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Article ; Online: Comorbidities and complications in Japanese patients with type 2 diabetes mellitus: Retrospective analyses of J-DREAMS, an advanced electronic medical records database.

Ohsugi, Mitsuru / Eiki, Jun-Ichi / Iglay, Kristy / Tetsuka, Jumpei / Tokita, Shigeru / Ueki, Kohjiro

2021 Volume 178, Page(s) 108845

Abstract: Aims: To investigate the prevalence of comorbid conditions/complications among Japanese patients with type 2 diabetes mellitus (T2DM) in a real-world setting.: Methods: We performed retrospective analyses of a large-scale database directly linked to ... ...

Abstract	Aims: To investigate the prevalence of comorbid conditions/complications among Japanese patients with type 2 diabetes mellitus (T2DM) in a real-world setting. Methods: We performed retrospective analyses of a large-scale database directly linked to electronic medical records, J-DREAMS (Japan Diabetes compREhensive database project based on an Advanced electronic Medical record System), to determine the prevalence of clinically significant comorbid conditions/complications among Japanese patients with T2DM aged ≥ 20 years with ≥ 1 clinical encounter at a referral center between April 1, 2017 and March 31, 2019. Results: Data were available for 10,151 patients (39.2% female). The mean age and T2DM duration were 66.0 years and 16.1 years, respectively. Only 0.5% had isolated T2DM, 6.6% had one comorbid condition/complication, and the remainder had multiple comorbid conditions/complications. Dyslipidemia (84.7%) and hypertension (75.1%) were the most common, followed by chronic kidney disease (35.4%), retinopathy (23.1%), and cardiovascular diseases (22.1%). Overall, 36.0% of patients were overweight/obese (body mass index ≥ 25 kg/m Conclusions: We revealed a high prevalence of comorbid conditions/complications, including chronic kidney and cardiovascular diseases, in Japanese patients with T2DM.
MeSH term(s)	Child, Preschool ; Comorbidity ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/epidemiology ; Electronic Health Records ; Female ; Humans ; Japan/epidemiology ; Male ; Prevalence ; Retrospective Studies
Language	English
Publishing date	2021-04-30
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	632523-3
ISSN	1872-8227 ; 0168-8227
ISSN (online)	1872-8227
ISSN	0168-8227
DOI	10.1016/j.diabres.2021.108845
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Article ; Online: Treatment patterns and satisfaction in patients with type 2 diabetes newly initiating oral monotherapy with antidiabetic drugs in Japan: results from the prospective Real-world Observational Study on Patient Outcomes in Diabetes (RESPOND).

Tajima, Atsushi / Tobe, Keisuke / Eiki, Jun-Ichi / Origasa, Hideki / Watada, Hirotaka / Shimomura, Iichiro / Tokita, Shigeru / Kadowaki, Takashi

BMJ open diabetes research & care

2022 Volume 10, Issue 6

Abstract: Introduction: To present longitudinal data from the Real-world Observational Study on Patient Outcomes in Diabetes (RESPOND) in Japan.: Research design and methods: In this multicenter, prospective, observational cohort study, patients with type 2 ... ...

Abstract	Introduction: To present longitudinal data from the Real-world Observational Study on Patient Outcomes in Diabetes (RESPOND) in Japan. Research design and methods: In this multicenter, prospective, observational cohort study, patients with type 2 diabetes mellitus (T2DM) newly initiated on monotherapy were followed up for 2 years. Primary outcomes included changes in treatment pattern over time, target hemoglobin A1c (HbA1c) attainment and treatment satisfaction per Oral Hypoglycaemic Agent Questionnaire (OHA-Q). Results: Among 1474 enrolled patients (male, 62.1%; mean age, 59.7 years; HbA1c, 8.08%), the oral antidiabetic drug (OAD) monotherapy prescription rate decreased to 47.2% and that of 2 and ≥3 OADs increased to 14.8% and 5.4% at 24 months, respectively. Switch/add-on OAD was associated with higher HbA1c and body mass index (BMI), baseline OAD being non-dipeptidyl peptidase-4 inhibitor (DPP-4i)/non-sodium glucose cotransporter-2 inhibitor (SGLT2i), diabetes complications, no comorbidities and consulting a diabetes specialist. The mean (SD) HbA1c (%) was 6.73 (0.85) at 24 months. Higher HbA1c, diabetes complications, cardiovascular disease, being employed, no hypertension and younger treating physician were associated with ≥2 OAD classes prescription or target HbA1c non-attainment at 24 months. OHA-Q subscale scores were significantly higher in patients achieving (vs not achieving) target HbA1c and in those continuing monotherapy (vs combination therapy). Baseline age (<65 years), sex (female), HbA1c, alcohol use, use of non-‍DPP-4i OADs or non-T2DM drugs, diabetes complications and cardiovascular disease had a significant negative impact, while EuroQol five-dimensional five-level and Summary of Diabetes Self-Care Activities-specific diet scores, BMI and unemployment had a significant positive impact on OHA-Q scores at 24 months. Conclusions: Primary outcomes show real-world treatment patterns and glycemic control over 2 years in patients with T2DM newly initiated on OAD monotherapy in Japan. Key factors associated with durability of initial monotherapy, target achievement or treatment satisfaction included baseline HbA1c, comorbidity and initial OAD choice.
MeSH term(s)	Aged ; Female ; Humans ; Male ; Middle Aged ; Blood Glucose ; Cardiovascular Diseases ; Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/epidemiology ; Dipeptidyl-Peptidase IV Inhibitors/therapeutic use ; Drug Therapy, Combination ; Glycated Hemoglobin ; Hypoglycemic Agents/therapeutic use ; Japan/epidemiology ; Patient Satisfaction ; Prospective Studies
Chemical Substances	Blood Glucose ; Dipeptidyl-Peptidase IV Inhibitors ; Glycated Hemoglobin ; Hypoglycemic Agents
Language	English
Publishing date	2022-12-13
Publishing country	England
Document type	Journal Article ; Multicenter Study ; Observational Study ; Research Support, Non-U.S. Gov't
ZDB-ID	2732918-5
ISSN	2052-4897 ; 2052-4897
ISSN (online)	2052-4897
ISSN	2052-4897
DOI	10.1136/bmjdrc-2022-003032
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Article ; Online: Factors associated with the glucose-lowering efficacy of sitagliptin in Japanese patients with type 2 diabetes mellitus: Pooled analysis of Japanese clinical trials.

Tajima, Naoko / Eiki, Jun-Ichi / Okamoto, Taro / Okuyama, Kotoba / Kawashima, Masaru / Engel, Samuel S

Journal of diabetes investigation

2019 Volume 11, Issue 3, Page(s) 640–646

Abstract: Aims/introduction: To explore the factors associated with the glucose-lowering efficacy of sitagliptin treatment in Japanese patients with type 2 diabetes mellitus.: Materials and methods: This was a post-hoc analysis of pooled data from seven ... ...

Abstract	Aims/introduction: To explore the factors associated with the glucose-lowering efficacy of sitagliptin treatment in Japanese patients with type 2 diabetes mellitus. Materials and methods: This was a post-hoc analysis of pooled data from seven sitagliptin phase II and III clinical studies carried out in Japan. All studies were double-blind, randomized, placebo-controlled, parallel-group and of 12-week duration. The analysis population consisted of 1,075 type 2 diabetes mellitus patients. In two of the trials, sitagliptin 50 mg and/or 100 mg daily were used as monotherapy; in five others, sitagliptin 50 mg daily was used as add-on treatment to ongoing pioglitazone, glimepiride, metformin, voglibose or glinides. Efficacy (reduction in hemoglobin A1c [HbA1c]) was evaluated in 12 sets of subgroups defined by demographic, glycemic, pancreatic β-cell function and insulin resistance parameters. An analysis of covariance model was used to evaluate the interaction between each parameter and efficacy. Results: Sitagliptin consistently provided a clinically meaningful reduction in HbA1c relative to placebo across all subgroups. Within subgroups, a greater absolute HbA1c reduction was associated with higher baseline HbA1c, fasting plasma glucose and 2-h post-meal glucose. Lower β-cell function, represented by homeostatic model assessment of β-cell function and insulinogenic index, was also associated with greater HbA1c reduction. In contrast, age, sex, body mass index, duration of type 2 diabetes mellitus and insulin resistance-related parameters did not interact with HbA1c changes. Conclusions: Sitagliptin treatment was associated with clinically meaningful improvement in glycemic control in all subgroups of Japanese patients with type 2 diabetes mellitus that were evaluated. Higher baseline glycemic status and lower baseline β-cell function were identified as factors associated with greater HbA1c reduction after sitagliptin treatment.
MeSH term(s)	Aged ; Asian People ; Diabetes Mellitus, Type 2/drug therapy ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Humans ; Hypoglycemic Agents/therapeutic use ; Japan ; Male ; Middle Aged ; Sitagliptin Phosphate/therapeutic use ; Treatment Outcome
Chemical Substances	Hypoglycemic Agents ; Sitagliptin Phosphate (TS63EW8X6F)
Language	English
Publishing date	2019-12-27
Publishing country	Japan
Document type	Journal Article ; Randomized Controlled Trial
ZDB-ID	2625840-7
ISSN	2040-1124 ; 2040-1116
ISSN (online)	2040-1124
ISSN	2040-1116
DOI	10.1111/jdi.13182
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Article ; Online: Dynamics of plasma active GLP-1 versus insulin and glucose concentrations during GLP-1 infusion in rat model of postprandial hyperglycemia.

Eiki, Jun-ichi / Yada, Toshihiko

Endocrine journal

2011 Volume 58, Issue 8, Page(s) 691–698

Abstract: In vitro studies in isolated pancreas and islets have shown that glucagon-like peptide-1 (GLP-1) promotes insulin release in a typical concentration-dependent manner. In contrast, the relationship between plasma GLP-1 and insulin concentrations in vivo ... ...

Abstract	In vitro studies in isolated pancreas and islets have shown that glucagon-like peptide-1 (GLP-1) promotes insulin release in a typical concentration-dependent manner. In contrast, the relationship between plasma GLP-1 and insulin concentrations in vivo is complicated, because GLP-1-promoted insulin release lowers blood glucose, which influences glucose-dependent insulinotropic ability of GLP-1. GLP-1 also stimulates insulin release via hepatoportal neuronal mechanism. Hence, the dynamic relationship between plasma active GLP-1 vs. insulin and glucose concentrations is obscure. In this study, we aimed to determine in vivo relationships between these parameters in rats. To mimic postprandial state, intraduodenal glucose challenge in anesthetized rats was performed, which can minimize the release of endogenous GLP-1. The glucose challenge induced the 1st phase and 2nd phase insulin release. GLP-1 infusion from jugular vein significantly and concentration-dependently enhanced area under the curve (AUC) of the 1st phase insulin, in which the minimum effective active GLP-1 concentration was 6.6 pmol/l. In contrast, bell-shaped dose responses were observed for both the 2nd phase and total insulin AUCs, in which a significant increase was obtained only with 11 pmol/l of active GLP-1 for total insulin AUC. A statistically significant reduction in the plasma glucose AUC was observed when active GLP-1 concentration was 11 pmol/l and 21 pmol/l. These results indicate that GLP-1 markedly enhances the 1st phase insulin release while less potently the 2nd phase insulin release, possibly due to a negative feedback regulation of β-cells via reduced plasma glucose levels by the enhanced 1st phase insulin release.
MeSH term(s)	Animals ; Area Under Curve ; Blood Glucose/analysis ; Blood Glucose/metabolism ; Disease Models, Animal ; Glucagon-Like Peptide 1/administration & dosage ; Glucagon-Like Peptide 1/analysis ; Glucagon-Like Peptide 1/blood ; Glucagon-Like Peptide 1/pharmacokinetics ; Glucose Tolerance Test ; Hyperglycemia/blood ; Hyperglycemia/drug therapy ; Hyperglycemia/pathology ; Infusions, Intravenous ; Insulin/analysis ; Insulin/blood ; Insulin/metabolism ; Kinetics ; Male ; Osmolar Concentration ; Rats ; Rats, Wistar
Chemical Substances	Blood Glucose ; Insulin ; Glucagon-Like Peptide 1 (89750-14-1)
Language	English
Publishing date	2011-06-15
Publishing country	Japan
Document type	Evaluation Studies ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1151918-6
ISSN	1348-4540 ; 0918-8959
ISSN (online)	1348-4540
ISSN	0918-8959
DOI	10.1507/endocrj.k11e-096
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Article ; Online: Interindividual variations in metabolism and pharmacokinetics of 3-(6-methylpyridine-3-yl-sulfanyl)-6-(4H-[1,2,4]triazole-3-yl-sulfanyl)-N-(1,3-thiazole-2-yl)-2-pyridine carboxamide, a glucokinase activator, in rats caused by the genetic polymorphism of CYP2D1.

Hasegawa, Takuro / Eiki, Jun-ichi / Chiba, Masato

Drug metabolism and disposition: the biological fate of chemicals

2014 Volume 42, Issue 9, Page(s) 1548–1555

Abstract: 3-(6-Methylpyridine-3-yl-sulfanyl)-6-(4H-[1,2,4]triazole-3-yl-sulfanyl)-N-(1,3-thiazole-2-yl)-2-pyridine carboxamide (Cpd-D) is a novel glucokinase activator that is being developed for the treatment of type 2 diabetes. Large interindividual variations ... ...

Abstract	3-(6-Methylpyridine-3-yl-sulfanyl)-6-(4H-[1,2,4]triazole-3-yl-sulfanyl)-N-(1,3-thiazole-2-yl)-2-pyridine carboxamide (Cpd-D) is a novel glucokinase activator that is being developed for the treatment of type 2 diabetes. Large interindividual variations were observed in the pharmacokinetics of Cpd-D in male Sprague-Dawley (SD) rats, which were subsequently divided into two phenotypes; >6-fold longer terminal-phase half-life and ∼10-fold larger AUC0-∞ values were observed in slow metabolizers (SM) than in fast metabolizers (FM) after the oral administration of Cpd-D. The thiohydantoic acid analog (M2) was the predominant metabolite detected in the urine, bile, and plasma after the oral administration of [(14)C]Cpd-D to the FM phenotypes of bile-duct cannulated SD rats. The liver microsomes prepared from FM phenotyped rats extensively formed M2 with the highest affinity (Km = 0.09 μM) and largest Vmax/Km value in primary metabolism, whereas those from SM phenotypes had little capacity to form M2. Of the rat cytochrome P450 isoforms tested, the formation of M2 was only catalyzed by recombinant CYP2D1. Sequence substitutions (418A/421C and 418G/421T) were detected in the CYP2D1 gene and were designated F and S alleles, respectively. The genotype-phenotype correlation analysis indicated that two S alleles were homozygous (S/S) in the SM phenotypes, whereas the FM phenotypes were either homozygous for the F-alleles (F/F) or heterozygous (F/S). These results indicated that the CYP2D1 polymorphism caused by nucleotide substitutions (418A/421C versus 418G/421T) was responsible for interindividual variations leading to the polymorphism in the major metabolism and pharmacokinetics of Cpd-D in male SD rats.
MeSH term(s)	Administration, Oral ; Alcohol Oxidoreductases/genetics ; Alcohol Oxidoreductases/metabolism ; Alleles ; Animals ; Area Under Curve ; Bile/metabolism ; Cytochrome P-450 Enzyme System/genetics ; Cytochrome P-450 Enzyme System/metabolism ; Cytochrome P450 Family 2 ; Genetic Association Studies ; Glucokinase/metabolism ; Half-Life ; Male ; Microsomes, Liver/metabolism ; Polymorphism, Genetic/genetics ; Pyridines/metabolism ; Pyridines/pharmacokinetics ; Rats ; Rats, Inbred F344 ; Rats, Sprague-Dawley ; Rats, Wistar
Chemical Substances	Pyridines ; Cytochrome P-450 Enzyme System (9035-51-2) ; Alcohol Oxidoreductases (EC 1.1.-) ; Cyp2d1 protein, rat (EC 1.14.14.1) ; Cytochrome P450 Family 2 (EC 1.14.14.1) ; Glucokinase (EC 2.7.1.2) ; pyridine (NH9L3PP67S)
Language	English
Publishing date	2014-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
DOI	10.1124/dmd.114.058081
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Article: Patient characteristics associated with improvement in glycemic control following addition of an oral antidiabetic drug to DPP-4 inhibitor monotherapy in Japanese patients with type 2 diabetes mellitus (JDDM 60).

Kawai, Koichi / Eiki, Jun-Ichi / Kanatsuka, Azuma / Motohashi, Shinobu / Wakana, Akira / Hayashi, Ai / Iglay, Kristy / Yamazaki, Katsuya / Tokita, Shigeru / Maegawa, Hiroshi

Diabetology international

2021 Volume 13, Issue 1, Page(s) 132–141

Abstract: Aims: The current study evaluated patient demographics and clinical characteristics that associated with HbA1c reduction following addition of one oral antidiabetic drug (OAD) to DPP4i monotherapy.: Methods: A retrospective study was conducted using ... ...

Abstract	Aims: The current study evaluated patient demographics and clinical characteristics that associated with HbA1c reduction following addition of one oral antidiabetic drug (OAD) to DPP4i monotherapy. Methods: A retrospective study was conducted using CoDiC database. Adult T2DM patients treated with sitagliptin monotherapy for ≥ 6 months and adding one OAD were extracted. Association between patient characteristics at the time of add-on OAD and following HbA1c reduction was assessed. Results: Of 444 included patients, mean age was 62 years and 33% were female. All add-on OAD classes demonstrated further HbA1c reduction ( Conclusion: The majority of Japanese T2DM patients on sitagliptin monotherapy who require an add-on OAD utilized BG or SU. There were 2 determinants of glycemic response: baseline HbA1c with BG and SU and gender with SU during add-on OAD therapy. Supplementary information: The online version contains supplementary material available at 10.1007/s13340-021-00514-5.
Language	English
Publishing date	2021-07-15
Publishing country	Japan
Document type	Journal Article
ZDB-ID	2574501-3
ISSN	2190-1686 ; 2190-1678
ISSN (online)	2190-1686
ISSN	2190-1678
DOI	10.1007/s13340-021-00514-5
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Article ; Online: Effect of short-term treatment with sitagliptin or glibenclamide on daily glucose fluctuation in drug-naïve Japanese patients with type 2 diabetes mellitus.

Suzuki, Ryo / Eiki, Jun-Ichi / Moritoyo, Takashi / Furihata, Kenichi / Wakana, Akira / Ohta, Yukari / Tokita, Shigeru / Kadowaki, Takashi

Diabetes, obesity & metabolism

2018 Volume 20, Issue 9, Page(s) 2274–2281

Abstract: Aims: To compare the effect of a dipeptidyl peptidase-4 inhibitor (DPP4-i) and a sulfonylurea (SU) on daily glucose fluctuation in drug-naïve Japanese patients with type 2 diabetes mellitus (T2DM).: Materials and methods: A total of 53 drug-naïve ... ...

Abstract	Aims: To compare the effect of a dipeptidyl peptidase-4 inhibitor (DPP4-i) and a sulfonylurea (SU) on daily glucose fluctuation in drug-naïve Japanese patients with type 2 diabetes mellitus (T2DM). Materials and methods: A total of 53 drug-naïve Japanese patients with T2DM (HbA1c, 7.0%-9.0%; fasting plasma glucose, 6.1 mmol/L or higher) were randomly assigned to either sitagliptin 50 mg qd or glibenclamide 2.5 mg per day (given in divided doses) in a 1:1 ratio. A continuous glucose monitoring (CGM) device was used to obtain 24-hour glucose profiles for each patient at baseline and at Week 2. The primary study endpoint was change from baseline in mean amplitude of glucose excursion (MAGE) during a 24-hour period. A key secondary endpoint was change from baseline in the standard deviation (SD) of 24-hour glucose levels. Results: After 2 weeks of treatment, a numerically greater reduction in MAGE from baseline was observed in the sitagliptin group compared with the glibenclamide group, but the between-treatment difference was not statistically significant (LS mean difference [95% CI]: -0.48 mmol/L [-1.31, 0.34]; P = .245). However, a significantly greater reduction in the change from baseline in SD was observed in the sitagliptin group compared with the glibenclamide group (LS mean difference [95% CI]: -0.33 mmol/L [-0.62, -0.03]; P = .029). Conclusions: This study suggests that the DPP4 inhibitor sitagliptin has a greater ability to reduce daily glucose fluctuation than the SU glibenclamide in drug-naïve Japanese patients with T2DM. ClinicalTrials.gov: NCT02318693.
MeSH term(s)	Aged ; Blood Glucose/analysis ; Blood Glucose Self-Monitoring ; Diabetes Mellitus, Type 2/blood ; Diabetes Mellitus, Type 2/drug therapy ; Dipeptidyl-Peptidase IV Inhibitors/administration & dosage ; Drug Administration Schedule ; Fasting/blood ; Female ; Glyburide/administration & dosage ; Humans ; Hypoglycemic Agents/administration & dosage ; Japan ; Male ; Middle Aged ; Sitagliptin Phosphate/administration & dosage ; Sulfonylurea Compounds/administration & dosage ; Treatment Outcome
Chemical Substances	Blood Glucose ; Dipeptidyl-Peptidase IV Inhibitors ; Hypoglycemic Agents ; Sulfonylurea Compounds ; Glyburide (SX6K58TVWC) ; Sitagliptin Phosphate (TS63EW8X6F)
Language	English
Publishing date	2018-06-11
Publishing country	England
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	1454944-x
ISSN	1463-1326 ; 1462-8902
ISSN (online)	1463-1326
ISSN	1462-8902
DOI	10.1111/dom.13364
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Zs.A 5442: Show issues

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Article ; Online: Metabolic activation of N-thiazol-2-yl benzamide as glucokinase activators: Impacts of glutathione trapping on covalent binding.

Iino, Tomoharu / Hashimoto, Noriaki / Hasegawa, Takuro / Chiba, Masato / Eiki, Jun-Ichi / Nishimura, Teruyuki

Bioorganic & medicinal chemistry letters

2010 Volume 20, Issue 5, Page(s) 1619–1622

Abstract: Glucokinase activators (GKAs) are currently under investigation as potential antidiabetic agents by many pharmaceutical companies. Most of GKAs reported previously possess N-aminothiazol-2-yl amide moiety in their structures because the aminothiazole ... ...

Abstract	Glucokinase activators (GKAs) are currently under investigation as potential antidiabetic agents by many pharmaceutical companies. Most of GKAs reported previously possess N-aminothiazol-2-yl amide moiety in their structures because the aminothiazole moiety interacts with glucokinase (GK) and shows strong GK activation. During the development of N-aminothiazol-2-yl amide derivatives, we identified a bioactivation and metabolic liability of 2-aminothizole substructure of GKA 3 by assessing covalent binding, metabolites in liver microsomes and glutathione (GSH) trap assay.
MeSH term(s)	Animals ; Benzamides/chemistry ; Benzamides/metabolism ; Benzamides/pharmacology ; Biotransformation/drug effects ; Enzyme Activation ; Glucokinase/metabolism ; Glutathione/metabolism ; Humans ; Hypoglycemic Agents/chemistry ; Hypoglycemic Agents/metabolism ; Hypoglycemic Agents/pharmacology ; Microsomes, Liver/metabolism ; Rats ; Sulfones/chemistry ; Sulfones/metabolism ; Sulfones/pharmacology ; Thiazoles/chemistry ; Thiazoles/metabolism ; Thiazoles/pharmacology
Chemical Substances	Benzamides ; Hypoglycemic Agents ; Sulfones ; Thiazoles ; benzamide (6X80438640) ; Glucokinase (EC 2.7.1.2) ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	2010-03-01
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2010.01.041
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Article ; Online: Effects of celiac superior mesenteric ganglionectomy on glucose homeostasis and hormonal changes during oral glucose tolerance testing in rats.

Kumakura, Atsushi / Shikuma, Junpei / Ogihara, Norikazu / Eiki, Jun-ichi / Kanazawa, Masao / Notoya, Yōko / Kikuchi, Masatoshi / Odawara, Masato

Endocrine journal

2013 Volume 60, Issue 4, Page(s) 525–531

Abstract: The liver plays an important role in maintaining glucose homeostasis in the body. In the prandial state, some of the glucose which is absorbed by the gastrointestinal tract is converted into glycogen and stored in the liver. In contrast, the liver ... ...

Abstract	The liver plays an important role in maintaining glucose homeostasis in the body. In the prandial state, some of the glucose which is absorbed by the gastrointestinal tract is converted into glycogen and stored in the liver. In contrast, the liver produces glucose by glycogenolysis and gluconeogenesis while fasting. Thus, the liver contributes to maintaining blood glucose level within normoglycemic range. Glycogenesis and glycogenolysis are regulated by various mechanisms including hormones, the sympathetic and parasympathetic nervous systems and the hepatic glucose content. In this study, we examined a rat model in which the celiac superior mesenteric ganglion (CSMG) was resected. We attempted to elucidate how the celiac sympathetic nervous system is involved in regulating glucose homeostasis by assessing the effects of CSMG resection on glucose excursion during an oral glucose tolerance test, and by examining hepatic glycogen content and hepatic glycogen phosphorylase (GP) activity. On the oral glucose tolerance test, CSMG-resected rats demonstrated improved glucose tolerance and significantly increased GP activity compared with sham-operated rats, whereas there were no significant differences in insulin, glucagon or catecholamine levels between the 2 groups. These results suggest that the celiac sympathetic nervous system is involved in regulating the rate of glycogen consumption through GP activity. In conclusion, the examined rat model showed that the celiac sympathetic nervous system regulates hepatic glucose metabolism in conjunction with vagal nerve innervations and is a critical component in the maintenance of blood glucose homeostasis.
MeSH term(s)	Animals ; Blood Glucose/analysis ; Catecholamines/blood ; Down-Regulation ; Ganglia, Sympathetic/surgery ; Ganglionectomy ; Glucagon/blood ; Glucose Tolerance Test ; Glycogen/biosynthesis ; Glycogen Phosphorylase, Liver Form/metabolism ; Glycogenolysis ; Homeostasis ; Insulin/blood ; Liver/blood supply ; Liver/innervation ; Liver/metabolism ; Male ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Splanchnic Circulation ; Weight Gain
Chemical Substances	Blood Glucose ; Catecholamines ; Insulin ; Glycogen (9005-79-2) ; Glucagon (9007-92-5) ; Glycogen Phosphorylase, Liver Form (EC 2.4.1.-)
Language	English
Publishing date	2013
Publishing country	Japan
Document type	Journal Article
ZDB-ID	1151918-6
ISSN	1348-4540 ; 0918-8959
ISSN (online)	1348-4540
ISSN	0918-8959
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Article ; Online: Ventromedial hypothalamic glucokinase is an important mediator of the counterregulatory response to insulin-induced hypoglycemia.

Levin, Barry E / Becker, Thomas C / Eiki, Jun-ichi / Zhang, Bei B / Dunn-Meynell, Ambrose A

Diabetes

2008 Volume 57, Issue 5, Page(s) 1371–1379

Abstract: Objective: The counterregulatory response to insulin-induced hypoglycemia is mediated by the ventromedial hypothalamus (VMH), which contains specialized glucosensing neurons, many of which use glucokinase (GK) as the rate-limiting step in glucose's ... ...

Abstract	Objective: The counterregulatory response to insulin-induced hypoglycemia is mediated by the ventromedial hypothalamus (VMH), which contains specialized glucosensing neurons, many of which use glucokinase (GK) as the rate-limiting step in glucose's regulation of neuronal activity. Since conditions associated with increased VMH GK expression are associated with a blunted counterregulatory response, we tested the hypothesis that increasing VMH GK activity would similarly attenuate, while decreasing GK activity would enhance the counterregulatory response to insulin-induced hypoglycemia. Research design and methods: The counterregulatory response to insulin-induced hypoglycemia was evaluated in Sprague-Dawley rats after bilateral VMH injections of 1) a GK activator drug (compound A) to increase VMH GK activity, 2) low-dose alloxan (4 mug) to acutely inhibit GK activity, 3) high-dose alloxan (24 microg), or 4) an adenovirus expressing GK short hairpin RNA (shRNA) to chronically reduce GK expression and activity. Results: Compound A increased VMH GK activity sixfold in vitro and reduced the epinephrine, norepinephrine, and glucagon responses to insulin-induced hypoglycemia by 40-62% when injected into the VMH in vivo. On the other hand, acute and chronic reductions of VMH GK mRNA or activity had a lesser and more selective effect on increasing primarily the epinephrine response to insulin-induced hypoglycemia by 23-50%. Conclusions: These studies suggest that VMH GK activity is an important regulator of the counterregulatory response to insulin-induced hypoglycemia and that a drug that specifically inhibited the rise in hypothalamic GK activity after insulin-induced hypoglycemia might improve the dampened counterregulatory response seen in tightly controlled diabetic subjects.
MeSH term(s)	Animals ; Diabetes Mellitus, Experimental/enzymology ; Enzyme Activation ; Glucokinase/metabolism ; Homeostasis ; Hypoglycemia/chemically induced ; Hypoglycemia/enzymology ; Insulin/pharmacology ; Kinetics ; Male ; Rats ; Rats, Sprague-Dawley ; Ventromedial Hypothalamic Nucleus/enzymology
Chemical Substances	Insulin ; Glucokinase (EC 2.7.1.2)
Language	English
Publishing date	2008-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db07-1755
Database	MEDical Literature Analysis and Retrieval System OnLINE

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