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The Journal of Clinical Endocrinology & Metabolism 87(6):2906 –2908 Copyright © 2002 by The Endocrine Society
QUICKI Is Useful for Following Improvements in Insulin Sensitivity after Therapy in Patients with Type 2 Diabetes Mellitus AKIRA KATSUKI, YASUHIRO SUMIDA, ESTEBAN C. GABAZZA, SHUICHI MURASHIMA, HIDEKI URAKAWA, KOHEI MORIOKA, NAGAKO KITAGAWA, TAKASHI TANAKA, RIKA ARAKI-SASAKI, YASUKO HORI, KANAME NAKATANI, YUTAKA YANO, AND YUKIHIKO ADACHI Third Department of Internal Medicine (A.K., Y.S., E.C.G., H.U., K.M., N.K., T.T., R.A.-S., Y.H., Y.Y., Y.A.), Department of Radiology (S.M.) and Department of Laboratory Medicine (K.N.), Mie University School of Medicine, Mie 514-8507, Japan To investigate whether quantitative insulin sensitivity check index (QUICKI) would be useful as an index of insulin resistance during the clinical course of type 2 diabetes mellitus, correlation between QUICKI and the index of the euglycemic hyperinsulinemic clamp study [clamp insulin resistance (clamp IR)] was evaluated in 60 patients with type 2 diabetes mellitus before and after treatment. The therapy program consisted of diet (1440 –1720 kcal/d) and exercise (walking 10,000 steps daily) for 6 wk. QUICKI and clamp IR were significantly correlated before (r ⴝ 0.598, P < 0.0001) and after (r ⴝ 0.583, P < 0.0001) treatment. Neither the slope nor the intercept of the linear corre-
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NSULIN RESISTANCE PLAYS an important role in the pathophysiology of type 2 diabetes mellitus (1). To date, various methods have been used to evaluate insulin sensitivity in vivo (2–5). Of these, the quantitative insulin sensitivity check index (QUICKI) has been recently reported to be a useful marker of insulin resistance in patients with type 2 diabetes mellitus (5–9). Previous studies have demonstrated the usefulness of QUICKI in different conditions, and it is particularly suitable for epidemiological survey (10 –14). QUICKI has been studied in sedentary nondiabetic adults, obese adolescents, and patients with polycystic ovary syndrome during treatment and in women with normal glucose tolerance and gestational diabetes mellitus during pregnancy (7, 15–17). However, its use in clinical practice for the follow-up of insulin resistance in type 2 diabetic patients during treatment has not been as yet evaluated. In the present study, we investigated whether QUICKI is correlated with the index of the euglycemic hyperinsulinemic clamp study [clamp insulin resistance (clamp IR)] in patients with type 2 diabetes mellitus before and after treatment. Subjects and Methods Subjects
This study comprised 60 Japanese patients with type 2 diabetes mellitus (age from 22– 69 yr old; Table 1). Type 2 diabetes mellitus was diagnosed in our patients at a local clinic 8.4 ⫾ 6.9 yr before the beginAbbreviations: clamp IR, Insulin resistance assessed by the euglycemic hyperinsulinemic clamp study; en%, energy percent; HbA1c, hemoglobin A1c; QUICKI, quantitative insulin sensitivity check index.
lation between QUICKI and clamp IR measured before treatment was significantly different from those measured after treatment (slopes; F ⴝ 0.002, P ⴝ 0.96, intercepts; F ⴝ 2.65, P ⴝ 0.11). During treatment, the values of both QUICKI (8% change; P < 0.0001) and clamp IR (38% change; P < 0.0001) significantly increased and their changes were significantly correlated (r ⴝ 0.415, P < 0.01). In conclusion, QUICKI may become a useful method for the follow-up of insulin resistance during the treatment of patients with type 2 diabetes mellitus. (J Clin Endocrinol Metab 87: 2906 –2908, 2002)
ning of this study. All patients received dietary (1440 –1720 kcal/d) and exercise (walking 10,000 steps/d) therapy without any drugs. Their blood sugar was in good control [hemoglobin A1c (HbA1c) ⬉ 6.5%] during the initial years; however, thereafter their blood sugar gradually increased (HbA1c ⭌ 8%) because of overeating and inactivity. Five of 60 patients received sulfonylureas (glibenclamide 2.5–5.0 mg/d) for about 3 yr before the beginning of the study; the blood sugar of these patients also worsened several months before admission due to overeating and inactivity. They were admitted in our clinical department for glycemia control. We categorized them as having type 2 diabetes mellitus based on the diagnostic criteria of the American Diabetes Association (18). There were 16 patients with peripheral neuropathy, 16 with simple diabetic retinopathy and 10 with microalbuminuria. None of them had macrovascular complications. Informed consent was obtained from all subjects before the beginning of the study.
Study protocol and methods After admission, the patients participated in a program of diet and exercise for 6 wk. The dietary treatment was as follows: 1440 –1720 kcal/d with a diet consisting of 20 energy percent (en%) protein, 25 en% fat, and 55 en% carbohydrates. During the exercise therapy, the patients walked 10,000 steps daily. The blood levels of glucose, HbA1c and insulin, and the values of QUICKI, clamp IR, the body fat area, and blood pressure were measured in all subjects within 1 wk after admission and 1 wk before discharge. Sulfonylureas were withdrawn 1 d before the clamp study. The plasma glucose level was measured by an automated enzymatic method. The HbA1c (normal value: 4.3–5.8%) was measured by HPLC. Serum insulin was measured using an immunoradiometric assay kit (Insulin Riabead II kit, Dainabot, Tokyo, Japan). The intra and interassay coefficients of variation of the assay were 2.0% and 2.1%, respectively. No significant cross-reactivity or interference were observed between insulin and proinsulin, C peptide, glucagon, secretin, and gastrin-I. QUICKI was calculated using the following formula: 1/ [log fasting serum insulin (U/ml) ⫹ log fasting plasma glucose (mg/dl)] (5).
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TABLE 1. Clinical and laboratory characteristics of patients with type 2 diabetes mellitus before and after treatment Before treatment
No. Sex (M/F) Age (yr) Duration of diabetes (yr)
After treatment
60 45/15 54.4 ⫾ 11.3 8.4 ⫾ 6.9 23.7 ⫾ 3.2 109.2 ⫾ 51.2 124.6 ⫾ 55.6
22.4 ⫾ 2.9a 96.3 ⫾ 50.1a 115.0 ⫾ 54.2
9.6 ⫾ 2.3 8.7 ⫾ 2.7
8.2 ⫾ 1.5a 6.4 ⫾ 1.5a
43.2 ⫾ 28.8
34.2 ⫾ 23.4
Clamp IR (mol/kg䡠min) QUICKI
34.4 ⫾ 17.1 0.343 ⫾ 0.036
47.5 ⫾ 16.6a 0.371 ⫾ 0.038a
Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg)
131.5 ⫾ 21.0
128.2 ⫾ 16.3
79.4 ⫾ 11.2
78.8 ⫾ 10.2
BMI (kg/m2) Visceral fat area (cm2) Subcutaneous fat area (cm2) HbA1c (%) Fasting plasma glucose (mmol/liter) Fasting serum insulin (pmol/liter)
Data are means ⫾ SD. a P ⬍ 0.001, Before vs. After treatment. Clamp IR was evaluated by the euglycemic hyperinsulinemic clamp technique using an artificial pancreas (STG-22, Nikkiso, Tokyo, Japan) (2, 4). At 0800 h, a priming dose of insulin (Humulin R, Eli Lilly & Co. Japan, Kobe, Japan) was administered during the initial 10 min in a logarithmically decreasing manner to rapidly raise serum insulin to the desired level (1200 pmol/liter); this level was then maintained by continuous infusion of insulin at a rate of 13.44 pmol/kg䡠min for 120 min. The mean insulin level from 90 –120 min after starting the clamp study was stable (before treatment: 1227.6 ⫾ 201.0 pmol/liter, after treatment: 1185.6 ⫾ 232.2 pmol/liter). Blood glucose was monitored continuously and maintained at the target clamp level (5.24 mmol/liter) by infusing 10% glucose. The mean amount of glucose given during the last 30 min was defined as a clamp IR. Body fat area was evaluated by a previously described method (19). At 0800 h, after an overnight fast of 12 h, all patients underwent single abdominal computed tomography scanning at the umbilical level in respiratory phase. Any ip regions having the same density as the sc fat layer were defined as a visceral fat area; this area was measured by tracing object contours on films using a computerized planimetric method. In addition, we measured blood pressure in supine position after a rest of 5 min.
Statistical methods Data were expressed as the means ⫾ sd. A t test was performed to compare the means of variables measured before and after treatment. The relationship of QUICKI with clamp IR was evaluated by univariate regression analysis. The regression lines before and after treatment were compared by analysis of covariance. The t test and correlations were carried out using the StatView 4.0 software program (Abacus Concepts, Berkeley, CA). Analysis of covariance was performed using the PRISM 2.0 software program (GraphPad Software, Inc., San Diego, CA). P value less than 0.05 was considered as statistically significant.
Results
Significant correlations were observed between QUICKI and clamp IR before (r ⫽ 0.598, P ⬍ 0.0001, Fig. 1, closed circles and solid line) and after (r ⫽ 0.583, P ⬍ 0.0001, Fig. 1, open circles and dotted line) treatment. Analysis of covariance showed that neither the slopes (50.93 ⫾ 9.05 vs. 50.37 ⫾ 8.66, F ⫽ 0.002, P ⫽ 0.96) nor the intercepts (y-intercept ⫽ ⫺11.20 vs. ⫺8.29, x-intercept ⫽ 50.68 vs. 45.39, F ⫽ 2.65, P ⫽ 0.11) of the regression lines between QUICKI and clamp IR before and after treatment were statis-
FIG. 1. Correlation between QUICKI and clamp IR in patients with type 2 diabetes mellitus before and after treatment. QUICKI was significantly correlated with clamp IR before (r ⫽ 0.598, P ⬍ 0.0001, F, solid line) and after (r ⫽ 0.583, P ⬍ 0.0001, E, dotted line) treatment. Neither the slopes (F ⫽ 0.002, P ⫽ 0.96) nor the intercepts (F ⫽ 2.65, P ⫽ 0.11) of the regression lines were significantly different before and after treatment.
tically different in magnitude. During treatment, in addition to improvement in the blood concentrations of glucose (26% change; P ⬍ 0.0001) and HbA1c (15% change; P ⬍ 0.0001), there was a significant increase in QUICKI (8% change; P ⬍ 0.0001) and clamp IR (38%change; P ⬍ 0.0001) (Table 1). Percent change of QUICKI was significantly correlated with that of clamp IR (r ⫽ 0.415, P ⬍ 0.01, Fig. 2). A significant relationship between QUICKI and clamp IR was observed before (r ⫽ 0.649, P ⬍ 0.0001) and after (r ⫽ 0.579, P ⬍ 0.0001) treatment when five patients treated with sulfonylureas were excluded. There was also a significant correlation between the percent changes of QUICKI and clamp IR (r ⫽ 0.416, P ⬍ 0.01) without these five patients. Discussion
The present study clearly demonstrated that QUICKI correlates significantly with clamp IR before and after treatment in patients with type 2 diabetes mellitus. Homeostasis model assessment has been reported to be of value for evaluating insulin resistance in type 2 diabetic patients treated with sulfonylureas (20). It was not possible to prove in our present study the accuracy of QUICKI in patients with type 2 diabetes mellitus under medication. In future studies, it would be necessary to assess the usefulness of QUICKI in type 2 diabetic patients receiving different types of medication. It is known that the degree of adipocity affects the relationship between QUICKI and clamp IR (5, 21). Although patients enrolled in our present study were nonobese as judged by their body mass index values, they were metabolically obese subjects because they had abnormal increase of visceral fat (22). However, further studies including typically obese patients should be performed. Duncan et al. (16) previously reported that QUICKI may not be useful as a clinical index of insulin resistance during exercise therapy in sedentary adults. However, the compar-
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5.
6. 7.
8. 9. 10. 11.
FIG. 2. Correlation between the percent change of QUICKI and clamp IR in patients with type 2 diabetes mellitus after therapy. There was a significant correlation between the percent changes of QUICKI and clamp IR (r ⫽ 0.415, P ⬍ 0.01).
ison of QUICKI with an index derived from the minimal model analysis of the unmodified frequently sampled iv glucose tolerance test (FSIVGTT) (23), and not with the index calculated during the gold standard euglycemic hyperinsulinemic clamp technique may explain the negative result (24). In conclusion, QUICKI may be a useful method not only for diagnosing insulin resistance but also for its follow-up during the treatment of patients with type 2 diabetes mellitus.
12. 13.
14.
15. 16. 17.
Acknowledgments Received December 27, 2001. Accepted March 8, 2002. Address all correspondence and requests for reprints to: Akira Katsuki, M.D., Third Department of Internal Medicine, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. E-mail:
[email protected].
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