Conditions under which diabetes is diagnosable with a one-time blood test Plasma glucose level Fa... more Conditions under which diabetes is diagnosable with a one-time blood test Plasma glucose level Fasting >126 mg/dL or and HbA1c≥6.5% Casual>200 mg/dL If the above conditions are not satisfied (Diabetes is not diagnosable with a one-time test.) Plasma glucose level Fasting 100-109 mg/dL 110-125 mg/dL Casual 140-199 mg/dL HbA1c 5.6-5.9% 6.0-6.4% Either of the above A ny of the above Performing a 75-g OGTT Desirable S trongly recommended
BACKGROUND While there is a concern about the increase in the occurrence of acute aortic dissecti... more BACKGROUND While there is a concern about the increase in the occurrence of acute aortic dissection (AAD) caused by the worsening of hypertension, mental stress, etc., there is a lack of data regarding the influence of disasters on this event. The aim of this study was to address this issue in the acute–subacute phase after the Kumamoto Earthquake occurred on 14 April 2016. METHODS We retrospectively investigated the impacts of the Kumamoto Earthquake on various cardiovascular diseases, including AAD, utilizing the medical records of patients in 16 hospitals in Kumamoto Prefecture during the period from 14 April to 30 June (78 days) in 2014, 2015, 2016, and 2017. RESULTS The occurrence of heart failure and venous thromboembolism increased significantly in the acute–subacute phase after the earthquake. When comparing the earthquake year (2016) to the non-earthquake years (2014, 2015, and 2017), the difference in the occurrences and mortalities of AADs were not significant. When other...
The PREDICTIVE TM Study of Japan was an open-label, non-randomized 52-week observational study to... more The PREDICTIVE TM Study of Japan was an open-label, non-randomized 52-week observational study to evaluate the safety and efficacy of insulin detemir when used in routine clinical practice. Patients with either type 1 or 2 diabetes in whom insulin detemir was to be prescribed but without a previous history of using insulin detemir were eligible to participate. The primary endpoint was an incidence of serious adverse drug reaction (SADR) for the entire observational period. Data were collected at baseline, 12, 26, and 52 weeks. A total of 3,519 patients were enrolled in 540 institutions between 2008 and 2009. Thirty patients (0.9%) reported 32 SADRs. The rate of total hypoglycemic episodes was 1.51 episodes/patient-year in patients with type 1 diabetes and 0.23 episodes/patient-year in patients with type 2 diabetes. The rate of total hypoglycemic episodes did not increase during the observational period. Significant reductions were observed at 52 weeks in HbA1c levels (0.51% in type 1 diabetes, P \ 0.001; 0.80% in type 2 diabetes, P \ 0.001), fasting glucose level (reduction of 22.1 mg/dl in type 1 diabetes, P \ 0.001; 25.6 mg/dl in type 2 diabetes, P \ 0.001), and intrapatient fasting glucose variability (coefficient of variance; reduction of 11.4% in type 1 diabetes, P \ 0.001; 4.1% for type 2 diabetes, P \ 0.001). Our results from the 52-week follow-up data of 3,345 Japanese patients with diabetes demonstrated that insulin detemir contributed to a lower incidence of SADRs (\1%) and suggested that treatment with detemir could provide better glycemic control without increasing hypoglycemic episodes.
Most kidney nephron components, including glomeruli and renal tubules, derive from the metanephri... more Most kidney nephron components, including glomeruli and renal tubules, derive from the metanephric mesenchyme. The overall differentiation into each component finishes at birth, but the molecular events linking the perinatal and adult kidneys remain elusive. Dullard was cloned from Xenopus kidneys, and encodes a phosphatase that negatively regulates BMP signalling. Here we report that Dullard deletion in the murine metanephric mesenchyme leads to failure of nephron maintenance after birth, resulting in lethality before adulthood. The nephron components are lost by massive apoptosis within 3 weeks after birth, leading to formation of a large hollow with a thin-layered cortex and medulla. Phosphorylated Smad1/5/8 is upregulated in the mutant nephrons, probably through cell-autonomous inhibitory effects of Dullard on BMP signalling. Importantly, administration of the BMP receptor kinase inhibitor LDN-193189 partially rescued the defects caused by Dullard deletion. Thus, Dullard keeps BMP signalling at an appropriate level, which is required for nephron maintenance in the postnatal period.
Acute exercise induces glucose uptake in skeletal muscle in vivo, but the molecular mechanism of ... more Acute exercise induces glucose uptake in skeletal muscle in vivo, but the molecular mechanism of this phenomenon remains to be identified. In this study, we evaluated the involvement of bradykinin in exercise-induced glucose uptake in humans and rats. In human studies, plasma bradykinin concentrations increased significantly during an ergometer exercise (20 minutes) in 8 healthy normoglycemic subjects and 6 well-controlled type 2 diabetic patients (mean hemoglobin A 1c [HbA 1c ], 6.4% ؎ 0.6%), but not in 6 poorly controlled type 2 diabetics (mean HbA 1c , 11.6% ؎ 2.6%). In rat studies, plasma bradykinin concentrations also significantly increased after 1 hour of swimming in nondiabetic and mildly diabetic (streptozotocin [STZ] 45 mg/kg intravenously [IV]) rats, but not in rats with severe diabetes (STZ 65 mg/kg IV). Glucose influx (maximum velocity [V max ]) and GLUT-4 translocation in skeletal muscle of nondiabetic rats significantly increased after 1 hour of swimming, but these increases were abrogated by subcutaneous infusion of bradykinin B 2 receptor antagonist HOE-140 (400 g • kg ؊1 • d ؊1). Insulin-stimulated tyrosine phosphorylation and phosphatidylinositol (PI) 3-kinase activity in response to insulin injection (20 U/kg IV) in the portal vein were significantly attenuated in exercised rats pretreated with HOE-140 compared with saline-treated exercised rats. Our results suggest that plasma bradykinin concentrations increase in response to acute exercise and this increase is affected by blood glucose status in diabetic patients. Moreover, the exercise-induced increase in bradykinin may be involved in modulating exercise-induced glucose transport through an increase of GLUT-4 translocation, as well as enhancement of the insulin signal pathway, during the postexercise period in skeletal muscle, resulting in a decrease of blood glucose.
Biochemical and Biophysical Research Communications, 2011
Angiopoietin-like protein family 4 (Angptl4) has been shown to regulate lipoprotein metabolism th... more Angiopoietin-like protein family 4 (Angptl4) has been shown to regulate lipoprotein metabolism through the inhibition of lipoprotein lipase (LPL). In familial hypercholesterolemia (FH), individuals lacking low-density lipoprotein receptor (LDLR) present not only hypercholesterolemia, but also increased plasma triglyceride (TG)-rich lipoprotein remnants, and develop atherosclerosis. In addition, the most common type of dyslipidemia in individuals with diabetes is increased TG levels. We first generated LDLR(-/-)Angptl4(-/-) mice to study the effect of Angptl4 deficiency on the lipid metabolism. Fasting total cholesterol, VLDL-C, LDL-C, HDL-C and TG levels were decreased in LDLR(-/-)Angptl4(-/-) mice compared with LDLR(-/-)Angptl4(+/+) mice. In particular, post olive oil-loaded TG excursion were largely attenuated in LDLR(-/-)Angptl4(-/-) mice compared with LDLR(-/-)Angptl4(+/+) mice. We next introduced diabetes by streptozotocin (STZ) treatment in Angptl4(-/-) mice and examined the impacts of Angptl4 deficiency. Compared with diabetic Angptl4(+/+) mice, diabetic Angptl4(-/-) mice showed the improvement of fasting and postprandial hypertriglyceridemia as well. Thus, targeted silencing of Angptl4 offers a potential therapeutic strategy for the treatment of dyslipidemia in individuals with FH and insulin deficient diabetes.
IntroductionGiven an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patient... more IntroductionGiven an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methodsWe registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.ResultsOf the registered, 5150 (group A:...
Background: Gestational diabetes insipidus (GDI) is a rare endocrine complication during pregnanc... more Background: Gestational diabetes insipidus (GDI) is a rare endocrine complication during pregnancy that is associated with vasopressinase overproduction from the placenta. Although increased vasopressinase is associated with placental volume, the regulation of placental growth in the later stage of pregnancy is not well known. Case presentation: A 16-year-old pregnant woman was urgently transferred to our hospital because of threatened premature labor when the Kumamoto earthquakes hit the area where she lived. During her hospitalization, she complained of gradually increasing symptoms of polyuria and polydipsia. The serum level of arginine vasopressin (AVP) was 1.7 pg/mL, which is inconsistent with central DI. The challenge of diagnostic treatment using oral 1-deamino-8-D-AVP (DDAVP) successfully controlled her urine and allowed for normal delivery. DDAVP tablets were not necessary to control her polyuria thereafter. Based on these observations, clinical diagnosis of GDI was confirmed. Pathophysiological analyses revealed that vasopressinase expression was more abundant in the GDI patient's syncytiotrophoblast in placenta compared with that in a control subject. Serum vasopressinase was also observed during gestation and disappeared soon after delivery. Vasopressinase is reportedly identical to oxytocinase or insulin regulated aminopeptidase (IRAP), which is an abundant cargo protein associated with the glucose transporter 4 (GLUT4) storage vesicle. Interestingly, the expression and subcellular localization of GLUT4 appeared to occur in a vasopressinase (IRAP)-dependent manner. Conclusion: Because placental volume may be associated with vasopressinase overproduction in GDI, vasopressinase (IRAP)/GLUT4 association appears to contribute to the growth of placenta in this case.
To assess the efficacy and safety of K-877 (Pemafibrate), a novel selective peroxisome proliferat... more To assess the efficacy and safety of K-877 (Pemafibrate), a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that possesses unique PPARα activity and selectivity, compared with placebo and fenofibrate in dyslipidaemic patients with high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels. This study was a double blind, placebo-controlled, parallel-group 12-week clinical trial. The study randomized 224 patients to K-877 0.025, 0.05, 0.1, 0.2 mg BID, fenofibrate 100 mg QD, or placebo (1:1:1:1:1:1) groups. Least squares mean percent changes from the baseline TG levels were -30.9%, -36.4%, -42.6%, -42.7% for the K-877 0.025, 0.05, 0.1, 0.2 mg BID respectively (p < 0.001), which were greater than that of the fenofibrate 100 mg QD (-29.7%, p < 0.001) group. Statistically significant improvements from the baseline HDL-C, very-low-density lipoprotein cholesterol, chylomicron cholesterol, remnant lipoprotein cholesterol, apolipo...
Tyrosine kinase inhibitors (TKIs) have been shown to affect glucose metabolism in patients with c... more Tyrosine kinase inhibitors (TKIs) have been shown to affect glucose metabolism in patients with chronic myeloid leukemia (CML); however, their precise mechanism of action remains unknown. We herein report the case of a 57-year-old diabetic CML patient who was resistant to imatinib and initially required 20 units of insulin daily to control his blood glucose levels. After the initiation of dasatinib, the patient's insulin requirements declined rapidly and insulin treatment was discontinued within two weeks. Meanwhile, the fasting C-peptide immunoreactivity increased two-fold, suggesting that dasatinib facilitated the recovery of insulin production. Dasatinib may therefore be beneficial for diabetic CML patients, especially those who require insulin treatment.
This trial evaluated the safety and efficacy of empagliflozin for 52 weeks as add-on to one other... more This trial evaluated the safety and efficacy of empagliflozin for 52 weeks as add-on to one other oral anti-diabetes therapy in Japanese patients with type 2 diabetes mellitus (T2DM). Patients on biguanide (n = 133), thiazolidinedione (n = 273), alpha-glucosidase inhibitor (n = 139), dipeptidyl-peptidase-4 inhibitor (n = 139), or glinide (n = 140) were randomized 1:1 to receive empagliflozin 10 mg or 25 mg double-blind as add-on therapy for 52 weeks. Patients on sulfonylurea (SU; n = 336) were randomized 2:2:1 to receive empagliflozin 10 mg or 25 mg double-blind or open-label metformin as add-on therapy for 52 weeks. The primary objective was to evaluate safety. Change from baseline in HbA1c at week 52 was a secondary endpoint. Adverse events (AEs) were reported in 67.6% to 84.6% of patients receiving empagliflozin. Confirmed hypoglycaemic AEs (plasma glucose ≤70 mg/dL and/or requiring assistance) were reported in 4.4% and 6.6% of patients receiving empagliflozin 10 mg and 25 mg as ...
The goal of the study was to examine the effects of sitagliptin dose-up or glimepiride dose-up in... more The goal of the study was to examine the effects of sitagliptin dose-up or glimepiride dose-up in Japanese patients with type 2 diabetes who were controlled inadequately by sitagliptin and glimepiride in combination. A multicenter, prospective, randomized, open-label study was carried out in 50 patients with type 2 diabetes treated with sitagliptin and low-dose glimepiride. The patients were randomly assigned to receive the addition of 50 mg/day sitagliptin or 0.5 mg/day glimepiride. The primary end-point was the percentage change in glycated hemoglobin (HbA1c). During a follow-up period, the difference in the percentage changes in HbA1c between the two groups was not significant (P = 0.13). However, HbA1c was significantly decreased by glimepiride dose-up (P < 0.01 vs baseline), but not by sitagliptin dose-up (P = 0.74). Univariate linear regression analyses showed that the percentage change in HbA1c was significantly associated with the serum level of arachidonic acid (AA) in b...
The fact that Metabolic Syndrome (MetS) increases the risk of atherosclerosis has been epidemiolo... more The fact that Metabolic Syndrome (MetS) increases the risk of atherosclerosis has been epidemiologically studied and proven; however, a prospective study on the prevalence of MetS in stroke patients has never been conducted because of the difficulty in diagnosis under critical illness in the acute phase. Therefore, we conducted a prospective multicenter study to investigate the prevalence of MetS in stroke patients with modified diagnostic criteria for MetS. Methods: Stroke patients admitted in the seven participating Emergency and Critical Care Centers within the two years from April 2007 were registered in this study as a prospective multicenter study. Inclusion criteria were 50 to 89 year-old stroke patients who presented within three days from the onset of symptoms. A total of 992 subjects were classified according to the stroke type and the prevalence of MetS and the associated risk factors were investigated. The participants in a medical checkup without any history of a stroke were enrolled as the control group, and compared between the two groups. Results: The prevalence of MetS as well as hyperglycemia and dyslipidemia in the infarction group was significantly higher than that in the non-stroke group. While the hemorrhage group showed no significant difference in the prevalence of MetS, only hypertension was significantly high. According to a subtype analysis, there is a significant correlation between waist circumference increment of the stroke patients and the prevalence of the risk factors of hypertension, hyperglycemia and dyslipidemia. Conclusions: Different risk factors are significantly related to the type of stroke.
Macrovascular complications are responsible for the high morbidity and mortality in patients with... more Macrovascular complications are responsible for the high morbidity and mortality in patients with diabetes. Peroxisome proliferatoractivated receptor c (PPARc) plays a central role in the process of adipocyte differentiation and insulin sensitization, and also possesses anti-atherogenic effects. Recently, some statins, angiotensin II type 1 receptor blockers and calcium channel blockers have been reported to activate PPARc. However, the impact of PPARc activation on diabetic macrovascular complications is not fully understood. It has been reported that the activation of PPARc by thiazolidinediones induces anti-atherogenic effects in vascular cells, including monocytes/macrophages, endothelial cells and smooth muscle cells, in atherosclerotic animal models and in clinical studies. We have reported that hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), which are used for treatment of hypercholesterolemia, activate PPARc and mediate anti-atherogenic effects through PPARc activation in macrophages. Also, telmisartan, an angiotensin type I receptor blocker, has been reported to have anti-atherogenic effects through PPARc activation. Furthermore, we have reported that nifedipine, a dihydropyridine calcium channel blocker, can activate PPARc, thereby mediating anti-atherogenic effects in macrophages. Therefore, statin therapy and part of anti-hypertensive therapy might produce beneficial effects through PPARc activation in hypercholesterolemic and/or hypertensive patients with diabetes, and PPARc might be a therapeutic target for diabetic macrovascular complications. In the present review, we focus on the anti-atherogenic effects of PPARc and suggest potential therapeutic approaches to prevent diabetic macrovascular complications.
1. Recent Prog Horm Res. 1993;48:291-339. The insulin receptor and its substrate: molecular deter... more 1. Recent Prog Horm Res. 1993;48:291-339. The insulin receptor and its substrate: molecular determinants of early events in insulin action. Kahn CR, White MF, Shoelson SE, Backer JM, Araki E, Cheatham B, Csermely P, Folli F, Goldstein BJ, Huertas P, et al. Joslin Diabetes Center, Department of Medicine Brigham and Women&amp;amp;amp;amp;amp;amp;#x27;s Hospital, Boston, Massachusetts. PMID: 7680139 [PubMed - indexed for MEDLINE]. Publication Types: Research Support, Non-US Gov&amp;amp;amp;amp;amp;amp;#x27;t; Research Support, US Gov&amp;amp;amp;amp;amp;amp;#x27;t, PHS; Review. MeSH Terms. ...
Since the discovery of insulin nearly 70 years ago, there has been no problem more fundamental to... more Since the discovery of insulin nearly 70 years ago, there has been no problem more fundamental to diabetes research than understanding how insulin works at the cellular level. Insulin binds to the alpha subunit of the insulin receptor which activates the tyrosine kinase in the beta subunit, but the molecular events linking the receptor kinase to insulin-sensitive enzymes and transport processes are unknown. Our discovery that insulin stimulates tyrosine phosphorylation of a protein of relative molecular mass between 165,000 and 185,000, collectively called pp185, showed that the insulin receptor kinase has specific cellular substrates. The pp185 is a minor cytoplasmic phosphoprotein found in most cells and tissues; its phosphorylation is decreased in cells expressing mutant receptors defective in signalling. We have now cloned IRS-1, which encodes a component of the pp185 band. IRS-1 contains over ten potential tyrosine phosphorylation sites, six of which are in Tyr-Met-X-Met motifs. During insulin stimulation, the IRS-1 protein undergoes tyrosine phosphorylation and binds phosphatidylinositol 3-kinase, suggesting that IRS-1 acts as a multisite &#39;docking&#39; protein to bind signal-transducing molecules containing Src-homology 2 and Src-homology-3 domains. Thus IRS-1 may link the insulin receptor kinase and enzymes regulating cellular growth and metabolism.
Conditions under which diabetes is diagnosable with a one-time blood test Plasma glucose level Fa... more Conditions under which diabetes is diagnosable with a one-time blood test Plasma glucose level Fasting >126 mg/dL or and HbA1c≥6.5% Casual>200 mg/dL If the above conditions are not satisfied (Diabetes is not diagnosable with a one-time test.) Plasma glucose level Fasting 100-109 mg/dL 110-125 mg/dL Casual 140-199 mg/dL HbA1c 5.6-5.9% 6.0-6.4% Either of the above A ny of the above Performing a 75-g OGTT Desirable S trongly recommended
BACKGROUND While there is a concern about the increase in the occurrence of acute aortic dissecti... more BACKGROUND While there is a concern about the increase in the occurrence of acute aortic dissection (AAD) caused by the worsening of hypertension, mental stress, etc., there is a lack of data regarding the influence of disasters on this event. The aim of this study was to address this issue in the acute–subacute phase after the Kumamoto Earthquake occurred on 14 April 2016. METHODS We retrospectively investigated the impacts of the Kumamoto Earthquake on various cardiovascular diseases, including AAD, utilizing the medical records of patients in 16 hospitals in Kumamoto Prefecture during the period from 14 April to 30 June (78 days) in 2014, 2015, 2016, and 2017. RESULTS The occurrence of heart failure and venous thromboembolism increased significantly in the acute–subacute phase after the earthquake. When comparing the earthquake year (2016) to the non-earthquake years (2014, 2015, and 2017), the difference in the occurrences and mortalities of AADs were not significant. When other...
The PREDICTIVE TM Study of Japan was an open-label, non-randomized 52-week observational study to... more The PREDICTIVE TM Study of Japan was an open-label, non-randomized 52-week observational study to evaluate the safety and efficacy of insulin detemir when used in routine clinical practice. Patients with either type 1 or 2 diabetes in whom insulin detemir was to be prescribed but without a previous history of using insulin detemir were eligible to participate. The primary endpoint was an incidence of serious adverse drug reaction (SADR) for the entire observational period. Data were collected at baseline, 12, 26, and 52 weeks. A total of 3,519 patients were enrolled in 540 institutions between 2008 and 2009. Thirty patients (0.9%) reported 32 SADRs. The rate of total hypoglycemic episodes was 1.51 episodes/patient-year in patients with type 1 diabetes and 0.23 episodes/patient-year in patients with type 2 diabetes. The rate of total hypoglycemic episodes did not increase during the observational period. Significant reductions were observed at 52 weeks in HbA1c levels (0.51% in type 1 diabetes, P \ 0.001; 0.80% in type 2 diabetes, P \ 0.001), fasting glucose level (reduction of 22.1 mg/dl in type 1 diabetes, P \ 0.001; 25.6 mg/dl in type 2 diabetes, P \ 0.001), and intrapatient fasting glucose variability (coefficient of variance; reduction of 11.4% in type 1 diabetes, P \ 0.001; 4.1% for type 2 diabetes, P \ 0.001). Our results from the 52-week follow-up data of 3,345 Japanese patients with diabetes demonstrated that insulin detemir contributed to a lower incidence of SADRs (\1%) and suggested that treatment with detemir could provide better glycemic control without increasing hypoglycemic episodes.
Most kidney nephron components, including glomeruli and renal tubules, derive from the metanephri... more Most kidney nephron components, including glomeruli and renal tubules, derive from the metanephric mesenchyme. The overall differentiation into each component finishes at birth, but the molecular events linking the perinatal and adult kidneys remain elusive. Dullard was cloned from Xenopus kidneys, and encodes a phosphatase that negatively regulates BMP signalling. Here we report that Dullard deletion in the murine metanephric mesenchyme leads to failure of nephron maintenance after birth, resulting in lethality before adulthood. The nephron components are lost by massive apoptosis within 3 weeks after birth, leading to formation of a large hollow with a thin-layered cortex and medulla. Phosphorylated Smad1/5/8 is upregulated in the mutant nephrons, probably through cell-autonomous inhibitory effects of Dullard on BMP signalling. Importantly, administration of the BMP receptor kinase inhibitor LDN-193189 partially rescued the defects caused by Dullard deletion. Thus, Dullard keeps BMP signalling at an appropriate level, which is required for nephron maintenance in the postnatal period.
Acute exercise induces glucose uptake in skeletal muscle in vivo, but the molecular mechanism of ... more Acute exercise induces glucose uptake in skeletal muscle in vivo, but the molecular mechanism of this phenomenon remains to be identified. In this study, we evaluated the involvement of bradykinin in exercise-induced glucose uptake in humans and rats. In human studies, plasma bradykinin concentrations increased significantly during an ergometer exercise (20 minutes) in 8 healthy normoglycemic subjects and 6 well-controlled type 2 diabetic patients (mean hemoglobin A 1c [HbA 1c ], 6.4% ؎ 0.6%), but not in 6 poorly controlled type 2 diabetics (mean HbA 1c , 11.6% ؎ 2.6%). In rat studies, plasma bradykinin concentrations also significantly increased after 1 hour of swimming in nondiabetic and mildly diabetic (streptozotocin [STZ] 45 mg/kg intravenously [IV]) rats, but not in rats with severe diabetes (STZ 65 mg/kg IV). Glucose influx (maximum velocity [V max ]) and GLUT-4 translocation in skeletal muscle of nondiabetic rats significantly increased after 1 hour of swimming, but these increases were abrogated by subcutaneous infusion of bradykinin B 2 receptor antagonist HOE-140 (400 g • kg ؊1 • d ؊1). Insulin-stimulated tyrosine phosphorylation and phosphatidylinositol (PI) 3-kinase activity in response to insulin injection (20 U/kg IV) in the portal vein were significantly attenuated in exercised rats pretreated with HOE-140 compared with saline-treated exercised rats. Our results suggest that plasma bradykinin concentrations increase in response to acute exercise and this increase is affected by blood glucose status in diabetic patients. Moreover, the exercise-induced increase in bradykinin may be involved in modulating exercise-induced glucose transport through an increase of GLUT-4 translocation, as well as enhancement of the insulin signal pathway, during the postexercise period in skeletal muscle, resulting in a decrease of blood glucose.
Biochemical and Biophysical Research Communications, 2011
Angiopoietin-like protein family 4 (Angptl4) has been shown to regulate lipoprotein metabolism th... more Angiopoietin-like protein family 4 (Angptl4) has been shown to regulate lipoprotein metabolism through the inhibition of lipoprotein lipase (LPL). In familial hypercholesterolemia (FH), individuals lacking low-density lipoprotein receptor (LDLR) present not only hypercholesterolemia, but also increased plasma triglyceride (TG)-rich lipoprotein remnants, and develop atherosclerosis. In addition, the most common type of dyslipidemia in individuals with diabetes is increased TG levels. We first generated LDLR(-/-)Angptl4(-/-) mice to study the effect of Angptl4 deficiency on the lipid metabolism. Fasting total cholesterol, VLDL-C, LDL-C, HDL-C and TG levels were decreased in LDLR(-/-)Angptl4(-/-) mice compared with LDLR(-/-)Angptl4(+/+) mice. In particular, post olive oil-loaded TG excursion were largely attenuated in LDLR(-/-)Angptl4(-/-) mice compared with LDLR(-/-)Angptl4(+/+) mice. We next introduced diabetes by streptozotocin (STZ) treatment in Angptl4(-/-) mice and examined the impacts of Angptl4 deficiency. Compared with diabetic Angptl4(+/+) mice, diabetic Angptl4(-/-) mice showed the improvement of fasting and postprandial hypertriglyceridemia as well. Thus, targeted silencing of Angptl4 offers a potential therapeutic strategy for the treatment of dyslipidemia in individuals with FH and insulin deficient diabetes.
IntroductionGiven an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patient... more IntroductionGiven an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methodsWe registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.ResultsOf the registered, 5150 (group A:...
Background: Gestational diabetes insipidus (GDI) is a rare endocrine complication during pregnanc... more Background: Gestational diabetes insipidus (GDI) is a rare endocrine complication during pregnancy that is associated with vasopressinase overproduction from the placenta. Although increased vasopressinase is associated with placental volume, the regulation of placental growth in the later stage of pregnancy is not well known. Case presentation: A 16-year-old pregnant woman was urgently transferred to our hospital because of threatened premature labor when the Kumamoto earthquakes hit the area where she lived. During her hospitalization, she complained of gradually increasing symptoms of polyuria and polydipsia. The serum level of arginine vasopressin (AVP) was 1.7 pg/mL, which is inconsistent with central DI. The challenge of diagnostic treatment using oral 1-deamino-8-D-AVP (DDAVP) successfully controlled her urine and allowed for normal delivery. DDAVP tablets were not necessary to control her polyuria thereafter. Based on these observations, clinical diagnosis of GDI was confirmed. Pathophysiological analyses revealed that vasopressinase expression was more abundant in the GDI patient's syncytiotrophoblast in placenta compared with that in a control subject. Serum vasopressinase was also observed during gestation and disappeared soon after delivery. Vasopressinase is reportedly identical to oxytocinase or insulin regulated aminopeptidase (IRAP), which is an abundant cargo protein associated with the glucose transporter 4 (GLUT4) storage vesicle. Interestingly, the expression and subcellular localization of GLUT4 appeared to occur in a vasopressinase (IRAP)-dependent manner. Conclusion: Because placental volume may be associated with vasopressinase overproduction in GDI, vasopressinase (IRAP)/GLUT4 association appears to contribute to the growth of placenta in this case.
To assess the efficacy and safety of K-877 (Pemafibrate), a novel selective peroxisome proliferat... more To assess the efficacy and safety of K-877 (Pemafibrate), a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that possesses unique PPARα activity and selectivity, compared with placebo and fenofibrate in dyslipidaemic patients with high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels. This study was a double blind, placebo-controlled, parallel-group 12-week clinical trial. The study randomized 224 patients to K-877 0.025, 0.05, 0.1, 0.2 mg BID, fenofibrate 100 mg QD, or placebo (1:1:1:1:1:1) groups. Least squares mean percent changes from the baseline TG levels were -30.9%, -36.4%, -42.6%, -42.7% for the K-877 0.025, 0.05, 0.1, 0.2 mg BID respectively (p < 0.001), which were greater than that of the fenofibrate 100 mg QD (-29.7%, p < 0.001) group. Statistically significant improvements from the baseline HDL-C, very-low-density lipoprotein cholesterol, chylomicron cholesterol, remnant lipoprotein cholesterol, apolipo...
Tyrosine kinase inhibitors (TKIs) have been shown to affect glucose metabolism in patients with c... more Tyrosine kinase inhibitors (TKIs) have been shown to affect glucose metabolism in patients with chronic myeloid leukemia (CML); however, their precise mechanism of action remains unknown. We herein report the case of a 57-year-old diabetic CML patient who was resistant to imatinib and initially required 20 units of insulin daily to control his blood glucose levels. After the initiation of dasatinib, the patient's insulin requirements declined rapidly and insulin treatment was discontinued within two weeks. Meanwhile, the fasting C-peptide immunoreactivity increased two-fold, suggesting that dasatinib facilitated the recovery of insulin production. Dasatinib may therefore be beneficial for diabetic CML patients, especially those who require insulin treatment.
This trial evaluated the safety and efficacy of empagliflozin for 52 weeks as add-on to one other... more This trial evaluated the safety and efficacy of empagliflozin for 52 weeks as add-on to one other oral anti-diabetes therapy in Japanese patients with type 2 diabetes mellitus (T2DM). Patients on biguanide (n = 133), thiazolidinedione (n = 273), alpha-glucosidase inhibitor (n = 139), dipeptidyl-peptidase-4 inhibitor (n = 139), or glinide (n = 140) were randomized 1:1 to receive empagliflozin 10 mg or 25 mg double-blind as add-on therapy for 52 weeks. Patients on sulfonylurea (SU; n = 336) were randomized 2:2:1 to receive empagliflozin 10 mg or 25 mg double-blind or open-label metformin as add-on therapy for 52 weeks. The primary objective was to evaluate safety. Change from baseline in HbA1c at week 52 was a secondary endpoint. Adverse events (AEs) were reported in 67.6% to 84.6% of patients receiving empagliflozin. Confirmed hypoglycaemic AEs (plasma glucose ≤70 mg/dL and/or requiring assistance) were reported in 4.4% and 6.6% of patients receiving empagliflozin 10 mg and 25 mg as ...
The goal of the study was to examine the effects of sitagliptin dose-up or glimepiride dose-up in... more The goal of the study was to examine the effects of sitagliptin dose-up or glimepiride dose-up in Japanese patients with type 2 diabetes who were controlled inadequately by sitagliptin and glimepiride in combination. A multicenter, prospective, randomized, open-label study was carried out in 50 patients with type 2 diabetes treated with sitagliptin and low-dose glimepiride. The patients were randomly assigned to receive the addition of 50 mg/day sitagliptin or 0.5 mg/day glimepiride. The primary end-point was the percentage change in glycated hemoglobin (HbA1c). During a follow-up period, the difference in the percentage changes in HbA1c between the two groups was not significant (P = 0.13). However, HbA1c was significantly decreased by glimepiride dose-up (P < 0.01 vs baseline), but not by sitagliptin dose-up (P = 0.74). Univariate linear regression analyses showed that the percentage change in HbA1c was significantly associated with the serum level of arachidonic acid (AA) in b...
The fact that Metabolic Syndrome (MetS) increases the risk of atherosclerosis has been epidemiolo... more The fact that Metabolic Syndrome (MetS) increases the risk of atherosclerosis has been epidemiologically studied and proven; however, a prospective study on the prevalence of MetS in stroke patients has never been conducted because of the difficulty in diagnosis under critical illness in the acute phase. Therefore, we conducted a prospective multicenter study to investigate the prevalence of MetS in stroke patients with modified diagnostic criteria for MetS. Methods: Stroke patients admitted in the seven participating Emergency and Critical Care Centers within the two years from April 2007 were registered in this study as a prospective multicenter study. Inclusion criteria were 50 to 89 year-old stroke patients who presented within three days from the onset of symptoms. A total of 992 subjects were classified according to the stroke type and the prevalence of MetS and the associated risk factors were investigated. The participants in a medical checkup without any history of a stroke were enrolled as the control group, and compared between the two groups. Results: The prevalence of MetS as well as hyperglycemia and dyslipidemia in the infarction group was significantly higher than that in the non-stroke group. While the hemorrhage group showed no significant difference in the prevalence of MetS, only hypertension was significantly high. According to a subtype analysis, there is a significant correlation between waist circumference increment of the stroke patients and the prevalence of the risk factors of hypertension, hyperglycemia and dyslipidemia. Conclusions: Different risk factors are significantly related to the type of stroke.
Macrovascular complications are responsible for the high morbidity and mortality in patients with... more Macrovascular complications are responsible for the high morbidity and mortality in patients with diabetes. Peroxisome proliferatoractivated receptor c (PPARc) plays a central role in the process of adipocyte differentiation and insulin sensitization, and also possesses anti-atherogenic effects. Recently, some statins, angiotensin II type 1 receptor blockers and calcium channel blockers have been reported to activate PPARc. However, the impact of PPARc activation on diabetic macrovascular complications is not fully understood. It has been reported that the activation of PPARc by thiazolidinediones induces anti-atherogenic effects in vascular cells, including monocytes/macrophages, endothelial cells and smooth muscle cells, in atherosclerotic animal models and in clinical studies. We have reported that hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), which are used for treatment of hypercholesterolemia, activate PPARc and mediate anti-atherogenic effects through PPARc activation in macrophages. Also, telmisartan, an angiotensin type I receptor blocker, has been reported to have anti-atherogenic effects through PPARc activation. Furthermore, we have reported that nifedipine, a dihydropyridine calcium channel blocker, can activate PPARc, thereby mediating anti-atherogenic effects in macrophages. Therefore, statin therapy and part of anti-hypertensive therapy might produce beneficial effects through PPARc activation in hypercholesterolemic and/or hypertensive patients with diabetes, and PPARc might be a therapeutic target for diabetic macrovascular complications. In the present review, we focus on the anti-atherogenic effects of PPARc and suggest potential therapeutic approaches to prevent diabetic macrovascular complications.
1. Recent Prog Horm Res. 1993;48:291-339. The insulin receptor and its substrate: molecular deter... more 1. Recent Prog Horm Res. 1993;48:291-339. The insulin receptor and its substrate: molecular determinants of early events in insulin action. Kahn CR, White MF, Shoelson SE, Backer JM, Araki E, Cheatham B, Csermely P, Folli F, Goldstein BJ, Huertas P, et al. Joslin Diabetes Center, Department of Medicine Brigham and Women&amp;amp;amp;amp;amp;amp;#x27;s Hospital, Boston, Massachusetts. PMID: 7680139 [PubMed - indexed for MEDLINE]. Publication Types: Research Support, Non-US Gov&amp;amp;amp;amp;amp;amp;#x27;t; Research Support, US Gov&amp;amp;amp;amp;amp;amp;#x27;t, PHS; Review. MeSH Terms. ...
Since the discovery of insulin nearly 70 years ago, there has been no problem more fundamental to... more Since the discovery of insulin nearly 70 years ago, there has been no problem more fundamental to diabetes research than understanding how insulin works at the cellular level. Insulin binds to the alpha subunit of the insulin receptor which activates the tyrosine kinase in the beta subunit, but the molecular events linking the receptor kinase to insulin-sensitive enzymes and transport processes are unknown. Our discovery that insulin stimulates tyrosine phosphorylation of a protein of relative molecular mass between 165,000 and 185,000, collectively called pp185, showed that the insulin receptor kinase has specific cellular substrates. The pp185 is a minor cytoplasmic phosphoprotein found in most cells and tissues; its phosphorylation is decreased in cells expressing mutant receptors defective in signalling. We have now cloned IRS-1, which encodes a component of the pp185 band. IRS-1 contains over ten potential tyrosine phosphorylation sites, six of which are in Tyr-Met-X-Met motifs. During insulin stimulation, the IRS-1 protein undergoes tyrosine phosphorylation and binds phosphatidylinositol 3-kinase, suggesting that IRS-1 acts as a multisite &#39;docking&#39; protein to bind signal-transducing molecules containing Src-homology 2 and Src-homology-3 domains. Thus IRS-1 may link the insulin receptor kinase and enzymes regulating cellular growth and metabolism.
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Papers by Eiichi Araki