Acarbose Administration Research Articles

Effect of acarbose on blood glucose profiles and plasma 1,5-anhydro-D-glucitol in type 2 diabetes poorly controlled by sulfonylurea therapy

Sixteen patients with type 2 diabetes poorly controlled by glibenclamide (7.5-10.0 mg/day) were treated with acarbose (100 mg tds) for one week and the effect on the blood glucose profile, 24-hour urinary glucose excretion, plasma fructosamine, and plasma 1,5-anhydro-D-glucitol (1,5-AG) level was determined. The blood glucose profile was more stable and levels were lower during acarbose administration. In some patients, this improvement was maintained after discontinuing acarbose. The M-value, an indicator of blood glucose fluctuations, decreased significantly from 33.2 +/- 3.0 (mean +/- SEM) in the run-in period to 13.4 +/- 2.4 during acarbose therapy (P < 0.001), and rose again to 26.5 +/- 4.4 (P < 0.001) in the follow-up period. The 24-hour urinary glucose excretion and plasma fructosamine decreased similarly (P < 0.001 and P < 0.01, respectively) during and after acarbose therapy. Plasma 1,5-AG levels did not change significantly during acarbose therapy, but increased markedly afterwards (from 19.3 +/- 3.1 mumol 1(-1) to 25.0) +/- 3.1 mumol l-1, P < 0.001). Plasma 1,5-AG levels were significantly correlated with urinary glucose excretion one week earlier (r = 0.513, P < 0.006). These findings suggest that acarbose may improve glycemic control in type 2 diabetic patients poorly controlled by sulfonylurea therapy and that plasma 1,5-AG might be used as a marker of glycemic control cooperating with other markers such as fructosamine and urinary glucose determination for monitoring the short-term response to antidiabetic therapy.

The Effect of the Timing and the Administration of Acarbose on Postprandial Hyperglycaemia

To clarify the optimum timing for ingestion of acarbose, a 100 mg dose of this oral hypoglycaemic agent was administered 30 min before, at the beginning, and 15 min after ingestion of a test meal, and the effects of the drug on blood glucose rises were compared with increases observed after a control meal (no drug). Twenty-four patients with Type 2 diabetes were included in a randomized, open, cross-over study. The smallest increases in blood glucose (p < 0.001) occurred when acarbose was taken at the beginning and 15 min after starting the test meal (3.3 +/- 1.6 mmol l-1 and 3.3 +/- 1.4 mmol l-1). The increase in blood glucose levels when acarbose was taken 30 min before the test meal was significantly higher (4.2 +/- 1.8 mmol l-1) and it was at its maximum following the control meal (5.2 +/- 1.7 mmol l-1). Similar results were observed when the effects of acarbose on insulin and C-peptide levels were measured. It is recommended that patients should be instructed to take acarbose with their first mouthful of food.

Pharmacology of α‐glucosidase inhibition

AbstractThe development of α‐amylase and brush‐border α‐glucosidase inhibitors is reviewed. The mode of action as well as pharmacological and pharmacodynamic properties of selected inhibitors with special regard to the most thoroughly investigated α‐glucosidase inhibitor acarbose are discussed. Inhibition of intestinal α‐glucosidases delays the digestion of starch and sucrose, flattens the postprandial blood glucose excursions, and thus mimics the effects of dieting on hyperglycaemia, hyperinsulinaemia and hypertriglyceridaemia. Therefore, the mechanism of α‐glucosidase inhibition represents the pharmacological optimization of the dietary principle of delayed carbohydrate absorption.In pre‐clinical studies using diabetic animals the oral administration of acarbose improved the metabolic state and reduced the blood glucose area under the curve. As a consequence, the process of non‐enzymatic glycation of proteins was retarded as indicated by reduced glycated haemoglobin, glomerular basement membranes or advanced glycation end‐products (AGEs) in collagen. These improved biochemical parameters correlated with beneficial effects against the development of diabetic nephropathy and neuropathy. Thus, the treatment of diabetic animals with acarbose does not only improve the metabolic state but has also the potential to delay, or possibly prevent, the development of diabetic complications.

The effect of acarbose on the intestinal metabolism of glucose in vitro.

The effect of acarbose on the intestinal metabolism of glucose was investigated using an in vitro perfused preparation of the isolated rat small intestine-pancreas. In preparations perfused without intraluminal sucrose administration, the total glucose recovered in the portal effluent and the portal values of lactate, pyruvate and alanine did not depend on whether or not acarbose [1.5 mg/kg body weight (b.w.)] was present in the intestinal lumen. The intestinal glucose and lactate contents were very low at the end of the experiment, and identical with or without acarbose. Insulin and glucagon concentrations remained constant during the whole perfusion period. After intraluminal administration of sucrose a clear increase in portal glucose concentration was observed, which was severely reduced by acarbose administration no changes in portal levels of lactate, pyruvate, alanine, insulin and glucagon were observed. The intestinal content of sucrose at the end of the study was significantly higher in the presence of acarbose (1.5 mg/kg b.w.), while the glucose concentration was low both with and without acarbose (0.20 +/- 0.08 vs 0.29 +/- 0.09 mmol/l respectively). These results suggest that acarbose does not influence the metabolic utilization of the glucose being translocated from the lumen.

The Effect of Acarbose on Blood Glucose Profiles of Type 2 Diabetic Patients Receiving Insulin Therapy

Nine patients with Type 2 diabetes receiving insulin therapy were treated with acarbose 100 mg thrice daily for 1 week to investigate the effect of acarbose on blood glucose control. Daily blood glucose profiles contained fewer excursions during acarbose administration and low levels were maintained. The M-value, an indicator of blood glucose fluctuation, decreased significantly from a run-in period value of 37.6 +/- 8.7 (SEM) to 16.7 +/- 4.0 during the acarbose period (p < 0.05) and rose again to 28.9 +/- 6.7 (p > or = 0.05) in the follow-up period. The 24-h urinary glucose excretion similarly decreased during acarbose administration. As expected, no decrease in HbA1C was observed due to the short treatment period. The 24-h urinary C-peptide excretions and serum lipids were not influenced by acarbose therapy. Frequent episodes of clinical hypoglycaemia were experienced while on acarbose therapy, indicating a decrease in insulin requirements. Adverse events such as flatulence and abdominal distention were observed in six out of nine cases. Symptoms were generally mild and well tolerated, only one patient dropped out because of diarrhoea and abdominal pain. We conclude that acarbose could usefully be administered to Type 2 diabetic patients treated with insulin to improve blood glucose control and reduce insulin requirement if the appropriate selection criteria were met.

Low-Dose Acarbose Improves Glycemic Control in NIDDM Patients Without Changes in Insulin Sensitivity

To examine the impact on metabolic control in NIDDM patients of the alpha-glucosidase inhibitor, acarbose, when administered at a low dose in powdered form. Six subjects were recruited for a double-blind cross-over trial using 25 mg powdered acarbose and a placebo 3 times a day with meals for 3 mo. In addition to parameters of diabetes control and body weight, glucose turnover and insulin sensitivity were measured with the hyperinsulinemic/euglycemic clamp technique combined with tracer kinetics. None of the subjects showed significant changes in FPG levels or body weight either on the 3-mo course of acarbose or placebo. HbA1c fell significantly from 10.6 +/- 1.0 to 9.4 +/- 1.3% (P = 0.05) during treatment with acarbose but failed to change on placebo (10.1 +/- 1.0 to 11.1 +/- 2.0%; P = 0.36). Basal HGP and glucose utilization were unchanged during either of the treatment periods, and hyperinsulinemia produced a similar degree of suppression of HGP before and after each treatment. At a physiological concentration, insulin failed to stimulate glucose clearance in these diabetic patients, and no improvement was seen with acarbose treatment. No changes in plasma lipids or lipoprotein profiles were demonstrated after 3 mo on acarbose. In acute studies, it was shown that administration of acarbose at a dose of 25 mg powder per meal significantly decreased the postprandial glycemic excursion. When administered in the powdered form at the low dose of 25 mg 3 times/day with meals over 3 mo, acarbose was well tolerated by the NIDDM patients and was without side effects. It improved glycemic control by reducing postprandial hyperglycemia, but had no effect on glucose turnover, insulin sensitivity, or lipid profile.

Lysosomal storage of glycogen as a sequel of α-glucosidase inhibition by the absorbed deoxynojirimycin derivative emiglitate (BAYo1248)

Effects of the two absorbable alpha-glucosidase inhibitors miglitol (BAYm1099) and emiglitate (BAYo1248) on hepatic and muscular glycogen concentrations were investigated in the rat after 3, 7, and 28 days. Both compounds were (orally) administered at very high doses (5-50-500 mg/kg b.wt.). In a second experiment, glycogen storage after oral administration of acarbose (1000 mg/kg b.wt.) was studied after 7 days. In a third protocol, hepatic glycogen concentrations were investigated in the fed rat after 7 days of either inhibitor at the respective highest dosage. In fasted rats, emiglitate induced a significant, dose-dependent increase of hepatic glycogen concentrations, which--at the dose of 500 mg/kg b.wt.--were present after 3, 7, and 28 days, but resulted in a significant increase of the liver weight after 28 days only. Light and electron microscopy proved that the increase in hepatic glycogen was due to lysosomal storage of glycogen only. Emiglitate in the amount of 5 mg/kg b.wt. did not induce significant changes either of glycogen concentrations or at the EM-level. While emiglitate also increased hepatic glycogen at a dosage of 50 mg/kg b.wt., miglitol led to significant storage of hepatic glycogen after 3, 7, or 28 days at the highest dose only. With miglitol (500 mg/kg b.wt.), only insignificant lysosomal storage of glycogen could be detected by electron and light microscopy, and liver weight was essentially unaffected. Both compounds displayed a dose-dependent tendency towards higher glycogen concentrations in the soleus muscle, which was significant with the highest dosage of either inhibitor. At an oral dose of o.i.d. 1000 mg/kg b.wt., the almost unabsorbable alpha-glucosidase inhibitor acarbose induced significantly increased glycogen concentrations both in the liver and in the soleus muscle after 7 days. With respect to an enormous enlargement of the lysosomes (EM) and in the absence of cytoplasmatic alpha-glycogen, this accumulation of glycogen must be attributed to lysosomal storage. In fed rats, all alpha-glucosidase inhibitors investigated significantly decreased postprandial hepatic glycogen concentrations (emiglitate greater than miglitol greater than acarbose), thereby reflecting the modulation of absorption. It is concluded that in the rat acarbose at approximately 1000 x ED50 may penetrate the intestinal mucosa at amounts significant enough to induce lysosomal storage of glycogen. Miglitol may cause some hepatocellular, lysosomal glycogen storage at a dose of 500 mg/kg b.wt., but no glycogen storage could be proven up to 100 x ED50 over 28 days.(ABSTRACT TRUNCATED AT 400 WORDS)

Lysosomal Glycogen Accumulation in Rat Liver and Its In Vivo Kinetics after a Single Intraperitoneal Injection of Acarbose, an α-Glucosidase Inhibitor

A single intraperitoneal injection of acarbose (400 mg/kg) into rats caused lysosomal accumulation of glycogen in the liver, mimicking the cytological characteristics of human glycogen storage disease type II (Pompe's disease). The animal model is therefore useful for studying the pathogenesis of the disease. In the present study, we applied this model to examine the lysosomal hydrolytic pathway of glycogen in vivo. To quantify the lysosomal glycogen, the lysosome-rich fraction was rapidly prepared from liver homogenate by agglutination in the presence of Ca2+. Then the fraction was treated with alpha-amylase in isotonic medium to remove cytosolic glycogen, followed by transfer to hypotonic conditions in the presence of Triton X-100 to destroy total glycogen. The amount of lysosomal glycogen was calculated from the difference between the glycogen levels measured before and after the treatment under hypotonic conditions, and then it was corrected based on measurements of the intactness (%) of lysosomes and the recovery (%) of the lysosomal marker enzyme (beta NAGase). We observed no measurable lysosomal glycogen in normal liver by this method, and this was confirmed by electron microscopy. After administration of acarbose, the lysosomal glycogen level increased to 2.5 mg/g liver within 2 days, and then decreased gradually at a rate of 0.4 mg/day/g. The accumulation of glycogen in the lysosomes at an initial velocity of 1.5 mg/day/g liver may be considered as the amount of glycogen that would normally be degraded by acid alpha-glucosidase. Therefore, assuming that the liver breaks down about 40 mg glycogen/day/g, we estimated that about 3% of the glycogen would be hydrolyzed by the lysosomal pathway.

Fate and effects of the α-glucosidase inhibitor acarbose in humans

Abstract The α-glucosidase inhibitor acarbose has been successfully used in diabetic patients to decrease the postprandial rise in blood glucose. The aim of the present experiments was to investigate the fate and effects of acarbose along the small intestine using a slow-marker perfusion technique. In 8 healthy volunteers, jejunal and ileal loads of acarbose, glucose, and total carbohydrates were determined following a liquid, 400-kcal formula meal containing either 200 mg of acarbose or placebo. Preprandial and postprandial plasma concentrations of glucose and several polypeptide hormones were determined. Recovery of acarbose during 4 h was 65% ± 9% (mean ± SEM) of ingested dose in the ileum but 94% ± 9% in the jejunum, indicating that the compound was neither degraded nor absorbed by the intestine to a major degree. After acarbose administration, ileal loads of glucose and total carbohydrates were considerably higher, whereas postprandial plasma concentrations of glucose, insulin, and gastric inhibitory polypeptide were lower when compared with placebo. The retardation of carbohydrate digestion to be inferred from these findings is confirmed by significantly elevated plasma concentrations of enteroglucagon after acarbose administration compared with placebo administration.

Fate and effects of the α-glucosidase inhibitor acarbose in humans: An intestinal slow-marker perfusion study

The α-glucosidase inhibitor acarbose has been successfully used in diabetic patients to decrease the postprandial rise in blood glucose. The aim of the present experiments was to investigate the fate and effects of acarbose along the small intestine using a slow-marker perfusion technique. In 8 healthy volunteers, jejunal and ileal loads of acarbose, glucose, and total carbohydrates were determined following a liquid, 400-kcal formula meal containing either 200 mg of acarbose or placebo. Preprandial and postprandial plasma concentrations of glucose and several polypeptide hormones were determined. Recovery of acarbose during 4 h was 65% ± 9% (mean ± SEM) of ingested dose in the ileum but 94% ± 9% in the jejunum, indicating that the compound was neither degraded nor absorbed by the intestine to a major degree. After acarbose administration, ileal loads of glucose and total carbohydrates were considerably higher, whereas postprandial plasma concentrations of glucose, insulin, and gastric inhibitory polypeptide were lower when compared with placebo. The retardation of carbohydrate digestion to be inferred from these findings is confirmed by significantly elevated plasma concentrations of enteroglucagon after acarbose administration compared with placebo administration.

The regulation of lipogenesis in vivo in the lactating mammary gland of the rat during the starved-refed transition. Studies wtih acarbose, a glucosidase inhibitor.

Depression of carbohydrate digestion by oral administration of acarbose, a glucosidase inhibitor, led to a 75% inhibition of the re-activation of lipogenesis in vivo in the mammary gland of 18 h-starved lactating rats refed with 5 g of chow diet. Rates of [1-14C]glucose incorporation in vitro into lipid and CO2 in mammary-gland acini isolated from refed animals were elevated compared with acini from starved rats, but acarbose treatment completely prevented this stimulation. Gastric intubation of glucose led to a large stimulation of lipogenesis in the mammary gland of starved lactating rats, similar to that induced by refeeding with chow diet; this was dependent on the amount of glucose given and the time elapsed between glucose administration and injection of 3H2O for the measurement of lipogenesis. The switch-on of lipogenesis in the mammary gland of starved lactating rats, by refeeding or by intubation of glucose, was associated with a decrease in the ratio of [glucose 6-phosphate]/[fructose 1,6-bisphosphate] in the gland, indicative of an increase in phosphofructokinase activity. A time-course study revealed that the ratio decreased rapidly over the first 30 min of chow refeeding, after which a large surge in lipogenesis was seen. Acarbose, given 25 min after the onset of refeeding, led to a stepwise increase in the ratio, in parallel with the observed decrease in lipogenic activity. It is concluded that the control of lipogenesis in the mammary gland is closely linked to the availability of dietary carbohydrate. An important site of regulation of lipogenesis in the gland appears to be at the level of phosphofructokinase. A possible role of insulin in the regulation of phosphofructokinase activity, and the acute modulation of insulin-sensitivity in the gland during the starved-refed transition, are discussed.

Effects of prolonged (6 months) alpha-glucosidase inhibition on blood glucose control and insulin requirements in patients with insulin-dependent diabetes mellitus.

To examine prolonged alpha-glucosidase inhibition on blood glucose control, Acarbose, a potent alpha-glucosidase inhibitor, was administered for six months to insulin-dependent diabetic patients. Acarbose administration significantly diminished postprandial blood glucose increases by 20-30% and reduced insulin requirements by about 40% in these patients. Symptoms related to its use almost disappeared after the first month of treatment. These results suggest that prolonged alpha-glucosidase inhibition improves glucose tolerance in patients with insulin-dependent diabetes mellitus. Thus, an agent like acarbose might be a useful adjunct to insulin in the treatment of diabetic patients.

Metabolic effects of acarbose administration in normal and diabetic rats

The effect of acarbose on cardiac and hepatic metabolism was investigated in normal and diabetic rats. Groups of rats were fed one of the three following diets for 7 days: (1) ground Purina chow, (2) ground Purina chow fortified with raw corn starch and sucrose, and (3) the above high carbohydrate diet, with added acarbose (40 mg/100 g food). At the end of the dietary period the rats were decapitated, and a sample of liver tissue was removed and frozen in liquid nitrogen. The heart was extirpated for subsequent perfusion by the Langendorff technique. Increases in liver and heart glycogen produced by the high carbohydrate diet in the normal rats were prevented completely when acarbose was incorporated into the food. In diabetic animals, liver glycogen was uniformly lower than normal, irrespective of the diet or the presence of acarbose. With animals fed the control diet, cardiac glycogen was higher in diabetic than in normal rats. The high carbohydrate diet caused a lowering of heart glycogen in diabetic rats and this reduction in glycogen content was reversed by including acarbose in the diet. Effects of isoproterenol on myocardial phosphorylase a activity were determined in hearts from normal and diabetic rats given one of the three diets. The high carbohydrate diet decreased the enzymatic response to the catecholamine in hearts from both normal and diabetic animals, and this phenomenon was prevented by the presence of acarbose in the diet. In diabetic rats fed any of the three diets, the activation of cardiac phosphorylase by isoproterenol was greatly accentuated. Measurements of heart uridine kinase showed that the activity of this enzyme was lower than normal in hearts from diabetic rats given either the control or the high carbohydrate diet. The presence of acarbose in the latter diet resulted in a significant decrease in cardiac uridine kinase activity in hearts from normal rats. The results of this study demonstrate the effectiveness of acarbose in modulating tissue metabolism in normal and diabetic animals.

The effect of alpha-glucosidase inhibition on intestinal disaccharidase activity in normal and diabetic mice

Acarbose is a potent alpha-glycosidase inhibitor which decreases postprandial hyperglycemia when administered with a carbohydrate-containing meal. The genetically diabetic mouse C57 BLKsJ db/db represents a model of type II, noninsulin dependent diabetes mellitus. Characteristic features of this animal include hyperglycemia, hyperinsulinemia, hyperphagia, and the development of obesity and widespread pathologic abnormalities. To evaluate the effects of Acarbose on intestinal disaccharidase activity, groups of normal and diabetic mice were given Acarbose as a drug-food mixture in doses of 20 (A-20) and 40 (A-40) mg 100 g food. Sucrase activity was measured in intestinal homogenates and on the mucosal surface of proximal, middle, and distal segments of jejunoileum. In normal mice, sucrase activity was significantly increased in mid- and distal-intestinal segments following 2 wk of Acarbose in both A-20 and A-40 groups. No changes were noted following 5 and 10 days of drug treatment. Acarbose did not influence body weight, food:water intake or fasting blood glucose. When compared to normal mice, untreated diabetics had significantly more protein, DNA, and sucrase activity throughout the small intestine. Following 10 wk of Acarbose administration, both A-20 and A-40 groups showed increased sucrase activity in intestinal homogenates of distal segments. Surface mucosal sucrase activity however was slightly decreased in proximal intestinal segments as a result of drug therapy, with no changes in middle and distal segments. Acarbose did not influence body weight, food intake or fasting blood glucose, but water consumption and glucosuria were significantly decreased. Experimental diabetes mellitus is associated with significant alterations in enzyme activity and protein content of the brush border membrane of the small intestine. Acarbose administration influences both sucrase activity and distribution in normal and diabetic mice. The mechanisms responsible for these changes and their potential clinical importance remain to be determined.

Effects of a glucosidase inhibitor (acarbose, BAY g 5421) on the development of obesity and food motivated behavior in Zucker (fafa) rats

BAY g 5421 (acarbose) inhibits carbohydrate digestion in the gut, thereby reducing the rate of glucose absorption. This experiment tested whether long term administration of acarbose to developing Zucker “fatty” (fafa) rats would, by reducing several lipogenic factors, attenuate lipid deposition and reduce the hyperphagia and increased food motivated behavior of these animals. From 7 to 20 weeks of life groups of fatty and lean (FaFa) control rats were fed 0, 20 or 40 mg acarbose/100 g maintenance diet (45% carbohydrate, 35% fat, 20% protein calories), while an additional fatty and lean group were pair-fed to respective 40 mg acarbose groups. Lean groups fed acarbose exhibited dose dependent reductions of body weight, insulin, triglycerides, retroperitoneal and epididymal pad weight, adipocyte size, LPL activity/cell (retroperitoneal pad only), and lipid deposition both in total grams of fat and as a percentage of carcass weight. Fatty groups fed acarbose exhibited dose dependent reductions of insulin, blood glucose, retroperitoneal pad weight, and, at one of the two doses used, significantly lowered body weight, (40 mg), triglycerides (20 mg) and cholesterol (20 mg). However, acarbose-fed fatty groups failed to show significant reductions of adipocyte size, number or LPL activity/cell in retroperitoneal and epididymal fat pads, and maintained their obese body composition, on a percentage basis, at levels not significantly different from that of the 0 mg fatty control group. Acarbose administration led to an initial dose dependent reduction of food intake in both genotypes, which persisted for the lean groups. Fatties fed the 20 mg dose showed a gradual tendency (ns) towards increased daily intake, lever pressed at elevated rates for food pellets, and refed at faster rates following fasting. Fatties fed the 40 mg dose maintained their daily intake at fatty control levels, did not lever press at elevated rates, and showed significantly reduced refeeding following fasting. The 40 mg fatty and both lean acarbose treated groups had decreased sucrose solution preference. Possible bases for these differing effects of the drug on feeding behavior by the groups are considered.