Antiatherogenic effect of pioglitazone in type 2 diabetic patients irrespective of the responsiveness to its antidiabetic effect

WSTĘP. Tiazolidinediony (TZD) to grupa leków zwiększających wrażliwość na insulinę, które stosuje się w leczeniu cukrzycy typu 2. Działają one także przeciwmiażdżycowo. Celem badania było wyjaśnienie zależności między przeciwmiażdżycowym a przeciwcukrzycowym działaniem pioglitazonu, leku z grupy TZD, u chorych na cukrzycę typu 2. MATERIAŁ I METODY. W badaniu wzięło udział 136 chorych na cukrzycę typu 2 narodowości japońskiej. Uczestników podzielono na 2 grupy: chorych leczonych pioglitazonem w dawce 30 mg na dobę przez 3 miesiące (n = 70) oraz pacjentów niepoddanych leczeniu (grupę kontrolną, n = 66). Podczas badania kontrolowano zmiany metabolizmu glikolipidów, stężenia w osoczu białka C-reaktywnego (CRP, C-reactive protein), leptyny i adiponektyny oraz prędkość fali tętna (PWV, pulse-wave velocity), aby przeanalizować zależność między przeciwmiażdżycowym a przeciwcukrzycowym działaniem pioglitazonu. WYNIKI. U osób leczonych pioglitazonem stwierdzono istotne obniżenie hiperglikemii, hiperinsulinemii i stężenia HbA1c oraz wzrost stężenia adiponektyny w osoczu w porównaniu z grupą kontrolną (p < 0,01). Ponadto, odnotowano istotne obniżenie stężenia CRP i PWV (p < 0,01). Przeciwmiażdżycowe działanie pioglitazonu zaobserwowano zarówno u pacjentów, u których nie uzyskano poprawy wyrównania cukrzycy, a redukcja stężenia HbA1c wynosiła poniżej 1% (n = 30) (nonresponders, osoby niepodatne na leczenie), jak i u chorych z dobrą odpowiedzią na terapię (responders, osoby podatne na leczenie), u których redukcja stężenia HbA1c przekraczała 1% (n = 40). Stosując model ANCOVA wykazano, że leczenie pioglitazonem wiązało się z niskimi wartościami CRP i PWV, niezależnie od zmian parametrów związanych z metabolizmem glukozy. WNIOSKI. W omawianym badaniu po raz pierwszy przedstawiono przeciwmiażdżycowe działanie pioglitazonu zarówno u chorych podatnych, jak i niepodatnych na przeciwcukrzycowe działanie leku. Wyniki badania sugerują, że pioglitazon może wywierać efekt przeciwmiażdżycowy niezależnie od wpływu na glikemię.INTRODUCTION. Thiazolidinediones (TZD), a class of insulin-sensitizing agents used clinically to treat type 2 diabetes, are also antiatherogenic. This study was designed to elucidate the relationship between the antiatherogenic and antidiabetic effects of pioglitazone, a TZD, in type diabetic patients. MATERIAL AND METHODS. A total of 136 Japanese type 2 diabetic patients were included and divided into two groups: the pioglitazone-treated group (30 mg daily 3 months) (n = 70) and the untreated control group (n = 66). The changes in glycolipid metabolism as well as plasma high-sensitivity C-reactive protein (CRP), leptin, adiponectin, and pulse wave velocity (PWV) were monitored to analyze the relationship between the antiatherogenic and antidiabetic effects of pioglitazone. RESULTS. The pioglitazone treatment significantly reduced hyperglycemia, hyperinsulinemia, and HbA1c levels and increased plasma adiponectin concentrations relative to the control group (P < 0.01). It also significantly decreased CRP and PWV (P < 0.01). The antiatherogenic effect was observed in both the nonresponders showing < 1% of reduction in HbA1c (n = 30) and responders showing > 1% of reduction (n = 40). ANCOVA revealed that treatment with pioglitazone was associated with a low CRP and PWV, independent of the changes in parameters related to glucose metabolism. CONCLUSIONS. This study represents the first demonstration of the antiatherogenic effect of pioglitazone in both nonresponders and responders with respect to its antidiabetic effect and suggests that pioglitazone can exert its antiatherogenic effect independently of its antidiabetic effect

Nationwide multicentre kidney biopsy study of Japanese patients with type 2 diabetes

金沢大学医薬保健研究域医学系Background. The clinical and pathologic manifestations of nephropathy due to type 2 diabetes are diverse, but large-scale pathologic studies with long-termobservations are limited. Methods. Kidney biopsies and clinical data of 600 patients with type 2 diabetes were collected retrospectively from 13 centres across Japan. Thirteen pathologic findings (nine glomerular lesions, two interstitial lesions and two vascular lesions) were clearly defined and scored. Results. During the observation period, there were 304 composite kidney events [dialysis, doubling of creatinine or reduction of estimated glomerular filtration rate (eGFR) by half], 31 instances of chronic kidney disease (CKD) G5D, 76 cardiovascular events and 73 deaths. The mean observation period was 72.4 months. The distribution of CKD heat map categories for the 600 patients was 103 green or yellow, 149 orange and 348 red. Even in the cases in the green and yellow category, diffuse lesions (81.6%), polar vasculosis (42.6%) and subendothelial space widening (35.1%) were commonly detected. Cox proportional hazard analysis revealed that the presence of nodular lesions [hazard ratio (HR) 21.1, 95% confidence interval (CI) 5.3-84.6], exudative lesions (HR 5.1, 95% CI 1.3-20.3) and mesangiolysis (HR 7.6, 95% CI 2.0-28.8) in cases in the green and yellow category were associated with significantly great impact on composite kidney events after adjustment for clinical risk factors. Conclusions. This nationwide study on kidney biopsy of 600 cases with type 2 diabetes revealed that pathologic findings (presence of nodular lesions, exudative lesions and mesangiolysis) were strong predictors of kidney events in low-risk patients. © The Author 2017.Embargo Period 12 month

Age-Related Renal Microvascular Changes: Evaluation by Three-Dimensional Digital Imaging of the Human Renal Microcirculation Using Virtual Microscopy

The renal microvasculature is targeted during aging, sometimes producing chronic kidney disease (CKD). Overdiagnosis of CKD in older persons is concerning. To prevent it, a new concept of “healthy aging” is arising from a healthy renal donor study. We investigated the renal microcirculatory changes of three older persons and compared them with that of one patient with nephrosclerosis using a three-dimensional (3D) reconstruction technique that we previously developed. This method uses a virtual slide system and paraffin-embedded serial sections of surgical material that was double-immunostained by anti-CD34 and anti-α smooth muscle actin (SMA) antibodies for detecting endothelial cells and medial smooth muscle cells, respectively. In all cases, the 3D images proved that arteriosclerotic changes in large proximal interlobular arteries did not directly induce distal arterial change or glomerulosclerosis. The nephrosclerotic patient showed severe hyalinosis with luminal narrowing of small arteries directly inducing glomerulosclerosis. We also visualized an atubular glomerulus and intraglomerular dilatation of an afferent arteriole during healthy aging on the 3D image and showed that microcirculatory changes were responsible for them. Thus, we successfully visualized healthy aged kidneys on 3D images and confirmed the underlying pathology. This method has the ability to investigate renal microcirculatory damage during healthy aging

High-resolution three-dimensional digital imaging of human renal microcirculation

科学研究費助成事業 研究成果報告書：基盤研究(C)2011-2014 課題番号：2359117

Membranous glomerulonephritis in a patient with anti-u1 ribonucleoprotein (RNP) antibody-positive mixed connective tissue disease: A case report

We report a 33-year-old Japanese man diagnosed with mixed connective tissue disease (MCTD) who developed nephrotic proteinuria. Both speckled antinuclear antibody (ANA) and anti-U1 ribonucleoprotein (RNP) antibody were positive, but anti-double-stranded DNA (dsDNA) antibody and anti-Smith (Sm) antibody were negative, while complement levels were normal. Renal biopsy revealed membranous glomerulonephritis (MGN) with diffuse thickening of the glomerular basement membrane (GBM) plus spike and bubble formation. Immunofluorescence demonstrated granular deposits of IgG and C3 along the GBM. Analysis of IgG subclasses showed predominant deposition of IgG1 and IgG4, unlike typical lupus nephritis in which there is predominant deposition of IgG1, IgG2, IgG3, and C1q. Electron microscopy identified numerous large electron-dense deposits (EDD) of various types in the subepithelial region of the GBM, but there were no EDD localized in the mesangium or subendothelium. Based on these findings, MGN was considered to be closely related to MCTD in this patient