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  • Endocrine Journal 2013, 60 (3), 283-290

    The Two main causes of hyperglycemia in type 2 diabetes mellitus are impaired insulin secretion and increased insulin resistance [1, 2]. Evaluation of insulin resistance (or sensitivity) and -cell function is impor-tant for understanding the disease status and selection of pharmacologic treatment. The gold standard of eval-uation of insulin sensitivity is glucose clamp test [3]. However, the test is limited to research use and is diffi-cult to perform at every medical institution. Although there are also other tests, they are often complex or inadequate [4, 5]. Homeostasis model assessment, first described by Matthews et al., is a method for esti-mating insulin sensitivity [6]. This model is based on

    Homeostasis model assessment of insulin resistance for evaluating insulin sensitivity in patients with type 2 diabetes on insulin therapy

    Kohei Okita, Hiromi Iwahashi, Junji Kozawa, Yukiyoshi Okauchi, Tohru Funahashi, Akihisa Imagawa and Iichiro Shimomura

    Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan

    Abstract. Homeostasis model assessment of insulin resistance (HOMA-IR) is a simple and useful method for evaluating insulin sensitivity. But it is difficult to apply to type2 diabetes patients treated with insulin. We have devised a method for measuring HOMA-IR and investigated the validity of HOMA-IR for evaluating insulin sensitivity in patients with type 2 diabetes on insulin therapy. In the first arm of the study, 19 poorly controlled diabetic subjects were treated with insulin and underwent euglycemic clamp study. Then the relationship between insulin resistance index assessed by the clamp test (clamp-IR) and HOMA-IR was investigated in these subjects. Log transformed HOMA-IR correlated with log transformed M/I values derived from the standard euglycemic clamp (r=-0.753, p=0.002). In the second arm of the study, we investigated the relationship between HOMA-IR and various clinical parameters in 156 patients with poorly controlled diabetes after glycemic control. Log transformed HOMA-IR correlated negatively with age (r=-0.292, p=0.0002), HDL-C (r=-0.342, p

  • 284 Okita et al.

    tion between HOMA-IR and M/I values derived from the standard euglycemic clamp was investigated.

    HOMA-IR was calculated using the following for-mula: HOMA-IR = FPG (mg/dL) fasting IRI (U/mL)/405. Before HOMA-IR was calculated, patients were switched to treatment with sulfonylurea (gliben-clamide 1.25 or 2.5 mg) instead of NPH insulin at the night of the day before the measurement to minimize the influence of insulin injected subcutaneously.

    The euglycemic-hyperinsulinemic clamp was per-formed according to the method of DeFronzo et al. [3] with a little modification using an artificial pan-creas (model STG-22, Nikkiso, Tokyo, Japan). Briefly, the test consisted of a 120-min euglycemic hyperinsu-linemic clamp period. During the clamp test, subjects received primed-constant infusion of regular insulin (1.45 mU/kg min, Eli Lilly, Indianapolis, IN) and an exogenous glucose infusion to maintain blood glucose levels at 100 mg/dL and to achieve the desired steady-state serum insulin level (100 U/mL). When the rate of exogenous glucose infusion reached a steady-state level, we evaluated insulin sensitivity as the average glucose infusion rate during the last 30 minutes divided by the average serum insulin level during the last 30 minutes (M/I).

    Study 2The study subjects were 156 Japanese with poorly

    controlled type 2 diabetes (79 men and 77 women) who had been admitted to Osaka University Hospital for glycemic control between 2001 and 2008. The clin-ical characteristics of the patients are listed in Table 2. Height and waist circumstance were measured in

    ible [12, 13]. Glycemic control is required before eval-uation of insulin sensitivity in patients with poor gly-cemic control. In this regard, insulin sensitivity should be evaluated after the control of blood glucose level in diabetic subjects. HOMA-IR can be used for evalua-tion of insulin resistance in patients on diet therapy or sulfonylureas [14] but might be not suitable for those on insulin therapy, because insulin treatment affects serum insulin levels, which in turn influences the feed-back system between the liver and cells. While it is necessary to evaluate insulin resistance in insulin users, HOMA-IR can only be used to evaluate insulin resis-tance in such patients after minimization of the effect of subcutaneously injected insulin.

    In this study, insulin resistance was evaluated with HOMA-IR in patients on short acting insulin with or without sulfonylureas. The aim of this study was to validate HOMA-IR in patients with insulin-induced glycemic control. First, we treated patients with poor glycemic control with insulin. Then, we evaluated the agreement between HOMA-IR and clamp-IR of subjects on insulin therapy (Study 1). After confirm-ing the validity of HOMA-IR in representing insulin resistance, we investigated the relationship between HOMA-IR and various clinical and biological param-eters that are associated with diabetes to determine the clinical usefulness of HOMA-IR (Study 2).

    Materials and Methods

    Study 1The study subjects were 19 Japanese type 2 diabet-

    ics [12 men and 7 women, aged 53.614.9 years, body mass index (BMI) 23.35.5 kg/m2, hemoglobin A1c (HbA1c) 8.71.2 %] who had been admitted to Osaka University Hospital for glycemic control between 2001 and 2006. The clinical characteristics of the patients are summarized in Table 1. On admission, all oral hypoglycemic agents were withdrawn, and all subjects were treated with diet(25-30 kcal/ kg standard body weight / day) and insulin (regular or ultrarapid insu-lin before each meal) for at least 2 weeks until fast-ing plasma glucose (FPG) fell to less than 140 mg/dL. NPH insulin was added before sleep in 10 sub-jects because their fasting plasma glucose was more than 140 mg/dL, though plasma glucose before sleep was less than 140 mg/dL. When FPG decreased to less than 140 mg/dL after treatment, insulin sensitivity was evaluated with HOMA-IR and clamp-IR. The correla-

    Table 1 Characteristics of the subjects of Study 1Males/females 19 (12 / 7) Age (years) 53.6 14.9 Body weight (kg) 60.019.1Body mass index (kg/m2 ) 23.35.5 HbA1c (%) 8.71.2 Fasting plasma glucose (mg/dL) 120.015.1Fasting C-peptide (ng/mL) 1.770.81Fasting immunoreactive insulin (U/mL) 8.27.6Insulin dose (U/day) 27.227.9HOMA-IR 2.452.38

    Data were collected after glycemic control, except for HbA1c, and expressed meansSD. HOMA-IR: homeostasis model assessment of insulin resistance

  • 285HOMA-IR in insulin-treated diabetics

    at 30 minutes after the 75g glucose load (insulin 0-30 min / PG 0-30 min).

    Daily urine samples were collected for measure-ments of urinary CPR. Venous blood sample were collected before breakfast for measurements of LDL-cholesterol, HDL-cholesterol, triglyceride and adi-ponectin. Plasma adiponectin levels were determined with an adiponectin ELISA kit (Otsuka Pharmaceutical Co., Tokushima, Japan), as described previously [17].

    The cases with insulin antibody that might have influence on glucose homeostasis were excluded from the studies.

    Written informed consent was obtained from all sub-jects, and the study was approved by the ethics com-mittee of Osaka University.

    Statistical analysisData are expressed as meanstandard deviation

    (SD). Pearsons correlation coefficient analysis was used to assess the relationship between HOMA-IR and various variables. A p value less than 0.05 was consid-ered significant. All analyses were performed using the Statview 5.5 software (SAS Institute, Cary, NC).

    standing position. Visceral fat area was estimated by bioelectrical impedance analysis (BIA), as described previously [15]. On admission, patients were being treated with diet alone (n=29, 18.6%), diet and hypo-glycemic agents (n=103, 66.0%), or diet and insulin (n=24, 15.4%). After admission, oral hypoglycemic agents were withdrawn in all but 9 patients, 24 subjects were treated with diet (25-30 kcal/ kg standard body weight / day) alone, 9 were treated with diet and sul-fonylureas, and 123 with insulin. Only regular or ultr-arapid insulin was used before each meal for at least 2 weeks until FPG decreased to less than 140 mg/dL. When FPG was more than 140 mg/dL while plasma glucose before going to bed was less than 140 mg/dL, NPH insulin was added before sleep.

    HOMA-IR was calculated as study1. Then we inves-tigated the relationship between HOMA-IR and vari-ous parameters (age, BMI, waist circumstance, eVFA, systolic blood pressure, diastolic blood pressure, log transformed triglycerides, LDL-cholesterol, HDL-cholesterol, HbA1c, urinary CPR, CPR, log trans-formed insulinogenic index, log transformed serum adiponectin and log transformed KITT).

    With regard to antihypertensive and hypolipidemic medications used at admission, 51.1% of subjects were treated with antihypertensive agents and 36.0% of subjects were treated with hypolipidemic agents. These agents were continued until improvement of glycemic control.

    Insulin tolerance test was carried out before break-fast after an overnight fast. Patients on NPH insulin were switched to sulfonylurea (glibenclamide 1.25 or 2.5 mg) at the night of the day before the test. Venous blood samples were collected for measurement of plasma glucose before and at 3, 6, 9, 12, 15 minutes after an intravenous bolus injection of regular insu-lin (Novorin R 0.1 U/kg body weight). Fifteen min-utes after insulin injection, the test was terminated by injection of glucose. Insulin sensitivity (KITT) was calculated from the linear slope of the plasma glucose concentration from 3 to