Activation of Skeletal Muscle Casein Kinase 11 by Insulin is not Diminished in Subjects with Insulin Resistance
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1 Activtion of Skeletl Muscle Csein Kinse 11 by Insulin is not Diminished in Subjects with Insulin Resistnce Ryo Med, Itmr Rz, Frncesco Zurlo, nd Jmes Sommercorn Clinicl Dibetes nd Nutrition Section, Ntionl Institute ofdibetes nd Digestive nd KidneY Diseses, Ntionl Institutes ofhelth, Phoenix, Arizon Abstrct Insulin resistnce, which my precede the development of noninsulin-dependent dibetes mellitus in Pim Indins, ppers to result from postreceptor defect in signl trnsduction in skeletl muscle. To identify the puttive postreceptor lesion responsible for insulin resistnce in Pim Indins, we investigted the influence of insulin on the ctivity of csein kinse II (CKII) in skeletl muscle of seven insulin-sensitive, four insulin-resistnt, nondibetic, nd five insulin-resistnt dibetic Pim Indins during 2 h hyperinsulinemic, euglycemic clmp. In sensitive subjects, CKII ws trnsiently ctivted reching mximum over bsl ctivity (42%) t 45 min before declining. CKII ws lso stimulted in resistnt (19%) nd dibetic (34%) subjects. Bsl CKII ctivity in resistnt subjects ws 40% higher thn in either sensitive or dibetic subjects, lthough the concentrtion of CKII protein, s determined by Western blotting, ws equl mong the three groups. Bsl CKII ctivity ws correlted with fsting plsm insulin concentrtions, suggesting tht the higher ctivity in resistnt subjects resulted from insulin ction. Extrcts of muscle obtined from ll three groups either before or fter insulin dministrtion were treted with immobilized lkline phosphtse, which reduced nd equlized CKII ctivity. These results suggest tht insulin stimultes CKII ctivity in humn skeletl muscle by mechnism involving phosphoryltion of either CKII or of n effector molecule, nd support the ide tht elevted bsl ctivity in resistnt subjects results from insulin ction. It ppers tht the bility of insulin to ctivte CKII in skeletl muscle is not impired in insulin-resistnt Pim Indins, nd tht the biochemicl lesion responsible for insulin resistnce occurs either downstrem from CKII or in different pthwy of insulin ction. (J. Clin. Invest : ) Key words: insulin signl trnsduction protein phosphoryltion protein kinse - - Introduction The Pim Indins hve the highest known prevlence of noninsulin-dependent dibetes mellitus (NIDDM),' disese tht This work hs ppered in bstrct form (1990. Dibetes 39(Suppl): 146. Address correspondence nd reprint requests to Dr. Jmes Sommercorn, Clinicl Dibetes & Nutrition Section, Ntionl Institutes of Helth, 4212 North 16th Street, Room 541, Phoenix, AZ Receivedf]r plbliction 18 JulY 1990 nd in revisefdjbrm 9 October Abbrevitions lused in this pper: CKII, csein kinse II; EGF, epiderml growth fctor; IGF-1, insulin-like growth fctor 1; NIDDM, noninsulin-dependent dibetes mellitus; PP,-I, the form of type I phosphtse comprising ctlytic subunit nd inhibitor 2. The Journl of Clinicl Investigtion, Inc. Volume 87, Mrch 1991, my be inherited s single utosoml gene (1). Longitudinl studies hve demonstrted tht subjects with norml glucose tolernce, who subsequently develop NIDDM, first develop impired glucose tolernce, condition tht is chrcterized by reduced cpcity of skeletl muscle to respond to circulting insulin (2). Insulin-resistnt subjects were found to hve lower rtes of insulin-stimulted, nonoxidtive glucose disposl (glycogen synthesis) in skeletl muscle thn did insulin-sensitive subjects (3), difference tht cn be explined by bnorml ctivtion of glycogen synthse in response to insulin in these subjects (4). Becuse insulin resistnce my be n expression of the genetic lesion ultimtely responsible for NIDDM, n understnding of its biochemicl nd moleculr bsis is criticl for understnding the cuse nd potentil tretment of the disese. Insulin resistnce results from filure in the mechnism of insulin signl trnsduction. Although this mechnism is not entirely understood, it is known tht reversible protein phosphoryltion is involved. The A-subunit ofthe insulin receptor is lignd-ctivted tyrosine protein kinse (5-7). The hormone promotes phosphoryltion of severl proteins on tyrosine nd lters the contents of phosphoserine nd phosphothreonine in other proteins (8). These ltter effects result from chnges in ctivities of vriety of serine/threonine-specific protein kinses (reviewed in reference 9) nd phosphtses (10-12) in response to insulin. Studies of insulin binding nd stimultion of the insulin receptor tyrosine protein kinse in skeletl muscle hve not reveled bnormlities tht could ccount for insulin resistnce in the Pim Indins (13). Becuse the insulin receptor cdnas from insulin-resistnt Pim Indins predict norml protein sequences (14, 15), the defect in insulin signl trnsduction tht ccounts for insulin resistnce ppers to occur fter the receptor. This postreceptor lesion ffects the ctivtion by insulin of both glycogen synthse (4) nd glycogen synthse phosphtse ( 1 2) in skeletl muscle. Becuse glycogen synthse is ctivted by dephosphoryltion, it is likely tht the defective ctivtion of the phosphtse ccounts for the bnorml response of glycogen synthse. Thus, the defect in the pthwy of insulin signl trnsduction is either in the structure of the phosphtse itself or in elements leding to the ctivtion of the phosphtse. The insulin-stimulted glycogen synthse phosphtse in humn skeletl muscle is type 1 enzyme (unpublished observtions). One form of this phosphtse, PP,-I, is complex comprising ctlytic subunit nd n inhibitor protein, inhibitor-2 (16). PP,-I is ctivted upon phosphoryltion of inhibitor-2 by glycogen synthse kinse 3, rection tht is enhnced by prior phosphoryltion of inhibitor-2 by csein kinse II (CKII) (17), n enzyme tht in cultured cells is ctivted in response to insulin ( 18, 19) nd other peptide growth fctors (18-20) nd to serum (21). Studies using isolted dipocytes suggest tht phosphoryltion of the CKII site in inhibitor-2 is enhnced in response to insulin (22). Thus, CKII my be in- Csein Kinse 11 in Htumn Muscle 1017
2 Tble I. Ptient Chrcteristics OGTT* results Group Age Height Body weight Body mss index Ft FPG 2 h PG yr cm kg kg/m2 % mg/dl Sensitive 26.7± ± ± ±2.9 23±4 92±4 111±7 Resistnt 39.2±2.7$ 170.0± ±9.3* 45.0±3.3 41±3 1 10±2 179±15* Dibetic 26.4± ± ± ±5.0 31±5 232±17* 373±22* * Orl glucose tolernce test; FPG, fsting plsm glucose; PG, plsm glucose. P < 0.05 compred with sensitive; * P < 0.01 compred with sensitive. strumentl in the mechnism of ctivtion of type 1 phosphtse by insulin. Accordingly, we hve exmined the influence of insulin on CKII ctivity in humn skeletl muscle to determine if n bnorml response in insulin-resistnt subjects might contribute to the mechnism of insulin resistnce. Methods Subjects. 16 Pim Indins (14 mles nd 2 femles) were dmitted to the Clinicl Dibetes nd Nutrition Section, Ntionl Institute of Dibetes nd Digestive nd Kidney Diseses, Ntionl Institute of Helth. After written informed consent ws obtined, subjects were given physicl exmintions including 12-led electrocrdiogrm. After n overnight fst, routine blood chemicl nd hemtologicl exmintions were performed. All subjects hd norml physicl exmintions, electrocrdiogrms, nd blood tests nd none ws tking medictions. Ech subject underwent 75-g orl glucose tolernce test fter receiving diet contining 200 g crbohydrte for t lest 2 d. Bsed on the rte of glucose disposl during hyperinsulinemic euglycemic clmp nd on criteri estblished by the Ntionl Dibetes Dt Group (23), the subjects were ctegorized s insulin-sensitive (n = 7; M vlue (glucose disposl rte) 2 8 mg/min * kg ft-free mss), insulin-resistnt, nondibetic (n = 4; M < 8), nd insulin-resistnt dibetic (n = 5; M. 8). Body ft ws estimted by underwter weighing with simultneous mesurement of residul lung volume (24). The chrcteristics of the ptients nd results of orl glucose tolernce tests re summrized in Tble I. Hyperinsulinemic euglycemic clmp nd muscle biopsy. After n overnight fst, the euglycemic clmp ws initited by primed continuous high dose insulin infusion (600 mu/min per m2) for 120 min s previously described (25). The plsm insulin concentrtion ws mesured by utomted rdioimmunossy (Concept 4: ICN Phrmceuticls, Inc., Horshm, PA) before the strt of the insulin infusion nd t 12.5, 27.5, 55, nd 90 min during the clmp. M vlue ws determined during the lst 40 min of the clmp. Percutneous muscle biopsies were tken from qudriceps femoris before nd t 15, 30, 45, 60, nd 90 min fter the strt of insulin infusion. After locl nesthesi of skin nd muscle fsci, incisions were mde t intervls of t lest 2 cm, 1-2 inches from the midline of both midlterl thighs. The muscle specimens were collected using Bergstrom needle nd frozen in liquid nitrogen within 5 s nd subsequently stored t -70 C. Glucose disposl rtes nd concentrtions of glucose nd insulin in plsm before nd t stedy sttes during the clmp re summrized in Tble II. Preprtion of muscle extrcts. Frozen biopsy specimens were lyophilized, dissected free of blood, ft, nd connective tissue, nd then powdered using mortr nd pestle. Powdered muscle ws mixed with buffer comprising 80 mm #-glycerophosphte, 20 mm EGTA, 15 mm MgCl2, ph 7.3, t rtio of 0.25 ml/mg nd disrupted t 4 C for 20 s using n OMNI 1000 homogenizer (OMNI Interntionl, Inc., Wterbury, CT) t high speed. The homogente ws centrifuged t 100,000 g for 30 min t 4 C nd the superntnt frction ws stored t -70 C. Csein kinse II ssy. CKII ctivity ws ssyed using peptide with the sequence Arg-Arg-Arg-Glu-Glu-Glu-Thr-Glu-Glu-Glu tht is specific substrte for CKII (26) nd tht is useful for mesuring CKII ctivity in extrcts of cells (27). Aliquots of muscle extrct (12 JAl) were incubted in finl volume of 30,ul t 30 C for 20 min in the presence of 50 mm Tris-HCI, ph 7.6, 10 mm MgCI2, 100 MM [,y-32pjatp (1,500-4,000 cpm/pmol) with or without 2 mm peptide in duplicte. Rections were strted by dding ATP nd were stopped by pplying 25 ul of the rection mixtures on Whtmn P-81 ppers (Whtmn Inc., Clifton, NJ), which were then wshed five times with 10 mm H3PO4 nd once with 95% ethnol nd dried. Rdioctivity ssocited with the ppers ws determined by liquid scintilltion spectrometry. The rtio of rdioctivity incorported in the presence of peptide substrte divided by rdioctivity incorported in its bsence ws 4.5±0.15 (men±se; n = 18). Kinse ctivity ws clculted on the bsis of net phosphoryltion of peptide. Assys were liner with both the mount of muscle extrct (5-15 Mg protein/ssy) nd with time up to 30 min (dt not shown). Alkline phosphtse tretment. Before tretment with lkline phosphtse, liquots of muscle extrcts (240 Ml) were concentrted to 60 MAl using Bio-Rd Ultrcent-30 concentrtors (Bio-Rd Lbortories, Richmond, CA) nd then diluted in 600 Ml of buffer A (15 mm Tble II. Glucose Disposl Rtes nd Concentrtions ofplsm Glucose nd Insulin during the Clmp Before the strt of clmp At stedy stte of clmp Group Glucose Insulin Glucose Insulin Glucose disposl rte mg/dl MU/mi mg/dl MU/mt mg/min * kg-ffm Sensitive 101±4 9.1±2.0 93±2 2382± ±0.7 Resistnt 131±5 41.3±6.0* 98±2 2845± ±0.7* Dibetic 227±19* 20.6± ±9* 2310± ±0.5* FFM, ft-free mss. * P < 0.05 compred with sensitive; * P < 0.01 compred with sensitive R. Med, I. Rz, F. Zurlo, nd J. Sommercorn
3 Tris-HCl, ph 7.9, 5 mm KCI, 0.5 mm MgCl2, 0.5 mm dithiothreitol, nd I mm phenylmethylsulfonyl fluoride) (20). The diluted extrcts were gin concentrted to 60 yl nd diluted with 600 ji of buffer A before being concentrted to Al. Two equl liquots of ech resultnt extrct in buffer A were incubted in totl volume of 120 Al with or without 1 U of lkline phosphtse (equilibrted in buffer A), in the presence of 100 jlm ZnCI2 t 230 for 15 min (20). Alkline phosphtse beds were then sedimented by centrifugtion nd CKII ctivity in the superntnt frction nd in the rection mix without phosphtse ws ssyed s described bove. For control rections, lkline phosphtse beds were boiled for 20 min, which inctivted the enzyme ssyed with p-nitrophenylphosphte s substrte. Western blotting. Aliquots of muscle extrcts tht ech contined 25 gg of protein were subjected to SDS-PAGE on 12.5% gel. Proteins were trnsferred from the gel to nitrocellulose using Bio-Rd Lbortories blotting pprtus t 60 V for 4 h in cold room. The nitrocellulose blot ws developed with ntiserum to bovine thymus CKII nd '251-protein A s described previously (27). After utordiogrphy, the bnds corresponding to the - nd,3-subunits ofckii were cut out, nd ssocited rdioctivity in ech ws determined by y-counting. The rdioctivity ssocited with both subunits ws liner with the mount of extrct protein up to 50 yg (dt not shown). Mterils. [y-32p]atp nd '251-protein A were purchsed from New Englnd Nucler, Boston, MA. Antiserum to bovine thymus CKII ws obtined from Dr. Michel Dhmus, University of Cliforni, Dvis, CA. The peptide with the sequence Arg-Arg-Arg-Glu-Glu- Glu-Thr-Glu-Glu-Glu ws obtined from Peninsul Lbortories, Inc., Belmont, CA. Immobilized lkline phosphtse ws purchsed from Sigm Chemicl Co., St. Louis, MO. Sttisticl nlysis. The dt presented re men vlues± 1 SE of the men. Comprisons of two smple mens were mde using Student's t test. Sttisticl significnce of the effect of insulin on CKII ctivity during the insulin infusion (Fig. 1) ws ssessed by repeted mesures nlysis of vrince. Results - E U IC Y DE 'E (-) E CL Time course ofinsulin-stimulted csein kinse II ctivity. Fig. 1 shows the effect of insulin on CKII ctivity mesured in ex) oi Time of Insulin Infusion (min) Figure 1. Activtion of csein kinse II by insulin in humn skeletl muscle. Muscle biopsies were tken before nd t vrious times during hyperinsulinemic, euglycemic clmp. The preprtion of muscle extrcts nd ssys of CKII ctivity re described in Methods. The dt re mens±sem for seven insulin-sensitive (o), four insulin-resistnt, nondibetic (x), nd five insulin-resistnt dibetic (m) subjects. The effect of insulin on CKII ctivity in ll three groups ws significnt (P < 0.05) s ssessed by repeted mesures nlysis of vrince. Bsl CKII ctivity (t = 0) in resistnt subjects ws significntly higher (P < 0.05) thn in sensitive or dibetic subjects s ssessed by Student's t test. trcts of humn skeletl muscle obtined during high dose insulin clmp. In sensitive subjects, CKII ctivity ws rpidly nd trnsiently stimulted. The effect ws essentilly mximl (37±8% over bsl) by 15 min nd persisted through 45 min (42± 1I1% over bsl) fter which ctivity begn to decline. The ctivtion ws biphsic in three subjects, which ccounts for the slightly lower ctivity t 30 min thn t 15 nd 45 min. CKII ctivity ws lso incresed in response to insulin in dibetics, however, in contrst to sensitive subjects, the ctivity remined elevted over the 90-min period exmined. The mximum ctivtion (34±7% over bsl) ws similr to tht seen in sensitive subjects, but it ws not chieved until 90 min. The time course of the response of CKII to insulin in nondibetic resistnt subjects ws similr to tht in the dibetics, but the mgnitude of ctivtion ( 19± 10%) ws only bout one-hlf tht chieved in the other groups. The mgnitude ofthe insulin effect in resistnt subjects my be limited becuse of higher bsl CKII ctivity nd limit to the mximum obtinble specific ctivity, which under our experimentl conditions ppers to be bout 3 pmol/min per mg dry muscle. Bsl CKII ctivity. To determine whether differences in bsl CKII ctivity mong the three groups could be explined by different concentrtions of CKII, three extrcts from ech group were subjected to immunoblot nlysis nd quntittion of both - nd /3-subunits of CKII. Fig. 2 shows n utordiogrm of the immunoblot. It is pprent from inspection tht the concentrtion of CKII is similr mong the three groups. An dditionl liquot of one smple (number 3) from ech group tht contined twice the mount of extrct protein ws nlyzed to demonstrte tht the blotting technique cn detect smll differences in CKII protein (see lso reference 18). Bnds corresponding to - nd /-subunits of CKII were excised nd ssocited rdioctivity ws determined by y-counting. CKII ctivity ws not correlted with the mount of either -subunit (r = -0.21) or /3-subunit (r = ), indicting tht the higher bsl CKII ctivity in resistnt subjects does not result from overexpression ofckii, but rther from elevted ctivity ofthe enzyme. Becuse insulin-resistnt nondibetic subjects were hyperinsulinemic, it is possible tht the elevted bsl CKII ctivity is the result of insulin ction. This possibility is sup-,3 S R x x3 l 2 3 2x ,.A... * ~~~~~~~~~~~~~ Figture 2. Immunoblot nlysis of csein kinse II in extrcts of humn skeletl muscle. Aliquots of extrcts tht ech contined 25 pg of totl protein were subjected to SDS-PAGE nd electrophoretic trnsfer to nitrocellulose. The blots were developed with CKII ntibody nd 1251-protein A nd n utordiogrm ws prepred s described previously (27). S1-S3 refer to smples from insulin sensitive subjects, R1-R3 from resistnt, nondibetics, nd Dl-D3 re smples from resistnt dibetic subjects. Lnes lbeled 2 x 3 contined 50 pg of protein from extrcts of sensitive, resistnt, nd dibetic subjects. D Csein Kinse II in Humn Muscle 1019
4 ported by the dt in Fig. 3, which shows tht mong ll subjects, bsl CKII ctivity ws correlted with fsting plsm insulin levels (r = 0.61; P < 0.02). Mechnism of insulin-stimulted csein kinse II. The mechnism by which insulin ctivtes CKII is not known. Previous studies hve shown tht insulin-stimulted CKII ctivity is stble to gel filtrtion ( 18) or ion-exchnge chromtogrphy (19), suggesting tht the kinse is covlently modified in response to insulin. Ackermn et l. (20) provided evidence tht the mechnism by which epiderml growth fctor stimultes CKII involves phosphoryltion of the enzyme or of n effector protein. Tretment of extrcts from EGF-stimulted cells with immobilized lkline phosphtse restored CKII ctivity to control levels. Subsequent studies hve shown tht EGF promotes phosphoryltion of the,3-subunit of CKII nd tht enzyme ctivity is tightly ssocited with the extent of its phosphoryltion (28). To determine if insulin ctivtes CKII by mechnism similr to tht of EGF, we treted extrcts of muscle, tken from ll three groups before nd fter insulin dministrtion, with immobilized lkline phosphtse. Fig. 4 shows tht tretment with lkline phosphtse reduced nd equlized CKII ctivity mong the extrcts. To verify tht this effect ws the result of phosphtse ctivity, control incubtions were done using phosphtse tht ws inctivted by heting t 100 C, which eliminted the bility of the lkline phosphtse to reduce CKII ctivity in the extrcts (Tble III). Thus, in ll three groups, the mechnism by which insulin stimultes CKII ctivity ppers to involve phosphoryltion of the enzyme or ofn effector molecule. Furthermore, becuse phosphtse tretment equlized bsl CKII ctivities, the higher bsl ctivity of CKII in resistnt subjects compred with the other groups pprently cn be ccounted for by similr phosphoryltion mechnism. This result lends further support to the interprettion tht higher bsl CKII ctivity is cused by the higher fsting insulin levels in resistnt subjects. Discussion Studies of the mechnism of insulin-resistnce in skeletl muscle of Pim Indins hve identified trget enzymes nd severl.o-._ ) n E > >. - C. E u ce E U 0 ) * O x X Fsting Insulin Concentrtion (pu/ml plsm) Figure 3. Reltionship between bsl csein kinse II ctivity nd the concentrtion of insulin in plsm of fsting subjects. The preprtion of extrcts nd ssys of CKII nd insulin re described in Methods. Subjects were either insulin sensitive (o), insulin-resistnt, nondibetic (x), or insulin-resistnt dibetic (v). CKII ctivity ws positively correlted with the concentrtion of insulin in plsm (r = 0.61; P < 0.02). x u > 1500 Y 500 u 0. Insulin -~I._ U Sensitive j 1 I + Resistnt + Dibetic Figure 4. Effect of lkline phosphtse on csein kinse II ctivity in extrcts of muscle obtined before nd fter insulin dministrtion. Extrcts were prepred from muscle of insulin-sensitive, insulin-resistnt, nondibetic nd insulin-resistnt dibetic subjects either before (-) or fter (+) dministrtion of insulin. Extrcts were ssyed for CKII ctivity before (open brs) nd fter tretment with immobilized lkline phosphtse (solid brs) s described in Methods. Dt re men±sem (n = 3). potentil elements of the insulin signl trnsduction pthwy tht re ffected. Glycogen synthse (4), glycogen synthse phosphtse (12), phosphorylse phosphtse (unpublished observtions), nd S6 Kinse (29) ll respond more slowly nd to lesser extent thn is norml. However, one criticl element of the pthwy, the insulin receptor, does not pper to be ffected in such wy s to contribute to insulin resistnce (13). Thus, the biochemicl defect in insulin signl trnsduction ppers to lie between the receptor nd vrious downstrem elements of the pthwy(s) of insulin ction. The simplest interprettion of the results of our studies is tht the bility of insulin to ctivte CKII is not impired in insulin-resistnt nondibetic subjects. Results presented in Fig. 1-3 suggest tht, in the bsl fsting stte, CKII in muscle of resistnt nondibetics is lredy ctivted by insulin to level greter thn tht in sensitive subjects. This my result from both the higher fsting insulin concentrtions in resistnt nondibetic subjects (Tble II nd Fig. 3) s well s the fct tht the insulin receptor in skeletl muscle of resistnt nondibetic subjects is more sensitive to insulin thn is the receptor from sensitive subjects (13). In ddition to the ctivtion by endogenous insulin, CKII ctiv- Tble III. Effect ofhet Inctivtion on the Ability ofalkline Phosphtse to Reduce Csein Kinse II Activity in Muscle Extrcts CKII Activity (% of control) Control 100 Alkline phosphtse 27.9±5.2 P < Heted lkline phosphtse 91.5±6.7 NS 10 muscle extrcts were incubted for 15 min t room temperture in the presence of 100MM ZnCl2 with either 1 U of lkline phosphtse or with the equivlent mount of het-inctivted lkline phosphtse or with neither (Control). After centrifugtion, superntnt frctions were ssyed for CKII ctivity s described in Methods. Dt re mens±sem R. Med, I. Rz, F. Zuirlo, nd J. Sommercorn
5 ity in muscles of resistnt subjects is incresed even further in response to infused insulin during the clmp, nd t ll time points, CKII ctivity in resistnt subjects is higher thn it is in muscle ofinsulin-sensitive subjects. Thus, CKII pprently prticiptes in insulin signl trnsduction either before the lesion responsible for insulin resistnce or in seprte pthwy of insulin ction tht is not ffected by the lesion. Evidence tht insulin signl trnsduction my involve more thn one pthwy hs been obtined from studies using either ntibodies to the norml insulin receptor (30) or mutted receptors trnsfected into norml cells (31, 32). In these studies, mnipultion of the receptor impirs some spects of insulin ction but not others. In prticulr, it ppers tht insulin my ffect nucler events, such s stimultion of mitosis nd possibly gene trnscription, by mens other thn those by which it influences metbolic pthwys. The lower mgnitude of increse in CKII ctivity in response to infused insulin in resistnt subjects likely results from the fct tht much of the potentil ctivtion hs been relized before the strt of the insulin infusion. This my lso ccount for the slower rise of CKII ctivity in response to infused insulin in these subjects thn in sensitive subjects. The response of CKII to insulin in resistnt subjects is likely n pproch to plteu, wheres in sensitive subjects, in which CKII ctivity strts lower, the response my reflect n initil rte of ctivtion Ṫhe response of CKII to infused insulin ppers to be bnorml in muscles ofinsulin-resistnt dibetic subjects (Fig. 1). The response is slower nd t ll but the 90-min timepoint, CKII ctivity is lower thn it is in muscles of insulin-sensitive subjects. However, the mgnitude of the increse, expressed s frctionl increse over bsl ctivity, ws similr in the dibetics nd normls (34 vs. 42%). It is possible tht the slower response of CKII in dibetics results from hormonl or metbolic responses tht re secondry to the development of dibetes. The response of CKII to infused insulin in resistnt nd dibetic subjects differs from tht in sensitive subjects in tht it is not trnsient ctivtion over the 90-min period studied. Becuse the stimultion of CKII ctivity tht occurs in response to insulin is countercted by the ction of phosphtse (Fig. 4), it is possible tht the decline of CKII ctivity in sensitive subjects tht occurs between 45 nd 90 min of insulin infusion involves dephosphoryltion of CKII or of n effector protein. The fct tht CKII ctivity in both resistnt nd dibetic subjects does not decline fter stimultion by insulin, my reflect the bnormlly low ctivtion of protein serine/ threonine phosphtse ctivity by insulin in these subjects (12). The lck of phosphtse stimultion lso my llow CKII to chieve higher mximum ctivity in resistnt subjects thn in sensitive subjects. Although the overll response of CKII to insulin is different between resistnt nd sensitive subjects, the difference probbly does not result from defect in getting the signl to CKII to ctivte it, but rther from defect in the bility to ctivte phosphtse, which could ttenute CKII ctivtion. Becuse the ctivtion of CKII does not pper to be impired by insulin resistnce, the bsis of bnorml ctivtion of type I protein phosphtse probbly involves other mechnisms tht influence its ctivity. These my include glycogen synthse kinse 3 (17), camp-dependent protein kinse cting through inhibitor 1, or the interction of the ctlytic subunit of the phosphtse with vriety of trgeting subunits (33). The mgnitude of ctivtion of CKII in muscle of insulinsensitive subjects in response to infused insulin ws 40% - over bsl ctivity, which is consistent with results of our erlier studies using 3T3-L 1 cells nd H4-IIE heptom cells (18). This is reltively modest ctivtion compred with the twoto tenfold stimultions of CKII in response to insulin, IGF- 1, EGF, nd serum tht hve been reported (19-21). The mgnitude of response depends of course on the ctivity of the enzyme in the bsl stte. We found tht lkline phosphtse tretment suppressed bsl CKII ctivity in extrcts of humn skeletl muscle by 75% (Fig. 4). Thus, it ppers tht in the bsl stte, CKII ctivity is lredy substntilly influenced by mens involving the sme mechnism by which it is ctivted in response to insulin. This fct probbly restricts the mgnitude of response of CKII to hormonl tretment. If one considers the CKII ctivity fter phosphtse tretment s theoreticl bsl ctivity, then the potentil rnge of response of CKII to insulin in humn muscle is bout six- to ninefold. In contrst to our findings, Ackermn nd Osheroff found no effect of lkline phosphtse on CKII ctivity mesured in extrcts ofhormone-nive A43 1 cells, suggesting tht their protocol for hndling cells before exposure to epiderml growth fctor ws effective in suppressing bsl CKII ctivity to minimum. These cells likely hd much greter potentil for CKII ctivtion, which chieved fivefold over bsl ctivity in response to EGF (20). Thus, the mgnitude ofckii ctivtion in response to hormone my be more function of the bsl ctivity thn it is ofthe mximum ctivity chieved in response to the hormone. Differences in bsl CKII ctivity my ccount for the considerble vrition in the mgnitude of response ofthe kinse to vrious hormones or growth fctors tht hve been reported. Acknowledgments We re grteful to Crol Lmkin nd the Nursing Stff for their cre of the subjects nd for ssistnce in performing clinicl procedures, to Rose Fields for technicl ssistnce, to Dr. Michel Dhmus for providing ntibody to CKII, to Chrlesett Lincoln for prepring the typescript, nd to the individuls who volunteered for these studies. References 1. Ymshit, T., W. Nejk, N. B. Rushforth, P. H. Bennett, nd H. Houser Pedigree nlysis of noninsulin-dependent dibetes mellitus in the Pim Indins suggests dominnt mode of inheritnce. Am. J. Hum. Genet. 36: Bogrdus, C Perspective: does insulin resistnce primrily ffect skeletl muscle? Dib/Metb. Rev. 5: Lillioj, S., D. M. Mott, J. K. Zwdzki, A. A. Young, W. G. Abbott, nd C. Bogrdus Glucose storge is mjor determinnt of in vivo "insulin resistnce" in subjects with norml glucose tolernce. J. Clin. Endocrinol. Metb. 5: Freymond, D., C. Bogrdus, M. Okubo, K. Stone, nd D. Mott Impired insulin-stimulted muscle glycogen synthse ctivtion in vivo in mn is relted to low fsting glycogen synthse phosphtse ctivity. J. Clin. Invest. 82: Zick, Y., J. Whittker, nd J. Roth Insulin stimulted phosphoryltion of its own receptor: ctivtion of tyrosine-specific protein kinse tht is tightly ssocited with the receptor. J. Biol. Chem. 258: Ksug, M., Y. Fujit-Ymguchi, D. L. Blithe, nd C. R. Khn Tyrosine-specific protein kinse ctivity is ssocited with the purified insulin receptor. Proc. Ntl. Acd. Sci. USA. 80: Petruzzelli, L., R. Herrer, nd 0. M. Rosen Insulin receptor is n insulin-dependent tyrosine protein kinse: copurifiction ofinsulin-binding ctivity nd protein kinse ctivity to homogeneity from humn plcent. Proc. Nil. Acd. Sci. USA. 81: Denton, R. M Erly events in insulin ction. Cyclic Nucleotide Protein Phosphoryltion Res. 20: Csein Kinse II in Humn Muscle 1021
6 9. Czech, M. P., J. K. Klrlund, K. A. Ygloff, A. P. Brdford, nd R. E. Lewis Insulin receptor signling: ctivtion of multiple serine kinses. J. Bio. Chem. 263: Lopez-Alrcon, L., M. Mojen, L. Monge, nd J. E. Feliu Stimultion ofpyruvte kinse phosphtse ctivity by insulin in isolted rt heptocytes. Biochem. Biophys. Res. Commun. 134: Chn, C. P., S. J. McNll, E. G. Krebs, nd E. H. Fisher Stimultion of protein phosphtse ctivity by insulin nd growth fctors in 3T3 cells. Proc. Ntl. Acd. Sci. USA. 85: Kid, Y., A. Esposito-Del Puente, C. Bogrdus, nd D. M. Mott Insulin resistnce is ssocited with reduced fsting nd insulin-stimulted glycogen synthse phosphtse ctivity in humn skeletl muscle. J. Clin. Invest. 85: Nyomb, B. L., V. M. Ossowski, C. Bogrdus, nd D. M. Mott Reltionship between insulin-sensitive tyrosine kinse ctivity nd in vivo insulin ction in mn. Am. J. Physiol. 258:E964-E Cm, A., A. P. Ptterson, T. Kdowki, H. Kdowki, G. Siegel, D. D'Ambrosio, S. Lillioj, J. Roth, nd S. I. Tylor The mino cid sequence of the insulin receptor is norml in n insulin-resistnt Pim Indin. J. Clin. Endocrinol. Metb. 70: Moller, D. E. A. Yokot, nd J. S. Flier Norml insulin-receptor cdna sequence in Pim Indins with NIDDM. Dibetes. 38: Cohen, P The structure nd regultion of protein phosphtses. Annu. Rev. Biochem. 58: DePoli-Roch, A. A Synergistic phosphoryltion nd ctivtion of ATP-Mg-dependent phosphoprotein phosphtse by FA/GSK-3 nd csein kinse II (PCO7). J. Biol. Chem. 259: Sommercorn, J., J. A. Mullign, F. J. Lozemn, nd E. G. Krebs Activtion of csein kinse II in response to insulin nd to epiderml growth fctor. Proc. Ntl. Acd Sci. USA. 84: Klrlund, J. K., nd M. P. Czech Insulin-like growth fctor I nd insulin rpidly increse csein kinse II ctivity in BALB/c 3T3 fibroblsts. J. Bio. Chem. 263: Ackermn, P., nd N. Osheroff Regultion of csein kinse II ctivity by epiderml growth fctor in humn A-43 1 crcinom cells. J. Biol. Chem. 264: Crroll, D., nd D. R. Mrshk Serum-stimulted cell growth cuses oscilltions in csein kinse II ctivity. J. Biol. Chem. 264: Lwrence, J. C., Jr., J. Hiken, B. Burnett, nd A. A. DePoli-Roch Phosphoryltion of phosphoprotein phosphtse inhibitor-2 (I-2) in rt ft cells. Biochem. Biophys. Res. Commun. 150: Ntionl Dibetes Dt Group Clssifiction nd dignosis of dibetes mellitus nd other ctegories of glucose tolernce. Dibetes. 28: Goldmn, R. F., nd E. R. Buskirk A method for underwter weighing nd the determintion of body density. In Techniques for Mesuring Body Composition. Brozek, J., Henschel, A., editors. Ntl. Acd. Sci. Ntl. Res. Council, Wshington, DC Bogrdus, C., S. Lillioj, K. Stone, nd D. Mott Correltion between muscle glycogen synthse ctivity nd in vivo insulin ction in mn. J. Clin. Invest. 73: Kuenzel, E. A., nd E. G. Krebs A synthetic peptide substrte specific for csein kinse II. Proc. Nll. Acd. Sci. USA. 82: Sommercorn, J., nd E. G. Krebs Induction of csein kinse II during differentition of 3T3-L1 cells. J. Biol. Chem. 262: Ackermn, P., C. V. C. Glover, nd N. Osheroff Stimultion of csein kinse II by epiderml growth fctor: reltionship between the physiologicl ctivity ofthe kinse nd the phosphoryltion stte ofits #-subunit. Proc. Ntl. Acd. Sci. USA. 87: Sommercorn, J., R. Fields, I. Rz, nd R. Med Abnorml ctivtion of S6 Kinse in insulin resistnce. FASEB (Fed. Am. J.) 4:2079. (Abstr.) 30. Ponzio, G., J. 0. Contreres, A. Debnt, V. Bron, N. Gutier, J. Dolis- Kitbgi, nd B. Rossi Use of n nti-insulin receptor ntibody to discriminte between metbolic nd mitogenic effects ofinsulin: correltion with receptor utophosphoryltion. EMBO (Eur. Mol. Biol. Orgn.) J. 7: Debnt, A., E. Cluser, G. Ponzio, C. Filloux, C. Auzn, J. 0. Contreres, nd B. Rossi Replcement of insulin receptor tyrosine residues nd 1163 does not lter the mitogenic effect of the hormone. Proc. Ntl. Acd. Sci. USA. 85: Thies, R. S., A. Ullrich, nd D. A. McClin Augmented mitogenesis nd impired metbolic signling medited by truncted insulin receptor. J. Biol. Chem. 264: Cohen, P., nd P. T. W. Cohen Protein phosphtse come ofge. J. Biol. Chem. 264: R. Med, I. Rz, F. Zurlo, nd J. Sommercorn
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