Diabetologia 9 Springer-Verlag 1982

Transcription

1 Diabetlgia (1982) 23: Diabetlgia 9 Springer-Verlag 1982 Originals Hepatic and Peripheral Insulin Resistance: A Cmmn Feature f ype 2 (Nn-Insulin-Dependent) and ype 1 (Insulin-Dependent) Diabetes Mellitus R. A. DeFrnz, D. Simnsn and. Ferrannini Department f Medicine, Yale University Schl f Medicine, New Haven, Cnnectitut, USA Summary. Hepatic glucse prductin (3H-glucse technique) and insulin-mediated glucse uptake (insulin clamp technique) were measured in 38 ype 2 (nn-insulin-dependent) and 11 ype 1 (insulin-dependent) diabetic patients. Fasting plasma glucse cncentratin was mml/1 in the frmer, and mml/1 in the latter grup; the respective fasting plasma insulin levels were mu/1 (p < versus mu/1 in 33 age-matched cntrl subjects), and mu/1 (p < 0.01 versus mu/1 in 36 yunger cntrl subjects). In the fasting state, hepatic glucse prductin was slightly increased (15%, 0.1 > p > 0.05) in the ype 2 diabetic patients and markedly elevated (65%, p < 0.001) in the ype 1 patients cmpared with their respective cntrl grups, In bth grups f diabetic subjects, the rates f hepatic glucse prductin were inapprpriately high fr the prevailing plasma glucse and insulin levels, indicating the presence f hepatic resistance t insulin. Basal plasma glucse clearance was als significantly reduced in bth the ype 2 (34%) and the ype 1 (14%) diabetic subjects. he fasting plasma glucse cncentratin crrelated directly with hepatic glu- cse prductin, and inversely with plasma glucse clearance. During the insulin clamp, plasma insulin was maintained at apprximately 100 mu/1 in all grups, while plasma glucse was maintained cnstant at the respective fasting levels. tal glucse uptake was reduced in bth the ype 2 ( versus 6.39 _ 0.25 mg - min -1 - kg -1 in the cntrl subjects, p < 0.01) and the ype 1 ( versus mg 9 min -1 9 kg -1, p < 0.01) diabetic patients. Insulin-stimulated glucse clearance was reduced t a similar extent in ype 2 (54%) and ype 1 (61%) diabetic subjects, and crrelated directly with fasting glucse clearance. hese results shw that insulin resistance is a cmmn feature f bth types f diabetes and can be demnstrated in the basal as well as the insulin-stimlated state. Bth hepatic and peripheral resistance t the actin f insulin cntribute t diabetic hyperglycaemia. Key wrds: ype 1 and ype 2 diabetes, insulin resistance, insulin-mediated glucse metablism, glucse clearance, hepatic glucse prductin. he presence f resistance t the glucse-lwering effect f insulin in nn-bese, ype 2 (nn-insulin-dependent) diabetic patients has been dcumented with a variety f techniques. hey include the insulin clamp technique [1, 2], the intravenus insulin tlerance test [3, 4], the cmbined intravenus insulin-ral glucse tlerance test [5], the frearm perfusin technique [6-8], the quadruple infusin prtcl f Ginsberg et al. [9], the smatstatin mdificatin f the quadruple infusin prtcl [10], and radiactive glucse istpe methds [11]. Althugh these studies have established that insulin resistance is quite frequent in ype 2 diabetes, its site (i. e., peripheral r hepatic) has nt been determined with certainty. Als cntrversial is the cntributin f glucse ver-prductin t the fasting hyperglycaemia in ype 2 diabetic patients since bth raised [12] and nrmal [13] rates f endgenus glucse utput have been reprted. Furthermre, it is nt clear whether the resistance t exgenus insulin infusin in these patients bears any relatin t the insulin resistance present in the fasting state. he infrmatin n insulin-stimulated glucse metablism in ype 1 (insulin-dependent) diabetic patients is discrdant. With the use f the cmbined intravenus insulin-ral glucse tlerance test, Himswrth and Kerr fund that abut ne-half f their insulin-dependent diabetic patients were resistant t the actin f insulin [5]. Mre recently, Haran et al. [14], using the smatstatin mdificatin f the quadruple infusin technique, have als demnstrated impaired insulin actin in mst ype 1 diabetic individuals. In cntrast, Ginsberg has reprted a nrmal respnse t insulin in a small grup f insulin-dependent diabetic patients [15]. hus, the prevalence and severity f insulin resistance X/82/0023/0313/$01.40

2 314 R. A. DeFrnz et al.: Hepatic and Peripheral Insulin Resistance in ype 1 diabetes (independent f insulin antibdies) as well as its tissue lcalizatin need t be re-evaluated. In the present study, we have used the euglycaemic insulin clamp technique in cmbinatin with the 3Hglucse methd t measure rates f glucse prductin and dispsal in bth ype 2 and ype 1 diabetic subjects, in the basal pstabsrptive state as well as during a sustained increase in the plasma insulin cncentratin. Subjects and Methd Subjects he study ppulatin cnsisted f 38 ype 2 and 11 ype 1 diabetic individuals. he mean (+ SM) ages f the tw grups were and 34 _+ 3 years, respectively. Since age per se is knwn t affect glucse tlerance [16], tw grups f cntrl subjects were included. hirty-six subjects with a mean age (+ SM) f years served as cntrls fr the ype I diabetic subjects, and 33 subjects with a mean age f years served as cntrls fr the ype 2 diabetic grup. he ideal bdy weights (based n medium frame individuals frm the Metrplitan Life Insurance ables, 1959) f the ype 2 and ype 1 diabetic subjects were % and %, respectively. he ideal bdy weights fr the tw cntrl grups were % and 104 +_ 1%, respectively. leven f the ype 2 diabetic patients had received previus therapy with ral hypglycaemic agents but nne had received any ral agent r ther medicatin fr at least 8 weeks befre the study. All f the diabetic patients had fasting plasma glucse cncentratins abve 6.7 mml/1 n multiple ccasins. he duratin f the diabetes in the ype 1 grup was 10 _+ 3 years, and their daily requirement f NPH insulin was units. One f the ype 1 diabetic subjects was als receiving a mrning dse f regular insulin f 10 units. he purpse, nature, and ptential risks f the study were explained t all subjects and their written vluntary cnsent was btained befre participatin. Study Prtcl All studies were perfrmed in the pstabsrptive state at 0800 h fllwing a h vernight fast. In the ype 1 diabetic grup, the last dse f NPH insulin was administered 24 h befre the study. Insulinmediated glucse metablism was quantitated with the insulin clamp technique as described previusly [1]. Fllwing a 120 rain (in the nrmal subjects) r a 180 rain (in the diabetic patients) cntrl perid t allw fr equilibratin f 3H-3-glucse, a prime-cntinuus (42.6 mu/ m 2 surface area per rain) infusin f crystalline prcine insulin (li Lily, Indianaplis, Indiana, USA) was administered fr 2 h t achieve cnstant physilgical hyperinsulinaemia. he plasma glucse cncentratin was maintained at basal, pre-infusin levels by determinatin f plasma glucse every 5 rain and the peridic adjustment f a variable infusin f a 20% glucse slutin [1]. Under these steadystate cnditins f cnstant glycaemia, the ttal amunt f glucse taken up by ali tissues f the bdy must be equal t the input f glucse int the bdy. he input f glucse is, in turn, equal t the sum f the exgenus glucse infusin rate and the rate f residual endgenus (hepatic) glucse prductin that remains unsuppressed by hyperinsulinaemia. he rate f endgenus glucse prductin was calculated by subtracting the exgenus glucse infusin rate frm the ttal rate f glucse appearance as measured frm the analysis f the 3H-3-glucse kinetics (see subsequent descriptin). In previus studies, we have shwn that hypergiycaemia per se will enhance insulin-mediated glucse uptake by a mass actin effect [17]. A similar effect f hyperglycaemia has been demnstrated in the presence f basal insulin levels [18]. herefre, in 11 f the 38 ype 2 diabetic subjects, fllwing the initiatin f the insulin infusin, the plasma glucse cncentratin was allwed t decrease apprximately t 6.7 retl/1 befre the exgenus glucse infusin was begun. In additin, five f the yung cntrl subjects were restudied under similar cnditins f hyperinsulinaemia but after elevatin f the plasma glucse cncentratin t levels similar t thse bserved in the insulin-dependent diabetic grup. his was accmplished by using the hyperglycaemic clamp technique [1] in cmbinatin with an exgenus insulin infusin. he exgenus insulin infusin was adjusted empirically, based n knwledge f the plasma insulin respnse during previus hyperglycaemic clamps perfrmed n the same individuals. In the cntrl grup, the 3H-3-glucse (New ngland Nuclear, Bstn, Massachusetts, USA) prime was 25 txci, and the cntinuus infusin was given at the rate f 0.25 gci/min. In the diabetic grup, the priming dse was increased in prprtin t the increase in fasting plasma glucse cncentratin. Plasma samples fr 3H-3-glucse specific activity were btained at 5-10 rain intervals fr the last 30 min. Fllwing the infusin f insulin, tritiated glucse specific activity was determined at 5-15 min intervals. Calculatins With the insulin clamp, ttal glucse metablism during a given time perid was calculated by adding the mean rate f endgenus glucse prductin t the mean glucse infusin rate during the same time perid. he glucse clearance was btained as the rati f the rate f ttal glucse metablism t the steady-state plasma glucse cncentratin during the insulin clamp. he steady-state plasma glucse and insulin levels were the means f values between rain. In the basal state, the rate f endgenus glucse prductin was calculated by dividing the infusin rate f 3H-3-glucse cunts by the mean plasma glucse specific activity measured during the last 30 rain f the cntrl perid. A steady-state plateau f glucse specific activity was achieved in all diabetic and cntrl subjects befre the start f insulin infusin. In the basal state, with cnstant glycaemia, the rate f glucse appearance equals the rate f glucse disappearance, and therefre prvides a measure f basal glucse metablism. he basal glucse clearance was determined by dividing the infusin rate f 3H-3-glucse cunts by the steady-state cncentratin f tritiated glucse cunts in plasma. During the insulin infusin, the glucse system is nt in steady-state. herefre, Steele's equatins, and a value f 0.65 fr the pl fractin [19], were used t cmpute ttal rates f glucse appearance. he rate f endgenus glucse prductin was then btained by subtracting the exgenus glucse infusin rate frm the ttal rate f glucse appearance. AlI data are presented as mean SM. Statistical cmparisns were perfrmed by the Student's t-test. Analytical Prcedures Plasma glucse cncentratin was measured by the glucse xidase methd with a Beckman glucse analyzer (Beckman Instruments, Fuilertn, Califrnia, USA). Plasma insulin cncentratin was determined by radiimmunassay using talc t separate bund frm free insulin [20]. he cefficients f variatin (inter-assay) fr ur high ( mu/i; mean + SM f determinatins), medium (48 _+ 2 mu/1), and lw ( mu/l) quality cntrls are 9.8%, 12.2%, and 14.0%, respectively. he intra-assay cefficient f variatin fr the quality cntrls is 9.8%. Recvery f insulin added t plasma is %. In the ype 1 diabetic grup, plasma free insulin cncentratin was determined by radiimmunassay as abve, after treatment f plasma with plyethylene glycl t remve insulin antibdies [21]. ritiated glucse specific activity was determined as described previusly [22]. Results Plasma Glucse and Insulin he mean fasting plasma glucse cncentratins in the cntrl, ype 2, and ype 1 diabetic subjects were , , and mml/1, respectively.

3 9 R. A. DeFrnz et al.: Hepatic and Peripheral Insulin Resistance 315 able I. Plasma insulin and glucse cncentratins in the basal state and during the insulin clamp studies Plasma insulin Plasma glucse Basal Steady-state Basal (mu/1) (mu/1) (retl/l) Steady-state Cefficient (mml/1) f variatin (%) Older cntrl subjects (n = 33) _ ype 2 diabetic subjects studied at hyperglycaemic levels (n = 27) 19 _ _ ype 2 diabetic subjects studied at euglycaemic levels (n = 11) Yunger cntrl subjects (n = 36) _ _ : ype 1 diabetic subjects (n = 11) 9 _ _ _+ 0.3 Yunger cntrl subjects studied at hyperglycaemic levels (n = 5) 14 _ _ _+ 0.4 Results are expressed as mean + SM 12 IO,.~ A 8 2=,..,1 4 2 FP<.F] I P<.l I FP<O.OS] Steady-stre glucse 5.0 level P<O.OI FP<.~ (mml/i ) Fig.1. tal glucse uptake in age-matched cntrl subjects ([-]), ype 2 (~:~) and ype 1 diabetic patients (NN) during a I mu 9 kg -1 9 min -1 insulin clamp study. he mean steady-state plasma glucse levels during the clamp study fr the varius experimental grups are given at the bttm f the bars. Data are expressed as mean + SM. he p values refer t unpaired t-test analysis During the insulin clamp, the plasma glucse was held clse t the basal level (able 1). In the 11 ype 2 diabetic subjects, in whm the plasma glucse cncentratin was allwed t drp befre initiating the exgenus glucse infusin, the mean steady-state glucse level during the clamp study was 6.6 _+ 0.2 mml/1. In the five cntrl subjects restudied at hyperglycaemic levels, the mean steady-state glucse cncentratin during the clamp study was mml/1. he stability f the plasma glucse cncentratin during the clamp I studies is indicated by the small cefficient f variatin (able 1). he fasting plasma insulin cncentratins in the lder cntrl subjects and ype 2 diabetic grup were and mu/l, respectively (p < 0.005). In the ype 1 diabetic grup, fasting plasma free insulin levels (9 _+ 1 mu/1) were slightly, thugh significantly (p < 0.01), lwer than in the yunger cntrl subjects ( mu/1). he steady-state insulin levels during the insulin clamp were similar in all the study grups (able 1). In the five cntrl subjects restudied under hyperglycaemic cnditins, the mean steadystate insulin levels during the euglycaemic ( mu/1) and hyperglycaemic (107 _+ 4 mu/1) clamp studies were virtually identical. Glucse Metablism During the insulin clamp, the ttal amunt f glucse taken up by the bdy ( min) in the 27 ype 2 diabetic subjects studied at their fasting glucse level ( mg 9 kg -1 9 min -1) was reduced by 28% cmpared with the age-matched cntrl subjects ( mg 9 kg -1 9 min-l,p < 0.01; Fig.l). he glucse clearance was reduced t an even greater extent (3.17 _ versus ml 9 kg -1 9 min-t,p < 0.001; Fig.2). In the 11 ype 2 diabetic subjects whse plasma glucse cncentratin was allwed t decrease t 6.6 mml/1 befre starting the clamp study, the ttal amunt f glucse metablized ( mg 9 kg-1 min -1) was significantly less than in the ype 2 diabetic individuals studied at fasting hyperglycaemic levels (p < 0.05) r the nrmal subjects (p < 0.001). Only ne f the ype 2 diabetic grup had a rate f glucse metablism that was within the mean + 1 SM bserved in the cntrl grup (Fig. 1). he glucse clear-

4 316 R.A. DeFrnz et al.: Hepatic and Peripheral Insulin Resistance ~'.= u ~ u FP<0.O01I I p< ] F-- ns~ 5.2 8,5 6.6 Steady-state glucse r rp<o.oolq I P<O.O01 I 5.0 9,2 9.6 LeveL (mml/i) Fig.2. tal plasma glucse clearance (ttal glucse uptake + steadystate plasma glucse cncentratin) in age-matched cntrl subjects (F-l), ype 2 (~) and ype 1 diabetic patients (~) during a 1 mu 9 kg -1 - min -~ insulin clamp study. he mean steady-state plasma glucse levels during the clamp study fr the varius experimental grups are given at the bttm f the bars. Data are expressed as mean SM. he p values refer t unpaired t-test analysis c- 13 l- ed (.3,,_,1 l i/1 13.._i Q_ 15.0 I "e' O / ' % e/,~ 9 // /, 9,~" / 9 // /' // /' 0 I ] I I I ndgenus glucse prductin (rng kg "n rain "1) Fig. 3. Relatinship between plasma glucse cncentratin and endgenus glucse prductin in the fasting state. he slid line is the regressin line fr the cntrl subjects; ype 2 (O) and ype 1 (9 diabetic subjects ance in the ype 2 diabetic subjects studied at euglycaemic levels (2.83 _ ml 9 kg -1 9 min -1) was similar t that bserved in ype 2 diabetic subjects studied at hyperglycaemic levels (Fig.2). In the ype 2 diabetic subjects studied at hyperglycaemic levels, the ttal amunt f glucse metablized during the insulin clamp was psitively crrelated (r = 0.50, p < 0.01) with the fasting plasma glucse cncentratin. A weak, inverse crrelatin between fasting plasma glucse and c- 15.0,,!-' l I.,. 4" c" U c" I0.0 (j.-"-. Ul m O O l 05.0 u~ 0_ \ \ '\ 0~ \ 9 \ "-- O ~"'- \ O ~ ~ \ 9, 9 ~ I I I I I GLucse clearance rate (ml kg "1 rain "I) Fig.4. Relatinship between plasma glucse cncentratin and plasma glucse clearance in the fasting state. he slid line is the regressin line fr the cntrl subjects; ype 2 (9 and ype 1 (O) diabetic subjects the glucse clearance during the clamp was als fund t exist (r = -0.30, 0.10 > p > 0.05). In the ype 2 diabetic subjects, the ttal amunt f glucse metablized ( min) (4.77 _ mg 9 kg -t min -1) was als significantly reduced by 32%, cmpared with cntrl subjects (7.03 _ mg 9 kg -1 9 min -t, p < 0.01; Fig. 1). he degree f impairment in glucse metablism in the ype 1 diabetic subjects is even mre striking when cmpared with the cntrl subjects wh were studied at cmparable degrees f hyperglycaemia and hyperinsulinaemia (12.14 _ mg 9 kg -1 9 min -1, p < 0.001). he rate f insulin-mediated glucse metablism was nt significantly different between ypes 1 and 2 diabetic subjects. he rate f glucse clearance in the ype 1 diabetic subjects ( ml 9 kg -t 9 min -t) was markedly reduced cmpared with cntrl subjects (7.83 _ ml 9 kg -1 9 min -1, p < 0.001; Fig.2) but was nt significantly different frm the ype 2 diabetic subjects ( ml 9 kg -1 9 min-1). he ttal rate f glucse metablism was psitively crrelated (r = 0.61, p < 0.05) with the fasting plasma glucse cncentratin9 In cntrast, the glucse clearance was inversely (r , p < 0.001) crrelated with the fasting plasma glucse. ndgenus Glucse Prductin In the basal, pst-absrptive state, plasma glucse cncentratin, glucse clearance and endgenus glucse

5 R. A. DeFrnz et al.: Hepatic and Peripheral Insulin Resistance 317 prductin were similar in the tw cntrl grups. hese data culd therefre be pled. A direct crrelatin was then fund t exist between fasting plasma glucse and the rate f endgenus glucse prductin (r , p < 0.05), whereas the glucse clearance was inversely related t the fasting plasma glucse cncentratin (r = , p < 0.05). In the ype 2 diabetic subjects, endgenus glucse prductin (2.50 _ mg 9 kg -1 9 min -1) was slightly, thugh nt significantly, greater than in the agematched cntrl (2.18 _ mg 9 kg -1 9 rain -1, 0.1 > p > 0.05). Fasting glucse clearance in the ype 2 diabetic subjects (1.54 _ ml 9 kg -1 9 min -1) was significantly lwer than in the cntrl subjects (2.23 _ mg 9 kg -~ min -1, p < 0.001). A strng, direct crrelatin existed between fasting plasma glucse cncentratin and endgenus glucse prductin (r , p < 0.001), whereas glucse clearance was weakly related t fasting plasma glucse in an inverse fashin (r = -0.31, 0.1 > p > 0.05) (Figs.3 and 4). In the ype 2 diabetic subjects, hepatic glucse prductin (3.51 _ mg 9 kg -1 9 min -1) was markedly increased cmpared with age-matched cntrls (2.13 _ mg 9 kg -1 min -1, p < 0.001). Fasting glucse clearance was lwer than nrmal (2.03 _ versus 2.35 _ ml. kg -~ 9 min-l). Fasting plasma glucse levels displayed a psitive crrelatin with the rates f glucse prductin (r = 0.87, p < 0.001), and a negative crrelatin with the rates f glucse clearance (r = 0.72, p < 0.01 ; Figs.3 and 4). During the clamp, hepatic glucse prductin in the cntrl subjects declined t 0.43 _ mg 9 kg -~ 9 min -1 within 20 min. Over the secnd hur f the clamp study, heaptic glucse prductin was suppressed by > 95% (t 0.08 _ mg 9 kg -1 9 min-1). In bth ype 2 and ype 1 diabetic subjects, the timecurse as well as the abslute degree f inhibitin f hepatic glucse prductin were similar t thse f the respective cntrl grups. Discussin he plasma glucse cncentratin is the result f tw prcesses, the rate f endgenus glucse prductin, and the rate f glucse remval by all the tissues in the bdy. In the pst-absrptive state, these tw rates are equal, and the plasma glucse level remains relatively cnstant. In the nrmal subjects in the present study, we fund a direct relatinship between fasting plasma glucse levels and the basal rates f endgenus glucse prductin (Fig. 3), and an inverse relatinship between fasting glucse cncentratin and glucse clearance (Fig. 4). his finding indicates that bth hepatic glucse prductin and glucse clearance are imprtant in maintaining euglycaemia in healthy subjects. he abve relatinships were cnserved in bth ype 1 and 2 diabetic subjects, suggesting that the mechanisms regulating the fasting level f plasma glucse are qualitatively unaltered in these patients. here were, hwever, several imprtant differences. First, the rates f endgenus glucse prductin tended t be higher in the ype 2 diabetic subjects, and were definitely increased in the ype 1 diabetic subjects. In fact, in virtutally every diabetic subject, whether ype I r ype 2 with fasting plasma glucse levels > 10 mml/1, endgenus glucse release was elevated in abslute terms. Mrever, even 'nrmal' rates f glucse prductin are inapprpriately high fr the assciated degree f hyperinsulinaemia and hyperglycaemia. In the nninsulin requiring diabetic patients, hepatic glucse prductin was elevated despite significant fasting hyperinsulinaemia. Furthermre, we have shwn previusly that in nrmal subjects hyperglycaemia effectively suppresses hepatic glucse prductin even in the presence f hypinsulinaemia [23]. hus, in ype 2 diabetic subjects, the liver is resistant t the restraining effect f bth insulin and/r hyperglycaemia n basal glucse release. Likewise, basal glucse prductin was increased in ype 1 diabetic subjects despite the presence f near nrmal basal insulin levels and marked hyperglycaemia. In summary, frank ver-prductin f glucse may result when insulin resistance is severe (ype 2 diabetes) r is assciated with sme degree f hypinsulinaemia (ype 1 diabetes). he secnd majr bservatin was that the plasma glucse clearance in the fasting state was reduced in bth ype 2 and ype 1 diabetic subjects. Here, it shuld be nted that in thse diabetics with fasting plasma glucse cncentratins > mml/1, the renal threshld fr glucse was presumably exceeded and significant glycsuria was present. Since urinary glucse lsses were nt quantitated in the present study, the calculated rates f plasma glucse clearance must have verestimated tissue glucse clearance by an amunt equal t urinary glucse clearance. Cnsequently, the actual rates f tissue glucse clearance wuld be even lwer than calculated, and their inverse relatin t fasting glucse levels strnger. hus, in ype 1 and ype 2 diabetic individuals, significant insulin resistance was present in the peripheral tissues in the basal state. It is f interest that the basal rates f glucse uptake (= rates f glucse prductin) were nt reduced, since the lwer glucse clearance rates were assciated with raised plasma glucse levels. Fasting hyperglycaemia, therefre, appears t serve a cmpensatry functin in driving glucse int cells which have a reduced specific capacity t take up glucse. Althugh it is implicit in the definitin f insulin resistance that nly insulin-dependent tissues (principally muscle and fat) are respnsible fr the impaired efficiency f glucse uptake, it cannt be excluded that the insulin-independent tissues (brain, red bld cells, renal medulla, and intestine) may als clear plasma glucse at a reduced rate.

6 318 R. A. DeFrnz et al.: Hepatic and Peripheral Insulin Resistance During the insulin clamp, ttal glucse uptake was decreased by 30% in the ype 2 and by 32% in the ype 1 diabetic grups (Fig. 1) despite their higher plasma glucse levels (8.3 and 9.6 versus 5.0 mml/1 in the cntrls). he magnitude f this defect is fully appreciated when glucse uptake is 'crrected' fr the plasma glucse cncentratin, i.e., by calculating the glucse clearance. Again, bth diabetic grups shwed a marked reductin in glucse clearance, and the similarity f this change in the tw grups is striking (61% versus 54%). Cmparing glucse clearance in subjects with widely different plasma glucse levels wuld prvide a biased assessment f the degree f insulin resistance if glucse clearance were itself affected by glucse cncentratin. hat this was nt the case in the present studies is shwn by tw facts. First, when the nrmal subjects were clamped at similar insulin but higher glucse levels (9.2 versus 4.9 mml/1), glucse clearance was essentially unchanged (Fig. 2), and ttal glucse uptake was increased in prprtin t the hyperglycaemia (Fig. 1). Secnd, and cnversely, when ype 2 diabetic subjects with fasting hyperglycaemia were rendered apprximately nrmglycaemic (6.6 mml/1) and then clamped at insulin levels similar t thse f the cntrls, glucse clearance was similar t that f the ype 2 diabetic subjects studied at hyperglycaemic levels (Fig. 2). hus, with plasma insulin levels in the high physilgical range (~ 100 mu/1), glucse clearance prvides a mre realistic index f the effect f insulin n glucse uptake by insulin-dependent tissues than des the ttal amunt f glucse metablized by the bdy. During the insulin clamp, hepatic glucse prductin was inhibited in bth ype 1 and ype 2 diabetic patients t the same extent as in nrmal subjects. he present experiments d nt answer the questin f whether suppressin f hepatic glucse prductin in diabetic patients might be impaired with small elevatins in plasma insulin cncentratin. Nevertheless, the present results d demnstrate that whatever deficit there might be in the ability f the diabetic liver t shut ff glucse release in respnse t insulin, this can be vercme by higher insulin levels (- 100 mu/1). he physilgical relevance f this bservatin is that, fllwing the ingestin f a glucse lad, prtal vein plasma insulin levels rise abve 100 mu/1, and remain elevated fr a cnsiderable length f time [24]. herefre, unless the insulin respnse t glucse administratin is severely deficient (as in ype 1 diabetic patients), failure f the liver t inhibit glucse release in respnse t glucse ingestin is nt likely t be a majr cntributry factr in pst-prandial hyperglycaemia. With regard t the site f insulin resistance under the cnditins f an insulin clamp experiment, reduced glucse uptake culd ccur either in the splanchnic r the peripheral tissues. In previus experiments we have shwn that the splanchnic bed is respnsible fr the uptake f nly 5-10% f an intravenusly administered glucse lad in nrmal man [25]. Recent studies in ype 2 diabetic patients, in which the insulin clamp technique was cmbined with hepatic vein catheterizatin, have cnfirmed this result (R.A.DeFrnz and J.Wahren, unpublished bservatins). herefre, the site f the impairment in insulin actin demnstrated in the diabetic subjects in this study must reside in peripheral tissues, mstly muscle. In cnclusin, the present results emphasize the imprtance f insulin resistance in bth ype 1 and ype 2 diabetic individuals. his impairment in insulin-actin is mst evident under hyperinsulinaemic cnditins but als manifests itself in the pst-absrptive state by an verprductin f glucse by the liver and a decreased rate f glucse clearance by peripheral tissues. Acknwledgments. We thank k Mishiwiec fr her help in perfrming the studies, Y. F. Wu fr technical assistance, and J. A. Palmieri, secretary-typist. Dr. R. Hendler kindly perfrmed the insulin determinatins. his wrk was supprted in part by NIH Research Grant AM 24092, NIH Divisin f Research Resurces Grant RR 00125, and PHS Internatinal Research Fellwship 1-F05-W References 1. DeFrnz RA, bin J, Andres R (1979) he glucse clamp technique. A methd fr the quantificatin f beta cell sensitivity t glucse and f tissue sensitivity t insulin. Am J Physil 237: Olefsky JM (1980) Insulin resistance and insulin actin. An in vitr and in viv perspective. Diabetes 30: Harrisn LC, Martin FIR, Melick RA (1976) Crrelatin between insulin receptr binding in islated fat cells and insulin sensitivity in bese human subjects. J Clin Invest 58: Beck-Nielsen H (1978) he pathgenic rle f an insulin receptr defect in diabetes mellitus f the bese. Diabetes 27: Himswrth HP, Kerr RB (1939) Insulin-sensitive and insulin-insensitive types f diabetes mellitus. 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