Diabetologia 9 Springer-Verlag 1991
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- Alicia Gilbert
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1 Diabetlgia (1991) 34:23% X Diabetlgia 9 Springer-Verlag 1991 Reduced glycgen synthase activity in skeletal muscle frm bese patients with and withut Type 2 (nn-insulin-dependent) diabetes mellitus P. Damsb 1,. Vaag 2,. Hther-Nielsen I and H. Beck-Nielsen 2 L Hvid6re Hspital, Klampenbrg and 2 Department f ndcrinlgy, dense University Hspital, Denmark Summary. In rder t evaluate the imprtance f a defect in insulin mediated nn-xidative glucse metablism and glycgen synthase activity in skeletal muscles in bese subjects with and withut Type 2 (nn-insulin-dependent) diabetes mellitus we studied: 10 lean and 10 bese cntrl subjects and 12 bese diabetic patients using the euglycaemic hyperinsulinaemic clamp technique (basal, 20 mu. (m 2) 1. min-1, 80 mu-(m0-1.min -1) in cmbinatin with indirect calrimetry. Muscle bipsies were taken frm m. vastus lateralis at each insulin level. We fund that nn-xidative glucse metablism culd be stimulated by insulin in all three grups (p < 0.01). The values btained at the highest insulin levels (arund 140 gu/ml) were lwer in bth bese grups cmpared t the lean cntrl subjects (118+21, , mg. (m 1 min ~ (p < 0.01) ). Insulin stimulatin f the glycgen synthase activity at a glucse-6-phsphate cncentratin f 0.1 mml/1 was absent in bth bese grups, while activities increased significantly in the lean cntrl subjects ( % t %, p < 0.01). Glycgen synthase activities at the highest insulin cncentratins nly differed significantly between lean cntrl subjects and bese diabetic patients (45 + 7% and %, p < 0.05). We cnclude that insulin resistance in peripheral tissues in bese subjects with and withut Type 2 diabetes may be partly explained by a reduced insulin mediated nn-xidative glucse metablism and that this abnrmality might be due t an absent insulin stimulatin f glycgen synthase in skeletal muscles. This enzyme defect is crrelated t besity itself. Key wrds: Type2 (nn-insulin-dependent) diabetes, besity, insulin resistance, nn-xidative glucse metablism, skeletal muscle, glycgen synthase. Insulin resistance in peripheral tissues f bese patients with Type 2 (nn-insulin-dependent) diabetes mellitus is reflected in bth reduced glucse xidatin and reduced nn-xidative glucse metablism [1-7]. The abnrmal nn-xidative glucse metablism seems t play the quantitatively mst imprtant rle [8, 9] and has furthermre been demnstrated in first degree relatives t Type 2 diabetic patients [10]. Therefre, this defect culd be f primary rigin. The key enzyme in this metablic pathway in skeletal muscle is glycgen synthase [11, 12], and has been fund t crrelate psitively t nn-xidative glucse metablism [13]. Glycgen synthase activity is reduced in bese Type 2 diabetic patients after a meal [14], and recently the imprtance f this defect fr the develpment f insulin resistance was further emphasized when it was shwn that patients with lw insulin-mediated glucse dispsal had a lwer glycgen synthase activity than lean subjects with nrmal glucse dispsal [15]. Whether this defect in glycgen synthase activity is due t besity itself r a characteristic feature in bese Type 2 diabetic patients remains unanswered. nther imprtant questin is whether the glycgen synthase defect is f primary rigin r a secndary event due t metablic abnrmalities such as high plasma glucse and nn-esterifled fatty acid (NF) values. T eliminate this "metablic insulin resistance", plasma glucse and NF values are generally nrmalized by acutely raised plasma insulin cncentratins. The questin is, hwever, whether this rapid increase in plasma insulin is able t reverse a metablic insulin resistance? If nt, a primary r secndary defect in glycgen synthase activities may nt be revealed by this methd. The purpse f ur study, therefre, was t investigate: 1. whether nn-xidative glucse metablism and glycgen synthase activity in skeletal muscle at physilgical insulin cncentratins was reduced in bese Caucasians with Type 2 diabetes, 2. whether these defects culd be explained by besity itself, and
2 24 3. whether the defects culd be vercme by an 8 h pre-investigatin perid with nrmalized plasma glucse values. Subjects and methds Subjects Twelve newly diagnsed bese patients with Type 2 diabetes (D) were studied and cmpared t 10 bese cntrl subjects (C), and 10 lean cntrl subjects (LC). The cntrl subjects were matched fr age and sex and had nrmal glucse tlerance and n family histry f diabetes. Clinical data are presented in Table 1. N patient had received any kind f anti-diabetic medicine, and nne suffered frm liver r kidney disease as evaluated by clinical and standard labratry examinatins. Nne had received any medicatin which is knwn t influence the glucse r lipid metablism. Prir t participatin the purpse and risks f the study were carefully explained t all the subjects and their infrmed cnsent was btained. The prtcl was apprved by the lcal thical Cmmittee f Cpenhagen and is in accrdance with the Helsinki Declaratin. Study prtcl Patients were admitted t the hspital in the evening befre the day f the study and cnnected t a glucse cntrlled insulin infusin system (Bistatr, Life Science Instruments, Miles Lab., lkhart, Ind., US). catheter was inserted int a drsal wrist vein fr cntinuus bld sampling and bld glucse analyses. Bld glucse was nrmalized befre midnight thrugh insulin infused via a catheter inserted int an antecubital vein in the cntralateral arm. The glucse analyser f the bistatr was calibrated hurly thrughut the night using a Beckman glucse analyser (Beckman Instruments, Fullertn, Calif., US). Bld glucse was clamped at retl/1 thrughut the night. In the mrning a blus f 25 gci 3-3H-glucse fllwed by a cntinuus infusin (0.25 gci/min) was given in rder t assess ttal glucse dispsal (Rd) [16]. uglycaemic hyperinsulinaemic clamp. Insulin infusins were perfrmed at three levels by a mdificatin f the technique f DeFrnz [17]. fter 2 h f tritiated glucse infusin, all subjects were studied fr 30 rain at their basal insulin levels. uglycaemia in diabetic patients was maintained by means f an insulin infusin (ctrapid, Nv, Bagsvaerd, Denmark) which was necessary t vercme the individual insulin resistance. and 2 (20 and 80 mu. (m e) - 1. rain i) were perfrmed by cntinuus insulin infusin. These insulin levels were chsen in rder t stay clse t physilgical insulin cncentratins fund in bese Type 2 diabetic patients. uglycaemia was maintained by an infusin f 20% glucse by the Bistatr (mde 7:0) and external infusin pumps (Infusmat). When glucse infusin frm the Bistatr exceeded 150 mg/min fr mre than 3 rain an external glucse infusin was started r increased by 100 mg/min. fter 120 rain f insulin infusin, the subjects were cnsidered t be in a cnditin f steady-state and the results presented are mean values fr the fllwing perid f 30 min, with bld samples cllected every 10 rain. Glucse dispsal. Ttal glucse dispsal (Rd) was calculated frm the plasma cncentratins f tritiated glucse and plasma glucse using Steele's nn-steady situatins equatin [18]. t the highest insulin level when the glucse prductin frm the liver presumably is zer, glucse infusin rates (GIR) were used t calculate glucse dispsal (Rd). Glucse and lipid xidatin. Indirect calrimetry was perfrmed using a cmputerized flwthrugh canpy gas analyser system (Deltatrac Metablic Mnitr, Datex Instr. Crp., Helsinki, Finland). Briefly, air is sucked at a rate f 40 l/rain thrugh a canpy placed ver the head f the subject. Samples f the inspired and expired air R Damsb et al.: Glycgen synthase in besity and diabetes Table L Clinical data f the grups studied Lean bese bese cntrl cntrl diabetic subjects subjects patients Sex (M/F) 7/3 7/3 10/2 ge (years) 51 (42-62) 47 (39-71) 51 (41-59) BMI (kg/m 2) 22.2 _ a a Fasting Plasma glucse (retl/l) _ _+ l b Plasma insulin (gu/ml) a a Fasting plasma glucse and insulin values were sampled n the mrning f the day befre the study a p < 0.01 cmpared t lean cntrl subjects; b p < 0.01 cmpared t lean and bese cntrl subjects are analysed fr xygen cncentratin using a paramagnetic differential xygen sensr and fr carbn dixide using an infrared carbn dixide sensr. Signals frm the gas analysers are prcessed by the cmputer, and xygen cnsumptin and carbn dixide prductin are calculated and recrded nce a rain. fter an equilibratin perid f 10 rain the average gas exchanges in the 30 min study perid were used t calculate rates f glucse xidatin and lipid xidatin. Nitrgen excretin was assessed frm urine samples thrughut the study perid and crrected fr changes in pl size [19]. Glucse, lipid and prtein xidatin was calculated frm Frayn's equatin [20]. Nn-xidative glucse dispsal was calculated as: Rd - xidized glucse, and expressed in units f rag- (m 2) - 1. rain- 1. Muscle bipsies. t the end f each study perid (basal, clamp 1 and clamp 2) a muscle bipsy was taken frm m. vastus lateralis 20 cm abve the knee, under lcal anaesthesia (2% lidcaine withut epinephrine) using a mdified BergstrCm needle (Stille-Werner, Cpenhagen, Denmark). Bipsies were immediately (within 20 s) frzen in liquid nitrgen. Befre the enzyme analyses muscle bipsies were freeze-dried and micrdissected free frm nn-muscle cnstituents (bld, fat and cnnective tissue). Thereafter, the muscle fibers were hmgenized and assayed by a mdificatin f the methd f Thmas et al. [14]. Briefly, glycgen synthase activity was estimated by incubatin f hmgenates with 14C-UDPG (0.3 mml/i) using glucse-6-phsphade (G6P) cncentratins f 0.0, 0.1 and 10.0 retl/1. nzyme activity was expressed as nml f 14C-UDPG incrprated int glycgen per rain per mg prtein extract. Maximal enzyme activity was determined at saturating cncentratins f G6P (10 retl/l). Fractinal velcity f glycgen synthase was calculated as a percentage f maximal activity. Bld samples. catheter was inserted int a hand vein in the cntralateral arm f the arm infused with insulin and glucse, and the hand was placed in a heated bx thrughut the study. Bld sampies were cllected befre the 3-3H-glucse infusin was started and every 30 rain, except during the study perids when sampling was made every 10 rain. Bld samples were cllected in fluride treated tubes fr determinatin f plasma glucse and plasma 3-3H-glucse activity, and in 2 ml aprtenin-heparin tubes fr determinatin f plasma insulin, C- peptide, and in ptassium-dt tubes fr determinatin f NF. Fr determinatin f plasma lactate 2 ml bld was precipitated in perchlric acid. Bld samples were immediately centrifuged at 5~ and plasma stred at - 70~ until assay. Plasma glucse was analysed by a rutine glucse xidase methd. Tritiated glucse was analysed as previusly described [21]. Plasma insulin [22], and C- peptide [23] cncentratins were measured with radiimmunlgi-
3 R Damsb et al.: Glycgen synthase in besity and diabetes 241 cal methds. Plasma NF and lactate were determined with a cmmercial kit using an autmated analyser (Cbas Mira, Rche, Basel, Switzerland). Statistical analysis Nn-parametric statistics were used: Mann Whitney test fr unpaired data and Wilcxn test fr paired data, and Spearmann test fr crrelatin analyses. significance level f 0.05 was chsen. ll values are presented as means SM unless therwise indicated..c_ T T Results U~ Plasma insulin 0 _= 10 The values achieved during the insulin infusins are shwn in Table 2. The basal insulin level in D was determined by the insulin infusin rate necessary t keep the diabetic patients nrmglycaemic. Insulin values btained at the highest clamp level were nt statistically significantly different between the three grups (p > 0.1). Rates f ttal glucse dispsal and glucse xidatin Values during each study perid are shwn in Table 3 and Figure 1. Bth glucse dispsal and xidative glucse metablism increased statistically significantly (p < 0.01) Table 2. Plasma insulin cncentratins (btu/ml) during euglycaemic hyperinsulinaemic clamp Lean bese bese cntrl cntrl diabetic subjects subjects patients Basal insulin 9.2 _ ~ b 20 mu- (m z) - 1. min _ mu- (m2)-~.min a p < 0.05; b p < 0.01 cmpared t lean cntrl subjects Table3. Glucse turnver (mg.(m2)-l.min -~) during the last 30 rain f: basal perid, clamp 1 and clamp 2, respectively Lean bese bese cntrl cntrl diabetic subjects subjects patients Basal Glucse level dispsal Glucse xidatin _ Glucse dispsal _+ 11 a 94 _+ 9 ~ Glucse xidatin 113 _ ~ Glucse dispsal _+ 35 a a, b Glucse xidatin c 97 8 a' b p < 0.01 cmpared t lean cntrl subjects; b p < 0.05 cmpared t bese cntrl subjects; c p < 0.05 cmpared t lean cntrl subjects LC C D Basal LC C I3 LC C D Fig. 1. Ttal glucse dispsal rate (rag- (m 2) 1. rain- ~) during basal perid, clamp I and clamp 2, in lean cntrl subjects (LC), bese cntrl subjects (C) and bese Type 2 (nn-insulin-dependent) diabetic patients (D). r-~ Nn-xidized glucse; ~ xidized glucse; * p < 0.01 cmpared t LC; +p < 0.05 D cmpared t C frm the basal state t each f the hyperinsulinaemic levels except fr the first insulin level in D (p > 0.5). t the highest insulin cncentratin bth bese grups had a statistically significant lwer ttal glucse dispsal and glucse xidatin than LC (p < 0.01). Nn-xidative glucse metablism Nn-xidative glucse metablism was increased abut ten-fld frm basal t the highest insulin level in LC, whereas the increases in C and D were abut six- and fur-fld, respectively (Fig. 1). In all three grups the increase was statistically significant (p < 0.01). t the highest insulin level the nn-xidative glucse metablism was significantly lwer in D cmpared t C (p <0.01) which again was lwer than in LC (p < 0.01). Nn-ester fatty acids ( N F ) Befre the study NF was significantly higher (p < 0.05) in D ( mml/1) cmpared t bth C and LC ( and 0.61 _ retl/l). NF were similar t cntrl subjects after nrmalizatin f bld glucse during the night (Fig. 2). During the clamp study insulin did nt suppress NF t the same degree in the bese grups as in the lean cntrl subjects (Fig. 2). t the highest insulin level NF cncentratins were suppressed t the same level in bth bese grups but were significantly higher than the lean cntrl subjects (D: , C: , LC: mml/1, p < 0.05). Lipid xidatin In LC lipid xidatin was suppressed with increasing insulin cncentratins (37 + 3, and rag. (m 2) -1. rain 1, p < 0.01). C shwed a minr suppressin which
4 242 R Damsb et ai.: Glycgen synthase in besity and diabetes 1.0 ~" ~ Fasting Night Basal Clamp I Fig. 2. Plasma NF (mml/1) the day befre the study (fasting), between and hurs in the mrning befre the study (night), and during basal perid, clamp i and clamp 2 level. *p < 0.01 cmpared t lean cntrl subjects; +p < 0.02 cmpared t bese cntrl subjects; czlean cntrl subjects; ~ bese cntrl subjects; bese diabetic patients TT[ 4 'C: l 3 2 e.. " "~ 1.'r.. --I LC C Basal D l LC C D I LC C D Fig.3. Lipid xidatin (mg. (m 2)- ~. min-~) during basal perid, clamp I and clamp 2 in lean cntrl subjects (LC), bese cntrl subjects (C) and bese Type 2 (nn-insulin-dependent) diabetic patients (D). * p < 0.01 cmpared t LC was nly statistically significant at high insulin cncentratins (39+3, 32+4 and 20+3mg.(m 2)-l.min-~, p <0.01), while D attained n statistically significant suppressin (36 + 4, and mg. (m 2)- ~. rain ~, p < 0.5) (Fig. 3). Glycgen synthase activity Maximal glycgen synthase activity (i. e. with 10 mml/1 G6P) did nt differ statistically significantly between the grups (LC: 4.9 +_ 0.9, C: , D: nml. min 1 mg prtein -1, p > 0.2) as seen in Figure 4. The maximal glycgen synthase activities remained unchanged during insulin infusins. Insulin increased fractinal velcities f glycgen synthase activity frm basal t the highest insulin level, measured withut G6R in LC ( % t %,p < 0.01) and in C (3.9 +_ 0.9% L g'; ~'~ " 5- l! % 8 g 9 III 0,,, = LC C D Fig.4. Individual values f maximal glycgen synthase activities (10 mml/1 glucse-6-phsphate (G6P)) at the basal insulin level, in lean cntrl subjects (LC), bese cntrl subjecsts (C), and bese diabetic patients (D). N statistically significant difference was fund between the three grups (p > 0.2) --~ 16 m q 9~ 12 gn 8 ~u. e- 4 r 0 I I I I I I I Plasma insulin ( U/ml) lq'ig. 5. Glycgen synthase activity, fractinal velcities (%) when n glucse-6-phsphate (G6P) was added t the suspensin. t the highest insulin level a significant difference was fund between lean cntrl subjects and bese diabetic patients (p < 0.05). /x Lean cntrl subjects; 9 bese cntrl subjects; 9 bese diabetic patients t %, p < 0.05), whereas n statistically significant stimulatin was seen in D ( % t 6.8 _+ 1.1%, p > 0.5). The maximal respnse (glycgen synthase fractinal velcity at highest insulin levels) were significantly lwer in D cmpared t LC (p < 0.05), whereas C vs D r C vs LC did nt differ (p > 0.1) as seen in Figure 5. Studying glycgen synthase activity at physilgical G6P cncentratins f 0.1 mml/1 (Fig.6), we fund a similar pattern except fr the C. N statistically significant stimulatin by insulin was seen in C and D (p > 0.1) but was bserved in LC (p < 0.01). t the highest insulin values, glycgen synthase activity was significantly
5 R Damsb et al.: Glycgen synthase in besity and diabetes ~" 3 ~ r u. 20 a 20 =5 ~ 10, 9 & Ill I I I I I I I Plasma insulin (pu/ml) Fig.6. Glycgen synthase activity, fractinal velcities (%) at physilgical glucse-6-phsphate (G6P) cncentratins (0.1 mml/1). t the highest insulin level a significant difference was fund between lean cntrl subjects and bese Type 2 (nn-insulin-dependent) diabetic patients (p < 0.05). /x Lean cntrl subjects; 9 bese cntrl subjects; 9 bese diabeticpatients Nn-xidative glucse metablism (mg. (m2) -l'min "1 ) Fig.8. The relatinship betweenincrease in glycgen synthase activity fractinal velcities (glucse-6-phsphate (G6P) 0.1 mml/1) and increase in nn-xidative glucse metablism during insulin infusins frm basal t high insulin level. Lean cntrl subjects; 9 bese cntrl subjects; 9 bese diabetic patients._> " x r r 50 :1 :51: 1' Glucse-6-Phsphate (mml/i) Fig. 7. llsteric activatin f glycgen synthase in the basal perid, calculated as the percentage f maximal activity in all three grups. Glycgen synthase activity analysed with n glucse-6-phsphate added, 0.1 mml/1 and 10 retl/1. N difference was fund between the three grups, Ds0 = 0.6 mml/l (p > 0.2). /x Lean cntrl subjects; bese cntrl subjects; 9 bese diabetic patients 3 ~>~ 2 ~n D. g'= &9 0 s s =" BMI (kg/m 2) 4'0 & Fig. 9. The relatinship between increase in glycgen synthase activity fractinal velcities (glucse-6-phsphate (G6P) 0.1 mml/1) during insulin infusin frm basal t high insulin level and besity expressed as BMI (kg/m2). ~ Lean cntrl subjects; bese cntrl subjects; 9 bese diabetic patients lwer in D cmpared with LC (p < 0.05) with C in between. The allsteric activatin f glycgen synthase by G6P is indicated in Figure 7 and shws that half maximal stimulatin f the enzyme seems t be btained by the same cncentratin f G6P (Ds0 = 0.60 mml/1) in LC, C and D (p > 0.2). In rder t investigate the imprtance f glycgen synthase activity (0.1 mml/1 G6P) in skeletal muscle fr systemic nn-xidative glucse metablism, we crrelated the insulin-stimulated increases f these tw variables during insulin stimulatin in all three grups, and fund a psitive crrelatin f r = 0.52 (p < 0.005). N statistical crrelatin was fund in any f the subgrups (Fig. 8). Since a reduced glycgen synthase activity seems t be linked t the tw bese grups, we crrelated the insulin mediated increase in glycgen synthase activity with BMI and fund a significantly negative crrelatin r = (p < 0.004) (Fig. 9). N statistically significant crrelatin was present in any f the subgrups.
6 244 Discussin Pr metablic cntrl in Type 2 diabetic patients resulting in hyperglycaemia and high cncentratins f NF, are presumably factrs prnuncing cellular insulin resistance (metablic insulin resistance) [3], and reducing glucse dispsal [3, 25]. Remval f these factrs pens the pssibility f investigating the effect f insulin alne n intracellular glucse metablism and the enzyme activities invlved. In this study a small insulin infusin nrmalized plasma glucse at 5 mml/1 fr 8 h prir t the investigatin, and lwered plasma NF in the diabetic patients t the same level as in the cntrl grups. During the euglycaemic hyperinsulinaemic clamp we fund that nn-xidative glucse metablism and glucse xidatin were nt stimulated t the same degree in bese subjects (C and D), as in lean subjects (LC), and lipid xidatin was hardly suppressed in the bese subjects. The quantitative majr defect in glucse dispsal was due t reduced nn-xidative glucse metablism. ssayed in the presence f physilgical G6P values, glycgen synthase activity was nt stimulated by physilgical insulin cncentratins in C and D. The dse respnse curves in the tw bese grups seemed parallel and were shifted t the right cmpared t lean cntrl grups. Glycgen synthase activity is crrelated t nnxidative glucse metablism and BMI, and the defect in this metablic pathway seems mainly t be linked t besity itself. Despite nrmal plasma glucse and NF values fr 8 h prir t the investigatin, bth lipid and glucse xidatin were fund t be insulin resistant during the study perid. Lipid xidatin was ttally suppressed in LC but nly suppressed by 50% and 25% in C and D, respectively. The enhanced lipid xidatin in the bese subjects inhibits glyclysis and might inhibit glucse strage thrugh negative feedback [7]. These data indicate that insulin resistance in the bese subjects was prbably nt secndary t metablic derangements, but may represent a primary (nt metablic) intracellular defect. The tendency, hwever, t a lwer nn-xidative glucse metablism and glycgen synthase activity in D cmpared t the findings in C may be f metablic rigin. Thus, the defect in insulin stimulatin f glycgen synthase activity in skeletal muscle is assciated with besity itself, but may be wrsened by metablic abnrmalities as seen in D. The vernight induced hyperinsulinaemia (per se) in the diabetic patients, culd be claimed t influence the glycgen synthase activity in this grup. Nne the less, the insulin sensitivity f this enzyme is extremely lw in Type 2 diabetic patients, and since an increase in plasma insulin f 10 gu/ml results in very small increases in glycgen synthase activity in LC, the hyperinsulinaemic effect in D (frm 22 ~tu/ml t 32 ~tu/ml) is unlikely t influence the enzyme activity during the night. It is mre likely, thugh, that muscle bipsies if taken during fasting hyperglycaemia, as in previus studies [13, 14], might increase glycgen synthase activity thrugh an increase in the allsteric activatin by G6P, and thereby partly cnceal an insulin effect n the enzyme. R Damsb et al.: Glycgen synthase in besity and diabetes The sensitivity f glycgen synthase t G6P in the basal state was fund t be identical in all three grups studied, leading us t the cnclusin that the allsteric activatin f the enzyme by G6P was nrmal. The finding f a mre prnunced defect in glycgen synthase fractinal velcity, when studied withut G6R cmpared t the results btained at 0.1 mml/1 f G6P supprts this cnclusin. Hyperglycaemia, in viv, partly cmpensates fr insulin resistance in Type 2 diabetic patients [14]. This cmpensatin culd be accmplished by an increase in allsteric activatin f glycgen synthase by G6R which is supprted by the nrmal t increased G6P cncentratins fund in Pima Indians [15]. In accrdance with this a defect in the glycgen synthase phsphatase has been prpsed [15, 26] and may be the lcatin f a primary defect. The defect in glycgen synthase activatin, hwever, culd als be due t an insulin receptr defect, but insulin receptr number has been fund t be nrmal in bese diabetic patients, whereas the kinase activity f the insulin receptr has been fund t be abnrmal [27-29]. Until nw, hwever, n crrelatin between glycgen synthase and insulin receptr kinase activity has been shwn. n the basis f this it is reasnable t hypthesize that the defect in insulin-stimulated glycgen synthase activity culd be due t an increased lipid xidatin in bese subjects, and furthermre a defect in glycgen synthase phsphatase in diabetic patients. Whether this defect is linked t a reduced insulin receptr kinase activity (r vice versa) has still t be studied, althugh the receptr kinase defect has been fund t be reversible in fat cells after weight lss [30], indicating that this defect is f secndary rigin. BMI was, in ur study, fund t crrelate negatively t the activity f glycgen synthase, indicating that besity itself may play a rle fr the enzyme defect. In supprt f this upper bdy besity has been fund t be crrelated t glycgen synthase activity in nn-diabetic wmen during insulin infusin [31]. Whether reduced glycgen synthase activity is a primary defect in bese subjects leading t insulin resistance, hyperinsulinaemia and eventually t besity is still an pen questin. Interestingly, insulin resistance in peripheral tissues in Pima Indians seems t be inherited [32], and first degree relatives t patients with Type 2 diabetes suffer frm a reduced glucse dispsal [33], and reduced nn-xidative glucse metablism even befre the ral glucse tlerance test is impaired [10]. In cnclusin, we fund that insulin stimulatin f glycgen synthase activity was reduced in skeletal muscle fim bese subjects with and withut Type 2 diabetes. The defect in insulin stimulatin f the enzyme culd nt be reversed in the diabetic patients despite 8 h nrmalizatin f plasma glucse and NF values, indicating that this defect may be f primary rigin t the diabetic state. The glycgen synthase activity defect seems t be assciated with besity itself and may be f primary rigin, but culd als be secndary t an increased lipid xidatin in bese subjects. cknwledgements: This study was supprted by grants frm the Danish Diabetes ssciatin. Ms. B. Mttlau and Ms.. Frman are gratefully acknwledged fr their skillfull technical assistance, Ms. K. Falhlt fr labratry facilities and technical assistance.
7 R Damsb et al.: Glycgen synthase in besity and diabetes References I. Kelley D, Mitraku, Marsh H et al. (1988) Skeletal muscle glyclysis, and strage f an ral glucse lad. J Clin Invest 88: DeFrnz R (1988) The triumvirate: beta-cell, muscle, liver. cllusin respnsible fr NIDDM. Diabetes 37:66% Beck-Nielsen H, Hther-Nielsen (1988) Insulin resistance. Diabetes nn 4: DeFrnz R, Simnsn D, Ferrannini (1982) Hepatic and peripheral insulin resistance: a cmmn feature f Type 2 (nninsulin-dependent) and Type 1 (insulin-dependent) diabetes mellitus. Diabetlgia 23: lefsky JM (1985) Pathgenesis f insulin resistance and hyperglycemia in nn-insulin-dependent diabetes mellitus. m J Med 79 [8uppl3 B]: Damsb R Hther-Nielsen, Beck-Nielsen H (1988) Reduced insulin stimulated glucse xidatin in bese Type 2 (nn-insulin-dependent) diabetic patients. Diabetlgia 31:483 (bstract) 7. Felber JR Ferrannini, Glay et al. (1987) Rle f lipid xidatin in pathgenesis f insulin resistance f besity and Type 2 diabetes. 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N ngl J Med 322: Mandarin LJ, Wright KS, Verity LS, Nichls J, Bell JM, Klterman G, Beck-Nielsen H (1987) ffects f insulin infusin n human skeletal muscle pyruvate dehydrgenase, phsphfructkinase and glycgen synthase. J Clin Invest 80: Bgardus C, Lillija S, Stne K, Mtt D (1984) Crrelatin between muscle glycgen synthase activity and in viv insulin actin in man. J Clin Invest 73: Wright KS, Beck-Nielsen H, Klterman G, Mandarin LJ (1988) Decreased activatin f skeletal muscle glycgen synthase by mixed-meal ingestin in NIDDM. Diabetes 37: Kida Y, Puente -D, Bgardus C, Mtt DM (1990) Insulin resistance is assciated with reduced fasting and insulin-stimulated glycgen synthase phsphatase activity in human skeletal muscle. J Clin Invest 85: Ferrannini, Del Prat S, DeFrnz R (1986) Glucse kinetics. Tracer methds. Methds Diabetes Res 2:10% DeFrnz R, Tbin JD, ndres R (1979) Glucse clamp technique, a methd fr quantifying insulin secretin and resistance. m J Physi1237: Steele R (1959) Influence f glucse lading and f injected insulin n hepatic glucse prductin. nn NY cad Sci 82: Tappy L, wen, Bden G (1988) ffect f hyperinsulinemia n urea pl size and substrate xidatin rates. Diabetes 37: Frayn KN (1983) Calculatin f substrate xidatin rates in viv frm gaseus exchange. m J Physi183: Hther-Nielsen, Schmitz, Bak J, Beck-Nielsen H (1987) nhanced hepatic insulin sensitivity, but peripheral insulin resistance in patients with Type 1 (insulin-dependent) diabetes. Diabetlgia 30: Heding LG (1%6) simplified insulin radiimmunassay methd. In: Labelled prteins in tracer studies. urpean tmic nergy Cmmunity, Brussels, pp HedingLG (1975) Radiimmunlgical determinatin f human C-peptide in serum. Diabetlgia 11: DeFrnz R, Ferrannini (1982) Influence f plasma glucse and insulin cncentratins n plasma glucse clearance in man. Diabetes 31: Randle PJ, Garland PB, Hales CN, Newshlme (1963) The glucse fatty-acid cycle. Its rle in insulin sensitivity and the metablic disturbances f diabetes meltitus. Lancet I: Freymnd D, Bgardus C, kub M, Stne K, Mtt D (1988) Impaired insulin-stimulated muscle glycgen synthase activatin in viv in man related t lw fasting glycgen synthase phsphatase activity. J Clin Invest 82: H~iring H, bermaier B, rmel Bet al. (1987) Insulin receptr kinase defects as a pssible cause f cellular insulin resistance. Diabetes Metab 13:284~ rner P, Pllare T, Lithell H, Livingstn JN (1987) Defective insulin receptr tyrsine kinase in human skeletal muscle in besity and Type 2 (nn-insulin-dependent) diabetes mellitus. Diabetlgia 30: Car JF, Sinha MK, Raju SM et al. (1987) Receptr kinase in human skeletal muscle frm bese subjects with and withut nninsulin dependent diabetes. J Clin Invest 79: Freidenberg GR, Reichart D, lefsky JM, Henry RR (1988) Reversibility f defective adipcyte insulin receptr kinase activity in nn-insulin-dependent diabetes mellitus. J Clin Invest 82: vans DJ, Murray R, Kissebah H (1984) Relatinship between skeletal muscle insulin resistance, insulin-mediated glucse dispsal, and insulin binding. J Clin Invest 74: Bgardus C, LiIlija S, Nymba BL et al. (1989) Distributin f in viv insulin actin in Pima Indians as mixture f three nrmal distributins. Diabetes 38: Laws, Stefanick ML, Reaven GM (1989) Insulin resistance and hypertriglyceridemia in nndiabetic relatives f patients with nn-insulin-dependent diabetes mellitus. J Clin ndcrinl Metab 69: Received: 28 May 1990 and in revised frm: 18 ctber 1990 Dr. R D amsb HvidCre Hspital miliekildevej 1 DK-2930 Klampenbrg Denmark 245
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