To elucidate the energy balance over a forest, seasonal changes in the water and energy exchanges... more To elucidate the energy balance over a forest, seasonal changes in the water and energy exchanges over a young larch forest (E-YL) in eastern Siberia were investigated and compared with the reported characteristics of a mature larch forest (W-ML) in the same region. Observations of the energy fluxes were conducted during the growing season from 15 April through 14 September 2000. The sum of the turbulent heat fluxes H and lE, ground heat flux G and heat storage change rate DS was generally in good agreement with the net radiation flux R NET , except when the friction velocity u * was <0.2 m s À1. Atmospheric instability also reduced the energy balance ratio EBR in the daytime. The EBR was defined as the ratio of the turbulent heat flux H + lE toward the available energy input R NET À G À DS for the reference horizontal plane, whereas the energy closure fraction CF was defined as the ratio of the net ecosystem heat exchange H + lE + DS atmosphere to the available energy input R NET À G À DS biomass for the biomass surface. EBR and CF had different features in their relationship to u * at night. The threshold to reject nighttime data at low u * values was estimated to be 0.2 m s À1 by the EBR, but >0.3 m s À1 by the CF. The averaged features of the CF relationships with u * and atmospheric stability z were similar to those reported for Canadian boreal forests. In contrast, hourly CF and hourly EBR were widely scattered. The probability functions of EBR for different wind velocities were consistent with previous results from large eddy simulation. To determine the seasonal course of daily flux values, the Bowen ratio energy budget method was used to estimate the turbulent heat fluxes. The daily latent heat flux maintained a value of approximately 50 W m À2 during the summer, whereas the daily sensible heat flux varied with changes in the available energy. The Bowen ratio had a clear ''U'' shape over the course of the growing season. The minimum values of approximately 1.
Journal of the Meteorological Society of Japan. Ser. II, 2013
A parameter set expressing the potential response used to simulate evapotranspiration was inferre... more A parameter set expressing the potential response used to simulate evapotranspiration was inferred from pooled data of leaf-level stomatal conductance in the Far East. We used Jarvis-type parameterization, which consists of restriction terms of light, air dryness, temperature, and soil water. Two parameter sets, pooled common (PC) and within-site (WS)
Forests cover approximately 30% of the total land surface of the Earth (FAO, 2005). They make eff... more Forests cover approximately 30% of the total land surface of the Earth (FAO, 2005). They make effective use of radiation input, as the albedo is lower and net radiation is higher above forest canopies than above other land cover types (e.g., McNaughton and Jarvis, 1983). Thus forests play an important role in energy and water partitioning processes. Approximately 25% of the global forest area is boreal forest, of which around 76% is in Russia (FAO, 2005). Investigation of water and energy exchanges between the forest and the atmosphere in boreal forests, especially those in Russia, is therefore essential to our understanding of the global hydrological cycle and energy balance. Boreal forests have a number of features that make them different from forests in other climate regions: monotonous vegetation, relatively sparse main canopy trees, and dense understory vegetation. Black and Kelliher (1989) reviewed earlier publications that calculated the evapotranspiration from understory vegetation (E U) using lysimeter or chamber methods, or through stomatal conductance measurements. They showed that the contribution of E U to evapotranspiration by the whole ecosystem (E O) ranged from 8 to 65%. Thus the boreal forest ecosystem has two main sources of evapotranspiration: overstory trees and understory vegetation on the forest floor. To understand the water and energy exchange processes between the boreal forest ecosystem and the atmosphere, we must observe E U and evaluate its contribution to E O. Since the 1990s, many researchers have attempted to observe the latent and sensible heat fluxes above understory vegetation using the eddy-covariance (EC) method (
Roughness length and zero-plane displacement over boreal, cool-and warm-temperate 2 forests were ... more Roughness length and zero-plane displacement over boreal, cool-and warm-temperate 2 forests were observed and parameterised using forest structure data. Previous mod-3 els for roughness length and zero-plane displacement using leaf area index and 4 frontal area index did not describe intersite differences, and the model for zero-5 plane displacement did not express seasonal variations with the change of leaf area 6 that was smaller in dense forest than in sparse forest. The observed results show 7 that intersite differences of normalised zero-plane displacement were related to stand 8 density, and seasonal variations were related to leaf area index at each forest, with 9 the degree depending on stand density. From these observations, a new concept is proposed for normalised zero-plane displacement: the basal part is primarily determined by the density of stems and branches (stand density), while the seasonal variation depends on the density of leaves (leaf area index), which is limited to the residual of the basal part. Based on this concept, a new model was developed and verified to express both intersite differences and seasonal variations in observed roughness length and zero-plane displacement.
The Spontaneously Diabetic Torii (SDT) rat is a rat model of nonobese type 2 diabetes mellitus, a... more The Spontaneously Diabetic Torii (SDT) rat is a rat model of nonobese type 2 diabetes mellitus, and hepatocellular adenomas have not been reported in this model. We report a hepatocellular adenoma with severe fatty change in a male 42-week-old SDT rat fed a high-fat diet. At necropsy, the animal had a whitish nodular mass of approximately 2 cm in diameter in the right medial lobe. Histologically, the mass was well demarcated from the surrounding tissues, slightly compressing the adjacent hepatic parenchyma and widely compartmented by fibrous connective tissues. The mass consisted of vacuolated tumor cells resembling hepatocytes with a solid and occasionally trabecular growth pattern. Abundant neutral lipids, which were positive for fat with Oil Red O stain and which ultrastructurally had moderately dense material, were contained within the vacuoles of the tumor cells. Immunohistochemically, the tumor cells showed an increase in immunoreactivity or number for Cytokeratin 8/18 and proliferating cell nuclear antigen but were negative for mesenchymal markers. From these findings, the mass could be distinguished from hepatocellular hyperplasia and was diagnosed as hepatocellular adenoma. In rats, hepatocellular adenoma accompanied by severe fatty change is rare, and this is the first report of a hepatocellular tumor with severe fatty change in a SDT rat.
The larch (Larix spp.) forest in eastern Siberia is the world's largest coniferous forest. It... more The larch (Larix spp.) forest in eastern Siberia is the world's largest coniferous forest. Its persistence is considered to depend on near-surface permafrost, and thus, forecast warming over the 21st century and consequent degradation of near-surface permafrost is expected to affect the larch forest in Siberia. However, predictions of these effects vary greatly, and many uncertainties remain about land - atmosphere interactions within the ecosystem. We developed an integrated land surface model to analyze how the Siberian larch forest will react to current warming trends. This model analyzed interactions between vegetation dynamics and thermo-hydrology, although it does not consider many processes those are considered to affect productivity response to a changing climate (e.g., nitrogen limitation, waterlogged soil, heat stress, and change in species composition). The model showed that, under climatic conditions predicted under gradual and rapid warming, the annual net primary p...
Journal of Pharmacology and Experimental Therapeutics, Jun 1, 2001
Insulin secretion from MIN6 cells (a pancreatic -cell line) induced by high glucose (greater tha... more Insulin secretion from MIN6 cells (a pancreatic -cell line) induced by high glucose (greater than 16.8 mM) was potentiated by a novel hypoglycemic agent [trans-4-(4-methylcyclohexyl)-4-oxobutyric acid (JTT-608)] (but not glibenclamide, a sulfonylurea). The extracellular Ca 2ϩ -free condition, a L-type Ca 2ϩ channel blocker (nifedipine) and an ATP-sensitive K ϩ channel opener, diazoxide, completely inhibited increases in cytosolic free Ca 2ϩ ([Ca 2ϩ ]i) and insulin secretion evoked by JTT-608 in the presence of extracellular Ca 2ϩ . An electrophysiological study using single-barreled microelectrode techniques demonstrated that membrane potential (V m ) and input resistance of the cell membrane (R i ) are depolarized and increased by JTT-608, respectively. The apparent transference number for K ϩ was also significantly decreased after the addition of JTT-608. These effects immediately occurred after addition of JTT-608 and very rapidly disappeared after removal of JTT-608, which has not been observed in sulfonylureas. Also, these effects of JTT-608 were diminished, but not completely by diazoxide. JTT-608 did not affect the specific binding of [ 3 H]glibenclamide to the sulfonylurea receptor. These findings suggest that JTT-608 mainly inhibits ATP-sensitive K ϩ channel activity via a binding site distinct from the sulfonylurea receptor and then depolarizes V m to open voltage-dependent L-type Ca 2ϩ channels. Subsequently, these events stimulate Ca 2ϩ entry to increase [Ca 2ϩ ]i and induce insulin secretion from MIN6 cells. Therefore, JTT-608 is a unique hypoglycemic agent that enhances high glucose-induced insulin secretion. The present findings indicate that JTT-608 is a more useful new class of therapeutic drug for patients with non-insulin-dependent diabetes mellitus, compared with sulfonylurea derivatives.
The Spontaneously Diabetic Torii-Lepr(fa) (SDT-fa/fa) rat, a new model of obese type 2 diabetes, ... more The Spontaneously Diabetic Torii-Lepr(fa) (SDT-fa/fa) rat, a new model of obese type 2 diabetes, shows obesity, hyperglycemia, and hyperlipidemia from 6 weeks of age. Diabetic complications such as nephropathy and cataract are observed with aging; however, blood pressure change with age has not previously been examined. In this study, blood pressure was periodically measured and the change was investigated. Blood pressure in male SDT-fa/fa rats was elevated at 8, 16, and 24 weeks of age, whereas the heart rate was not changed. In addition to hyperglycemia, hyperlipidemia, and proteinuria, hyperleptinemia and increased urine angiotensinogen were observed in SDT-fa/fa rats. Blood pressure and heart rate in the male original SDT (SDT-+/+) rat did not significantly change. In conclusion, the SDT-fa/fa rat is a promising model, showing significant hypertension with diabetes mellitus.
1 We examined the eects of the novel hypoglycaemic agent JTT-608 [trans-4-(4-methylcyclohexyl)-4-... more 1 We examined the eects of the novel hypoglycaemic agent JTT-608 [trans-4-(4-methylcyclohexyl)-4-oxobutyric acid] on insulin secretion using rat pancreatic islets, and analysed the mechanism of its eect. 2 JTT-608 augmented 8.3 mM glucose-induced insulin secretion dose-dependently, and there was a stimulatory eect of 100 mM JTT-608 at both moderate and high concentrations (8.3, 11.1 and 16.7 mM) of glucose, but not at low concentrations (3.3 and 5.5 mM). In perifusion experiments, both phases of insulin release were enhanced, and the eect was eliminated 10 min after withdrawal of the agent. 3 In the presence of 200 mM diazoxide and a depolarizing concentration (30 mM) of K + , there was an augmentation of insulin secretion by 100 mM JTT-608, not only under high levels of glucose but also under low levels, and the eects were abolished by 10 mM nitrendipine. 4 JTT-608 augmented insulin secretion from electrically permeabilized islets in the presence of stimulatory concentrations (0.3 and 1.0 mM) of Ca 2+ , and the intracellular Ca 2+ concentration ([Ca 2+ ] i ) response under 16.7 mM glucose, 200 mM diazoxide, and 30 mM K + was also increased. 5 The cyclic AMP content in the islets was increased by 100 mM JTT-608, and an additive eect to 1 mM forskolin was observed, but not to 50 mM 3-isobutyl-1-methylxanthine (IBMX). JTT-608 inhibited phosphodiesterase (PDE) activity dose-dependently. 6 We conclude that JTT-608 augments insulin secretion by enhancing Ca 2+ ecacy and by increasing Ca 2+ in¯ux. This appears to be a result of the increased intracellular cyclic AMP concentration due to PDE inhibition. Insulinotropic mechanism of JTT-608 902 E. Mukai et al British Journal of Pharmacology, vol 129 (5) Insulinotropic mechanism of JTT-608 904 E. Mukai et al British Journal of Pharmacology, vol 129 (5) Insulinotropic mechanism of JTT-608 906 E. Mukai et al
Animal science journal = Nihon chikusan Gakkaiho, Jan 5, 2016
The onset and progression of type II diabetes is closely related to environmental factors, in par... more The onset and progression of type II diabetes is closely related to environmental factors, in particular dietary habit. Moreover, the environmental exposures very early in life can influence the risk for development of type II diabetes later in life. In this study, we investigated pathophysiological changes in the pups of maternal Spontaneously Diabetic Torii (SDT) rats that were fed a high-fat diet (HFD) throughout gestation and lactation. Maternal SDT rats were continued on HFD for 5 weeks, from day 8 of gestation to day 21 after birth, and biological analyses of the pups were performed from 2 to 22 weeks of age. Results of serum lipid levels in pups from dams fed HFD were higher than pups from dams fed a standard diet, and the onset of diabetes was significantly accelerated in pups from dams fed HFD. In pathological analyses, pups from dams fed HFD showed increases in liver weight and vacuolation of hepatic cells at 2 weeks of age. In conclusion, the metabolic disorder of lipids ...
During an investigation of drugs for improving the beta-cell response to glucose, we found that 4... more During an investigation of drugs for improving the beta-cell response to glucose, we found that 4-cyclohexyl-4-oxobutyric acid selectively improved glucose-stimulated insulin release and glucose tolerance in both normal and diabetic rats. A series of 4-cycloalkyl-4-oxobutyric acids and related compounds were synthesized and evaluated for their effects on the glucose tolerance test and fasting euglycemia. This study elucidated the structural requirements for drug activity and determined that the optimum compound was 4-(trans-4-methylcyclohexyl)-4-oxobutyric acid 7 (JTT-608). This compound improved glucose tolerance from an oral dose of 3 mg/kg and did not change fasting euglycemia even at an oral dose of 30 mg/kg. Selective improvement of glucose-induced insulin secretion was observed in studies using neonatal streptozotocin rats (nSTZ rats) and perfused pancreases isolated from nSTZ rats.
Some nutrients, such as carbohydrate, fat and protein, are known to stimulate satiety. However, t... more Some nutrients, such as carbohydrate, fat and protein, are known to stimulate satiety. However, the effect of sn-2-monoacylglycerol (2-MG), one of the digestive products of triglycerides, on food intake is still unclear. In the present study, the effects of 2-MG on food intake and diarrhea were evaluated and compared with long-chain fatty acid (LCFA) in rats by intrajejunal infusion. Intrajejunal infusion of 2-MG reduced food intake. In addition, 2-MG did not induce diarrhea at the condition that it comparably reduced food intake as compared with LCFA. These results suggest that 2-MG stimulates satiety without inducing diarrhea, different from LCFA.
w Ž . We investigated the pharmacological effects of a new anti-hyperglycemic agent, x acid , in ... more w Ž . We investigated the pharmacological effects of a new anti-hyperglycemic agent, x acid , in normal and neonatally streptozotocin-treated rats. In normal rats, JTT-608 improved glucose tolerance at 3-30 mgrkg, doses Ž . Ž . that did not cause a decrease in fasting blood glucose levels. In contrast, tolbutamide 10-100 mgrkg and glibenclamide 1-3 mgrkg caused a persistent decrease in fasting blood glucose levels, and tolbutamide only improved glucose tolerance at 10-100 mgrkg.
To elucidate the energy balance over a forest, seasonal changes in the water and energy exchanges... more To elucidate the energy balance over a forest, seasonal changes in the water and energy exchanges over a young larch forest (E-YL) in eastern Siberia were investigated and compared with the reported characteristics of a mature larch forest (W-ML) in the same region. Observations of the energy fluxes were conducted during the growing season from 15 April through 14 September 2000. The sum of the turbulent heat fluxes H and lE, ground heat flux G and heat storage change rate DS was generally in good agreement with the net radiation flux R NET , except when the friction velocity u * was <0.2 m s À1. Atmospheric instability also reduced the energy balance ratio EBR in the daytime. The EBR was defined as the ratio of the turbulent heat flux H + lE toward the available energy input R NET À G À DS for the reference horizontal plane, whereas the energy closure fraction CF was defined as the ratio of the net ecosystem heat exchange H + lE + DS atmosphere to the available energy input R NET À G À DS biomass for the biomass surface. EBR and CF had different features in their relationship to u * at night. The threshold to reject nighttime data at low u * values was estimated to be 0.2 m s À1 by the EBR, but >0.3 m s À1 by the CF. The averaged features of the CF relationships with u * and atmospheric stability z were similar to those reported for Canadian boreal forests. In contrast, hourly CF and hourly EBR were widely scattered. The probability functions of EBR for different wind velocities were consistent with previous results from large eddy simulation. To determine the seasonal course of daily flux values, the Bowen ratio energy budget method was used to estimate the turbulent heat fluxes. The daily latent heat flux maintained a value of approximately 50 W m À2 during the summer, whereas the daily sensible heat flux varied with changes in the available energy. The Bowen ratio had a clear ''U'' shape over the course of the growing season. The minimum values of approximately 1.
Journal of the Meteorological Society of Japan. Ser. II, 2013
A parameter set expressing the potential response used to simulate evapotranspiration was inferre... more A parameter set expressing the potential response used to simulate evapotranspiration was inferred from pooled data of leaf-level stomatal conductance in the Far East. We used Jarvis-type parameterization, which consists of restriction terms of light, air dryness, temperature, and soil water. Two parameter sets, pooled common (PC) and within-site (WS)
Forests cover approximately 30% of the total land surface of the Earth (FAO, 2005). They make eff... more Forests cover approximately 30% of the total land surface of the Earth (FAO, 2005). They make effective use of radiation input, as the albedo is lower and net radiation is higher above forest canopies than above other land cover types (e.g., McNaughton and Jarvis, 1983). Thus forests play an important role in energy and water partitioning processes. Approximately 25% of the global forest area is boreal forest, of which around 76% is in Russia (FAO, 2005). Investigation of water and energy exchanges between the forest and the atmosphere in boreal forests, especially those in Russia, is therefore essential to our understanding of the global hydrological cycle and energy balance. Boreal forests have a number of features that make them different from forests in other climate regions: monotonous vegetation, relatively sparse main canopy trees, and dense understory vegetation. Black and Kelliher (1989) reviewed earlier publications that calculated the evapotranspiration from understory vegetation (E U) using lysimeter or chamber methods, or through stomatal conductance measurements. They showed that the contribution of E U to evapotranspiration by the whole ecosystem (E O) ranged from 8 to 65%. Thus the boreal forest ecosystem has two main sources of evapotranspiration: overstory trees and understory vegetation on the forest floor. To understand the water and energy exchange processes between the boreal forest ecosystem and the atmosphere, we must observe E U and evaluate its contribution to E O. Since the 1990s, many researchers have attempted to observe the latent and sensible heat fluxes above understory vegetation using the eddy-covariance (EC) method (
Roughness length and zero-plane displacement over boreal, cool-and warm-temperate 2 forests were ... more Roughness length and zero-plane displacement over boreal, cool-and warm-temperate 2 forests were observed and parameterised using forest structure data. Previous mod-3 els for roughness length and zero-plane displacement using leaf area index and 4 frontal area index did not describe intersite differences, and the model for zero-5 plane displacement did not express seasonal variations with the change of leaf area 6 that was smaller in dense forest than in sparse forest. The observed results show 7 that intersite differences of normalised zero-plane displacement were related to stand 8 density, and seasonal variations were related to leaf area index at each forest, with 9 the degree depending on stand density. From these observations, a new concept is proposed for normalised zero-plane displacement: the basal part is primarily determined by the density of stems and branches (stand density), while the seasonal variation depends on the density of leaves (leaf area index), which is limited to the residual of the basal part. Based on this concept, a new model was developed and verified to express both intersite differences and seasonal variations in observed roughness length and zero-plane displacement.
The Spontaneously Diabetic Torii (SDT) rat is a rat model of nonobese type 2 diabetes mellitus, a... more The Spontaneously Diabetic Torii (SDT) rat is a rat model of nonobese type 2 diabetes mellitus, and hepatocellular adenomas have not been reported in this model. We report a hepatocellular adenoma with severe fatty change in a male 42-week-old SDT rat fed a high-fat diet. At necropsy, the animal had a whitish nodular mass of approximately 2 cm in diameter in the right medial lobe. Histologically, the mass was well demarcated from the surrounding tissues, slightly compressing the adjacent hepatic parenchyma and widely compartmented by fibrous connective tissues. The mass consisted of vacuolated tumor cells resembling hepatocytes with a solid and occasionally trabecular growth pattern. Abundant neutral lipids, which were positive for fat with Oil Red O stain and which ultrastructurally had moderately dense material, were contained within the vacuoles of the tumor cells. Immunohistochemically, the tumor cells showed an increase in immunoreactivity or number for Cytokeratin 8/18 and proliferating cell nuclear antigen but were negative for mesenchymal markers. From these findings, the mass could be distinguished from hepatocellular hyperplasia and was diagnosed as hepatocellular adenoma. In rats, hepatocellular adenoma accompanied by severe fatty change is rare, and this is the first report of a hepatocellular tumor with severe fatty change in a SDT rat.
The larch (Larix spp.) forest in eastern Siberia is the world's largest coniferous forest. It... more The larch (Larix spp.) forest in eastern Siberia is the world's largest coniferous forest. Its persistence is considered to depend on near-surface permafrost, and thus, forecast warming over the 21st century and consequent degradation of near-surface permafrost is expected to affect the larch forest in Siberia. However, predictions of these effects vary greatly, and many uncertainties remain about land - atmosphere interactions within the ecosystem. We developed an integrated land surface model to analyze how the Siberian larch forest will react to current warming trends. This model analyzed interactions between vegetation dynamics and thermo-hydrology, although it does not consider many processes those are considered to affect productivity response to a changing climate (e.g., nitrogen limitation, waterlogged soil, heat stress, and change in species composition). The model showed that, under climatic conditions predicted under gradual and rapid warming, the annual net primary p...
Journal of Pharmacology and Experimental Therapeutics, Jun 1, 2001
Insulin secretion from MIN6 cells (a pancreatic -cell line) induced by high glucose (greater tha... more Insulin secretion from MIN6 cells (a pancreatic -cell line) induced by high glucose (greater than 16.8 mM) was potentiated by a novel hypoglycemic agent [trans-4-(4-methylcyclohexyl)-4-oxobutyric acid (JTT-608)] (but not glibenclamide, a sulfonylurea). The extracellular Ca 2ϩ -free condition, a L-type Ca 2ϩ channel blocker (nifedipine) and an ATP-sensitive K ϩ channel opener, diazoxide, completely inhibited increases in cytosolic free Ca 2ϩ ([Ca 2ϩ ]i) and insulin secretion evoked by JTT-608 in the presence of extracellular Ca 2ϩ . An electrophysiological study using single-barreled microelectrode techniques demonstrated that membrane potential (V m ) and input resistance of the cell membrane (R i ) are depolarized and increased by JTT-608, respectively. The apparent transference number for K ϩ was also significantly decreased after the addition of JTT-608. These effects immediately occurred after addition of JTT-608 and very rapidly disappeared after removal of JTT-608, which has not been observed in sulfonylureas. Also, these effects of JTT-608 were diminished, but not completely by diazoxide. JTT-608 did not affect the specific binding of [ 3 H]glibenclamide to the sulfonylurea receptor. These findings suggest that JTT-608 mainly inhibits ATP-sensitive K ϩ channel activity via a binding site distinct from the sulfonylurea receptor and then depolarizes V m to open voltage-dependent L-type Ca 2ϩ channels. Subsequently, these events stimulate Ca 2ϩ entry to increase [Ca 2ϩ ]i and induce insulin secretion from MIN6 cells. Therefore, JTT-608 is a unique hypoglycemic agent that enhances high glucose-induced insulin secretion. The present findings indicate that JTT-608 is a more useful new class of therapeutic drug for patients with non-insulin-dependent diabetes mellitus, compared with sulfonylurea derivatives.
The Spontaneously Diabetic Torii-Lepr(fa) (SDT-fa/fa) rat, a new model of obese type 2 diabetes, ... more The Spontaneously Diabetic Torii-Lepr(fa) (SDT-fa/fa) rat, a new model of obese type 2 diabetes, shows obesity, hyperglycemia, and hyperlipidemia from 6 weeks of age. Diabetic complications such as nephropathy and cataract are observed with aging; however, blood pressure change with age has not previously been examined. In this study, blood pressure was periodically measured and the change was investigated. Blood pressure in male SDT-fa/fa rats was elevated at 8, 16, and 24 weeks of age, whereas the heart rate was not changed. In addition to hyperglycemia, hyperlipidemia, and proteinuria, hyperleptinemia and increased urine angiotensinogen were observed in SDT-fa/fa rats. Blood pressure and heart rate in the male original SDT (SDT-+/+) rat did not significantly change. In conclusion, the SDT-fa/fa rat is a promising model, showing significant hypertension with diabetes mellitus.
1 We examined the eects of the novel hypoglycaemic agent JTT-608 [trans-4-(4-methylcyclohexyl)-4-... more 1 We examined the eects of the novel hypoglycaemic agent JTT-608 [trans-4-(4-methylcyclohexyl)-4-oxobutyric acid] on insulin secretion using rat pancreatic islets, and analysed the mechanism of its eect. 2 JTT-608 augmented 8.3 mM glucose-induced insulin secretion dose-dependently, and there was a stimulatory eect of 100 mM JTT-608 at both moderate and high concentrations (8.3, 11.1 and 16.7 mM) of glucose, but not at low concentrations (3.3 and 5.5 mM). In perifusion experiments, both phases of insulin release were enhanced, and the eect was eliminated 10 min after withdrawal of the agent. 3 In the presence of 200 mM diazoxide and a depolarizing concentration (30 mM) of K + , there was an augmentation of insulin secretion by 100 mM JTT-608, not only under high levels of glucose but also under low levels, and the eects were abolished by 10 mM nitrendipine. 4 JTT-608 augmented insulin secretion from electrically permeabilized islets in the presence of stimulatory concentrations (0.3 and 1.0 mM) of Ca 2+ , and the intracellular Ca 2+ concentration ([Ca 2+ ] i ) response under 16.7 mM glucose, 200 mM diazoxide, and 30 mM K + was also increased. 5 The cyclic AMP content in the islets was increased by 100 mM JTT-608, and an additive eect to 1 mM forskolin was observed, but not to 50 mM 3-isobutyl-1-methylxanthine (IBMX). JTT-608 inhibited phosphodiesterase (PDE) activity dose-dependently. 6 We conclude that JTT-608 augments insulin secretion by enhancing Ca 2+ ecacy and by increasing Ca 2+ in¯ux. This appears to be a result of the increased intracellular cyclic AMP concentration due to PDE inhibition. Insulinotropic mechanism of JTT-608 902 E. Mukai et al British Journal of Pharmacology, vol 129 (5) Insulinotropic mechanism of JTT-608 904 E. Mukai et al British Journal of Pharmacology, vol 129 (5) Insulinotropic mechanism of JTT-608 906 E. Mukai et al
Animal science journal = Nihon chikusan Gakkaiho, Jan 5, 2016
The onset and progression of type II diabetes is closely related to environmental factors, in par... more The onset and progression of type II diabetes is closely related to environmental factors, in particular dietary habit. Moreover, the environmental exposures very early in life can influence the risk for development of type II diabetes later in life. In this study, we investigated pathophysiological changes in the pups of maternal Spontaneously Diabetic Torii (SDT) rats that were fed a high-fat diet (HFD) throughout gestation and lactation. Maternal SDT rats were continued on HFD for 5 weeks, from day 8 of gestation to day 21 after birth, and biological analyses of the pups were performed from 2 to 22 weeks of age. Results of serum lipid levels in pups from dams fed HFD were higher than pups from dams fed a standard diet, and the onset of diabetes was significantly accelerated in pups from dams fed HFD. In pathological analyses, pups from dams fed HFD showed increases in liver weight and vacuolation of hepatic cells at 2 weeks of age. In conclusion, the metabolic disorder of lipids ...
During an investigation of drugs for improving the beta-cell response to glucose, we found that 4... more During an investigation of drugs for improving the beta-cell response to glucose, we found that 4-cyclohexyl-4-oxobutyric acid selectively improved glucose-stimulated insulin release and glucose tolerance in both normal and diabetic rats. A series of 4-cycloalkyl-4-oxobutyric acids and related compounds were synthesized and evaluated for their effects on the glucose tolerance test and fasting euglycemia. This study elucidated the structural requirements for drug activity and determined that the optimum compound was 4-(trans-4-methylcyclohexyl)-4-oxobutyric acid 7 (JTT-608). This compound improved glucose tolerance from an oral dose of 3 mg/kg and did not change fasting euglycemia even at an oral dose of 30 mg/kg. Selective improvement of glucose-induced insulin secretion was observed in studies using neonatal streptozotocin rats (nSTZ rats) and perfused pancreases isolated from nSTZ rats.
Some nutrients, such as carbohydrate, fat and protein, are known to stimulate satiety. However, t... more Some nutrients, such as carbohydrate, fat and protein, are known to stimulate satiety. However, the effect of sn-2-monoacylglycerol (2-MG), one of the digestive products of triglycerides, on food intake is still unclear. In the present study, the effects of 2-MG on food intake and diarrhea were evaluated and compared with long-chain fatty acid (LCFA) in rats by intrajejunal infusion. Intrajejunal infusion of 2-MG reduced food intake. In addition, 2-MG did not induce diarrhea at the condition that it comparably reduced food intake as compared with LCFA. These results suggest that 2-MG stimulates satiety without inducing diarrhea, different from LCFA.
w Ž . We investigated the pharmacological effects of a new anti-hyperglycemic agent, x acid , in ... more w Ž . We investigated the pharmacological effects of a new anti-hyperglycemic agent, x acid , in normal and neonatally streptozotocin-treated rats. In normal rats, JTT-608 improved glucose tolerance at 3-30 mgrkg, doses Ž . Ž . that did not cause a decrease in fasting blood glucose levels. In contrast, tolbutamide 10-100 mgrkg and glibenclamide 1-3 mgrkg caused a persistent decrease in fasting blood glucose levels, and tolbutamide only improved glucose tolerance at 10-100 mgrkg.
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Papers by Takeshi Ohta