher insulin absorption compared with the microparticles having larger sizes, resulting in greater hypoglycemic effects without detectable mucosal damage. In fact, SS-ILP demonstrated higher mucoadhesive capacity to the jejunum and the ileum than those of L-ILP. Moreover, SS-ILP's enhancement effect of insulin mucosal absorption showed a site-specificity, demonstrating maximum effect at the ileal segment. These results imply that the particle size and delivery site are very important factors for ILP with respect to increasing the bioavailability of insulin following oral administration.

Pathophysiology of impaired pulsatile insulin release.

Plasma insulin displays 5-10 min oscillations. In Type 2 diabetes the regularity of the oscillations disappears, which may lead to insulin receptor down-regulation and glucose intolerance and explain why pulsatile delivery of the hormone has a greater hypoglycemic effect than continuous delivery. The rhythm is intrinsic to the islet. Variations in metabolism, cytoplasmic Ca(2+) concentration ([Ca(2+)](i)), other hormones, neuronal signaling and possibly beta-cell insulin receptor expression have been implicated in the regulation of plasma insulin oscillations. Most of these factors are important for amplitude-regulation of the insulin pulses. Although evidence exists supporting a role of both metabolism and [Ca(2+)](i) as pacemakers of the pulses, metabolic oscillations probably have a primary role and [Ca(2+)](i) oscillations a permissive role. Results from islets from animal models of diabetes suggest that altered plasma insulin pattern could be due to lowering of pulse amplitude of insulin oscillations rather than alterations in their frequency. Supporting a role of metabolism, altered plasma insulin oscillations were found in MODY2, MIDD and glycogenosis Type VII, which are linked to alterations in glucokinase, mitochondrial tRNALeu(UUR) and phosphofructokinase. Plasma insulin oscillations require coordination of islet secretory activities in the pancreas. The intrapancreatic ganglia have been suggested as coordinators. The diabetes-associated neuropathy may contribute to the deranged pattern as indicated by glucose intolerance in chagasic patients. Continued investigation of the role and regulation of pulsatile insulin release will lead to better understanding of the pathophysiology of impaired pulsatile insulin release, which could lead to new approaches to restore normal plasma insulin oscillations in diabetes and related diseases.

Pulsatile insulin has greater hypoglycemic effect than continuous delivery.

The relative hypoglycemic effects of pulsatile versus steadily infused insulin have been examined in six normal subjects in whom pancreatic insulin output was suppressed by somatostatin-14. Soluble insulin was infused continuously overnight on one occasion and on another occasion the same quantity was given in pulses of 2-min duration with a gap of 11 min. The mean plasma glucose concentrations were lower when pulsed insulin was given [mean for the last hour: 4.66 +/- 0.08 mmol/L (+/- SEM) versus 5.53 +/- 0.06 mmol/L (+/- SEM) for steady infusion], diverging significantly (P less than 0.05 paired t test) 7 h after the start of the study. The specific binding of 125I(A14)mono-iodo-insulin to monocytes was greater after pulsed insulin (2.9% with pulsed versus 2.4% with steadily infused insulin at tracer-only point; P less than 0.02 paired t test). Thus, intravenous insulin has greater hypoglycemic effect when pulsed, possibly mediated by greater insulin receptor binding.

Pulsatile insulin has greater hypoglycemic effect than continuous delivery

Pulsatile insulin has greater hypoglycemic effect than continuous delivery