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Gastroenterology and Hepatology Research
Journal of GHR 2013 March 21 2(3): 449-457 ISSN 2224-3992 (print) ISSN 2224-6509 (online) Interaction of Insulin with Prokinetic Drugs in STZ-induced
Diabetic Mice
Mohamed A Fouad, Hekma A Abd El latif, Mostafa E El Sayed Mohamed A Fouad Shalaby, Department of Pharmacology, R&D Erythromycin tended to decrease blood glucose level and increase Senior specialist pharmacist, Kahira Pharmaceutical Company, Cairo, serum insulin level after one week of daily dose administration in diabetic mice. Erythromycin potentiated the effect of insulin given on Hekma A Abd El latif, Professor and head of Pharmacology & blood glucose level and serum insulin level where other prokinetic Toxicology, Faculty of Pharmacy, Cairo University, Giza, Egypt agents failed to do so after repeated dose administration in diabetic Mostafa E El Sayed, Professor of Pharmacology & Toxicology, mice.Metoclopramide or erythromycin in combination with insulin Faculty of Pharmacy, Cairo University, Giza, Egypt significantly (P<0.05) decreased small intestinal transit in diabetic Correspondence to: Mohamed A Fouad Shalaby, Research spe- mice, which was less than that of insulin alone. Administration of cialist pharmacist, Department of Pharmacology, R&D, Kahira Phar- test prokinetic drugs along with insulin antagonized the action of maceutical Company, Cairo, Egypt. [email protected] insulin on xylose absorption. These combinations also increased the Telephone: +01220997029 Fax: +00-20-22025477 rate of glucose absorbed from the gut. Received: September 20, 2012 Revised: November 28, 2012 CONCLUSIONS: The present study suggests that prokinetic drugs
Accepted: November 18, 2012 could potentially improve glycemic control in diabetic gastroparesis Published online: March 21, 2013 by allowing a more predictable absorption of nutrients, matched to the action of exogenous insulin. The use of prokinetics i.e. erythromycin may be interesting in the clinic in order to decrease the need for insulin in diabetic patients. The dose of insulin may be AIM: Prokinetic drugs have been used for gastroparesis in diabetic
safely decreased with erythromycin in chronic treatments. patients for a relatively long time already and some data about the interactions with insulin in the clinic should be available. To 2013 ACT. All rights reserved.
study the possible interactions of metoclopramide, domperidone or erythromycin in streptozotocin (STZ)-induced diabetic mice treated Key words: Streptozotocin; Gastrointestinal motility; Insulin; Pro-
with insulin in different parameters. kinetic drugs; Intestinal absorption METHODS: Effects of the individual as well as combined drugs
were studied in diabetic mice via estimation of the blood glucose
Fouad MA, Abd El latif HA, El Sayed ME. Interaction of Insulin and serum insulin levels, small intestinal transit, gastric emptying, with Prokinetic Drugs in STZ-induced Diabetic Mice. Journal of xylose absorption and glucose tolerance tests. The groups included Gastroenterology and Hepatology Research 2013; 2(3): 449-457 were normal control, diabetic control, insulin 2 IU/kg (s.c.), Available from: URL: http://www.ghrnet.org/index./joghr/ metoclopramide 20 mg/kg (p.o.), domperidone 20 mg/kg (p.o.) and erythromycin 6 mg/kg (p.o.) individually and in combination. The first set of experiments was carried out to investigate the subchronic Diabetes mellitus is the most common cause of gastroparesis and effect of one week of daily dose of the tested drugs individually disturbed gastric and small intestine motility. Gastroparesis is a as well as the combination of insulin with each prokinetic drug in syndrome characterized by delayed gastric emptying in absence of diabetic mice on blood glucose and serum insulin levels. The other mechanical obstruction of stomach. The cardinal symptoms include five sets of experiments were carried out to investigate the acute postprandial fullness (early satiety), nausea, vomiting, bloating, or effect of a single dose of each drug individually and in combination epigastric pain. Symptoms attributable to gastroparesis are reported on blood glucose and serum insulin levels, small intestinal transit, by 5 to 12% of patients with diabetes[1,2]. There is an association gastric emptying, oral xylose absorption and glucose tolerance tests.
between self-reported glycemic control and psychological distress and RESULTS: The study included test prokinetic drugs i.e.,
development of gastrointestinal symptoms in diabetics[3]. Impaired metoclopramide (20 mg/kg), domperidone (20 mg/kg) and function of the gastrointestinal tract related to diabetes mellitus results erythromycin (6 mg/kg), as well as insulin (2 IU/kg), which from diabetic autonomic neuropathy, impaired sensory innervation was individually effective in decreasing SIT, enhancing GE and and a direct effect of persistent hyperglycemia[4]. Once established, increasing xylose absorption significantly (P<0.05) in diabetic mice.
diabetic gastroparesis tends to persist, despite amelioration of glycemic 2013 ACT. All rights reserved.
Fouad MA et al . Insulin interaction with prokinetic drugs in diabetic mice control. Thus, gastric emptying and symptoms are stable during≥12 were used. Insulin injection was diluted with normal saline solution years follow-up, despite improved glycemic control[5]. Gastroparesis for obtaining a suitable strength. Hydroxypropylmethylcellulose affects nutritional state and, in diabetics, it also has deleterious effects (1%) was used as vehicle to administer prokinetic drugs. The other on glycemic control and secondary effects on organs that lead to reagents were the highest grade of commercially available products.
increased mortality[6]. First-line treatment includes restoration of nutrition and medications using prokinetic drugs. Therefore, searching for therapeutic interventions of prokinetic drugs that will improve the Control groups received the equal volumes of vehicle through specific alterations associated with diabetic gastroparesis represents the corresponding routes. The groups included were normal control, most important aim of the present study. Prokinetic drugs have been diabetic control, insulin 2 IU/kg (s.c.), metoclopramide 20 mg/kg used for gastroparesis in diabetic patients for a relatively long time (p.o.), domperidone 20 mg/kg (p.o.) and erythromycin 6 mg/kg (p.o.) already and some data about the interactions with insulin in the clinic individually and in combination. The doses were selected based on should be available. It deemed of interest to investigate the possible the earlier reports and recommended clinical doses and prior pilot drug-drug interactions, which may develop from co-administration of experiments[10,11,12]. Metoclopramide, domperidone or erythromycin insulin and certain prokinetic drugs i.e. metoclopramide, domperidone in the dose mentioned above were given alone 15 minutes before and erythromycin. Also, the study aims to warn about the possibility the administration of insulin/vehicle. Insulin was given 50 minutes that prokinetics might increase the hypoglycemic effect of insulin. before determination of blood glucose and serum insulin levels. Prokinetic drugs, commonly used to treat delayed gastric emptying, Six main sets of experiments were carried out. The first set of have variable effects on small intestinal motility, and little is known experiments carried out to investigate the subchronic effect of one about their effects on glucose absorption. The prokinetic drugs act week of daily dose of insulin, metoclopramide, domperidone and primarily through neurons since peristalsis is based on neural reflexes. erythromycin individually as well as the combination of insulin with Dopamine antagonists such as metoclopramide and domperidone[7] are metoclopramide, domperidone or erythromycin in STZ-induced used in this study. Motilides such as erythromycin enhances peristalsis diabetic male mice on blood glucose and serum insulin level. The by acting on motilin receptors[8].
other five sets of experiments carried out to investigate the acute In the present study, streptozotocin (STZ)-induced diabetic mice were effect of a single dose of insulin, metoclopramide, domperidone and treated with insulin, prokinetic agents i.e. metoclopramide, domperidone erythromycin individually as well as the combination of insulin with or erythromycin individually and in combination. Acute and subchronic metoclopramide, domperidone or erythromycin on blood glucose and study were carried out to determine whether the prokinetic drugs could serum insulin level, small intestinal transit, gastric emptying, oral improve the blood glucose level and neuropathy changes in diabetic xylose absorption and glucose tolerance tests.
conditions treated with insulin. This was achieved by measuring some of the biochemical parameters affected by persistent hyperglycemia Experimental induction of diabetes via estimation of blood glucose and serum insulin levels. Acute Diabetes mellitus was induced in overnight fasted mice by a single study were carried out to determine the effect of the test drugs on the intraperitoneal injection of freshly prepared solution of streptozotocin gastrointestinal tract motility represented in small intestinal transit and 100 mg/kg body weight in 0.1 M cold citrate PH 4.5[13,14]. The gastric emptying, knowing that all of the prokinetic drugs used produce animals were allowed to drink 5% glucose solution to overcome acute actions on the gut. The rate of gastric emptying is an important STZ-induced hypoglycemia[15]. The control mice were injected determinant of carbohydrate absorption and thus of the blood glucose with citrate buffer alone. Two week following STZ injection, blood profile[9]. Oral xylose absorption and glucose tolerance tests were used samples were collected from the tail venopuncture of the mice and as representative indices of carbohydrates absorption changes. used for the estimation of blood glucose levels using advanced Glucometer ACCU-CHEK (Roche, Germany)[16,17]. Overnight fasted MATERIALS AND METHODS
mice with blood glucose level above 200mg/dL were selected and used in the present study.
Animals
Healthy adult male albino mice weighting between 20-30 g were
used in the present study. They were obtained from the animal house
Measurement of blood glucose and serum insulin levels
of the research department of Kahira pharmaceutical company, Cairo, Blood was collected from reto-orbital venous plexus according to Egypt. All animals were fed a standard pellet chow and had free the method of Cocchetto[18]. Blood was collected using heparinized access to water. They were maintained under controlled laboratory microhematocrit capillaries into Wassermann tubes. Blood glucose conditions (temperature, humidity) throughout the study. New level was measured using advanced Glucometer ACCU-CHEK. groups of mice were recommended for each test done. Animals were Serum was separated by centrifugation at 11000 rpm for 2 min. and sacrificed under mild ether anesthesia. Experiments were conducted serum glucose level was determined immediately using glucose in accordance with the guidelines set by the animal's health research kit[19]. There is no significant difference in glucose levels between ethics training initiative, Egypt.
the two methods. The remaining amount of serum was kept frozen at -20ºC for insulin determination. Serum insulin was estimated Drugs and Reagents
by immunoradiometric assay (IRMA) technique[20] using insulin Insulin (Regular insulin, Novonordisk, Denmark), Metoclopramide IRMA Kit. This estimation was done 2 min before drug/vehicle (Memphis Pharmaceutical Co., Cairo, Egypt), Domperidone (El administration and 50 min after insulin/vehicle administration. Kahira Pharmaceutical Co., Cairo, Egypt) and Erythromycin ethylsuccinate (Abbott Laboratories, Cairo, Egypt) were obtained. Small intestinal transit (SIT)
Glucose Reagent Kit (Biomerieux, France), Insulin IRMA Kit The passage of a charcoal meal through the gastrointestinal transit IM3210 (Immunotech Beckman coulter, Czech Republic), in mice was used as parameter for intestinal motility[21,10]. Overnight Streptozotocin (Sigma Aldrich Chemie, Germany), Phloroglucinol fasted mice were treated with test prokinetic drug orally 45 min and/ (Sigma chemical Co., USA) and D-xylose (Acros Organics, USA) or insulin subcutaneously 30 min before administration of charcoal 2013 ACT. All rights reserved. Fouad MA et al . Insulin interaction with prokinetic drugs in diabetic mice meal (0.3 mL of a 5% suspension of charcoal in 2% hydroxypro glucose solution (2.5 g/kg of body weight) was orally administered, pylmethylcellulose solution). After 20 min, animals were killed and blood was taken from the tail vein at 0, 30, 60 and 120 by cervical dislocation just after mild ether anesthesia. Abdomen min afterward. Blood glucose concentrations were determined opened, the charcoal marker was identified in the small intestine and immediately using an Accu-chek (Roche Diagnostics, Germany).The tied immediately to avoid movement of marker. The entire intestine difference between the value of the diabetic control group and the was removed by cutting at pyloric and ileocaecal ends and then diabetic treated groups represent the amount of glucose absorption washed in water. The distance the meal was traveled through the from the intestine affected by the different drugs used in this study intestine as indicated by the charcoal is measured and expressed as in addition to other factors. The extent of absorption of the glucose percent of the total distance from the pylorus to the caecum. was estimated using the total area under the curve, which represents Small intestinal transit (SIT)=(Distance travelled by charcoal / blood glucose level from t0 to t120. AUCtotal is calculated using the Total length of the small intestine)×100.
trapezoidal rule from t0 to t120.

Gastric emptying
Gastric emptying was determined by the phenol red method[22,12]. All data were expressed as the mean±standard error with 6 to 10 The test prokinetic drug was given alone 45 min before mice per group. Statistical analysis was performed using two ways administration of phenol red meal. Insulin (s.c.) was injected 30 analysis of variance (ANOVA) followed by Tukey-Kramer multiple min before the administration of the meal. A solution of 1.5% Hydr comparisons test. For all the statistical tests, the level of significance oxypropylmethylcellulose containing 0.05% phenol red as a marker was fixed at P< 0.05.
was given intragastrically (0.5 mL/mouse) to overnight fasted mice. 15 min later, Animals were sacrificed by cervical dislocation just after mild ether anesthesia. The abdominal cavity was opened, and Effects of insulin and certain prokinetic drug individually or
the cardiac and pyloric ends of the stomach were clamped, then the combined on blood glucose and serum insulin levels in STZ-
stomach was removed and washed with normal saline. The stomach induced diabetic mice.
was cut into pieces and homogenized with 25 mL of 0.1 N NaOH. Figure 1 and Figure 3 showed antihyperglycemic effect of insulin The suspension was allowed to settle for 1 h, and then 5 mL of the against STZ-induced diabetic mice. Acute administration of insulin supernatant was added to 0.5 mL of 20% trichloroacetic acid (w/v) (2 IU/kg) significantly (p<0.05) decreased blood glucose level and centrifuged at 3000 rpm for 20 min. To one ml of supernatant 4 to 45.37±4.57 mg/dL and increased serum insulin level to 1.96± mL of 0.5 N NaOH was added. The absorbance of this pink colour 0.1 uIU/kg in diabetic mice close to hypoglycemic value. Acute liquid was measured using spectrophotometer at 560nm (Model: effect of single dose of Metoclopramide (20 mg/kg), Domperidone Shimadzu 150-20). Phenol red recovered from animals that were (20 mg/kg) or erythromycin (6 mg/kg) individually did not affect sacrificed immediately after administration of the test meal was blood glucose level and serum insulin level in diabetic mice. Acute used as a standard (0% emptying). Gastric emptying (%) in the 15 effect of metoclopramide, domperidone or erythromycin did not min period was calculated according to the following equation: affect the action of insulin on blood glucose and serum insulin Gastric emptying (GE) %=100 – (X × Y-1 × 100); X=Absorbance level (Figure 1, Figure 2). Erythromycin tended to decrease blood of phenol red recovered from the stomach of animals sacrificed glucose level and increase serum insulin level after one week of 15 min after test meal; Y=mean (n=5) absorbance of phenol red daily dose administration in diabetic mice. Daily dose administration recovered from the stomachs of control animals (killed at 0 min of insulin (2 IU/kg) for one week significantly (p<0.05) decreased following test meal).
blood glucose level to 45.94±2.6 mg/dL and increased serum insulin level to 2.01±0.02 uIU/kg in diabetic mice close to hypoglycemic Oral D-xylose Loading Test
value. There is no interaction between insulin and the test prokinetic This test measures intestinal carbohydrates absorption by calculating namely metoclopramide or domperidone on blood glucose level the plasma concentration of D-xylose after ingestion of a known and serum insulin level after one week of daily dose administration amount of d-xylose[23,24]. The test prokinetic drug was given alone 45 in diabetic mice. On the other hand, Combination of insulin and min before administration of xylose. Insulin (s.c.) was injected 30 erythromycin significantly (p<0.05) decreased blood glucose level min before the administration of xylose. A 30% solution containing to 22.9±1.91 mg/dL and increased serum insulin level to 2.18±0.12 D-xylose (0.8 g/kg body weight) was administrated by oral gavage to uIU/kg in diabetic mice (Figure 3, Figure 4). overnight fasted mice. After 60 min of xylose administration, blood samples were drawn from retro-orbital venous plexus and blood Small intestinal transit
samples were centrifuged at 11 000 rpm for 2 min, plasma xylose The normal control value of the small intestinal transit was 56.61 concentrations were measured using a colorimetric assay. The assay ±2.58 % of the total length of the small intestine. Induction of involved incubation of 20 μL of plasma with 1 mL of colour reagent diabetes in mice significantly (p<0.05) increased SIT to 76.9±6.12%. containing 1 g phloroglucinol in 200 mL glacial acetic acid and 20 Insulin at dose (2 IU/kg) significantly (p<0.05) decreased SIT in mL concentrated HCL and heated for 4 min at 100˚C, followed by diabetic mice to 61.05±3.85% as compared to diabetic control group. reading of the absorbance at 554 nm using spectrophotometer (Model: The test prokinetic drugs namely metoclopramide (20 mg/kg), Shimadzu 150-20).
domperidone (20 mg/kg) and erythromycin (6 mg/kg) significantly (p<0.05) decreased SIT in the diabetic mice to 50.04±2.42%, 48.7 Oral Glucose Tolerance Test
±4.53%, and 43.05±3.5% respectively. Either of metoclopramide The OGTT was used to evaluate intestinal absorption. The test was or erythromycin in combination with insulin significantly (p<0.05) carried out according to the method of Stûmpel et al and Sachin decreased SIT in diabetic mice and this effect was less than that of et al[25,26]. After the mice were fasted for 12 h, the test compound insulin alone. Domperidone did not affect the action of insulin on was administered half an hour before the glucose loading. A 50% SIT in diabetic mice (Table 1). 2013 ACT. All rights reserved.
Fouad MA et al . Insulin interaction with prokinetic drugs in diabetic mice Blood glucose level (% of diabetic control) Blood glucose level (% of diabetic control) Normal control (Citrate buffer) Diabetic control (STZ 100 mg/kg) Insulin (2 IU/kg sc) Metoclopramide (20 mg/kg po) Normal control (Citrate buffer) Diabetic control (STZ 100 mg/kg) Insulin (2 IU/kg sc)+Metoclopramide (20 mg/kg po) Insulin (2 IU/kg sc) Metoclopramide (20 mg/kg po) Domperidone (20 mg/kg po) Insulin (2 IU/kg sc)+Metoclopramide (20 mg/kg po) Insulin (2 IU/kg sc)+Domperidone (20 mg/kg po) Domperidone (20 mg/kg po) Erythromycin (6 mg/kg po) Insulin (2 IU/kg sc)+Domperidone (20 mg/kg po) Insulin (2 IU/kg sc)+Erythromycin (6 mg/kg po) Erythromycin (6 mg/kg po) Insulin (2 IU/kg sc)+Erythromycin (6 mg/kg po) Figure 1 Acute effect of a single dose of insulin, metoclopramide,
domperidone and erythromycin individually as well as the combination
Figure 3 Subchronic effect of one week daily dose administration of insulin,
of insulin with metoclopramide, domperidone or erythromycin on blood metoclopramide, domperidone and erythromycin individually as well as the glucose level in STZ-induced diabetic mice. Values represent the mean±s.e.m. combination of insulin with metoclopramide, domperidone or erythromycin of eight mice per group. * Significantly different from the normal control on blood glucose level in STZ-induced diabetic mice. Values represent the value at P<0.05. a Significantly different from the diabetic control value at P mean±s.e.m. of eight mice per group. * Significantly different from the normal <0.05. b Significantly different from insulin value at P<0.05.
control value at P<0.05. a Significantly different from the diabetic control value at P<0.05. b Significantly different from insulin value at P<0.05. Serum insulin level (% of diabetic control) Serum insulin level (% of diabetic control) Normal control (Citrate buffer) Diabetic control (STZ 100 mg/kg) Insulin (2 IU/kg sc) Metoclopramide (20 mg/kg po) Insulin (2 IU/kg sc)+Metoclopramide (20 mg/kg po) Normal control (Citrate buffer) Diabetic control (STZ 100 mg/kg) Domperidone (20 mg/kg po) Insulin (2 IU/kg sc) Metoclopramide (20 mg/kg po) Insulin (2 IU/kg sc)+Domperidone (20 mg/kg po) Insulin (2 IU/kg sc)+Metoclopramide (20 mg/kg po) Erythromycin (6 mg/kg po) Domperidone (20 mg/kg po) Insulin (2 IU/kg sc)+Erythromycin (6 mg/kg po) Insulin (2 IU/kg sc)+Domperidone (20 mg/kg po) Figure 2 Acute effect of a single dose of insulin, metoclopramide,
Erythromycin (6 mg/kg po) domperidone and erythromycin individually as well as the combination Insulin (2 IU/kg sc)+Erythromycin (6 mg/kg po) of insulin with metoclopramide, domperidone or erythromycin on serum Figure 4 Subchronic effect of one week daily dose administration of insulin,
insulin level in STZ-induced diabetic mice. Values represent the mean±s.e.m. metoclopramide, domperidone and erythromycin individually as well as the of eight mice per group. * Significantly different from the normal control combination of insulin with metoclopramide, domperidone or erythromycin value at P<0.05. a Significantly different from the diabetic control value at on serum insulin level in STZ-induced diabetic mice. Values represent the P<0.05. b Significantly different from insulin value at P<0.05. mean±s.e.m. of eight mice per group. * Significantly different from the normal control value at P<0.05. a Significantly different from the diabetic control value at P<0.05. b Significantly different from insulin value at P<0.05. The normal control value of the gastric emptying was 72.50±1.68 % of the total amount of the phenol red meal given. High blood to 95.87±2.41%, 76.38±7.67%, 90.92±4.92% and 84.77±2.11% glucose level in diabetic control mice delayed GE significantly respectively compared with diabetic control mice. Administration (p<0.05) to 55.23±9.30%. Insulin (2 IU/kg), metoclopramide (20 of prokinetic drugs namely metoclopramide, domperidone or mg/kg), domperidone (20 mg/kg) or erythromycin (6 mg/kg) in the erythromycin along with insulin (2 IU/kg) did not affect the action doses employed increased gastric emptying significantly (p<0.05) of insulin on GE (Table 1).
2013 ACT. All rights reserved.
Fouad MA et al . Insulin interaction with prokinetic drugs in diabetic mice Table 1 Effects of insulin and prokinetic drugs alone and in combination on
small intestinal transit and gastric emptying in diabetic mice.
Normal control(Citrate buffer) Diabetic control (STZ 100 mg/kg) 76.90±6.12 * 55.23±9.30 * Insulin (2 IU/kg s.c.) 61.05±3.85 a 95.87±2.41 *a Metoclopramide (20 mg/kg p.o.) 50.04±2.42 ab 76.38±7.67 ab Insulin (2 IU/kg s.c.)+Metoclopramide (20 mg/kg p.o) 54.30±3.46 a 94.91±1.01 *a Domperidone (20 mg/kg p.o.) 48.70±4.53 ab 90.92±4.92 *a Insulin (2 IU/kg s.c.)+Domperidone (20 mg/kg p.o) 62.60±3.07 a 92.87±1.14 *a Erythromycin (6 mg/kg p.o.) 43.05±3.50 ab 84.77±2.11 a Insulin (2 IU/kg s.c.)+Erythromycin (6 mg/kg p.o) 49.14±4.57 ab 90.86±3.20 *a Values represent the mean±SE. of eight mice per group; * Significantly different from the normal control value at P<0.05; a Significantly different Blood glucose level (mg/dL) from the diabetic control value at P<0.05. b Significantly different from insulin value at P<0.05.
30-' 0' 30' 60' 120' 240' Normal control (Citrate buffer) Diabetic control (STZ 100 mg/kg) Insulin (2 IU/kg sc) Δ Metoclopramide (20 mg/kg po) Insulin (2 IU/kg sc)+Metoclopramide (20 mg/kg po) Domperidone (20 mg/kg po) Insulin (2 IU/kg sc)+Domperidone (20 mg/kg po) Erythromycin (6 mg/kg po) Insulin (2 IU/kg sc)+Erythromycin (6 mg/kg po) Figure 6 Effect of a single dose of insulin, metoclopramide, domperidone
and erythromycin individually as well as the combination of insulin with
Serum insulin level (% of diabetic control) metoclopramide, domperidone or erythromycin on oral d-glucose tolerance test in STZ-induced diabetic mice. Values represent the mean±s.e.m. of Normal control (Citrate buffer) Diabetic control (STZ 100 mg/kg) eight mice per group. * Significantly different from the normal control Insulin (2 IU/kg sc) Metoclopramide (20 mg/kg po) value at P<0.05. a Significantly different from the diabetic control value at Insulin (2 IU/kg sc)+Metoclopramide (20 mg/kg po) P<0.05. b Significantly different from insulin value at P<0.05. Domperidone (20 mg/kg po) Insulin (2 IU/kg sc)+Domperidone (20 mg/kg po) Erythromycin (6 mg/kg po) diabetic mice demonstrated basal hyperglycemia (399±14 mg/dL) Insulin (2 IU/kg sc)+Erythromycin (6 mg/kg po) which remained above 400 mg/dL during all time points determined. Figure 5 Effect of a single dose of insulin, metoclopramide, domperidone
The peak increase in serum glucose concentrations in diabetic mice and erythromycin individually as well as the combination of insulin was observed after 60 min of glucose treatment, while that of normal with metoclopramide, domperidone or erythromycin on oral d-xylose mice observed after glucose loading, indicating delayed glucose absorption test in STZ-induced diabetic mice. Values represent the mean homeostasis in diabetic mice. STZ significantly (p<0.05) increased ± s.e.m. of eight mice per group. * Significantly different from the normal the area under the curve (Figure 7). Insulin at dose (2 IU/kg) control value at P<0.05. a Significantly different from the diabetic control significantly (p<0.05) decrease blood glucose level to 107.16±8.51 value at P<0.05. b Significantly different from insulin value at P<0.05. mg/dl and 100 mg/dL after 30 min and 60 min of glucose loading resp. and the effects persisted till 120 min (Figure 6). The area under Oral d-xylose absorption test
the curve was significantly reduced to 226.53±12.28 mg/dL. 120 min The normal control value of serum d-xylose concentration was 1.63 (Figure 7). Metoclopramide at dose (20mg/kg) did not affect blood ±0.10 mg/mL after 60 min of d-xylose administration (0.8 g/kg).
glucose level where BGL was 487.5±13.6 mg/dL and 505.5±14.55 The amount of xylose absorbed from the GIT significantly (p<0.05) mg/dL after 30 min and 60 min of glucose loading respectively. decreased in the diabetic mice to 0.606±0.03 mg/mL as compared to While domperidone at dose 20 mg/kg and erythromycin at dose 6 normal control group. Insulin (2 IU/kg), metoclopramide (20 mg/kg), mg/kg produced significant (p<0.05) increase in blood glucose level domperidone (20 mg/kg) and erythromycin (6 mg/kg) in the doses reach to 590±13 mg/dL, 590.8±17.4 mg/dL and 622±23.11 mg/dL, employed individually increased xylose absorption to 1.64±0.16 mg/ 631.5±21.48 mg/dL after 30 min and 60 min of glucose loading ml, 0.989±0.03 mg/mL, 1.162±0.03 mg/mL and 1.469±0.03 mg/mL respectively (Figure 6). In addition, domperidone and erythromycin respectively. Administration of prokinetic drugs i.e. metoclopramide, significantly (p<0.05) increased the area under the curve (Figure 7). domperidone or erythromycin along with insulin antagonized the Administration of metoclopramide, domperidone or erythromycin action of insulin (2 IU/kg) on xylose absorption (Figure 5). There is along with insulin significantly (p<0.05) increases blood glucose antagonism between insulin and the test prokinetic drugs on xylose level as compared to insulin treated value (Figure 6). Combination absorption in diabetic mice.
of insulin with metoclopramide, domperidone or erythromycin significantly (p<0.05) increased the area under the curve as compared Oral d-glucose tolerance test
to insulin treated value (Figure 7). The oral glucose tolerance test (OGTT) can be used to evaluate blood glucose homeostasis and also indirectly evaluate glucose absorption. As shown in figure 6, glucose load (2.5 gm/kg) in normal mice produced rapid increase in blood glucose levels at 30min and Findings of the present investigation revealed that STZ-induced returned to baseline values within 120 min. In contrast, STZ-induced diabetes resulted in a significant increase in small intestinal transit 2013 ACT. All rights reserved.
Fouad MA et al . Insulin interaction with prokinetic drugs in diabetic mice transporter SGLT1[42]. In the present study, STZ-induced diabetic mice demonstrated basal hyperglycemia which remained above 400 mg/dL during all time points determined. The capacity of the small intestine to absorb glucose increases in experimentally induced diabetic animals as a consequence of the enhanced activity and abundance of SGLT1 as shown by Fedorak et al[43] suggesting SGLT1 as a potential target for glycemic control in diabetic animals. STZ- induced diabetic mice exhibited severe hyperglycemia with increased Na+ dependent glucose uptake activity compared with normal AUC (mg/dL.120 min) 400 mice[44]. Acute effect of insulin induced hypoglycemia increased xylose absorption and glucose absorption from the GIT in the diabetic mice. In the present study, the effects of insulin on the intestinal absorption of sugar did not differentiate between an effect of insulin Normal control (Citrate buffer) Diabetic control (STZ 100 mg/kg) on the absorption capacity of the mucosa and other factors that may Insulin (2 IU/kg s.c.) Metoclopramide (20 mg/kg po) affect total sugar absorption. Some studies have shown that the effect Insulin (2 IU/kg sc)+Metoclopramide (20 mg/kg po) of insulin leads to increase Na+ dependent glucose carrier activity Domperidone (20 mg/kg po) in the small intestine, which leads to increase glucose absorption[45]. Insulin (2 IU/kg sc)+Domperidone (20 mg/kg po) Some studies reported that insulin induced hypoglycemia accelerates Erythromycin (6 mg/kg po) gastric empting in type 1 diabetes[37], which decrease time of Insulin (2 IU/kg sc)+Erythromycin (6 mg/kg po) movement of sugar from stomach to the small intestine, in addition to Figure 7 Effect of a single dose of insulin, metoclopramide, domperidone
its therapeutic effect by decreases the rate of glucose production and and erythromycin individually as well as the combination of insulin with increases the rate of glucose utilization by cells[46].
metoclopramide, domperidone or erythromycin on the area under the curve of blood glucose concentrations during oral glucose absorption test By studying the prokinetic drugs in the current study individually, in STZ-induced diabetic mice. Values represent the mean±s.e.m. of eight domperidone (20 mg/kg po) was found to be the most effective mice per group. * Significantly different from the normal control value at prokinetic agent in the diabetic mice when compared to diabetic P<0.05. a Significantly different from the diabetic control value at P<0.05. control group as well as the other prokinetic drugs. Domperidone, b Significantly different from insulin value at P<0.05.
metoclopramide and erythromycin significantly (p<0.05) decreased small intestine transit and accelerated gastric emptying in STZ- and significant decrease in gastric emptying. Abnormalities in gastric induced diabetic mice. Similar results have been reported by recent emptying and small intestinal motor functions were also reported in studies[47,48,49,50,51]. The inhibitory effect of domperidone on small diabetic mice[27,28]. The mechanism of action of increased intestinal intestinal transit is probably mediated via its action on dopamine transit may be, partially, due to increased cholinergic and decreased since it is dopamine antagonist[52]. Dopamine has an indirect beta-adrenergic receptor activities in diabetic animals[29]. The delay inhibitory effect via inhibition of cholinergic transmission in the in gastric emptying could be partially attributed to the decrease myenteric plexus, which regulates the gastrointestinal tract[53]. It in the number of myenteric neurons in stomach as a result of could be suggested that metoclopramide produced its action through diabetes[30,31,32]. Similarly, the increased in intestinal transit could be inhibition of presynaptic and postsynaptic D2 receptors, stimulation mediated through the same mechanism. All of the stomach's smooth of presynaptic excitatory 5-HT4 receptors and/or antagonism of muscle cells have the ability to produce electric depolarizations presynaptic inhibition of muscarinic receptors. The aforementioned "slow waves" from resting potential. These rhythmic contractions are in accordance with that given by Valenzuela et al[54]. The action of are thought to originate in the non-smooth muscle pacer cells in the erythromycin is probably mediated via its agonistic activity to motilin interstitial cells of Cajal[33]. Gastric emptying is delayed because the receptors, which accelerates gastric emptying[8,33].
number of gastric interstitial cells (ICCs) is markedly diminished Metoclopramide significantly increased xylose absorption but in diabetes[34]. Data of the current study showed that insulin induce did not affect glucose absorption in STZ-induced diabetes. These hypoglycemia significantly attenuated small intestinal transit and finding is in harmony with that given by Paul et al[55]. The action of accelerated gastric emptying in diabetic mice. These results are metoclopramide is mediated via increased plasma concentrations partly in agreement with earlier reports[35,36,37,38]. The mechanism of of glucagon like peptide-1 and glucose dependant insulinotropic action of the obtained results might be due to direct effect of insulin polypeptide, which responsible for delay in glucose absorption, this and not only due to antidiabetic effect of insulin that decreased blood action did not affect rate of xylose absorption. Domperidone (20 glucose level leading to decrease SIT. This effect could be due to mg/kg) and erythromycin (6 mg/kg p.o.) significantly increased counter-regulation of hypoglycemia. The mechanisms of insulin on xylose absorption and glucose absorption in the diabetic mice as stomach could be mediated via insulin stimulant effect on the vagus compared to diabetic control group. The effect of erythromycin could nerve as reported by Quigley et al[39].
be mediated through the action of erythromycin on motilin receptors Data of the present investigation showed that STZ-induced in the GIT. The action of erythromycin is probably mediated via diabetes resulted in a significant decrease in xylose absorption. its agonistic activity to motilin receptors, which accelerates gastric This result is in agreement with Fuessl[40]. The decrease in xylose emptying and increases the rate of sugars absorption.
absorption could be mediated via decreasing the rate of gastric Combination of domperidone (20 mg/kg), metoclopramide (20 emptying which resulted from elevation in BGL as reported by the mg/kg) or erythromycin (6 mg/kg) with insulin (2 IU/kg) decreased present study. This explanation coincides with that given by Rayner the amount of xylose absorbed from the GIT as compared to insulin et al[9] and Marianne et al[41].
given alone in the diabetic mice which indicates antagonistic Recent studies have shown that modifications of systemic interaction between each two drugs on xylose absorption. It is glycemia in OGTT reflect the activity of the intestinal glucose difficult to satisfactory explain this action on the bases of the few 2013 ACT. All rights reserved.
Fouad MA et al . Insulin interaction with prokinetic drugs in diabetic mice lectures available on the two drugs in this respect. Combination REFERENCES
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