Br. J. clin. Pharmac. (1990), 30, 391-396

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

P. H. JOUBERT, H. L. VENTER & G. N. FOUKARIDIS Department of Pharmacology and Therapeutics, Medical University of Southern Africa, PO Medunsa, Pretoria 0204, South Africa

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. Keywords alpha-glucosidase inhibitors miglitol acarbose oral hypoglycaemic agents

Introduction The alpha-glucosidase inhibitors are drugs that well absorbed with a 100% systemic bioavail- interfere with the conversion of disaccharide to ability (Ramsch et al., 1986). In view of its monosaccharide in the gastrointestinal tract. systemic absorption and structural resemblance They have been developed as adjuncts to the to glucose, we recently investigated the effect of diet in the management of diabetes mellitus and 50 mg of miglitol given 30 min before a 75 g oral are used to decrease the rate of entry of glucose glucose load to assess whether there are any into the systemic circulation after carbohydrate systemic effects on glucose homeostasis or effects ingestion. After a starch load, these agents de- on glucose transport in the gastro-intestinal tract. crease post-prandial blood glucose levels in In this study it was found that miglitol produced healthy volunteers (Hillebrandt et al., 1986; a significant post-peak reduction in plasma glucose Joubert et al., 1985) as well as in patients with levels in healthy volunteers (Joubert et al., 1987). diabetes mellitus (Schnack etal., 1986; Walton et Serum insulin levels appeared to be unaffected. al., 1979). As the blood glucose-lowering effect of alpha- The two drugs of this type that have been glucosidase inhibitors has, up to now, in clinical studied the most extensively are acarbose and settings, been considered purely as an effect on miglitol. The former is a pseudotetrasaccharide carbohydrate digestion in the gastrointestinal which is poorly absorbed from the gastrointestinal tract and a systemic blood glucose lowering effect tract, the mean systemic bioavailability being had not been described previously, a further between 0.5 and 1.6% (Putter, 1980). Miglitol, similar study appeared to be necessary. Firstly we on the other hand, is a small molecule, closely felt it necessary to confirm or refute our previous related to glucose in the pyranose form and is findings and secondly to compare the effect of Correspondence: Dr P. H. Joubert, Department of Pharmacology and Therapeutics, Medical University of Southern Africa, PO Medunsa, Pretoria 0204, South Africa

391 392 P. H. Joubert, H. L. Venter & G. N. Foukaridis miglitol with that of acarbose. As the latter drug has the same mechanism of action in the gut, but is poorly absorbed, one would expect a systemic effect to be absent or much less than with miglitol. For this study a 100 mg of each of the drugs were used.

Methods Nine healthy Caucasian male volunteers between the ages of 21 and 40 years, who were non- smokers and within 10% of ideal body mass . (Metropolitan Life Insurance tables) participated I m .n in the study. They were free of significant lab- Figure 1 Mean blood glucose levels after a 75 g oral oratory and clinical abnormalities as evidenced glucose load (O h) on placebo (@), miglitol (o) and by physical examination, an electrocardiogram acarbose (A). and appropriate laboratory blood and urine tests. The study was conducted according to the guide- lines of the declaration of Helsinki. Approval was obtained from the South African Medicines -9i Control Council and the Research and Ethics Committee of the Medical University of Southern Africa. All volunteers gave informed written consent. r R . r d t. .e,. 'i 4' | ; i } , ¢ i $; S W .,),. t s; i ; i £ sj ;2FNL 3't '' '' ^; 0 >2 On each of the 3 test days, separated by a -5 wash-out period of at least 7 days, volunteers reported to our clinical laboratory at 7.30 h after .Sx...rBj $;;.S ;..|:.s! s ...wRs;,.S .^%.;^ !<* ',...e.><...... >r;'exsr an overnight fast. On each occasion they received 1xF,.tZ*-;;;;-t...... ;d, o '_ ^Isdzi,X,'}.§ j.¢J>r;f identical tablets of either placebo, 100 mg miglitol I .I 1 or 100 mg acarbose in a double-blind randomized u-1 0 A:1 A.2-*3 fashion. Thirty minutes later they received orally lime.it) 75 g glucose dissolved in 250 ml water. Blood Figure 2 Mean serum insulin levels after a 75 g oral samples were obtained through an indwelling glucose load (O h) on placebo (e), miglitol (o) and size 21 butterfly needle in a suitable arm vein at acarbose (A). -35, -30, 0, 15, 30, 45, 60, 90, 120 and 180 min, where 0 min was the time of glucose administra- tion. Blood glucose determinations were done using placebo and miglitol they did not differ signifi- a fluorescence polarization immunoassay (Abbot) cantly from placebo. The glucose curves are and plasma insulin by radioimmunoassay (CIS depicted in Figure 1 whereas Table 1 depicts the Bioindustries). Serum levels of miglitol and P values for the statistical analysis. acarbose were determined by the laboratories of In terms of areas under the curve (AUCs) for the department of Pharmacology of the Univer- glucose the values (mean ± s.d.) were 301 + sity of the Orange Free State usingp-nitrophenyl- 248, 240 ± 65 and 189 ± 72 mmol min-' for alpha-D-glucopyranose as a substrate and using placebo, acarbose and miglitol respectively. The u.v. spectrophotometry to detect the formation Pvalues (Wilcoxon test) were 0.594 (acarbose vs ofp-nitrophenol (Muller & Hillebrandt, 1986). placebo), 0.112 (miglitol vs placebo) and 0.0155 Data points for the three regimens were com- (miglitol vs acarbose). pared statistically using the Wilcoxon test. Insulin values showed the same pattern as the glucose values (Figure 2, Table 2), but there were no significant differences between the treat- Results ment groups (Table 1). The serum levels ofthe drugs in relation to the Miglitol produced a significant depression of placebo glucose curve are shown in Figure 3. It post-peak blood glucose levels when compared shows that the glucose peak is reached well with placebo and with acarbose. Although acar- before that of miglitol and also the poor absorp- bose values appeared to be between that for tion of acarbose. Effect ofmiglitol and acarbose after glucose load 393

E 00 e - r- - 00

c,9 O00~ Oc, O SiOO~~~0cnO$

CD C> t- 4 4

00 0 6 6 6 6 0 9NN > 00 Wi 0 knS0N

Sien0 2 00 0c (I , Si0 0-ac

o *

^- - 0 5%9+ 0 e- 00 oe

2e + o o 6 6 o o C* C C* C1

.: o 6 6 6 6 6 0 c) o ... rtS00 Sfl c7 00 e14 ene q W- e ON

Cu S:

o _ ° C;6 6c80°3; 6 6c; 6c; C _ N St - C)~~~~~~~~~~~c sotn Wo ^ No4 N

.co _ \0 \0 N 00 i0e

Aew Cqs 7 ^ r C) +2ijX8 }i>i=Xmaco 394 P. H. Joubert, H. L. Venter & G. N. Foukaridis

OA lflO7% V- O ~.0 cn N r t- r- C4 \0s r- "- A E : 3 (Ni (NI 0 - -o 1 o-T-4 - esie- --)

4),4Cu tL W Oo o \0T-4W O 0o

-rF cr t T- r- "- W) el cn C1 _4 cn " - N I.. i

C1 U:1t W) 00 0sN (4 O It t- oo\0 " -_V_4 tben WI 04"me "4 N

Cu

Co .C :Ztn' \0(I 0D-ON cO\.6\6 ~t- \6 e-r 4) la.cn 0 :3 cS Cu E -o "- 0% IRT ON a,, ) 00 D0 Cu ef -i %1O Cu 0 0E

4)0~ ) 4)llIt 1 14 1 \ t: i ; 4

(D4)04

0 vr< Effect ofmiglitol and acarbose after glucose load 395

n A = 50 mg 1200 9' 20- B = 100 mg L- 10ooo 8 E 0 (a E Co o 800 7 zD 0) ._ E a) m 600 ) 0) / 6 0 0 400 5 m E 0)- 200 4 ° cn), ~_T m W U) VP-nir X--YFt ' - A B o i 2 3 A T Time (h) B Figure 3 Mean ± s.d. serum levels ofmiglitol (0) and acarbose (0) related to the glucose curve (---) on O' placebo. Placebo Miglitol

10 Discussion The post-prandial lowering of blood glucose by E alpha-glucosidase inhibitors such as miglitol and E G) U) acarbose after a starch load, is well established. 0 .A The mechanism of action is the inhibition of the 0 5 last step in carbohydrate digestion, namely the B conversion of disaccharide to monosaccharide 0-o (glucose) and a consequent decrease in the rate 0 of entry of glucose into the systemic circulation. The current study confirms our previous find- OL ings that miglitol also lowers post-prandial blood Placebo Miglitol glucose after a glucose load. The nature of the Figure 4 Box and whisker plots of insulin to glucose blood glucose curves is however different after a ratio and blood glucose found in this study (100 mg glucose load when compared with a starch load. miglitol) and a previous study using 50 mg miglitol. After a starch load, the time to peak and the peak height of the plasma glucose curve are reduced. These two parameters are however for the carrier. Interference with absorption could unchanged after a glucose load and plasma still be an explanation if one takes cognizance of glucose suppression occurs post-peak. Acarbose, the fact (Figure 3) that the glucose peak occurred which is poorly absorbed, appeared to have no well before the miglitol peak. It could be possible effect at all or perhaps an effect between that of that at this stage where the amount of glucose placebo and miglitol. The insulin curves appeared still being absorbed is relatively small, inter- to show the same trends as the glucose curves, ference with absorption can now become mani- but none of the differences between the drugs fest. were statistically significant. If miglitol interfered with systemic glucose One could speculate on several mechanisms transport mechanisms one would expect an in- that could explain the effects observed when one crease in blood glucose levels. If one wants to considers the structural similarity between miglitol postulate an effect to explain our findings, a and glucose. As studies done in guinea-pig facilitation and not inhibition of transport needs jejunum (Steinke, 1986) indicated that miglitol to be presumed. utilizes the same active transport system as A further possible explanation could be en- glucose, one could expect miglitol to compete hanced insulin release, but there is no evidence with glucose for active transport across various from our data for this. The literature in fact membranes. If competition for transport across reports a depression of insulin release from the the gut wall occurred, one would expect a de- rat isolated pancreas (Goke et al., 1984). If one crease in pre-peak blood glucose values. As this compares box and whisker plots of the data of was not the case, such an effect is unlikely. On this study (100 mg miglitol) with that of our the other hand for 100 mg of drug to interfere previous study with 50 mg (Joubert etal., 1987) it visibly with the absorption of 75 g of glucose seems as if the two doses have similar blood would need an extremely high relative affinity glucose lowering effects, but the higher dose 396 P. H. Joubert, H. L. Venter & G. N. Foukaridis showed a tendency for insulin to decrease (Figure If this effect of miglitol could be elucidated 4). In view, however, of the complex homeostatic more clearly, it could lead to more rational ideas relationship between glucose and insulin, these about dosage and timing of the dose. Further- observations should be treated with reservation. more one could look for similar chemical struc- The appearance of the miglitol blood glucose tures with a more pronounced effect. curve could also be consistent with enhanced glucose disposition, e.g. uptake into the cell or We would like to thank Sister P. Dali, Sister G. Modi- conversion to glycogen. On appearances this selle, Sister L. Mathibe, Mr A. Modipane and Mr M. seems the most likely explanation, but further Fata for technical assistance and Mrs L. Swart and Mrs investigation is indicated. R. Kahler for preparation of the manuscript.

References Goke, B., Fehrmann, C., Folsch, U. R. & Creutzfeldt, Brodech, E., pp. 139-151. Weinheim: Verlag W. (1984). Influence of a new absorbable inhibitor Chemie. of alpha-glucosidase on the rat pancreas. Digest. Ramsch, K. D., Wetzelsberger, N., Putter, J. & Maul, Dis. Sci., 29, 951-954. W. (1985). Pharmacokinetics and metabolism of Hillebrandt, I., Boehme, K., Graefe, K. H. & Wehling, the 1-deoxynojirimycin derivatives (BAY m 1099 K. (1986). The effect of new alpha-glucosidase and BAY o 1240). Diab. Res. clin. Pract. Suppl. 1, inhibitors (BAY m 1099 and BAY o 1248) on meal Abstract 1199. stimulated increases in glucose and insulin in man. Schnack, C., Roggla, G. & Luger, A. (1986). Effects Klin. Wochenschr., 64, 393-396. of the alpha-glucosidase inhibitor 1-deoxynojiri- Joubert, P. H., Foukaridis, G. N. & Bopape, M. L. mycin (BAY m 1099) on postprandial blood glucose, (1987). Miglitol may have a blood glucose lowering serum insulin and c-peptide levels in type II diabetic effect unrelated to inhibition of alpha-glucosidase. patients. Eur. J. clin. Pharmac., 30, 417419. Eur. J. clin. Pharmac., 31, 723-724. Steinke, W. (1986). Intestinal absorption mechanism Joubert, P. H., Venter, C. P., Joubert, H. F. & of the glucosidase inhibitor BAYm 1099. Naunyn- Hillebrandt, I. (1985). The effect of a 1-deoxyno- Schmiedeberg's Arch. Pharmac., 332, Suppl: jirimycin derivative on post-prandial blood glucose Abstract 162. and insulin levels in healthy black and white volun- Walton, R. J., Scheriff, I. T. & Noy, G. A. (1979). teers. Eur. J. clin. Pharmac., 28, 705-708. Improved metabolic profiles in insulin-treated dia- Mtiller, F. 0. & Hillebrandt, I. (1986). Acarbose betic patients given an alpha-glucosidase inhibitor. (BAY g 5421) kinetics in healthy volunteers. Acta Br. med. J., 1, 220-221. Pharmac. Tox., 59, suppl. V: 303. Putter, J. (1980). Studies on the pharmacokinetics of (Received 23 January 1990, acarbose in humans. In Enzyme inhibitors, ed accepted 10 May 1990)