Long-term suppression of postprandial hyperglycaemia with acarbose retards the development of neuropathies in the BB/W-rat

Diabetologia, Apr 1992

Summary The effect of the α-glucosidase inhibitor acarbose on postprandial hyperglycaemia was explored in the spontaneously diabetic BB/W-rat. Acarbose-treatment (5 mg·kg body weight−1·day−1) of diabetic BB/W-rats maintained on small doses of insulin, was associated with a 40% reduction in the 24-h glucose area compared to non-treated diabetic rats. Over a 4 month treatment period this reduction in cumulative hyperglycaemia resulted in a complete prevention of autonomic polyneuropathy as indicated by R-BAR values. The development of somatic polyneuropathy in the BB/W-rat was significantly attenuated by acarbose treatment with a partial prevention of the characteristic nerve conduction velocity slowing during the first 3 months of diabetes, but no longer at 4 months. Characteristic structural abnormalities associated with diabetes in this model, such as axonal atrophy and axo-glial dysjunction, were significantly but only partially prevented in rats treated with acarbose for a diabetes duration of 4 months. These data suggest that postprandial lowering of hyperglycaemia resulting in a decrease in cumulative hyperglycaemia retards the development of diabetic polyneuropathies in the BB/W-rat.

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Long-term suppression of postprandial hyperglycaemia with acarbose retards the development of neuropathies in the BB/W-rat

Diabetologia Long-term suppression of postprandial hyperglycaemia with acarbose retards the development of neuropathies in the BBfW-rat A. A. E Sima I 1 S. Chakrabarti 0 1 0 DepartmentofPathology , UniversityofManitoba,Winnipeg , Canada 1 Departments of Pathologyand InternalMedicineand MichiganDiabetesResearchand TrainingCenter , UniversityofMichigan, Ann Arbor,Michigan , USA Summary. The effect of the c~-glucosidaseinhibitor acarbose on postprandial hyperglycaemiawas explored in the spontaneously diabetic BB/W-rat. Acarbose-treatment (5 mg-kg body weight-t, day-I) of diabetic BB/W-rats maintained on small doses of insulin, was associated with a 40 % reduction in the 24-h glucose area compared to non-treated diabetic rats. Over a 4 month treatment period this reduction in cumulative hyperglycaemia resulted in a complete prevention of autonomic polyneuropathy as indicated by R-BAR values. The development of somatic polyneuropathy in the BB/Wrat was significantly attenuated by acarbose treatment with a partial prevention of the characteristic nerve conduction velocity slowing during the first 3 months of diabetes, but no longer at 4 months. Characteristic structural abnormalities associated with diabetes in this model, such as axonal atrophy and axo-glial dysjunction, were significantly but only partially prevented in rats treated with acarbose for a diabetes duration of 4 months. These data suggest that postprandial lowering of hyperglycaemiaresulting in a decrease in cumulative hyperglycaemia retards the development of diabetic polyneuropathies in the BB/W-rat. Postprandial hyperglycaemia; autonomic neuropathy; somatic neuropathy; BB/W-rat - 9 Springer-Vertag1992 The diabetic polyneuropathies are common secondary complications of diabetes mellitus and contribute significantly to the morbidity and mortality associated with this disease [ 1-4 ]. The pathogenesis of diabetic polyneuropathies is a topic of lively controversy, although metabolic abnormalities secondary to hyperglycaemia, microvascular abnormalities as well as independent predisposing genetic factors are probably the major mechanisms involved in the genesis of the neuropathic complications [ 5-9 ]. Epidemiological studies associate the incidence of clinically overt neuropathy with duration of diabetes and glycaemic control, suggesting that cumulative hyperglycaemia may be a major contributing factor [ 3, 10, 11 ]. Although attractive, this hypothesis has never been tested under strict experimental conditions. The spontaneously diabetic BB/W-rat has emerged as a valuable experimental model with which to explore the pathogenesis and natural history of diabetic neuropathy, since it develops diabetic neuropathies that closely mimic those seen in man [ 2, 12-14 ]. As in human diabetic subjects the BB/W-rat develops autonomic neuropathy with a progressive decrease in heart beat variability reflecting vagal neuropathy [ 15, 16 ]. The somatic neuropathy is characterized by a progressive decrease in nerve conduction velocity that precedes and accompanies the development of structural abnormalities affecting the node of Ranvier and the internodal axon of myelinated fibres [ 12, 13, 17 ], analogous to the neuroanatomical lesions seen in diabetic neuropathic patients [ 18-20 ]. In order to explore the discriminative effect of the degree of hyperglycaemia on the development of somatic and autonomic polyneuropathies in the BB/W-rat, diabetic animals were given the a-glucosidase inhibitor acarbose (BAY g 5421; Miles Inc., West Haven, Conn., USA) from onset of diabetes for a period of 4 months. This compound is a potent competitive inhibitor of small intestine c~-glucosidase and significantly suppresses postprandial increases in blood glucose and insulin responses in the rat and man [ 21-24 ]. In this report we demonstrate that lowering of postprandial hyperglycaemia resulting in a decreased 24-h glucose area is associated with attenuated developments of autonomic and somatic polyneuropathies in the BB/W-rat. Materials and m e t h o d s Animals Twelve pre-diabetic male BB/W-rats and six age-matched nondiabetes-prone male BB/W-ratswere obtained from the National Institutes of Health's Colony at the University of Massachusetts, Worcester, Massachusetts, U S A . A t the time of diabetes detection, identified by glucosuria (Test Tape; Eli Lilly Canada Inc., Toronto, Ontario, Canada), diabetic rats were started on small daily doses (0.5-3.0 U/day) of protamine zinc insulin (PZI) (Connaught-Novo Inc., Toronto, Ontario, Canada), in order to prevent ketoacidosis from occurring. The insulin doses were titrated daily based on urine volume and glucose content. Six diabetic and six non-diabetic control rats were given free access to rat chow (Lab Blox F-6; Wayne Animal Diets, Winnipeg, Manitoba, Canada) and water. The remaining six diabetic rats were given rat chow ad-mixed with 20 mg acarbose/100 g chow (BAY g 5421) equivalent to a daily dose of no less than 5 mg/kg body weight. All animals were maintained in airfiltered metabolic cages with a 12-h light cycle. Clinical monitoring Body weight, urine volume, and glucosuria were monitored daily. Blood glucose was measured weekly in tail-vein blood samples by Ames Eyetone (Miles Laboratory Ltd., Rexdale, Ontario, Canada). In addition, non-treated and acarbose-treated diabetic rats were monitored with respect to blood glucose levels at 2-h intervals, for four separate 24 h cycles, one during each month of the 4 month treatment protocol. Glycated haemoglobin was measured in tailvein blood samples every month using an affinity chromatography test kit (Glyco-Test, Pierce Chemical Co., Rockford, Ill., USA). R - B A R monitoring Animals were anaesthetized with diethyl ether (Fisher Scientific Co., Fair Lawn, N J, U S A ) and simultaneous analog movement, E C G and respiration signals were obtained as previously described in detail [ 15, 25 ]. The computed R-statistics ( R - B A R ) defined as the vector mean of the R spikes wrapped around a circle, the circumference of which represents the time of one respiration. Each RB A R value represents the mean of R-BAR's obtained during a 5 min movement free recording. R - B A R data were obtained monthly during the experiment. Nerve conduction velocity Animals were anaesthetized with diethyl ether. Nerve conduction velocity (NCV) was then determined non-invasively in the sciatictibial conducting system in a temperature-controlled environment as previously described in detail [ 13, 17 ]. The left sciatic nerve was stimulated at the sciatic notch and at the ankle with bipolar electrodes using supramaximal stimuli of 8 V. Evoked muscle potentials were collected from the first interosseous space of the hind paw and displayed on an oscilloscope. N C V was calculated by subtracting the distal from the proximal latency, measured from stimulus artifact to take-off of the evoked potential, and divided by the distance between the two stimulating electrodes. Tissue collection Animals were anaesthetized with sodium pentobarbitol (50 mg/kg body weight). The sural nerve of the right side was fixed in situ for 10 min with a cacodylate-buffered (pH 7.40) 2.5 % glutaraldehyde fixative. The sural nerve was then carefully dissected and left in the same fixative for 4 h at 4~ and post-fixed in cacodylate-buffered 1% osmic tetroxide (pH 7.4) for 2 h. The distal portion of the nerve sample was dehydrated in ethanol and embedded in Epon. Ultrathin cross- and longitudinal sections were stained with aqueous uranyl acetate and lead citrate for electron microscopic examination. The proximal portion of the nerve was used for teased fibre preparations in unpolymerized Epon. Structural examinations Myelinated fibre size, fibre density and fibre occupancy were calculated from semi-thin (0.5 gm) toluidine blue-stained sections of the entire sural nerve. The cross-sectional area of each myelinated fibre was digitized and the endoneurial area planimetered with the aid of a Hewlett-Packard computerized digitizer as previously described in detail [ 13 ]. The extent of axonal atrophy was assessed by scoring of teased fibres displaying excessive myelin wrinkling and expressed as a percentage of examined fibres as previously described [ 18 ]. The degree of axonal atrophy was assessed independently by calculating the axon/myelin ratio of a mean of 92 + 6 systematic randomly chosen fibres from each sural nerve. Electron micrographs of cross-sectioned fibres with a magnification of 27,420 times were used to examine the relationship between the natural logarithm of the axonal area and the number of myelin lamellae. This relationship decreases with axonal atrophy. Axonal degeneration was assessed from teased fibre preparations and expressed as a percentage of total fibres. Abnormalities of the node of Ranvier were examined by scoring of teased fibres exhibiting paranodal swelling, paranodal demyelination, and intercalated nodes. All teased fibre abnormalities as well as fibres exhibiting a normal morphology were examined from 106 _+2 ~30 E 20 _= o m 10 5 0 Insulin I I I ~" I I [ [ I I I 10.00 ]2.00 ]4.00 16.00 18.00 20.00 22.0000.00 02.00 04.00 06.00 08.00 Time Fig. 1. The means of 2-h blood glucose levels in six non-treated and six acarbose-treated diabetic BB/W-rats are compared. The data was obtained from four 24-h cycles, hence each data point represents 24 examinations. Acarbose-treated diabetic rats demonstrate a significant reduction in the postprandial glucose levels, most marked during the night hours. The total reduction in glucose area was 40 %. Open circles ( 9 ) represent non-treated diabetic rats and closed circles ( 9 ) acarbose-treated diabetic rats 30.0 > 20.0 er < In 10.0 Duration of diabetes (months) teased fibres per nerve and expressed as a percentage of the total number of teased fibres as previously described [ 18, 26 ]. The frequency of axo-glial dysjunction was examined electron microscopically from a mean of 276 _+14 terminal myelin loops per nerve. The frequency of myelin loops devoid of axo-glial junctions (axo-glial dysjunction) was expressed as a percentage of the total myelin loops [17]. Statistical analysis Data are expressed as means _+SEM. The significance of differences was calculated using Student's paired t-test. Results Clinical findings N o n - t r e a t e d diabetic rats showed the characteristic decline in b o d y weight gain. A c a r b o s e - t r e a t e d diabetic rats showed a b o d y weight gain that was not significantly different f r o m that of n o n - t r e a t e d diabetic rats (Table 1). B o t h acarbose-treated and n o n - t r e a t e d diabetic rats d e m o n s t r a t e d polyuria ( > 30 ml/24 h) and glucosuria ( > 2 g/100ml). In contrast non-diabetic control rats showed a 24-h urinary output of less than 5 ml and no glucosuria. The insulin requirements of n o n - t r e a t e d and a c a r b o s e - t r e a t e d diabetic rats were similar (1.72 + 0.06 U/day vs 1.62 + 0.08 U/day). Weekly blood glucose levels m e a s u r e d at 15.00 hours were similarly increased in b o t h n o n - t r e a t e d and acarbosetreated diabetic rats c o m p a r e d to non-diabetic control rats (Table 1). However, w h e n blood glucose levels were monitored o v e r 24-h periods, a m a r k e d difference e m e r g e d between n o n - t r e a t e d and a c a r b o s e - t r e a t e d rats, the latter showing a 40 % reduction in the 24-h glucose area (Fig. 1). This reduction in blood glucose levels was most m a r k e d during the postprandial night hours and was reflected in lower glycated h a e m o g l o b i n levels in a c a r b o s e - t r e a t e d diabetic rats c o m p a r e d to n o n - t r e a t e d diabetic rats (Table 1). The daily food intake was similar in acarbose t r e a t e d (37.6 g/day) and n o n - t r e a t e d diabetic rats (39.2 g/day), whereas non-diabetic control rats c o n s u m e d s o m e w h a t less (33.8 g/day). A c a r b o s e was well tolerated and t r e a t e d rats only occasionally showed loose stools. R-BAR monitoring T h e vagal autonomic n e u r o p a t h y in the diabetic BB/Wrat is characterized by a progressive decrease in R - B A R values, which p r e c e d e s and accompanies the d e v e l o p m e n t of structural abnormalities [ 16 ]. Four m o n t h s of u n t r e a t e d diabetes showed a progressive decline in R - B A R - v a l u e s to 56 % of n o r m a l values (Fig. 2). A c a r b o s e - t r e a t e d animals showed a significant (p <0.001) and complete prevention of this decrease, suggesting that suppression of postprandial h y p e r g l y c a e m i a had a protective effect on the d e v e l o p m e n t of autonomic neuropathy. N C V monitoring N o n - t r e a t e d diabetic BB/W-rats showed the characteristic decrease in N C V over the 4-month observation period (Fig.3). A similar but milder N C V deficit was noted in a c a r b o s e - t r e a t e d rats which showed significantly faster N C V ' s at months 1, 2, and 3 (p < 0.001) but not after 4 m o n t h s of t r e a t m e n t (Fig. 3). Axonal structural changes M e a n myelinated fibre size was significantly decreased in n o n - t r e a t e d diabetic rats (p < 0.05; Table 2). No protective effect on myelinated fibre size could be d e m o n s t r a t e d following acarbose t r e a t m e n t (Table 2). Fibre density and occupancy showed no change in u n t r e a t e d or acarbose50.0  E 45.0 t,J Z 40.0 9 k ", Duration of diabetes (months) Fig.3. Nerve conduction velocities (NCV) in control, diabetic and acarbose-treated diabetic rats. Acarbose treatment had a partial preventive effecton NCV for 3 months (p < 0.001)but it did not persist at 4 months of diabetes. Triangles (A) represent control rats, open circles ( 9 ) diabetic rats, and closed circles ( 9 ) represent acarbose-treated diabetic rats treated BB/W-rats when c o m p a r e d to non-diabetic control rats (data not shown). M o r e sensitive m e a s u r e m e n t s of axonal atrophy such as excessive wrinkling of myelihated fibres in teased fibre preparations (Fig. 4) and axonmyelin ratio (Fig. 5), showed significant axonal atrophy in non-treated diabetic rats which was significantly but incompletely p r e v e n t e d by acarbose t r e a t m e n t (Figs.4 and 5). Waller degeneration was not affected by acarbose t r e a t m e n t (Table2), whereas the frequency of regenerating fibres was significantly increased (p < 0.001) following acarbose t r e a t m e n t (Table 2). Nodal changes Both h u m a n [ 18 ] and murine diabetes [ 12 ] are characterized by a sequence of nodal neuroanatomical abnormalities consisting of p a r a n o d a l swelling, axo-glial dysjunction, p a r a n o d a l demyelination, and remyelinated, so called intercalated nodes. These sequential changes were all significantly increased in n o n - t r e a t e d diabetic rats (Table 3), and with the exception of axo-glial dysjunction were all completely p r e v e n t e d by acarbose treatment. Although the frequency of axo-glial dysjunction was decreased by almost 40 % (Fig. 6) following acarbose treatment, it was not completely p r e v e n t e d by lowering of postprandial hyperglycaemia. D i s c u s s i o n A c a r b o s e is a pseudotetrasaccharide that acts as a competitive inhibitor of pancreatic c~-amylase and several intestinal a-glucosidases but with a particular affinity for sucrase. W h e n given orally together with carbohydrates it prevents glucose u p t a k e and decreases the postprandial increase in blood glucose [ 21, 23, 24 ]. T h e remaining unabsorbed carbohydrates are degraded by microorganisms in the large bowel. As expected from the action of acarbose, the present study resulted in a substantial decrease of postprandial hyperglycaemia that was reflected by a 40 % reduction of the 24-h glucose area. It is therefore likely that long-term t r e a t m e n t with this c o m p o u n d will decrease the magnitude of cumulative hyperglycaemia believed to be a m a j o r risk factor in the d e v e l o p m e n t of secondary diabetic complications [ 2, 3 ]. In keeping with this notion, previous studies on the effect of acarbose have d e m o n s t r a t e d decreased glomerular mesangial expansion and reduced deposition of glomerular immunoglobulins in kidneys of diabetic db/db mice [27]. A c a r b o s e also reduces non-enzymatic glycation and the formation of a d vanced glycation end products in extracellular matrices such as the glomerular b a s e m e n t m e m b r a n e [ 28 ]. Diabetic neuropathies are believed to be initiated by hyperglycaemia and its effect on the polyol pathway leading to secondary abnormalities of myo-inositol m e t a b o lism and N a / K - A T P - a s e activity in peripheral nerve [ 2, 7 ]. We have previously d e m o n s t r a t e d that interventions aimed at correcting various steps of this cascade of m e t a bolic abnormalities in the BB/W-rat result in acute normalization of biochemical and functional abnormalities [ 26, 29, 30 ], and in long-term studies prevention of structural abnormalities [ 31, 32 ]. T h e s e interventions have included normalization of hyperglycaemia with vigorous insulin therapy, aldose reductase inhibition with normalization of the polyol pathway as well as myo-inositol supplementation. In the present study the reduction of the total glucose load on peripheral nerve, achieved mainly by lowering the 20 g = e" m ._= > o X W .E lo* T Control Diabetic Diabetic + Acarbose Fig.4. The frequency of excessive myelin wrinkling, a measure of the extent of axonal atrophy, is compared in control, diabetic, and acarbose-treated diabetic rats. Acarbose treatment resulted in a significant 55 OYoreduction of excessive myelin wrinkling :r p < 0.001 vs control and acarbose-treated rats; and **p < 0.001 vs diabetic rats Fig.5. Acarbose-treated diabetic rats (b) showed a significant but partial (p < 0.05) prevention of the characteristic decrease in axon/myelin ratio compared to diabetic rats (c) indicating a less severe axonal atrophy. However, both acarbose-treated (b), and diabetic rats (c) showed lower axon-myelin ratios than control rats (a) (p < 0.005 andp < 0.001 respectively) hyperglycaemic p e a k during postprandial night hours, resulted in similar effects as those previously described. Although the affinity of aldose reductase, the key e n z y m e in the polyol pathway, is low for glucose, the level of hyperglycaemia in the n o n - t r e a t e d BB/W-rat is sufficient to significantly increase the concentration and the activity of the aldose reductate e n z y m e and to enhance polyol pathway activity [ 33 ]. T h e lowering of cumulative hyperglycaemia in the present study, particularly the reduction of the night hours' peaks, m a y therefore be sufficient to substantially reduce the activity of the polyol pathway and t h e r e f o r e p r e v e n t autonomic p o l y n e u r o p a t h y and attenuate the d e v e l o p m e n t of somatic p o l y n e u r o p a t h y in the BB/W-rat. The a u t o n o m i c p o l y n e u r o p a t h y in the BB/Wrat characterized by decreased R - B A R - v a l u e s , was completely p r e v e n t e d by 4 months of acarbose t r e a t m e n t and 5.0 3.0 " t1.0 the somatic p o l y n e u r o p a t h y identified by slowed N C V and characteristic n e u r o a n a t o m i c a l abnormalities was partially p r e v e n t e d by the s a m e regimen. This discrepancy in the effect of acarbose on autonomic vs somatic p o l y n e u r o p a t h y in the BB/W-rat is consistent with develo p m e n t of somatic p o l y n e u r o p a t h y m o r e easily c o m p a r e d to autonomic p o l y n e u r o p a t h y under similar hyperglycaemic conditions in this animal m o d e l [ 12 ]. Axonal atrophy, a characteristic lesion of b o t h murine and h u m a n diabetic somatic p o l y n e u r o p a t h y [ 13, 19, 20 ], was m a r k e d l y but incompletely p r e v e n t e d by acarbose. This is in a g r e e m e n t with a complete prevention of axonal atrophy following long-term t r e a t m e n t with an aldose reductase inhibitor in the BB/W-rat and a significant imp r o v e m e n t of axonal atrophy in h u m a n diabetic neurop a t h y following 18 months of aldose reductase inhibitor t r e a t m e n t [ 31, 33, 34 ]. Similarly the increase in the frequency of regenerating fibres in a c a r b o s e - t r e a t e d rats parallels the findings following other modes of metabolic correction of the diabetic nerve [ 31, 32 ], suggesting that the consequences of hyperglycaemia deprives the diabetic nerve of its regenerative capacity. In conclusion, the present study has d e m o n s t r a t e d that acarbose effectively reduces postprandial hyperglycaemia in the spontaneously diabetic BB/W-rat, and that this effect retards the d e v e l o p m e n t of diabetic n e u r o p a t h y in this animal model, indicating that the magnitude of cumulative hyperglycaemia is a m a j o r factor in the developm e n t of diabetic neuropathies. Acknowledgements. This study was supported in part by grants from Miles, Inc., New Haven, Connecticut, USA, the Canadian Medical Research Council (MT-10673,MA-10674) and National Institutes of Health (DK-38304). The authors are indebted to Ms. E. Moore for preparing the manuscript. R e f e r e n c e s Prof. A. A. E Sima Michigan Diabetes Research and TrainingCenter The Universityof Michigan 1331 East Ann Street Box 0580 Ann Arbor, MI 48109 USA 1. Melton LJ , Dyck PJ ( 1987 ) Epidemiology . In: Dyck PJ , Thomas PK , Asbury AK , Winegrad AI , Porte D Jr (eds) Diabetic neuropathy . 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A. A. F. Sima, S. Chakrabarti. Long-term suppression of postprandial hyperglycaemia with acarbose retards the development of neuropathies in the BB/W-rat, Diabetologia, 1992, 325-330, DOI: 10.1007/BF00401199