Tokuji Itoh

The time course of islet cell antibodies (ICA) and serum C-peptides responses (CPRs) to oral glucose tolerance tests (OGTTs) were studied prospectively up to 60 (mean 35) mo in 32 ICA-positive subjects [28 with non-insulin-dependent diabetes (NIDDM) and 4 subjects with impaired glucose tolerance (IGT); mean age 45 yr], 96 matched subjects [56 with NIDDM, 8 with IGT, and 32 normal first-degree relatives of patients with insulin-dependent diabetes (IDDM); mean age 45 yr] who were negative for ICA at the beginning of the study. In addition, the effects of human leukocyte antigens(HLA) on the time course of ICA and (β-cell function were evaluated. In 10 subjects (8 with NIDDM and 2 with IGT) who were ICA positive, ICA became undetectable, even by sensitive ICA assay, 15 ± 2 mo (mean ± SE) after initiation of this study. In these subjects, integrated serum CPR values (σCPR) and 2-h blood glucose values in response to OGTTs improved significantly (P < .05-.01). In contrast, the remaining 22 subjects who were ICA positive were persistently positive for ICA. CPR and blood glucose responses deteriorated progressively in these 22 subjects, and 7 subjects in this group progressed to the insulin-dependent state. Serum CPR and blood glucose responses to OGTTs showed no remarkable changes in 64 patients (56 with NIDDM and 8 with IGT) and 32 normal first-degree relatives of patients with IDDM who remained negative for ICA throughout the study. The frequencies of HLABW54 and HLA-DR4 in 10 subjects who became ICA negative during the follow-up period were lower than those in 22 subjects with ICA throughout the study (uncorrected P < .02). The frequencies of these two antigens were higher in the 22 subjects with persistently positive ICA than in normal controls (uncorrected P < .02), whereas these differences were not observed in 10 subjects who became ICA negative during the study. The reversed β-cell function after negative conversion of ICA observed in our study yields a new insight into the natural history of type I diabetes, especially in late-onset cases. It suggests that HLA-related genetic predisposition is a prerequisite to the slowly progressive β-cell destruction through pancreatic autoimmunity.

Pharmacokinetic models of insulin were examined in order to describe a plasma concentration-time profile after subcutaneous (s.c.) administration of insulin to the patients with insulin-dependent diabetes mellitus (IDDM) or non-insulin-dependent diabetes mellitus (NIDDM). Diabetic subjects were restricted to those with fasting plasma insulin levels around the lowest limit for insulin assay (5 microU/ml). A one-compartment open model with first-order absorption and elimination was appropriate for estimating the plasma concentration-time profile of insulin injected or infused subcutaneously. In the case of continuous s.c. insulin infusion (CSII) for 1 h at the rate of 3 ml/h (2--3 U/ml), the absorption rate constant (Ka), elimination rate constant (Ke), and distribution volume (Vd) were 0.026 +/- 0.001 min-1 (mean +/- SEM; absorption half-life: 27 min), 0.013 +/- 0.005 min-1 (elimination half-life: 53 min), and 1.99 +/- 0.49 L/kg body wt, respectively. These values did not differ significantly from those generated by single bolus s.c. injection of undiluted insulin (40 U/ml). The calculated areas under the plasma insulin concentration-time curves from time zero to infinity ([AUC] 0 infinity) did not differ after each mode of administration, while the [AUC] 0 infinity after CSII was about 32% of that following intravenous bolus injection (P less than 0.01). The following conclusions can be drawn from these results: (1) the plasma concentration-time profile of insulin after CSII or bolus s.c. injection can be analyzed by pharmacokinetic modeling, (2) the absorption kinetics of insulin did ot differ significantly between two modes of s.c. insulin administration in the patients with IDDM or NIDDM, and (3) the insulin after CSII or single bolus s.c. injection seems to be degraded at the s.c. site to the same extent.

Islet cell antibodies (ICA) were measured in Japanese patients with insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) by a standard, indirect immunofluorescence method (IF method) and by a newly established, threelayer immunofluorescence method applying a biotin-avidin system (BAS method). In addition, the relationship between ICA and HLA was studied in IDDM patients. ICA titers detected by the BAS method correlated well with those determined by the standard IF method (rs = 0.987, P < 0.01). The BAS method had about an eightfold higher sensitivity for ICA than the IF method. The overall prevalence of ICA detected by the BAS method (ICA-BAS) versus that by the IF method (ICAIF) was 41% (82/198) versus 28% (56/198) in IDDM patients and 3% (19/593) versus 2% (14/593) in patients with NIDDM. In IDDM patients, ICA-BAS was all positive <1 mo after the onset of diabetes, while the prevalence of ICA-IF was 83% (20/24) during the same period. The prevalence of ICA-IF decreased rapidly with the duration of disease, reaching a value of 6% (3/55) in the patients with a disease duration of 10 yr or more. The incidence of ICA-BAS also decreased with the duration of disease, although to a lesser degree than ICA-IF. No association was found between HLA types and persistence of ICA-BAS or -IF. These results suggest that pancreatic autoimmune processes occur in almost all Japanese IDDM patients. Although IDDM is less common in Japan than among Caucasians, the prevalence of ICA seems to be the same. The higher sensitivity of the BAS method may be of significant diagnostic value, especially in patients with a long duration of disease.

The effect of sex on longitudinal changes in serum C-peptide immunoreactivity (CPR) response to the oral glucose tolerance test (OGTT) was examined up to 48 mo in 30 islet cell antibody-positive (ICA+), non-insulin-dependent diabetes mellitus (NIDDM) subjects (15 men, 15 women) who were matched for age, duration of diabetes, and mode of treatment. The subjects were recruited from 2858 NIDDM patients screened for ICA between 1980 and 1984. In male NIDDM subjects, CPR levels to OGTT decreased insidiously, and 8 of 15 men developed the insulin-dependent state with abolished CPR. Only 2 female NIDDM subjects progressed to the insulin-dependent state (P less than .05, women vs. men). Thus, CPR in female subjects tended to decrease less than in male subjects. There were no significant differences between the two groups in human leukocyte antigens (HLA) or titer of ICA during the follow-up period. These results suggest that maleness is a major risk factor for slowly progressive beta-cell dysfunction in adult-onset insulin-dependent diabetes mellitus (IDDM).