Comparative study of the usefulness of a novel insulin therapy in Japanese patients with Type 2 diabetes for concomitant use of an oral antidiabetic agent with twice-daily dosing either of insulin aspart, biphasic insulin aspart-30, or insulin detemir: Two times Insulin injection Combined with oral therapy Efficacy Study (TWICE study).

OBJECTIVES: It is common to treat type 2 diabetes by regular injections of insulin. We compared the efficacy and safety of twice-daily administration of short-acting, premixed, and long-acting insulins. METHODS: This was a multi-center, randomized, open-label, 52-week study. Patients were randomized to administer twice daily short-acting analog insulin (Aspart) plus a sulfonylurea (SU), premixed 70/30 analog insulin (Mix), or long-acting insulin (Detemir) plus a glinide derivative. RESULTS: Twelve (mean baseline HbA1c 9.86±1.71%), eight (9.24±1.14%), and eight (11.26±1.81%) patients were treated with Aspart, Mix, or Detemir, respectively, for 52 weeks. After 12 weeks, the reductions in HbA1c were similar in the groups. A further significant reduction in HbA1c occurred between weeks 12 and 52 in the Detemir, but not the Aspart or Mix groups. After 52 weeks, the target of an HbA1c <7.4% was achieved in 16.7% of the Aspart group, 37.5% of the Mix group, and 12.5% of the Detemir group (no significant differences among the three groups by χ2 analysis). The mean changes from baseline in blood glucose concentration measured after breakfast, and before and after dinner, were also similar in each group. CONCLUSIONS: Early and meaningful reductions in HbA1c were achieved by twice-daily administration of a premix, aspart plus an SU, and detemir plus a glinide, without severe hypoglycemia or an increase in body mass. However, the target HbA1c was achieved in relatively few participants, perhaps due to an insufficient dose of insulin or the small study size.

The ratio of leptin to adiponectin can be used as an index of insulin resistance.

The level of leptin increases with obesity, whereas that of adiponectin decreases with obesity. It is reported that the ratio of leptin to adiponectin (L/A) is associated with insulin resistance. It is difficult to evaluate insulin resistance in diabetic patients who have a dysfunction of insulin secretion. The aim of this study was to examine whether the L/A ratio is a useful marker for insulin resistance in diabetic patients. We examined L/A in the serum of a total of 139 Japanese patients with type 2 diabetes mellitus (66 women and 73 men) and 7 healthy individuals recruited in our hospital. Changes in the levels of leptin and adiponectin were observed using the oral glucose tolerance test and a hyper- and euglycemic clamp test. Twenty-one patients with type 2 diabetes mellitus were observed for more than 6 months after treatment with pioglitazone, and 31 patients with type 2 diabetes mellitus were observed for more than 6 months after the treatment with metformin. The mean value of L/A in 139 Japanese patients with type 2 diabetes mellitus was 1.22 +/- 1.41 (1.68 +/- 1.76 in women, 0.81 +/- 0.80 in men; P = .0002). In the clamp tests, L/A correlated with glucose infusion rate (GIR) (r(2) = 0.26, P = .0034). The correlation of L/A and GIR indicated a stronger correlation than either leptin (r(2) = 0.144, P = .03) or adiponectin alone (r(2) = 0.023, P = .41), or the homeostasis model assessment of insulin resistance (r(2) = 0.103, P = .08). The average hemoglobin A(1c) (HbA(1c)) improved from 10.2% +/- 1.2% to 9.2% +/- 1.6% (P = .0037) in 6 months after treatment with pioglitazone. Our results indicate pioglitazone to be effective for HbA(1c) improvement in subjects with high L/A and low L/A. The average HbA(1c) improved from 9.2% +/- 0.9% to 8.0% +/- 1.2% (P = .0002) in 6 months after treatment with metformin. Our results indicate metformin to be effective for HbA(1c) improvement in subjects with a low L/A. In conclusion, we demonstrate that L/A is different between male and female subjects. The correlation of L/A and GIR by the euglycemic hyperinsulinemic clamp test suggests that L/A is a useful indicator for the choice of drug to treat diabetes mellitus.

Subclinical hypothyroidism is related to lower heel QUS in postmenopausal women.

Recent findings suggest that thyroid stimulating hormone (TSH) is a negative regulator of skeletal remodeling by reducing both differentiation of osteoblasts and formation of osteoclasts. In addition, increased fracture risk in untreated hypothyroid patients has been reported to begin up to 8 years before diagnosis. The aim of the present study was to evaluate the effect of subclinical hypothyroidism on bone structure by using the heel QUS. Subjects were outpatients without any past or present history of thyroid disease. Among 210 postmenopausal women, 22 of 33 patients (Hypo), who had elevated serum TSH concentration (TSH>or=4 microU/ml) with normal serum free thyroxine (FT4) concentration, agreed to join to this study. We also randomly selected 24 control subjects (Cont) from 176 postmenopausal women with normal thyroid status. Calcaneus osteo sono assessment indices (OSI) of right feet were measured using the ultrasound bone densitometry AOS-100. Serum TSH concentrations in Hypo patients (5.31 +/- 1.3 microU/ml) were higher than those in Cont patients (2.05 +/- 1.1 microU/ml), and there was significant difference of FT(4) concentrations (Cont 1.33 +/- 0.15 ng/dl; Hypo 1.19 +/- 0.17 ng/dl). OSI and its Z-score in Hypo subjects (OSI, 2.138 +/- 0.152; Z-Score -0.322 +/- 0.504 SD, Mean SD) were significantly lower than those in Cont subjects (OSI, 2.347 +/- 0.243; Z-Score 0.322 +/- 0.91 SD, Mean +/- SD). Simple regression statistical analysis showed that OSI decreased according to the increase of serum TSH concentration (n = 47, P<0.037). In addition, multiple regression analysis showed that the elevation of serum TSH concentration was associated with the decrease of OSI. These results suggest that the elevation of serum TSH concentration in subclinical hypothyroidism affects not bone turnover but bone structure as assessed by QUS.

Seasonal changes of serum 25-hydroxyvitamin D and intact parathyroid hormone levels in a normal Japanese population.

We conducted an observational study in order to assess the prevalence of hypovitaminosis D and its seasonal changes, in the Tokai area (N35.3 E137.0), in 197 normal subjects in Japan. The mean serum 25-hydroxyvitamin D (25-OHD) level measured by direct radioimmunoassay (RIA) was lowest at the end of winter, and highest at the end of summer (15.1+/-7.1 ng/ml in March; 21.5+/-5.5 ng/ml in June; 31.6+/-5.6 ng/ml in September; 23.1+/-5.3 ng/ml in December; mean+/-SD). The prevalence of hypovitaminosis D (<20 ng/ml) was 86.7%, 33.4%, 1.0%, and 26.0% in March, June, September, and December, respectively. Mean plasma intact parathyroid hormone (iPTH) concentration was lowest at the end of summer and highest at the end of winter (28.2+/-9.3 pg/ml in March; 21.7+/-7.0 pg/ml in June; 19.8+/-6.9 pg/ml in September; and 25.7+/-9.2 pg/ml in December; mean+/-SD). Serum 25-OHD was inversely associated with iPTH (coefficient, -0.223; r=0.251; P<0.001). Serum 25-OHD levels were higher in men than in women. The serum 25-OHD level was positively associated with age, body weight, and body mass index, but not with body fat content. These results suggest a high prevalence of hypovitaminosis D associated with elevation of iPTH in Japan, in winter, even in a sunny area.

The relationship between glycemic control and plasma vascular endothelial growth factor and endothelin-1 concentration in diabetic patients.

Understanding the causes of diabetic vascular complications has become an increasingly important issue because of the rapidly rising prevalence of diabetes. Recently discovered vasoconstrictors and angiogenesis regulators, such as endothelin (ET) and vascular endothelial growth factor (VEGF), have been intensely studied for possible pathogenic roles in diabetic vascular complications. The present study was undertaken to clarify the effect of glycemic control on serum VEGF and plasma ET-1 concentrations in diabetic patients, and to identify other factors that may cause fluctuations of these substances. Plasma VEGF and ET-1 concentrations of 45 hospitalized diabetic patients and 54 control subjects were measured by enzyme immunoassay (EIA) and radioimmunoassay (RIA), respectively. Plasma VEGF was elevated in poorly controlled diabetic patients compared with healthy subjects and plasma VEGF concentrations declined after hospitalized treatment with either insulin or oral hypoglycemic agents in combination with diet. There was a significant correlation between plasma VEGF concentration and both fasting plasma glucose (FPG) and hemoglobin A(1c) (HbA(1c)). Plasma ET-1 in poorly controlled diabetic patients was higher than in healthy controls, but improved glycemic control did not affect plasma ET-1 concentrations. Thus, poor glycemic control causes increased levels of plasma VEGF, which may result in hypertension and vascular complications in diabetes. Short-term treatment resulting in good glycemic control can improve levels of VEGF and may provide beneficial effects on diabetic vascular complications.

Genetic variations in calpain-10 gene are not a major factor in the occurrence of type 2 diabetes in Japanese.

The 112/121 haplotype combination defined by the UCSNP-43, -19, and -63 alleles in the calpain-10 gene is associated with type 2 diabetes in Mexican Americans. To determine whether this genetic variation constitutes risk of type 2 diabetes in Japanese, we investigated its frequency in 177 patients with type 2 diabetes and 172 controls. Though this variation occurs in Japanese more frequently than in Mexican Americans, there is no significant difference in frequency between diabetic (29.9%) and control (31.9%) subjects. We also screened all exons and the putative promoter of the calpain-10 gene for mutations in 96 of the genotyped patients, resulting in the identification of 7 coding variants, including 3 missense mutations and 5 nucleotide alterations in the promoter. However, their frequencies all are similar in patients and controls, suggesting that these genetic variations are not a major factor in the occurrence of type 2 diabetes in Japanese, although they could yet be associated with various phenotypes of the disease.

Distinctive response of thyroid-infiltrating mononuclear cells to B cell activation through CD40 and interleukin-4 in Graves' patients.

The possible role of abnormal T cell-dependent B-cell activation in Graves' disease was investigated by comparing lymphocyte subset distribution and the production of soluble CD8 (sCD8), sCD23, IL-10 and IL-12 by peripheral blood cells (PBMC) and thyroid-infiltrating lymphocytes (TL) in vitro. In TL, the percentage of CD8(+) cells was slightly higher and the sCD8 concentration was significantly higher than in PBMC. The ratio CD23(+) cells to CD20(+) cells (activated B/pan B cells) was increased in TL compared to PBMC from Graves' or normal controls, although the percentage of CD20(+) cells was decreased. Compared to PBMC in Graves' disease, the relative ratio of IL-10 to IL-12 release (IL-10/IL-12) by unstimulated TL was increased, despite a lack of significant difference between PBMC and TL in mean values for either IL-10 or IL-12 secretion. Incubating PBMC with a combination of anti-CD40 monoclonal antibodies and interleukin-4 (IL-4) resulted in B cell activation, reflected in an increase in the sCD23 level in both controls and Graves' patients, but especially prominent in the latter. Stimulation with anti-CD40 antibody and IL-4 also decreased the percentage of CD8(+) cells in PBMC but not TL from both Graves' disease and normal controls, and the percentage of CD8(+) cells in TL was higher than PBMC after the stimulation. The sCD23 concentration in TL was decreased compared to PBMC both in patients with Graves' disease and normal controls. However, in contrast to the increased responses observed in Graves' PBMC or normal controls after stimulation, sCD23 levels remained the same in stimulated TL from Graves' patients. This combination of B cell stimulants increased production of IL-10 in PBMC but not in TL obtained from patients with Graves' disease, and the increased IL-10/IL-12 ratio declined to a value no different from that in PBMC group after stimulation. Thus, T cell-dependent B-cell activation via a CD40 pathway may cause a shift in the Th(1)/Th(2) balance to Th(2) dominance in Graves' disease, while increased CD8(+) cells in TL may suppress sCD23 production and IL-10-producing Th(2) cells.