To determine the glucose and insulin concentrations at which glucose transport is rate limiting for insulin-mediated glucose uptake and metabolism in muscle, glucose clearance was determined in the presence of glucose concentrations ranging from trace to 20 mM and in the absence or presence of insulin in the perfused rat hindlimb. In the absence of insulin and at submaximally stimulating insulin concentrations glucose clearance was constant up to 7 mM glucose and then decreased as the glucose concentration was raised. At maximally stimulating insulin concentrations glucose clearance was constant up to 2 mM glucose and then decreased. The decrease in glucose clearance between 2 and 7 mM glucose in the presence of maximally stimulating insulin concentrations could not be accounted for by competition among glucose molecules for the glucose transport system. The results suggest that at physiological glucose concentrations in the presence of maximally stimulating insulin concentrations the rate-limiting step for insulin-mediated glucose uptake and metabolism in muscle shifts from glucose transport to some step beyond transport.

Abstract.The relationship between blood levels of N-carboxymethyl-lysine (CML) or pentosidine and the severity of microangiopathy was investigated in patients with type 2 diabetes. Blood CML and pentosidine levels were measured by ELISA in 97 type 2 diabetics (46 men and 51 women). CML and pentosidine levels were significantly higher in patients with chronic renal failure than in those with normoalbuminuria, microalbuminuria, or macroalbuminuria (all p<0.05). Among the diabetics without nephropathy (n = 49), blood CML levels were significantly higher in the patients who had proliferative diabetic retinopathy than in those without retinopathy or those who had background retinopathy (both p<0.01). In contrast, blood pentosidine levels showed no significant differences among the three retinopathy groups. These findings suggest that the blood level of CML is related to the severity of both nephropathy and retinopathy, while the pentosidine level is only related to the severity of nephropathy. ADVANCED glycation end-products (AGE) form excessive cross-links between tissue proteins, thereby changing the structure of the extracellular matrix and altering the function of various cells via the AGE receptor. In diabetics, it has been shown that AGE levels increase in the blood and tissues prior to the onset of microangiopathy, and the AGE level has been reported to show a correlation with the progression of retinopathy and nephropathy [1][2][3][4]. More than 10 kinds of AGE have been identified to date, which differ with regard to their cross-links and fluorescence properties as well as the location and extent of their presence in various tissues [5,6]. However, the role of each of these compounds in the onset and progression of diabetic complications has not been investigated in detail. In this study, we measured the blood levels of two types of AGE, N-carboxymethyl-lysine (CML) and pentosidine, in patients with type 2 diabetes and assessed the relationship between these substances and the severity of diabetic retinopathy or nephropathy. Materials and MethodsThe subjects were 97 inpatients of our hospital with type 2 diabetes mellitus (46 men and 51 women). On the day after admission, fasting blood samples were taken from the patients, and the fasting plasma glucose (FPG), hemoglobin A 1C (HbA 1c ), creatinine, CML, and pentosidine levels were measured. Height and body weight were also determined for calculation of the BMI. FPG and creatinine were measured by an enzymatic method, HbA 1c was determined by high performance liquid chromatography(HPLC), and CML [7] and pentosidine [8] were measured by enzyme-linked immunosorbent assay (ELISA) as described below.

Aim:To evaluate the long-term outcome of stereotactic body radiotherapy in patients with small hepatocellular carcinoma who were ineligible for resection or ablation therapies.Methods: A total of 65 patients with 74 hepatocellular carcinomas (median tumor size 16 mm) were enrolled in the present study. They were treated with the prescribed dose of 48 Gy in four fractions at the isocenter. We extended the observation period and analyzed long-term outcomes, including overall survival, progression-free survival, local control, and various prognostic factors, in these patients. Results:The median follow-up period was 41 months for all patients and 62 months for surviving patients. The 3-and 5-year overall survival rates were 56.3% (95% confidence interval, 44.1-68.5%) and 41.4% (95% confidence interval, 28.7-54.1%), respectively. The 3-and 5-year progression-free survival rates were 25.4% (95% confidence interval, 14.0-36.8%) and 10.6% (95% confidence interval, 1.5-19.8%), respectively. The 3-and 5-year local control rates were both 100% (95% confidence interval 100%). Liver toxicities exceeding grade 3 were observed in 15 patients (23.1%). The proportion of patients who had grade ≥3 toxicities did not increase. Adverse effects (grade ≤2) presented as significant prognostic factors of overall survival, while TNM stage (T1N0M0) was a significant prognostic factor of progression-free survival after multivariate analysis.Conclusions: Stereotactic body radiotherapy was effective for patients with small hepatocellular carcinomas who were ineligible for resection or ablation therapies. The incidence of grade ≥3 adverse effects did not increase, even after longer follow-up times.

SummaryThis study describes the generation of a novel transgenic Rev1-overexpressing transgenic mouse and the role of Rev1 expression level on chemically induced tumorigenesis. Following MNU treatment, Rev1 promoted mutagenesis and suppressed apoptosis in proportion to the level of overexpression, resulting in accelerated tumorigenesis.

The objective of this study was to clarify the influence of pioglitazone (Pio) on proinsulin (PI) in patients with type 2 diabetes mellitus. The subjects were 55 patients with type 2 diabetes. Among them, 18, 18, and 19 patients were respectively treated with Pio alone (group P), gliclazide (Gli) alone (group G), or Pio plus Gli (group PG) for 12 weeks. Fasting blood samples were obtained before and after treatment and were used to measure fasting plasma glucose (FPG), HbA1C, immunoreactive insulin (IRI), and PI. The levels of FPG, HbA1C, and IRI showed a significant decrease after treatment with Pio in groups P and PG. Treatment with Pio also caused PI to decrease significantly (group P: from 24.7 +/- 12.9 (mean +/- SD) to 14.0 +/- 6.2 pmol/L, p < 0.01, group PG: from 24.3 +/- 11.3 to 14.4 +/- 6.5 pmol/L, p < 0.01). In group G, treatment with Gli caused FPG and HbA1C to decrease significantly, but PI showed no change (21.5 +/- 12.3 to 21.6 +/- 10.4 pmol/L, p = n.s.). In patients with type 2 diabetes, treatment with Pio achieved an improvement of glycemic control and reduced the load on the pancreatic beta cells.