To compare the metabolic consequences of insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM), glycemic control and energy metabolism were evaluated in 18 children displaying IDDM and 19 NIDDM adult patients. With rising concentrations of fasting blood glucose (FBG), hemoglobin A1C and free fatty acid, the percentage of the ratio of resting energy expenditure (REE) to predicted REE expressed as %REE increased and the respiratory quotient (RQ) decreased. The linear regression between RQ and FBG showed the same gradient in IDDM and NIDDM although the RQ in IDDM was always 0.07 lower than that in NIDDM given various FBG concentrations. Those patients whose RQ values were less than 0.7, indicating ketone body production, included 8 (44%) IDDM and 2 (11%) NIDDM patients. These results may explain the relatively greater manifestation of ketoacidosis in IDDM

Chiba, Noriko

Kuroda, Yasuhiro

Matsuda, Junko

Miyamoto, Ken-ichi

Shuto, Emi

Takata, Kazumi

Takeda, Eiji

Tawara, Mariko

Yamanaka, Hisami

Yokota, Ichiro

Tokushima University Institutional Repository

INTRODUCTIONInsulin stimulates the cellular uptake of glucose andsubsequent glucose oxidation by suppressing free fattyacid (FFA) levels and fat oxidation (1). Insulin alsoactivates pyruvate dehydrogenase (2, 3), which controlsthe entry of carbohydrates into the tricarboxylic acidcycle. Insulin-mediated glucose utilization is diminished inthe presence of elevated plasma FFA concentration inpatients with diabetes mellitus (4, 5). Fatty acid and itsoxidation stimulate gluconeogenesis, which inhibitsglucose uptake and glycolysis in liver (6, 7). In addition, apositive correlation has been reported between plasmaFFA concentration or lipid oxidation and hepatic glucoseproduction in non-insulin-dependent diabetes mellitus(NIDDM) patients (8, 9).Elevated concentrations and the increased oxidationof plasma FFA have been shown to induce insulinresistance (10-12). Insulin resistance is a characteristicfeature of NIDDM (8, 13, 14). In contrast, insulinresistance has not been demonstrated to be significant intreated insulin-dependent diabetes mellitus (IDDM) (15).However, it has been demonstrated that the cellular effectof insulin is reduced in IDDM (16-18). In addition,adolescents with poorly controlled IDDM have asignificant degree of hepatic insulin resistance (19).In this study, the relationship between glycemic controland indices of energy metabolism such as resting energyexpenditure (REE) and respiratory quotient (RQ) wasevaluated to compare the pattern of energy metabolism inIDDM and NIDDM patients.PATIENTS AND METHODSPatientsThe study population consisted of 18 IDDM childrenwho attended a summer camp for diabetic children and 19NIDDM adult patients admitted to Tokushima UniversityHospital for dietary education and glycemic control. Thephysical characteristics of the subjects are shown in Table1. Body mass index tended to be higher in NIDDMpatients. IDDM patients underwent dietary therapy andreceived insulin. NIDDM patients were treated with eitherdiet alone or oral hypoglycemic agents or both. FourNIDDM patients were re-studied after treatment for onemonth. Informed consent in this study was obtained fromall subjects.Energy metabolism studiesThe REE was studied using open-circuit indirectcalorimetry (Calorie Scale, Chest MI, Tokyo) employing atransparent ventilated hood system while the IDDMchildren attended camp or on the second day of admissionComparison of energy metabolism in Insulin-Dependent andNon-Insulin-Dependent diabetes mellitusKazumi Takata＊, Noriko Chiba＊, Mariko Tawara＊, Hisami Yamanaka＊ Emi Syuto＊,Ken-ichi Miyamoto＊, Ichiro Yokota†, Junko Matsuda†, Yasuhiro Kuroda†and Eiji Takeda＊＊Department of Clinical Nutrition ; and †Department of Pediatrics, The University of Tokushima School ofMedicine, Tokushima, JapanAbstract : To compare the metabolic consequences of insulin-dependent diabetes mellitus (IDDM)and non-insulin-dependent diabetes mellitus (NIDDM), glycemic control and energy metabolismwere evaluated in 18 children displaying IDDM and 19 NIDDM adult patients. With risingconcentrations of fasting blood glucose (FBG), hemoglobin A1C and free fatty acid, the percentage ofthe ratio of resting energy expenditure (REE) to predicted REE expressed as %REE increased andthe respiratory quotient (RQ) decreased. The linear regression between RQ and FBG showed thesame gradient in IDDM and NIDDM although the RQ in IDDM was always 0.07 lower than that inNIDDM given various FBG concentrations. Those patients whose RQ values were less than 0.7,indicating ketone body production, included 8 (44%) IDDM and 2 (11%) NIDDM patients. Theseresults may explain the relatively greater manifestation of ketoacidosis in IDDM. J. Med. Invest. 44 :67-71, 1997Key Words : insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, energy metabolism, respiratoryquotientReceived for publication July 14, 1997 ; accepted August 5, 1997.１ Address correspondence and reprint requests to Eiji Takeda, M.D.,Ph.D., Department of Clinical Nutrition, The University of TokushimaSchool of Medicine, 3-18-15, Kuramoto-cho, Tokushima, Japan.The Journal of Medical Investigation Vol.44 1997６７for NIDDM patients. The system was calibrated beforeeach test with a reference gas mixture (95% O2 and 5%CO2). The REE was measured for 15 min between 7 : 00and 8 : 00 after a 12-h overnight fast. Energy expenditurewas calculated from the respiratory gas exchange using astandard equation (20). The RQ and protein oxidation ratewere calculated from measurements of daily urinarynitrogen excretion. Urinary nitrogen production wascalculated from measured daily urinary urea elimination(21). Fat and carbohydrate utilizations were calculatedfrom the nonprotein RQ (20). Percentages of the ratioof REE to predicted REE which was obtained fromrecommended dietary allowances for the Japanese (22),were expressed as % REE.AnalysisThe plasma glucose concentration was measured by theglucose oxidase method using a Beckman glucoseanalyzer II (Beckman Instrument, Fullerton, CA). FFAlevel was assayed by a fluorometric method (23).Hemoglobin A1C (HbA1C) concentration in blood wasmeasured by high-pressure liquid chromatography and itsreference level for the assay was 5-7%. Body compositionincluding lean body mass was assessed by a bioelectricimpedance analysis. All data are presented as means±SD.Statistical analyses were performed using Student's t testfor unpaired data and the Wilcoxon matched pairs test fornonparametric data.RESULTS1) Physical and metabolic parameters in IDDM andNIDDM patients (Table 1)Fasting blood glucose (FBG) and HbA1C concentrationsin NIDDM individuals were not significantly differentfrom those of IDDM patients. In contrast, % REE and FFAconcentrations were higher while the RQ was lower inIDDM patients than those of NIDDM. These resultsindicated that the rates of energy expenditure and lipidoxidation in IDDM were significantly elevated than thoseof NIDDM patients. However glycemic control asestimated by FBG and HbA1C concentrations were thesame in both IDDM and NIDDM patients.2) Relationship between FBG or HbA1C and % REE or RQin IDDM and NIDDM patients% REE demonstrated a positive correlation with bothFBG (r=0.490, p<0.05) and HbA1C (r=0.477, p<0.05) inIDDM individuals. These parameters also showed samevalues in NIDDM patients although they were notsignificant (Figure 1 A and 1 B). RQ was found to have aninverse correlation with HbA1C in NIDDM (r=-0.652,p<0.01) but was not remarkable in IDDM (Figure 2 A).Moreover, RQ had an inverse correlation with the FBG inboth IDDM (r=-0.718, p<0.001) and NIDDM (r=-0.580,p<0.01) (Figure 2 B). The linear regression was similarfor both IDDM and NIDDM patients. However, RQ valuesin IDDM individuals were always 0.07 lower than those inNIDDM, indicating a 17% higher lipid oxidation ratein IDDM than in NIDDM patients at various FBGconcentrations.3) Relationship between FFA and FBG in IDDM andNIDDM patients (Figure 3)FFA concentrations in IDDM were more widelyTable 1. Physical and metabolic parameters in IDDM and NIDDMpatients1. IDDM, insulin-dependent diabetes mellitus ; NIDDM,non-insulin-dependent diabetes mellitus ; BMI, body mass index ;FBG, fasting blood glucose ; HbA1C, glycohemoglobin ; FFA, freefatty acid ; % REE, resting energy expenditure(REE)/predictedenergy expenditure (BEE)x 100 ; RQ, respiratory quotient.2. x±standard deviation (SD).3-5. Significant difference between IDDM and NIDDM, 3, p<0.02 ;4, p<0.001 ; 5, p<0.005.Fig. 1. Relationship between A) HbA1C (IDDM : r=0.477, p<0.05,NIDDM : ns.) and B) FBG (IDDM : r=0.490, p<0.05, NIDDM : ns.)and % REE in IDDM (■ - - - - and) and NIDDM (△ and )patients.IDDM1(n=18)NIDDM1(n=19)Age (y)BMI (kg/m2)FBG (mg/dl)HbA1c (%)FFA (μEq/l)% REE (%)RQ11.9±2.7218.9±2.9175±998.64±1.6928±421133±250.707±0.0654.4±12.924.1±4.8186±849.29±2.2628±4183115±1440.768±0.065K. Takata et al. Energy metabolism in IDDM and NIDDM６８distributed than those in NIDDM. FFA concentrationswere positively related with FBG (r=0.655, p<0.01) inIDDM, although this relationship was not significant inNIDDM.4) Relationship between % REE and RQ in IDDM andNIDDM patients (Figure 4)A remarkable inverse relationship between % REE andRQ was observed in both IDDM (r=-0.670, p<0.01) andNIDDM patients (r=-0.520, p<0.05) (Figure 4). However,the slope between those parameters was steeper in IDDMthan in NIDDM. The lines corresponding to IDDM andNIDDM values crossed at 122 of % REE and 0.740 of RQ.In marked contrast, RQ values were found to be less than0.7, which indicated the production of ketone bodies (24),in 8 (44%) of 19 IDDM patients and 2 (11%) of 19 NIDDMpatients, respectively.5) Effects of treatment on % REE and RQ in NIDDMpatientsAs shown in Table 2, a one-month period of treatmentof 4 NIDDM patients resulted in improvement of FBG,HbA1C and FFA values. Likewise, % REE decreasedremarkably while RQ slightly increased. Thus, all thebiochemical and metabolic parameters improved withtreatment.Fig. 2. Relationship between A) HbA1C (IDDM : ns, NIDDM :r= -0.652, p<0.01) and B) FBG (IDDM : r= -0.718, p<0.001, NIDDM :r= -0.580, p<0.01) and RQ in IDDM (■ - - - - and) and NIDDM (△and ) patients.Fig. 3. Relationship between FBG and FFA in IDDM (■ - - - - and,r= -0.655, p<0.01) and NIDDM (△ and , ns.) patients.Fig. 4. Relationship between % REE and RQ in IDDM (■ - - - - and,r= -0.670, p<0.01) and NIDDM (△ and , r= -0.520, p<0.05)patients.Table 2. Effects of glycemic control on % REE and RQ in NIDDMpatients1. FBG, fasting blood glucose ; HbA1C, glycohemoglobin ; FFA,free fatty acid ; REE, resting energy expenditure ; RQ, respiratoryquotient.2. x±standard deviation (SD).3. Significantly different than before treatment, p<0.05.Before(n=4)After(n=4)FBG (mg/dl)1HbA1c (%)1FFA (μEq/l)1% REE (%)1RQ1183±91210.1±2.8667±309119±150.753±0.05153±73.8.7±1.7593±236108±930.779±0.05The Journal of Medical Investigation Vol.44 1997 ６９DISCUSSIONThe negative correlation between FBG or FFA andRQ suggests that low insulin levels exert their regulatoryeffect on intracellular glucose and fat metabolism bycontrolling the availability of FFA substrate for fatoxidation, which in turn inhibits glucose oxidation. Indiabetic patients, FFA oxidation consumes nicotinamideadenine dinucleotide, thereby resulting in an accumula-tion of acetyl CoA, a powerful allosteric inhibitor ofpyruvate dehydrogenenase (25, 26). A prolonged effect ofdecreased glucose oxidation is an increase in pyruvatedehydrogenase kinase activity, which in turn leadsto enhanced phosphorylation and inactivation of thepyruvate dehydrogenase complex (27). On the otherhand, the accumulation of acetyl CoA activates pyruvatecarboxylase, the first enzymatic step in the gluconeo-genesis pathway (25), thus making more pyruvateavailable for gluconeogenesis (28). Furthermore, oxidationof FFA provides energy for gluconeogenesis andstimulates it in an FFA concentration dependent manner(29). It is conceivable that increased FFA concentrationcontributes to the excessive rates of gluconeogenesis inIDDM and NIDDM patients. Therefore, increased REE isassociated with a degree of glucose intolerance in bothIDDM and NIDDM (30). The reduction in REE afterimproved glycemic control was also observed inassociation with an increase in RQ, reflecting reductionsof lipid oxidation and hepatic glucose production (31).RQ in IDDM was 0.07 lower than that of NIDDM patientsat various FBG concentrations. These results indicate thatthe lipid oxidation rate was 17% higher in IDDM thanNIDDM. Since the RQ of ketogenesis is zero, a measurednonprotein RQ of less than 0.70 is conceivable when a netsynthesis of ketone bodies occurs without furtheroxidation but with subsequent retention and/or excretion(24). Thus, ketone bodies appear in plasma as products ofincreased FFA oxidation in poorly controlled diabeticpatients. IDDM patients have a greater tendency tomanifest ketoacidosis than NIDDM because % REE isinversely correlated with RQ to a much greater degree inIDDM than NIDDM. Thus, the pattern of energymetabolism in IDDM patients is quite different from thatin NIDDM patients. This may result from a propensity byIDDM patients to synthesize ketone bodies.Skutches et. al. have demonstrated a reduced respon-siveness of adipose tissue to insulin-stimulated glucoseoxidation in the presence of acetone, acetol, and 1,2-propanediol which was not readily reversible after thewithdrawal of acetone from drinking water (32). 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Comparison of energy metabolism in Insulin-Dependent and Non-Insulin-Dependent diabetes mellitus

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Comparison of energy metabolism in Insulin-Dependent and Non-Insulin-Dependent diabetes mellitus

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