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Insulin Intervention in Slowly Progressive Insulin-Dependent (Type 1) Diabetes Mellitus

Department of Internal Medicine (T.M.), Saitama Social Insurance Hospital, Saitama 330-0074, Japan; Third Department of Internal Medicine (S.T., N.H., H.S., T.K.), Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan; Department of Internal Medicine (A.S., S.Y.) and Department of Laboratory Medicine (I.T.), Keio University, Tokyo 160-8582, Japan; Department of Internal Medicine (O.F.), Saiseikai Central Hospital, Tokyo 108-0073, Japan; Department of Internal Medicine (A.Kas), Tokyo Denryoku Hospital, Tokyo 160-0016, Japan; Diabetes Center (A.Kan), Chiba Central Medical Center, Chiba 264-0017, Japan; Department of Endocrinology and Metabolism (T.K.), Toranomon Hospital, Tokyo 105-8470, Japan

Address all correspondence and requests for reprints to: Tetsuro Kobayashi, M.D., Ph.D., Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan. E-mail: tetsurou{at}yamanashi.ac.jp.

Objective: We tested the hypothesis that insulin therapy rather than sulfonylurea (SU) treatment is preferable to reverse or preserve β-cell function among patients with slowly progressive insulin-dependent (type 1) diabetes (SPIDDM) or latent autoimmune diabetes in adults.

Methods: This multicenter, randomized, nonblinded clinical study screened 4089 non-insulin-dependent diabetic patients for glutamic acid decarboxylase autoantibodies (GADAb). Sixty GADAb-positive non-insulin-requiring diabetic patients with a 5-yr duration or shorter of diabetes were assigned to either the SU group (n = 30) or the insulin group (n = 30). Serum C-peptide responses to annual oral glucose tolerance tests were followed up for a mean of 57 months. The primary endpoint was an insulin-dependent state defined by the sum of serum C-peptide values during the oral glucose tolerance test (C-peptide) less than 4 ng/ml (1.32 nmol/liter).

Results: The progression rate to an insulin-dependent state in the insulin group (three of 30, 10%) was lower than that in the SU group (13 of 30, 43%; P = 0.003, log-rank). Longitudinal analysis demonstrated that C-peptide values were better preserved in the insulin group than in the SU group. Multiple regression analysis demonstrated that insulin treatment, a preserved C-peptide response, and a low GADAb titer at entry were independent factors in preventing progression to an insulin-dependent state. Subgroup analysis suggested that insulin intervention was highly effective for SPIDDM patients with high GADAb titers [10 U/ml (180 World Health Organization U/ml)] and preserved β-cell function [C-peptide 10 ng/ml (3.31 nmol/liter)] at entry. No severe hypoglycemic episodes occurred during the study.

Conclusions: Insulin intervention to preserve β-cell function is effective and safe for patients with SPIDDM or latent autoimmune diabetes in adults.