Regulation of the Absorption of Dietary Carbohydrate in Man by Two New Glycosidase Inhibitors

Gut: first published as 10.1136/gut.27.12.1471 on 1 December 1986. Downloaded from

(ut, 1986, 27, 1471-1478

Regulation of the absorption of dietary carbohydrate in man by two new glycosidase inhibitors

R H TAYLOR, HELEN M BARKER, ELIZABETH A BOWEY, AND JEAN E CANFIELD From the Department of Gastroenterology and Nuttritiotn, Central Middlesex Hospital, London

SUMMARY Two new reversible inhibitors of intestinal a-glycosidases (BAY mlO99 & o1248) have been derived from deoxynojirimycin. Their inhibitory substrate specificity has been investigated in man using test meals of the dietary carbohydrates, sucrose, maltose, and starch. Both inhibitors abolished the postprandial glycaemic rise after sucrose and mlO99 50 mg did after maltose and starch, whereas o1248 20 mg had no effect after maltose and only a small effect after starch. Breath hydrogen evolution, as an indirect measure of malabsorption, showed that the reduced glycaemic responses, particularly after sucrose, were associated with considerable substrate malabsorption. Dose response studies showed that lower doses of both inhibitors could reduce postprandial glycaemia significantly without causing malabsorption. Both inhibitors were tolerated well. These two new enzyme inhibitors have different substrate specificity in man and can, in appropriate dose, regulate postprandial glycaemia by selective inhibition of brush border enzymes without causing malabsorption. In addition to their therapeutic importance, they provide a valuable experimental model of specific intestinal enzyme deficiency states. http://gut.bmj.com/ The postprandial rise in blood glucose is determined proteins or carbohydrates and are unstable, non- by a number of dietary, gastrointestinal, hormonal, specific or irreversible. and metabolic factors. The aimount of available The first pure synthetic glycoside hydrolase in- carbohydrate;' its physical form2 and complexity;3 hibitor was the pseudotetrasaccharide acarbose the presence of dietary protein, faO and dietary (Fig. la) which was isolated from culture of various fibre" in the meal are all important dietary deter- genera of Actinomycetes.7 It is a stable compound minants of the rate of absorption. Abnormalities of and a powerful inhibitor of sucrase and maltase on September 25, 2021 by guest. Protected copyright. the small intestinal mucosa and enzyme deficiencies activity in vitro8 9 and in vivo in the rat"' and in can slow digestion and thus absorption. The rates of man. " It was the first inhibitor to be shown to have hepatic carbohydrate metabolism, insulin release, a reversible effect in the short term' 2 13 and it has no and peripheral glucose uptake also regulate blood effect on monosaccharide transport mechanisms.'4 glucose levels. Stable partial inhibition of sucrase activity can be Awareness of the importance of close control of obtained with this inhibitor'8 in which the rate of blood glucose concentrations in reducing the long onset and the steady state are dose related.'" In term complications of diabetes stimulated research test meal studies in man with acarbose the glycaemic into new ways of stabilising postprandial glycaemia. response to sucrose was greatly reduced, that to One approach to this has been by the use of specific starch was moderately impaired, and to maltose was inhibitors of the intestinal a-glycosidase hydrolases, reduced slightly. The reduction in glycaemic re- because all dietary carbohydrate, with the exception sponse was associated with evidence of carbo- of lactose, is digested by these intestinal enzymes. hydrate malabsorption. "I There are many naturally occurring substances Two new a-glycoside hydrolase inhibitors derived which inhibit these enzymes, but most are complex from l-deoxynojirimycin have now been synthesised in microbial culture. Both nojirimycin (Fig lb), Addrcss..or corrcspondcncc Dr R 11 Tayllor. I)cpt of (Gastrocntcrolog anfld synthesised by various species of Streptomiyces and Nuitrition, C entral Middle.scx Hospital Acto Lanc. Iondon NWI() 7NS strains of the genus Bacillus, and its reduced form, Rccclivvc tfor pLuhbli;ltonI 22 April 1986I 1-deoxynojirimycin (Fig ic), are potent inhibitors 1471 Gut: first published as 10.1136/gut.27.12.1471 on 1 December 1986. Downloaded from

1472 Taylor, Barker, Boivey, atnd Catnficld Acarbose ( Nojirimycin) 0) 1- Deoxy 'iJrimej )CH2ODH H CHoe Hoo cHoH HO

0so' 4CH20

140 C"

O Bay mlO99 a)By o1248 C,H CH-CH2OH2 IOH2CHT-O-COOC2Hs

Fig. 1 Structure of acarbose, nojirim vcin, I-deoxynojirim ycin and the deoxvnzojirittm vci'n derivatives, BA Y m1099 and o1248.

of mammalian intestinal brush border a-glycoside water; with 200 ml cold water to drink. Each hydrolases in vitro, but not of a-amylase.'7 21 Two substrate was taken on three separate occasions with derivatives of l-deoxynojirimycin with modified side either ml(99 50 mg, o1248 20 mg or a placebo of chains, designated BAY m1099 and o1248, have identical appearance at the start of the meal. These been produced (Figs ld,e). Both are potent in- doses were chosen to be equipotent on the basis of hibitors of specific rat intestinal ax-glycoside hydro- the results of the animal studies.23-> Tablets were http://gut.bmj.com/ lases in vitro.22 In studies of intestinal perfusion in given double blind in randomised order. The three

the rat in vivo the inhibitors have been shown to tests for each substrate were done within a three have reversible effects and to have different patterns week period with at least five days washout period of substrate specificity.f23-25 between tests. Subjects followed the saime routine ot In these studies the two new inhibitors have been activity and meals on the day before each test, fasted used in man firstly to establish their substrate overnight and took test meals at the sarme time on

specificity and secondly to find dose levels at which each occasion. Subjects were seated at rest for the on September 25, 2021 by guest. Protected copyright. postprandial blood glucose concentrations are con- first two hours of each test and were then allowed trolled by slowing absorption, without causing restricted activity over the next two hours. None of malabsorption of dietary carbohydrate with its the subjects had any history of allergy or drug associated symptoms of flatulence, distension, and intolerance or had taken antibiotics in the previous osmotic diarrhoea. month. No other medication was tiaken in the test period. Finger prick blood samples were t-aken using Methods Autolets (Owen Mumford Ltd, Woodstock, Oxon) into bottles containing 0(2 mg sodium fluoride and SUBSTRATE SPECIFICITY STUDY 0-6 mg potassium oxalate for measurement of blood Six healthy male subjects (mean age 30 years, range glucose, using an enzymatic method detected by ain 27-33; 1 1 1 (%, range 84-130% desirable weight-6) oxygen electrode (Yellow Springs Instruments, took nine oral 50 g carbohydrate tolerance tests Model 27).2' Finger prick samples were taken every consisting of sucrose, maltose or starch with 400 ml 15 minutes from 0 to 60 minutes and then at 90 and water. In order to give a palatable and representa- 120 minutes. Venous blood was taken before and tive form of dietary starch, instant mashed potato three hours after the start of each study for was used (Winfield brand, 62 g containing 50 g measurement of haematological indices and for starch, 4 g protein)' 27 made up with 200 ml hot biochemical measurements including urea, electro- Gut: first published as 10.1136/gut.27.12.1471 on 1 December 1986. Downloaded from

Reglulationi of tlie absorption of'dietarx' carbohydrate in lfla(il bl tl'(o)i11e,2gvcosid(ase illlilitirbs14 1473 lytes, calcium, phosphate, liver function tests, amy- considerable rise in breath hydrogen concentration lase, urate, cholesterol, and triglyceride. from 45 minutes onwards. The results aire shown in End expiratory breath samples were taken using a Figure 2 together with the melan symllptom scores modified Haldtane-Priestley tube29 for the measure- during the 24 hours after dosing for distcnsion (D), ment of brecath hydrogen concentration with a flatulence (F) aind loose motions (LM) for the two hydrogen electrode (Exhaled Hydrogen Monitor, different inhibitors and placebo taken with sucrose. GMI Medical Ltd, Renfrew). End expiratory None of those with loose motions opened their samples were taken every 15 minutes from 0 to 150 bowels in the first two hours after dosing. The minutes and then every 30 minutes to 240 minutes. symptoms reported after ol248 were more severe A rise in breath hydrogen was taken as an indirect than those after m 1099. Breath hydrogenl concentra- indication of malabsorption of carbohydrate. tions were also higher after oll248, though the A proportional relationship between the amount differences between individual times or in the areas of carbohydrate malabsorbed and the hydrogen under the curves were not significantly different. concentration in expired alveolar air has been The effects seen alfter mcaltose were mlarkedly reported.3¢ 32 In an attempt to calibrate each sub- different (Fig. 3). The postprandial glycaeemic rise ject's malabsorption, a separate study was done in was reduced considerably by m1099 but o1248 had which end expiratory breath hydrogen concentra- no significacnt effect. There was a small rise in breath tion was measured after 25 g of the non-absorbable hydrogen after maltose with m1099 but the symp- sugar lactulose. The ratio of the integrated breath toms reported were mild. Breath hydrogen levels hydrogen response (area under the curve) from the and symptoms after o1248 and maltose were the test meal to that from 25 g lactulose was used to same as after the placebo with maltose. estimate the amount of carbohydrate malabsorbed The postprandial glycaemic rise after starch was in the experimental situation for each individual. reduced moderately by ol.248 and miarkedly by Any symptoms or adverse reactions during the 24 m1099 (Fig. 4). There was a small, late rise in breaith hours after dosing were recorded by the subjects. The symptoms of distension, flatulence and loose motions which would be expected to be associated with malabsorption of carbohydrate were each

recorded on a numerical scale of 0 (absent), I I.

(mild), 2 (moderate) or 3 (severe). http://gut.bmj.com/ n=60--W* D)OSE RESIONSE STUD)Y mlm.9664r.: r*6 In pilot studies sucrose absorption was found to be -1248. .20 64. inhibited more than that of the other substrates in 3; the presence of the inhibitors. In therapeutic use this would be the limiting substrate because it would be malabsorbed at lower inhibitor dose levels than

other substrates. For this reason sucrose was used as on September 25, 2021 by guest. Protected copyright. the substrate in the dosage studies. .3 Six different healthy male subjects (mean age 28 I years (23-30); 106% (98-121) desirable weight) 0 Im took 50 g sucrose in 400 ml water on seven T T occasions. They took the following doses of inhibitors: mlO99 12 5, 25 or 50 mg; o1248 5, 10 or 20 mg; or a placebo of identical appearance, double blind in randomised order. All other experimental details were as described above. Statistical analysis wais done using Student's t test. Vtalues given are means ± standard errors. The studies had the approval of the Ethics Committee of the Brent Hlealth Authority. Tm (rrn) Results Fig. 2 Blood( glucose anl b-ealie hvdr-ogeii respons.e)1ls aiIcr SUBSTRATF SPEC'IFClIrTY siurose 50 g with placebo., inI 099 or o124S. MeIan.s X inplom Both inhibitors abolished the postprandial gly- .score.s for disten.sio,, (D), flatulence (F) aid loose miolion.s caemic rise after sucrose 50 g and resulted in a (LM). (Glucose: I ininiolll I mng/100 ()il). Gut: first published as 10.1136/gut.27.12.1471 on 1 December 1986. Downloaded from

1474 Taylor, Barker, Bowey, and Canfield hydrogen after m1O99 but not after o1248. The generally mild symptoms experienced were not significantly different between treatments and may Z well be a consequence of the bulk of the semisolid 6 starch meal. The amounts of the substrates which were malab- t1- .1 sorbed in the presence of the two inhibitors, as calculated by the ratio of areas under the breath 3 as 2 hydrogen curves, are shown in Table 1. DOSE RESPONSE 0O The effects of the three different dose levels of * 120 m1O99 on postprandial glycaemia after 50 g sucrose are shown in Figure 5 compared with the rise after

Table I Amount ofcarbohydrate malabsorbed (g) > 40 calculatedfrom hydrogen production with 25 g lactulose L- I - ._ - . , Substrate 0 60 90 120. 23b. Sucrose 50 g Maltose 50 g Starch 50 g

Fig. 3 Blood glucose and breath hydrogen responses after m1099 5() mg 38+4 16±9 5±4 maltose 50 g with placebo, m1099 or o1248. Mean symptom o1248 20 mg 49+8 0±1 3+1 scores for distension (D), flatulence (F) and loose motions (LM). (Glucose: I mmolIl ==18 mgIlOO ml).

Sucros eo .g . 101

_. http://gut.bmj.com/ 6: t n j Lft~S

I .- , I: -1 on September 25, 2021 by guest. Protected copyright. 0 30E901.) 20 r. f. 3 I. I. 4 160 -D M. i

.40- a.,i ,, 0 .. '60. T 90 120 240 Tkne (mn) Tint

Reglulationi of the absorption ofdietary carbohydrate in man by two tlew glycosidase inhibitors 1475 sucrose with placebo. With increasing dose the Table 2 Amount ofsiucrose mailabsorbed (g) f/oin 50 g postprandial rise is reduced and the peak delayed. load at different inihibitor doses, calcuilatedfrotIihydrogen The low dose (12.5 mg) caused no rise in breath production with 25 g lactulose hydrogen and no symptoms. The intermediate dose m1099 12 5 mg 0+1 o1248 5 nimg 13±4 (25 mg) caused a slight rise in breath hydrogen but 215 mg 4±4 10 mlg 24±4 negligible symptoms. The high dose had similar 50 mg 24+6 2(1 nig 3(±4 effects in terms of breath hydrogen release and symptoms as had been found in the first study. Even the lowest dose of o1248 (5 mg) caused a marked reduction in postprandial glycaemia, a moderate rise in breath hydrogen and some disten- dose levels. The only symptoms of any severity sion and flatulence. The 10 mg and 20 mg doses which were reported were the predicted ones almost abolished the postprandial glycaemic rise, associated with the effects of fermentation of caused marked evolution of hydrogen and symp- malabsorbed carbohydrate and osmotic diarrhoea. toms of similar severity at both dose levels (Fig. 6). A few minor symptoms, such as headache and The results at 20 mg were closely similar to those tiredness, were reported but these ocurred as found with the first group of subjects in the substrate frequently in the placebo studies as after the specificity study. inhibitors. There were no abnormalities of haema- The amounts of the 50 g sucrose load which were tology or biochemistry found either before or after malabsorbed in the dose response study, as calcu- any of the tests in any of the volunteers, nor were lated by the ratio of areas under the breath there any consistent differences between the pre- hydrogen curves, are given in Table 2. Both and post-test values in any study. compounds were well tolerated by all subjects at all Discussion The results show that both these inhibitors are very effective in reducing postsucrose glycaemia. o1248

z 20 mg, however, has a relatively small effect on E lPlacebo n=6 * poststarch glycaemia and no effect on postmaltose E o1248 '5mg n=6 v v glycaemia. The effects of o1248 are similar to those ol248 1( n-6 http://gut.bmj.com/ )mg ___ reported previously with acarbose 200 mg.'' In u contrast, glycaemia after maltose and starch is D reduced by m1099 50 mg very effectively without appreciable malabsorption being caused. The differences in substrate specificity suggest that there may well be differences in the inhibitors' enzyme specificity in the intact gut. Both inhibitors are obviously 0. Time (min) 3_ effective against sucrase and m1(99 appears to be on September 25, 2021 by guest. Protected copyright. effective brush border maltases, other than .6L^t against O S 10 20 sucrase, whereas o1248 seems to have negligible _ D F LM effect there. Inhibition of brush border maltase activity by m1099 would explain the reduction in y JI glycaemia after both maltose and starch but the lack > 1------of effect of o1248 on maltose absorption suggests that its effect on starch absorption must be at a 0 ....I different level. These observations are in keeping with the findings of in vivo intestinal perfusion mo studies in the rat,23 25 but they contrast with the results of Lembcke et a122 who found that iti vitro 0 60 120 180 240 o1248 was as potent an inhibitor of isolated glu- Time (min) coamylase and maltase from mucosal homogenates as was m 1099. Because maltose and malto- Fig. 6 Blood glucose and(c breath hvdrog,ent respotise.s - esI onses oligosaccharides are end products of amylase diges- aftier slucrose 50 g wit/i placebo or ol248, or 20 mg. Mean swln.iptomi wscores for diste5 usion1(D), tion of starch, this suggests that the definite reduc- flatulence (F) anid loose motion.s (LM). (IGlucose: tion of poststarch glycaemia by o1248 cannot be I mmolll 18 mng/Il1)G ml). explained fully by a specific effect on brush border Gut: first published as 10.1136/gut.27.12.1471 on 1 December 1986. Downloaded from

1476 7'lalor, Barker, Boivev, (adt ('Cailnield maltases. It must therefore be due in part to an with sucrose were similar to those after acarbose inhibitory effect on luminal amylase activity of 200 mg with sucrose. Like aicarbose. o1248 did not whatever source. In vitro studies with purified cause malabsorption of matltose or stairch. Despite at-amylase, however, have shown negligible inhibi- the limitations of the technique, the dose response tion of enzyme activity by m1099 or o1248 (Bayer studies suggest that the amount of sucrose malab- AG, unpublished observations). The explanation of sorbed was broiadly dose related. It seems thatt by this paradox is not clear but may lie in the fact that using a lower dose of m 1 099 it is possible to regulate both a-dextrinase and glucoamylase are active post-sucrose glycaemina without causing mantlabsorp- in hydrolysing malto-oligosaccharides with chain tion, as was found with acarbose 50 mg,1 and it lengths up to nine or more glucose residues. These seems likely that (an even lower dose of ol248 than enzymes may contribute some 'amylase-like' activity 5 mg would hatve a similalr effect. It is not only to digestion of starch already partly broken down to theriapeutic-ally undesirtable to produce malabsorp- shorter chain lengths in preparation. HPLC tion of carbohydraite but in the reguliation of analysis33 of the potato, as eaten by the subjects, diabetes it is essential to be confident that all however, showed that less than l/o of the carbohy- carbohydrate that has been ingested is being drate present consisted of chains of less than eight absorbed and not lost to fermentiation in the colon. glucose residues. Because sucrose is the most sensitive substratte for The doses used in the substrate specificity studies this, this is bound to be the limiting factor, unless it were based on intestinal perfusion studies in the rat is totailly excluded from the diet. in which these doses were equipotent in inhibiting Maltose is not at commonly ingested dietary the disappearance of luminal sucrose.23 As the carbohydrate but is important in these studies inhibitory effect of these doses appears to be almost because it is a major luminal digestion product of total after sucrose 5t) g, it is difficult to be sure starch thiat is then hydrolysed att the brush border. whether this is a true equivalence in man. The dose The results suggest thiat the inhibitory effect of response studies suggest that the high dose (20 mg) m l(t)99 on poststarch glycaemia in man could be of o1248 was much more potent in man in inhibiting explained entirely by inhibition of maltase activity. sucrase activity than was the high dose (50 mg) of In these studies, however, o1248 had negligible m 1099. effect on maltose absorption but had a greater effect The potent sucrase inhibitory effect of both on starch absorption. This suggests that, despite the inhibitors has resulted in almost complete malab- unpublished in v,itro data, the compound appears to sorption of the carbohydrate load with its associated hiave some inhibitory effect on armylasc activity ill http://gut.bmj.com/ symptoms. The differences between the calculated l'il!O in man. amounts of sucrose malabsorbed in the presence of The symptoms reported in these studies only mO99 50 mg and o1248 20 mg in the two study occurred in the presence of the indirect breaith groups are because of considerable individual varia- hydrogen evidence of malabsorption of carbo- tions in breath hydrogen evolution after lactulose hydrate. In circumstainces where cairbohydrate up- and the inherently limited precision of this indirect take wats slowed but complete. the only symptomiis test.34 These results must be treated with consider- reported were minimail aind occurred as frcquently able caution, however, they have some value in on placebo ais they did in the presenice of the on September 25, 2021 by guest. Protected copyright. giving an indication of the scale of malabsorption inhibitors. It seems possible therefore to regulate produced and the proportions for the two inhibitors the rate of carbohydrate uptake using these inhibi- are the same for both groups. There was some tors aind to reducc the postprandial glycilclllc peak evidence of malabsorption of maltose with mlt)99 without causing undesirable mailabsorption or symp- but not with ol-248, though few symptoms were toms. These compounds appear to have a therapeu- reported with either. There was no breath hydrogen tic potential in the regulation of blood glucose in evidence of starch malabsorption with either inhibi- patients who haive an impalirment of carbohydrate tor but some symptoms were reported. Intestinal metabolism and, in particular, in diabetes. The transit of the starch meal was probably much slower inhibitory properties of o1248 are similar to those of than that of the sugar solutions.32 Hydrogen evolu- aicarbose but it appears to be 1t) times more potent tion as an indication of malabsorption may thus have than acarbose. The inhibitory profile of mnlt)99 is occurred later than the four hour collection period, appreciably different antd its potency seems to lie as is hinted by the late rise in breath hydrogen after between those of acarbose and o1248. The results o1248. The volume of the meal and the dietary fibre suggest that ml()99, with a broader spectruni of present in the potato may both have contributed to substriate specificity, may be a. more effective symptoms reported over the 24 hour period. The therapeutic agent. They also suggest that, even if amounts of hydrogen evolved after ol248 20 mg sucrose is excluded rigorously from the diet, a dose Gut: first published as 10.1136/gut.27.12.1471 on 1 December 1986. 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Regulation ofthe absorption of dietary carbohydrate in mlan by two new glycosidase inhibitors 1477

of ml1099 25 mg at mealtimes may be sufficient to 15 Barker HM, Canfield JE, Taylor RH. Stable dose- In addition to related partial inhibition of sucrase activity can be regulate postprandial glycaemia. their produced by a glycoside hydrolase inhibitor. Clin Sci therapeutic potential, these derivatives of deoxyno- 1983S; 65: 9-lOP. jirimycin have considerable scientific interest in that 16 Taylor RH. Barker HM. Canfieid JE. Intestinal they provide a reversible experimental model of sucrase inhibition by a reversible inhibitor: initial and intestinal enzyme deficiency syndromes both in steady state kinetics. Gastroenterology 1983; 84: 1333. animals and man. 17 Inouye S. Tsuruoka T, Niida T. The structure of nojirimycin, a piperidinose sugar antibiotic. J An7tiobio- RHT was a Wellcome Senior Research Fellow in tics 1968; 19: 288-92. 18 Inouye S. Tsuruoka T, Ito T, Niida T. Structure and Clinical Science. Funding and assistance from The synthesis of nojirimycin. Tetraihedroni 1968; 24: 2125- Wellcome Trust and the Pharmaceutical Division, 44. Bayer UK Ltd are gratefully acknowledged. Sup- 19 Schmidt DD, Frommer W, Muller L, Truscheit E. plies of BAY mIO99, o1248 and placebo tablets Glucosidase-Inhibitoren aus Bazillen. Naturwissen- were kindly provided by Bayer AG Leverkusen. schafteni 1979; 66: 584-85. 20 Niwa T, Inouye S. Tsuruokat T, Koaze Y. Niida T. Nojirimycin as a potent inhibitor of glucosidase. Agric References Biol C(lem 1970; 34: 966-68. I Jenkins DJA, Wolevcr TMS, Taylor RH. et al. 21 Reese ET Parrish FW. Ettlinger M. Nojirimycin and Glycaemic index of foods: a physiological basis for d-glucono-15-lactone as inhibitors of carbohydrases. carbohydrate cxchange. Am J Clini Niitr 1981; 34: Carboh1drate Res 1971; 18: 381-88. 362-66. 22 Lembcke B. F6lsch UR, Creutzfeldt W. Effect of 1- 2 O'Dea K, Nestel PJ, Antonoff L. Physical factors deoxynojirimycin derivatives on small intestinal dis- influencing postprandial glucose and insulin rcsponses accharidase activities and on active transport iIn vitro. to starch. Am J Cli/i Nlitr 1980; 33: 760-65. Digestioni 1985; 31: 120-27. 3 Crapo PA, Recaven G. Olefsky J. Plasma glucosc and 23 Taylor RH. Barker HM. Bowey EA. Canfield JE. insulin responses to orally administered simple and Selective inhibition of intestinal disaccharide absorp- complex carbohydrates. Diabetes 1976; 25: 741-47. tion by deoxynojirimycin-derived glycosidase inhibi- 4 Fajans SS, Floyd JC, Knopf RF, Conn JW. Et't'ect of tors. /in Sci 1984; 67: 41P. amino acids and proteins on insulin secretion in man. 24 Taylor RH, Barker HM, Bowey EA, Canfield JE. Rec Prog Horm Res 1967; 23: 617-62. Intestinal monosaccharide transport is unimpaired by 5 McSwiney BA, Spurrell WR. The eft'ect of fat on deoxynojirimycin-derived glycosidase inhibitors. Clin gastric motility. J Physiol 1935; 84: 41-49. Sci 1984; 67: 63P. http://gut.bmj.com/ 6 Jenkins DJA, Wolever TMS, Leeds AR, et al. Dietary 25 Taylor RH, Barker HM, Bowey EA, Canfield JE. Two fibres, fibre analogues and glucose tolerance: import- selective inhibitors of intestinal carbohydrate absorp- ance of viscosity. Br Med J 1978; 1: 1392-94. tion. [Abstracti Gut 1984; 25: A1155-56. 7 Schmidt DD, Frommer W, Jungc B, et al. a-glu- 26 Metrop Life Insur Co. Desirable weights of adults. In: cosidase inhibitors: new complex oligosaccharides of Diem K, Lentner C, eds. Documenta Geigy: scientific microbial origin. Nalurwissenschaften 1977; 64: 535-36. tables, 7th ed. Basle: J R Geigy, 1970: 712. 8 Truscheit E, Frommer W, Junge B, Muiller L, Schmidt 27 Jenkins DJA, Ghafari H, Wolever TMS, et al. DD, Wingender W. Chemistry and biochemistry of Relationship between rate of digestion of foods and on September 25, 2021 by guest. Protected copyright. microbial a-glucosidase inhibitors. A igewadidte Chemie postprandial glycaemia. Diabetologia 1982; 22: 450-55. Int Ed Engl 1981X 20: 744-61. 28 Clark LC. A polarographic enzyme electrode for the 9 Caspary WF, Graf SD. Inhibition of human intestinal measurement of oxidase substrates. In: Kessler M, ca-glucosidehydrolases by a new complex oligosacchar- Bruley DF, Clark LC, Lubbers DW, Silver IA, Strauss ide. Res Exp Med (Bert) 1979; 175: 1-6. J, eds. OxVgen supply. Baltimore: University Park 10 Barker HM, Taylor RH. Maltase and sucrase inhibition Press, 1973: 120-28. by acarbose: a paradoxical effect in vivo. Br J 29 Metz G, Gassull MA, Leeds AR, Blendis LM, Jenkins Pharmacol 1983; 78: 65p. DJA. A simplc method of measuring breath hydrogen 11 Jenkins DJA, Taylor RH, Goff DV, et al. Scope and in carbohydrate malabsorption by end-expiratory sam- specificity of acarbose in slowing carbohydrate absorp- pling. C/lin Sci Mol Med 1976; 50: 237-40. tion in man. Diabetes 1981; 30: 951-54. 30 Bond JH, Levitt MD. Use of pulmonary hydrogen 12 Taylor RH, Barker HM. Rcversibility of sucrase measurements to quantitate carbohydrate absorption. inhibition by acarbose in in viVO perfusion of the rat J Clin lInvest 1972; 51: 1219-25. jejunum. [Abstract] Glit 1982; 23: A913. 31 Caspary WF. Sucrose malabsorption in man after 13 Taylor RH, Barker HM. Recovcry of intestinal sucrase ingestion of (x-glucosidchydrolasc inhibitor. LanIcet and maltase activity after inhibition by acarbose in 1978; i: 1231-33. vivo. Clin Sci 1983; 64: 52P. 32 Rcad NW, Miles CA, Fisher D, et al. Transit of a meal 14 Taylor RH, Barker HM. Intestinal glucosc and fructose through the stomach, small intestine and colon in absorption is unimpaircd when sucrase is inhibited by normal subjects and its role in the pathogenesis of acarbose. [Abstract] Proc Nuiir Soc 1983; 42: 89A. diarrhoea. Gastroeniterology 1980; 79: 1276-82. Gut: first published as 10.1136/gut.27.12.1471 on 1 December 1986. Downloaded from

1478 Taylor, Barker, Bowey, and Canfield

33 Grimble GK, Barker HM, Taylor RH. Chromatro- 34 Lembcke B, Fo1sch UR, Caspary WF, Ebert R, graphic analysis of sugars in physiological fluids by Creutzfeldt W. Influence of metronidazole on the post-column reaction with cuprammonium - a new and breath hydrogen response and symptoms in acarbose- highly sensitive method. Anal Biochem 1983; 128: induced malabsorption of sucrose. Digestion 1982; 25: 422-28. 186-93. http://gut.bmj.com/ on September 25, 2021 by guest. Protected copyright.