Diet and oral agents in diabetes therapy

ORA-004-001 EFFECTS OF DIETARY OMEGA 3 FATTY ACID ON MEMBRANE COMPOSITION AND GLYCAEMIC CONTROL IN ANIMAL MODELS OF TYPE I AND TYPE II DIABETES

SULLIVAN D, YUE D, CAPOGRECO C, McLENNAN S, NICKS J, COONEY G, TURTLE J and HENSLEY W. Departments of Clinical Biochemistry and Endocrinology, Royal Prince Alfred Hospital, Sydney Australia.

Marine omega 3 fatty acids (w3 FA) have been shown to increase insulin sensitivity. This study was designed to investigate the effects of w3 FA on erythrocyte membrane FA composition and diabetic control in animal models of type I (etreptozotocin rat) and type II (gold thioglucose injected CBA/T6 mice) diabetes. Normal (N) and diabetic (D) animals were fed fish oil (FO) or corn oil (CO) for 8 weeks at a dosage of 300 ug/day for rats and 100ug/day for mice.

Type I diabetic rats had lower membrane arachidonic acid (N=28.1~4.2%, D=24.9~1.9%, mean~SD) and higher linoleic acid (N=i0.9!2.9%, D=14.7~3.6%). FO caused a significant rise in erythrocyte membrane eicosapentaenoic (EPA} and docoxahaxaenoic (DOC) acid in both N and D rats. The increase occurred at the expense of arachidonic acid and was greater in D rats. FO did not affect glycosylated haemoglobin (GHb) or plasma insulin.

In Type II diabetes, erythrocyte membrane arachidonic acid was higher (N=II.7±2.8%, D=15.2~3.2%) and linoleic acid was lower (N=13.4±2.1%, D=9.7±1.9%). FO treatment also increased membrane EPA and DOC but at the expense of both arachidonie and linoleic acid and the increase was the same in N and D. FO treatment reduced GHb of diabetic animals (CO diabetic=9.5±l.2%, FO diabetic= 6.5!2,9%, p<0.05) and further increased the hyperinsulin- aemia (CO diabetic= 135~40uU/ml, FO diabetic=170±39uU/ml, p<0.05).

These results showed that the incorporation of w3 FA into cell membrane is different in Type I and Type II diabetes. This may be due to difference in the activity of desaturase, an insulin-dependent enzyme which regulates the conversion of FA to arachidonic acid. FO treatment can improve diabetic control in Type II diabetes but this effect may be mediated by increased insulin secretion rather than changes in insulin sensitivity. Supported by an Apex Foundation Grant of the Australian Diabetes Foundation.

ORA-004-002 FRUCTOSE IMPROVES INSULIN SENSITIVITY IN TYPE II DIABETIC PATIENTS

V A KOIVISTO, H YKI-J~VINEN Helsinki University Hospital, II Department of Medicine, Helsinki, Finland

We examined the effect of dietary fructose on metabolic control and insulin sensitivity i 9 i0 type II diabetic patients (age 61~3 yrs, body mass index 27.5ZI.3 kg/m~). The study consisted of two 3-week periods, which were carried out in a double blind, randomized fashion one month apart. During both periods, the patients were hospitalized and were given 20% of total carbohydrate calories (45-64 g/day) either as fructose in juice (fructose period) or complex carbohydrates in food (control period). During fructose diet, fasting blood glucose fell from 9.7Zi.0 mmol/l to 7.5~0.5 mmol/l (p<0.05), C-peptide from 2.5±0.3 ug/l to 2.0±0.2 ug/l (p<0.01), whereas serum insulin, cholesterol and triglyceride levels remained unchanged. During the control diet, fasting blood glucose, C-peptide and insulin levels remained unchanged, whereas serum cholesterol and triglyceride concentrations fell (p<0.02). Insulin sensitivity was determined with insulin clamp technique by maintaining plasma glucose at approximately 7 mmol/l and insulin at 90 mU/l, similarly in each study. During fructose diet, insulin-mediated glucose uptake increased from 3.67~0.30 mg/kg/min to 4.93Z0.75 mg/kg/min (p<0.05), whereas control diet failed to enhance body sensitivity to insulin. Body weight remained unchanged during both diets. In conclusion: I) Dietary fructose ingested on isocaloric basis decreases fasting blood glucose concentrations and enhances body sensitivity to insulin in patients with type II diabetes. 2) Thus, fructose may be a beneficial carbohydrate in the diet of type II diabetic patients.

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ORA-004-003 EFFECTS OF LONG TERN ALPHA-GLUCOSIDASE INHIBITION ON METABOLIC CONTROL, C-PEPTIDE SECRETION, HEPATIC GLUCOSE OUTPUT AND PERIPHERAL INSULIN SENSITIVITY IN TYPE I I DIABETIC PATIENTS.

CH.SCHNACK, R.PRAGER, JOHANNA WINKLER, RENATE KLAUSER AND G.SCHERNlliANER Department of Medicine I I , Division of Endocrinology & Metabolism, University of Vienna, Vienna, Austria

The administration of 1 Desoxynojirimycin, Miglitol (N), a recently developed alpha-glucosidase inhibitor can improve metabolic control in type II diabetic patients, as it was shown in a number of short term studies. In the present report the effects of long term administration of N on blood glucose (Bl) diurnal profiles and HbAIC levels were investigated. In addition the effects of M medication on C-Peptide secretion, hepatic glucose output (determined by tracer techniques using 3H3 glucose) and peripheral insulin resistance (euglycae~ic clamp) were evaluated. 15 type II diabetic patients {mean age 62+_11, mean diabetes duration 10+_5 years~ SD, 8 on insulin and O on sulfonylurea treatment) with moderate metabolic control (HbAIc 7.5 rel~) were treated for 8 weeks with either M (3xlO0 mg) or placebo (P) using a double blind cross-over design. With N medication a significant reduction of postprandial OG levels compared to P was observed (p 0.0025 at g.o0, 10.00, 19.00, 20.00; p 0.05 at 13.00 and 21.00). Fasting BG was not influenced by M treatment. A moderate reduction of HbAIc levels was detected with M medication compared to P (g.5+0.4 vs. IO._OL~0.4, rel %~ SEN; p 0.05). C-Peptide diurnal profiles were not influenced significantly by M administration, no matter whether patients were on insulin or sulfonylurea treatment, However, postprandial C-peptide secretion was significantly decreased by M (p 0.02). Hepatic glucose output both in the basal state (2.45+0.22 (M), 2.5+0.2 (P) mg/kg/min ~ SEN) and during euglycaemic clamp conditions (0.37_+0.13 (M), 0.35+0.19 (P) mp/kg/min +__SEN) was not affected by M treatment. Furthermore peripheral BG disposal rate was not influenced by any intervention (4.5_+0.(3 (N), 4.(_+0.45 (P) mg/kg/min +_SEW}. In conclusion, it was shown that the inhibitory effect of Miglitol on postprandial BG increase persists in longterm treatment associated with decreased C-peptide secretion causing a moderate reduction of HbAIc levels. However, hepatic glucose output and peripheral insulin sensitivity are not influenced by Niglitol long-term medication.

ORA-004-004 E F F E C T S OF A NEW T H E R A P E U T I C TOOL ( D I E T H Y L A M I N O E T H Y L D E X T R A N ) ON I N S U L I N AND P P S E C R E T I O N I N NIDDM P A T I E N T S .

F F A L L U C C A , w~1~l V A S T A , E P U G L I E S I , ~GF D E L L E F A V E , MB A N ~ A L E , M P I T A R O , E S C I U L L O , A F R A N C O , S DE LUCA, A : ~ K L D O I ~ k T O . D i a b e t e s U n l t a n d W G a s t r o e n t e r o l o g y . ~ t , I n s t . C I . M e d l c a 2, L a S a p l e n z a U n i v . , R o m e . W N O s p e d a l e C X v £ 1 e , Urbtno_ I t a l y .

D 1 e t h y l a m l n o e t h y l d e x t r a n (DEAD) i s a d r u g c u r r e n t l y u s e d i n t h e t r e a t m e n t o f h y p e r l i p X d e m i a s a n d r e c e n t l y r e p o r t e d t o i n f l u e n c e c a r b o h y d r a t e m e t a b o l i s m i n n o n d i a b e t i c s u b j e c t s . We s t u d l e d t h e e f f e c t s o f D E A D o n g l u c o s e m e t a b o l i s m , i n s u l i n ( IRI ) a n d p a n c r e a t i c p o l y p e p t i d e (PP) s e c r e t i o n , i n 4 0 N I D D M p a t i e n t s t r e a t e d w i t h d i e t a l o n e ( g r o u p i : t 0 p a t i e n t s ) o r w i t h s u l f o n y l u r e a s ( g r o u p s 2 a n d 3: 15 p a t i e n t s e a c h ) . D E A D w a s a d d e d t o t h e p r e v i o u s t r e a t m e n t i n g r o u p s t a n d 2 ( t .5 g / 2 4 h ) a n d r e p l a c e d s u l ~ o n y l u r e a s i n g r o u p 3 ( 3 g / 2 ~ h ) . E a c h s u b j c t p e r f o r m e d ~ s t a n d a r d b r e a k f a s t s (BTT; 2 0 0 g m i l k + 5 0 g b r e a d ) a t t i m e s 0 , 7, 3 0 d a y s o f t r e a t m e n t a n d 3 0 d a y s a f t e r D E A E D s u s p e n s i o n . I n n i l t h r e e g r o u p s D E A E D t r e a t m e n t w a s a c c o m p a n i e d b y a s i g n i f i c a n t r e d u c t i o n o f p l a s m a c h o l e s t e - r o l a n d t r i g l y c e r l d e s p a s w e l l a s b y a m a r k e d r e d u c t i o n o f I R I l e v e l s , a s s o - c i a t e d w i t h a s i g n i f i c a n t i n c r e a s e o f t h e P P r e s p o n s e t o B T T . A f t e r c o m b i n e d t h e r a p y ( d l e t / O H A +DEAED) , t h e p l a s m a g l u c o s e l e v e l s w e r e s i g n i f i c a n t l y r e d u - c e d a n d t h e s a m e w a s t r u e f o r H b A i c ( g r o u p I: 6 . 8 3 ! 0 . 2 3 v s 7 . 8 1 ± 0 . 2 5 ; g r o u p 2, 7 .95 .*0 .37 v s 8 . 5 4 ± 0 . 3 9 X); t h e s u s p e n s i o n o f D E A E D w o r s e n e d t h e m e t a b o l i c c o n - i r a 1 . T h e m e t a b o l i c c o n t r o l o n 3 g / 2 ~ h DEAED w a s s i m i l a r t o t h a t o n OHA; a s l g - n l f i c a n t I m p r o v e m e n t w a s o b s e r v e d r e a s s u m l n g O H A . I n c o n c l u s i o n D E A E D a l o n e o r i n a s s o c i a t i o n w l t h O H A m a y b e h e l p f u l t o i m p r o v e g l u c o s e m e t a b o l i s m , i n s u l i n r e s i s t a n c e a n d l i k e l y s o m e d a m a g e o f t h e a u t o n o m i c n e r v o u s s y s t e m i n NIDDM,

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ORA-004-005 SULFONYLUREA ENHANCE IN VIVO GLUCOSE DISPOSAL IN NIDDM-PATIENTS IN THE PRESENCE OF UNCHANGED ACTIVITIES OF INSULIN BINDING, RECEPTOR KINASE AND GLYCOGEN SYNTHASE IN SKELETAL MUSCLE

J F BAK, O SCHMITZ, N S S~RENSEN, O PEDERSEN University Clinic of Internal Medicine, Medical Dept. III, Arhus Amtssygehus, Arhus, Denmark.

To elucidate if sulfonylurea mediate their stimulating effect on glucose disposal to peripheral tissues through improved insulin receptor functions and/or increased glucose storage capacity, we have studied the effect of gliclazide in 7 newly diagnosed NIDDM subjects (145+20 % of ideal weight) before and after 8 weeks of glielazide therapy (80 mg x 3, daily). Throughout the study period the patients had unchanged dietary intake and unchanged level of physical activity. Before and after gliclazide therapy, quadrieeps biopsies were obtained at fasting insulinemia and during the euglycemic clamp at a steady state insulin level of 300 mU/l . Glielazide treatment decreased mean diurnal blood glucose (13.1+1.8 vs. 8.8+1.9 retool/I, p<0.01) and HbAlc (9.5_+0.6 vs. 7.5_+0.6 %, p<0.01), whereas mean diurnal plasma insulin level (29.7+5.5 vs. 36.4+7.1 mU/1, p>0.05) increased. The insulin-stimulated glucose disposal rate was increased by gliclazide: 2.7_+0.7 vs. 3.7+0.9 mg/kg /min at 70 mU/ l plasma insulin and 5.7+1.0 vs. 7.6+1.3 mg/kg /min at 300 mU/l hyperinsulinemia (p<0.02) and insulln-inhibited hepatic glucose production was significantly improved (p<0.05). Skeletal muscle insulin binding and receptor kinase-mediated phosphorylation of exogenous peptide were unaffected by gliclazide at both fasting and high steady state plasma insulin levels. Neither did gliclazide have any impact on total activity of muscle glycogen synthase or on sensitivity of the enzyme to glucose-6-phosphate. In conclusion: The effect of sulfonylurea on insulin-stimulated glucose disposal to peripheral tissues in NIDDM patients 1) is expressed in the face of unaltered activities of skeletal muscle insulin receptors, 2) is mediated through an enhanced glucose oxidation and/or glycolysis, rather than an increased glucose storage.

ORA-0(O-006 REDUCTION BY GLIPIZIDE OF THE METABOLIC CLEARANCE RATE OF INSULIN IN TYPE 2 DIABETIC PATIENTS : AN ADDITIONAL MECHANISM FOR THE PHARMACOLOGICAL ACTIVITY OF SULFONYLUREA ?

A.J. SCHEEN, M. CASTILLO, G. PAOLISSO and P.J. LEFEBVRE Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, University of Liege, C.H.U. Sart-Tilman, B-4000 LIEGE 1 , Belgium.

Several studies have shown that gl ip iz ide increases plasma insulin but not C-peptide levels after a meal in type 2 diabetic patients, suggesting that this sulfonylurea compound may enhance availa- b i l i t y of peripheral insulin by extrapancreatic mechanisms. However, the use of the insulin / C- peptide rat io to estimate insulin metabolism has been severely cr i t ized so that more rel iable measurement of the metabolic clearance rate (MCR) of insulin is required. Therefore, we studied the effect of gl ip iz ide on the MCR of insulin measured during a classical 2-hour euglycemic hyper- insulinemic glucose clamp. MCR of insulin was calculated by dividing the constant insulin infu- sion rate (0.1U.kg-l.h-1) by steady-state plasma free insulin levels, after correction for chan- ges in residual endogenous insulin secretion using plasma C-peptide determinations. Ten non obese type 2 diabetic patients recently treated by insulin due to secondary fai lure to oral therapy were studied in a randomized order after two 6-week periods of treatment : either with subcutaneous injections of insulin alone or with insulin plus oral administration of gl ip iz ide 3 x 10 mg/day. When the test was performed after treatment with insulin plus gl ip iz ide and 30 min after ingestion of 10 mg gl ip iz ide, the MCR of glucose was not signif icantly modified but the MCR of insulin was signif icantly reduced from 23.3 ± 2.9 to 18.9 ± 2.0 ml.kg-l.min-1 (P<O.05). Moreover, this reduction was greater (from 21.5 ± 4.5 to 15.0 ± 2.4 ml.kg-l.min-1 , P <0.025) in the five pa- t ients who showed a signif icant fa l l in HbA1c levels during the combined therapy than in the five patients who did not show such an improvement in their metabolic control (from 25.1 ± 4.1 to 22.8

2.0 ml.kg-l.min-1 , N.S.). In conclusion, our results confirm that gl ip iz ide decreases the metabolic clearance rate of insu- l in in non obese type 2 diabetic patients, an effect which may play a role in the hypoglycemic action of this sulfonylurea compound.

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ORA-004-007 A NEW ORAL HYPOGLYCEMIC AGENT, AD-4833, REDUCES INSULIN RESISTANCE IN WISTAR FATTY RAT

H IKEDA, S TAKETOMI, Y SUGIYAMA, T SOHDA, K MEGURO, T FUJITA Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan

Insulin resistance is one of pathogenic factors for non-insulin-dependent diabetes mellitus (NIDDM). AD-4833, 5-(4-[2-(5-ethyl-2-pyridyl)ethoxy]- benzy 0-2,4-thiazolidinediOne, is a promising candidate to lower hyper- glycemia by reducing insulin resistance. The genetically obese-hypergly- cemic rats, Wistar fatty, were used to test the action of AD-4833, because they develop severe insulin resistance in the peripheral tissues (muscle and adipose tissue) and liver. AD-4833 administered orally (0.3-3 mg/kg/ day for 7 days) reduced hyperglycemia, hyperlipidemia, and hyperinsulinemia in male fatty rats in a dose-dependent manner. AD-4833 improved glucose tolerance and glycemic response to exogenous insulin, increased overall clearances of glucose and triglyceride, and decreased hepatic glucose production. These effects on glucose and lipid metabolism seem to be due to increased insulin sensitivity and responsiveness in the peripheral tissues and liver, because AD-4833 increased insulin-stimulated glycogen synthesis and glycolysis in the isolated soleus muscles, and insulin- stimulated glucose oxidation and lipogenesis in adipocytes. The latter effects were not accompanied by any changes in insulin binding. The actions of insulin mimickers (vanadate and vitamin K5) , which act on post-insulin binding sites, on these metabolic events were also potentiated by AD-4833. These findings suggest that AD-4833 can improve glucose and lipid metabolism by reducing insulin resistance on the post-binding system. Therefore, AD-4833 may be efficacious for treating NIDDM.

ORA-004-008 EFFECT OF A VASCULAR-PROTECTING VENOTONIC AGENT ON ABNORMAL CAPILLARY PERMEABILITY TO ALBUMIN IN THE DIABETIC PATIENT.

P. VALENSI, A. BEHAR, M. de CHAMPVALLINS, F. COHEN BOULAKIA, J-R. ATTALI. Unit~ de diab&tologie, Universit~ PARIS NORD, BObigny, M~decine Nucl~aire, HOPITAL BROUSSAIS, Paris. IRIS, Neuilly-sur-Seine. FRANCE.

The aim of this work was to test the effect of a venotonic agent with vascular-protecting properties on capillary permeability to albumin with a method derived from the Landis test, using 99 m technetium-labelled albumin. Albumin retention was measured by external detection (residual radioactivity after removal of venous compression). The Fast Fourier Transform of the radioactivity disappearance curve reflects the lymphatic resorption of albumin (reproducibili ty shown in i0 controls by the good correlation between 2 tests carried out less than 2 months apart : p <0.001). Eleven patients (7 NIDD and 4 IDD), with ages ranging from 39 to 67 years, diabetic for 1 to 19 years, were treated for 28 to 40 days with 5682 SE (450 mg Diosmine + 50 mg Hesperidine) 2 Tab/day. Seven patients had diabetic retinopathy, 1 had proteinuria, 7 peripheral neuropathy, and 6 were well-controlled hypertensive patients. If antidiabetic or antihypertensive treatment was being given at the time it was continued during the test. Albumin retention always abnormal at the start (~8 %), became normal in i0 patients and improved in 1 patient. The initially abnormal lymphatic resorption in i0 patients became normal in 4 patients. In another group of 15 diabetic patients not being treated with a vascular protector, the initially abnormal test remained abnormal 5 to 48 months later. These results suggest that an increase in capillary permeability to albumin can be corrected with this venotonic agent even in diabetics with microangiopathy. A study with controls is now being done.

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