The effect of miglitol and acarbose after an oral glucose load: a novel hypoglycaemic mechanism?

1. Alpha-glucosidase inhibitors such as miglitol and acarbose lower blood glucose after a starch load in healthy volunteers and diabetic patients by interfering with the conversion of disaccharide to monosaccharide in the gastrointestinal tract. 2. The effect of placebo, 100 mg miglitol and 100 mg acarbose given 30 min prior to a 75 g oral glucose load was investigated in nine healthy Caucasian volunteers. 3. Miglitol produced a statistically significant fall in post-peak blood glucose levels when compared with placebo and acarbose. Serum insulin did not change significantly. 4. As miglitol is well absorbed and acarbose is not, it is suggested that miglitol has a systemic hypoglycaemic effect, probably related to its close structural similarity to glucose, which warrants further investigation.     

Inhibition of glycemic and hormonal responses after repetitive sucrose and starch loads by different doses of the alpha-glucosidase inhibitor miglitol (BAY m 1099) in man.

In two randomized, placebo-controlled, double-blind studies, the efficacy, duration of action and tolerability of a single morning dose of 25, 50, and 100 mg miglitol (BAY m 1099), an absorbable inhibitor of intestinal alpha-glucosidases, were assessed after repetitive sucrose or maize-starch loads (50 g of carbohydrates in 400 ml of water each at 08.00, 12.00, and 17.00 h). With sucrose, miglitol reduced the postprandial rise in blood glucose, serum insulin and serum gastric inhibitory polypeptide concentrations at any dosage. This effect was dose-dependent and confined to the first carbohydrate load in the morning, thus indicating the duration of alpha-glucosidase inhibition of less than 4 h. Sucrose malabsorption, indicated by breath hydrogen responses, occurred dose-dependently with 50 and 100 mg, but not with 25 mg of miglitol. Similarly, symptoms of carbohydrate malabsorption were absent with 25 mg of the inhibitor and mild to moderate after 50 and 100 mg of miglitol. With starch as the substrate, BAY m 1099 led to a significant amelioration of glycemic and hormonal rises after the first meal, but not thereafter. A numerical dose dependency was recognized, but this was not significant at the 5% level. Symptoms of carbohydrate malabsorption were absent with 25 mg and negligible with 50 mg BAY m 1099, but occurred almost regularly with the 100-mg dose. Breath hydrogen concentrations increased gradually with the dose of miglitol administered. A single morning dose of 25-100 mg of miglitol thus may be useful for the control of postprandial hyperglycemia after breakfast. Due to the duration of action of less than 4 h, this substance should be given with the three main meals.     

Miglitol, a new alpha-glucosidase inhibitor

Miglitol (Bay m 1099, Bayer) is a second generation alpha-glucosidase inhibitor. It is a derivative of 1-desoxynojirimycin, and binds reversibly to the brushborder alpha-glucosidase enzymes. In contrast to its parent drug (acarbose, Bay g 5421, Bayer), miglitol is almost completely absorbed in the small intestine. It has to be taken with each main meal, and through its effect on carbohydrate digestion it blunts the postprandial blood glucose increase. Miglitol has no or a very small effect on fasting blood glucose levels. The blood-glucose lowering effects of miglitol in patients with Type 2 diabetes are lower than those of the frequently-used sulphonylurea compounds. Long-term studies show that a moderate average reduction of HbA1c of 0.3-0.7% point from baseline can be achieved. An advantage over sulphonylurea is the effect on serum insulin levels: miglitol therapy leads to slightly lower postprandial levels of serum insulin, whereas chronic sulphonylurea treatment usually increases serum insulin levels. This insulin-sparing effect may, in theory, lead to a lesser weight gain or even no weight gain and reduced risk of hypoglycaemia during chronic treatment. Long-term experience in Type 1 diabetic patients is limited. Similarly, miglitol may lead to reduced postprandial glucose excursions, slightly reduced insulin requirements and perhaps, as a consequence, a lower risk of hypoglycaemia. More long-term data are needed to fully assess to the clinical use of miglitol in these patients.     

Miglitol (Bay m 1099) has no extraintestinal effects on glucose control in healthy volunteers

In this double-blind, cross-over, placebo-controlled, randomized study, possible extraintestinal effects of miglitol, an absorbable α-glucosidase inhibitor, were investigated. Sixteen healthy male volunteers underwent two 75  g oral glucose tolerance tests with concomitant administration of miglitol or placebo. Peak and post-peak areas under the curve values for blood glucose, serum insulin and serum C-peptide after miglitol were not different from those found after placebo. The post-peak AUC-ratio (AUC (peak, 180  min) on miglitol/AUC (peak, 180  min) on placebo) was for glucose 1.15 (CI 0.94–1.40, P =0.16), for insulin 1.12 (CI 0.95–1.33, P =0.17) and for C-peptide 0.98 (CI 0.81–1.18, P =0.82). It is concluded that miglitol exerts no clinically relevant extraintestinal effects on glucose control.     

Miglitol,a new α-glucosidase inhibitor

Miglitol (Bay m 1099, Bayer) is a second generation α-glucosidase inhibitor. It is a derivative of 1-desoxynojirimycin, and binds reversibly to the brushborder α-glucosidase enzymes. In contrast to its parent drug (acarbose, Bay g 5421, Bayer), miglitol is almost completely absorbed in the small intestine. It has to be taken with each main meal, and through its effect on carbohydrate digestion it blunts the postprandial blood glucose increase. Miglitol has no or a very small effect on fasting blood glucose levels. The blood-glucose lowering effects of miglitol in patients with Type 2 diabetes are lower than those of the frequently-used sulphonylurea compounds. Long-term studies show that a moderate average reduction of HbA1c of 0.3 - 0.7% point from baseline can be achieved. An advantage over sulphonylurea is the effect on serum insulin levels: miglitol therapy leads to slightly lower postprandial levels of serum insulin, whereas chronic sulphonylurea treatment usually increases serum insulin levels. This insulin-sparing effect may, in theory, lead to a lesser weight gain or even no weight gain and reduced risk of hypoglycaemia during chronic treatment. Long-term experience in Type 1 diabetic patients is limited. Similarly, miglitol may lead to reduced postprandial glucose excursions, slightly reduced insulin requirements and perhaps, as a consequence, a lower risk of hypoglycaemia. More long-term data are needed to fully assess to the clinical use of miglitol in these patients.     

Effect of KAD-1229, a novel hypoglycaemic agent,on plasma glucose levels after meal load in type 2 diabetic rats

1. The effects of KAD-1229 (a novel non-sulphonylurea agent), voglibose (an alpha-glucosidase inhibitor) and nateglinide (a non-sulphonylurea antihyperglycaemic agent) on hyperglycaemia induced by a meal load were assessed in diabetic rats. 2. KAD-1229 suppressed the increase in plasma glucose levels seen after a meal load and the area under the curve for plasma glucose levels (AUCglucose) up to 5 h after the meal load. 3. Voglibose also suppressed the increase in plasma glucose levels; however, a significant decrease in AUCglucose following voglibose was not observed. 4. Nateglinide suppressed the increase in plasma glucose levels at 30 min and 1 h after the meal load; however, plasma glucose levels was above control thereafter and the AUCglucose was not decreased. 5. The results indicate that KAD-1229 has an antihyperglycaemic effect and KAD-1229 is suggested to be a suitable agent for controlling post-prandial hyperglycaemia.     

Cardiovascular Risk Factors Associated with Insulin Resistance

Patients with type 2 diabetes mellitus have a greater risk of cardiovascular disease than nondiabetic individuals. These patients are often insulin resistant and have an associated clustering of risk factors that contribute to cardiovascular disease. The risk factors include dyslipidemia, hypertension, altered hemostasis, and chronic inflammation. A primary objective in the management of type 2 diabetes mellitus is normalization of blood glucose levels; however, some of the oral drugs used to control blood glucose levels have significant effects on these risk factors. In this article, we review the current data involving the modification of these cardiovascular risk factors by the biguanide (metformin), the thiazolidinediones (troglitazone, rosiglitazone, and pioglitazone), the alpha-glucosidase inhibitors (miglitol, acarbose), and the insulin secretagogs (glyburide [glibenclamide], glipizide, chlorpropamide, tolbutamide, tolazamide, glimepiride, repaglinide, and nateglinide). Generally, the thiazolidinediones improve hemostasis and endothelial function and reduce blood pressure, while having variable effects on dyslipidemia. Metformin improves dyslipidemia and altered hemostasis and decreases plasma C-reactive protein levels with little or no effect on blood pressure. Data on the effects of the alpha-glucosidase inhibitors and insulin secretagogs are sparse; however, these drugs appear to have little or no effect on cardiovascular risk factors.     

1-Deoxynojirimycin and related compounds inhibit glycogenolysis in the liver without affecting the concentration of phosphorylase a

Administration in vivo of the alpha-glucosidase inhibitors 1-deoxynojirimycin and its derivatives BAY m 1099 (miglitol) and BAY o 1248 resulted in a dose- and time-dependent decrease in the rate of hepatic glycogenolysis induced by glucagon. This represents a direct effect on the liver, since it could be reproduced on isolated hepatocytes. The amount of glucose produced by hepatocytes over a period of 10-20 min after addition of glucagon was decreased by about 70, 60 and 45% in the presence of maximally effective concentrations of BAY o 1248, deoxynojirimycin, and BAY m 1099, respectively. Half-maximal effects were observed at inhibitor concentrations between 20 and 100 microM. The concentrations of phosphorylase a and glycogen synthase a were not affected by inclusion of the alpha-glucosidase inhibitors in the hepatocyte suspensions. Thus, the antiglycogenolytic action of these compounds is not mediated by an altered activation state of the rate-limiting enzymes of glycogenolysis and of glycogen synthesis.     

Influence of food intake on the absorption and effect of glipizide in diabetics and in healthy subjects

Summary The influence of a standardized breakfast on the single dose (5 mg) kinetics and effects of glipizide was examined in 9 healthy volunteers and in 14 diabetics not previously exposed to a sulfonylurea. In the volunteers, glipizide caused an increase in plasma insulin and a reduction in blood glucose both during continued fasting and when the drug was taken with the breakfast. Food intake did not influence the peak concentration, the elimination half-life or the bioavailability of the drug. However, food intake significantly delayed the absorption of glipizide by about 0.5 h. In the patients, glipizide produced a significant increase in plasma insulin and a significant diminution of the rise in blood glucose in response to the meal. Starting at breakfast and for 45 min thereafter serum glipizide concentrations were significantly higher when the drug was taken 0.5 h before the meal, than when ingested concurrently with it. With the former treatment, the increase in plasma insulin occurred earlier and the blood glucose reduction was pronouncedly greater than with the latter treatment. As the absorption of glipizide may be delayed by concurrent breakfast, this may help to explain, why the administration of glipizide 0.5 h before breakfast led to a more appropriate relation between the serum concentration of the drug and the metabolic impact of the meal, thereby promoting more appropriate insulin release and better glucose disposition than after concurrent intake of the drug and breakfast.     

Influence of food and age on the single-dose kinetics and effects of tolbutamide and chlorpropamide

Summary The influence of food intake (standardized breakfast) on the oral single-dose kinetics and effects of tolbutamide (0.5 g) and chlorpropamide (250 mg) was investigated in young, healthy volunteers. The single-dose kinetics of the two drugs was also studied in elderly healthy subjects. There was great interindividual variation in the elimination rate of both drugs, but food intake influenced neither their AUCs nor their rates of absorption and elimination. The peak concentration of chlorpropamide, but not that of tolbutamide, was reduced by food intake. The peak concentrations of serum tolbutamide were approximately doubled by an increase in dose from 0.5 to 1.0 g, and from 1.0 to 2.0 g. At no time did tolbutamide 0.5 g affect the plasma insulin level, neither in the fasting nor in the non-fasting state. However, this dose did reduce the blood glucose level during fasting and the increase in blood glucose in response to the meal. The latter effect was recorded within 30 min, when the serum level of tolbutamide still was close to zero. Plasma insulin concentrations did increase within 30 min after a higher dose of tolbutamide (1.0 g), when the serum concentration of tolbutamide was about 50 µmol/l. Between 2.5 and 8 h after administration of chlorpropamide 250 mg, serum drug concentrations were lower than those following tolbutamide 0.5 g. The blood glucose response was smaller and occurred later, being significant at 2 h, when the serum concentration of the drug was about 70 µmol/l. There was no significant change in plasma insulin. There was no significant pharmacokinetic difference between young and elderly subjects, except that the peak concentration of tolbutamide was higher in the latter. It appears that both for tolbutamide and chlorpropamide there is great interindividual variation in drug disposition, but food intake does not influence the bioavailability of either drug. The effect of any particular drug concentration seems dependent upon the blood glucose level and hence upon the elapsed time since the last meal. Both drugs can reduce blood glucose without an alteration in the peripheral blood concentration of insulin. This may reflect an extrapancreatic effect of the drugs, but it could also be an expression of increased insulin secretion, which is not detected because of enhanced hepatic degradation of the hormone released into the portal circulation. The observations made in young individuals are also probably relevant for elderly subjects.