Matthews et al. (1) demonstrated that the homeostasis model assessment of insulin resistance (HOMA-IR) is closely correlated with the insulin sensitivity index assessed by euglycemic clamp in only a few patients with type 2 diabetes. Emoto et al. (2) and Bonora et al. (3) also reported that HOMA-IR provided a good correlation in the clamp studies in a relatively greater number of diabetic subjects. However, it has been recognized among some investigators that the HOMA-IR shows relatively low value when the insulin secretion decreases in patients with advanced type 2 diabetes, because the HOMA-IR is a product of fasting glucose and insulin levels. On the other hand, several investigators have recently proposed methods to assess insulin sensitivity using an oral glucose tolerance test (OGTT). Stumvoll et al. (4) disclosed that the OGTT can assess insulin sensitivity in nondiabetic subjects. Even in type 2 diabetes, an index proposed by Matsuda and DeFronzo (5) was correlated to clamp-derived insulin sensitivity. Although these parameters from the OGTT decrease with worsening of glucose tolerance, the values inversely increase once the total insulin secretion declined. They have not been fully validated in Japanese subjects, especially in various grades of type 2 diabetes. In this study, we proposed a new index from the results of the OGTT and compared them with the M-value obtained from the clamp method.

We studied 113 Japanese subjects (72 men and 41 women; aged 35–79 years, mean 58.9 years; BMI 16.2–32.0 kg/m2, mean 24.1 kg/m2) with varying degrees of glucose tolerance. The subjects underwent a euglycemic clamp study and a 75-g OGTT. Subjects were divided into five groups: 1) normal glucose tolerance (NGT), n = 42; 2) impaired glucose tolerance (IGT), n = 26; 3) type 2 diabetes with normal fasting plasma glucose (FPG <110 mg/dl) (DM-NFG), n = 13; 4) type 2 diabetes with impaired fasting plasma glucose (FPG 110–125 mg/dl) (DM-IFG), n = 18; and 5) type 2 diabetes with diabetic fasting plasma glucose (FPG ≥ 126 mg/dl) (DM-DFG), n = 14. None of the patients were treated with insulin or oral antidiabetic drugs. Insulin sensitivity was measured by the euglycemic-hyperinsulinemic glucose clamp technique using an artificial pancreas (Model STG-22; Nikkiso, Tokyo) and expressed as the M-value. A standard 75-g OGTT was performed; plasma samples for glucose and insulin were obtained at 0, 30, 60, 90, 120, and 180 min after the glucose load. Insulin sensitivity was assessed as the insulin sensitivity index (ISI) calculated using the OGTT values by three previously proposed formulas. The first index, proposed by Matsuda and DeFronzo (5), was calculated as follows:

\[\mathrm{ISI}-\mathrm{M}{=}100,000/\sqrt{({[}0-\mathrm{min\ PG}{\times}0-\mathrm{min\ IRI}{]}{\times}{[}\mathrm{mean\ PG}{\times}\mathrm{mean\ IRI}{]})}\]

The second index, proposed by Stumvoll et al. (4), was calculated as follows:

\[\mathrm{ISI-S}{=}0.226{-}0.0032{\times}\mathrm{BMI}{-}0.0000645{\times}120-\mathrm{min\ IRI}{-}0.00375{\times}90-\mathrm{min\ PG}\]

The third index, proposed by Gutt et al. (6), was calculated as follows:

\[\mathrm{ISI-G}{=}m/(0-\mathrm{min\ PG}{+}120-\mathrm{min\ PG}){\times}\ 0.5/\mathrm{log}(0-\mathrm{min\ IRI}{+}120-\mathrm{min\ IRI}{\times}0.5)\]

where m is the glucose uptake rate in peripheral tissues, calculated as m = (75,000 mg + [0-min PG − 120-min PG] × 0.19 × body weight)/120 min. This study was performed in accordance with the Helsinki Declaration, and written informed consent was obtained from each participant.

In the present study, the M-value decreased linearly with worsening of glucose tolerance (NGT, 7.71 ± 1.86 mg · kg−1 · min−1; IGT, 5.15 ± 1.55 mg · kg−1 · min−1; DM-NFG, 3.22 ± 0.80 mg · kg−1 · min−1; DM-IFG, 2.73 ± 0.73 mg · kg−1 · min−1; and DM-DFG, 2.51 ± 0.63 mg · kg−1 · min−1; r = −0.804, P < 0.0001, by Spearman’s correlation test). To search a new index of insulin sensitivity, stepwise multiple regression analysis was performed with the M-value as the dependent variable and glucose and insulin concentrations during the OGTT as the independent variables. The multiple regression analysis yielded the following equation (R2 = 0.581, P < 0.0001):

\[\mathrm{ISI-K}{=}13.192{-}0.712{\times}0-\mathrm{min\ PG}{-}0.341{\times}120-\mathrm{min\ PG}{+}0.002{\times}30-\mathrm{min\ IRI}{-}0.003{\times}90-\mathrm{min\ IRI}\]

The M-value was best correlated with the ISI-K (r = 0.762, P < 0.0001), followed by the ISI-G (r = 0.692, P < 0.001), the ISI-S (r = 0.559, P < 0.001), the ISI-M (r = 0.214, P = 0.023), and HOMA-IR (r = −0.257, P = 0.006). Furthermore, we adapted the ISI-K to a large number of subjects with various degrees of glucose intolerance. A series of 551 subjects underwent a 75-g OGTT and were divided into five groups: 1) NGT, n = 238; 2) IGT, n = 211; 3) DM-NFG, n = 40; 4) DM-IFG, n = 34; and 5) DM-DFG, n = 28. The present study showed that the area under the curve (insulin) decreased linearly with a progression of diabetes (from DM-NFG to DM-IFG to DM-DFG), whereas HOMA-IR showed an inverted U-shape relationship (Table). It is possible that the apparent lower HOMA-IR in subjects with advanced type 2 diabetes might be explained by the β-cell failure and insulin deficiency. The ISI-M also showed a U-shape relationship, and both the ISI-S and ISI-G increased linearly with a progression of diabetes, but only the ISI-K significantly decreased (Table). In Japanese subjects, the total insulin secretion during OGTT increased until the FPG level reached 110 mg/dl, but decreased after the inflection point (7). It has been recognized that the compensatory function of the pancreatic β-cell in Japanese subjects is lower than that observed in Caucasian subjects. Ethnic differences may be a factor that determines the role of decreased insulin secretion (8). In conclusion, this equation (ISI-K) may be applicable to even type 2 diabetic Japanese subjects, who are often hypoinsulinemic.

Table —

Insulin secretion and insulin sensitivity in various degrees of glucose tolerance

NGTIGTDM-NFGDM-IFGDM-DFGP*
AUC (insulin) 744 ± 359 927 ± 508 916 ± 527 769 ± 479 579 ± 356§ 0.0307 
HOMA-IR 1.62 ± 0.95 1.96 ± 1.23 1.97 ± 1.27 2.52 ± 1.48§ 2.26 ± 1.36 0.1101 
ISI-M 6.91 ± 3.38 5.43 ± 2.92 5.75 ± 4.42 4.82 ± 2.81 5.25 ± 2.75 0.5032 
ISI-S 0.108 ± 0.017 0.082 ± 0.025 0.064 ± 0.022§ 0.071 ± 0.022§ 0.072 ± 0.022§ 0.1283 
ISI-G 83.2 ± 21.6 53.0 ± 12.3 35.7 ± 8.4§ 37.1 ± 9.8§ 37.8 ± 12.1 0.2856 
ISI-K 7.04 ± 0.77 5.51 ± 0.88 4.06 ± 0.93§ 3.42 ± 0.92§ 2.37 ± 1.51§# <0.0001 
NGTIGTDM-NFGDM-IFGDM-DFGP*
AUC (insulin) 744 ± 359 927 ± 508 916 ± 527 769 ± 479 579 ± 356§ 0.0307 
HOMA-IR 1.62 ± 0.95 1.96 ± 1.23 1.97 ± 1.27 2.52 ± 1.48§ 2.26 ± 1.36 0.1101 
ISI-M 6.91 ± 3.38 5.43 ± 2.92 5.75 ± 4.42 4.82 ± 2.81 5.25 ± 2.75 0.5032 
ISI-S 0.108 ± 0.017 0.082 ± 0.025 0.064 ± 0.022§ 0.071 ± 0.022§ 0.072 ± 0.022§ 0.1283 
ISI-G 83.2 ± 21.6 53.0 ± 12.3 35.7 ± 8.4§ 37.1 ± 9.8§ 37.8 ± 12.1 0.2856 
ISI-K 7.04 ± 0.77 5.51 ± 0.88 4.06 ± 0.93§ 3.42 ± 0.92§ 2.37 ± 1.51§# <0.0001 

Data are mean ± SD.

*

P is the significant correlation among the three diabetic groups (DM-NFG, DM-IFG, and DM-DFG) by Spearman’s correlation test.

P < 0.01,

P < 0.05 vs. NGT;

§

P < 0.01 vs. IGT;

P < 0.01,

P < 0.05 vs. DM-NFG;

#

P < 0.05 vs. DM-IFG. ISI-G, insulin sensitivity index proposed by Gutt et al.; ISI-K, insulin sensitivity index proposed by Kanauchi; ISI-M, insulin sensitivity index proposed by Matsuda et al.; ISI-S, insulin sensitivity index proposed by Stumvoll et al.

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Address correspondence to Dr. Masao Kanauchi, First Department of Internal Medicine, Nara Medical University, 840, Shijo-cho, Kashihara, Nara 634-0813, Japan. E-mail: kanauchi@nmu-gw.naramed-u.ac.jp.