Reduction of postprandial blood glucose by theα-glucosidase inhibitor Miglitol (BAY m 1099) in Type II diabetes

Summary The dose-dependency of the effects of the -glucosidase inhibitor Miglitol (BAY m 1099) was investigated in 8 Type II diabetic patients.Administration of increasing doses of Miglitol once daily in the morning on four consecutive days concomitantly with a standardized meal containing 50 g starch led to a dose-dependent reduction in the maximal increase in the postprandial blood glucose level and in postprandial incremental AUC of blood glucose. The latter was significant for 50, 100, 75 and 200 mg Miglitol. Bay m 1099 also markedly retarded the appearance of the peak postprandial blood glucose concentration, which indicates delayed carbohydrate absorption.Serum insulin levels, documented as incremental AUCs of the serum insulin excursions, were not reduced dose dependently, because of the impaired insulin secretory capacity of the patients.     

Effect of an alpha-glucosidase inhibitor (BAY m 1099) on post-prandial blood glucose and insulin in type II diabetics

Summary The effect of a new alpha-glucosidase inhibitor (BAY m 1099), a 1-deoxynojirimycin derivative, was studied in 10 black patients with Type II diabetes mellitus. It produced significant lowering of blood glucose concentration after standardized maize porridge meals. No significant untoward effects were noted. BAY m 1099 appears to offer potential benefit in the management of Type II diabetics, and more extensive clinical investigation is warranted.     

Anti-hyperglycaemic action of BRL 26830, a novel beta-adrenoceptor agonist, in mice and rats

BRL 26830, (R*,R*)-(+/-)-methyl 4-[2-[(2-hydroxy-2-phenylethyl)amino] propyl] benzoate, is a new orally active anti-hyperglycaemic agent. In 24 hr-fasted rats and mice, BRL 26830 decreased the blood glucose concentration following the administration of a subcutaneous glucose load. It also improved oral and intravenous glucose tolerance in 24 hr-fasted rats and decreased the post-prandial blood glucose concentration following the consumption of the complete, milk-based, meal "Nutrament". BRL 26830 produced a dose-related increase in the plasma insulin concentration and since it was inactive in lowering blood glucose in streptozotocin-diabetic rats, it is likely that its acute action on glucose tolerance was through the stimulation of insulin secretion. In contrast to the sulphonylurea, glibenclamide, BRL 26830 had no effect on the blood glucose concentration in 5 hr-fasted rats and only produced a transient reduction in 24 hr-fasted rats. BRL 26830 did not improve glucose tolerance when given acutely to hyperinsulinaemic C57BL/6 ob/ob mice. However, chronic treatment of these mice with BRL 26830 for 14-43 days resulted in a significant improvement in glucose tolerance.     

Insulin release by tolbutamide and glibenclamide

Summary Glibenclamide, a second generation sulfonylurea, produced the same pattern of insulin release from the perfused rat pancreas as did tolbutamide. The stimulatory effect was closely dependent on the glucose concentration present. Both agents enhanced insulin secretion at 5–10 mM glucose, whereas no additional insulin was released when maximally stimulating levels of glucose (20 and 30 mM) were present. The concentrations of glibenclamide stimulating insulin release were 100–400 times lower than equieffective levels of tolbutamide. At glucose levels of 3 or 8 mM, however, glibenclamide did not liberate significantly more insulin from the pancreas than did tolbutamide. Thus the differences of tolbutamide and glibenclamide were quantitative rather than qualitative. Although the active concentrations differed the effects produced were comparable.     

Effects of theα-glucosidase inhibitor 1 desoxynojirimycin (BAY M 1099) on postprandial blood glucose,serum insulin and C-peptide levels in type II diabetic patients

Summary Bay m 1099 is a newly developed inhibitor of intestinal-glucosidase. Its ability to lower postprandial plasma glucose, serum insulin and C-peptide levels in Type II diabetics has been investigated. Fifteen obese Type II diabetic patients with inadequate metabolic control during sulphonylurea treatment received a standardized diet and were treated either with Bay m 1099, b.d. (100 mg before breakfast and dinner) or placebo for 3 days, according to a double-blind cross-over design. The postprandial blood glucose level was significantly lower during Bay m 1099 treatment compared to placebo after breakfast and dinner (AUC after breakfastp<0.001). The reduced postprandial hyperglycaemia was associated with a decrease in meal stimulated serum insulin and C-peptide levels. Thus, Bay m 1099 may be a useful addition in the treatment of Type II diabetic patients.     

Effect of forskolin on islet cyclic AMP,insulin secretion,blood glucose and intravenous glucose tolerance in rats

Summary The in vivo effect of forskolin on insulin release, blood glucose and intravenous glucose tolerance test has been studied in the rat. In addition in vitro experiments on the effect of forskolin on islet cAMP and insulin release have been performed for comparison purposes.In batch incubated islets forskolin increased cAMP levels concentration dependently, the EC₅₀ being approximately 25 M. The maximal effect occurred after 5 min. In the presence of 2.8 mM glucose 10M forskolin did not stimulate insulin release; however, it potentiated both phase of 11.1 mM glucose induced insulin secretion.I. v. administration of 1.5 mg/kg of forskolin increased blood glocose levels in rats, which was associated with significant elevation of serum insulin. During an i. v. glucose tolerance test forskolin potentiated the insulin releasing capacity of glucose but did not significantly affect blood glucose levels. It is conceivable that cAMP per se does not initiate but rather amplifies insulin release by glucose. Since the synergistic effect of forskolin and glucose on insulin release in vivo is not associated with increased elimination rate it is possible that forskolin exhibits additional effects which counteract the glucose lowering action of insulin.     

Ethnic differences in human lymphocytic cyclic AMP production after isoprenaline stimulation and propranolol blockade.

The stimulatory effects of isoprenaline on human lymphocytic cyclic AMP (cAMP) and blockade by propranolol were studied in vitro in healthy Black and White volunteers. Basal levels of lymphocytic cAMP were significantly higher in Blacks than in Whites. Stimulation with isoprenaline caused a dose-related increase in cAMP, which was in concentrations of 10(-9) to 10(-5)M significantly greater in Blacks than in Whites. Blockade by 10(-4)M propranolol did not affect basal cAMP levels significantly, but increases in cAMP levels were significantly smaller in both groups after 10(-9) to 10(-2)M isoprenaline, while differences between cAMP levels in Blacks and Whites were still significant at concentrations 10(-9) to 10(-3)M. The increased cAMP concentration in lymphocytes of Blacks probably reflects a higher degree of beta 2-adrenoceptor activity which could be due to either a greater number and/or greater sensitivity of lymphocytic beta 2-adrenoceptors in Blacks than in Whites.     

Glucose tolerance,plasma insulin and lipids in diabetic subjects before and after treatment with a new sulfonylurea compound,Ro 6-4563

Summary The effects of a new sulfonylurea (Ro 6-4563) have been studied on glucose tolerance, plasma insulin, lipids, and lipoprotein pattern in 29 patients with maturity onset diabetes. After 4 weeks of treatment 3 different reactions have been distinguished and are discussed: I. No response, viz. same glucose tolerance and insulin levels before and after treatment. II. Improved glucose tolerance without increased insulin levels. III. Improved glucose tolerance with higher insulin levels. Sulfonylurea treatment had no effect on plasma lipids or lipoprotein pattern. Clinically good blood sugar control could not be correlated with good lipid control. Response II supports the view that sulfonylurea compounds do not necessarily act by increasing plasma insulin levels.Research fellow supported by F. Hoffman - La Roche, Basle, Switzerland. Present address: Dept. of Pharmacology University of Southern California Medical School. 2025 Zonal Avenue, Los Angeles, Ca. 90 033 U.S.A.     

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.     

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.     

Assessment of effects of beta-blocking drugs on blood glucose levels and insulin hypoglycaemia in rats

The effects of acutely administered propranolol, pratolol and tolamolol on blood glucose levels and insulin hypoglycaemia in the rat were studied. The absolute changes in blood glucose levels produced by all the compounds were smaller than those likely to be regarded as important in the clinical situation. Therefore, none of them interacted with insulin to any significant extent or markedly affected blood glucose levels.     

Effect of the urotensin-II receptor antagonist palosuran on secretion of and sensitivity to insulin in patients with Type 2 diabetes mellitus

AIMS

To investigate the effects of palosuran, a nonpeptidic, potent and selective antagonist of the urotensin-II receptor, on insulin and glucose regulation in 20 diet-treated patients with Type 2 diabetes mellitus in a double-blind, placebo-controlled, randomized, crossover, proof-of-concept study.

METHODS

After 4 weeks'' oral treatment with 125 mg palosuran or placebo b.i.d., effects on insulin secretion and sensitivity and blood glucose levels were assessed by means of a hyperglycaemic glucose clamp, meal tolerance test, homeostasis model assessment-insulin resistance score, and daily self-monitoring of blood glucose. Plasma concentrations of palosuran were determined for 12 h on the last day of intake.

RESULTS

Palosuran did not affect second-phase insulin response (primary end-point) during the hyperglycaemic glucose clamp in comparison with placebo [paired difference of −1.8 µU ml⁻¹, 95% confidence interval (CI) −7.8, 4.2]. Likewise, no effects of palosuran were detected on the first-phase insulin response, or on insulin secretion and blood glucose levels during the meal tolerance test or on homeostasis model assessment-insulin resistance score. No clinically significant effects on daily blood glucose profiles were observed during the study. Geometric mean C_max and AUC_τ (95% CI) and median t_max (range) in this patient population were 180 ng ml⁻¹ (125, 260), 581 ng·h ml⁻¹ (422, 800) and 3.0 h (0.67, 4.3), respectively.

CONCLUSIONS

The results of this study indicate that antagonism of the urotensin-II system does not influence insulin secretion or sensitivity or daily blood glucose levels in diet-treated patients with Type 2 diabetes.     

Acarbose actions on insulin resistance and inflammatory parameters during an oral fat load

The aim of this study was to evaluate the effects of acarbose on inflammatory biomarkers and insulin resistance in diabetic patients before and after a standardized oral fat load (OFL). Ninety six patients were assigned to take acarbose 50mg three times a day and 92 to take placebo; after the first month acarbose was titrated to 100mg three times a day. We evaluated the following parameters at the baseline, and after 1, 2 and 7months: body mass index (BMI), glycemic control, fasting plasma insulin, post-prandial plasma insulin, homeostasis model assessment insulin resistance index (HOMA-IR), blood pressure, lipid profile, soluble intercellular adhesion molecule-1 (sICAM-1), interleukin-6 (IL-6), high-sensitivity C reactive protein (Hs-CRP), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble E-selectin (sE-selectin). Furthermore, at the baseline and at the end of the study all patients underwent OFL, and an euglycemic hyperinsulinemic clamp to evaluate M value and total glucose requirement. Acarbose was better than placebo in improving glycemic and lipid profile, and HOMA-IR. Furthermore, acarbose gave a decrease of fasting plasma insulin, post-prandial insulin, s-ICAM-1, sVCAM-1, IL-6, and Hs-CRP, not observed with placebo, even if no significant differences between the two groups were observed. During the second OFL performed after the therapy with acarbose, we observed a significant decrease of all inflammatory parameters' peaks compared to the OFL administered at baseline. Acarbose was more effective than acarbose in reducing the post-OFL peaks of the various parameters included the inflammatory markers, after 7months of therapy.     

Differences among Black and White young adults on prior attempts and motivation to help a smoker quit

This study assessed differences between Black and White young adults on prior attempts and motivation to help a smoker quit. A total of 1,621 undergraduates (912 Black, 709 White; 63% female) ages 18-24 years completed a cross-sectional survey. Overall, 54% reported they had previously tried to help someone else stop smoking (52% among Blacks vs. 58% among Whites, p=0.016). Among nonsmokers who indicated they were close to a smoker whom they thought should quit, Blacks were most often concerned about a family member whereas Whites endorsed concern most often for a friend (p<0.001). Blacks were more likely than Whites to indicate interest in learning ways to help this smoker to quit (p<0.001) but there was no significant differences on motivation level (46% of Blacks and 42% of Whites reported they were "very" or "extremely" motivated to help this person quit). After adjusting for gender, the results remained unchanged. Tobacco control efforts could focus on optimizing these supportive behaviors as well as expressed motivation and interest in helping a smoker to quit among young adult nonsmokers.     

Antidepressant use and glycemic control

Rationale

Past research on the association of antidepressant medication use with glycemic control abnormalities has produced mixed results.

Objective

To examine the association of antidepressant use with glycemic control abnormalities and screen-positive diabetes in a representative population sample of US adults without a diagnosis of diabetes.

Methods

Using data from adult participants of the National Health and Nutrition Examination Survey (NHANES, 2005–2010), the association of antidepressant use with continuous measures of HbA1c, fasting blood sugar, 2-h oral glucose tolerance test, insulin sensitivity and screen-positive diabetes according to HbA1c, fasting blood sugar and 2-h oral glucose tolerance test were assessed.

Results

Antidepressant use was not associated with increased levels of HbA1c, fasting blood sugar, 2-h oral glucose tolerance test, reduced insulin sensitivity or increased prevalence of screen-positive diabetes. Results were mostly consistent across sociodemographic groups and across different lengths of exposure, different classes of antidepressants and levels of body mass index.

Conclusions

In this representative population sample, antidepressant use was not associated with an increased risk of abnormalities in glycemic control or undetected diabetes. Positive findings from past research may be attributable to detection bias, in that individuals prescribed antidepressants may be more likely to be tested and diagnosed with diabetes.     

Insulin concentrations and insulin sensitivity after short-term amiloride in healthy subjects

We have evaluated the short-term effects of amiloride on insulin action in vivo, since amiloride is known to impair insulin action in vitro.Seven healthy subjects were treated according to a randomized, double-blind, cross-over protocol. The treatment periods were 3 days each with amiloride 15 mg daily and placebo. Insulin action on glucose turnover was assessed directly after each treatment period with the hyper-insulinaemic euglycaemic glucose clamp technique.At the two insulin concentrations studied ( 30 mU·l^–1 and 200 mU·l^–1), the glucose infusion rate required to maintain constant euglycaemia did not differ after either amiloride or placebo. The rates of glucose production and utilization were also similar, whereas the so-called insulin sensitivity index at the lower insulin concentration was significantly reduced (by about 15 %) after amiloride. Moreover, amiloride produced significantly higher fasting insulin and C-peptide concentrations, whereas fasting glucose and NEFA concentrations were unaltered.In conclusion, these data suggest that short-term amiloride slightly impairs insulin sensitivity with respect to glucose uptake. However, overall glucose homoeostasis does not appear to be affected, probably due to a compensatory rise in plasma insulin.     

Differential effects of methylxanthines on local cerebral blood flow and glucose utilization in the conscious rat

Summary The aim of this study was to test the effects of the three classical methylxanthines, theophylline, caffeine and theobromine, on local cerebral blood flow and glucose utilization. Equimolar doses (1.6 mol/kg/min i.v.) of theophylline and caffeine produced increases in local cerebral glucose utilization and decreases in local cerebral blood flow. These compounds, therefore, re-set the ratio of cerebral blood flow per unit of glucose utilization at a lower level. These results are interpreted with respect to the known adenosine antagonist properties of caffeine and theophylline. Theobromine, a substance with less significant adenosine antagonist properties, had minimal effects on local cerebral blood flow and glucose utilization at a dose of 1.6 mol/kg/min i.v. These data may provide supportive evidence for the hypothesis that adenosine plays an important role in cerebral blood flow-metabolism coupling.Part of this work has previously been presented at the Deutsche Pharmakologische Gesellschaft March 13–16, 1984 on Mainz     

Long term treatment of moderate hypertension with penbutolol (Hoe 893d) III. Effects on glucose tolerance and insulin production

Summary Studies in seven patients with moderate hypertension were done to explore the effect of the non-selective beta-receptor blocking agent penbutolol on blood glucose and plasma insulin levels under fasting conditions, and following a glucose load. Oral penbutolol 20–30 mg, twice daily for 3–8 months, produced no change in fasting levels of blood glucose and plasma insulin, or in the blood glucose response following an oral or iv glucose load. The initial insulin response to intravenous glucose was similar before and during penbutolol treatment. The total integrated insulin response following iv glucose increased slightly during treatment when measured from insulin zero level, but was unaltered when calculated from the initial basal insulin level. Following oral glucose the total integrated insulin response was not affected by treatment with penbutolol.     

The effects of clofibrate on plasma glucose,lipoproteins, fibrinogen,and other biochemical and haematological variables in patients with mature onset diabetes mellitus

Summary We have studied the effects of clofibrate treatment on glucose tolerance and plasma insulin, plasma triglyceride, cholesterol and non-esterified fatty acid (NEFA) levels, and on various haematological variables (including plasma fibrinogen level, red cell flexibility, whole blood viscosity, and plasma -thromboglobulin level) in patients with mature-onset diabetes. Twenty-two patients (11 men and 11 women) were randomly allotted to treatment with clofibrate, 1 g twice daily, or a corn-oil placebo for 12 weeks, and then changed to the alternate medication for another 12 weeks. Half the patients took clofibrate in the first 12 weeks of the study, and half took the placebo. The patients stayed on their usual diet, and 13 also took tolbutamide before and during the trial. The trial was double-blind. At the beginning, middle and end of the trial fasting measurements were made, and plasma glucose, insulin, triglyceride, and NEFA concentrations were then measured repeatedly during the next 8 h (from 8.00 a. m. to 4 p. m.), to allow calculation of the mean 8-h concentration of these substances. In general, plasma concentrations of glucose, triglyceride, cholesterol, NEFA and fibrinogen were lower when the patients were taking clofibrate then when they were taking the corn-oil placebo, but higher when taking the placebo than at entry to the trial. We favour the explanation that clofibrate has lowered these concentrations, when compared with the placebo. The alternative interpretation, that 2 g per day of the placebo increases plasma concentrations of glucose, triglyceride, cholesterol, NEFA and fibrinogen, and that clofibrate has little effect, seems unlikely. The first interpretation, that clofibrate has a positive effect when compared with an inert placebo, has been adopted when interpreting the results. Clofibrate treatment led to a 15% lower fasting blood glucose level, and 11% lower mean 8-h glucose concentration than did placebo (p<0.01) but it did not significantly change plasma insulin concentration. The fasting and mean 8-hour concentrations of plasma triglyceride and fasting plasma cholesterol concentrations were reduced by clofibrate (by 44%, 33% and 10% respectively, p<0.05). Clofibrate decreased the fasting plasma NEFA level by 27% (p<0.01), and the mean 8-h plasma NEFA concentration by 23% (p<0.05). A weak relationship between the mean 8-h levels of plasma NEFA and plasma glucose (r=0.49, p<0.05) was consistent with the suggestion that the change in plasma glucose could, in part, be due to a change in NEFA concentration. The mean plasma fibrinogen concentration was decreased 23% by clofibrate (p<0.01). There was a positive correlation between the observed decrease during treatment and the baseline fibrinogen concentration (r=0.80, p<0.001), i. e. the greatest decrease occurred in those subjects with the highest plasma fibrinogen concentrations. Whole blood viscosity fell slightly, but erythrocyte flexibility was not significantly changed by clofibrate. The mean haemoglobin concentration and leucocyte count fell slightly during clofibrate treatment and the platelet count rose. -thromboglobulin was not affected. Clofibrate treatment was associated with rises in plasma albumin, urea, creatine kinase and aspartate aminotransferase, and falls in plasma bilirubin, -glutamyl-transpeptidase and alkaline phosphatase. Most of these changes occurred within the reference range.     

Weight concerns and smoking in Black and White female smokers

We examined whether the weight concerns of Blacks and Whites who enroll in smoking-cessation treatment differed from women who declined treatment. Black (n=100) and White (n=100) female smokers completed four measures of weight concern. Whites reported more general weight concern and smoking-specific weight concern than Blacks did. Treatment enrollers reported more general and smoking-specific weight concerns than decliners did. After controlling for BMI, SES, and number of cigarettes, ethnicity accounted for significant variance in general and smoking-specific weight concerns. Overall, Blacks reported less weight concerns than the Whites did, but when Blacks enrolled in treatment, these differences were less apparent.