腹膜透析(PD)患者の非外傷性腎破裂(SRR)に関する報告は少ない。我々は血性排液を伴う腹痛を主訴に来院し、SRRの診断に至った一例を経験した。原因は仮性動脈瘤であり、選択的経カテーテル動脈塞栓術(TAE)により止血を得た。TAEの前後で残存腎機能の低下は15〜25%にとどまり、PDを継続することが可能であった。PD患者のSRRに対し、残腎機能温存を考慮した選択的TAEが有用と考えられた。(著者抄録)

現在腹膜透析は、腹膜劣化による被嚢性腹膜硬化症(EPS)の発症リスクを加味して5〜8年を目途に他の腎代替療法へ移行されていることが多い。EPSのリスク増加因子として高濃度ブドウ糖液、酸性透析液、腹膜炎などが示されているが、以前の透析液や方法からの変遷が、腹膜劣化速度やEPS発症率にも影響を及ぼしている可能性がある。今回、種々の理由により8年を超えて腹膜透析を行った30例について、腹膜機能や予後などについて検討した。(著者抄録)

We examined the potential contributions of oxidative stress and thromboxane A2 (TXA2) to the development of regional heterogeneity in hypertensive glomerular injury using stroke-prone spontaneously hypertensive rats (SHRSP), an animal model of human essential hypertension. We also examined the effect of antioxidant treatment on the regional expression of thromboxane synthase (TXAS) mRNA using a microdissection method. Increases in the glomerular expression of TXAS mRNA were observed in the SHRSP at 15 weeks of age compared with those in the age-matched normotensive control Wistar-Kyoto (WKY) rats: 2.4-fold and 3.1-fold in the superficial and juxtamedullary glomeruli, respectively (P < 0.05). The heme oxygenase-1 mRNA expression was markedly increased (greater than eightfold, P < 0.05) in both the superficial and juxtamedullary glomeruli in the SHRSP compared with the expression in the WKY rats. In contrast to our expectations, the treatment of SHRSP with tempol (a superoxide dismutase mimetic) significantly (P < 0.05) increased the TXAS mRNA expression in the superficial glomeruli and did not improve the histological injury or albuminuria, which were both aggravated. Moreover, ozagrel (a TXAS inhibitor) had a suppressive effect on the TXAS mRNA expression and significantly (P < 0.05) improved the histological injury. These results indicated that although TXA2 and oxidative stress are linked to each other, TXA2 rather than oxidative stress may be a better therapeutic target to improve hypertensive glomerular injury.

Cell adhesion molecule 1 (CADM1) is an immunoglobulin superfamily member strongly expressed on renal tubular epithelia in the urinary tract. Enzymatic cleavage of its ectodomain increases in chronic kidney disease (CKD), and is assumed to contribute to tubulointerstitial lesion formation. Because the cleaved ectodomain fragments are likely to be released into the urine, a sandwich enzyme-linked immunosorbent assay (ELISA) system for urinary CADM1 was developed using two anti-ectodomain antibodies. Urinary CADM1 concentrations in patients with CKD based on various forms of glomerulonephritis and nephropathy (n = 127) were measured. A total of 44 patients (35%) had elevated CADM1 concentrations over the normal upper limit (362 pg/mL), with a mean of 1,727 pg/mL. Renal biopsy specimens of all patients were pathologically scored for tubulointerstitial lesions using epithelial degeneration, interstitial inflammation, and fibrosis. There were no correlations between urinary CADM1 concentrations and pathological scores or any widely used renal markers, including glomerular filtration rate (GFR), but there was a weak inverse correlation between pathological scores and GFR (R2 = 0.292). Notably, this correlation gradually increased in patients with increasing CADM1 concentrations, and reached a maximum R2 (0.899) at a cutoff of 1,569 pg/mL. The results of this study suggest that urinary CADM1 is a useful marker indicating tubulointerstitial damage from elevated GFR levels in CKD.

Summary: We here report a case of nivolumab-induced acute granulomatous tubulointerstitial nephritis in a patient with gastric cancer. A 68-year-old woman with recurrent gastric cancer developed acute kidney injury associated with kidney enlargement and urinary leukocytes after 38 cycles of nivolumab treatment. A diagnosis of acute granulomatous tubulointerstitial nephritis was made based on kidney biopsy findings. Immunohistochemistry revealed expression of programmed cell death–ligand 1 (PD-L1) in degenerated epithelial cells of collecting tubules. Among infiltrating immune cells, aggregation of T cells was more extensive than that of B cells, with CD4+ T cells outnumbering CD8+ T cells, consistent with the relative numbers of these cells in the circulation. Treatment with methylprednisolone (1.0 mg/kg daily) led to a rapid improvement in renal function and reduction in the number of circulating CD4+ T cells. Prompt administration of high-dose corticosteroid is thus recommended after diagnosis of this adverse event of nivolumab treatment by kidney biopsy.

Cryoglobulinemia can induce systemic vasculitis affecting various organs such as skin, peripheral nerves, and kidney. The disease can induce chronic organ failure and even be life-threatening. Cryofiltration has been applied for the treatment of cryoglobulinemic vasculitis. We have experienced four cases with mixed cryoglobulinemia showing severe and progressive clinical manifestations, including skin purpura, nephrotic syndrome, acute kidney injury, and peripheral neuropathy. Cryofiltration in conjunction with conventional pharmacological therapies appeared to be safe and effective. After the treatments, plasma cryoglobulins were markedly reduced and the disease was well controlled. Although its efficacy has not yet been well established, this report can be another evidence showing efficacy of cryofiltration for treatment of mixed cryoglobulinemia.

SIRT1 is an NAD-dependent deacetylase. One important role of SIRT1 is its deacetylation activity in the modulation of cell stress signals via epigenetics. In podocytes, SIRT1 regulates the expression of important genes such as PGC-1α, Foxo4, p65 and STAT3, which act to maintain podocyte function by modulating the levels of histone acetylation. Here, we confirmed that SIRT1 protects podocytes by maintaining PGC-1α via its deacetylase-activated transcriptional activity in mitochondria and podocytes. We then showed that the alteration of Foxo4 (forkhead box O4) acetylation and decrease in SIRT1 promote podocyte apoptosis in diabetic nephropathy, resulting in the gradual development of diabetic nephropathy. Next, we showed that advanced glycation end products (AGEs) induced p65 and STAT3 acetylation in human podocytes. Decreased Sirt1 activity in podocytes results in the development of proteinuria and kidney injury via the acetylation of p65 and STAT3. These findings suggest that the beneficial effects of SIRT1 in diabetic nephropathy act via the deacetylation of transcription factors. In addition to its essential role in regulating the epigenetics of podocytes, we recently showed that SIRT1 is necessary to maintaining the function of slit membranes and podocytes. The actin cytoskeleton becomes vulnerable to various stresses, including oxidative stress, which in turn leads to the derangement and effacement of foot processes, slit membrane dysfunction, and proteinuria. SIRT1 protects podocytes and prevents glomerular injury by deacetylating cortactin and changing cortactin localization, thereby maintaining the integrity of the actin cytoskeleton. We expect that SIRT1 will be shown to sufficiently suppress the development of kidney dysfunction and will be proven useful in the near future. The clinical application of SIRT1-activated chemical agents has just started, and results are eagerly anticipated.

63歳男。腎硬化症による慢性腎不全、陳旧性心筋梗塞および慢性心房細動による低心機能のため通院中であった。著しい低心機能のため腹膜透析を選択したが、透析開始後より体液量コントロールに難渋した。透析開始後3年を経た頃より、再度下腿浮腫の増強、胸水の増加がみられたため加療目的で入院となった。第3病日よりトルバプタンを投与したところ、腹膜透析での除水量が1000→2500mL程度まで増加した。除水量増加に伴い、1週間で約4kgの体重減少と胸水の消失を認めた。BNPは4232.1→77.5pgへ著明に低下した。尿量は明らかな増加を認めなかった。血中尿素窒素およびクレアチニン値に有意な変化はなかった。血清ナトリウム濃度は131→134mEq/Lへ上昇した。

It is known that endoplasmic reticulum (ER) stress is provoked under diabetic conditions and is possibly involved in the development of insulin resistance. In this study, using ER stress-activated indicator (ERAI) transgenic mice which express green fluorescent protein under ER stress conditions, we directly evaluated the effects of a diabetic agent pioglitazone on in vivo ER stress under diabetic conditions. In high fat and high sucrose diet-induced diabetic ERAI transgenic juice, 8 weeks of pioglitazone treatment reduced the accumulation of fat droplets in the liver and attenuated the development of insulin resistance. In the liver of the ERAI transgenic mice, ERAI fluorescence activity was clearly reduced as early as after 4 weeks of pioglitazone treatment, preceding the improvement of insulin resistance. In addition, after the pioglitazone treatment, serum free fatty acid and triglyceride levels were decreased, and serum adiponectin levels were increased. These data indicate that pioglitazone treatment suppresses ER stress in the liver which may explain, at least in part, the pharmacological effects of pioglitazone to reduce insulin resistance.

Type 2 diabetes is one of the most prevalent and serious metabolic diseases in the world, and insulin resistance and pancreatic beta-cell dysfunction are the hallmarks of the disease. It has been suggested that endoplasmic reticulum (ER) stress is provoked under diabetic conditions and is possibly involved in the development of insulin resistance. In this study, using ER stress-activated indicator (ERAI) transgenic mice which express green fluorescent protein (GFP) under ER stress conditions, we directly monitored in vivo ER stress in various insulin target tissues such as liver, fat, and muscle in diabetic mice with insulin resistance induced by high fat and high sucrose (HF/HS) diet treatment. In the liver of the ERAI transgenic mice, ERAI fluorescence activity was clearly observed as early as after 4 weeks of HF/HS diet treatment, whereas it was not detected at all in the fat and muscle even after 12 weeks of HF/HS diet treatment. These results suggest that induction of ER stress is associated with the development of insulin resistance and that ER stress in the liver may facilitate the development of insulin resistance in the whole body. This is the first report to directly monitor in vivo ER stress in various insulin target tissues during the development of insulin resistance. In addition, our present results suggest that ERAI transgenic mice are very useful for evaluating in vivo ER stress, especially in the liver, during the development of insulin resistance. (c) 2007 Elsevier Inc. All rights reserved.

To determine the impact of blood glucose profile, involving fluctuation and excursion of blood glucose levels, on glycated proteins, we evaluated the association among the daily profile of blood glucose, and glycated albumin (GA) and HbA1c levels in patients with type 1 diabetes (n = 93) and type 2 diabetes (n = 75). GA levels were strongly correlated with HbA1c levels in type 1 (r = 0.85, P< 0.0001) and type 2 diabetes (r = 0.61, P< 0.0001), respectively. HbA1c levels were similar between patients with type 1 and type 2 diabetes, while GA levels were significantly higher in type 1 diabetes. Thus the ratio of GA levels to HbAlc levels was significantly higher in type 1 diabetes than that in type 2 diabetes (3.32 ± 0.36 vs. 2.89 ± 0.44, p< 0.001). The degrees of GA levels and HbA1c levels correlated with maximum and mean blood glucose levels in patients with type 1 and type 2 diabetes. Stepwise multivariate analysis revealed that GA levels independently correlated with maximum blood glucose levels in type 1 diabetes (F =43.34, P< 0.001) and type 2 diabetes (F = 41.57, P< 0.001). HbA 1 c levels also independently correlated with maximum blood glucose levels in type 1 diabetes (F = 34.78, P< 0.001), as well as being correlated with mean blood glucose levels in type 2 diabetes (F = 11.28, P< 0.001). In summary, GA could be a better marker for glycemic control than glycated hemoglobin in diabetic patients, especially for evaluating glycemic excursion, which is considered to be a major cause of diabetic angiopathy.

It has been shown that oxidative stress and activation of the c-Jun N-terminal kinase (JNK) pathway induce the nucleocytoplasmic translocation of the pancreatic transcription factor PDX-1, which leads to pancreatic beta-cell dysfunction. In this study, we have shown that the forkhead transcription factor Foxo1/FKHR plays a role as a mediator between the JNK pathway and PDX-1. Under oxidative stress conditions, Foxo1 changed its intracellular localization from the cytoplasm to the nucleus in the pancreatic beta-cell line HIT-T15. The overexpression of JNK also induced the nuclear localization of Foxo1, but in contrast, suppression of JNK reduced the oxidative stress-induced nuclear localization of Foxo1, suggesting the involvement of the JNK pathway in Foxo1 translocation. In addition, oxidative stress or activation of the JNK pathway decreased the activity of Akt in HIT cells, leading to the decreased phosphorylation of Foxo1 following nuclear localization. Furthermore, adenovirus-mediated Foxo1 overexpression reduced the nuclear expression of PDX-1, whereas repression of Foxo1 by Foxo1-specific small interfering RNA retained the nuclear expression of PDX-1 under oxidative stress conditions. Taken together, Foxo1 is involved in the nucleocytoplasmic translocation of PDX-1 by oxidative stress and the JNK pathway.

Type 2 diabetes is the most prevalent and serious metabolic disease affecting people all over the world. Pancreatic P-cell dysfunction and insulin resistance are the hallmark of type 2 diabetes. Normal P-cells can compensate for insulin resistance by increasing insulin secretion and/or beta-cell mass, but insufficient compensation leads to the onset of glucose intolerance. Once hyperglycemia becomes apparent, beta-cell function gradually deteriorates and insulin resistance aggravates. Under diabetic conditions, oxidative stress and endoplasmic reticulum stress are induced in various tissues, leading to activation of the c-Jun N-terminal kinase pathway. The activation of c-Jun N-terminal kinase suppresses insulin biosynthesis and interferes with insulin action. Indeed, suppression of c-Jun N-terminal kinase in diabetic mice improves insulin resistance and ameliorates glucose tolerance. Thus, the c-Jun N-terminal kinase pathway plays a central role in pathogenesis of type 2 diabetes and could be a potential target for diabetes therapy. (c) 2006 Elsevier Ltd. All rights reserved.

OBJECTIVE - The binding of advanced glycation end products (AGES) to their receptor (RAGE) plays an important role in the development of diabetic vascular complications. In the present study, we examined circulating endogenous secretory RAGE (esRAGE) levels in subjects with type 1 diabetes and explored the possible association between esRAGE levels and the severity of diabetic vascular complications. RESEARCH DESIGN AND METHODS - Circulating esRAGE levels in serum were examined in 67 Japanese type 1 diabetic patients (22 men and 45 women, age 24.0 +/- 4.4 years [means +/- SD]) and 23 age-matched healthy nondiabetic subjects (10 men and 13 women aged 24.9 +/- 1.4 years). Daily urinary albumin excretion, the presence of retinopathy, and intimamedia thickness (IMT) of the carotid artery were also evaluated. We further explored the association between esRAGE levels and severity of diabetic vascular complications. RESULTS - Circulating esRAGE levels were significantly lower in subjects with type 1 diabetes than in nondiabetic subjects (0.266 +/- 0.089 vs. 0.436 +/- 0,121 ng/ml, respectively, P < 0.0001) and was inversely correlated with HbA(1c), (AlC) levels (r = -0.614, P < 0.0001). In addition, multivariate regression analysis demonstrated that AlC was an independent risk factor for a low esRAGE value. Furthermore, circulating esRAGE levels were inversely correlated with carotid IMT (r = -0.325, P = 0.0017) and was one of the independent risk factors for IMT thickening. Furthermore, there was a significant difference (P = 0.0124) in esRAGE levels between patients without retinopathy (0.286 +/- 0.092 ng/ml) and those with retinopathy (0.230 +/- 0.074 ng/ml). CONCLUSIONS - Circulating esRAGE levels were significantly lower in type 1 diabetic patients than in nondiabetic subjects and were inversely associated with the severity of some diabetic vascular complications.

Peripheral vascular disease (PVD) has been reported to cause deterioration in insulin sensitivity. The precise mechanism of insulin resistance induced by PVD has not been clarified. To elucidate the mechanism causing impaired insulin action and glucose metabolism under peripheral ischemic conditions, we determined glucose turnover and glucose tolerance in hindlimb-ischernic (FAL) rats. The right femoral artery was ligated in hindlimb-ischemic (FAL) rats, while the artery was only exposed in the Sham operated (Sham) rats used as a control. Two weeks after the ligation, glucose tolerance was impaired and plasma insulin levels were significantly increased in FAL rats compared with Sham rats after intraperitoneal glucose loading (2 g kg(-1)). Under euglycemic hyperinsulinemic clamp conditions, the glucose infusion rate was significantly lower in FAL rats compared with Sham rats, but there was no significant difference in the glucose disappearance rate between the two groups. Hyperinsulinemia suppressed endogenous glucose production by 50% in Sham rats, while the suppression was 20% in FAL rats, indicating hepatic insulin resistance in FAL rats. mRNA analysis of isolated liver after the clamp experiment revealed that glucokinase mRNA, but not PEPCK and glucose-6-phosphatase mRNA, was significantly lower in FAL rats compared with Sham rats. In conclusion, chronic hindlimb ischemia impaired glucose tolerance associated with insulin resistance in the liver rather than the peripheral tissues. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

Type 2 diabetes is the most prevalent and serious metabolic disease affecting people all over the world. Pancreatic beta-cell dysfunction and insulin resistance are the hallmark of type 2 diabetes. Normal beta-cells can compensate for insulin resistance by increasing insulin secretion and/or beta-cell mass, but insufficient compensation leads to the onset of glucose intolerance. Once hyperglycemia becomes apparent, beta-cell function gradually deteriorates and insulin resistance aggravates. Under diabetic conditions, oxidative stress and endoplasmic reticulum stress are induced in various tissues, leading to activation of the c-Jun N-terminal kinase pathway. The activation of c-Jun N-terminal kinase suppresses insulin biosynthesis and interferes with insulin action. Indeed, suppression of c-Jun N-terminal kinase in diabetic mice improves insulin resistance and ameliorates glucose tolerance. Thus, the c-Jun N-terminal kinase pathway plays a central role in pathogenesis of type 2 diabetes and could be a potential target for diabetes therapy. (C) 2005 Elsevier Ltd. All rights reserved.

Pancreatic beta-cell dysfunction and insulin resistance are observed in type 2 diabetes. Under diabetic conditions, oxidative stress and ER stress are induced in various tissues, leading to activation of the JNK pathway. This JNK activation suppresses insulin biosynthesis and interferes with insulin action. Indeed, suppression of the JNK pathway in diabetic mice improves insulin resistance and ameliorates glucose tolerance. Thus, the JNK pathway plays a central role in pathogenesis of type 2 diabetes and may be a potential target for diabetes therapy.

MafA, a recently isolated pancreatic beta-cell-specific transcription factor, is a potent activator of insulin gene transcription. In this study, we show that MafA overexpression, together with PDX-1 ( pancreatic and duodenal homeobox factor-1) and NeuroD, markedly increases insulin gene expression in the liver. Consequently, substantial amounts of insulin protein were induced by such combination. Furthermore, in streptozotocin-induced diabetic mice, MafA overexpression in the liver, together with PDX-1 and NeuroD, dramatically ameliorated glucose tolerance, while combination of PDX-1 and NeuroD was much less effective. These results suggest a crucial role of MafA as a novel therapeutic target for diabetes.

Diabetes is the most prevalent and serious metabolic disease, and the number of diabetic patients worldwide is increasing. The reduction of insulin biosynthesis in pancreatic beta-cells is closely associated with the onset and progression of diabetes, and thus it is important to search for ways to induce insulin-producing cells in non-beta-cells. In this study, we showed that a modified form of the pancreatic and duodenal homeobox factor 1 (PDX-1) carrying the VP16 transcriptional activation domain (PDX-1/VP16) markedly increases insulin biosynthesis and induces various pancreas-related factors in the liver, especially in the presence of NeuroD or neurogenin 3 (Ngn3). Furthermore, in streptozotocin-induced diabetic mice, PDX-1/VP16 overexpression, together with NeuroD or Ngn3, drastically ameliorated glucose tolerance. Thus PDX-1/VP16 expression, together with NeuroD or Ngn3, markedly induces insulin gene transcription and ameliorates glucose tolerance. This approach warrants further investigation and may have utility in the treatment of diabetes.

To determine the role of the endoplasmic reticulum (ER) in diabetes, Akita mice, a mouse model of type 2 diabetes, were mated with either heterozygous knockout mice or two types of transgenic mice of 150-kDa oxygen-regulated protein (ORP150), a molecular chaperone located in the ER. Systemic expression of ORP150 in Akita mice improves insulin intolerance, whereas the exclusive overexpression of ORP150 in pancreatic beta-cells of Akita mice did not change their glucose tolerance. Both an insulin tolerance test and hyperinsulinemiceuglycemic clamp revealed that ORP150 enhanced glucose uptake, accompanied by suppression of oxidized protein. Furthermore, ORP150 enhanced the insulin sensitivity of myoblast cells treated with hydrogen peroxide. These data suggest that ORP150 plays an important role in insulin sensitivity and is a potential target for the treatment of diabetes.

Type 2 diabetes is one of the most prevalent and serious metabolic diseases in the world, and insulin resistance and pancreatic beta-cell dysfunction are the hallmarks of the disease. In this study, we have shown that endoplasmic reticulum ( ER) stress, which is provoked under diabetic conditions, plays a crucial role in the insulin resistance found in diabetes by modifying the expression of oxygen-regulated protein 150 (ORP150), a molecular chaperone that protects cells from ER stress. Sense ORP overexpression in the liver of obese diabetic mice significantly improved insulin resistance and markedly ameliorated glucose tolerance. Conversely, expression of antisense ORP150 in the liver of normal mice decreased insulin sensitivity. The phosphorylation state of IRS-1 and Akt, which are key molecules for insulin signaling, and the expression levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, key enzymes of gluconeogenesis, were also altered by ORP150 overexpression. This is the first report showing that ER stress plays a crucial role in the insulin resistance found in diabetes and thus could be a potential therapeutic target for diabetes.

To investigate the dose-dependent effect of free fatty acid (FFA) on the hepatic glucose uptake (HGU), we determined hepatic glucose fluxes by a dual tracer technique during the basal state and euglycemic hyperinsulinemic clamp combined with a portal glucose load in three groups of rats given saline (saline), low-dose lipid (lipid-L), or high-dose lipid infusion (lipid-H). In the basal state, lipid infusion dose-dependently increased plasma FFA (saline, 400 50; lipid-L, 550 30; lipid-H, 1700 +/- 270 mumol l(-1); mean +/-S.E). Endogenous glucose production (EGP) in lipid-H was 63.5 +/- 5.5 mumol kg(-1) min(-1) and significantly higher than in the saline and lipid-L (40.2 +/- 12.9, 47.6 +/- 3.1 mumol kg(-1) min(-1), respectively). During euglycemic hyperinsulinemic clamp, plasma FFA decreased to 130 +/- 30 mumol l(-1) in saline, but remained at basal levels in lipid-L and lipid-H (470 +/- 30 and 1110 +/- 180 mumol l(-1), respectively). Insulin-suppressed EGP was complete in saline and lipid-L, but impaired in lipid-H (38.0 +/- 6.4 mumol kg(-1) min(-1)). Elevated FFA dose-dependently reduced HGU (saline, 12.2 +/- 0.9; lipid-L, 8.6 +/- 0.6; lipid-H, 4.7 +/- 1.4 mumol kg(-1) min(-1)). In conclusion, acutely elevated FFA impairs HGU as well as insulin-mediated suppression of EGP during hyperinsulinemic clamp with portal glucose loading. Impaired hepatic glucose uptake associated with elevated FFA may contribute to the development of insulin resistance in obesity and type 2 diabetes. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

The c-Jun N-terminal kinase (JNK) pathway is known to be activated under diabetic conditions and to possibly be involved in the progression of insulin resistance. In this study, we examined the effects of modulation of the JNK pathway in liver on insulin resistance and glucose tolerance. Overexpression of dominant-negative type JNK in the liver of obese diabetic mice dramatically improved insulin resistance and markedly decreased blood glucose levels. Conversely, expression of wild type JNK in the liver of normal mice decreased insulin sensitivity. The phosphorylation state of crucial molecules for insulin signaling was altered upon modification of the JNK pathway. Furthermore, suppression of the JNK pathway resulted in a dramatic decrease in the expression levels of the key gluconeogenic enzymes, and endogenous hepatic glucose production was also greatly reduced. Similar effects were observed in high fat, high sucrose diet-induced diabetic mice. Taken together, these findings suggest that suppression of the JNK pathway in liver exerts greatly beneficial effects on insulin resistance status and glucose tolerance in both genetic and dietary models of diabetes.

The JNK pathway is known to be activated in several tissues in the diabetic state, and is possibly involved in the development of insulin resistance and suppression of insulin biosynthesis. Here we show a potential new therapy for diabetes using cell-permeable JNK-inhibitory peptide. Intraperitoneal administration of the peptide led to its transduction into various tissues in vivo, and this treatment markedly improved insulin resistance and ameliorated glucose tolerance in diabetic mice. These data indicate that the JNK pathway is critically involved in diabetes and that the cell-permeable JNK-inhibitory peptide may have promise as a new therapeutic agent for diabetes.

Oxidative stress is produced under diabetic conditions and is likely involved in progression of pancreatic P-cell dysfunction found in diabetes. Possibly due to low levels of antioxidant enzyme expressions, P-cells are vulnerable to oxidative stress. When beta-cell-derived cell lines or isolated rat islets were exposed to oxidative stress, insulin gene expression was markedly decreased. Furthermore, when diabetic C57BL/ KsJ-db/db mice were treated with antioxidants, glucose tolerance was ameliorated. Histological analyses of the pancreata revealed that the P-cell mass is significantly larger in the mice treated with the antioxidants. The antioxidant treatment also preserved the amounts of insulin content and insulin mRNA. As a possible mechanism underlying the phenomena, expression of pancreatic and duodenal homeobox factor-1 (PDX-1), an important transcription factor for the insulin gene, was more clearly visible in the nuclei of islet cells after the antioxidant treatment. Furthermore, oxidative stress induces nucleocytoplasmic translocation of PDX-1 through activation of the c-Jun N-terminal kinase (JNK) pathway, which leads to suppression of insulin gene expression. Taken together, oxidative stress and consequent activation of the JNK pathway are involved in progression of P-cell dysfunction found in diabetes, and thus are a therapeutic target for diabetes. (C) 2004 Prous Science. All rights reserved.

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophins, has been reported to ameliorate hyperglycemia in obese diabetic animal models. To elucidate the mechanism of BDNF on glucose metabolism, we determined the glucose turnover under basal and euglycemic hyperinsulinemic (insulin infusion rate, 54 pmol (.) kg(-1) (.) min(-1)) clamp conditions in obese insulin-resistant rats, male Zucker fatty rats, which had been acutely administered a subcutaneous injection of BDNF (20 mg/kg) (n = 9, BDNF) or vehicle (n = 8, vehicle). Under the basal condition, acute administration of BDNF did not affect the blood glucose level, plasma insulin level, rate of glucose disappearance (Rd), and endogenous glucose production (EGP). Under the clamp condition, the glucose infusion rate (GIR) was significantly higher in BDNF than in vehicle (mean +/- SD, 61.4 +/- 19.1 v 41.4 +/- 4.9 mumol (.) kg(-1) (.) min(-1), P < .05). There was no significant difference in Rd and EGP between the 2 groups under the clamp condition, but the insulin-mediated suppression ratio of endogenous glucose production in BDNF was significantly greater than in vehicle (48.9 +/- 22.2 v 22.4% +/- 20.6%, P < .05). In BDNF, mRNA expressions of hepatic phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) were comparable to those of vehicle, while hepatic glucokinase (GK) mRNA expression was significantly higher (1.57 +/- 0.33 v 1.03 +/- 0.17, P < .05). We conclude that BDNF mainly improves hepatic insulin resistance in obese insulin-resistant rats, probably by affecting the hepatic GK flux. Copyright 2003, Elsevier Science (USA). All rights reserved.

症例は53歳の男性でインスリン抵抗性糖尿病を有するWerner症候群の患者である. 空腹時インスリン値は24μU/mlと高値であり, euglycemic hyperinsulinemic clamp時のブドウ糖注入率 (GIR) は3.70mg/kg/minと低下していた. やせ型 (BMI14.2kg/m2), 体脂肪率の少ない (4.9%) 患者であったが, pioglitazone 30mg/日を投与したところ, 投与12週間後にGIRは5.20mg/kg/minと上昇し, 空腹時血糖値は187mg/dlから105mg/dlに低下, 1.5-anhydroglucitolは2.3μg/mlから4.4μg/mlと上昇した. 空腹時インスリン値は投与8週, 12週後に27μU/ml, 22μU/mlと変化は認めなかった. 血糖値の低下はインスリン感受性改善によるものと考えられ, 体脂肪の少ない本患者でもpioglitazoneが有効と考えられた. 以上のことより, 本患者では一般的に提唱されているthiazolidinedione系薬物の作用機序 (脂肪細胞のPPARγを活性化する) とは異なったメカニズムが働いていることが示唆された.

Patients with NIDDM (35 males and 21 females, mean age 57.2±12.2 years, BMI 24.9±4.5kg/m2, 25.9±9.5% body fat) were hospitalized and treated with diet plus exercise therapy for 2 weeks. Serum leptin levels (lep) were significantly higher in females than in males (5.4±4.1 vs 9.2±5.5 ng/dl, p = 0.0066). Lep was significantly decreased from 6.9+5.1 ng/dl to 5.4±4.1 ng/dl (p = 0.0066), but there were no gender differences in the changes in lep. Lep was positively correlated with body fat (r= 0.744, p< 0.0001), BMI (r=0.690, p< 0.0001), fasting insulin (r=0.375, p = 0.0048) and HOMA-IR (r=0.324, p=0.0160) on admission. However, there was no significant relationship between lep and any of the glycemic parameters. Body fat seemed to be a major determinant for lep. Furthermore, multiple regression analysis showed that insulin level was an independent determinant for lep. We have concluded that leptinemia in NIDDM was determined primarily by body fat and secondarily by the serum insulin level. Lep was significantly decreased in a subject who showed no change in weight for 2 weeks. We assume that this was related to calorie restriction. Therefore, we need to evaluate lep in NIDDM from the perspective of food intake. © 1999, THE JAPAN DIABETES SOCIETY. All rights reserved.

軽度肥満NIDDMでは食事療法,運動療法が治療の基本を成すが,これらの治療法にて血糖コントロール不良のため薬物療法を選択する場合には,SU剤に比べ,長期投与によりインスリン感受性改善作用を有するα-グルコシダーゼ阻害薬であるアカルボースが臨床的に有用である

インスリン分泌能が保持されたNIDDM患者におけるα-グルコシダーゼ阻害薬単独療法の血糖コントロール改善効果を薬価が同等であるacarbose 300mg/日とvoglibose 0.6mg/日にて比較・検討,acarboseの臨床的並びに経済的有用性が明かとなった

症例は53歳の男性でインスリン抵抗性糖尿病を有するWerner症候群の患者である. 空腹時インスリン値は24μU/mlと高値であり, euglycemic hyperinsulinemic clamp時のブドウ糖注入率 (GIR) は3.70mg/kg/minと低下していた. やせ型 (BMI14.2kg/m2), 体脂肪率の少ない (4.9%) 患者であったが, pioglitazone 30mg/日を投与したところ, 投与12週間後にGIRは5.20mg/kg/minと上昇し, 空腹時血糖値は187mg/dlから105mg/dlに低下, 1.5-anhydroglucitolは2.3μg/mlから4.4μg/mlと上昇した. 空腹時インスリン値は投与8週, 12週後に27μU/ml, 22μU/mlと変化は認めなかった. 血糖値の低下はインスリン感受性改善によるものと考えられ, 体脂肪の少ない本患者でもpioglitazoneが有効と考えられた. 以上のことより, 本患者では一般的に提唱されているthiazolidinedione系薬物の作用機序 (脂肪細胞のPPARγを活性化する) とは異なったメカニズムが働いていることが示唆された.

In diabetes, ASK-JNK pathway is considerably involved to oxidative stress and endoplasmic reticulum stress. So, we could think that this pathway was key pathway to improve insulin resistance. Moreover, to adjust this ASK-JNK pathway it can become a therapeutic target to type 2 diabetic patients, and it expects a possibility that this intervention will lead to prevention and slowly progression of diabetic complication in the future.