Mitsuo Fukushima

Hypoadiponectinemia is associated with visceral fat accumulation and insulin resistance in Japanese men with type 2 diabetes mellitus.

The aim of the present study was to investigate the association of serum adiponectin concentration with regional adiposity and insulin resistance in subjects with type 2 diabetes mellitus. A total of 73 Japanese men with type 2 diabetes (aged 59 +/- 11 years and body mass index [BMI] 23.8 +/- 3.0 kg/m(2), mean +/- SD) were studied. Fasting serum adiponectin and leptin concentrations were determined by radioimmunoassay. Regional adiposity was measured by abdominal computed tomography (CT) at the umbilical level, and insulin resistance was estimated by homeostasis model assessment (HOMA-R). Univariate regression analysis showed that serum adiponectin levels were negatively correlated with subcutaneous and visceral fat areas. With multivariate regression analysis, visceral fat area was a predominant determinant of serum adiponectin levels. In contrast, subcutaneous fat area was strongly associated with serum leptin concentrations. Among subcutaneous and visceral fat areas, BMI, and serum leptin levels, both subcutaneous and visceral fat areas were independently associated with HOMA-R. In another model incorporating serum adiponectin levels, serum adiponectin levels were selected as an independent determinant of HOMA-R instead of visceral fat area. In conclusion, hypoadiponectinemia was associated with visceral fat accumulation rather than subcutaneous fat depot in Japanese men with type 2 diabetes mellitus. Both subcutaneous and visceral fat accumulation contribute to insulin resistance in these subjects, and the contribution of visceral fat may be mediated, in part, by hypoadiponectinemia.

GIP and GLP‐1, the two incretin hormones: Similarities and differences

Gastric inhibitory polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are the two primary incretin hormones secreted from the intestine on ingestion of glucose or nutrients to stimulate insulin secretion from pancreatic β cells. GIP and GLP‐1 exert their effects by binding to their specific receptors, the GIP receptor (GIPR) and the GLP‐1 receptor (GLP‐1R), which belong to the G‐protein coupled receptor family. Receptor binding activates and increases the level of intracellular cyclic adenosine monophosphate in pancreatic β cells, thereby stimulating insulin secretion glucose‐dependently. In addition to their insulinotropic effects, GIP and GLP‐1 play critical roles in various biological processes in different tissues and organs that express GIPR and GLP‐1R, including the pancreas, fat, bone and the brain. Within the pancreas, GIP and GLP‐1 together promote β cell proliferation and inhibit apoptosis, thereby expanding pancreatic β cell mass, while GIP enhances postprandial glucagon response and GLP‐1 suppresses it. In adipose tissues, GIP but not GLP‐1 facilitates fat deposition. In bone, GIP promotes bone formation while GLP‐1 inhibits bone absorption. In the brain, both GIP and GLP‐1 are thought to be involved in memory formation as well as the control of appetite. In addition to these differences, secretion of GIP and GLP‐1 and their insulinotropic effects on β cells have been shown to differ in patients with type 2 diabetes compared to healthy subjects. We summarize here the similarities and differences of these two incretin hormones in secretion and metabolism, their insulinotropic action on pancreatic β cells, and their non‐insulinotropic effects, and discuss their potential in treatment of type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00022.x, 2010)

Pathogenic Factors Responsible for Glucose Intolerance in Patients With NIDDM

To define the pathogenic factors responsible for glucose intolerance in NIDDM, we estimated insulin secretory capacity, SI, and SG in 11 healthy, nondiabetic subjects and 9 NIDDM patients who had no SI impairment. All subjects studied were nonobese and normotensive. Each underwent a 75-g OGTT and a modified FSIGT: glucose was administered (300 mg/kg body weight), and insulin was infused (20 mU/kg over 5 min) from 20 to 25 min after the administration of glucose. SI and SG were estimated by Bergmans minimal-model method. The insulin response to oral glucose was significantly lower in NIDDM patients than in normal control subjects. First-phase insulin secretion expressed as the integrated area of plasma insulin above the basal level during the first 20 min was much smaller in NIDDM subjects (214 ±112 pM · min) than in control subjects (4643 ± 885 pM · min, P < 0.01). S, was not statistically different in normal control subjects (1.27 ± 0.18 × 10−4 min−1 · pM−1) versus diabetic patients (1.62 ± 0.33 × 10−4 min−1 · pM−1). However, SG was significantly lower in diabetic subjects (1.11 ± 0.17 × 10−2 min−1) than in control subjects (2.35 ± 0.26 × 10−2 min−1 P < 0.01). These results suggest that impaired insulin secretion and decreased SG are the factors responsible for glucose intolerance of Japanese NIDDM patients with normal insulin sensitivity. Because SI and SG are the factors responsible for glucose intolerance of NIDDM patients with insulin resistance, it is conceivable that decreased SG is common in NIDDM patients regardless of their SI index.

Impaired β-cell function and insulin sensitivity in Japanese subjects with normal glucose tolerance

The development of type 2 diabetes mellitus is characterized by both impaired beta-cell function and increasing insulin resistance. To clarify the roles of them in developing type 2 diabetes, we evaluated insulin resistance by HOMA-IR and insulin secretion by HOMA beta-cell in 453 Japanese subjects whose fasting plasma glucose (FPG) and HbA(1c) levels were within normal range. HOMA beta-cell was found to decrease in the over 30 years groups, while HOMA-IR increased with body mass index (BMI). To analyze the reserve capacity of insulin secretion and insulin sensitivity, the 67 of them, who underwent a standard oral glucose tolerance test and were diagnosed with normal glucose tolerance (NGT), were divided into four degrees of BMI age-adjusted to 50 years. They were compared for insulinogenic index and ISI composite proposed by Matsuda and DeFronzo across the range of BMI. ISI composite was significantly less in the highest BMI group, while insulin secretion did not increase in the higher BMI groups. The subjects with higher BMI had remarkably lower insulinogenic indices than those with lower BMI. These data suggest that insulin secretory reserve is insufficient to compensate for increased insulin resistance in Japanese people with NGT at about 50 years of age.

β Cell Dysfunction Versus Insulin Resistance in the Pathogenesis of Type 2 Diabetes in East Asians

Type 2 diabetes (T2DM) is one of the most serious global health problems and is mainly a result of the drastic increase in East Asia, which includes over a fourth of the global diabetes population. Lifestyle factors and ethnicity are two determinants in the etiology of T2DM, and lifestyle changes such as higher fat intake and less physical activity link readily to T2DM in East Asians. It is widely recognized that T2DM in East Asians is characterized primarily by β cell dysfunction, which is evident immediately after ingestion of glucose or meal, and less adiposity compared to the disease in Caucasians. These pathophysiological differences have an important impact on therapeutic approaches. Here, we revisit the pathogenesis of T2DM in light of β cell dysfunction versus insulin resistance in East Asians and discuss ethnic differences in the contributions of insulin secretion and insulin resistance, together with incretin secretin and action, to glucose intolerance.

Predictive value of chemotherapy-induced neutropenia for the efficacy of oral fluoropyrimidine S-1 in advanced gastric carcinoma

Myelosuppression that occurs during chemotherapy has been reported to be a predictor of better survival in patients with breast or lung carcinomas. We evaluated the prognostic implications of chemotherapy-induced neutropenia in advanced gastric carcinoma. Data from a prospective survey of oral fluoropyrimidine S-1 for advanced gastric cancer patients in Japan were reviewed. We identified 1055 untreated patients with adequate baseline bone marrow function. During treatment with S-1, a total of 293 (28%) patients experienced grade 1 or higher neutropenia. The adjusted hazard ratio of death for the presence of neutropenia, as compared with the absence of such toxicity, from a multivariate Cox model was 0.72 (95% confidence interval, 0.54–0.95; P=0.0189) for grade 1 neutropenia, 0.63 (0.50–0.78; P<0.0001) for grade 2 neutropenia and 0.71 (0.51–0.98; P=0.0388) for grade 3–4 neutropenia. These findings suggest that the occurrence of neutropenia during chemotherapy is an independent predictor of increased survival in patients with advanced gastric cancer, whereas the absence of such toxicity indicates that the dosages of drugs are not pharmacologically adequate. Monitoring of neutropenia in patients who receive chemotherapy may contribute to improved drug efficacy and favourable survival.

Insulin sensitivity, insulin secretion, and glucose effectiveness in anorexia nervosa: A minimal model analysis

The aim of the present study was to estimate insulin secretion, insulin sensitivity (SI), and glucose effectiveness (SG) in subjects with anorexia nervosa. Eight nondiabetic anorectic patients who were dietary restricters and 16 age- and sex-matched healthy control subjects without family history of diabetes were studied. They underwent a modified frequently sampled intravenous glucose tolerance test; glucose (300 mg/kg body weight) was administered and insulin (4 mU/kg body weight/min) was infused from 20 to 25 minutes after administration of glucose. SI and SG were estimated by Bergmans minimal model method. Basal glucose (75.5 +/- 2.1 v 87.1 +/- 1.7 mg/dL) and insulin (3.6 +/- 0.4 v 6.3 +/- 0.5 microU/mL) concentrations were significantly lower in anorectic patients than in control subjects (P < .01). No significant difference was observed in glucose disappearance rate (KG) between the anorectic and control subjects (1.56 +/- 0.5 v 2.26 +/- 0.15%/min). Insulin secretion assessed by the integrated area of plasma insulin above basal level during the first 20 minutes after intravenous stimulation with glucose was significantly decreased in anorectic patients (283 +/- 69 microU.mL-1 x min) compared with control subjects (529 +/- 63 microU.mL-1 x min, P < .05). SI was significantly increased in anorectic patients compared with control subjects (11.2 +/- 1.2 v 7.5 +/- 1.0 x 10(-4) min-1 +/-.[microU/mL]-1, P < .05). However, SG was significantly decreased in anorectic patients (0.015 +/- 0.003 min-1) compared with control subjects (0.023 +/- 0.002 min-1, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin sensitivity, insulin secretion, and glucose effectiveness in obese subjects: A minimal model analysis

The aim of the present study was to estimate insulin sensitivity (SI), insulin secretion, and glucose effectiveness in 14 obese subjects who were further divided into two groups: one with normal glucose tolerance and the other with impaired glucose tolerance (IGT). Glucose tolerance was determined by criteria of the World Health Organization. All subjects were Japanese. They underwent a modified frequently sampled intravenous glucose tolerance test: glucose (300 mg/kg body weight) was administered, and insulin (20 mU/kg body weight given over 5 minutes) was infused from 20 to 25 minutes after administration of glucose. SI and glucose effectiveness at basal insulin (SG) were estimated by Bergmans minimal model method. Body mass index (33.0 +/- 1.8 v 30.9 +/- 1.5 kg/m2, P > .05) and fasting insulin level (127.9 +/- 30.0 v 107.4 +/- 14.4 pmol/L, P > .05) were higher in obese IGT subjects than in normal obese subjects, but were not statistically significant. With regard to fasting glucose level, obese subjects with IGT (5.9 +/- 0.3 mmol/L) had significantly higher levels than those with normal glucose tolerance (5.1 +/- 0.2 mmol/L, P < .01). There was no significant difference in SI between the two groups (0.53 +/- 0.10 v 0.56 +/- 0.13 x 10(-4).min-1.pmol/L-1, P > .05). Pancreatic insulin secretion expressed as the integrated area of plasma insulin above the basal level during the first 19 minutes was significantly lower in obese subjects with IGT (3,366 +/- 1,495 pmol/L.min) than in those with normal glucose tolerance (16,400 +/- 4,509 pmol/L.min, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin sensitivity, insulin secretion, and glucose effectiveness in subjects with impaired glucose tolerance: A minimal model analysis

The aim of the present study was to estimate insulin secretion, insulin sensitivity (SI), and glucose effectiveness (SG) in non-obese Japanese subjects with impaired glucose tolerance (IGT). Ten IGT subjects (five men, five women) and 15 normal-tolerance subjects (seven men, eight women) without a family history of diabetes were studied. They underwent a modified frequently sampled intravenous glucose tolerance test (FSIGT); glucose (300 mg/kg body weight) was administered, and insulin (20 mU/kg over 5 minutes) was infused from 20 to 25 minutes after the administration of glucose. SI and SG were estimated by Bergmans minimal model method. No significant difference was observed in body mass index ([BMI] 22.1 +/- 0.8 v 21.1 +/- 0.5 kg/m2), fasting plasma glucose (5.19 +/- 0.18 v 5.07 +/- 0.11 mmol/L), and insulin levels (50.7 +/- 7.3 v 45.2 +/- 4.5 pmol/L) of subjects with IGT and normal controls. The glucose disappearance rate (KG) was significantly lower in subjects with IGT than in normal-tolerance subjects (1.57 +/- 0.20 v 2.09 +/- 0.15%/min, P < .05). Pancreatic insulin secretion expressed as the integrated area of plasma insulin above the basal level during the first 20 minutes was lower in IGT subjects (2,556 +/- 572 pmol/L x min) than in normal-tolerance subjects (4,957 +/- 800 pmol/L x min, P < .05). SI was not statistically different between the two groups (0.84 +/- 0.13 x 10(-4) v 1.14 +/- 0.15 x 10(-4).min-1.pmol/L-1). However, SG was significantly lower in subjects with IGT than in normal controls (0.013 +/- 0.002 v 0.023 +/- 0.002 min-1, P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Bone marrow mononuclear cells versus G-CSF-mobilized peripheral blood mononuclear cells for treatment of lower limb ASO: pooled analysis for long-term prognosis.

In this study, we report the comparative result of long-term clinical prognoses for patients with no-option critical limb ischemia (CLI) caused by arteriosclerosis obliterans, who are implanted with autologous bone marrow mononuclear cells (BMMNC; n=74) or G-CSF-mobilized (M)-PBMNC (n=111), as no information is available on how the two treatments compare in terms of long-term prognosis, such as survival or amputation. We performed pooled analysis using data from two previous cohort studies. All patients had disease of Fontaine classification III or IV. The endpoints were OS and amputation-free survival (AFS). After adjustment for history of dialysis and Fontaine classification, there was no significant difference between the two treatments with respect to OS (hazard ratio (HR)=1.49; 95% confidence interval (CI)=0.74–3.03, P=0.26) or AFS (HR=0.96; 95% CI=0.61–1.51, P=0.87). The negative prognostic factors affecting OS or AFS were the small number of CD34-positive cells collected, history of dialysis, Fontaine classification, male sex and older age. These results suggest that there was no significant difference in long-term prognosis between patients treated with BMMNC and those treated with M-PBMNC. The number of CD34-positive cells collected was an important prognostic factor for amputation and death.