Effect of preceding drug therapy on the renal and cardiovascular outcomes of combined sodium-glucose cotransporter-2 inhibitor and glucagon-like peptide-1 receptor agonist treatment in patients with type 2 diabetes and chronic kidney disease.

AIM: To conduct a post hoc subgroup analysis of patients with type 2 diabetes (T2D) from the RECAP study, who were treated with sodium-glucose cotransporter-2 (SGLT2) inhibitor and glucagon-like peptide 1 receptor agonist (GLP-1RA) combination therapy, focusing only on those patients who had chronic kidney disease (CKD), to examine whether the composite renal outcome differed between those who received SGLT2 inhibitor treatment first and those who received a GLP-1RA first. METHODS: We included 438 patients with CKD (GLP-1RA-first group, n = 223; SGLT2 inhibitor-first group, n = 215) from the 643 T2D patients in the RECAP study. The incidence of the composite renal outcome, defined as progression to macroalbuminuria and/or a ≥50% decrease in estimated glomerular filtration rate (eGFR), was analysed using a propensity score (PS)-matched model. Furthermore, we calculated the win ratio for these composite renal outcomes, which were weighted in the following order: (1) both a ≥50% decrease in eGFR and progression to macroalbuminuria; (2) a decrease in eGFR of ≥50% only; and (3) progression to macroalbuminuria only. RESULTS: Using the PS-matched model, 132 patients from each group were paired. The incidence of renal composite outcomes did not differ between the two groups (GLP-1RA-first group, 10%; SGLT2 inhibitor-first group, 17%; odds ratio 1.80; 95% confidence interval [CI] 0.85 to 4.26; p = 0.12). The win ratio of the GLP-1RA-first group versus the SGLT2 inhibitor-first group was 1.83 (95% CI 1.71 to 1.95; p < 0.001). CONCLUSION: Although the renal composite outcome did not differ between the two groups, the win ratio of the GLP-1RA-first group versus the SGLT2 inhibitor-first group was significant. These results suggest that, in GLP-1RA and SGLT2 inhibitor combination therapy, the addition of an SGLT2 inhibitor to baseline GLP-1RA treatment may lead to more favourable renal outcomes.

Influence of the combination of SGLT2 inhibitors and GLP-1 receptor agonists on eGFR decline in type 2 diabetes: post-hoc analysis of RECAP study.

Accumulating evidence has demonstrated that both SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1Ra) have protective effects in patients with diabetic kidney disease. Combination therapy with SGLT2i and GLP1Ra is commonly used in patients with type 2 diabetes (T2D). We previously reported that in combination therapy of SGLT2i and GLP1Ra, the effect on the renal composite outcome did not differ according to the preceding drug. However, it remains unclear how the initiation of combination therapy is associated with the renal function depending on the preceding drug. In this post hoc analysis, we analyzed a total of 643 T2D patients (GLP1Ra-preceding group, n = 331; SGLT2i-preceding group, n = 312) and investigated the differences in annual eGFR decline. Multiple imputation and propensity score matching were performed to compare the annual eGFR decline. The reduction in annual eGFR decline in the SGLT2i-preceding group (pre: -3.5 ± 9.4 mL/min/1.73 m2/year, post: -0.4 ± 6.3 mL/min/1.73 m2/year, p < 0.001), was significantly smaller after the initiation of GLP1Ra, whereas the GLP1Ra-preceding group tended to slow the eGFR decline but not to a statistically significant extent (pre: -2.0 ± 10.9 mL/min/1.73 m2/year, post: -1.8 ± 5.4 mL/min/1.73 m2/year, p = 0.83) after the initiation of SGLT2i. After the addition of GLP1Ra to SGLT2i-treated patients, slower annual eGFR decline was observed. Our data raise the possibility that the renal benefits-especially annual eGFR decline-of combination therapy with SGLT2i and GLP1Ra may be affected by the preceding drug.

The concomitant use of sodium-glucose co-transporter 2 inhibitors improved the renal outcome of Japanese patients with type 2 diabetes treated with glucagon-like peptide 1 receptor agonists.

Aims: This study aimed to clarify the renal influence of glucagon-like peptide 1 receptor agonists (GLP1Ras) with or without sodium-glucose co-transporter 2 inhibitors (SGLT2is) on Japanese patients with type 2 diabetes mellitus (T2DM). Methods: We retrospectively extracted 547 patients with T2DM who visited the clinics of members of Kanagawa Physicians Association. The progression of albuminuria status and/or a ≥ 15% decrease in the estimated glomerular filtration rate (eGFR) per year was set as the renal composite outcome. Propensity score matching was performed to compare GLP1Ra-treated patients with and without SGLT2i. Results: After matching, 186 patients in each group were compared. There was no significant difference of the incidence of the renal composite outcomes (17% vs. 20%, P = 0.50); however, the annual decrease in the eGFR was significantly smaller and the decrease in the urine albumin-to-creatinine ratio was larger in GLP1Ra-treated patients with the concomitant use of SGLT2is than in those without it (-1.1 ±â€…5.0 vs. -2.8 ±â€…5.1 mL/min/1.73 m2, P = 0.001; and -0.08 ±â€…0.61 vs. 0.05 ±â€…0.52, P = 0.03, respectively). Conclusion: The concomitant use of SGLT2i with GLP1Ra improved the annual decrease in the eGFR and the urine albumin-to-creatinine ratio in Japanese patients with T2DM.

Renoprotective effects of combination treatment with sodium-glucose cotransporter inhibitors and GLP-1 receptor agonists in patients with type 2 diabetes mellitus according to preceding medication.

AIMS: Combination therapy with sodium-glucose cotransporter inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1Ras) is now of interest in clinical practice. The present study evaluated the effects of the preceding drug type on the renal outcome in clinical practice. METHODS: We retrospectively extracted type 2 diabetes mellitus patients who had received both SGLT2i and GLP1Ra treatment for at least 1 year. A total of 331 patients in the GLP1Ra-preceding group and 312 patients in the SGLT2i-preceding group were ultimately analyzed. Either progression of the albuminuria status and/or a ≥30% decrease in the eGFR was set as the primary renal composite outcome. The analysis using propensity score with inverse probability weighting was performed for the outcome. RESULTS: The incidences of the renal composite outcome in the SGLT2i- and GLP1Ra-preceding groups were 28% and 25%, respectively, with an odds ratio [95% confidence interval] of 1.14 [0.75, 1.73] (p = .54). A logistic regression analysis showed that the mean arterial pressure (MAP) at baseline, the logarithmic value of the urine albumin-to-creatinine ratio at baseline, and the change in MAP were independent factors influencing the renal composite outcome. CONCLUSION: With combination therapy of SGLT2i and GLP1Ra, the preceding drug did not affect the renal outcome.

Nivolumab-induced fulminant type 1 diabetes with precipitous fall in C-peptide level.

We describe here a case of nivolumab-induced type 1 diabetes, which developed within 9 days of treatment. The case highlights the importance of frequent monitoring of glucose after initiation of nivolumab treatment.

Detection of Autonomic Nervous System Abnormalities in Diabetic Patients by 24-hour Ambulatory Blood Pressure Monitoring.

OBJECTIVE: To determine the relationship between 24-hr blood pressure (BP) fluctuations and autonomic nervous system dysfunction in diabetic patients using non-invasive ambulatory blood-pressure monitoring (ABPM) system. METHODS: The subjects were 39 diabetic patients free of cardiovascular diseases. 24-hr BP was monitored by a non-invasive ABPM system. The relationships among 24-hr BP fluctuations and various clinical parameters relevant to diabetes and hypertension were analyzed. RESULTS: Patients were divided into the diurnal hypertension (DH, n=4), diurnal and nocturnal hypertension (DNH, n=9), normotension (N, n=14), and nocturnal hypertension (NH, n=12) groups. DH and/or NH was observed in 25 (64%) patients: 13 had DH (≥135/85 mmHg), 21 had NH (≥120/70 mmHg), and 9 had both. Furthermore, 4 patients with DH but no NH (diurnal/nocturnal+/ - ); 9 (+/+); 14 ( - / - ); and 12 ( - /+). The R-R interval coefficient of variation on the EKG (CV-RR) was significantly different among the groups (N>NH>DNH>DH). CONCLUSION: Autonomic nervous system dysfunction in diabetic patients had a negative influence on 24-hr fluctuations in BP. Monitoring nighttime hypertension and daily BP variation using ABPM diabetic is a potentially useful approach for identifying autonomic nervous system dysfunction and associated abnormal BP patterns that cannot be detected by routine check-ups.

Atypical Ketoacidosis and Protracted Hyperglycosuria after Treatment with Ipragliflozin, an SGLT2 Inhibitor.

We herein present the case of a 21-year-old diabetic obese woman who developed ketoacidosis following the administration of ipragliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor. At the time of admission, although her serum glucose level was only 175 mg/dL, laboratory tests showed ketoacidosis. Interestingly, hyperglycosuria persisted, even after the discontinuation of ipragliflozin. This is the first report of non-hyperglycemic ketoacidosis that might have been caused by protracted hyperglycosuria after the discontinuation of ipragliflozin. The development of non-hyperglycemic ketoacidosis should be monitored following the discontinuation of SGLT2 inhibitors, especially in patients who start to feel unwell and exhibit protracted hyperglycosuria after the discontinuation of treatment.

Glomerular expression of CTGF, TGF-beta 1 and type IV collagen in diabetic nephropathy.

BACKGROUND: In development of progressive extracellular matrix accumulation, connective tissue growth factor (CTGF) may act as a downstream mediator of transforming growth factor-beta 1 (TGF-beta 1). However, the association and the correlation of these cytokines and extracellular matrix accumulation in human diabetic nephropathy (DN) is not fully understood. METHODS: To explore the possible involvement of TGF-beta 1 and CTGF in extracellular matrix accumulation in DN, high-resolution in situ hybridization with digoxigenin-labeled antisense oligonucleotides to CTGF, TGF-beta 1 and type IV collagen mRNAs were performed in DN and in histologically normal human kidney (NHK). To quantify expression of each mRNA, the fraction of all nuclear cells that were positively stained in the cytoplasm was determined in at least 10 randomly selected cross-sections of nonsclerotic glomeruli. RESULTS: Both in DN and in NHK, CTGF, TGF-beta 1 and type IV collagen mRNAs were mainly expressed by glomerular mesangial, visceral epithelial and parietal epithelial cells. The percentages of positive glomerular resident cells were significantly higher for each mRNA in DN compared with NHK. Especially, the expression of CTGF mRNA was also notably increased in case of DN with only mild histopathologic lesions. The extent of expression of each mRNA was significantly correlated to that of each other mRNA examined. CONCLUSION: Our study indicated that CTGF and TGF-beta may play an important role in glomerular histopathologic change in DN.

[Case of rheumatoid arthritis with various histological lesions of the kidney].

We experienced a case of rheumatoid arthritis with nephrotic syndrome. A renal biopsy specimen from this patient showed various renal histological changes. The patient was a 50-year-old man who was diagnosed as having rheumatoid arthritis in 1987. We performed a renal biopsy because he had persistent proteinuria from March in 2002. The renal biopsy specimen showed amyloid AA and P protein deposition in the glomeruli. Moreover mild mesangial proliferation was recognized. IgA-deposition in the mesangial area, and granular-deposition of IgG along the glomerular capillary wall were also observed. In electron microscopy, electron dense deposits were recognized in the mesangial area and subepithelium of the glomerular basement membrane. From these findings, we diagnosed amyloid nephropathy, IgA nephritis and membranous nephropathy. Renal biopsy of patients with RA is useful not only for precise diagnosis, but also for selection of the appropriate treatment.

[Clinical significance of IgM deposition in the mesangium and mesangial hypercellularity in adult minimal change nephrotic syndrome].

Minimal change nephrotic syndrome(MCNS) typically shows no abnormalities in light microscopy. However, there are some minor light microscopic abnormalities that are considered to be MCNS variants. In pediatric nephrology, some researchers have reported that IgM deposition in the mesangium and mesangial hypercellularity are related to the response to steroid therapy and the long-term course. However, it is not clear whether IgM deposition in the mesangium and mesangial hypercellularity is responsible for the clinical course or the steroid response of patients with adult MCNS. To investigate the clinical importance of IgM deposition in the mesangium and mesangial hypercellularity, clinical records, follow up data, and renal samples of 47 patients with MCNS were reviewed. We also compared the histological data with those of a normal control group (n = 5). In our study, the presence of mesangial IgM deposition did not predict the patient's clinical course or responsiveness to steroid therapy. Increase in the number of nuclei in the glomeruli and PAS-positive area also did not correlate with the clinical course or responsiveness to steroid therapy. The data suggest that mesangial IgM deposits and increased mesangial cellularity in adult MCNS may not predict the clinical course or steroid response. However, we investigated only 47 samples in this study, therefore, further studies are necessary to identify the importance of IgM deposition in the mesangium and mesangial hypercellularity in adult MCNS.

Exercise Therapy for Management of Type 2 Diabetes Mellitus: Superior Efficacy of Activity Monitors over Pedometers.

We compared the efficacy of activity monitor (which displays exercise intensity and number of steps) versus that of pedometer in exercise therapy for patients with type 2 diabetes. The study subjects were divided into the activity monitor group (n = 92) and pedometer group (n = 95). The primary goal was improvement in hemoglobin A1c (HbA1c). The exercise target was set at 8,000 steps/day and 20 minutes of moderate-intensity exercise (≥3.5 metabolic equivalents). The activity monitor is equipped with a triple-axis accelerometer sensor capable of measuring medium-intensity walking duration, number of steps, walking distance, calorie consumption, and total calorie consumption. The pedometer counts the number of steps. Blood samples for laboratory tests were obtained during the visits. The first examination was conducted at the start of the study and repeated at 2 and 6 months. A significant difference in the decrease in HbA1c level was observed between the two groups at 2 months. The results suggest that the use of activity level monitor that displays information on exercise intensity, in addition to the number of steps, is useful in exercise therapy as it enhances the concept of exercise therapy and promotes lowering of HbA1c in diabetic patients.

Upregulation of α3ß1-Integrin in Podocytes in Early-Stage Diabetic Nephropathy.

Background. Podocyte injury plays an important role in the onset and progression of diabetic nephropathy (DN). Downregulation of α3ß1-integrin expression in podocytes is thought to be associated with podocyte detachment from the glomerular basement membrane, although the mechanisms remain obscure. To determine the mechanism of podocyte detachment, we analyzed the expression levels of α3ß1-integrin in podocytes in early and advanced stages of DN. Methods. Surgical specimens from DN patients were examined by in situ hybridization, and the expression levels of α3- and ß1-integrin subunits in glomeruli of early (n = 6) and advanced (n = 8) stages were compared with those of normal glomeruli (n = 5). Heat-sensitive mouse podocytes (HSMP) were cultured with TGF-ß1 to reproduce the microenvironment of glomeruli of DN, and the expression levels of integrin subunits and the properties of migration and attachment were examined. Results. Podocytes of early-stage DN showed upregulation of α3- and ß1-integrin expression while those of advanced stage showed downregulation. Real-time PCR indicated a tendency for upregulation of α3- and ß1-integrin in HSMP cultured with TGF-ß1. TGF-ß1-stimulated HSMP also showed enhanced in vitro migration and attachment on collagen substrate. Conclusions. The results suggested that podocyte detachment during early stage of DN is mediated through upregulation of α3ß1-integrin.

Long-term glycemic control in Japanese type 2 diabetes patients after switching treatment from twice-daily premixed insulin to once daily insulin glargine.

OBJECTIVE: To examine the clinical utility of once-daily insulin glargine, we studied the clinical course of patients who were switched to from twice-daily premixed insulin to once daily insulin glargine. METHODS: The study was conducted at Tokai University hospital in 20 patients with type 2 diabetes, whose treatment regimens were switched from twice-a-day premixed insulin formulation to once-a-day insulin glargine. Changes in various clinical indexes were studied during a 3-year period after the switch. We also compared the well-controlled group (hemoglobin A1c, HbA1c, levels maintained at less than 6.9%) and poorly-controlled group (HbA1c levels at 7.4% or higher). RESULTS: During the 3-year period, all patients showed significant decrease in HbA1c levels and tendency for reduced daily dose of insulin. Although both BMI and insulin dose tended to decrease in the well-controlled group, they increased in the poorly controlled group. CONCLUSION: The findings suggest that in type 2 diabetes, once-a-day insulin glargine could be more useful than twice-a-day premixed insulin formulation. Poor adherence was observed in the poorly-controlled group, namely lack of thoroughness in self-monitoring of blood glucose and adherence to diet and exercise therapy, thus emphasizing the importance of diabetes education.

Effects of liraglutide, a human glucagon-like peptide-1 analogue, on body weight, body fat area and body fat-related markers in patients with type 2 diabetes mellitus.

OBJECTIVE: To evaluate the effects of six-month liraglutide treatment on body weight, visceral and subcutaneous fat and related markers in Japanese type 2 diabetic patients. METHODS: A total of 59 patients with type 2 diabetes were treated with liraglutide (0.3 mg/day for ≥1 week and then 0.6 mg/day for ≥1 week, gradually increasing the dose to 0.9 mg/day) for six months. Changes in body weight, body mass index (BMI), HbA1c, the fasting blood glucose level, visceral and subcutaneous fat areas, hepatic and renal CT values and the associated markers proinsulin, adiponectin and pentraxin (PTX) 3 were measured. RESULTS: The study included one treatment-naïve patient, 10 patients who were switched from oral antidiabetic drugs and 35 patients who were switched from insulin therapy. At six months after treatment, the preprandial blood glucose levels were higher (148.8±40.5 mg/dL) than the baseline values (130.8±36.7, p<0.05); however, body weight, BMI and abdominal circumference were lower, and the liver/kidney CT ratio improved significantly from 1.64±0.44 at baseline to 1.78±0.42. An analysis of the patients who were not pretreated with insulin resistance ameliorators showed that six months of liraglutide treatment significantly decreased the subcutaneous but not visceral fat areas, significantly decreased the serum adiponectin levels and significantly increased the serum PTX3 levels. CONCLUSION: In addition to its glucose-lowering effects, liraglutide exhibits weight loss promotion actions, reducing subcutaneous fat areas in particular. The weight and total fat area reduction properties of liraglutide are likely to be beneficial when this medication is used in combination with other oral antidiabetic drugs and insulin.

Insulin glargine improves glycemic control and quality of life in type 2 diabetic patients on hemodialysis.

BACKGROUND: Diabetic patients on hemodialysis often experience severe hypoglycemia during intensive insulin therapy using conventional neutral protamine hagedorn (NPH) or nonintensive therapy with premixed insulin. Insulin glargine can simulate normal basal insulin secretion. We investigated the efficacy and safety of switching from NPH to glargine in type 2 diabetes patients on hemodialysis. METHODS: Hemodialysis patients who were being treated with NPH-based basal-bolus insulin therapy, regular insulin, NPH insulin or premixed insulin were switched to glargine. The target early morning fasting blood glucose (FBG) level was 110 mg/dL. Any increase in glargine dose was coupled with a reduction in the dose of any regular or rapid-acting insulin analogue as far as possible while maintaining a constant daily insulin dose. FBG, HbA(1c), daily insulin dosage, percentage of basal insulin dose in total daily insulin dose, body weight and incidence of hypoglycemic events were evaluated during the study period. Quality of life (QOL) was measured with a short questionnaire. RESULTS: HbA(1c) improved significantly during the observation period after switching. The daily insulin dose was reduced from 20.1 ± 15.2 to 18.1 ± 15.1 U/day, although the change was not statistically significant. FBG decreased significantly from 174.4 ± 58.7 to 126.2 ± 27.7 mg/dL. Body weight measured after dialysis did not change, and there were no changes in hemoglobin or hematocrit. The frequency of hypoglycemic episodes decreased significantly. QOL reports with switching to glargine were improved compared with those before switching. CONCLUSION: The results suggest that glargine is useful, can improve QOL of diabetic patients on hemodialysis, and achieve better glycemic control than NPH.

Expression of transcription factor Snai1 and tubulointerstitial fibrosis in progressive nephropathy.

BACKGROUND: Tubulointerstitial fibrosis (TIF) is seen as the final stage of progressive nephropathy, and the degree of TIF is reported to be a major determinant in renal outcomes. In recent years, epithelial-mesenchymal transition (EMT) and the zinc-finger transcription factor snail homolog 1 (Snai1) have each been implicated in the mechanism of TIF. The relationship between EMT and these transcription factors is unclear, however, so in this study we attempted to elucidate the correlation between the expression of Snai1 and clinical markers. METHODS: We performed immunohistochemical staining on human renal tissue obtained from patients with diabetic nephropathy (DN), IgA nephropathy (IgAN), minimal change disease (MCD) and minor glomerular abnormality (MGA) using anti-Snai1 and anti-vimentin antibodies. We counted Snai1-positive and Snai1/vimentin double positive tubular epithelial cells. RESULTS: Snai1 protein was mainly observed in the nuclei of flattened, damaged tubular epithelial cells, especially in IgAN and DN, and positive cell numbers were significantly higher in IgAN than in MGA, MCD or DN. Snai1/vimentin double staining showed that some vimentin-positive tubular epithelial cells also contained Snai1-positive nuclei, and double positive cell numbers were increased in IgAN and DN. Statistical analysis revealed positive correlations between Snai1/vimentin double positive cell numbers and proteinuria and creatinine in IgAN. Positive correlations were also seen between Snai1/vimentin double positive cell numbers and the severity of proteinuria in DN. CONCLUSIONS: The results of this study indicate that Snai1 plays an important role in TIF in patients with progressive nephropathy.

Efficacy of long-acting insulin analog insulin glargine at high dosage for basal-bolus insulin therapy in patients with type 2 diabetes.

OBJECTIVE: Attempts to achieve strict glycemic control with basal-bolus insulin therapy required increased dosages of neutral protamine Hagedorn (NPH) insulin. However, high dosage of NPH insulin often occurs nocturnal hypoglycemia. Insulin glargine can simulate normal basal insulin secretion with its flat time-action profiles. To confirm the efficacy of insulin glargine we investigated the type 2 diabetic patients on basal-bolus insulin therapy whose basal insulin was switched from NPH insulin to insulin glargine. METHODS: The Japanese 400 patients with type 2 diabetes on basal-bolus insulin therapy whose basal insulin was switched from NPH insulin to insulin glargine were followed-up. After the switching, the basal insulin was increased with reference to the self-monitoring of blood glucose results, with the aim of maintaining fasting blood sugar (FBS) level at 110 mg/dL, and simultaneously reducing the bolus insulin dosage to maintain the total daily insulin dosage. RESULTS: We were able to lower FBS significantly with almost no serious hypoglycemia. HbA1c also improved significantly. The improvements in FBS and HbA1c levels did not require a significant increase in the total insulin dosage. CONCLUSION: Our results suggest that basal insulin supplementation using insulin glargine is a useful method to control not only FBS but also HbA1c.

Effectiveness of basal-supported oral therapy (BOT) using insulin glargine in patients with poorly controlled type 2 diabetes.

OBJECTIVE: To determine the clinical usefulness of basal-supported oral therapy (BOT) using insulin glargine in Japanese patients with type 2 diabetes. METHODS: We compared HbA1c levels, body weight, and insulin doses before the introduction of BOT and in the final month of the observation period in 122 patients with type 2 diabetes who received BOT with insulin glargine between October 2007 and July 2009. To exclude the possible effects of seasonal changes in glycemic control, 57 of the 122 patients were followed-up for one year and examined for changes in HbA1c levels, body weight, and insulin dose. RESULTS: Examination of all cases (n=122) showed a significant decrease in HbA1c (before BOT: 8.7±1.8, after: 7.1±1.1%), but no significant change in body weight (before: 63.1±16.1, after: 63.8±17.0 kg). The mean observation period was 10.5±6.4 months. Insulin doses were significantly increased during the study. HbA1c levels improved significantly in patients on non-insulin-secreting drugs (biguanide, α-glucosidase inhibitor and thiazolidine derivatives) than those on insulin-secreting drugs (SU agents and glinides). CONCLUSION: BOT with insulin glargine is a useful strategy that can achieve good glycemic control in clinical practice without causing serious hypoglycemia. The introduction of BOT before exhaustion of pancreatic ß cells may increase its effectiveness.

Lectin-like oxidized LDL receptor-1 (LOX-1) expression in the tubulointerstitial area likely plays an important role in human diabetic nephropathy.

OBJECTIVE: Diabetic nephropathy (DN) is a common cause of end-stage renal disease. However, the precise mechanism of DN, which involves the role of lipid, is still not fully understood. Lectin-like oxidized LDL receptor-1 (LOX-1) is a type II single-transmembrane protein that binds oxidized low density lipoprotein (Ox-LDL). This study examined the expression of LOX-1 mRNA in renal tissues from type 2 diabetes patients with DN using in situ hybridization (ISH). PATIENTS AND METHODS: Renal tissues were obtained from 15 type 2 patients with DN and 5 minimal change nephrotic syndrome (MCNS), membranous nephropathy (MN) and normal human kidney (NHK). Glomerular and tubulointerstitial LOX-1 mRNA expression was evaluated by ISH. Results The cells positive for LOX-1 mRNA were identified in the glomeruli of DN, MCNS, MN and NHK, however, there was no positive signal in the tubulointerstitial area in MCNS and NHK. Some cells positive for LOX-1 mRNA were detectable in the tubulointerstitial area in DN and MN. In the results of glomerular staining, there was no significant difference between them. There was a significant correlation between the tubulointerstitial LOX-1 expression and the degree of the tubulointerstitial damage and urinary protein in DN. CONCLUSION: Increased expression of LOX-1 mRNA in the tubulointerstitial area may be closely linked to the development and progression of human DN, and in particular the tubulointerstitial damage.

Hypertrophy and loss of podocytes in diabetic nephropathy.

OBJECTIVE: The loss of podocytes has been reported to have a role in the onset and progression of diabetic nephropathy (DN). Although structural changes such as podocyte hypertrophy are considered to be associated with podocyte loss, the relationship has not been thoroughly investigated using human DN renal tissues. METHODS: The subjects were 17 patients with DN diagnosed histopathologically by renal biopsy. Immunostaining was performed with antibodies for Wilm's tumor 1 (WT1) and synaptopodin (SPD), which are markers of podocytes, to determine the number of podocytes and assess podocyte hypertrophy. RESULTS: The number of podocytes was decreased in DN patients compared with the controls. An inverse correlation was observed between the number of podocytes and both the urinary protein excretion and the extent of mesangial expansion. Podocyte hypertrophy was also more marked in DN patients compared with controls. CONCLUSION: Based on these results, podocyte loss and hypertrophy were suggested to be involved in the development and progression of human DN.