Kinori Kosaka

Risk factors for worsening to diabetes in subjects with impaired glucose tolerance

SummaryIn a 5–12 year follow-up study of 288 subjects with impaired glucose tolerance after a 100-g glucose load, 48 worsened to overt Type 2 (non-insulin-dependent) diabetes with the elevation of fasting blood glucose. The initial level of blood glucose was a major predictor of subsequent worsening to diabetes. In addition, subjects with a lower insulin response to glucose showed a higher incidence of worsening to the disease, irrespective of blood glucose levels. Multivariate analysis indicated that a diminished insulin response and a high maximal body weight index, as well as a high level of fasting and 2-h glucose values at the initial 100-g oral glucose tolerance test were significant independent risk factors for the development of diabetes in Japanese subjects.

Immunogenetic and Clinical Characterization of Slowly Progressive IDDM

OBJECTIVE To examine the clinical and immunogenetic heterogeneity of IDDM. RESEARCH DESIGN AND METHODS We divided 207 IDDM patients into groups based on the interval from clinical onset to initiation of insulin therapy: group A (<3 mo, acute clinical-onset group, n = 134), group B (3–12 mo, intermediate group, n = 31), and group C (>13 mo, slowly progressive group, n = 42). Immunogenetic and clinical markers were compared between group A and group C. RESULTS The mode age of onset was higher in group C (52 yr) than group A (10 yr). Group C had a higher prevalence of islet cell antibodies (42.9%, 18 of 42) than group A (25.4%, 34 of 134, P = 0.05). Serum C-peptide immunoreactivity assayed by radioimmunoassay in response to a 100-g oral glucose tolerance test was significantly higher in group C uhan in group A. Group C patients were also more likely to have a family history of NIDDM (26.1%, 11 of 42) among their first-degree relatives than group A patients (11.2%, 15 of 134, P = 0.039). The prevalences of family history of IDDM and endocrine autoimmune diseases were not different between groups C and A. The frequency of complications of endocrine autoimmune disease was not different between group A (6.7%, 9 of 134) and group C (2.3%, 1 of 42). Significant associations with two class I major histocompatibility complex antigens (HLA-A24 and -Bw54) and one class II antigen (HLA-DR4) were observed in group A. Group A patients were assocciated with three diabetogenic HLA-DQ haplotypes including DQA1*0301-DQB1*0401, DQAl*0301-DQBl*0302, and DQA1 *0301-DQB 1*0303. In contrast, group C lacked the association with class I antigens, although HLA-DR4 and HLA-DQA1* 0301-DQB 1*0401 were more common in this group than in control subjects. CONCLUSIONS These results indicate that the clinical subtype with slowly progressive course (slowly progressive IDDM) has distinct findings including late-age onset, high prevalence of islet cell antibodies, preserved β-cell function, and high family history of NIDDM. An additive effect of class I and class II major histocompatibility complex antigens is suggested as an explanation for the acute clinical manifestations and more severe β-cell destruction in group A patients.

Increase in insulin response after treatment of overt maturity-onset diabetes is independent of the mode of treatment.

SummaryThe changes in insulin response to a 100 g glucose tolerance test after treatment by diet, sulphonylurea and insulin were compared in non-ketotic diabetic patients who had fasting blood glucose concentrations higher than 160 mg/100 ml. Patients were selected so that their pre-treatment and post-treatment blood glucose levels were comparable between different treatment groups. Their insulin responses were poor initially but increased significantly when the diabetic state was improved by each treatment. The degree of improvement of insulin response was similar between different treatment groups, when their fasting blood glucose decreased below 140 mg/100 ml and the glucose tolerance curves were improved to a similar extent. Preand post-treatment ∑ IRI values (sum of insulin values during glucose tolerance test, mean±SD) were 102±50 and 200±37 μU/ml in diet-treated group (n = 28), 90±40 and 195±53 μU/ml in sulphonylurea-treated-group (n=48), and 83±28 and 193±38 μU/ml in insulin-treated group (n = 13), respectively. The data suggest that the poor insulin response in overt diabetes results not only from an inherent insensitivity of B-cells to glucose but also from the metabolic derangement of diabetes. Poor insulin response and overtly diabetic metabolism seems to form a vicious cycle.

DEFECTIVE IMMUNE-ADHERENCE (C3b) RECEPTOR ON ERYTHROCYTES FROM PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

Erythrocytes from 56 patients with systemic lupus erythematosus (SLE) were tested for the immune-adherence (C3b) receptor reactivity for incubation with aggregated human gamma-globulin (AHG) in the presence of complement. The reactivity of the C3b receptors was expressed as the highest two-fold dilution of AHG that induced haemagglutination. Erythrocytes from 37 (66%) of the SLE patients failed to show any detectable reactivity with AHG, whereas the erythrocytes of only 1 of 51 normal controls matched for age and sex were found to be unreactive. The defect of the C3b receptor reactivity was persistent and could not be restored even after SLE patients had gone into remission with steroid therapy. Moreover, the defect was found frequently in the relatives of patients without detectable immune-adherence reactivity. Owing to its high prevalence and persistence in SLE, the defective erythrocyte C3b receptor may be a useful marker for identifying SLE patients and those predisposed to the disease.

Effects of Troglitazone: A new hypoglycemic agent in patients with NIDDM poorly controlled by diet therapy

OBJECTIVE To investigate the clinical efficacy of troglitazone, a newly developed oral hypoglycemic agent, in patients with NIDDM. RESEARCH DESIGN AND METHODS There were 284 NIDDM patients (20–82 years of age) whose glycemic control while on a diet was judged stable but was judged unsatisfactory (fasting plasma glucose [FPG] ≥ 8.3 mmol/l) when entered into a multicenter and double-blind study with parallel groups study. They were randomly allocated into two groups, the troglitazone group (the T group: 400 mg/day p.o.) and the placebo group (the P group), and were treated with test drugs for 12 weeks. RESULTS We evaluated efficacy in 136 patients of the T group and 126 patients of the P group. There was no significant difference in any of baseline characteristics between the T and P groups. In the T group, FPG and HbA1c decreased significantly after treatment (before versus after, FPG 10.1 ± 1.6 vs. 8.8 ± 1.9 mmol/l, P < 0.001; HbA1c: 8.6 ± 1.5 vs 8.1 ± 1.7%, P < 0.001). FPG and HbA1c did not change after treatment in the P group (before versus after, FPG 10.1 ± 1.8 vs. 9.9 ± 2.1 mmol/l; HbA1c 8.5 ± 1.5 vs. 8.6 ± 1.6%). Of 136 patients in the T group, 62 (45.6%) were classified as responders. Serum triglyceride level also decreased in the T group but not in the P group. Body weight increased slightly only in the T group. There were no differences in changes in blood pressure between the two groups. No serious adverse events occurred in either group. CONCLUSIONS Troglitazone at 400 mg/day decreased FPG and HbA1c significantly in NIDDM patients who had failed to respond to diet therapy. Troglitazone, developed as a drug to enhance insulin action, can be a useful hypoglycemic agent for the treatment of NIDDM.

Insulin Responses in Equivocal and Definite Diabetes, with Special Reference to Subjects Who Had Mild Glucose Intolerance but Later Developed Definite Diabetes

Insulin secretory responses during the 100-gm. glucose tolerance test (GTT) were studied in subjects who had or had had glucose intolerance. Patients who had metabolic diseases other than diabetes were excluded. The ratio (ΔIRI/ΔBS) of increments of blood insulin to blood sugar 30 minutes after glucose load was used as the most sensitive index to detect the abnormality of early Insulin release In diabetes. In patients with definite diabetes (I.e., those whose fasting blood sugar values (FBS) were or had been higher than 140 mg./lOO ml. or who had diabetic retinopathy), ΔIRI/ΔBS ratios were almost invariably subnormal regardless of FBS levels and the types of glucose tolerance at the time of GTT. In the rest of the patients (equivocal diabetics), ΔIRI/ΔBS ratios were either normal or subnormal. The decrease in ΔIRI/ΔBS was a fairly stable characteristic of each individual; in 330 equivocal diabetics, only 28 cases (8.4 per cent) moved between high-and low-insulin-responder groups during the follow-up. In 39 patients who had equivocal diabetes at the initial examination but subsequently developed definite diabetes (20 who began to have FBS above 140 mg./lOO ml. and 19 who developed retinopathy), the insulin response were already subnormal at the initial GTT and remained low throughout the follow-up periods, although their glucose tolerance varied between normal, borderline, and diabetic types. Thus, definite diabetes occurred exclusively in the low-insulin-responder group among equivocal diabetics. The decrease in insulin response to glucose seems to be a more Inherent, specific, and stable feature of true diabetes than glucose intolerance, because it precedes the occurrence and persists after the remission of derangement of carbohydrate metabolism in definite diabetes.

HbA1c 5·7–6·4% and impaired fasting plasma glucose for diagnosis of prediabetes and risk of progression to diabetes in Japan (TOPICS 3): a longitudinal cohort study

BACKGROUND The clinical relevance of the diagnostic criteria for prediabetes to prediction of progression to diabetes has been little studied. We aimed to compare the prevalence of prediabetes when assessed by the new glycated haemoglobin A(1c) (HbA(1c)) 5·7-6·4% criterion or by impaired fasting glucose, and assessed differences in progression rate to diabetes between these two criteria for prediabetes in a Japanese population. METHODS Our longitudinal cohort study included 4670 men and 1571 women aged 24-82 years without diabetes at baseline (diabetes was defined as fasting plasma glucose ≥7·0 mmol/L, self-reported clinician-diagnosed diabetes, or HbA(1c) ≥6·5%) who attended Toranomon Hospital (Tokyo, Japan) for a routine health check between 1997 and 2003. Participants with a baseline diagnosis of prediabetes according to impaired fasting glucose (fasting plasma glucose 5·6-6·9 mmol/L) or HbA(1c) 5·7-6·4%, or both, were divided into four groups on the basis of baseline diagnosis of prediabetes. Rate of progression to diabetes was assessed annually. FINDINGS Mean follow-up was 4·7 (SD 0·7) years. 412 (7%) of 6241 participants were diagnosed with prediabetes on the basis of the HbA(1c) 5·7-6·4% criterion. Screening by HbA(1c) alone missed 1270 (61%) of the 2092 prediabetic individuals diagnosed by a combination of impaired fasting glucose and HbA(1c) 5·7-6·4%. Overall cumulative probability of progression to diabetes did not differ significantly between participants with prediabetes discordantly diagnosed by either HbA(1c) or impaired fasting glucose alone (incidence was 7% for HbA(1c) alone [n=412 individuals and 30 incident cases] and 9% for impaired fasting glucose alone [n=1270, 108 cases]; log-rank test, p=0·3317). Multivariate-adjusted hazard ratios for incident diabetes were 6·16 (95% CI 4·33-8·77) for those diagnosed with prediabetes by impaired fasting glucose alone and 6·00 (3·76-9·56) for diagnosis by HbA(1c) alone, and were substantially increased to 31·9 (22·6-45·0) for diagnosis by both impaired fasting glucose and HbA(1c) compared with normoglycaemic individuals. INTERPRETATION Diagnosis of prediabetes by both the new HbA(1c) criterion and impaired fasting glucose identified individuals with an increased risk of progression to diabetes. Although the new HbA(1c) criterion identified fewer individuals at high risk than did impaired fasting glucose, the predictive value for progression to diabetes assessed by HbA(1c) 5·7-6·4% was similar to that assessed by impaired fasting glucose alone. The two tests used together could efficiently target people who are most likely to develop diabetes and allow for early intervention. FUNDING Japan Society for the Promotion of Science; Ministry of Health Labor and Welfare, Japan.

Small doses of subcutaneous insulin as a strategy for preventing slowly progressive beta-cell failure in islet cell antibody-positive patients with clinical features of NIDDM.

We report a pilot study to determine the preventive effect of small doses of insulin injected subcutaneously on slowly progressive β-cell damage in islet cell antibody (ICA)-positive patients with apparent NIDDM. Ten NIDDM patients who were ICA+ were divided into two groups of five. In the insulin group (age: 51 ± 8 years [mean ± SD], sex: 3 men and 2 women), intermediate-type insulin (3–16 U/day) was given once or twice daily as a subcutaneous injection. The sulfonylurea (SU) group (age: 48 ± 11 years, sex: 3 men and 2 women) was initially treated with a SU agent. Changes in β-cell function, as indicated by serum C-peptide responses and blood glucose values during a 100-g oral glucose tolerance test, as well as ICA and GAD antibody status, were evaluated for up to 30 months in both groups. ICA status became negative in four of five patients in the insulin group. ICA status did not become negative in any of the patients in the SU group (P = 0.047 vs. insulin group). ICA status was persistently positive in two patients whose β-cell function eventually progressed to an insulin-dependent state and fluctuated in the remaining three patients. In the insulin group, GAD antibody status became negative in one of four initially GAD antibody–positive NIDDM patients. In the SU group, GAD antibody status was persistently positive in three NIDDM patients (NS vs. insulin group). The serum C-peptide response improved significantly within 6 and 12 months in the insulin group, whereas it decreased progressively in the SU group. The changes in C-peptide response were significantly different between the two groups at 6, 12, 24, and 30 months. Two-hour blood glucose and HbA1 values were unchanged in the insulin group, but they increased in the SU group. Subcutaneous small doses of insulin, resulting in a high rate of negative conversion of ICA and an improved serum C-peptide response, may be effective in treating ICA+ NIDDM patients who are at high risk for slowly progressive β-cell failure.

Time Course of Islet Cell Antibodies and β-Cell Function in Non-Insulin-Dependent Stage of Type I Diabetes

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.

Granulocytosis and colony-stimulating activity (CSA) produced by a human squamous cell carcinoma.

A patient with a squamous cell carcinoma accompanied by a marked granulocytosis (100,000/mm3) of unknown origin was examined for Colony‐Stimulating Activity (CSA). The pleural fluid and the tumor extract revealed high CSA. The floating cells in the pleural fluid were successfully transplanted into nude mice as a localized tumor with cyst formation. The tumor invariably caused a marked granulocytosis (100,000–300,000/mm3) with induction of a conspicuous splenic granulopoiesis in the transplanted mice. High CSA were demonstrated in their cystic fluid as well. Media conditioned by the primary cultures of these tumor cells revealed the same CSA, demonstrating the direct production of CSA by the tumor itself. These results indicate the presence of human CSA producing tumor and that such a tumor may in part account for a marked granulocytosis of unknown origin observed in some patients with cancer. Cancer 43:605–610, 1979.