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Biomedical subjects

Nobuya Inagaki

Publications and source records attributed to Nobuya Inagaki.

At least 19 recordsLinked to original sources
PubMed2025

Cardiovascular risk reduction with glucagon-like peptide-1 receptor agonists is proportional to HbA1c lowering in type 2 diabetes: An updated meta-regression analysis incorporating FLOW and SOUL trials.

AIMS: To evaluate relationships of cardiovascular and kidney outcomes with glycemic or bodyweight reductions in randomised placebo-controlled trials of glucagon-like peptide-1 receptor agonists (GLP-1RAs), incorporating data from FLOW and SOUL trials. MATERIALS AND METHODS: PubMed and EMBASE were searched up to 22 August 2025 for placebo-controlled randomized trials of oral or bolus-type, subcutaneous GLP-1RAs reporting major adverse cardiovascular events (MACE; a composite of cardiovascular death, myocardial infarction, and stroke) in adults with type 2 diabetes. The primary outcome was MACE; secondary outcomes included heart failure (HF) and kidney outcomes. Random-effects meta-analyses were followed by meta-regression evaluating associations with HbA1c and bodyweight reduction. RESULTS: A total of 73&#x2009;263 individuals were included from 10 trials (ELIXA, LEADER, SUSTAIN-6, EXSCEL, Harmony Outcomes, PIONEER 6, REWIND, AMPLITUDE-O, FLOW, and SOUL). GLP-1RAs reduced MACE by 14% (hazard ratio: 0.86; 95% CI: 0.82 to 0.91; p <0.001), as well as hospitalisation for HF and the composite kidney outcome (both p <0.001). Meta-regression showed that every 1% extra reduction in HbA1c corresponded to a 27% lower HR for MACE (p&#x2009;=&#x2009;0.015; R2&#x2009;=&#x2009;0.61). While HbA1c reduction was not significantly associated with secondary outcomes, the directionality was consistent with MACE. Bodyweight change was not associated with any of the analysed endpoints, including MACE (p&#x2009;=&#x2009;0.13; R2&#x2009;=&#x2009;0.21). CONCLUSIONS: HbA1c reduction, not bodyweight change, was significantly and proportionally associated with MACE risk reduction. HbA1c lowering may serve as a useful surrogate for the cardiovascular improvements associated with GLP-1RAs in type 2 diabetes.

Humans↗
PubMed2006

Adult pancreatic islets require differential pax6 gene dosage.

Pax6, a paired homeodomain transcription factor, plays crucial roles in morphogenesis of eye, central nervous system, and pancreatic islets. Recently, heterozygosity for pax6 mutation has been reported in some individuals with glucose intolerance and aniridia. To investigate the role of pax6 for pancreatic islet function, we examined the pancreatic phenotype of small eye rat strain (rSey(2)) with a point mutation in the pax6 locus resulting in truncated PAX6 proteins. Analyses of the insulin secretory profile of heterozygous rSey(2)/+ revealed that insulin secretion is significantly increased in response to membrane-depolarizing stimuli such as arginine, tolbutamide, and KCl. The processes of insulin granule exocytosis were suggested to be enhanced in rSey(2)/+. On the other hand, pancreatic insulin and glucagon content and islet architecture in rSey(2)/+ showed no significant differences compared to wild-type. These findings indicate differential requirements for pax6 gene dosage in displaying function and maintaining architecture of adult pancreatic islets.

Aging↗
PubMed2006

Gatifloxacin acutely stimulates insulin secretion and chronically suppresses insulin biosynthesis.

Gatifloxacin can cause both hypoglycemia and hyperglycemia in both diabetic and non-diabetic patients. Gatifloxacin recently has been reported to stimulate insulin secretion by inhibition of ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells. Gatifloxacin-induced hypoglycemia is associated with concomitant use of sulfonylureas, and usually occurs immediately after administration of the drug. We find that gatifloxacin acutely stimulates insulin secretion from mouse pancreatic islets and that glibenclamide has additive effects on gatifloxacin-induced insulin secretion. On the other hand, gatifloxacin-induced hyperglycemia often takes several days to develop. We also demonstrate that chronic gatifloxacin treatment decreases islet insulin content by inhibiting insulin biosynthesis, which process may be associated with gatifloxacin-induced hyperglycemia. Moreover, discontinuation of gatifloxacin results in improved insulin secretory response. These data clarify the differing mechanisms of gatifloxacin-induced hyper- and hypoglycemia, and suggest that blood glucose levels should be carefully monitored during gatifloxacin administration, especially in elderly patients with renal insufficiency, unrecognized diabetes, or other metabolic disorders. Because the risk of potentially life-threatening dysglycemia is increased during gatifloxacin therapy, these findings have important implications for clinical practice.

Animals↗
PubMed2006

The spontaneously diabetic Torii rat with gastroenteropathy.

The spontaneously diabetic Torii (SDT) rat was recently recognized as a new animal model of non-obese type 2 diabetes. As the severe diabetic ocular complications seen in SDT rats already have been investigated, we examined another common diabetic complication, gastroenteropathy. Male SDT rats developed diabetes at 20 weeks and diarrhea at 28 weeks of age. Gastrointestinal motility was evaluated at 28 weeks by measuring the distance of small intestinal transit by oral administration of the non-absorbed marker, arabic gum. SDT rats exhibited greater intestinal transit distance than control SD rats (54.1+/-2.6% versus 43.0+/-1.2%). Insulin treatment of SDT rats begun at 20 weeks of age produced improved stool and reduced intestinal transit distance (41.4+/-0.3%). Morphologically, the SDT rats exhibited longer villi and heavier weight of intestine compared to control SD rats. These results suggest that the SDT rat may be a useful animal model for studies of diabetic gastroenteropathy.

Animals↗
PubMed2006

Characterization and classification of ATP-binding cassette transporter ABCA3 mutants in fatal surfactant deficiency.

The ATP-binding cassette transporter ABCA3 is expressed predominantly at the limiting membrane of the lamellar bodies in lung alveolar type II cells. Recent study has shown that mutation of the ABCA3 gene causes fatal surfactant deficiency in newborns. In this study, we investigated in HEK293 cells the intracellular localization and N-glycosylation of the ABCA3 mutants so far identified in fatal surfactant deficiency patients. Green fluorescent protein-tagged L101P, L982P, L1553P, Q1591P, and Ins1518fs/ter1519 mutant proteins remained localized in the endoplasmic reticulum, and processing of oligosaccharide was impaired, whereas wild-type and N568D, G1221S, and L1580P mutant ABCA3 proteins trafficked to the LAMP3-positive intracellular vesicle, accompanied by processing of oligosaccharide from high mannose type to complex type. Vanadate-induced nucleotide trapping and ATP-binding analyses showed that ATP hydrolysis activity was dramatically decreased in the N568D, G1221S, and L1580P mutants, accompanied by a moderate decrease in ATP binding in N568D and L1580P mutants but not in the G1221S mutant, compared with the wild-type ABCA3 protein. In addition, mutational analyses of the Gly-1221 residue in the 11th transmembrane segment and the Leu-1580 residue in the cytoplasmic tail, and homology modeling of nucleotide binding domain 2 demonstrate the significance of these residues for ATP hydrolysis and suggest a mechanism for impaired ATP hydrolysis in G1221S and L1580P mutants. Thus, surfactant deficiency because of ABCA3 gene mutation may be classified into two categories as follows: abnormal intracellular localization (type I) and normal intracellular localization with decreased ATP binding and/or ATP hydrolysis of the ABCA3 protein (type II). These distinct pathophysiologies may reflect both the severity and effective therapy for surfactant deficiency.

ATP-Binding Cassette Transporters↗
PubMed2006

SUIT, secretory units of islets in transplantation: An index for therapeutic management of islet transplanted patients and its application to type 2 diabetes.

Evaluation of a patient's pancreatic beta-cell function is important in both diagnosis and treatment of diabetes. We sought to determine beta-cell function with a single sampling of blood. Examination of fasting blood glucose (F-BG, mM) and C-peptide (F-CPR, nM) levels in seven post-islet-transplanted states of four patients revealed a linear relationship between F-BG and F-CPR. Assuming that normal subjects aged <40 years have 100% pancreatic beta-cell function, we developed the secretory units of islets in transplantation (SUIT) as an index of beta-cell function by the formula: 250 x F-CPR/(F-BG-3.43). The SUIT index was correlated with the stimulated C-peptide levels not only in islet-transplanted patients (R2 = 0.68, P < 0.05) but also in type 2 patients (R2 = 0.34, P < 0.001). Since the SUIT index can be calculated from data obtained at a single fasting blood sampling and predict the pancreatic beta-cell function, the formula may be a useful tool in clinical management of diabetes.

Blood Glucose↗
PubMed2006

System for simultaneously monitoring heart and breathing rate in mice using a piezoelectric transducer.

We propose a novel system for simultaneously monitoring the heart rate (HR) and breathing rate (BR) of anesthetized mice using a piezoelectric transducer (PZT) placed under the body. It is known that a PZT, which transforms mechanical vibrations into electrical signals, can detect heart sounds and breathing movements. However, no PZT system has been reported for simultaneous and continuous monitoring of HR and BR, possibly due to difficulties in eliminating noises and errors caused by the amplitude fluctuation of heart sounds and breathing movements. These difficulties were overcome by custom-designed analogue circuitry and a microprocessor program, resulting in detection of HR and BR with a high reliability compared to the values obtained from ECG and a conventional airflow sensor. We believe that this practical and easy-to-use system can be applied to a wide variety of basic and clinical research fields.

Algorithms↗
PubMed2006

A single transplantation of the islets can produce glycemic stability and reduction of basal insulin requirement.

We investigated glycemic stability and insulin requirement 1 month after a single transplantation of the islets from non-heart-beating donors or a living donor. Overall blood glucose levels decreased immediately after transplantation. The M-value and mean amplitude of glycemic excursions (MAGE) decreased significantly from 53.0 (range, 8.9-91.0) to 4.2 (0.6-8.8, P<0.05) and from 8.5 mM (4.8-11.7) to 3.3 mM (2.0-4.5, P<0.05), respectively. The values after transplantation were lower than the first quartile of 102 type 2 diabetic control patients. The estimated HbA1c level decreased significantly from 7.9% (5.7-10.9) to 5.4% (4.7-5.9, P<0.05). The supplement of basal insulin decreased 43% from 0.31 units/kg/day (0.16-0.37) to 0.18 units/kg/day (0-0.22, P<0.05), while that of stimulated insulin did not decrease significantly, from 0.28 units/kg/day (0.13-0.51) to 0.21 units/kg/day (0-0.41). Thus, only one islet transplantation can be sufficient to attain metabolic stability, probably by effective supply of basal insulin secretion, sufficient to avoid life-threatening severe hypoglycemia and prevent or delay the progress of secondary complications of diabetes by decreasing the HbA1c level.

Adult↗
PubMed2006

Diphenylhydantoin suppresses glucose-induced insulin release by decreasing cytoplasmic H+ concentration in pancreatic islets.

Diphenylhydantoin (DPH), which is clinically used in the treatment of epilepsy, inhibits glucose-induced insulin release from pancreatic islets by a mechanism that remains unknown. In the present study, DPH is shown to suppress glucose-induced insulin release concentration-dependently. In dynamic experiments, 20 microm DPH suppressed 16.7 mm glucose-induced biphasic insulin release. DPH also suppressed insulin release in the presence of 16.7 mm glucose, 200 microm diazoxide, and 30 mm K+ without affecting the intracellular Ca2+ concentration. DPH suppressed ATP content and mitochondrial membrane hyperpolarization in the presence of 16.7 mm glucose without affecting glucose utilization, glucose oxidation, and reduced nicotinamide adenine dinucleotide phosphate fluorescence. DPH increased cytoplasmic pH in the presence of high glucose, but the increase was abolished under Na+ -deprived conditions and HCO3- -deprived conditions, suggesting that Na+ and HCO3- transport across the plasma membrane are involved in the increase in cytoplasmic pH by DPH. Alkalization by adding NH4+ to the extracellular medium also suppressed insulin release, ATP content, and mitochondrial membrane hyperpolarization. Because ATP production from the mitochondrial fraction in the presence of substrates was decreased by increased pH in the medium, DPH suppresses mitochondrial ATP production by reducing the H+ gradient across mitochondrial membrane. Using permeabilized islets, the increase in pH was shown to decrease Ca2+ efficacy at a clamped concentration of ATP in the exocytotic system. Taken together, DPH inhibits glucose-induced insulin secretion not only by inhibiting mitochondrial ATP production, but also by reducing Ca2+ efficacy in the exocytotic system through its alkalizing effect on cytoplasm.

Adenosine Triphosphate↗
PubMed2006

Factors responsible for deteriorating glucose tolerance in newly diagnosed type 2 diabetes in Japanese men.

Hyperglycemia frequently continues to worsen even after the diagnosis of overt diabetes. The aim of this study is to evaluate the factors contributing to increasing glucose intolerance after onset of type 2 diabetes in Japanese subjects. Five hundred fifty newly diagnosed type 2 diabetic patients were classified into 3 degrees of hyperglycemia based on plasma glucose levels estimated by 75-g oral glucose tolerance test: diabetes mellitus with isolated fasting hyperglycemia (DM/IFH), DM with isolated postchallenge hyperglycemia (DM/IPH), and DM with fasting and postchallenge hyperglycemia (DM/FPH). In addition, the DM/IFH and DM/IPH groups were subdivided to clarify the determinants of fasting and postchallenge hyperglycemia. Insulin secretion was evaluated by insulinogenic index, and insulin sensitivity was evaluated by composite index of insulin sensitivity (ISI composite). The insulinogenic index in DM/IFH was highest of the 3 groups (P < .0001). The insulinogenic index in DM/IPH was higher than in DM/FPH (P < .0001). The international sensitivity index composite in DM/IPH was highest of the 3 groups (P < .05). Although impaired early-phase insulin secretion plays the crucial role in deterioration from DM/IFH to DM/FPH in Japanese subjects, impaired early-phase insulin secretion and decreased insulin sensitivity both are factors in deterioration from DM/IPH to DM/FPH. In addition, comparison of subgroups of DM/IFH and DM/IPH shows that although decreased early-phase insulin secretion plays the more significant role in postchallenge hyperglycemia in Japanese subjects, insulin sensitivity is the more important factor in fasting hyperglycemia.

Adult↗
PubMed2005

Niemann-Pick type C disease: novel NPC1 mutations and characterization of the concomitant acid sphingomyelinase deficiency.

Niemann-Pick type C (NPC) disease is an inherited lipid storage disorder characterized by the lysosomal accumulation of free cholesterol in affected cells. Three novel mutations in the NPC1 gene (c.3615delA, c.2000C > T, and c.2240delT) were detected in two unrelated patients with the severe phenotype of NPC. The analyses showed that the c.2240delT mutation, which causes a premature stop at codon 748, resulted in nonsense-mediated decay of the mutant transcripts. Immunoblotting analyses for the NPC1 protein did not detect the mutant proteins in COS-1 cells transiently transfected with the two mutant NPC1 cDNA constructs (c.3615delA and c.2000C > T). In NPC cells, sphingomyelin accumulates with cholesterol, leading to an identical subcellular distribution of both lipids. Acid sphingomyelinase (ASM), which is responsible for the lysosomal hydrolysis of sphingomyelin, is partially reduced in NPC fibroblasts. Therefore, NPC fibroblasts were studied to determine if ASM activity was perturbed due to the accumulation of cholesterol. However, these studies demonstrated that the subcellular localization of ASM was preserved, suggesting that the high content of lysosomal cholesterol was not responsible for the decreased ASM activity.

Animals↗
PubMed2005

Cloning of ABCA17, a novel rodent sperm-specific ABC (ATP-binding cassette) transporter that regulates intracellular lipid metabolism.

The A subclass of the ABC (ATP-binding cassette) transporter superfamily has a structural feature that distinguishes it from other ABC transporters, and is proposed to be involved in the transmembrane transport of endogenous lipids. Here we have cloned mouse and rat full-length cDNAs of ABCA17, a novel ABC transporter belonging to the A subclass. Mouse and rat ABCA17 proteins comprise 1733 and 1773 amino acid residues respectively, having 87.3% amino acid identity; mouse ABCA17 has amino acid identities of 55.3% and 36.7% with mouse ABCA3 and sea urchin ABCA respectively. RNA blot and quantitative real-time PCR analyses showed that ABCA17 mRNA is expressed exclusively in the testis. Examination of testis by in situ hybridization showed that ABCA17 mRNA is expressed in germ cells, mainly spermatocytes, in the seminiferous tubule. Immunoblot analysis using a specific antibody showed that ABCA17 is a protein of 200 kDa, and immunohistochemical analysis demonstrated that the protein is detected in the anterior head of sperm and elongated spermatids. ABCA17 was localized in the endoplasmic reticulum in transiently transfected HEK293 cells. Metabolic labelling analysis showed that intracellular esterified lipids, including cholesteryl esters, fatty acid esters and triacylglycerols, were significantly decreased in HEK293 cells stably expressing ABCA17 compared with untransfected cells. These results suggest that ABCA17 may play a role in regulating lipid composition in sperm.

ATP-Binding Cassette Transporters↗
PubMed2005

Expression of ABCA2 protein in human vestibular schwannoma and peripheral nerve.

ABCA2, which belongs to the A subclass of the ATP-binding cassette (ABC) transporter superfamily, is predominantly expressed in the cytoplasm of oligodendrocytes and Schwann cells, the myelin-forming cells in brain and peripheral nerve, respectively. Here, we demonstrate by immunoblot and immunohistochemistry that ABCA2 is expressed in benign vestibular schwannomas, which contain neither axons nor compact myelin. The expression patterns of ABCA2 in combination with other markers showed phenotypic heterogeneity in schwannomas. The majority of cells in fascicular Antoni type A areas coexpressed ABCA2, Ca2+-binding protein S100beta, and p75 nerve growth factor receptor. In contrast, considerably varied expression levels of ABCA2 and p75 were more prominent in hypocellular type B areas than in type A areas. These data suggest that ABCA2 may be useful as a marker for cellular characterization of schwannomas.

ATP-Binding Cassette Transporters↗
PubMed2005

The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus.

CONTEXT: Known genes in maturity-onset diabetes of the young account for only a fraction of families with dominantly inherited diabetes in Japan. There should be as-yet-unidentified genes that account for the rest of the patients. OBJECTIVE: To identify and characterize the mutation responsible for a Japanese family with dominantly inherited diabetes mellitus. SUBJECTS: Members of a four-generation family with dominantly inherited diabetes mellitus observed in three generations. None of the patients in this family had permanent neonatal diabetes. One had transient neonatal diabetes, one had childhood diabetes, and the others had adult-onset diabetes without autoantibodies or insulin resistance. METHODS: Screening of the chromosomal location of the gene by a genome-wide linkage analysis followed by candidate gene sequencing. Confirmation of the functional significance of the identified mutation by the population survey and the physiological analysis. RESULTS: We identified a novel mutation (C42R) in the KCNJ11 gene coding for the Kir6.2 subunit of the pancreatic ATP-sensitive potassium channel. The patch-clamp experiments using the mutated KCNJ11 showed that the mutation causes increased spontaneous open probability and reduced ATP sensitivity. The effect, however, was partially compensated by the reduction of functional ATP-sensitive potassium channel expression at the cell surface, which could account for the milder phenotype of our patients. CONCLUSIONS: These results broaden the spectrum of diabetes phenotypes caused by mutations of KCNJ11 and suggest that mutations in this gene should be taken into consideration for not only permanent neonatal diabetes but also other forms of diabetes with milder phenotypes and later onset.

Amino Acid Substitution↗
PubMed2005

Neuroprotection by KATP channels.

The substantia nigra pars reticulata, the area with the highest expression of ATP-sensitive potassium channels in the brain, plays a pivotal role in suppressing the propagation of generalized seizures by its silence. Mice lacking the Kir6.2 subunit of the channels were extremely susceptible to generalized seizures after brief hypoxia. The nigral neuron activity, which is among highest in the brain, was rapidly inactivated during hypoxia by the opening of the post-synaptic ATP-sensitive potassium channels in normal mice, while the neuron activity was enhanced in the mutant mice. During seizure, the cerebral metabolic rate of oxygen increases more than under any other circumstance, leading ultimately to irreversible cell damage. Thus, rapid minimization of energy consumption during metabolic stresses such as hypoxia may be effective protection from the seizure-induced lethal effects. The ATP-sensitive potassium channels in the reticulata neurons may be involved in the protection mechanism against energy-consuming generalized seizure by earlier response to hypoxia than those in other, less active neuron types.

Adenosine Diphosphate↗
PubMed2005

Three measures of tumor necrosis factor alpha activity and insulin resistance in nonobese Japanese type 2 diabetic patients.

The aim of the present study was to investigate the relationship between insulin resistance and tumor necrosis factor alpha (TNF-alpha) as well as soluble TNF receptors (sTNF-R), body mass index (BMI), leptin, adiponectin, and serum lipid profile including triglycerides in nonobese Japanese patients with type 2 diabetes. A total of 88 nonobese Japanese type 2 diabetic patients were studied. The duration of diabetes was 11.0 +/- 0.8 years. In conjunction with BMI, glycosylated hemoglobin (HbA1c), fasting concentrations of plasma glucose, serum lipids (triglycerides, high-density lipoprotein cholesterol, and total cholesterol), serum leptin, serum adiponectin, serum TNF-alpha, and soluble TNF receptors (sTNF-R1 and sTNF-R2) were also measured. Insulin resistance was estimated by the insulin resistance index of homeostasis model assessment. Insulin resistance was positively correlated with BMI, triglycerides, leptin, and total cholesterol and negatively correlated with adiponectin and high-density lipoprotein cholesterol. In contrast, insulin resistance was not associated with TNF-alpha, nor sTNF-R (sTNF-R1 and sTNF-R2) in our diabetic patients. There was no significant relationship between the 3 measures of TNF-alpha system (TNF-alpha, sTNF-R1, and sTNF-R2) and BMI, serum triglycerides, leptin, or adiponectin in these patients. From these results, it can be concluded that peripheral levels of TNF-alpha system activity are not a major factor responsible for insulin resistance in nonobese Japanese type 2 diabetic patients.

Adult↗