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Molecular and Cellular Biochemistry 178: 69–75, 1998.© 1998 Kluwer Academic Publishers. Printed in the Netherlands.

Muscle metabolism and quality (MQI) inprediabetic sedentary man

Jan Karlsson1 and Ragnhild Rønneberg2

1OBLA AB, Vaxholm, Sweden; 2Pronova Biocare as, Lysaker, Norway

Received 4 February 1997; accepted 28 May 1997

Abstract

Twelve pairs of healthy sedentary males matched for their body mass index (BMI) with either a low insulin response (LIR; astage of prediabetes) or a high (HIR; controls) to a standardized glucose infusion test (GIT) were studied in respect to theirexercise capacities (W

OBLA, W

SL and relative W

OBLA: W

OBLA × W

SL–1 × 100), muscle fiber composition (%ST), muscle citrate

synthase activity (CS), muscle ubiquinone (MUQ), MUQ over %ST (muscle quality index, MQI), and peripheral insulinsensitivity (PIS) as described with insulin-clamp techniques (SIGITmean). LIR and HIR displayed normal PIS and positiverelationships versus exercise capacity. LIR’s but not HIR’s relative W

OBLA was related to CS as earlier only documented in

endurance athletes but at a lower level than in athletes. This pointed at a poor peripheral oxygen delivery in LIR. LIR’s MQIdecreased relative to HIR’s the higher the muscle CS indicating radical related muscle trauma in LIR as in athletes. LIR representingprediabetes described muscle anomalies, which could represent prestages of the lesions observed in type-2 diabetes. They areclaimed to be responsible for insulin-, glucose-, lipid-resistance, and peripheral circulatory resistance. (Mol Cell Biochem 178:69–75, 1998)

Key words: LIR, HIR, prediabetics, exercise capacity, muscle fibers, muscle oxidative capacity, antioxidants, ubiquinone, vitaminQ, muscle quality index, MQI, metabolic syndrome X, MSX

Address for offprints: J. Karlsson, OBLA AB, Box 242, S-185 23 Vaxholm, Sweden

Introduction

Otherwise healthy male persons but with a low insulinresponse (LIR) to a standardized glucose infusion test (GIT)and a sedentary life-style have a depressed percent distribu-tion of slow twitch muscle fibers (%ST) in comparison withmoderately active controls [1, 2]. Such controls have anormal, high insulin response (HIR) to GIT [3]. Subjects witha low insulin response are considered to be prediabetics [3].An equally depressed %ST was, however, also found to bepresent in healthy controls but matched for an equallysedentary life-style as the prediabetics [1, 4].

An elevated preponderance of fast twitch muscle fibers(%FT) means a reduced capillary density, an elevatedperipheral circulatory resistance and an intra-arterial, elevatedsystolic blood pressure (SBP) during standardized exercise[5]. This has been suggested to be the explanation to theenhanced SBP at rest and with exercise in essential hyper-

tensive patients [6]. This patient group is rich in FT fibers ascompared to healthy, normotensive controls [6, 7]. Confinedto a poor capillary density and/or enhanced %FT [8] is adepressed peripheral insulin sensitivity [9, 10, 11]. Theperipheral insulin resistance related to type-2 diabetesmellitus has, however, been coupled to additional, patho-logical changes in the capillary anatomy [12, 13]. Capillarydensity seems to be more related to anatomy and endowmentrather than to hormonal regulatory features [14, 15]. This iscontrast to peripheral insulin sensitivity, which seems to begoverned by additional features than capillary density per se[15]. Physical training in type-2 diabetes is known to enhancecapillary density but seems not to affect peripheral insulinsensitivity [16].

In a recent report we have described in apparently healthy,moderately physically active male persons and after a chronicmixed diet that: (1) muscle ubiquinone (MUQ) contentincreased with %ST, and (2) the ratio muscle ubiquinone over

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%ST (muscle quality index, MQI) was constant [17]. MQIdid decrease though in a subgroup of healthy males: marathonrunners [4, 18]. The latter finding was interpreted as theantioxidant related muscle ubiquinone content fractiondecreased with %ST. This suggestion was supported by theMQI decrease versus a simultaneous increase in musclecitrate synthase (CS) activity in endurance athletes [18]. TheMQI decrease put forth an antioxidant net depletion andoxidative trauma related to oxygen turn-over [19].

In a separate report it was demonstrated that both a lowmuscle ubiquinone and a low MQI impaired blood glucosedisappearance and enhanced plasma insulin with a standar-dized glucose infusion test (GIT) [4]. Marathon runners, whoare low insulin responders by nature [20] and with a low MQI,compensated this with an increased peripheral insulinsensitivity [4]. This is in line with others’ findings thattraining per se means a less dependence on insulin for bloodglucose control [21]. Such circumstances leave the possibilityopen as to whether there exists a non-insulin related, ‘humoralfactor’ governed muscle glucose uptake with exercise and/or in trained subjects as experimentally indicated [22, 23].

Sedentary but otherwise healthy low-insulin-respondershave a normal peripheral insulin sensitivity in an somato-statin-insulin-glucose infusion test (SIGIT) but is consideredto represent a stage of prediabetes [1, 3]. This could indicatethat the peripheral, capillary bound characteristics establishedin type-2 diabetes have either not yet been developed or arenot activated. It was therefore felt of interest to further pursuestudies in sedentary, low insulin responders and propercontrol persons how they regulate peripheral insulin sensi-tivity and blood glucose control in relation to muscle oxida-tive metabolism.

Materials and methods

Sedentary male volunteers were recruited and subjected to astandardized glucose infusion test (GIT) [1, 24, 25], asomatostatin-insulin-glucose infusion test (SIGIT) [26],graded cycle ergometer exercise test [27] and needle musclebiopsies to the lateral portion of the thigh (M. vastus lateralis)[28] over a period of 3–5 weeks. The volunteers had for anextended period of time been on a regular, mixed Scandi-navian diet, which is documented to be poor in antioxidantnutrients and omega-3 fatty acids (vitamin F

1) [29, 30]. They

reported in the inclusion interviews that they had had no foodsupplement (nutratherapy) or had been treated with anyethical drugs during the immediate 3 months prior to theinvestigations. A total of thirty-seven [37] sedentary volun-teers were accepted for further studies [1].

GIT was based on an i.v. bolus injection of 0.5 g glucose× kg–1 body weight (BW) (20% solution) followed by acontinuous infusion for 60 min of 0.02 g × kg–1 × min–1 (15%

solution). As high insulin responders (HIR, n = 16) andcontrols were considered those with a normal biphasic insulinresponse. Their plasma insulin level after 5 min was withinthe two highest quartiles in healthy man. Low-insulin-responders (LIR, n = 21) and prediabetics [3] were those withan insulin response below the upper boarder of the lowerquartile in healthy man. Data obtained from the initial 10 min(5–10 min) were referred to as acute phase GIT and later data(20–60 min) as late phase GIT [1]. From the original 37volunteers, 12 matched pairs were obtained for the presentcomputations and presentation based on their body massindex (BMI), providing muscle fiber and ubiquinone datawere available. The subjects were all clinically healthy. Allprocedures were approved by the local Ethical Committee.

Peripheral, predominantly muscle bound qualities ofsignificance for glucose metabolism and ‘insulin sensitivity’can be measured with the somatostatin-insulin-glucoseinfusion test (SIGIT) [26]. This procedure is well correlatedto the hyperinsulinemic, euglycemic clamp technique [31].SIGIT includes a 150 min i.v. infusion of somatostatin (270µg × h–1; Stilamin®, Serono, S.p.A., Rome, Italy), insulin (0.4mU × kg–1 × min–1; Actrapid Human®, Novo Industri A/S,Copenhagen, Denmark) and glucose (6 mg × kg–1 × min–1 asa 15% solution) including human albumin to prevent adheringto glass surfaces. Blood samples were drawn at 0, 30, 60, 90,120 and 150 min from the contralateral, anticubital vein andanalyzed as in GIT. Peripheral insulin sensitivity was expressedas mean blood glucose values at 90, 120 and 150 min(SIGITmean) [1].

Exercise capacity was determined with graded cycleergometer exercise tests with frequent analyses of bloodlactate concentration [32]. The exercise intensities corre-sponding to:1. a blood lactate concentration of 4 mmol × 1–1 (W

OBLA, and

WOBLA

× kg–l body weight (BW))and2. symptom limited (‘maximal’) exercise capacity (W

SL)

were obtained [33]. Relative WOBLA

(%WOBLA

) was com-puted as the W

OBLA fraction of W

SL (W

OBLA × W

SL–1 × 100)

[27, 33]. Peak blood lactate was defined as the bloodlactate concentration at termination of the highest (‘peak’)exercise intensity.Muscle biopsies were analyzed for muscle fiber composi-

tion expressed as percent distribution of slow twitch (ST),oxidative (‘red’) or type I muscle fibers (%ST) [34], muscleubiquinone (MUQ) content [35], and muscle citrate synthase(CS) activity ad modum Lin [36, 37]. Muscle quality index(MQI) to mark for radical induced muscle metabolic lesionswas also computed as MUQ × %ST–1 × 100 and presented asunits [17, 38].

Data are presented as means ± 1 SEM. Conventionalparametric statistics have been applied. Statistical analysiswere performed as two-tailed Student t-test for paired data.

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Correlation coefficients were examined by analysis of linearregression. A ‘p’ value less than 0.05 (< 0.05) was consideredstatistically significant.

Results

Prediabetics and their control persons were almost identicalin respect to their antropometry (Table 1). Minor statisticaldifferences existed, however, in respect to body size, with thecontrols being taller and tended to be heavier (p < 0.1).

Relative WOBLA

tended to be lower in prediabetics than inthe controls (p < 0.1). Peak blood lactate concentration wasalso higher in prediabetics than in their controls indicating ahigher energy output by means of muscle glycogenolysis andfermentation (Table 1).

Late phase GIT glucose was elevated in prediabetics incontrast to in the controls (Table 1). SIGITmean bloodglucose level was, however, identical in the two groups (Table1). SIGITmean decreased (controls) or tended to decrease(prediabetics) with W

OBLA exercise capacity (Fig. 1A). In

respect to exercise capacity, one trait differed between the two

groups: relative WOBLA

versus muscle citrate synthase (CS)activity. Relative W

OBLA increased in prediabetics with muscle

citrate synthase but not in the controls (Fig. 1B).To further scrutinize the differences in the periphery

between the two groups, correlation matrices were obtained(Figs 2A and 2B). In controls but not in prediabetics strongcorrelations were seen between muscle citrate synthase onone hand and muscle ubiquinone content and MQI on theother. Muscle citrate synthase and ubiquinone correlated inprediabetics to exercise capacity but not in controls. Thiscould indicate the presence of muscle metabolic lesions inprediabetics with increased muscle oxidative metabolism. Onan individual level MQI increased in controls with musclecitrate synthase but was virtually flat in prediabetics andcorresponded to the lower range in controls (Fig. 3, Table 1).MQI in prediabetics corresponded also to the lower MQIrange in endurance athletes (mean 0.63 ± 0.13 (SEM) units)[4]. This is indicative of muscle trauma in sedentary predia-betics the higher the muscle citrate synthase activity as earlierseen in marathon runners [18].

Table 1. Mean values ± 1 SEM for different examined parameters in 12pairs of male volunteers recruited with a low insulin respons (LIR,considered prediabetics) or a high insulin respons (HIR) as controls to astandardized glucose infusion test (GIT)

Parameter All LIR HIR

Age, yrs 36.7 ± 1.2 36.3 ± 2.4 36.3 ± 2.0Height, cm 179 ± 1 176 ± 2 181 ± 1*Weight, kg 71.9 ± 1.1 69.9 ± 2.5 74.3 ± 1.1BMI, kg × cm–2 22.5 ± .3 22.6 ± .6 22.6 ± .3GIT glucose, mmol/l

early phase 17.5 ± 0.4 17.4 ± 0.7 17.7 ± 0.5late phase 18.4 ± 1.0 20.5 ± 1.1 16.4 ± 1.5#

GIT insulin, pmol/learly phase 339 ± 47 195 ± 29 484 ± 69†

late phase 495 ± 119 302 ± 68 638 ± 225#

SIGITmean, 5.8 ± .04 5.1 ± .5 5.8 ± .7mmol/lWOBLA, W 214 ± 8 222 ± 12 230 ± 16WOBLA × kg–1 2.9 ± .1 3.1 ± .1 3.1 ± .2BW,W × kg–1

WSL, W 263 ± 8 280 ± 17 267 ± 14Relative WOBLA 82 ± 2 80 ± 3 86 ± 3(%WOBLA)Peak blood lactate 6.0 ± .9 7.1 ± .6 5.3 ± .9#

mmol × 1–1

Muscle %ST, % 38 ± 2 38 ± 4 40 ± 4Muscle UQ 0.27 ± .03 0.28 ± .06 0.27 ± .03mg × g–1 dwMuscle CS 0.49 ± .03 0.52 ± .03 0.47 ± .04µkat × g–1 dwMuscle Quality 0.70 ± .08 0.56 ± .08 0.73 ± .20Index (MQI), units

*p < 0.05; #p < 0.01; †p < 0.001.

Fig. 1. (A) The individual relationship in low-insulin-responders (LIR)considered to be prediabetics but otherwise healthy and their controls (high-insulin-responders, HIR) between peripheral insulin sensitivity as measuredby SIGITmean and WOBLA exercise capacity corrected for body weight. (B)The individual relationships in prediabetics (LIR) and their controls (HIR)between relative WOBLA and muscle citrate synthase (CS) activity in thelateral portion of the thigh (M. vastus lateralis).

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Discussion

The major findings in the otherwise healthy but sedentary,low-insulinresponders, i.e. prediabetics, were:1. prediabetics’ peripheral insulin sensitivity was as in

controls positively related to exercise capacity2. prediabetics’ but not controls’ relative W

OB LA (%W

OBLA)

was, as earlier seen in endurance athletes, related to musclecitrate synthase activity

3. in prediabetics relative WOBLA

tended to be lower, and peakblood lactate higher than in controls indicating adequatemuscle carbohydrate stores in prediabetics for their higherglycogenolytic, fermentative energy output

4. prediabetics’ muscle antioxidant depots appeared to havebeen subjected to a similar trauma as in marathon runners– muscle ubiquinone depletion – the higher the musclecitrate synthase activity

5. prediabetics’ skeletal muscle metabolism was in spite ofthe same muscle fiber composition differently regulatedthan in controls

6. it is suggested that these differences in prediabetics versustheir controls are synonymous with the pathologicalchanges manifested in type-2 diabetes and responsible fornot only insulin- and lipid- resistance but also the corre-sponding peripheral circulatory resistance.

The difference between prediabetics and controls in relativeW

OBLA (W

OBLA × W

SL–1 × 100, %W

OBLA), showing only the

former to display a positive relationship with muscle citratesynthase activity, is provocative. Whereas W

OBLA is confined

to muscle oxidative capacity and molecular oxygen (O2)

delivery capacity (‘aerobic’ power), WSL is depending onboth oxidative and fermentation (‘anaerobic’) pathways [27].W

OBLA as an increased fraction of W

SL – increased relative

WOBLA

- is usually interpreted as an increased physicalconditioning status confined to: (a) less reliance on fermen-tation; (b) decreased muscle and blood lactates; and (c)increased lactate oxidation rates, etc. [27, 39].

The changes in muscle lactate metabolism with trainingstatus is related to a muscle LD isozyme shift towards more‘heart specific’ and oxidative LD isozymes [2]. These LDisozymes are more inclined to oxidize lactate than to reducepyruvate in glycogenolysis.

The prediabetics’ increase in relative WOBLA

versus musclecitrate synthase activity is suggested to mark for a lesion inmuscle molecular oxygen turn-over not present in theircontrols. The rational for this suggestion is that such arelationship has earlier been seen only with heavy eliteendurance training and related to the subsequently enhancedoxygen extraction in contracting muscles [40, 41]. Thecomparable hindrance (‘bottle-neck’) in prediabetics andtheir oxygen transport is most probably located on the musclefiber and/or capillary level (see below). The combination ofoxygen turn-over with an increased fermentation rate (‘acid-ity’) and the subsequent enhanced electron pressure in thecontracting muscle is synonymous with an increased forma-tion rate of reactive, oxygen-centered radical species (oxy-radicals) corresponding to up to 15% of oxygen utilization[19]. This is synonymous with a subsequent oxidative traumathreat (‘oxygen-burst injury’) [30, 42]. Inflammatory pro-cesses in the muscle capillary bed have also been documentedin relation to radical trauma due to antioxidant depletion [43].

The depressed MQI with muscle citrate synthase in thepresent prediabetics in contrast to their controls displayed another finding seen in trained populations and/or with training[30]. This suggested also a radical related trauma and a netubiquinone consumption in the present prediabetics. Radical

Fig. 2. (A and B) Correlation matrices in controls (HIR, A) and prediabetics(LIR, B) between exercise capacity, blood glucose control (late phase –LP – plasma glucose and insulin in GIT), peripheral insulin sensitivity(SIGITmean) and markers for muscle metabolism: muscle citrate synthaseactivity (MCS), ubiquinone content (MUQ) and muscle quality index (MQI;ubiquinone content over percent distribution of slow twitch musclefibers, MUQ × %ST–1 × 100).

Fig. 3. Muscle quality index (MQI, see Fig. 2) versus muscle citratesynthase (CS) activity in prediabetics (LIR) and their controls (HIR).

73

trauma in the present prediabetic muscle is further supportedby the previously observed shift in muscle polyunsaturatedfatty acids (PUFA) observed in type-2 diabetic muscle [44].Diabetics have also increased malondealdehyde (MDA)levels indicating on-going radical trauma and fatty acidperoxidation [45]. This is in line with the present antioxidantdepression and observed effects on polyunsaturated fattyacids in general and the essential fatty acid (EFA) class:omega-3 fatty acids (vitamin F

1), in particular [30, 46–48].

It seems reasonable to first seek explanation to antioxidantdepression in contracting muscles and their oxidative metabo-lism [30]. Muscle metabolism in healthy man is confined tomuscle fiber composition. The two main muscle fiber types:slow twitch (ST, ‘red’ or oxidative) and fast twitch (FT,‘white’ or glycogenolytic) muscle fibers, have differentmuscle biochemical machineries [2, 30]. This is partlydepending on endowment [49] but also on adaptation pro-cesses [50]. Lately it has been documented that also intra-uteral gestation affects individual muscle fiber composition[51]. The ST fiber is synonymous with a more dense capillarysupply, enhanced oxygen delivery and oxidative enzymeactivities, enhanced antioxidant enzyme activity, enhancedinsulin receptor density, an efficient fatty acid mobilizationfrom plasma lipids (muscle lipoprotein lipase, LPL, receptorsand activity), enhanced lactate oxidation, etc than the FT fiber[2, 30, 52, 53]. ST rich muscles have also a more rapid,efficient and smooth regulation of central and peripheralcirculation [2, 54]. Subjects rich in ST fibers adapt moreefficiently to endurance type exercise than those rich in FTfibers [50]. The FT fiber and its performance context is inmany aspects in concert with traits referred to as, or confinedto the ‘Metabolic-Syndrome-X (MSX)’, ‘Metabolic-Cardio-vascular-Syndrome’, or the ‘Atherothrombogenic Syndrome(ATS)’ [55, 56]. A poor intrauteral gestation has been shownto promote both %FT and MSX [57].

In the heart, citrate synthase is related to a number ofmarkers for oxidative metabolism as myoglobin, ubiquinone,LD heart specific isozymes, lactate oxidation, a high creatinekinase (CK) activity in the mitochondria (CKmit), etc. [37,58, 59]. In skeletal muscle of endurance trained personsmuscle citrate synthase activity is positively related to %ST,myoglobin, ubiquinone, negatively to gross lactate dehydro-genase activity (LD), but positively to the heart specific LDisozymes and lactate oxidation [2, 39, 60]. Both in the heartand in trained skeletal muscle the oxidative metabolicpotential is related to different expressions for muscle power(‘work’) as heart ventricle pressure [58] or exercise capacityboth in absolute terms, e.g. W

OBLA, or in relative terms:

relative WOBLA

[2, 30].Based on comparisons with these data from normal heart

and endurance adapted skeletal muscle it seems reasonableto suggest that the present prediabetics had a differentregulation of their muscle metabolic properties than their

controls in spite the same muscle fiber composition expressedas % FT. Whether this difference is related to endowment, alow birthweight, or to injury-adaptation in the contractingmuscles can only be speculated upon. This difference leavesalso the question open, whether prediabetics have, as sug-gested for endurance trained prediabetics, additional, non-insulin-dependent ways to accommodate a ‘humoral factor’governed muscle glucose uptake as experimentally indicatedin animals [22, 23, 61].

Rolf Luft and associates have suggested that low-insulin-responders represent a prediabetic stage [62]. They have animpaired insulin release but a normal peripheral insulinsensitivity [63]. This is contrast to endurance athletes with alow insulin respons, who have an enhanced peripheralsensitivity [1, 20, 64]. Endurance athletes can as a result oftheir enhanced insulin receptor and postreceptor functionsdownregulate their glucose stimulated insulin release. Theirskeletal muscle has evidently alternative means for a mem-brane bound glucose transport, as they can sustain evensubstantial metabolic lesions (‘overuse’ injury) and maintaina proper carbohydrate metabolism [4]. In sedentary predia-betics with their poor insulin production and unsaturatedinsulin receptors [14] it is mandatory to compensate with analternative upregulation of their peripheral carbohydratemuscle metabolism in a ‘training-adaptation-like’ fashion.The present prediabetics appeared to have similarities in theirmuscle metabolism with endurance athletes not accounted forin previous studies. Is their ‘normal peripheral insulinsensitivity’ a result of an upregulation in parallel to thetraining-like adaptations in respect to relative W

OBLA or MQI

and indicative of non-insulin glucose uptake pathways? Thisalternative pathway for glucose uptake could be identical tothe suggested, ‘humoral factor’ governed muscle glucoseuptake [22, 23, 61]. This ‘humoral factor’ does not need tobe identical to the post insulin receptor function synonymouswith the ‘glucose transporter proteins’ of which at least onefraction (GLUT 4) is ‘exercise dependent’ [65, 66].

The suggested alternative, non-insulin-dependent pathwayfor muscle glucose uptake in endurance athletes and seden-tary prediabetics is by definition included in the SIGITmeasurements. This implies that SIGITmean not only marksfor peripheral insulin sensitivity as suggested [26] but alsofor this extra-insulin regulated means for glucose transportover the cell membrane. This would offer a ‘short-cut’ in thediabetic muscle to the capillary endothelium regulated insulintranslocation to the muscle membrane and subsequent,‘normal’ glucose uptake [14]. Earlier studies have docu-mented that in established type-2 diabetes, muscle capillaryanomalies are present [11, 12, 67]. It has also been shown thatin contrast to healthy man [3], physical conditioning in type-2 diabetes does not change peripheral glucose metabolism inspite of a muscle capillary density increase [16]. Takentogether, this points at major differences between diabetic and

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healthy muscles in man. It is suggested from the present resultsthat to some extent these differences are established alreadyin prediabetics versus their healthy controls. These differencesin muscle capillary anatomy and function might explain theinsulin- and glucose resistance, increased peripheral circulatoryresistance and borderline or established essential hypertension,but also lipidresistance or lipid intolerance seen in type-2diabetes [15, 68]. These are also the clinical dispositionsincluded in metabolic syndrome X (MSX) [69, 70].

To summarize, subjects with a low insulin response and asedentary lifestyle (LIR, referred to as prediabetics) showedin contrast to equally sedentary but high insulin responders(HIR) as control persons different adaptation mechanisms intheir leg muscle metabolism to exercise. In sedentary pre-diabetics a training-like effect in muscle oxygen metabolismwas documented earlier seen only in endurance athletes. Thissuggested a reduced oxygen transport related to a poor musclecapillary density most probably combined with pathologicalchanges in the capillaries’ anatomy. Combined with this, areduced muscle antioxidant power the higher the oxidativecapacity was observed in prediabetics. These anomalies inotherwise healthy prediabetics might be identical to thoseseen in type-2 diabetes patients and referred to as insulin- andglucose resistance, lipidresistance or -intolerance, andresponsible for circulatory hypertension. They could alsorepresent a common denominator for muscle metabolicsyndrome X (MSX).

References

1. Pigon J, Karlsson J, Östenson C-G: Physical fitness and insulinsensitivity in human subjects with a low insulin response to glucose.Clin Sci 87: 187–192, 1994

2. Karlsson J: Localized muscular fatigue: role of muscle metabolism andsubstrate depletion. In: RS Hutton, DI Miller (eds). Exercise and SportsSciences Review. Philadelphia: Franklin Institute Press, 1979, pp 1–42

3. Efendic’ S, Luft R, Wajngot A: Aspects of pathogenesis of type 2diabetes. End Rev 5: 395–410, 1984

4. Karlsson J, Rønneberg R: Endurance athletes, insulin secretion andmuscle quality. Can J Cardiol 12: 1037–1043, 1996

5. Frisk-Holmberg M, Jorfeldt L, Juhlin-Dannfelt A, Karlsson J: Leg bloodflow during exercise in man in relation to muscle fibre composition.Acta Physiol Scand 112: 339–342, 1981

6. Juhlin-Dannfelt A, Frisk-Holmberg M, Karlsson J, Tesch P: Centraland peripheral circulation in relation to muscle fibre composition innormo- and hypertensive man. Clin Sci 56: 335–340, 1979

7. Karlsson J, Wahlberg F, Kaijser C, Sannersedt R: Blood pressureresponse in relation o blood lactate during exercise in patients withessential hypertension. Int J Sports Med 6: 169–173, 1985

8. Andersen P: Capillary density in skeletal muscle of man. Acta PhysiolScand 95: 203–205, 1975

9. Lithell H, Lindgärde F, Hellsing K, Lundqvist G: Body weight, skeletalmuscle morphology, and enzyme activities in relation to fasting seruminsulin concentration and glucose tolerance in 48 year old man. Diabetes30: 19–25, 1981

10. Richter EA, Garetto LP, Goodman MN, Ruderman NB. Enhancedmuscle glucose metabolism after exercise: Modulation by local factors.Am J Physiol 246: E476–E482, 1984

11. Lillioja S, Young AA, Culter CL, Ivy JL: Skeletal muscle capillarydensity and fiber type are possible determinants of in vivo insulinresistance in man. J Clin Invest 80: 415–424, 1987

12. Siperstein MD, Norton W, Unger RH, Madison LL: Muscle capillarybasement membrane width in normal, diabetic and prediabeticpatients. Trans Assoc Am Phys 79: 330–347, 1966

13. McVeigh GE, Brennan GM, Johnston GD et al.: Impaired endotheliumdependent and independent vasodilation in patients with Type 2 (non-insulin dependent) diabetes mellitus. Diabetologia 35: 771–776, 1992

14. Björntorp P:. Visceral obesity: a ‘Civilization Syndrome’. Obesity Res1: 206–222, 1993

15. Björntorp P: The relationship between obesity and diabetes. In: KGMMAlberti, P Zimmet, RA DeFronzo, H Keen (eds). InternationalTextbook of Diabetes Mellitus, 2nd edn. London: John Wiley & SonsLtd, 1996, pp 1–17

16. Allenberg K, Johansen K, Saltin B: Skeletal muscle adaptations tophysical training in type II (non-insulin-dependent) diabetes mellitus.Acta Physiol Scand 223: 365–373, 1988

17. Karlsson J, Lin L, Sylvén C, Jansson E: Muscle ubiquinone in healthyphysically active males. Mol Cell Biochem 156: 169–172, 1996

18. Karlsson J, Lin L, Rønneberg R: Marathon performance, fibertypes, enzymes and antioxidant quality (MQI) in leg muscles. Inpreparation

19. Sawyer DT: O2! Who would have imagined all the biological processesthat involve oxygen? CHEMTECH: 369–375, 1988 (June)

20. Wirth A, Diem C, Mayer H, M´örl H, Vogel I, Björntorp P: PlasmaC-peptide and insulin in trained and untrained subjects. J Appl Physiol39: 1157–1175, 1981

21. Houmard JA, Shinebarger MH, Dolan PL, Leggett-Frazier N et al.:Exercise training increases GLUT-4 protein concentration in pre-viously sedentary middle-aged man. Am J Physiol 264: E896–E901,1993

22. Goldstein MS: Humoral factor of hypoglycemia in muscular exercise.Am J Physiol 200: 67–70, 1961

23. Gao J, Gulve EA, Holloszy J: Contraction-induced increase in muscleinsulin sensitivity: requirement for a serum factor. Am J Physiol 266:E186–E192, 1995

24. Nesher R, Cerasi E: Biphasic insulin release as the expression ofcombined ihibitory and potentiating effects of glucose. Endocrinology121: 1017–1021, 1987

25. Cerasi E: The plasma insulin response to glucose infusion in healthysubjects and in diabetes. Acta Endocrinol (Copenh.) 55: 278–304, 1967

26. Harano Y, Ohgaku S, Hidaka H, Haneda K, Kikkawa R, Shigeta Y:Glucose, insulin and somatostatin infusion for the determination ofinsulin sensitivity. J Clin Endocrinol Metab 45: 1124–1127, 1977

27. Karlsson J, Jacobs I: Onset of blood lactate accumulation duringmuscular exercise as a threshold concept. Int J Sports Med 3: 190–201, 1982

28. Bergström J: Muscle electrolytes in man. Acta Physiol Scand (Suppl.68): 1–87, 1962

29. Skjervold H: Lifestyle diseases – human diet. Meieriosten 19: 527–529, 1991

30. Karlsson J: Antioxidants and exercise. Champaign, IL: Human KineticsPublishers, Inc, 1–218, 1996

31. Ho LT, Chang ZY, Wang JT et al.: Insulin sensitivity in offsprings ofpatents with type 2 diabetes mellitus. J Appl Physiol 7: 31–34, 1990

32. Karlsson J, Jacobs I, Sjödin B et al.: Semi-automatic blood lactateassay: Experiences from an exercise laboratory. Int J Sports Med 4:52–55, 1982

33. Karlsson J. Muscle exercise, energy metabolism and blood lactate.

75

In: L Tavazzi, PE di Prampero (eds). The Anaerobic Threshold.Physiological and Clinical Significance. Basel: Karger, 1986, pp 35–46

34. Thorstensson A: Muscle strength, fibre types and enzyme activitiesin man. Acta Physiol Scand (Suppl 443): 1–45, 1976

35. Edlund P-O: Determination of coenzyme Q10, α-tocopherol andcholesterol in biological samples by coupled-column liquid chroma-tography with coulometric and ultraviolet detection. Journ Chromat425: 87–97, 1988

36. Lowry OH, Passonneau JV: A flexible system on enzymatic analysis.Academic Press, New York, 1972, pp 1–185

37. Lin L, Sotonyi P, Somogyi E et al.: Coenzyme Q10 content in differentparts of the normal human heart. Clin Physiol 8: 391–398, 1988

38. Karlsson J, Lin L, Gunnes S, Sylvén C, Åström H: Muscle ubiquinonein male effort angina patients. Mol Cell Biochem 156: 173–178, 1996

39. Karlsson J, Sjödin B, Thorstensson A, Hultén B, Frith K. LDHisozymes in skeletal muscle of endurance and strength trained subjects.Acta Physiol Scand 93: 150–156, 1975

40. Saltin B, Blomqvist G, Mitchell JH, Johnson RL, Wildenthal K,Chapman CB: Response to exercise after bed rest and training.Circulation 37–38 (Suppl VII): 1–78, 1968

41. Sjödin B, Jacobs I, Karlsson J: Onset of bloc lactate accumulation andenzyme activities in M. vastus lateralis in man. Int J Sports Med 2:166–170, 1981

42. Werns S: Strategies to limit reperfusion injury. In: EJ Topol (ed).Acute Coronary Intervention. Alan R. Liss Inc., New York, 1988,pp 271–279

43. Scalvini T, Marocolo D, Cerudelli B, Sleiman I et al.: Pravastatin-associated myopathy. Report of a case. Recenti Prog Med 86: 198–200, 1995

44. Pan DA, Lillioja S, Wilner MR, Kriketos AD: Skeletal musclemembrane lipid composition is related to adiposity and insulin action.J Clin Invest 96: 2802–2808, 1995

45. Noberasco G, Odetti P, Boeri D, Maiello M, Adezatti L: Malondialde-hyde (MDA) level in diabetic subjects. Biomed Pharmacoter 45: 193–196, 1991

46. Karlsson J: Heart and skeletal muscle ubiquinone or CoQ10 as aprotective agent against radical formation in man. In: G Benzi (ed).Advances in Myochemistry. John Libbey, London, 1987, pp305–318

47. Lindh G, Karlsson J, Rønneberg R: Plasma nutrients in joint and musclepain patients before and after nutritional therapy. J Nutr Environ Med7: 15–26, 1997

48. Karlsson J, Rønneberg R: Muscle metabolism, antioxidants, MQI andplasma vitamin F in man. In preparation

49. Komi PV, Karlsson J: Physical performance, skeletal muscle enzymeactivites and fibre types in monozygous and dizygous twins of bothsexes. Acta Physiol Scand (Suppl 462): 1–28, 1979

50. Örlander J, Kiessling K-H, Karlsson J, Ekblom B: Low intensitytraining, inactivity and resumed training in sedentary men. Acta PhysiolScand 101: 351–362, 1977

51. Barker DJP, Hales CN, Fall CDH, Osmond C, Phipps K, Clark PMS.Type 2 (non/insulin dependent) diabetes mellitus, hypertension andhyperlipidemia (syndrome X), relation to reduced fetal growth.

Diabetologia 36: 62–67, 199352. Saltin B, Gollnick PD: Skeletal muscle adaptability: Significance

for metabolism and performance. In: LD Peach, RH Adrian, SRGeiger (eds). Handbook of Physiology. Section 10: Skeletal Muscle.Baltimore: Williams and Wilkins Company, 555–631, 1983

53. Jenkins RR, Friedland R, Howald H: The relationship of oxygen uptaketo superoxide dismutase and catalase activity in humans skeletalmuscle. Int J Sports Med 5: 11–14, 1984

54. Shepherd JT, Blomqvist CG, Lind AR, Mitchell JH, Saltin B. Static(isometric) exercise: Retrospection and introspection. Circ Res 48(Suppl I): 179–188, 1981

55. Reaven GM: Role of insulin resistance in human disease. Diabetes37: 1595–1607, 1988

56. Cigolini M, Seidell JC, Targher G, Deslypere JP: Fasting serum insulinin relation to components of the metabolic syndrome in Europeanhealthy men: The European Fat Distribution Study. Metabolism 44:35–40, 1995

57. Phillips DI, Barker DJ, Hales CN, Hirst S, Osmond C: Thinness atbirth and insulin resistance in adult life. Diabetologia 37: 150–154,1994

58. Lin L, Sylvén C, Sotonyi P, Somogyi E, Kaijser L, Jansson E: Lactatedehydrogenase and its isoenzyme activites in different parts of thenormal heart. Cardiovasc Res 23: 601–606, 1989

59. Sylven C, Lin L, Kallner P, Sotonyi P, Somogyi E, Jansson E:Dynamics of creatine kinase shutle enzymes in the human heart. Eur JClin Invest 21: 350–354, 1991

60. Terrados N, Melichna J, Sylvén C, Jansson E, Kaijser K. Effects oftraining at stimulated altitude on performance and muscle metaboliccapacity in competitive road cyclists. Acta Physiol Scand 57: 203–209, 1988

61. Karlsson J, Rosell S, Saltin B: Carbohydrate and fat metabolism incontracting canine skeletal muscle. Pflügers Arch 331: 57–69, 1972

62. Cerasi E, Luft R: ‘What is inherited – and what is added’ hypothesisfor pathogenesis of diabetes mellitus. Diabetes 16: 615–627, 1967

63. Pigon J: Aspect of pathogenesis of low insulin response in man.Stockholm: Karolinska Institute: 1–40, 1994

64. King DS, Staten MA, Kohrt WM, Dalsky GP, Elahii D, Holloszy JO:Insulin secretory capacity in endurance trained and untrained youngmen. Am J Physiol 259: E155–E161, 1990

65. Coderre L, Kandror KV, Vallega G, Pilch PF: Identification andcharacterization of an exercise-sensitive pool of glucose transportersin skeletal muscle. J Biol Chem 270: 27584–27588, 1995

66. Kandror KV, Pilch PF: Compartmentalization of protein traffic ininsulin-sensitive cells. Am J Physiol 271: El–E14, 1996

67. Siperstein MD, Unger RH, Madison LL: Studies of muscle capillarybasement membranes in normal, diabetic, and prediabetic patients. JClin Invest 47: 1973–1999, 1968

68. Karlsson J, R�ønneberg R: Muscle fibers, MQI and metabolicsyndrome X (MSX). 1997, In preparation

69. Björntorp P: The regulation of adipose tissue distribution in humans.Int J Obes Relat Metab Disord 20: 291–302, 1996

70. Krone W, Meinertz T: Metabolic syndrome as a cardiovascular riskfactor. Herz 20: 2–4, 1995