The association between end-stage diabetic nephropathy and methylenetetrahydrofolate reductase genotype with macroangiopathy in type 2 diabetes mellitus.

The T/T genotype of the methylenetetrahydrofolate reductase C677 T gene polymorphism is associated with elevated homocysteine levels and presumably with increased atherosclerotic risk. We evaluated the interaction between this gene polymorphism and end-stage diabetic nephropathy on the observed prevalence of macroangiopathy in type 2 diabetes mellitus. The methylenetetrahydrofolate reductase 677 C/T genotypes were determined in 174 type 2 diabetic patients: 80 with and 94 without renal failure due to diabetic nephropathy. In the patients with renal failure, the T/T genotype and T allele were significantly associated with macroangiopathy (T/T; 31 % vs. 2 %, P = 0.0001 T allele; 59 % vs. 29 %, P = 0.00014), whereas the associations were not significant in the patients without renal failure. In the multiple logistic regression analysis, age (10 years OR 4.05 [1.79 - 9.31], P < 0.0005) and 677 T allele (6.84 [2.12 - 22.05], P = 0.0013) were significantly associated with macroangiopathy in the patients with renal failure. In conclusion, this study demonstrated that the 677 T/T genotype and T allele of MTHFR were significantly associated with macroangiopathy in type 2 diabetic patients with renal failure. The MTHFR 677 T allele, together with renal dysfunction due to diabetic nephropathy, could be a strong risk factor for atherosclerotic disease.

Intercellular adhesion molecule-1 (ICAM-1) polymorphism is associated with diabetic retinopathy in Type 2 diabetes mellitus.

AIMS: Leucocyte adhesion to the diabetic retinal vasculature has been implicated in the pathogenesis of diabetic retinopathy. We evaluated the relationship between genetic polymorphisms in leucocyte and endothelial cell adhesion molecules and diabetic retinopathy in Type 2 diabetes mellitus. METHODS: We determined ICAM-1, platelet endothelial cell adhesion molecule-1 (PECAM-1), and leucocyte endothelial adhesion molecule-1 (LECAM-1) genotypes in 81 patients with and 50 without diabetic retinopathy. RESULTS: The frequency of ICAM-1 469KK genotype and K allele were significantly higher in the patients with diabetic retinopathy than in those without retinopathy (genotype 42% vs. 20%, chi2 = 6.70, P = 0.035; allele 66% vs. 50%, chi2 = 6.49, P = 0.011). With regard to the PECAM-1 V125L and LECAM-1 P213S polymorphisms, there were no significant associations between the distribution of genotypes or allele frequencies and the presence of diabetic retinopathy. Independent of other risk factors, the ICAM-1 469KK genotype was associated with a 3.51-fold increased risk for retinopathy. CONCLUSIONS: These data suggest that the ICAM-1 469KK genotype could be a genetic risk factor for retinopathy in Type 2 diabetes mellitus.

Simplification for measuring input function of FDG PET: investigation of 1-point blood sampling method.

UNLABELLED: The current method for quantitative FDG PET study requires application of multiple arterial blood sampling for measuring the input function, but the procedure is invasive and complicated. The purpose of this study was to establish a 1-point blood sampling technique that gives data comparable with the data of more elaborate serial arterial sampling. METHODS: We established a time point for 1-point arterial sampling that exhibited the highest correlation between plasma radioactivity at the time point and the real integrated value (IV) of the measured input function obtained by multiple arterial sampling in 120 patients and the smallest coefficient of variation of the real IV divided by plasma radioactivity at the time point in 120 patients. Scaling factors for estimation at each sampling point were determined, and a reference table was established to make the supposed input function. RESULTS: The optimal time for 1-point arterial sampling was 12 min after FDG injection. A good correlation was observed between the real IVs and those estimated from 1-point arterial blood sampling at 12 min using the supposed input function (n = 120; P < 0.001). The time point at which the difference between values of arterial and venous blood disappeared was 40 min after FDG injection. The percentage errors of IV estimation by 1-point sampling were 1.70% (n = 120) for arterial blood at 12 min and 3.64% (n = 10) for venous blood at 40 min. CONCLUSION: We conclude that the simplified 1-point sample method works in a manner that is comparable with serial arterial sampling and should be useful for clinical PET.

[Fluorine-18 labeled 6-fluoro-L-dopa: systematization and evaluation of its usefulness].

6-[18F]Fluoro-L-dopa (L-3,4-dihydroxy-6-[18F]fluorophenylalanine; 6-[18F]FDPA) is useful to assess presynaptic dopamine metabolism in central nervous system. In this paper, we report on the usefulness of the 6-[18F]FDOPA synthesis system developed for the routine synthesis. This system consists of the 6-[18F]FOPA synthesis and the separation units in conjunction with controller using a personal computer. The synthesis time of 6-[18F]FDOPA was 73 minutes. The typical yield and specific activity were 1.4-2.4 GBq and 244-270 MBq/mumol at the end of synthesis, respectively, under the irradiation condition of 50 microA for 130 minutes. The radiochemical yields of 6-[18F]FDOPA were 31.3-38.7% based on the [18F]acetylhypofluorite, and the results were affected with the condition of potassium acetate (AcOK) to produce gaseous [18F]acetylhypofluorite. This system is useful for the routine production of 6-[18F]FDOPA because of its high yield and high specific activity while maintaining AcOK in good condition, and decreasing the radiation exposure for chemist.

Diabetic renal failure and serum accumulation of the creatinine oxidative metabolites creatol and methylguanidine.

Diabetic patients (n = 23) with chronic renal failure (CRF) accumulate the creatinine (Cr) oxidative metabolites creatol (CTL) and methylguanidine (MG; a uremic toxin) in their sera. Analysis of serum CTL, a key intermediate in mammalian Cr catabolism into MG, is shown to offer some useful diagnostic information on CRF, especially in the determination of an initial stage of pathological renal failure. The sera of all diabetic (n = 23) and nondiabetic (n = 20) patients with CRF (s-Cr > 1.25 mg/dl) contained s-CTL (> 2 micrograms/dl), whereas those from normal subjects (n = 18) and diabetic patients (n = 18) without CRF contained no detectable s-CTL. A similar accumulation of s-MG was observed, but only when s-Cr was higher than 2.0 mg/dl. Although each s-CTL (Y: microgram/dl, Y': mol/l) and s-MG level (Z: microgram/dl, Z': mol/l) is highly correlated with s-Cr (X: mg/dl, X': mol/l) in a normal equation, Y or Z = AX + B, an alternative correlation in a second-order equation, Y or Z = alpha X2 + beta X, could also fit well. Since the quadratic equation can be convertible to Y/X or Z/X = alpha X + beta [Y'/X' or Z'/X' = alpha' X+ beta'] and active oxygen species, especially hydroxyl radicals, convert Cr into CTL, Y/X, Y'/X', Z/X and Z'/X' values which might be a kind of indices for oxygen stress (oxidative stress) increased in proportion to the increased severity of CRF in such patients. Although its meaning and interpretation are still debatable, diabetic CRF patients had a significantly higher alpha' value (2.2) than that (0.89) of nondiabetic CRF patients. All serum values for Cr, CTL and MG were measured with HPLC.

Lymphocytic hypophysitis presenting with diabetes insipidus: case report and literature review.

Lymphocytic adenohypophysitis is an autoimmune disorder of the anterior pituitary gland which usually occurs in a women in the postpartum period. It has been considered that lymphocytic hypophysitis is confined to the adenohypophysis sparing the neurohypophysis, and that diabetes insipidus is not a clinical feature of the disorder. Here we report the case of a 50-year-old woman with lymphocytic hypophysitis which presented with diabetes insipidus. MRI indicated homogeneous swelling of the whole pituitary gland, loss of the normal high intensity of the posterior pituitary, and thickening of the pituitary stalk. A biopsied specimen of the pituitary revealed diffuse lymphocytic infiltration. The diabetes insipidus was controlled by the administration of DDAVP. The anterior pituitary function was not greatly damaged, and no hormonal replacement therapy was necessary. We suggest that this case represents a variant of lymphocytic adenohypophysitis and/or lymphocytic infundibuloneurohypophysitis, in which the chronic inflammatory process involves the infundibulum, adenohypophysis and neurohypophysis.

Creatol, a creatinine metabolite, as a useful determinant of renal function.

Analysis of creatol (CTL, 5-hydroxycreatinine), an oxidative creatinine (Cr) metabolite, in serum and urine of human subjects has indicated that CTL is a useful determinant of renal function. The existence itself of serum CTL (s-CTL) could be a diagnostic sign for chronic renal failure (CRF): in all normal subjects, s-CTL was undetectable, but s-CTL was detectable in sera of all patients with CRF (s-Cr: > 2.0 mg/dl). And the s-CTL values increased in proportion to the severity of CRF in such patients. Furthermore, the molar ratio (CTL/Cr) in both urine and serum increased significantly in proportion to the severity of CRF. Our results indicated not only hyperproduction of CTL but also higher oxygen stress in patients according to the progression of CRF. The diagnostic importance of the CTL value and the CTL/Cr ratio are discussed.

Prediction of insulin dependent diabetes mellitus in non-obese diabetic mice by the endogeneous tumor necrosis factor-alpha level.

The non-obese diabetic (NOD) mouse is an animal model of human insulin dependent diabetes mellitus (IDDM). In this strain, the serum concentration of tumor necrosis factor-alpha (TNF alpha) after OK432 (a streptococcal preparation) stimulation is much lower than in any other non-diabetic control strain. Female NOD mice which have a higher incidence of diabetes have significantly lower TNF alpha level (6.5 +/- 4 U/ml, mean +/- SEM) than do male NOD mice (21 +/- 5 U/ml) (P < 0.02) which have lower incidence of diabetes. On the basis of these results, we designed a prospective study to evaluate the relationship between the serum TNF alpha concentration and the incidence of diabetes in individual male NOD mice. Mice were studied until 30 weeks of age. During this period four of eight mice with a low TNF alpha level (TNF alpha < or = 1.1 U/ml) became diabetic, whereas none of eighteen mice with a high TNF alpha level (TNF alpha > 1.1 U/ml) developed overt diabetes. These results indicate that by measuring of endogeneous TNF alpha level after stimulation by OK432, one could predict IDDM in male NOD mice.

Relationship between erythrocyte sorbitol content and diabetic microangiopathy in patients with non-insulin-dependent diabetes mellitus: the study of a diet loading test.

To determine whether erythrocyte sorbitol content could become an indicator of diabetic microangiopathy, we studied the relationship between the changes in erythrocyte sorbitol content in response to diet loading and diabetic microangiopathy in patients with non-insulin-dependent diabetes mellitus. The increase of change in erythrocyte sorbitol content (delta Sor) after diet loading (420 kcal) significantly correlated with that of plasma glucose levels (delta BS). The patients with less than or equal to 40 m/s of motor or sensory nerve conduction velocity (MCV and SCV) had significantly higher delta Sor and delta Sor/delta BS values than those with greater than 40 m/s of MCV and SCV; nevertheless, there were no significant differences in delta BS between the two groups. Furthermore there was a significant negative correlation between nerve conduction velocity and delta Sor and Delta Sor/delta BS values. On the other hand, the patients with nephropathy or retinopathy showed no significant increase in delta Sor or delta Sor/delta BS compared with patients without these complications. The results demonstrated that delta Sor and delta Sor/delta BS could become indicators of the presence or severity of diabetic neuropathy. Furthermore the more significant participation of alteration in the polyol pathway in the pathogenesis of neuropathy than of the other microangiopathies was suggested.

[Interferon-alpha and gamma product in peripheral blood of patients with thyroid diseases].

To investigate the immunological process in various thyroid disease, we measured interferon-alpha, -gamma (IFN-alpha,-gamma, natural killer (NK) activity, and lymphocyte subsets in the peripheral blood of 27 patients with Basedow's disease (BD) (M:F = 9:18), 8 with Hashimoto's thyroiditis (HT) (2:6), 5 with idiopathic hypothyroidism (1HT) (1:4), and normal controls (C). IFN-alpha, -gamma levels were measured by bioassay with Dye-uptake method, and NK activity was measured by the LDH method. The mean +/- SD levels of IFN-gamma in BD, HT, IHT, and C (N = 217) were 173.9 +/- 88.0, 288.0 +/- 134.9, 120.4 +/- 38.0 and 173.9 +/- 88.01U/ml, respectively. The IFN-gamma level was higher in HT (p less than 0.05) than in controls, and lower in BD (p less than 0.02). Moreover, this IFN-gamma level did not correspond with the titers of thyroid hormones; TSH, anti-microsome antibody, and anti-TSH-receptor antibody in peripheral blood. However, IFN-alpha levels and NK activity in the patients of every group were similar to those in controls. The ratios of lymphocyte subsets of peripheral blood were measured by cytofluorometry with monoclonal antibodies. The mean +/- SD levels of T cells in BD, HT, IHT and C were 75.9 +/- 7.0, 83.4 +/- 7.2, 85.2 +/- 5.7, 82.3 +/- 5.8%, and those of B cells were 17.5 +/- 6.1, 10.9 +/- 4.2, 8.0 +/- 5.8, 10.9 +/- 5.0%, respectively. The ratio of T cells was higher in IHT (p less than 0.05) and lower in BD (p less than 0.01) than in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of media conditioned by concanavalin A activated spleen cells on pancreatic islet cells.

The effect of media conditioned by concanavalin A-activated spleen cells (C-sup) on insulin release and its islet cell cytotoxicity were studied. In a functional study, C-sup significantly inhibited both basal insulin release and glucose-stimulated insulin release. Morphologically, C-sup had a destructive effect on isolated islets after 72 h incubation. Islet cell cytotoxicity was shown by lactate dehydrogenase (LDH) release assay after 5 days incubation with C-sup in a dose-dependent manner. These results suggest that acceleration of the onset of diabetes in young diabetes prone (DP) Bio-Breeding/Worcester (BB/W) rats following the injection of C-sup may depend on the suppressive and cytotoxic effects of C-sup on pancreatic islet cells.

Dietary treatment ameliorates overt diabetes and decreased insulin secretion to glucose, induced by overeating in impaired glucose tolerant mice.

Overt diabetes (NIDDM) was induced by overeating in neonatally streptozocin (60 mg/kg.BW) treated impaired glucose tolerant mice. We imposed a food restriction and a high fiber diet to evaluate the effects of dietary treatment in this NIDDM model mouse. Furthermore, insulin secretion after the dietary treatment was studied using the perfused pancreas technique. One group of IGT mice (SZ) was maintained on ordinary mouse chow during 6 to 14 weeks of age. The others received a cookie and chocolate mashed diet (C.C. diet) to induce overt diabetes during 6 to 10 weeks of age. Thereafter, the mice with induced overt diabetes were divided according to their diet treatment. The C.C. diet was continued in one group (SZC) for 4 weeks, and the others were divided into a food restriction group (SZR: 4 g/mouse/day of ordinary mouse chow, for 4 weeks) and a high fiber diet group (SZF: 20% W/W of cellulose in ordinary mouse chow, for 8 weeks). The mean caloric intake/mouse/day in SZC, SZR and SZF were 140, 80 and 98% of that in SZ, respectively. Amelioration of hyperglycemia and impaired glucose tolerance was noted in SZR and SZF. A better glycemic control was obtained in SZF with keeping a normal growth rate. On the pancreas perfusion, the insulin secretion to 30 mM glucose was improved in SZR and SZF. Furthermore, the incremental first phase peak insulin release to 30 mM glucose in SZF was significantly greater than that in SZC (SZF, 10.5 +/- 1.0 vs. SZC, 4.5 +/- 1.9 microU/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Islet cell surface antibodies preferentially inhibit glucose-stimulated insulin release in vitro.

The effect of islet surface antibodies (ICSA) on in vitro insulin release was studied. Isolated rat islets were incubated in the presence of immunoglobulin preparations from patients with insulin-dependent and non-insulin-dependent diabetes mellitus (IDDM, NIDDM) and healthy subjects, and stimulated with D-glucose, L-arginine or tolbutamide. After incubation, the amount of insulin release from the rat islets was determined. The immunoglobulin preparations from 5 newly diagnosed IDDM patients who were positive for ICSA, and from 5 age-matched healthy subjects were examined. Even in the absence of complement or lymphocytes, immunoglobulin fractions positive for ICSA significantly inhibited low and high concentrations of glucose-stimulated insulin release compared with normal control (P less than 0.02), but had little influence on insulin release after stimulation with tolbutamide. Arginine-stimulated insulin release was almost the same in ICSA-positive immunoglobulin fractions and the control. Immunoglobulin fractions negative for ICSA either from four patients with recently diagnosed IDDM or from four newly diagnosed NIDDM patients had only negligible effect on insulin release after stimulation with glucose. These results suggest that ICSA in IDDM patients, even in the absence of complement or lymphocytes, may preferentially interfere with the mechanisms of glucose-stimulated insulin release in the pancreatic B cells.

Overt diabetes induced by overeating in neonatally STZ-treated impaired glucose tolerant mice: long-term follow up study.

This study has investigated the effect of a long period of overeating on the glycemic control and pancreatic beta-cell function in neonatally streptozocin treated impaired glucose tolerant mice. Neonatally streptozocin (60 mg/kg) treated male ICR mice with 150-200 mg/dl of fed blood glucose levels were divided into two groups at 6 weeks of age. One group was maintained on a cafeteria diet (SZC) and the other on ordinary mouse chow (SZ) until 30 weeks of age. Normal male ICR mice were divided into a cafeteria diet group (CC) and an ordinary chow group (Cont). SZC and CC consumed 134-124% of the caloric intake in SZ and Cont throughout the study. Marked elevation of the fed blood glucose level was observed and the glucose tolerance was progressively impaired in SZC. On pancreas perfusion at 30 weeks of age, insulin secretion to 30 mM glucose in SZC was significantly decreased compared with that in SZ. That in CC was slightly decreased compared with that in Cont. The pancreatic insulin concentration in SZC was significantly less than that in SZ. We conclude that chronic hyperglycemia, induced by the long period of overeating, accelerated the selective loss of beta-cell sensitivity to glucose. Even in normal mice that did not have marked hyperglycemia, insulin secretion to glucose was suppressed, probably by chronic stimulation of the beta-cell due to the long period of dietary excess.

[Clinical study of combination chemotherapy with mitomycin C, vindesine and cisplatin (MVP therapy) in advanced non-small cell lung cancer].

Thirty-seven patients with inoperable non-small cell lung cancer were treated with the combination chemotherapy (MVP therapy) with mitomycin C (8 mg/m2), vindesine (3 mg/m2 X 2) and cisplatin (60 mg/m2). The partial responders were 13 cases (35%), and the median survival time was 271 days. In this study the cisplatin dose was less than in any other report of "MVP" therapy. But both the response rate and the median survival time did not differ from those reported elsewhere. The side effects (bone marrow suppression, renal toxicity, etc.) were mild, and did not prevent the continuance of this therapy. Thus, we could repeat more than 6 courses of "MVP" therapy for 8 patients. Nowadays, it is difficult to obtain complete responders with any chemotherapy for inoperable non-small cell lung cancer. To prolong lives of patients and maintain good quality of life, we recommend chemotherapy with low toxicity in often-repeatable courses.