Effects of 1,5-anhydro-D-glucitol on insulin secretion both in in vitro and ex vivo pancreatic preparations.

Organ bath experiments are conventionally used to investigate the physiological actions and effects of hormones and drugs on organ responses. We developed an experimental method to reproduce insulin secretion from isolated rat pancreas preparations, to investigate substances that promote insulin secretion ex vivo. 1,5-anhydro-D-glucitol (1,5-AG) is found in foods, and exists in humans and rodents; however, whether 1,5-AG stimulates insulin secretion remains unclear. This study aimed to assess the effects of short-term 1,5-AG stimulation on insulin secretion in both ex vivo and in INS-1E (rat-derived) cells in vitro. Our results indicated that 1,5-AG had no potency to increase the proportion of insulin outflow both in ex vivo and in vitro experiments. Insulin outflow significantly increased upon stimulation with 10 µM glimepiride, a member of the sulfonylurea class of drugs, ex vivo. Glucose-stimulated insulin secretion was observed not only in INS-1E cells but also in rat pancreatic preparations. Our findings demonstrated that short-term exposure to 1,5-AG had no effect on insulin secretion in rats.

Uric acid lowering in relation to HbA1c reductions with the SGLT2 inhibitor tofogliflozin.

An integrated analysis was performed with data from 4 phase 2 and phase 3 studies of tofogliflozin in which patients with type 2 diabetes mellitus received the sodium-glucose cotransporter 2 inhibitor tofogliflozin for up to 24 weeks. Sex differences, baseline haemoglobin A1c (HbA1c) and serum uric acid (UA) levels, and log10 -transformed urinary N-acetyl-ß-D-glucosaminidase ratio were significantly correlated with the reduction in serum UA levels at both 4 and 24 weeks in multivariate analysis (respectively, P < .0001). The decrease in HbA1c levels was greatest in the group with the highest baseline HbA1c level (quartile 4; HbA1c > 8.6%) and lowest in the group with the lowest baseline HbA1c level (quartile 1; HbA1c ≤ 7.4%). The decrease in serum UA levels was greatest in the quartile 1 group and lowest in the quartile 4 group. In most groups, the maximum decrease in serum UA levels was seen in the first 4 weeks, while the maximum decrease in HbA1c was seen at week 24. Thus, serum UA levels were significantly decreased in patients with moderate HbA1c levels.

Relationship between postprandial glucose level and carotid artery stiffness in patients without diabetes or cardiovascular disease.

BACKGROUND: The aim of this study was to evaluate the relationship between postprandial glucose level and atherosclerosis in patients without diabetes and cardiovascular disease by determining carotid ultrasonographic variables and serum levels of 1,5-anhydroglucitol (1,5-AG). METHODS: The subjects were 72 patients without diabetes and cardiovascular disease being treated for hypertension or dyslipidemia. The clinical characteristics of all subjects, including the serum level of 1,5-AG, which appears to be well suited for monitoring postprandial hyperglycemia, were evaluated after an overnight fast. The average intima-media thickness (IMT) and the average pulsatility index (PI) of the right and left common carotid arteries were determined with high-resolution ultrasonography and used as ultrasonographic variables. The subjects were divided into a lower 1,5-AG group (n = 36) and a higher 1,5-AG group (n = 36). We evaluated the relationship between clinical characteristics and ultrasonographic variables of the carotid artery in both groups. RESULTS: The average PI in the Lower 1,5-AG group was significantly higher than that in the Higher 1,5-AG group, but the average IMT did not differ between the groups. Linear regression analysis, with the ultrasonographic variables as the dependent variables, with 1,5-AG as the independent variable, and adjusted for other clinical characteristics, showed significant correlation between 1,5-AG and the PI but not between 1,5-AG and IMT. CONCLUSION: Our results suggest that postprandial hyperglycemia increases carotid artery stiffness, but not morphological change, in patients without diabetes or cardiovascular disease.

Low-molecular-weight lipoprotein (a) and low relative lymphocyte concentration are significant and independent risk factors for coronary heart disease in patients with type 2 diabetes mellitus: Lp(a) phenotype, lymphocyte, and coronary heart disease.

BACKGROUND: The aim of the present prospective study was to examine whether lipoprotein (a) [Lp(a)] phenotypes and/or low relative lymphocyte concentration (LRLC) are independently associated with coronary heart disease (CHD) in patients with type 2 diabetes mellitus (T2DM). METHODS: Serum Lp(a) concentration, Lp(a) phenotypes, and RLC were analyzed in 214 subjects. Lp(a) phenotypes were classified into 7 subtypes according to sodium dodecyl sulfate-agarose gel electrophoresis by Western blotting. Subjects were assigned to the low-molecular-weight (LMW (number of KIV repeats: 11-22) ) and high-molecular-weight (HMW( number of KIV repeats: >22 )) Lp(a) groups according to Lp(a) phenotype and to the LRLC (RLC: <20.3%) and normal RLC (NRLC; RLC: ≥20.3%) groups according to RLC. A CHD event was defined as the occurrence of angina pectoris or myocardial infarction during the follow-up period. RESULTS: During the follow-up period, 30 cases of CHD events were verified. Neutrophil count showed no correlation with CHD, while relative neutrophil concentration and RLC showed positive and negative correlations, respectively, with CHD. The Cox proportional hazard model analysis revealed the following hazard ratios adjusted for LMW Lp(a), LRLC, and LMW Lp(a) + LRLC: (4.31; 95% confidence interval [CI], 1.99-9.32; P < 0.01, 3.621; 95% CI, 1.50-8.75; P < 0.05, and 7.15; 95% CI, 2.17-23.56; P < 0.01, respectively). CONCLUSIONS: Our results suggest that both LMW Lp(a) and LRLC are significant and independent risk factors for CHD and that the combination thereof more strongly predicts CHD in patients with T2DM.

[Overview of drug therapy in elderly diabetic patients].

General treatment principles for elderly diabetic patient with type 2 diabetes are the same as those of adult care. However, hypoglycemia and other adverse effects of glucose-lowering treatment are more common in older patients. Understanding the advantages and disadvantages of each antihyperglycemic drug class helps clinicians individualize therapy for elderly patients. Especially, given the heterogeneity of the older adult population, the risk of hypoglycemia must be carefully considered before using sulfonylureas and insulin regimen. Less stringent goals for glycemic control are recommended for frail elderly diabetic patients with limited life expectancy, advanced diabetes complications, or extensive comorbid conditions. The aggressive management of cardiovascular risk factors, such as hypertension, dyslipidemia, obesity, inactivity or smoking, is likely to have even greater benefits.

The effects of postprandial glucose and insulin levels on postprandial endothelial function in subjects with normal glucose tolerance.

BACKGROUND: Previous studies have demonstrated that postprandial hyperglycemia attenuates brachial artery flow-mediated dilation (FMD) in prediabetic patients, in diabetic patients, and even in normal subjects. We have previously reported that postprandial hyperinsulinemia also attenuates FMD. In the present study we evaluated the relationship between different degrees of postprandial attenuation of FMD induced by postprandial hyperglycemia and hyperinsulinemia and differences in ingested carbohydrate content in non-diabetic individuals. METHODS: Thirty-seven healthy subjects with no family history of diabetes were divided into 3 groups: a 75-g oral glucose loading group (OG group) (n = 14), a test meal group (TM group) (n = 12; 400 kcal, carbohydrate content 40.7 g), and a control group (n = 11). The FMD was measured at preload (FMD0) and at 60 minutes (FMD60) and 120 (FMD120) minutes after loading. Plasma glucose (PG) and immunoreactive insulin (IRI) levels were determined at preload (PG0, IRI0) and at 30 (PG30, IRI30), 60 (PG60, IRI60), and 120 (PG120, IRI120) minutes after loading. RESULT: Percentage decreases from FMD0 to FMD60 were significantly greater in the TM group (-21.19% ± 17.90%; P < 0.001) and the OG group (-17.59% ± 26.64%) than in the control group (6.46% ± 9.17%; P < 0.01), whereas no significant difference was observed between the TM and OG groups. In contrast, the percentage decrease from FMD0 to FMD120 was significantly greater in the OG group (-18.91% ± 16.58%) than in the control group (6.78% ± 11.43%; P < 0.001) or the TM group (5.22% ± 37.22%; P < 0.05), but no significant difference was observed between the control and TM groups. The FMD60 was significantly correlated with HOMA-IR (r = -0.389; P < 0.05). In contrast, FMD120 was significantly correlated with IRI60 (r = -0.462; P < 0.05) and the AUC of IRI (r = -0.468; P < 0.05). Furthermore, the percentage change from FMD0 to FMD120 was significantly correlated with the CV of PG (r = 0.404; P < 0.05), IRI60 (r = 0.401; p < 0.05) and the AUC of IRI (r = 0.427; P < 0.05). No significant correlation was observed between any other FMDs and glucose metabolic variables. CONCLUSION: Differences in the attenuation of postprandial FMD induced by different postprandial insulin levels may occur a long time postprandially but not shortly after a meal.

Urinary N-acetyl-ß-D-glucosaminidase levels are positively correlated with 2-hr plasma glucose levels during oral glucose tolerance testing in prediabetes.

BACKGROUND: Urinary N-acetyl-ß-D-glucosaminidase (NAG) excretion is increased in patients with impaired glucose tolerance (IGT). This study investigated when during the oral glucose tolerance test (OGTT) the plasma glucose, urine glucose, and insulin levels correlate most strongly with urinary N-acetyl-ß-d-glucosaminidase (NAG) levels in prediabetic subjects. METHODS: The OGTT was administered to 80 subjects who had not yet received a diagnosis of diabetes mellitus (DM) and in whom HbA1c levels were ≤6.8% and fasting plasma glucose levels were <7.0 mmol/l. Forty-two subjects had normal glucose tolerance (NGT), 31 had impaired glucose tolerance (IGT), and 7 had DM according to World Health Organization criteria. Serum levels of cystatin C, the estimated glomerular filtration rate, the urinary albumin-to-creatinine (Cr) ratio, urinary and serum ß2-microglobulin, and urinary NAG were measured as markers of renal function. RESULTS: NAG levels were significantly higher in subjects with DM and in subjects with IGT than in subjects with NGT. No significant associations were observed between glycemic status and other markers of renal function. Multiple linear regression analysis showed that the NAG level was positively correlated with plasma glucose levels at 120 min of the OGTT and was associated with the glycemic status of prediabetic patients. CONCLUSION: These results suggest that postprandial hyperglycemia is an independent factor that causes renal tubular damage in prediabetes patients.

Correlation between asymptomatic leukocyturia and urinary N-acetyl-ß-d-glucosaminidase in women.

Urinary N-acetyl-ß-d-glucosaminidase (NAG) has been suggested as a marker for early diabetic nephropathy. This study aimed to prospectively investigate the relationship between asymptomatic leukocyturia (ASL) and NAG in women. One hundred and five female outpatients aged 31-86 years were selected for a 10-year follow-up study. We regarded ASL to be present if two consecutive samples were found to have 10 or more leukocytes/high-power field at 400× magnifications in a centrifuged midstream urine sample both at baseline and 10 years later. The urinary activities of NAG to creatinine ratios (NAG index) were measured in random spot urine samples. Patients without ASL at the beginning of the study were followed. The patients with ASL had diabetes mellitus more frequently than those without ASL at baseline and after 10 years. Residual urine volume and the NAG index were significantly higher in the former than in the latter (p = 0.014 and p = 0.002, respectively) at baseline. During the observation period, 15 patients had ASL (30.6%). Although a gradual increase in the NAG index was found during the study in both patients who had ASL and those who did not, the mean NAG index was significantly higher in the latter during study period (6.4 ± 3.0 vs. 9.8 ± 5.5, p = 0.004, 9.4 ± 5.2 vs. 11.5 ± 6.4, p = 0.328, respectively). On multiple logistic regression analysis, the NAG index at the beginning of the study was an independent predictor of ASL. These results demonstrate that the NAG index may serve as an indicator of ASL in women.

Oral glucose loading attenuates endothelial function in normal individual.

BACKGROUND: We evaluated the relationship between glucose fluctuation and vascular endothelial function. MATERIAL AND METHODS: We recruited 25 healthy individuals with no family history of diabetes (14 subjects and 11 controls). Brachial artery flow-mediated dilation (FMD) and elapsed time when the after-hyperaemia maximum brachial artery diameter is reached; the peak times (PT) of each study subject were measured before and at 60, 120, and 180 min after 75-g oral glucose loading. FMD and PT of controls were measured for four consecutive hours in the fasting state from morning. Also, brachial-ankle pulse wave velocity (baPWV) of each subject was measured at 180 min after 75-g oral glucose loading. RESULTS: Flow-mediated dilation of the study subjects was significantly lower at 60, 120 and 180 min than at pre-load, and significantly lower than that of the controls at 60 and 120 min, but not significantly different at 0 and 180 min. There was no significant difference between the PT of the subjects and the controls during 75-g oral glucose loading. In contrast, the PT of the subjects was significantly shorter than that of the controls at 120 and 180 min, but showed no significant difference at 0 and 60 min. Moreover, baPWV had no significant relationship with FMD. CONCLUSIONS: Our study showed that oral glucose loading attenuates FMD and shortens elapsed time at the maximum after-hyperaemia diameter, and the effect of glucose fluctuation on atherosclerosis in individuals with normal glucose tolerance remains despite only the attenuation of endothelial function.

[An elderly patient with senile dementia showing acquired hemophilia A].

We report a case of an 82-year-old woman with senile dementia who was hospitalized at a specialist dementia hospital for 10 months. She had swelling of the left shoulder joint, subcutaneous hematoma in the left upper arm, and anemia was noted on blood examination. Her serum hemoglobin level was lower than normal at 4.6 g/dL, but there was no sign of gastrointestinal disease or gastrointestinal bleeding, and her stool specimens were negative for occult blood. Hematoma subsequently appeared on her chest and back. She had a low activation level of factor VIII (<1%), a high concentration of acquired inhibitors of factor VIII (18.5 BU/mL), and prolonged activated partial thromboplastin time (83.1 seconds). The possibility of drug-induced anemia or hematoma were ruled out. We diagnosed acquired hemophilia A (AHA), and suspected that this was the cause of her hematomas. We began treatment of her AHA with oral prednisolone and intravenous infusion of factor VIII. The bleeding improved, but she later died due to bacterial pneumonia. AHA is very rare, with a reported annual incidence of 0.1/100,000 in Japan. However, it is necessary to consider such a rare disease when we encounter bleeding in elderly patients.

[A case of ileus caused by a fecalith in an elderly patient with severe dementia].

An 82-year-old woman with severe dementia, living in a nursing home, had severe chronic constipation, possibly due to the presence of multiple risk factors for constipation such as a past history of abdominal open surgery, diabetes, hypothyroidism, and bedridden status. She visited our department accompanied by nursing staff with complaints of nausea and vomiting. Abdominal X-ray films and computed tomography (CT) images showed ileus. We diagnosed strangulation ileus, and performed an emergency laparotomy. There was a mobile cystic lesion located 180 cm from the ileocecal junction which was causing the intestinal obstruction. The cystic lesion was surgically removed via an enterotomy. The greatest dimensions of the cystic lesion were 5 × 3 cm, and it was histologically diagnosed as a fecalith. We report a rare case of ileus caused by a fecalith in an elderly patient.

The Effects of Trypsin Inhibitor on Insulin Secretion Using Rat Pancreas in an Organ Bath.

BACKGROUND/AIM: We developed an experimental method to reproduce insulin secretion from isolated rat pancreas preparations using an organ bath system. However, secretion of trypsin, another pancreatic enzyme, interferes with insulin production in such systems. We aimed to ascertain the minimum trypsin inhibitor (TI), dose for obtaining a sustained, stable rate of insulin secretion. MATERIALS AND METHODS: The action of TI (1-10 µg/ml) on pancreatic preparations of male Wistar-Imamichi rats in organ bath experiments was assessed by measuring insulin, amylase, and trypsin activity. RESULTS: The level of insulin outflow remained steady in the TI-treated samples, in contrast to that in the untreated control, where insulin secretion decreased over time. The level of amylase outflow did not change significantly. Trypsin activity was significantly lower in the TI-treated samples than in the control. CONCLUSION: Even low concentrations of TI can maintain insulin secretion by inhibiting trypsin activity in organ bath experiments.

Development of an organ bath technique for isolated rat pancreas preparations to assess the effect of 1,5-AG on insulin secretion.

To investigate substances related to insulin secretion, we reported a convenient experimental method to reproduce insulin secretion from isolated rat pancreas preparations using an organ bath. While the method has experimental utility for investigating insulin secretion, optimization of the experimental design is still needed. The level of insulin outflow in the control decreased over time in our previous study. Decreasing serum 1,5-anhydroglucitol (1,5-AG) levels is also known to be shown in patients with worsening glycemic control. There is one in vitro report demonstrated that 1,5-AG induced insulin release. It appears that discussion needs to be deepened further on it. In this study, we investigated the effect of 1,5-AG on insulin secretion through to optimize the condition of endocrine function using the ex vivo organ bath technique. The level of insulin outflow in the control and 1,5-AG groups decreased over time in the organ bath experiment. To analyze the effect of trypsin on reduced insulin secretion, pancreas preparation was treated with soybean trypsin inhibitor (TI). Insulin outflow levels of the TI group were significantly higher than the control group. An enzyme indicator of tissue damage tended to be lower in the TI group. There was no significant enhancement of insulin secretion by 1,5-AG. The present study demonstrated the utility of TI application for the organ bath technique. This finding supported the development of an organ bath technique for the assessment of the effects of novel therapeutics on insulin secretion.

Lack of relationship between blood glucose-lowering activity of colestimide and serum cholecystokinin (CCK) concentrations in patients with type 2 diabetes.

Colestimide has been reported to lower blood glucose levels in patients with type 2 diabetes and hypercholesterolemia. We investigated the mechanism of the hypoglycemic activity of colestimide by examining changes in serum cholecystokinin (CCK) and insulin concentrations before and after its 2-week oral administration. A total of seven type 2 diabetes inpatients with hypercholesterolemia received colestimide after their blood glucose levels had stabilized. We daily measured plasma glucose levels and serum lipid concentrations, calculated Body Mass Index (BMI), and determined whole-day changes in serum immunoreactive insulin (IRI) and CCK concentrations in all study subjects. We daily measured plasma glucose levels, as well as serum IRI and CCK concentrations at 10 time points for measurement. Plasma glucose levels, as well as serum IRI and CCK concentrations before and after the 2-week oral administration of colestimide were compared. The means of total cholesterol levels and BMI decreased significantly after administration. At time points for measurement (10 : 00 and 12 : 00), plasma glucose levels decreased significantly after administration (P=0.026 and P=0.009, respectively). Diurnal changes in serum IRI and CCK concentrations were not observed after administration, except for the IRI concentration at 20: 00. The effect of colestimide on CCK may not explain the mechanism of its blood glucose-lowering activity in patients with type 2 diabetes and hypercholesterolemia.

[A case of Creutzfeldt-Jakob disease with codon 129 polymorphism and codon 180 point mutation].

We report a 79-year-old Japanese man with histlogically-diagnosed Creutzfeldt-Jakob disease (CJD) with codon 129 polymorphism and codon 180 point mutation. At the time of the first examination, we diagnosed and treated as Alzheimer's disease with cerebrovascular disease because of laterality of cortex accumulation and an accumulation decrease of perforating branch areas at the SPECT ((123)I-IMP). His status rapidly progressed to an apallic state and died of lung abscess 12 months later. None of the members of his family had neuromuscular disorders. EEG (electroencephalogram) did not reveal periodic synchronous discharges (PSD). Prion protein gene analysis showed Codon 129 polymorphism (Met/Val) and codon 180 point mutation (Val/Ile). The autopsy findings revealed spongiform changes and numerous senile plaque formation in the cerebral cortex. The hippocampus and the cerebellar cortex were well preserved and did not show lacunar infarctions. CJD patients with combination of the codon 180 point mutation and codon 129 polymorphism of the PrP gene have rarely been reported.

Colestimide lowers plasma glucose levels and increases plasma glucagon-like PEPTIDE-1 (7-36) levels in patients with type 2 diabetes mellitus complicated by hypercholesterolemia.

BACKGROUND: Colestimide has been reported to lower blood glucose levels in patients with type 2 diabetes complicated by hypercholesterolemia. AIM: To examine the mechanism by which colestimide decreases plasma glucose levels in the above patients. METHODS: A total of 16 inpatients with type 2 diabetes complicated by hypercholesterolemia received colestimide for 1 week after their plasma glucose levels stabilized. We measured plasma glucose, serum immunoreactive insulin (IRI), serum lipid, plasma glucagon, and plasma glucagon-like peptide-1 (GLP-1) levels. These variables at baseline and 1 week of colestimide administration were compared. RESULTS: Preprandial plasma glucose levels (baseline: 132 +/- 33 mg/dL vs. completion: 118 +/- 43 mg/dL, P=0.073) tended to decrease after colestimide administration, while 1-hr postprandial plasma glucose levels (baseline: 208 +/- 49 mg/dL vs. completion: 166 +/- 30 mg/dL, P<0.001) and 2-hr postprandial plasma glucose levels (baseline: 209 +/- 56 mg/dL vs. completion: 178 +/- 39 mg/dL, P=0.015) decreased significantly at 1 week of colestimide administration. The 2-hr postprandial plasma GLP-1 level was significantly (P=0.015) higher at 1 week of colestimide administration as compared with the baseline level, while there were no significant changes in preprandial and 1-hr postprandial plasma GLP-1 levels. CONCLUSIONS: The GLP-1-increasing activity of colestimide may explain, at least in part, the mechanism of its blood glucose-lowering activity in patients with type 2 diabetes complicated by hypercholesterolemia.