Shin Amemiya

Antioxidants in the serum of children with insulin-dependent diabetes mellitus

To determine whether alteration in serum antioxidant status is related to the increased oxidative stress as a cause of diabetic angiopathy, we measured both the antioxidant activity (AOA) and total peroxyl radical-trapping antioxidant parameter (TRAP), and their component individual antioxidants in serum of children with insulin-dependent diabetes mellitus (IDDM). The AOA was measured as the ability to inhibit lipid autoxidation in brain homogenates. TRAP was assayed as the ability to delay lipid peroxidation induced by an azo initiator. Antioxidants measured were ceruloplasmin, transferrin, and albumin as components of AOA; and ascorbic acid, uric acid, protein sulfhydryl, and alpha-tocopherol as components of TRAP. Serum AOA appeared to be decreased in the diabetics in relation to poor glycemic control, corresponding to the decrease in transferrin and albumin. Serum haptoglobin level was also decreased in the diabetics. Similarly, the directly measured TRAP value was decreased in the diabetic serum mainly due to the decreased contribution of unidentified chain-breaking antioxidants, despite the increase in ascorbic acid and alpha-tocopherol. The decrease in both types of antioxidant activity in the diabetic serum, as new findings, suggests that a defective serum antioxidant status contributes to the increased oxidative stress in IDDM.

Pathogenic factors of glucose intolerance in obese Japanese adolescents with type 2 diabetes.

We attempted to identify the pathogenic factors involved in the progression to type 2 diabetes in obese Japanese adolescents. Subjects included 18 nondiabetic obese adolescents, 12 obese adolescents with type 2 diabetes on diet therapy, 10 obese adolescents with type 2 diabetes manifesting ketosis at onset or with a history of treatment with hypoglycemic agents, and 26 non-obese adolescent control subjects. The first-phase insulin response (FPIR), glucose disappearance constant (Kg), glucose effectiveness (Sg), and insulin sensitivity (S(I)) were obtained using an insulin-modified frequently sampled intravenous glucose tolerance test (FSIGT) and a minimal model analysis. The disposition index (DI, by FPIR x S(I)) was determined to assess any endogenous insulin effect. The results showed that Kg was decreased significantly (P = .0006) with the progression to severe diabetes in the obese groups. Although S(I) and Sg did not differ significantly among the 3 obese groups, both parameters were significantly lower in each obese group versus the non-obese controls. As a result of the significant decrease in FPIR (P < .0001), the DI decreased (P = .0006) with the progression to severe diabetes in the obese groups. In conclusion, an early manifestation of type 2 diabetes with occasional ketosis at onset may result from beta-cell dysfunction to glucose stimulation. This finding is demonstrated by the relatively low FPIR to decreased S(I) in obese Japanese adolescents, as well as the low Sg as a synergic role in glucose intolerance. The present findings from a Japanese population for pathogenic factors aside from obesity may help us to gain a better understanding of the progression to adolescent, early-onset, obese type 2 diabetes and its severity.

Role of IGF binding protein-1 in the dawn phenomenon and glycemic control in children and adolescents with IDDM

OBJECTIVE To clarify the involvement of IGF binding protein (IGFBP)-1 in the dawn rise in plasma glucose and in the overall glycemic control in patients with IDDM. RESEARCH DESIGN AND METHODS Seventy patients with IDDM were divided into three groups according to pubertal development. Blood samples were obtained for measuring plasma glucose, IGFBP-1, and free insulin at 2200, 0500, and 0700 over a 2-day period. Levels of HbA1c, IGF-1, and IGFBP-3 were determined at 0700. Urinary growth hormone (GH) was collected overnight. To examine its frequency, the dawn phenomenon was defined on the basis of the following: 1) change in plasma glucose from 0500 to 0700, 2) plasma glucose level at 0700, and 3) no antecedent hypoglycemia. RESULTS There was a statistically significant link between the dawn changes in plasma glucose and IGFBP-1 (r = 0.37, P < 0.01). The former was not related to the change in free insulin or to the overnight urinary GH level. In stepwise regression analyses, plasma glucose at 0700 = 0.03 IGFBP-1 (P < 0.01) + 0.525 HbA1c (P < 0.01) + 3.696 (R2 = 51%). Approximately half of the patients in each group exhibited the dawn phenomenon; 38% of patients with HbA1c < 8% also showed the dawn phenomenon. CONCLUSIONS We have demonstrated a statistically significant link between the morningrisk in IGFBP-1 and plasma glucose. The free fraction of IGF-1 modulated by acute changes in IGFBP-1 may play a direct role. The dawn phenomenon may occur regardless of pubertal stage or glycemic control in children and adolescents with IDDM.

Altered synthesis of renin in patients with insulin-dependent diabetes: plasma prorenin as a marker predicting the evolution of nephropathy☆

Plasma active renin (PARC) and plasma total renin (PTRC) were measured in 72 patients with childhood-onset IDDM and 37 control subjects in the supine posture. The diabetic patients were divided into three groups: group A, 55 patients with normoalbuminuria; group B, 11 patients with microalbuminuria; and group C, 6 patients with overt proteinuria. The levels of PTRC were 125 +/- 51, 240 +/- 124 and 580 +/- 285 ng/l in groups A, B and C, respectively; all of which were significantly higher than 114 +/- 33 ng/l in the control subjects. On the other hand, the ratios of plasma active to total renin, ARC/TRC, were 18.1 +/- 12.5, 10.7 +/- 6.7, and 2.9 +/- 1.4% in groups A, B and C, respectively; all of which were in turn significantly lower than 24.8 +/- 8.7% in the control subjects. Among the diabetic groups, PTRC became higher and ARC/TRC became lower in conjunction with the degree of albuminuria. The acute increments of PARC and PTRC during a standing load test were subsequently observed in 7 patients of group A, 5 of group B, 4 of group C, 13 patients with non-diabetic glomerulonephritis, and 6 control subjects. The ratios of increments of PARC to that of PTRC, delta ARC/delta TRC, were 48.3 +/- 22.3, 35.1 +/- 10.4 and 8.4 +/- 8.1% in groups A, B, C, respectively; all of which were significantly lower than 84.2 +/- 48.6% in the control subjects. Patients with non-diabetic glomerulonephritis showed, to a lesser degree, low ratio of delta ARC/delta TRC (60.4 +/- 37.9%) in conjunction with higher level of PTRC (249 +/- 89 ng/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Association of angiotensin-converting enzyme gene polymorphism with lipid profiles in children and adolescents with insulin-dependent diabetes mellitus.

We attempted to clarify the association between angiotensin-converting enzyme (ACE) gene polymorphism and the other predictive factors for macroangiopathy in children and adolescents with uncomplicated insulin-dependent diabetes mellitus (IDDM). Sixty-three patients were divided into 3 groups according to the ACE genotypes. The lipid profiles were evaluated according to ACE genotypes. The level of lipoprotein(a) (Lp(a)) in the II genotype was significantly lower than that in groups with the D allele. Lp(a) significantly correlated with apo B/apo A-I (p < 0.001, r = 0.63) and atherogenic index (AI = (total cholesterol – high-density lipoprotein cholesterol)/high-density lipoprotein cholesterol; p = 0.004, r = 0.36). We suggest that the D allele may affect the level of Lp(a) and the other lipid profiles in IDDM.

Autoantibody Against ICA512 Did Not Improve Test Sensitivity for Slowly Progressive IDDM in Adults

only 1) if symptoms suggestive of hypoglycemia were of sufficient severity to seek medical advice; 2) if whole venous blood glucose levels were <2.5 mmol/1 at the time of symptoms; 3) if symptoms were relieved by eating carbohydrate. Of the 162 nondiabetic twins, 5 sought medical advice with hypoglycemic symptoms relieved by carbohydrate; hypoglycemia was confirmed on extensive testing in only 3 of them. All 3 subjects were twins of IDDM patients, 2 of these 3 twins subsequently developed diabetes. However, in one (S.C.), hypoglycemia was probably due to self-injection of insulin since she was admitted unconscious to the hospital at age 15 years with a blood glucose of 0.9 mmol/1 and normal serum Cpeptide level (0.049 nmol/1), despite an extremely high serum insulin level (1,380 pmol/1) indicating an exogenous source of insulin. This twin already had impaired glucose tolerance, islet cell antibodies (ICA), and glutamic acid decarboxylase 65 (GAD65) antibodies but had no insulin autoantibodies; IDDM developed at age 19 years. Thus, spontaneous clinical hypoglycemia was detected in just 1 of the 55 twins who developed diabetes under observation. This twin (VS.), started having symptomatic hypoglycemia after large meals (blood glucose on three occasions of 2.0 mmol/1) at age 34 years. She developed diabetes 4 years later with GAD65 antibodies and decreased first-phase insulin response. Her diabetes is controlled by diet alone at present. The third twin (C.A.) with documented hypoglycemia (blood glucose on three occasions <2.5 mmol/1) remains nondiabetic without antibodies and is, we estimate, unlikely to develop diabetes. Symptoms of hypoglycemia before the onset of NIDDM have been reported to be common (5) but alone are not sufficient to establish the diagnosis. Furthermore, low blood glucose levels may occur without symptoms (6). By strict diagnostic criteria, spontaneous hypoglycemia occurred in only 2 of 162 twins (1.2%) and then only in twins of IDDM patients. Extrapolating from our observations in twins, we conclude that clinical hypoglycemia, whether fictitious or real, is not a feature of the prediabetic period.

The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT): initial aims and impact of the family history of type 1 diabetes mellitus in Japanese children

Abstract: The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT) was established in July 1994 with the chief aim to improve the quality of therapy for type 1 diabetes in children, an entity far less common in Japan than in Europe. We proposed four initial research topics: (i) to determine the current status of medical care and glycemic control in Japanese children with type 1 diabetes mellitus; (ii) to standardize the measurement of hemoglobin A1c; (iii) to establish a registry of a large cohort of patients in order to enable prospective studies to improve the quality of therapy for children with type 1 diabetes in Japan; and (iv) to enable participants of the JSGIT to hold a workshop twice annually.

Age of onset, not type of onset, affects the positivity and evanescence of IA-2 antibody

Autoantibody against IA-2 (IA-2A) was found to be discordant with autoantibody against glutamic acid decarboxylase (GADA) with respect to both positivity and titer in Japanese, the same as in Caucasians. In this study, 247 type 1 diabetic patients were tested in order to clarify how the type of onset, age of onset, and duration of diabetes affect the frequency and evanescence of IA-2A. Among the young onset patients, the frequency of IA-2A was higher (52.2%), but evanescent (54.5, 66.7 and 36.7% in the insulin therapy duration < or =1, 2-5 years, and > or =6 years groups, respectively), whereas among adult onset patients, the frequency was lower (19.3%) but persistent (19.6, 13.3 and 23.5%, respectively). In addition, in the follow-up study, two of three IA-2A-positive young onset patients converted to negative in only three years, while all five adult onset patients remained positive for over 5 years. Among the adult onset patients, IA-2A frequency was similar in the slowly progressive type and the abrupt onset type. In view of the above findings, IA-2A positivity and evanescence in type 1 diabetic patients appear to be affected by age of onset, not type of onset.

Decreased activity of plasma cholesteryl ester transfer protein in children and adolescents with insulin-dependent diabetes mellitus

The aims of the present study were to determine whether the activity of cholesteryl ester transfer protein (CETP) is altered in the plasma of children and adolescents with insulin‐dependent diabetes mellitus (IDDM), and whether high‐density lipoprotein‐cholesterol (HDL‐C) levels reflect CETP activity. Plasma CETP activity was measured by a micromethod for radioisotopic assay, using exogenous lipoproteins as donor and acceptors. The study subjects were 22 Japanese children and adolescents with IDDM (8M, 14F) with a mean age of 13.0 y. They were non‐obese and did not suffer from any significant nephropathy. The age‐matched control group consisted of 20 children (10M, 10F) with a mean age of 12.7 y. Serum triglycerides were significantly decreased, while the levels of HDL‐C and apolipoprotein (apo) A1 were markedly increased, in the IDDM patients. Plasma CETP activity was significantly lower in the IDDM patients than in the control children. None of the anthropometric indices nor the biochemical data correlated significantly with CETP activity in the IDDM patients. Suppression of CETP along with the putative activation of lipoprotein lipase due to peripheral hyperinsulinism appears to induce synergistically the increase in HDL‐C in IDDM children.

The association of Ala45Thr polymorphism in NeuroD with child-onset Type 1a diabetes in Japanese

Recently Iwata et al. reported that the polymorphism in NeuroD exon 2(Ala45Thr) was associated with adult-onset Type 1 diabetes in Japanese. Furthermore, the mutations in the NeuroD as a regulator of insulin transcription have been reported to result in Type 2 diabetes. We, therefore, aimed to clarify the role of this Ala45Thr polymorphism in the susceptibility to Type 1a, immune-mediated, diabetes of child-onset Japanese patients. Eighty patients with child-onset Type 1 diabetes were examined along with 121 non-diabetic subjects as the controls. The polymorphism in Ala45Thr was defined using the PCR-RFLP method. The GAD Ab, IA-2 Ab, HLA-DRB1 genotypes and residual beta-cell function at 3 years from onset were evaluated in relation to the difference in this polymorphism. The frequency of the Ala45Thr heterozygotes was significantly higher in the Type 1 diabetic patients than in the controls (21.3 versus 9.9%, P=0.0252). The frequency of loss of beta-cell function was higher in heterozygotes patients than in wild type homozygotes patients (P=0.0112). Type 1 diabetic patients with DRB1*0901 allele showed a significantly higher frequency, 27.9%, of the Ala45Thr variant than the controls (P=0.0041). In conclusion, the Ala45Thr polymorphism contributes to the risk of development of, and to the early deterioration of beta-cell function, in Type 1a diabetes among the Japanese population.