Publications by authors named "Tsukasa Morii"

25 Publications

  • Page 1 of 1

Sodium-glucose cotransporter 2 inhibition attenuates protein overload in renal proximal tubule via suppression of megalin O-GlcNacylation in progressive diabetic nephropathy.

Metabolism 2020 12 16;113:154405. Epub 2020 Oct 16.

Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan. Electronic address:

Aims: The crosstalk between sodium-glucose cotransporter 2 (SGLT2) inhibition and a membrane-associated endocytic receptor megalin function involved in renal proximal tubular protein overload in progressive diabetic nephropathy (DN) is uncertain. Here, we determined whether SGLT2 inhibition affects megalin endocytic function through suppressing its O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) and protects the diabetic kidney from protein overload.

Materials And Method: We treated 8-week-old male non-obese and hypoinsulinemic KK/Ta-Ins2 (KK/Ta-Akita) mice which develop progressive DN with an SGLT2 inhibitor ipragliflozin or insulin for 6 weeks, and investigated the endocytic function (proximal tubular protein reabsorption), renal expression and O-GlcNAcylation of megalin along with their effects on renal phenotypes including histology and biochemical markers.

Results: The treatment with ipragliflozin, but not insulin, suppressed megalin O-GlcNAcylation and accelerated its internalization, resulting in reduction in proximal tubular reabsorption of the highly filtered plasma proteins such as albumin and neutrophil gelatinase-associated lipocalin. These alterations following the ipragliflozin treatment contributed to amelioration of proximal tubular protein overload, mitochondrial morphological abnormality, and renal oxidative stress and tubulointerstitial fibrosis.

Conclusions: The present study provides a novel crosstalk mechanism between SGLT2 inhibition and megalin underlying the potential renal benefits of SGLT2 inhibition in DN.
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http://dx.doi.org/10.1016/j.metabol.2020.154405DOI Listing
December 2020

Magnitude of slowing gastric emptying by glucagon-like peptide-1 receptor agonists determines the amelioration of postprandial glucose excursion in Japanese patients with type 2 diabetes.

J Diabetes Investig 2020 Mar 25;11(2):389-399. Epub 2019 Jul 25.

Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.

Aims/introduction: Pharmacological levels of glucagon-like peptide-1 (GLP-1) can decelerate gastric emptying (GE) and reduce postprandial glucose levels. Most previous studies have used liquid meals to evaluate GE. We evaluated the effects of GLP-1 receptor agonists (GLP-1 RAs) on GE and postprandial glucose excursion in Japanese type 2 diabetes mellitus patients using a combination of solid and liquid meals.

Materials And Methods: In this single-center, prospective, open-label study, nine healthy individuals and 17 patients with type 2 diabetes mellitus consumed a 460-kcal combination of a solid and liquid meal labeled with C-acetic acid. GE was measured from t = 0 to 150 min in a continuous C breath test. Eight participants with type 2 diabetes mellitus were administered GLP-1 RAs, and we examined the relationship between GE and blood glucose excursion.

Results: There were no differences in the average GE coefficient (GEC) and lag time between the healthy and type 2 diabetes mellitus groups. However, the type 2 diabetes mellitus group showed larger GEC variations (P < 0.05). The coefficient of variation of R-R intervals was a significant predictor of GEC in type 2 diabetes mellitus patients (P < 0.01). The short-acting GLP-1 RA reduced the GEC at 1 month (P = 0.012), whereas the long-acting GLP-1 RA did not significantly change the GEC after treatment. A positive relationship was observed between postprandial glucose excursion from T to T and the GEC (r  = 0.75; P < 0.01).

Conclusions: The reduction in GE rate by the administration of GLP-1 RAs can predict the improvement in postprandial glucose excursion in type 2 diabetes mellitus patients.
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http://dx.doi.org/10.1111/jdi.13115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078094PMC
March 2020

Inhibition of GIP signaling extends lifespan without caloric restriction.

Biochem Biophys Res Commun 2019 06 17;513(4):974-982. Epub 2019 Apr 17.

Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University Graduate School of Medicine, Japan. Electronic address:

Aims/introduction: Caloric restriction (CR) promotes longevity and exerts anti-aging effects by increasing Sirtuin production and activation. Gastric inhibitory polypeptide (GIP), a gastrointestinal peptide hormone, exerts various effects on pancreatic β-cells and extra-pancreatic tissues. GIP promotes glucose-dependent augmentation of insulin secretion and uptake of nutrients into the adipose tissue.

Materials And Methods: Gipr and Gipr mice were used for lifespan analysis, behavior experiments and gene expression of adipose tissue and muscles. 3T3-L1 differentiated adipocytes were used for Sirt1 and Nampt expression followed by treatment with GIP and α-lipoic acid.

Results: We observed that GIP receptor-knockout (Gipr) mice fed normal diet showed an extended lifespan, increased exploratory and decreased anxiety-based behaviors, which are characteristic behavioral changes under CR. Moreover, Gipr mice showed increased Sirt1 and Nampt expression in the adipose tissue. GIP suppressed α-lipoic acid-induced Sirt1 expression and activity in differentiated adipocytes.

Conclusions: Although maintenance of CR is difficult, food intake and muscle endurance of Gipr mice were similar to those of wild-type mice. Inhibition of GIP signaling may be a novel strategy to extend the lifespan of diabetic patients.
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http://dx.doi.org/10.1016/j.bbrc.2019.04.036DOI Listing
June 2019

Importance of physical evaluation using skeletal muscle mass index and body fat percentage to prevent sarcopenia in elderly Japanese diabetes patients.

J Diabetes Investig 2019 Mar 8;10(2):322-330. Epub 2018 Sep 8.

Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.

Aims/introduction: To investigate the prevalence of sarcopenia, its related factors and indicators of physical evaluation in elderly diabetes patients.

Materials And Methods: This was a cross-sectional observation study. A total of 267 diabetes patients (159 men, 108 women) aged >65 years were recruited in the present study. Skeletal muscle mass index, grip strength and usual gait speed were measured to diagnose sarcopenia according to the Asian Working Group for Sarcopenia. Body composition was measured using bioelectrical impedance analysis. Body mass index (BMI) and body fat percentage were evaluated in quartiles to investigate the relationship with sarcopenia. A multiple logistic regression analysis examined sarcopenia-related factors.

Results: The prevalence of sarcopenia in all participants was 18.7% and increased with age. Sarcopenia decreased as BMI increased (P < 0.01, Cochran-Armitage test). In contrast, the third quartile body fat percentage group showed the lowest prevalence of sarcopenia. A strong positive correlation was observed between body mass and skeletal muscle mass indices (R = 0.702-0.682). Multiple logistic regression analysis showed that sarcopenia was associated with lower BMI, non-use of metformin and lower bone mineral content in men (P < 0.05), and lower bone mineral content, lower serum levels of albumin and older age in women (P < 0.05).

Conclusions: The present study suggests that diabetes patients with a high body fat percentage in addition to low BMI might develop sarcopenia. It is suggested that physical management in elderly diabetes patients should be carried out based on the evaluation of BMI and body fat percentage to prevent sarcopenia.
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http://dx.doi.org/10.1111/jdi.12908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400206PMC
March 2019

Activation of GLP-1 receptor signalling alleviates cellular stresses and improves beta cell function in a mouse model of Wolfram syndrome.

Diabetologia 2018 10 28;61(10):2189-2201. Epub 2018 Jul 28.

Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, Japan.

Aims/hypothesis: Loss of functional beta cells results in a gradual progression of insulin insufficiency in Wolfram syndrome caused by recessive WFS1 mutations. However, beta cell dysfunction in Wolfram syndrome has yet to be fully characterised, and there are also no specific treatment recommendations. In this study, we aimed to characterise beta cell secretory defects and to examine the potential effects of a glucagon-like peptide-1 (GLP-1) receptor agonist on diabetes in Wolfram syndrome.

Methods: Insulin secretory function was assessed by the pancreatic perfusion method in mice used as a model of Wolfram syndrome. In addition, granule dynamics in living beta cells were examined using total internal reflection fluorescence microscopy. Acute and chronic effects of exendin-4 (Ex-4) on glucose tolerance and insulin secretion were examined in young Wfs1 mice without hyperglycaemia. Molecular events associated with Ex-4 treatment were investigated using pancreatic sections and isolated islets. In addition, we retrospectively observed a woman with Wolfram syndrome who had been treated with liraglutide for 24 weeks.

Results: Treatment with liraglutide ameliorated our patient's glycaemic control and resulted in a 20% reduction of daily insulin dose along with an off-drug elevation of fasting C-peptide immunoreactivity. Glucose-stimulated first-phase insulin secretion and potassium-stimulated insulin secretion decreased by 53% and 59%, respectively, in perfused pancreases of 10-week-old Wfs1 mice compared with wild-type (WT) mice. The number of insulin granule fusion events in the first phase decreased by 41% in Wfs1 beta cells compared with WT beta cells. Perfusion with Ex-4 increased insulin release in the first and second phases by 3.9-fold and 5.6-fold, respectively, in Wfs1 mice compared with perfusion with saline as a control. The physiological relevance of the effects of Ex-4 was shown by the fact that a single administration potentiated glucose-stimulated insulin secretion and improved glucose tolerance in Wfs1 mice. Four weeks of administration of Ex-4 resulted in an off-drug amelioration of glucose excursions after glucose loading in Wfs1 mice, with insulin secretory dynamics that were indistinguishable from those in WT mice, despite the fact that there was no alteration in beta cell mass. In association with the functional improvements, Ex-4 treatment reversed the increases in phosphorylated eukaryotic initiation factor (EIF2α) and thioredoxin interacting protein (TXNIP), and the decrease in phosphorylated AMP-activated kinase (AMPK), in the beta cells of the Wfs1 mice. Furthermore, Ex-4 treatment modulated the transcription of oxidative and endoplasmic reticulum stress-related markers in isolated islets, implying that it was able to mitigate the cellular stresses resulting from Wfs1 deficiency.

Conclusions/interpretation: Our study provides deeper insights into the pathophysiology of beta cell dysfunction caused by WFS1 deficiency and implies that activation of the GLP-1 receptor signal may alleviate insulin insufficiency and aid glycaemic control in Wolfram syndrome.
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http://dx.doi.org/10.1007/s00125-018-4679-yDOI Listing
October 2018

Stromal cell-derived factor-1 is upregulated by dipeptidyl peptidase-4 inhibition and has protective roles in progressive diabetic nephropathy.

Kidney Int 2016 10 27;90(4):783-96. Epub 2016 Jul 27.

Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.

The role of stromal cell-derived factor-1 (SDF-1) in the pathogenesis of diabetic nephropathy and its modification by dipeptidyl peptidase-4 (DPP-4) inhibition are uncertain. Therefore, we studied this independent of glucagon-like peptide-1 receptor (GLP-1R) signaling using two Akita diabetic mouse models, the diabetic-resistant C57BL/6-Akita and diabetic-prone KK/Ta-Akita. Increased SDF-1 expression was found in glomerular podocytes and distal nephrons in the diabetic-prone mice, but not in kidneys from diabetic-resistant mice. The DPP-4 inhibitor linagliptin, but not the GLP-1R agonist liraglutide, further augmented renal SDF-1 expression in both Glp1r(+/+) and Glp1r(-/-) diabetic-prone mice. Along with upregulation of renal SDF-1 expression, the progression of albuminuria, glomerulosclerosis, periglomerular fibrosis, podocyte loss, and renal oxidative stress was suppressed in linagliptin-treated Glp1r(+/+) diabetic-prone mice. Linagliptin treatment increased urinary sodium excretion and attenuated the increase in glomerular filtration rate which reflects glomerular hypertension and hyperfiltration. In contrast, selective SDF-1 receptor blockade with AMD3100 reduced urinary sodium excretion and aggravated glomerular hypertension in the Glp1r(+/+) diabetic-prone mice. Thus, DPP-4 inhibition, independent of GLP-1R signaling, contributes to protection of the diabetic kidney through SDF-1-dependent antioxidative and antifibrotic effects and amelioration of adverse renal hemodynamics.
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http://dx.doi.org/10.1016/j.kint.2016.06.012DOI Listing
October 2016

TCF1 links GIPR signaling to the control of beta cell function and survival.

Nat Med 2016 Jan 7;22(1):84-90. Epub 2015 Dec 7.

Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.

The glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor transduce nutrient-stimulated signals to control beta cell function. Although the GLP-1 receptor (GLP-1R) is a validated drug target for diabetes, the importance of the GIP receptor (GIPR) for the function of beta cells remains uncertain. We demonstrate that mice with selective ablation of GIPR in beta cells (MIP-Cre:Gipr(Flox/Flox); Gipr(-/-βCell)) exhibit lower levels of meal-stimulated insulin secretion, decreased expansion of adipose tissue mass and preservation of insulin sensitivity when compared to MIP-Cre controls. Beta cells from Gipr(-/-βCell) mice display greater sensitivity to apoptosis and markedly lower islet expression of T cell-specific transcription factor-1 (TCF1, encoded by Tcf7), a protein not previously characterized in beta cells. GIP, but not GLP-1, promotes beta cell Tcf7 expression via a cyclic adenosine monophosphate (cAMP)-independent and extracellular signal-regulated kinase (ERK)-dependent pathway. Tcf7 (in mice) or TCF7 (in humans) levels are lower in islets taken from diabetic mice and in humans with type 2 diabetes; knockdown of TCF7 in human and mouse islets impairs the cytoprotective responsiveness to GIP and enhances the magnitude of apoptotic injury, whereas restoring TCF1 levels in beta cells from Gipr(-/-βCell) mice lowers the number of apoptotic cells compared to that seen in MIP-Cre controls. Tcf7(-/-) mice show impaired insulin secretion, deterioration of glucose tolerance with either aging and/or high-fat feeding and increased sensitivity to beta cell injury relative to wild-type (WT) controls. Hence the GIPR-TCF1 axis represents a potential therapeutic target for preserving both the function and survival of vulnerable, diabetic beta cells.
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http://dx.doi.org/10.1038/nm.3997DOI Listing
January 2016

Poorly-controlled acromegaly accompanied by subclinical adrenal Cushing's syndrome after surgery for multiple endocrine tumors.

Intern Med 2015 15;54(6):617-20. Epub 2015 Jan 15.

Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University Graduate School of Medicine, Japan.

A 48-year-old woman diagnosed with acromegaly 21 years earlier presented at our hospital with a left adrenal tumor. Her medical history included breast cancer, thyroid cancer and an incompletely resected growth hormone (GH)-producing pituitary adenoma. Endocrinological and radiological examinations revealed subclinical adrenal Cushing's syndrome. She subsequently underwent left adrenalectomy, followed by glucocorticoid replacement therapy. Her GH and insulin-like growth factor-1 levels were insufficiently controlled, and pegvisomant was administered in addition to octreotide acetate. Following adrenalectomy, a giant hepatic hemangioma and papillary thyroid carcinoma in the residual right lobe developed, indicating the high risk of tumor development in patients with acromegaly.
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http://dx.doi.org/10.2169/internalmedicine.54.2782DOI Listing
September 2015

The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential.

Kidney Int 2014 Mar 23;85(3):579-89. Epub 2013 Oct 23.

Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.

Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone that has an antioxidative protective effect on various tissues. Here, we determined whether GLP-1 has a role in the pathogenesis of diabetic nephropathy using nephropathy-resistant C57BL/6-Akita and nephropathy-prone KK/Ta-Akita mice. By in situ hybridization, we found the GLP-1 receptor (GLP-1R) expressed in glomerular capillary and vascular walls, but not in tubuli, in the mouse kidney. Next, we generated C57BL/6-Akita Glp1r knockout mice. These mice exhibited higher urinary albumin levels and more advanced mesangial expansion than wild-type C57BL/6-Akita mice, despite comparable levels of hyperglycemia. Increased glomerular superoxide, upregulated renal NAD(P)H oxidase, and reduced renal cAMP and protein kinase A (PKA) activity were noted in the Glp1r knockout C57BL/6-Akita mice. Treatment with the GLP-1R agonist liraglutide suppressed the progression of nephropathy in KK/Ta-Akita mice, as demonstrated by reduced albuminuria and mesangial expansion, decreased levels of glomerular superoxide and renal NAD(P)H oxidase, and elevated renal cAMP and PKA activity. These effects were abolished by an adenylate cyclase inhibitor SQ22536 and a selective PKA inhibitor H-89. Thus, GLP-1 has a crucial role in protection against increased renal oxidative stress under chronic hyperglycemia, by inhibition of NAD(P)H oxidase, a major source of superoxide, and by cAMP-PKA pathway activation.
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http://dx.doi.org/10.1038/ki.2013.427DOI Listing
March 2014

SOD1, but not SOD3, deficiency accelerates diabetic renal injury in C57BL/6-Ins2(Akita) diabetic mice.

Metabolism 2012 Dec 25;61(12):1714-24. Epub 2012 May 25.

Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.

Superoxide dismutase (SOD) is a major defender against excessive superoxide generated under hyperglycemia. We have recently reported that renal SOD1 (cytosolic CuZn-SOD) and SOD3 (extracellular CuZn-SOD) isoenzymes are remarkably down-regulated in KK/Ta-Ins2(Akita) diabetic mice, which exhibit progressive diabetic nephropathy (DN), but not in DN-resistant C57BL/6- Ins2(Akita) (C57BL/6-Akita) diabetic mice. To determine the role of SOD1 and SOD3 in DN, we generated C57BL/6-Akita diabetic mice with deficiency of SOD1 and/or SOD3 and investigated their renal phenotype at the age of 20 weeks. Increased glomerular superoxide levels were observed in SOD1(-/-)SOD3(+/+) and SOD1(-/-)SOD3(-/-) C57BL/6-Akita mice but not in SOD1(+/+)SOD3(-/-) C57BL/6-Akita mice. The SOD1(-/-)SOD3(+/+) and SOD1(-/-)SOD3(-/-) C57BL/6-Akita mice exhibited higher glomerular filtration rate, increased urinary albumin levels, and advanced mesangial expansion as compared with SOD1(+/+)SOD3(+/+) C57BL/6-Akita mice, yet the severity of DN did not differ between the SOD1(-/-)SOD3(+/+) and SOD1(-/-)SOD3(-/-) C57BL/6-Akita groups. Increased renal mRNA expression of transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF), reduced glomerular nitric oxide (NO), and increased renal prostaglandin E2 (PGE2) production were noted in the SOD1(-/-)SOD3(+/+) and SOD1(-/-)SOD3(-/-) C57BL/6-Akita mice. This finding indicates that such renal changes in fibrogenic cytokines, NO, and PGE2, possibly caused by superoxide excess, would contribute to the development of overt albuminuria by promoting mesangial expansion, endothelial dysfunction, and glomerular hyperfiltration. The present results demonstrate that deficiency of SOD1, but not SOD3, increases renal superoxide in the setting of diabetes and causes overt renal injury in nephropathy-resistant diabetic mice, and that SOD3 deficiency does not provide additive effects on the severity of DN in SOD1-deficient C57BL/6-Akita mice.
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http://dx.doi.org/10.1016/j.metabol.2012.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360989PMC
December 2012

Modulation of renal superoxide dismutase by telmisartan therapy in C57BL/6-Ins2(Akita) diabetic mice.

Hypertens Res 2012 Feb 10;35(2):213-20. Epub 2011 Nov 10.

Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.

Renal superoxide excess, which is induced by an imbalance of the superoxide-producing enzyme NAD(P)H oxidase and the superoxide-scavenging enzyme superoxide dismutase (SOD) under hyperglycemia, increases oxidative stress and contributes to the development of diabetic nephropathy. In this study, we treated non-obese and hypoinsulinemic C57BL/6-Ins2(Akita) (C57BL/6-Akita) diabetic mice with telmisartan (5 mg kg(-1) per day), an angiotensin II type 1 receptor blocker, or amlodipine (5 mg kg(-1) per day), a calcium channel blocker, for 4 weeks and compared the effects of these two anti-hypertensive drugs on renal NAD(P)H oxidase, SOD and transcription factor Nrf2 (NF-E2-related factor 2), which is known to upregulate several antioxidant enzymes including SOD. Vehicle-treated C57BL/6-Akita mice exhibited higher renal NAD(P)H oxidase and lower renal SOD activity with increased levels of renal superoxide than the C57BL/6-wild-type non-diabetic mice. Interestingly, telmisartan treatment not only reduced NAD(P)H oxidase activity but also enhanced SOD activity in C57BL/6-Akita mouse kidneys, leading to a reduction of renal superoxide levels. Furthermore, telmisartan-treated C57BL/6-Akita mice increased the renal protein expression of SOD and Nrf2. In parallel with the reduction of renal superoxide levels, a reduction of urinary albumin levels and a normalization of elevated glomerular filtration rate were observed in telmisartan-treated C57BL/6-Akita mice. In contrast, treatment with amlodipine failed to modulate renal NAD(P)H oxidase, SOD and Nrf2. Finally, treatment of C57BL/6-Akita mice with apocynin, an NAD(P)H oxidase inhibitor, also increased the renal protein expression of SOD and Nrf2. Collectively, our data suggest that NAD(P)H oxidase negatively regulates renal SOD, possibly by downregulation of Nrf2, and that telmisartan could upregulate renal SOD by the suppression of NAD(P)H oxidase and subsequent upregulation of Nrf2, leading to the amelioration of renal oxidative stress and diabetic renal changes.
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http://dx.doi.org/10.1038/hr.2011.176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3273720PMC
February 2012

Reduction of circulating superoxide dismutase activity in type 2 diabetic patients with microalbuminuria and its modulation by telmisartan therapy.

Hypertens Res 2011 Dec 4;34(12):1302-8. Epub 2011 Aug 4.

Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.

Growing evidence indicates that oxidative stress induced by excessive superoxide has a central role in the pathogenesis of diabetic nephropathy (DN). Telmisartan, one of the currently available angiotensin II type 1 receptor blockers (ARBs), has been shown to exert a more powerful proteinuria (albuminuria) reduction in patients with DN, but whether the prominent renoprotective effect of telmisartan is mediated through enhancing antioxidant defense capacity and reducing oxidative stress has not been fully elucidated. The present study first revealed that the serum activity of superoxide dismutase (SOD) responsible for superoxide removal is reduced in the DN stage of microalbuminuria, but not in normoalbuminuria in type 2 diabetic patients. We next examined the alteration of SOD and oxidative stress following an 8-week treatment with telmisartan (40 mg per day) in 12 type 2 diabetic patients with microalbuminuria. Interestingly, the telmisartan treatment not only reduced the circulating levels of two oxidative stress markers, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nitrotyrosine (NT), but also enhanced serum SOD activity. Notably, a significant correlation was observed between the increase in serum SOD activity and the reduction in albuminuria. We further compared the anti-oxidative effect of telmisartan with that of losartan, another member of the ARB class, by implementing an 8-week interval crossover treatment with these ARBs in another 12 microalbuminuric type 2 diabetic patients. The patients showed higher serum SOD activity, and lower circulating levels of 8-OHdG and NT, during treatment with telmisartan than with losartan. These results suggest that telmisartan has a more potent antioxidative effect through its ability to enhance SOD activity in type 2 diabetic patients with microalbuminuria.
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http://dx.doi.org/10.1038/hr.2011.127DOI Listing
December 2011

[Incretin-related medicine (GLP-1 receptor agonists, DPP-IV inhibitors)].

Nihon Rinsho 2010 Nov;68 Suppl 9:181-5

Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University Graduate School of Medicine.

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November 2010

Efficacy and safety of patient-directed titration of once-daily pre-dinner premixed biphasic insulin aspart 70/30 injection in Japanese type 2 diabetic patients with oral antidiabetic drug failure: STEP-AKITA study.

J Diabetes Investig 2011 Jan;2(1):63-70

Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University Graduate School of Medicine, Hondo ; Department of Medicine, Saitama Medical Center, Jichi Medical University, Omiya, Saitama, Japan.

Unlabelled: Aims/Introduction:  To clarify clinical characteristics related to optimal glycemic control achieved after adding once-daily pre-dinner biphasic insulin aspart 70/30 (BIAsp 30) in Japanese type 2 diabetic (T2D) patients with oral antidiabetic drug (OAD) failure.

Materials And Methods:   Under this regimen, we evaluated changes in HbA1c levels and daily self-monitoring blood glucose (BG) profiles, as well as the incidences of hypoglycemia and retinopathy progression. The patients adjusted BIAsp 30 dosages themselves every 3-4 days according to a pre-determined algorithm to achieve fasting BG levels of 101-120 mg/dL. HbA1c levels were expressed as Japan Diabetes Society values.

Results:   Of 29 enrolled patients, 22 (HbA1c levels, 8.5 ± 1.5% [mean ± SD]) and 20 patients completed the 16- and 24-week follow-up, respectively. At 16 weeks 68.2 and 45.5%, and at 24 weeks 80.0 and 35% of patients had achieved HbA1c levels of <7.0 and <6.5%, respectively. The patients who had achieved optimal glycemic control, including daytime postprandial BG profiles after treatment, had lower post-breakfast BG excursions at baseline, shorter diabetes durations and younger age. No severe hypoglycemic episodes were recorded. Progression of retinopathy was observed in 3 of the 29 enrolled patients.

Conclusions:   Lower post-breakfast BG excursions, shorter diabetes duration and younger age in Japanese T2D patients with OAD failure might warrant optimal glycemic control with safety after adding once-daily pre-dinner BIAsp 30 initiating regimen. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00062.x, 2010).
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http://dx.doi.org/10.1111/j.2040-1124.2010.00062.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008017PMC
January 2011

Effects of long-term pravastatin treatment on serum and urinary monocyte chemoattractant protein-1 levels and renal function in type 2 diabetic patients with normoalbuminuria.

Ren Fail 2007 ;29(7):791-6

Division of Endocrinology, Metabolism and Geriatric Medicine, Department of Internal Medicine, Akita University School of Medicine, Akita, Japan.

To explore the renoprotective and anti-inflammatory effects of pravastatin, we analyzed the changes in renal function and urinary monocyte chemoattractant protein-1 (MCP-1) level as a renal tubulointerstitial inflammatory biomarker and serum MCP-1 level as a systemic inflammatory biomarker following the introduction of treatment with 10 mg/day of pravastatin in 10 hyperlipidemic type 2 diabetic patients with normoalbuminuria. Twelve months of the pravastatin treatment did not affect urinary levels of albumin, transferrin, N-acetylglucosaminidase, or MCP-1 in the hyperlipidemic diabetic patients, whereas the treatment significantly reduced serum levels of MCP-1 in the patients. The pravastatin treatment effectively lowered low-density lipoprotein cholesterol (LDL-C) levels in the hyperlipidemic diabetic patients to levels nearly to those in 11 non-hyperlipidemic type 2 diabetic patients with normoalbuminuria. Interestingly, serum MCP-1 levels were significantly lower in the hyperlipidemic patients treated with pravastatin than in the non-hyperlipidemic patients. No significant correlation was observed between serum LDL-C and MCP-1 levels in all the data in the hyperlipidemic patients before and after the pravastatin treatment and in the non-hyperlipidemic patients. These results collectively indicate that pravastatin may ameliorate systemic vascular inflammation rather than local renal inflammation in hyperlipidemic type 2 diabetic patients with normoalbuminuria, independent of its cholesterol-lowering effects.
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http://dx.doi.org/10.1080/08860220701543056DOI Listing
January 2008

[Assessment of compliance for oral medicines with MMSE, Mini-Mental State Examination, in hospitalized elderly patients].

Yakugaku Zasshi 2007 Oct;127(10):1731-8

Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita City 010-8543, Japan.

The minimental state examination (MMSE) is a widely used, standardized method to assess cognitive function including movement-related disorders with high reliability. We studied the relationship between MMSE scores and the ability to take oral medications correctly (ingestion compliance) in 70 elderly inpatients (mean age 71.3+/-7.0 years). Patients with abnormal glucose tolerance as determined by an HbA(1c) level of 5.8% or greater including diabetes showed a trend of lower MMSE scores compared with patients with normal glucose tolerance, and the scores were negatively correlated with HbA1c, age, and systolic blood pressure (P<0.05). Self-management in taking oral medications was very difficult in 4 patients whose MMSE scores were 21 points or less. Thus ingestion supervisions by nurses were required in these patients. Furthermore, 9 of 12 noncompliant patients had MMSE scores ranging from 22 to 26 points. We instructed these patients to take medications in a one-dose package as a useful tool to improve compliance. The MMSE score was 27 or higher in 44 of 54 compliant patients, and 10 patients had scores ranging from 21 to 26. The sensitivity and specificity for noncompliance at an MMSE score cut-off point of 26 were 75.0% and 81.5%, respectively. In conclusion, it is necessary to coordinate ingestion methods matched to each patient according to their abilities to comply with medication schedules. They should be preevaluated with the MMSE to improve ingestion compliance. The MMSE is a recommended test in hospitalized elderly patients for the assessment of the ability to take medications safely.
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http://dx.doi.org/10.1248/yakushi.127.1731DOI Listing
October 2007

Effect of selective cyclooxygenase-2 (COX-2) inhibitor treatment on glucose-stimulated insulin secretion in C57BL/6 mice.

Biochem Biophys Res Commun 2007 Nov 27;363(1):37-43. Epub 2007 Aug 27.

Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.

Previous studies have shown that Prostaglandin E(2) (PGE(2)) inhibits glucose-stimulated insulin secretion. However, the role of cyclooxygenase (COX)-1 vs. COX-2 derived PGE(2) production in glucose-stimulated insulin secretion remains poorly understood. Here we investigated the expression of COX-1 and COX-2 in pancreatic islets and the effect of selective inhibition of COX-1 and COX-2 on glucose-stimulated insulin secretion using C57BL/6 (B6) mice. Although immunofluorescence histochemistry showed the constitutive expression of both COX-1 and COX-2 in B6 mouse pancreatic islets, insulin secretion and hyperglycemia after glucose loading were ameliorated in B6 mice treated with selective COX-2 inhibitor (SC58236) for 18 weeks. Interestingly, incubation with selective COX-2 inhibitor for 24h led to a reduction in PGE(2) production in pancreatic islets isolated from B6 mice. In addition, selective COX-2 inhibition enhanced insulin secretion from the isolated islets. These results collectively suggest that selective inhibition of COX-2 enhances glucose-stimulated insulin secretion through a reduction in PGE(2) production in pancreatic islets.
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http://dx.doi.org/10.1016/j.bbrc.2007.08.090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211567PMC
November 2007

Possible relationship between adiponectin and renal tubular injury in diabetic nephropathy.

Endocr J 2006 Dec 12;53(6):745-52. Epub 2006 Sep 12.

Division of Endocrinology, Metabolism, and Geriatric Medicine, Department of Internal Medicine, Akita University School of Medicine, Japan.

Adiponectin is an adipose-derived protein which has anti-inflammatory and anti-atherogenic properties in addition to insulin-sensitizing effects. To date, the role of adiponectin in the pathogenesis of diabetic nephropathy remains unclear. The aim of the present study was to explore the relationship between adiponectin and renal tubular injury in diabetic nephropathy. We determined serum and urinary adiponectin levels in type 2 diabetic patients with normoalbuminuria (n = 19), microalbuminuria (n = 18), and overt diabetic nephropathy (n = 16), and then analyzed the correlations between serum and urinary adiponectin, urinary N-acetylglucosaminidase (NAG) as a clinical marker of renal tubular injury, urinary monocyte chemoattractant protein-1 (MCP-1) as an inflammatory marker in renal tubulointerstitium, and clinical markers of renal disease. Notably, serum and urinary adiponectin levels were significantly increased in patients with overt diabetic nephropathy compared to those with normoalbuminuria and microalbuminuria. In univariate linear regression analysis, serum adiponectin levels were positively correlated with serum creatinine (r = 0.648, P<0.0001), urinary albumin (r = 0.583, P<0.0001), urinary NAG (r = 0.406, P<0.01), urinary MCP-1 (r = 0.514, P<0.0001), and urinary adiponectin (r = 0.691, P<0.0001) levels in all diabetic patients. Urinary adiponectin levels were also positively correlated with serum creatinine (r = 0.729, P<0.0001), urinary albumin (r = 0.799, P<0.0001), urinary NAG (r = 0.701, P<0.0001), and urinary MCP-1 (r = 0.801, P<0.0001) levels in all diabetic patients. Multiple linear regression analysis showed that serum creatinine and urinary adiponectin levels were independently associated with serum adiponectin levels (r(2) = 0.522), and that serum creatinine, urinary NAG, urinary MCP-1, and serum adiponectin levels were independent determinants of urinary adiponectin levels (r(2) = 0.851). These results collectively indicate that renal insufficiency and tubular injury possibly play a contributory role in increases in serum and urinary adiponectin levels in overt diabetic nephropathy. We presume that an increase in circulating adiponectin in overt diabetic nephropathy might be a physiological response to mitigate renal tubular injury and to prevent the further progression of diabetic nephropathy through its anti-inflammatory and anti-atherogenic effects.
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http://dx.doi.org/10.1507/endocrj.k06-016DOI Listing
December 2006

Effects of antidiabetic treatment with metformin and insulin on serum and adipose tissue adiponectin levels in db/db mice.

Endocr J 2005 Aug;52(4):427-33

Division of Endocrinology, Metabolism and Geriatric Medicine, Department of Internal Medicine, Akita University School of Medicine, Akita.

Decreased circulating levels of adiponectin, a novel adipose-derived adipocytokine, in obesity possibly contribute to the development of insulin resistance which is a major factor in the pathogenesis of type 2 diabetes. The present study was conducted to examine whether circulating and adipose tissue adiponectin levels are modulated by chronic treatment with metformin and intensive treatment with insulin in murine models of obesity and type 2 diabetes, db/db mice with a C57BL/KsJ genetic background. Nine-week-old male db/db mice were treated with metformin, insulin, and vehicle for 4 weeks. Expectedly, metformin treatment led to inhibition of weight gain and improvement of hyperinsulinemia. Insulin treatment lowered fasting blood glucose levels to normal values, although it sustained hyperinsulinemic state. However, after 4 weeks of treatment, serum adiponectin levels were not significantly elevated in either metformin-treated or insulin-treated db/db mouse group (14.2 +/- 0.7 and 16.7 +/- 1.0 microg/ml, respectively) compared to vehicle-treated group (14.9 +/- 0.6 microg/ml). Similarly, adipose tissue adiponectin levels determined by Western blot analysis were not increased in either metformin-treated or insulin-treated group relative to vehicle-treated group. Recent studies have shown that adiponectin possibly has the same physiological effects on lipid and glucose metabolism that metformin has. Therefore, an elevation in blood concentration of metformin following the treatment might lead to suppression in adiponectin synthesis in adipose tissue, independent of inhibition in weight gain and improvement in hyperinsulinemia by metformin treatment. The present results indicate that adiponectin is not involved in the mechanism by which metformin treatment enhances insulin sensitivity. Moreover, our results suggest that adiponectin synthesis in adipose tissue may be suppressed under hyperinsulinemic state sustained by insulin treatment, even though hyperglycemia is markedly reduced. We conclude that antidiabetic treatment with metformin and insulin does not affect circulating and adipose tissue adiponectin levels.
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http://dx.doi.org/10.1507/endocrj.52.427DOI Listing
August 2005

Parallel increase in urinary excretion rates of immunoglobulin G, ceruloplasmin, transferrin, and orosomucoid in normoalbuminuric type 2 diabetic patients.

Diabetes Care 2004 May;27(5):1176-81

Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University School of Medicine, Akita, Japan.

Objective: Increased urinary excretions of several plasma proteins with different molecular radii <55 A and different isoelectric points (pI), such as IgG, ceruloplasmin, transferrin, and orosomucoid, have been independently reported to precede the development of microalbuminuria in diabetic patients. We examined whether increases in urinary excretions of these proteins would be in parallel in the same patient.

Research Design And Methods: Urinary excretion rates of proteins mentioned above in timed overnight urine samples were evaluated in 61 normoalbuminuric type 2 diabetic patients (group D) aged 40-60 years and in 17 age-matched control subjects (group C).

Results: The excretion rates of these proteins were significantly higher in group D than in group C. These exhibited a strong linear correlation with each other and had a weak correlation with the excretion rate of N-acethylglucosaminidase. The excretion rate of alpha2-macroglobulin with large molecular radii of 88 A was not different between groups C and D, nor did they have any correlations with the excretion rates of the other proteins. Creatinine clearance and blood pressure levels in group D were significantly higher than those in group C.

Conclusions: In normoalbuminuric diabetic patients, excretion rates of plasma proteins with molecular radii <55 A increased in parallel with each other. In view of our previous finding that urinary excretions of these plasma proteins selectively increased in parallel with enhanced glomerular filtration rate after acute protein loading, the present finding may be explained by renal hemodynamic changes, such as increased intraglomerular hydraulic pressure.
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http://dx.doi.org/10.2337/diacare.27.5.1176DOI Listing
May 2004

Efficacy of immunoglobulin and prednisolone in diabetic amyotrophy.

Endocr J 2003 Dec;50(6):831-2

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http://dx.doi.org/10.1507/endocrj.50.831DOI Listing
December 2003

Increased urinary excretion of monocyte chemoattractant protein-1 in proteinuric renal diseases.

Ren Fail 2003 May;25(3):439-44

Department of Geriatric Medicine, Akita University School of Medicine, Hondo, Akita, Japan.

Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that is produced mainly by tubular epithelial cells in kidney and contributes to renal interstitial inflammation and fibrosis. More recently, we have demonstrated that urinary MCP-1 excretion is increased in proportion to the degree of albuminuria (proteinuria) and positively correlated with urinary N-acetylglucosaminidase (NAG) levels in type 2 diabetic patients. Based on these findings, we have suggested that heavy proteinuria, itself, probably aggravates renal tubular damage and accelerates the disease progression in diabetic nephropathy by increasing the MCP-1 expression in renal tubuli. In the present study, to evaluate whether urinary MCP-1 excretion is increased in the proteinuric states not only in diabetic nephropathy but also in other renal diseases, we examined urinary MCP-1 levels in IgA nephropathy patients with macroalbuminuria (IgAN group; n = 6), and compared the results with the data obtained from type 2 diabetic patients with overt diabetic nephropathy (DN group; n = 23) and those without diabetic nephropathy (non-DN group; n = 27). Urinary MCP-1 excretion levels in non-DN, DN, IgAN groups were 157.2 (52.8-378.5), 346.1 (147.0-1276.7), and 274.4 (162.2-994.5) ng/g creatinine, median (range), respectively. Expectedly, urinary MCP-1 and NAG excretion levels in DN and IgAN groups were significantly elevated as compared with non-DN group. Therefore, we suggest that MCP-1 expression in renal tubuli is enhanced in proteinuric states,irrespective of the types of renal disease, and that increased MCP-1 expression probably contributes to renal tubular damage in proteinuric states.
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http://dx.doi.org/10.1081/jdi-120021156DOI Listing
May 2003

Association of monocyte chemoattractant protein-1 with renal tubular damage in diabetic nephropathy.

J Diabetes Complications 2003 Jan-Feb;17(1):11-5

Department of Geriatric Medicine, Akita University School of Medicine, 1-1-1 Hondo, Japan.

Monocyte chemoattractant protein-1 (MCP-1), is a chemokine that mediates renal interstitial inflammation, tubular atrophy, and interstitial fibrosis by recruiting monocytes/macrophages into renal tubulointerstitium. Recent studies have demonstrated that protein overload in renal tubular cells up-regulates MCP-1 gene and its protein expression. Therefore, we hypothesized that increased expression of MCP-1 in renal tubuli, probably triggered by an increase in the leakage of plasma protein from glomerular capillary to tubular fluid, may contribute to renal tubular damage and accelerate the progression of diabetic nephropathy. To test this hypothesis, we examined urinary excretion levels of MCP-1 and N-acetylglucosaminidase (NAG), a sensitive marker of renal tubular damage, in Japanese Type II diabetic patients with normoalbuminuria (n=29), microalbuminuria (n=25), and macroalbuminuria (n=18). The median urinary excretion level of MCP-1 in patients with macroalbuminuria (394.4 ng/g creatinine) was significantly elevated compared to the levels in patients with normoalbuminuria and microalbuminuria (159.6 and 193.9 ng/g creatinine, respectively). Furthermore, the urinary MCP-1 excretion level was positively correlated with urinary excretion levels of albumin (r=.816, P<.001) and NAG (r=.569, P<.001) in all subjects. These results suggest that MCP-1 is produced in renal tubular cells and released into urine in proportion to the degree of proteinuria (albuminuria), and that increased MCP-1 expression in renal tubuli contributes to renal tubular damage. Therefore, we conclude that heavy proteinuria itself may accelerate the progression of diabetic nephropathy by increasing the MCP-1 expression in renal tubuli.
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http://dx.doi.org/10.1016/s1056-8727(02)00176-9DOI Listing
July 2003

Effect of metformin on adipose tissue resistin expression in db/db mice.

Biochem Biophys Res Commun 2002 Nov;298(3):345-9

Department of Geriatric Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.

Resistin, a novel adipose-derived protein, has been proposed to cause insulin-resistant states in obesity. To evaluate whether an insulin-sensitizing drug, metformin, regulates adipose tissue resistin expression, murine models of obesity and diabetes, db/db mice, were treated with metformin (metformin group), insulin (insulin group), and vehicle (control group) for 4 weeks, followed by analyzing resistin protein expression in their adipose tissues. Unexpectedly, resistin protein expression was increased by 66% in the metformin group relative to the control group, while it did not differ between the insulin and control groups. Hyperinsulinemia was improved in the metformin group, while the insulin group exhibited severe hyperinsulinemia, similar to the control group. Furthermore, in comparison between obese mice (db/db mice) and age-matched lean controls, resistin protein expression was reduced by 58% in the obese mice with severe hyperinsulinemia. These data collectively suggest that resistin expression may be suppressed by hyperinsulinemia and that metformin may upregulate resistin expression via the improvement of hyperinsulinemia in obesity.
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http://dx.doi.org/10.1016/s0006-291x(02)02464-6DOI Listing
November 2002

Increased urinary excretion of N-acetylglucosaminidase in subjects with impaired glucose tolerance.

Ren Fail 2002 Jan;24(1):69-75

Department of Geriatric Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.

N-acetylglucosaminidase (NAG) is a lysosomal enzyme produced by renal proximal tubular cells and has been widely used as a marker, which indicates a degree of renal tubular damage. An increase in urinary NAG excretion is though to result from the renal tubular damage. The aim of this study was to evaluate whether even mild hyperglycemia causes an increase in urinary excretion of NAG, which is a renal tubular protein. We examined urinary NAG excretion in overnight urine in 22 Japanese men with impaired glucose tolerance (IGT) for more than two years (IGT group) and 41 healthy control subjects matched in age, gender, BMI and blood pressure (control group). Urinary NAG excretion levels of IGT group and control group were 2.89 (1.23-7.97) and 2.22 (0.60-4.93) U/g creatinine, median (range), respectively. The IGT group showed significantly higher urinary excretion of NAG compared to the control group (p < 0.01). Several studies have indicated that plasma proteins filtered through the glomerular capillary may have intrinsic renal toxicity. Recently, we have reported that urinary excretion of plasma proteins (ceruloplasmin, IgG4 and IgG) with molecular radii of approximately 45-55 A is increased in subjects with IGT compared to healthy control subjects with normal glucose tolerance. Considering the present result together with our recent finding, we suggest that increased urinary excretion of NAG in the mildly hyperglycemic subjects may be due to the adverse effects of the plasma proteins highly filtered through the glomerular capillary on tubular cells.
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http://dx.doi.org/10.1081/jdi-120002662DOI Listing
January 2002