Reduced Plasma Glucose Levels Research Articles

The effects of rosiglitazone and metformin on the plasma concentrations of resistin in patients with type 2 diabetes mellitus

Resistin is a protein secreted from adipose tissue that is thought to play a role in insulin sensitivity. We examined the effects of rosiglitazone and metformin on the plasma resistin levels in individuals with type 2 diabetes mellitus. Patients with type 2 diabetes mellitus who showed poor glycemic control with glimepiride (4 mg/d) were randomized to rosiglitazone (4 mg/d) and metformin (500 mg bid) treatment groups. All subjects continued glimepiride treatment as well. The plasma concentrations of resistin were measured at baseline and at 6 months of treatment for both groups. The anthropometric parameters, fasting plasma glucose, HbA1c, total cholesterol, triglyceride, high-density lipoprotein cholesterol, free fatty acids, and adiponectin concentrations were also measured. After 6 months of treatment, the reduction in plasma glucose levels was similar between the 2 groups. There were no significant changes in the lipid profiles of either group during the study period. The plasma resistin levels decreased in the rosiglitazone group (2.49 ± 1.93 vs 1.95 ± 1.59 ng/ml; P < .05) but increased in the metformin group (2.61 ± 1.69 vs 5.13 ± 2.81 ng/ml; P < .05). The plasma adiponectin concentrations were increased in the rosiglitazone group (2.91 ± 1.46 vs 4.23 ± 1.77 μg/ml; P < .05) but were unchanged in the metformin group. In summary, rosiglitazone treatment decreased the plasma resistin levels whereas metformin treatment increased them in patients with type 2 diabetes mellitus showing poor glycemic control with sulfonylurea therapy. These results suggest that the observed changes in plasma resistin levels are not the consequences of improved insulin resistance, nor are they consequences of glycemic control. Considering the potential role of resistin in insulin resistance, decrease in resistin levels may contribute to improving insulin action with rosiglitazone treatment.

The effects of dietary flaxseed on the Fischer 344 rat. III. Protection against CCl4-induced liver injury

The hepatotoxic effect of carbon tetrachloride (CCl(4)) administered by gavage at 0.25 ml CCl(4) (1:1 in olive oil) per 100 g body weight was examined 24 h later in regular chow fed (RC) and 10% flax chow fed (FC) male and female Fischer 344 rats. CCl(4)-treated RC rats were subdued, lethargic and unkempt. CCl(4)-treated FC rats were much less affected. CCl(4) treatment resulted in loss of weight in RC and FC rats. In males, the weight loss was 6.7% body mass in RC rats compared to 5.6% body mass in FC rats. In females, the weight loss was 7.5% body mass in both RC and FC rats. While CCl(4) treatment increased the level of the liver injury marker plasma alanine aminotransferase (ALT) in RC rats, this CCl(4) effect was significantly attenuated in FC rats. In male rats, the ALT increase was 435-fold in RC rats and 119-fold in FC rats, over that of their respective controls. In female rats, the ALT increase was 454-fold in RC rats and 381-fold in FC rats, over that of their respective controls. These results provide evidence that flax consumption protects the liver against injury and that the extent of the protection is sex dependent. CCl(4) had no effect on the plasma level of gamma-glutamyltranspeptidase (gammaGT) in RC and FC rats supporting the contention that plasma gammaGT is not a useful marker for acute liver injury which is seen in this model. The activity of gammaGT was increased in the livers of FC rats compared to RC rats: 2.7-fold in males and 1.5-fold in females. In RC rats, the activity of liver gammaGT was decreased by CCl(4) treatment: 70% in the male and 25% in the female. However, this CCl(4) effect was reversed or abolished by flax consumption. Compared to RC rats: in male FC rats, CCl(4) actually increased the activity of liver gammaGT 1.28-fold; while in female FC rats, the depressing effect of CCl(4) treatment was abolished. The flax-induced preservation of gammaGT in the liver in response to injury may be involved in the observed hepatoprotection through generation of GSH. In RC male rats, CCl(4) treatment effected a 25% reduction in plasma glucose levels. There was no decrease in CCl(4)-treated FC male rats. In female rats, CCl(4) treatment effected a 21% decrease in plasma glucose levels in both RC and FC rats. In conclusion, multiple parameters for acute CCl(4)-induced injury were attenuated in the FC compared to the RC rat. That flaxseed consumption conferred greater protection against liver injury in the male than in the female suggests an involvement of the estrogenic lignan component of flaxseed. We discuss the possibility that this hepatoprotection is through a flax lignan-induced increase in reduced glutathione related to a flax effect on the activity of liver gammaGT in the resting state and the maintenance of its activity in response to injury.

Salacia oblonga improves cardiac fibrosis and inhibits postprandial hyperglycemia in obese zucker rats

Diabetes has a markedly greater incidence of cardiovascular disease than the non-diabetic population. The heart shows a slowly developing increase in fibrosis in diabetes. Extended cardiac fibrosis results in increased myocardial stiffness, causing ventricular dysfunction and, ultimately, heart failure. Reversal of fibrosis may improve organ function survival. Postprandial hyperglycemia plays an important role in the development of type 2 diabetes and cardiovascular complications, and has been proposed as an independent risk factor for cardiovascular diseases. Salacia oblonga (S.O.) is traditionally used in the prevention and treatment of diabetes. We investigated the effects of its water extract on cardiac fibrosis and hyperglycemia in a genetic model of type 2 diabetes, the obese Zucker rat (OZR). Chronic administration of the extract markedly improved interstitial and perivascular fibrosis in the hearts of the OZR. It also reduced plasma glucose levels in non-fasted OZR, whereas it had little effect in the fasted animals, suggesting inhibition of postprandial hyperglycemia in type 2 diabetic animals, which might play a role in improvement of the cardiac complications of OZR. Furthermore, S.O. markedly suppressed the overexpression of mRNAs encoding transforming growth factor βs 1 and 3 in the OZR heart, which may be an important part of the overall molecular mechanisms. S.O. dose-dependently inhibited the increase of plasma glucose in sucrose-, but not in glucose-loaded mice. S.O. demonstrated a strong inhibition of α-glucosidase activity in vitro, which is suggested to contribute to the improvement of postprandial hyperglycemia.

Multiple sources of endogenous opioid peptide involved in the hypoglycemic response to 15 Hz electroacupuncture at the Zhongwan acupoint in rats

A decrease in plasma glucose levels was observed in rats which received electroacupuncture (EA) stimulation at the Zhongwan acupoint. In the present study, the role of the adrenal gland in this hypoglycemic response to EA at high frequency (15 Hz) was investigated on adrenalectomized (ADX) normal rats. There was a sharper decrease in plasma glucose by EA stimulation in the fasting ADX group than in the fasting sham-operated group. Naloxone blocked this hypoglycemic response to EA stimulation in rats which received ADX. Stimulation of EA failed to elicit an increase in plasma β-endorphin and insulin levels in ADX rats. Similar results were observed in sham and ADX mice. EA stimulation of ADX mice can reduce plasma glucose levels. Furthermore, naloxone abolished the hypoglycemic response to EA stimulation in mice. Such a hypoglycemic response to EA stimulation was also observed in μ-opioid receptor knockout mice (MOR-KOM). Mediation by another opioid peptide should also be considered in future experiments. We conclude that multiple sources of endogenous opioid peptide participated in the lowering of plasma glucose in rats induced by EA stimulation at higher frequency (15 Hz) at the Zhongwan acupoint. Increase in β-endorphin levels from the adrenal gland enhances the secretion of insulin, there by reducing plasma glucose levels, and is partially involved in this EA stimulation.

Hypoglycemic activity of Bauhinia candicans in diabetic induced rabbits

The effect of different fractions of methanolic extract of Bauhinia candicans leaves were investigated on experimentally-induced diabetic rabbits. The crude extracts (8 mg/kg) showed hypoglycemic activity along with a reduced urinary glucose excretion. Among the fractions, the highest activity was exhibited by the butanolic fraction (fraction III). Moreover, fraction III reduced plasma glucose level also in normal, as well as, glucose loaded rabbits. These results suggest that B. candicans increases the peripheral metabolism of glucose.

Effect of cocoa powder extract on plasma glucose levels in hyperglycaemic rats

This study was carried out to examine the effect of cocoa extract (CE) on plasma glucose levels in hyperglycaemic rats induced with streptozotocin. Three concentrations of CE were used to study its effect on oral glucose tolerance test (OGTT). In the normal group, CE at 0.5 per cent concentration had significantly reduced the glucose level (p&lt;0.05) at 0 and 60 min, 1.0 per cent at 0 (p&lt;0.05), 60 (p&lt;0.01) and 180 min (p&lt;0.01), 3.0 per cent at 60 (p&lt;0.05) and 180 min (p&lt;0.01) as compared to control. In hyperglycaemic group, 3.0 per cent CE had reduced the glucose level significantly (p&lt;0.05) at 60 as compared to control. Based on the results from OGTT, 3.0 per cent concentration was used to evaluate the effect of CE in a 2‐week study. There was no significant difference in reduced plasma glucose levels and lipid profiles in hyperglycaemic and normal rats, which were given basal diet enriched with 3.0 per cent CE extracted from cocoa powder as compared to the control (basal diet).

Type 2 diabetes mellitus: what is the optimal treatment regimen?

Treatment options for type 2 diabetes mellitus currently consist of insulin sensitizers, α-glucosidase inhibitors, secretagogues, and insulin. However, the emphasis on initial therapy has been shifting from secretagogues and α-glucosidase inhibitors to insulin sensitizers such as metformin and the thiazolidinediones (TZDs). This article outlines the benefits of treatment with sensitizers vis à vis α-glucosidase inhibitors and secretagogues as part of a comprehensive treatment algorithm for type 2 diabetes. Secretagogues and α-glucosidase inhibitors effectively lower plasma glucose levels only, whereas insulin sensitizers reduce several important cardiac risk factors in addition to reducing plasma glucose levels. TZDs, in particular, are also beneficial for their ability to preserve or even rejuvenate pancreatic β-cell function. The treatment algorithm has a layered approach, beginning with a combination of insulin-sensitizer therapy and incrementally progressing to triple oral therapy with the addition of secretagogues and, if necessary, the addition of subcutaneous insulin to maintain glycemic control.

Bioadhesive Fluorescent Microspheres as Visible Carriers for Local Delivery of Drugs. II: Uptake of Insulin-Loaded PCEFB/PLGA Microspheres by the Gastrointestinal Tract

Uptake of novel inherently fluorescent microspheres composed of a luminescent polyanhydride, poly[p-(carboxyethylformamido)- benzoic anhydride] (PCEFB), and poly(lactide-co-glycolide) (PLGA) (2:1, weight ratio) by the gastrointestinal tract was evaluated by fluorescent microscopy. Oral efficiency of the incorporated insulin also was determined by measuring reduction of plasma glucose levels after feeding diabetic rats with a single dose of the microspheres. We found that PCEFB/PLGA microspheres could adhere to the intestinal epithelium and traverse the absorptive cells. A large number of the spheres were observed in spleen, whereas few were detected in liver within the evaluated period of time. Apparent reduction of the plasma glucose levels was observed over a span of 6 h postfeeding. The unique properties of the delivery system such as biodegradability, bioadhesivity, and inherently luminescent characteristics render it an ideal “visible” tracer for monitoring oral fate of polymeric microspheres.

Exercise training attenuated the PKB and GSK-3 dephosphorylation in the myocardium of ZDF rats.

Cardiac dysfunction is a severe secondary effect of Type 2 diabetes. Recruitment of the protein kinase B/glycogen synthase kinase-3 pathway represents an integral event in glucose homeostasis, albeit its regulation in the diabetic heart remains undefined. Thus the following study tested the hypothesis that the regulation of protein kinase B/glycogen synthase kinase-3 was altered in the myocardium of the Zucker diabetic fatty rat. Second, exercise has been shown to improve glucose homeostasis, and, in this regard, the effect of swimming training on the regulation of protein kinase B/glycogen synthase kinase-3 in the diabetic rat heart was examined. In the sedentary Zucker diabetic fatty rats, glucose levels were elevated, and cardiac glycogen content increased, compared with wild type. A 13-wk swimming regimen significantly reduced plasma glucose levels and cardiac glycogen content and partially normalized protein kinase B-serine473, protein kinase B-threonine308, and glycogen synthase kinase-3alpha phosphorylation in Zucker diabetic fatty rats. In conclusion, hyperglycemia and increased cardiac glycogen content in the Zucker diabetic fatty rats were associated with dysregulation of protein kinase B/glycogen synthase kinase-3 phosphorylation. These anomalies in the Zucker diabetic fatty rat were partially normalized with swimming. These data support the premise that exercise training may protect the heart against the deleterious consequences of diabetes.

Isoleucine, a potent plasma glucose-lowering amino acid, stimulates glucose uptake in C 2C 12 myotubes

To examine which branched-chain amino acids affect the plasma glucose levels, we investigated the effects of leucine, isoleucine, and valine (0.3 g/kg body weight p.o.) in normal rats using the oral glucose tolerance test (OGTT, 2 g/kg). A single oral administration of isoleucine significantly reduced plasma glucose levels 30 and 60 min after the glucose bolus, whereas administration of leucine and valine did not produce a significant decrease. Oral administration of valine significantly enhanced the plasma glucose level at 30 min after the glucose administration and leucine had a similar effect at 120 min. At each measurement timepoint, the insulin levels of the treated groups were lower than that of the control group. We then investigated the effects of leucine, isoleucine or valine at the same concentration (1 mM) on glucose metabolism in C 2C 12 myotubes in the absence of insulin. Glucose consumption was elevated by 16.8% in the presence of 1 mM isoleucine compared with the control. Conversely, 1 mM leucine or valine caused no significant changes in glucose consumption in the C 2C 12 myotubes. The 2-deoxyglucose uptake of C 2C 12 myotubes significantly increased upon exposure to 1–10 mM isoleucine and 5–10 mM leucine. However, isoleucine caused no significant difference in glycogen synthesis in C 2C 12 myotubes, although leucine and valine caused a significant increase in intracellular glycogen compared with the control. The isoleucine effect on glucose uptake was mediated by phosphatidylinositol 3-kinase (PI3K), but was independent of mammalian target of rapamycin (mTOR). These results suggest that isoleucine stimulates the insulin-independent glucose uptake in skeletal muscle cells, which may contribute to the plasma glucose-lowering effect of isoleucine in normal rats.

Transdermal delivery of insulin from poloxamer gel: ex vivo and in vivo skin permeation studies in rat using iontophoresis and chemical enhancers

Gels are considered to be the most suitable delivery vehicle for iontophoresis, as they can be easily amalgamated with the iontophoretic delivery system and can also match the contours of the skin. Insulin was used as a model peptide for large peptides in the molecular weight range of 3–7 kDa. A gel formulation of insulin was formulated using poloxamer 407 and was evaluated by ex vivo and in vivo skin permeation studies in rat with chemical enhancer and/or iontophoresis. The poloxamer gel was physically and chemically stable during the storage period. In ex vivo studies, both linoleic acid and menthone in combination with iontophoresis showed a synergistic enhancement of insulin permeation. The plasma insulin concentration (PIC) was highest with linoleic acid pre-treatment, in agreement with ex vivo permeation studies, but the reduction in plasma glucose levels (PGL) was comparable to iontophoresis. Menthone pre-treatment resulted in rapid attainment of peak PIC, but the reduction in PGL was less than other treatment groups. There was no direct relation between PIC and PGL and is attributed to the fact that the action of insulin in mediated by a cascade of cellular mechanisms, before a reduction in PGL is observed. However, iontophoresis either alone or in combination with linoleic acid produced a reduction in PGL to the extent of 36–40%. A combination of chemical enhancers and iontophoresis caused greater skin irritation than when either of them was used alone.

Comparison of a high-protein disease-specific enteral formula with a high-protein enteral formula in hyperglycemic critically ill patients

Aims: To determine whether a specific high-protein enteral formula with a similar caloric percentage of fat and carbohydrates achieves greater control over glycemic levels and reduces insulin requirements in hyperglycemic critically ill patients when compared to a control high-protein enteral formula. Design: A prospective, randomized, controlled, single-blind trial in two University Hospital Intensive Care Units in Spain. Methods: We enrolled 50 patients with diabetes mellitus or stress hyperglycemia with basal glycemia ≥160 mg/dl and indication for enteral nutrition ≥5 days. Patients with severe kidney failure, liver failure or obesity were excluded from the study. In the first 48 h of admission, after randomization, 26 patients received the study diet and 24 patients received the control diet. The variables were monitored for 14 days. The Harris–Benedict formula with a fixed stress factor of 1.2 was used to calculate caloric needs. Insulin was administered by continuous infusion. An intention-to-treat analysis was performed. Results: On admission, there were no differences between the study and control group in plasma glucose levels (mg/dl) (190.9±45 vs 210.3±63) and capillary glucose levels (mg/dl) (226.1±73 vs 213.8±67). After the feeding trial, there were differences between the study and control group in plasma glucose levels (mg/dl) (176.8±44 vs 222.8±47, P=0.001), capillary glucose levels (mg/dl) (163.1±45 vs 216.4±56, P=0.001), insulin requirements/day (IU) 8.73 (2.3–27.5) vs 30.2 (21.5–57.1) ( P=0.001), insulin/received carbohydrates (UI/g) 0.07 (0.02–0.22) vs 0.18 (0.11–0.35) ( P=0.02) and insulin/received carbohydrates/kg 0.98 (0.26–3.59) vs 2.13 (1.44–4.58) ( P=0.04). These differences remain in a day-to-day comparison. There were no differences in the analytical tests, or in digestive or infectious complications. Intensive Care Unit length of stay, mechanical ventilation and mortality were similar in both groups. Conclusions: Hyperglycemic critically ill patients fed with a high-protein diet with a similar caloric percentage of fat and carbohydrates show a significant reduction in plasma glucose levels, capillary glucose levels and insulin requirements in comparison to patients on a conventional high-protein diet. This better glycemic control do not modify Intensive Care Unit length of stay, infectious complications, mechanical ventilation and mortality.

Brain-derived neurotrophic factor modulates glucagon secretion from pancreatic alpha cells: its contribution to glucose metabolism.

Brain-derived neurotrophic factor (BDNF) reduces plasma glucose levels in obese db/db diabetic mice and is speculated to produce its effects via the hypothalamus, the regulatory centre of satiety and the autonomic nervous system. The potential effect of BDNF directly on peripheral endocrine organs, however, remains to be clarified. Here we report the effects of BDNF on hormonal secretion from pancreatic islets of Langerhans using their isolated culture. In an immunohistochemical study, mouse pancreatic alpha cells were stained specifically with the anti-TrkB (a specific receptor for BDNF) antibody. After 7 days culture of isolated islets of the normal mouse pancreas, 10 ng/ml BDNF decreased the secretion of glucagon per 6 h significantly less than that of the control (p = 0.016). In contrast, there were no significant changes in insulin secretion or glucagon and insulin contents in the islets cultured under the same conditions. In vivo administration of BDNF (10 mg/kg/day) to normal mice for 7 days significantly decreased their food consumption (p < 0.05). The fasting plasma glucose levels were decreased on day 7 compared with day 1 more significantly in BDNF-treated mice (p = 0.043) than in pair-fed control mice (p = 0.14). In newborn BDNF-knockout mice, fasting plasma glucose levels increased in the order of homozygote, heterozygote and wild type (p = 0.033). No apparent immunohistochemical abnormality was observed for pancreatic glucagon in the BDNF-knockout mice. These data suggest that BDNF affects glucose metabolism not only with its anorectic effect but also with modulated glucagon secretion from pancreatic alpha cells.

Hypoglycemic properties of aqueous bark extract of Ceiba pentandra in streptozotocin-induced diabetic rats

The claim by Nigerian traditional herbal medicine practitioners that the silk cotton tree, Ceiba pentandra L. Gaertn (Bombacaceae) barks extract has antidiabetic properties was investigated. Diabetes mellitus was induced with streptozotocin and graded doses of the aqueous bark extract were then administered ad libitum in drinking water to the experimentally diabetic rats for 28 days. Administration of the aqueous bark extract caused a statistically significant reduction in plasma glucose level in streptozotocin induced diabetic rats. The extract appeared non-toxic as evidenced by normal serum levels of AST, ALT, ALP and bilirubin. The data appear to support the hypoglycemic effects of C. pentandra.

Prevention of experimental diabetic cataract by Indian Ayurvedic plant extracts.

The efficacy of Momordica charantia (MC), Eugenia jambolana (EJ), Tinospora cordifolia (TC) and Mucuna pruriens (MP) was assessed in the prevention of murine alloxan dibetic cataract. Alloxan (120 mg/kg) was used as the diabetogenic agent. While controls and diabetic controls did not receive any plant extract, treated rats received lyophilized aqueous extract of MC and EJ (200 mg/kg p.o.), alcohol extract of TC (400 mg/kg) and MP (200 mg/kg p.o.) every day until 4 months. Serum glucose concentration was assessed and cataracts examined with both the naked eye and through a slit lamp. Of the eight animals in the diabetic control group, four developed cortical cataract (stage IV) by day 90 while the remaining four developed it by day 100. The incidence rate of cataract in MC, EJ, TC and MP treated groups at 120 days was only 0, 0, 1 and 2. Oral feeding of MC, EJ, TC and MP extracts for 1 month produced a fall of 64.33%, 55.62%, 38.01% and 40.17%, respectively, in the serum glucose levels in comparison with the 48 h level. After 2 months of treatment, the respective values were 66.96%, 59.85%, 40.41% and 45.63%. MC and EJ prevented the development of cataract while the protective effect was less with TC and MP along with a significant reduction of plasma glucose levels (p < 0.001).

Efeito hipoglicêmico de rações à base de berinjela (Solanum melongena,L.) em ratos

Os objetivos do presente trabalho foram verificar se dietas ricas em berinjela apresentam efeito hipoglicêmico, se contribuem para o retardamento de absorção da glicose pós-prandial e se a fração fibra solúvel está correlacionada com estes efeitos. Os experimentos foram realizados com ratos Wistar machos adultos, normais e diabéticos, que receberam rações à base de caseína, berinjela com casca e sem casca, e de casca de berinjela por um período de 42 dias. A glicose sangüínea foi determinada no início do experimento e aos 13, 21, 34 e 42 dias. Os testes orais de tolerância à glicose (TOTG) foram realizados no final do experimento. Os resultados mostraram que as rações à base de farinha de berinjela com casca e de casca de berinjela apresentaram redução nos níveis de glicose. Este efeito não foi significativo para a ração à base de farinha de berinjela sem casca. Os animais do grupo diabético que receberam ração à base de berinjela com casca apresentaram menor área sob a curva de glicose, do que os dos grupos controle (ração à base de caseína e de berinjela com casca) e do que o do grupo diabético que recebeu a ração de caseína. Este efeito não foi observado nos animais que receberam ração à base de berinjela sem casca e casca de berinjela. Estes resultados indicam a presença de um composto responsável pelo efeito hipoglicêmico na casca de berinjela e que a pectina solúvel da ração não foi suficiente para promover tal efeito, mas que a administração contínua de pectina solúvel contribuiu para a melhora da TOTG.

Regulated transport of the glucose transporter GLUT4.

In muscle and fat cells, insulin stimulates the delivery of the glucose transporter GLUT4 from an intracellular location to the cell surface, where it facilitates the reduction of plasma glucose levels. Understanding the molecular mechanisms that mediate this translocation event involves integrating our knowledge of two fundamental processes--the signal transduction pathways that are triggered when insulin binds to its receptor and the membrane transport events that need to be modified to divert GLUT4 from intracellular storage to an active plasma membrane shuttle service.

Substrate utilization and hormonal responses to moderate intensity exercise during pregnancy and after delivery

Objective: This study was undertaken to examine substrate utilization and hormonal responses to moderate intensity exercise in the same group of women across gestation. Study design: Glucose, triglyceride, insulin, glucagon, cortisol, growth hormone, and blood urea nitrogen levels were measured in 12 women at rest and after exercise. Heart rate, oxygen uptake, and respiratory exchange ratio were measured at rest and during exercise. Urine urea nitrogen levels, urine volume, and creatinine levels were measured 24 hours before and after exercise. Each woman completed a 30-minute treadmill walk at 65% of her predicted maximal heart rate at the same time of day during the 22nd and 33rd weeks of gestation and at 14 weeks after delivery. Results: There were no significant differences between exercise trials in oxygen uptake, respiratory exchange ratio, or heart rate. Pregnancy elevated resting triglyceride levels but lowered plasma glucose levels. Exercise during pregnancy caused a reduction in plasma glucose levels but elevated circulating triglyceride levels (P < .05). Resting levels of cortisol, growth hormone, and insulin were elevated during pregnancy compared with after delivery, but resting glucagon levels were not affected by pregnancy. Exercise caused circulating levels of cortisol, growth hormone, and glucagon to increase (P < .05). The exercise-induced change in the cortisol level was greater during pregnancy than that after delivery. The exercise-induced changes in growth hormone and glucagon levels were greatest after delivery compared with those during pregnancy (P < .05). Exercise reduced insulin levels (P < .05), with the greatest reduction at 33 weeks' gestation. There were no significant differences in urine urea nitrogen excretion as a result of exercise. Conclusions: Certain substrate and hormonal responses to exercise are altered as pregnancy progresses. Quantitatively, protein appears to be a relatively unimportant fuel during a 30-minute bout of moderate intensity exercise in this group of women evaluated during pregnancy and after delivery. Furthermore, a 30-minute bout of moderate intensity exercise would not be expected to compromise fetal amino acid availability. (Am J Obstet Gynecol 2002;186:757-64.)

Oral delivery of insulin from enteric-coated capsules containing sodium salicylate: effect on relative hypoglycemia of diabetic beagle dogs

The hypoglycemic effect of Eudragit S100 enteric-coated capsules containing sodium salicylate as an absorption promoter formulated with insulin in various ways: as physical mixture, by wet granulation or in suppository bases (polyethylene glycol 4000 or Witepsol W35) was studied in hyperglycemic beagle dogs. The capsules containing insulin formulated with sodium salicylate (50 mg) and prepared by either physical mixing or wet granulation using 10% polyvinyl pyrollidone gave almost the same results producing a maximum reduction in plasma glucose level ( C max) of 81.53±8.21 and 79.59±5.75%, T max of 6 and 5 h, area under the curve (AUC) of 69.37±48.64 and 57.98±23.15% reduction hour (% red. h) and resulting in relative hypoglycemia (RH) of 8.73±6.12 and 7.29±2.91%, respectively. Formulation of insulin with sodium salicylate in PEG 4000 produced a lower AUC of 37.30±10.36% red. h and RH of 4.69±1.3%. While, formulation in Witepsol W35 (0.5, 1.0 and 2.0 g) that was sieved to produce particle size of 180–315 μm and filled in enteric-coated capsules showed that formulating insulin and sodium salicylate in 1 g base is the best formulation. It produced 25% reduction in plasma glucose levels of the hyperglycemic beagle dogs at T max of 4 h and the largest AUC of 100.10±25.72% red. h, resulting in the highest RH of 12.59±3.23%. In conclusion, 25–30% reduction in plasma glucose levels and RH of about 12.5% relative to subcutaneous injection of regular soluble insulin can be achieved by formulating insulin in Witepsol W35 (1 g) with sodium salicylate (50 mg) as an absorption promoter, reducing the resulting mass into particle size 180–315 μm, packing into hard gelatin capsules and coating with Eudragit S100.

Effect of Bioadhesive Polymers, Sodium Salicylate, Polyoxyethylene-9-lauryl Ether, and Method of Preparation on the Relative Hypoglycemia Produced by Insulin Enteric-Coated Capsules in Diabetic Beagle Dogs

ABSTRACTThe hypoglycemic effect of oral insulin capsules coated with pH-dependent Eudragit® S100 and containing various absorption promoters was studied in hyperglycemic beagle dogs. The absorption enhancers used were bioadhesive polymers, sodium salicylate, and non-ionic surfactants. A comparative study of the bioadhesive polymers, polycarbophil (PC), hydroxypropyl methylcellulose (HPMC), and carbopol 934 in insulin-coated capsules revealed no significant difference between the insulin capsules containing these polymers, giving relative hypoglycemia (RH) values ranging from 4.3±2.3% to 6.5±5.1%. It was also found that the method of preparation of the mixture of the bioadhesive polymer with insulin either by physical mixing or freeze-drying did not affect the RH values obtained. Sodium salicylate, when used in insulin enteric-coated capsules (50 mg) mixed with insulin as a physical mixture, or prepared by wet granulation using 10% polyvinyl pyrollidone (PVP), or by freeze-drying, produced RH values ranging from 7.3±2.9% to 9.4±3.7%. When sodium salicylate (100 mg) was used with insulin in freeze-dried granules an RH value of 10±2.6% was produced. As the dose of insulin increased from 6 to 9 U/kg, the area under curve (AUC) of the enteric-coated capsules containing 50 mg sodium salicylate increased from 73.2±27.8% to 121.4±102.7% reduction, but the RH did not change significantly. Insulin capsules containing polyoxyethylene-9-lauryl ether (POELE) used in its optimum concentration (2%), found in these experiments, produced RH of 9.5±6.8% when prepared as granules by wetting with a few drops of absolute alcohol in the presence of PC (50 mg). Insulin capsules containing lower (1%) or higher (3%) concentrations of POELE and prepared with PC, 50 mg by wet granulation produced lower RH of about 6%. The enteric-coated oral insulin capsules containing insulin (6 or 9 U/kg) and sodium salicylate (50 mg) as an absorption promoter, together with the bioadhesive polymer polycarbophil (50 mg), and prepared either by wet granulation using ethanol or by freeze-drying, are the best formulations to be used. They achieved a reduction in plasma glucose levels of about 25–30% and RH of about 10%. Also insulin (9 U/kg) capsules containing 2% POELE produced a 28% reduction in plasma glucose levels and RH of 9.6±6.8%.