Yasuhiko Iwamoto

Effect of New Oral Antidiabetic Agent CS-045 on Glucose Tolerance and Insulin Secretion in Patients with NIDDM

Objective To study the effects of CS-045, a newly developed thiazolidine analogue, on glucose tolerance and insulin response to oral glucose load in patients with non-insulin-dependent diabetes mellitus (NIDDM). Research Design and Methods Nineteen NIDDM patients (mean ± SD age 48.9 ± 9.4 yr) whose previous glycemic control on diet and/or sulfonylurea (SU) therapy was judged stable but unsatisfactory (> 7.8 mM) were selected for this study. CS-045 (400 mg/day p.o.) was given alone or together with the previous SU drugs for 12 wk. A 75-g oral glucose tolerance test (OGTT) was performed before and after CS-045 treatment. Results The following results were found after CS-045 treatment. 1) Fasting plasma glucose (FPG) and HbA1c decreased (n = 19, FPG, 11.0 ± 2.4 vs. 8.4 ± 2.7 mM [before vs. after], P < 0.001; HbA1c, 8.0 ± 1.1 vs. 7.4 ± 1.3%, P < 0.005), and glucose tolerance markedly improved. 2) Fasting insulin (immunoreactive insulin [IRI]) and insulin response during OGTT decreased (n = 19, fasting IRI, 77.4 ± 49.8 vs. 56.5 ± 24.6 pM [before vs. after], P < 0.05; area under the curve of IRI, 540.3 ± 350.5 vs. 426.4 ± 216.3 pM.h, P < 0.05). Conclusions CS-045 is effective in improving glucose tolerance without stimulation of insulin secretion in NIDDM, suggesting an effect in improving insulin sensitivity.

Serum proinsulin levels at fasting and after oral glucose load in patients with type 2 (non-insulin-dependent) diabetes mellitus.

SummaryA simple and sensitive human proinsulin radioimmunoassay system was developed using guinea pig antiproinsulin serum, which cross-reacted neither with human insulin nor C-peptide. The recognition site of the antiserum seems to be located near the junction between the B chain and C-peptide. With this assay system, we studied the serum proinsulin concentration at fasting and after an oral 100 g glucose load in 25 healthy subjects, 21 subjects with impaired glucose tolerance and 40 patients with Type 2 (non-insulin-dependent) diabetes mellitus. At fasting, serum proinsulin was 5.8±3.3 pmol/l in normal subjects as compared to 9.5±6.9 pmol/l (p<0.05) in subjects with impaired glucose tolerance and 12.6±7.5 pmol/l (p<0.001) in diabetic patients. The molar ratio of proinsulin to insulin was also increased in subjects with impaired glucose tolerance or diabetes compared to control subjects. After a 100 g oral glucose load, serum proinsulin increased more slowly than insulin. The proinsulin response after an oral glucose load was augmented in subjects with impaired glucose tolerance and diabetes, while the insulin response decreased with the elevation of fasting plasma glucose. Diabetic patients with high fasting plasma glucose had a very poor insulin response, but the proinsulin response was similar to control subjects. There was a linear correlation between summed proinsulin values and summed insulin values, but the slope of the regression line was steeper in diabetic patients than in control subjects. There was a relative increase in serum proinsulin both in subjects with impaired glucose tolerance and diabetic patients. We suggest that B cells may release ‘immature’ granules richer in proinsulin content as well as mature granules in the over-stimulated state.

Genetic analysis of HLA class II alleles and susceptibility to type 1 (insulin-dependent) diabetes mellitus in Japanese subjects.

SummaryAlthough HLA-DQB1 alleles encoding aspartic acid at position 57 (Asp-57) are protective against Type 1(insulin-dependent) diabetes mellitus in Caucasians, most Japanese Type 1 diabetic patients carry at least one Asp-57 DQB1 allele. We analysed the DRB1, DQA1 and DQB1 genes of 99 Japanese patients and 86 control subjects with polymerase chain reaction and sequence-specific oligonucleotide hybridization. We found that (1) the DQA1*0301 allele was significantly increased in Type 1 diabetic patients (RR 7.8,pc < 0.0001); (2) the DRB1*0405 (Dw15) allele, which is a subtype of DR4 haplotype, was significantly increased in DR4-positive patients (RR 12.0,pc < 0.001); and (3) although the DRw8-DQw8 haplotype was positively associated with Type 1 diabetes, the DRBl*0406-DQw8 haplotype was decreased in the diabetic patients. These data indicate that DRB 1 and DQA1 genes also confer susceptibility to Type 1 diabetes in Japanese.

Hyperinsulinaemia in obesity is not accompanied by an increase in serum proinsulin/insulin ratio in groups of human subjects with and without glucose intolerance.

SummarySerum proinsulin is disproportionately elevated compared to insulin in Type 2 (non-insulin-dependent) diabetes mellitus. We studied the effect of obesity on serum proinsulin with varying degrees of glucose intolerance. Serum proinsulin and insulin were measured during a 75 g oral glucose tolerance test in 73 obese and 74 non-obese subjects with normal, borderline or diabetic-type glucose tolerance. Proinsulin was assayed by a direct radioimmunoassay using proinsulin-specific antiserum. Fasting serum proinsulin and insulin and the summed values of proinsulin and insulin during oral glucose tolerance test were significantly, or tended to be, higher in obese subjects than in those without obesity in each category of glucose tolerance. However, the molar ratio of proinsulin to insulin was nearly the same between obese and non-obese groups with a similar degree of glucose tolerance. On the other hand, the proinsulin/insulin ratio increased progressively with the deterioration of glucose tolerance. We conclude that proinsulin secretion is disproportionately increased in the presence of glucose intolerance but not by obesity itself. Each Beta cell seems to function normally in obese subjects while glucose tolerance remains normal.

Onset age-dependent variations of three islet specific autoantibodies in Japanese IDDM patients

The age related incidence rate of insulin-dependent diabetes mellitus shows a bimodal distribution, not only in Caucasians but also in Japanese. To evaluate the onset age-related autoimmune profile at presentation in insulin-dependent diabetes mellitus (IDDM), glutamic acid decarboxylase (GAD) autoantibody, islet cell antibody (ICA), and insulin autoantibody (IAA) were measured in 137 newly diagnosed Japanese IDDM patients with onset ages between 0-29 years. The prevalence of GAD autoantibody was significantly increased from the lowest (32%) in the 0-5 years onset age group to 75% in the 13-19 years onset age group (P < 0.05), whereas the IAA prevalence significantly decreased from the peak (48%) in the 6-12 years onset age group to 10% in the 20-29 years onset age group (P < 0.05). The ICA prevalence was increased from the lowest (32%) in the 0-5 years onset age group to the highest (53%) in the 20-29 years onset age group similar to that for the GAD autoantibody. Such results demonstrate that there was age-related autoimmune characteristics at presentation of IDDM in Japanese as well as in Caucasians.

HLA DR antigens in adult-onset and juvenile-onset Japanese insulin-dependent diabetic patients

In order to discover the HLA DR antigens linked to Japanese insulin-dependent diabetes (IDDM), and to relate them to the clinical features, HLA DR antigens were examined in 75 IDDM patients including 56 adult-onset cases. Among the tested HLA DR antigens, 4, w9 and w13 were significantly more frequent in IDDM (55%, 47% and 27% respectively). The relative risk was 1.71 for DR4, 2.81 for DRw9 and 4.74 for DRw13. DR2 was significantly less frequent and the relative risk was 0.14. The distribution of DR antigens did not differ between juvenile-onset and adult-onset IDDM, males and females, or cases with and without thyroid autoantibodies. Homozygotes for DRw9 were, but those for DRw13 and DR4 were not more frequent than expected by a random combination. Heterozygotes for DR4 and w9 were less frequent while other heterozygotes for high-risk antigens were as frequent as expected. 97% of IDDM had either DR4, w9 or w13. In conclusion, HLA DR4, w9 and w13 were significantly increased in patients with both juvenile- and adult-onset IDDM. There was no surplus increase in the frequency of IDDM patients with two high-risk HLA DR antigens, more than expected from random combination of each of these DR antigens. Clinical features did not differ among IDDM patients with each of these three antigens.

Lack of association of the insulin gene region with Type 1 (insulin-dependent) diabetes mellitus in Japanese subjects

SummaryAlthough the insulin gene region is implicated in susceptibility to Type 1 (insulin-dependent) diabetes mellitus in Caucasians, significance of this region to Type 1 diabetes in Japanese remains unclear because the class 1 alleles (shorter insertion) of the variable number of tandem repeat in the 5′ region of the insulin gene are predominant in both diabetic and nondiabetic subjects. The 5′ insulin gene polymorphism was analysed in 75 Japanese patients and 69 control subjects with a precise method using PvuII and a polymorphism specific probe, which enabled us to divide class 1 alleles into four subclasses. Allelic frequencies were not significantly different between Type 1 diabetic patients and control subjects. The polymorphism in the 3′ untranslated region of the insulin gene (1127/ PstI) was also analysed and found to be tightly linked to the 5′ insulin gene polymorphism, and thus was not associated with diabetes. Interaction between HLA-DR and the insulin gene region, which was reported in the French study, was not observed in Japanese. These results suggest that the insulin gene region is not a valuable genetic risk factor for Type 1 diabetes in Japanese.

A cognitive/behavioral approach to type 1 diabetic females with recurrent binge eating: a 3-year follow-up study

Abstract Objective : To describe a comprehensive, cognitive/behavioral approach to the treatment of type 1 diabetic females with recurrent binge eating and to assess its effectiveness. Research design and methods : At the first visit to our outpatient clinic, type 1 diabetic females with recurrent binge eating ( n =28) were diagnosed as either bulimia nervosa (BN) or binge-eating disorder (BED), and underwent “outpatient counseling at first visit”. After a period of observation by the referring physician, patients without sufficient improvement were encouraged to undergo “integrated inpatient therapy”. According to the eating disorder diagnosis and the presence/absence of inpatient therapy, patients were divided into four groups: BN-inpatients, n =9; BN-outpatients, n =9; BED-inpatients, n =2; BED-outpatients, n =8. Glycosylated hemoglobin (HbA1c); psychological measures assessing eating disorder psychopathology (EDI), depression (SDS), and anxiety (STAI); binge eating and purging behavior for each group were compared between first visit and follow-up. Results : In BED-outpatients, significantly lower HbA1c, SDS score, and frequency and amount of binge eating were seen at 3 years after first visit. In BN-inpatients, significantly lower HbA1c; EDI, SDS, and STAI scores; frequency and amount of binge eating; and rate of purging behaviors were seen at 3 years after discharge. Conclusions : Type 1 diabetic females with recurrent binge eating were effectively treated. BED patients were successfully treated on an outpatient basis, while BN patients needed inpatient therapy.