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Insulin tolerance test predicts the effectiveness of insulin sensitizers in japanese type 2 diabetic patients

Introduction The purpose of this study was to assess the efficacy of the insulin tolerance test (ITT) in predicting the effectiveness of insulin sensitizers in type 2 diabetic patients. Methods We retrospectively reviewed 360 consecutive patients with type 2 diabetes admitted to Osaka University Hospital, Japan. In 163 of these hospitalized patients, insulin resistance was evaluated by the ITT after their blood glucose level was ameliorated. We then analyzed the association between their clinical characteristics and their glycemic control 6 months after discharge. Results The rate constant for plasma glucose disappearance, K ITT, was negatively correlated with body mass index (BMI), waist circumference (WC), and visceral fat area (VFA). The median value of K ITT was 1.56 (%/min). In the K ITT > 1.56 group (n=81), hemoglobin A1c (HbA1c) significantly increased in both patients treated with insulin sensitizers (n=10) and patients not treated with insulin sensitizers (n=71). In the K ITT ≤1.56 group (n=82), HbA1c significantly increased in patients not treated with insulin sensitizers (n=60); however, it was maintained well in the patients treated with insulin sensitizers (n=22). When the patients were divided and analyzed according to the median values of BMI, WC, or VFA, the glycemic control change was not different between the two groups with insulin sensitizers for each parameter. Conclusion Insulin sensitizers were effective in type 2 diabetic patients with high insulin resistance estimated by the ITT. The ITT could be useful to predict the effectiveness of insulin sensitizers.


INTRODUCTION
Type 2 diabetes mellitus is characterized by decreased insulin secretion and insulin sensitivity in varying degrees. [1][2][3][4] In Japanese diabetic patients, impaired insulin secretion is emphasized rather than insulin resistance, 5 but insulin resistance also plays an important role in the deterioration of glucose tolerance. 6,7 Recent studies have shown that the homeostasis model assessment of insulin resistance (HOMA-IR) in Japanese patients with type 2 diabetes was significantly higher than that for subjects with normal glucose tolerance. 7,8 The prevalence of metabolic syndrome (MetS), which is characterized by insulin resistance 9 defined by the criteria proposed by a Japanese study group, 10 has reached as much as 45.9% in male and 28.0% in female Japanese type 2 diabetic patients. 11 Therefore, it is important to consider insulin sensitizers in treating Japanese type 2 diabetics as well as insulin secretagogues.
Insulin sensitizers, such as pioglitazone and metformin, are available, and are expected to improve glycemic control in patients with insulin resistance. However, it has not yet been fully clarified which characteristics in diabetic patients determine the efficiency of insulin sensitizers in each patient.
The euglycemic hyperinsulinemic clamp is regarded as the gold standard technique for measurement of in-vivo insulin action, 12 but it requires sophisticated equipment, several hours of work, and considerable expense to use. By contrast, the insulin tolerance test (ITT) is simpler, easy to perform, and a more practical method than the clamp. The glucose disappearance rate calculated from the ITT (K ITT ) has a close correlation with glucose clamp studies. [13][14][15] We hypothesized that we could predict the effectiveness of insulin sensitizers in patients using the results of the ITT. In this study, we retrospectively reviewed consecutive subjects with type 2 diabetes mellitus admitted to Osaka University Hospital, Japan, whose insulin resistance had been evaluated by the ITT. We analyzed the association between the effectiveness of insulin sensitizers and K ITT in these patients.

Patients
We retrospectively reviewed 360 consecutive subjects with type 2 diabetes mellitus admitted to Osaka University Hospital from 2001 to 2008.
Following admission, all of the patients were treated by diet alone or diet plus insulin for at least 2 weeks, until fasting plasma glucose (FPG) was below 7.0 mmol/L. After FPG reached the target level, insulin resistance was evaluated by the ITT, and 32 patients among them were treated with insulin sensitizers, according to the judgment of physicians. Then, we retrospectively analyzed the clinical characteristics and the glycemic control 6 months after discharge.

Measurements
The ITT was performed after an overnight fast, as previously described. 13 Blood samples were collected every 3 minutes for 15 minutes after intravenous regular insulin injection (0.1 U/kg).
The plasma glucose half-time (t ½ ) was calculated from the slope of the least square analysis of the plasma glucose concentrations from 3 to 15 minutes after insulin injection. K ITT was calculated with the formula 0.693/t ½ .
A 75 g oral glucose tolerance test and a glucagon stimulation test were performed, as previously described. 16

Statistical Analyses
Data are presented as the mean±standard deviation (SD). Comparison of variables between groups was done with the Mann-Whitney nonparametric test, or an unpaired Student's t test. Pearson's correlation coefficient analysis was used to assess the cross-sectional relationships between K ITT and other variables.
Comparison of HbA 1c at the time of discharge (or within 1 month after discharge) and 6 months after discharge in each group was done with a paired Student's t test.

Insulin Tolerance Test
The ITT was performed in 163 out of 360 patients.

Patient Groups
The patients were divided into two groups according to the median value of K ITT : K ITT ≤1.56

Clinical Characteristics of the Patients
The clinical characteristics of the patients of the K ITT ≤1.56 group and the K ITT >1.56 group  Figure 1. Management protocol for type 2 diabetic patients. After hospitalization, patients were treated until fasting plasma glucose (FPG) was below 7.00 mmol/L. The insulin tolerance test (ITT) was performed in 163 of the patients to evaluate insulin resistance. According to the median value of the rate constant for plasma glucose disappearance calculated from the insulin tolerance test (K ITT ; 1.56%/min), the patients were divided into two groups: K ITT ≤1.56 and K ITT >1.56. These two groups were further divided into two subgroups: with or without insulin sensitizers at discharge. Insulin sensitizers were thiazolidinedione (pioglitazone) (TZD) and/or biguanide (metformin or buformine) (BG). Patient hemoglobin A 1c (HbA 1c ) levels were evaluated at the time of discharge (or within 1 month after discharge) and 6 months later. (100-150) mg/day for buformine.

Glycemic Control After Discharge
Glycemic control around the time of discharge and 6 months after discharge are shown in

DISCUSSION
In this study, we have shown the possible usefulness of ITT for selecting patients for   . Glycemic control after discharge. Glycemic control around the time of discharge and 6 months after discharge are shown. The levels of hemoglobin A 1c (HbA 1c ) significantly increased in the rate constant for plasma glucose disappearance calculated from the insulin tolerance test (K ITT ) ≤1.56 without insulin sensitizers group, the K ITT >1.56 with insulin sensitizers group and the K ITT >1.56 without insulin sensitizers group. However, HbA 1c did not increase in the K ITT ≤1.56 with insulin sensitizers group. BG=biguanide (metformin or buformine); NS=not significant; TZD=thiazolidinediones (pioglitazone).
sensitizers was the same as that in the K ITT >1.56 group with insulin sensitizers. Therefore, the good glycemic control obtained in the K ITT ≤1.56 group with insulin sensitizers might be derived from the higher insulin resistance estimated by ITT, and the efficacy of insulin sensitizers. Also, patients with insulin sensitizers were not selected at random. The numbers of patients with insulin sensitizers in the K ITT ≤1.56 and the K ITT >1.56 groups are different and small. However, our data showed the significant difference of the effectiveness of insulin sensitizers among these subgroups.

CONCLUSION
In summary, insulin sensitizers were more effective for glycemic control in type 2 diabetic patients with higher insulin resistance estimated by the ITT. The ITT could be useful for predicting the effectiveness of insulin sensitizers. Further prospective studies are needed to confirm the usefulness of the ITT.