Diabetes-induced hyperfiltration in adenosine A(1)-receptor deficient mice lacking the tubuloglomerular feedback mechanism

AIMS: Glomerular hyperfiltration is commonly found in diabetic patients early after the onset of disease. This is one of the first indications of the development of progressive diabetic nephropathy. It has been proposed that glomerular hyperfiltration is caused by decreased delivery of electrolytes to the macula densa due to the increased sodium and glucose reabsorption in the proximal tubule, which would increase the glomerular filtration rate (GFR) via the tubuloglomerular feedback (TGF) mechanism. In this study, we investigated the role of TGF in diabetes-induced glomerular hyperfiltration by inducing diabetes in adenosine A(1)-receptor knockout (A1AR(-/-)) mice known to lack a functional TGF mechanism. METHODS: Diabetes was induced by alloxan (75 mg kg(-1) bw) injected into the tail vein. The 24-hour urinary electrolyte excretion was measured in metabolic cages, the GFR determined by inulin clearance under isoflurane-anaesthesia, and histological changes evaluated. RESULTS: All alloxan-treated animals developed hyperglycaemia (> or =20 mm). Normoglycaemic animals had a similar GFR independent of genotype (A1AR(+/+) 9.3 +/- 0.5 vs. A1AR(-/-) 10.1 +/- 0.8 microL min(-1)g(-1) bw) and diabetes resulted in similar glomerular hyperfiltration in both groups (A1AR(+/+) 14.0 +/- 1.7, n = 9 vs. A1AR(-/-) 15.3 +/- 1.9 microL min(-1)g(-1) bw). Diabetic animals had a similar tendency to develop interstitial fibrosis, whereas the glomerular volume was similar in both genotypes, and unaltered by diabetes. CONCLUSIONS: This study shows that the A1AR(-/-) mice develop diabetes-induced glomerular hyperfiltration, demonstrating that the TGF mechanism is not the major cause of the development of hyperfiltration. Furthermore, the hyperfiltration in the present study was not related to alterations in the glomerular filtration area.     

Effect of strict glycemic control on renal hemodynamic response to amino acids and renal enlargement in insulin-dependent diabetes mellitus

BACKGROUND. Many patients with insulin-dependent diabetes mellitus have an increase in the glomerular filtration rate and renal enlargement early in the course of their disease. Both these changes may be risk factors for the later development of diabetic nephropathy. Their cause is not known, but they could be due to augmented renal responses to the increase in plasma amino acid concentrations that occurs when dietary protein intake is high, a factor known to increase glomerular filtration and renal blood flow in normal subjects. METHODS. We measured the glomerular filtration rate and renal plasma flow after an overnight fast and during an infusion of amino acids in 12 patients with insulin-dependent diabetes mellitus and 9 normal subjects. The diabetic patients were studied when they were hyperglycemic, when they were euglycemic after an insulin infusion for 36 hours, and after intensive insulin therapy for 3 weeks. Kidney volume was measured by ultrasonography before and after the period of intensive insulin therapy. RESULTS. The glomerular filtration rate and renal plasma flow were normal after fasting when the patients were hyperglycemic (mean [+/- SE] fasting plasma glucose level, 11.5 +/- 0.7 mmol per liter). After the amino acid infusion, these values increased more in the patients (glomerular filtration rate, 2.65 +/- 0.07 ml per second per 1.73 m2 of body-surface area; renal plasma flow, 13.30 +/- 0.68 ml per second per 1.73 m2; P less than 0.05 for both) than in the normal subjects (2.25 +/- 0.08 and 11.20 +/- 0.65 ml per second per 1.73 m2, respectively). The 36-hour infusion of insulin in the diabetic patients did not alter the glomerular filtration rate or renal plasma flow either before or during the amino acid infusion. After three weeks of intensive insulin therapy (fasting plasma glucose level, 5.3 +/- 0.2 mmol per liter), the glomerular filtration rate and renal plasma flow after the amino acid infusion (2.33 +/- 0.03 and 11.30 +/- 0.43 ml per second per 1.73 m2, respectively) were similar to those in the normal subjects. The kidney volumes in the normal subjects and the patients with diabetes were 219 +/- 14 and 312 +/- 14 ml per 1.73 m2, respectively (P less than 0.01); the volume decreased to 267 +/- 22 ml per 1.73 m2 (P less than 0.001) in the diabetic patients after three weeks of intensive insulin therapy, which was not significantly different from the volume in the normal subjects (P = 0.1). CONCLUSIONS. Conventionally treated diabetic patients who have normal renal function while fasting have augmented renal hemodynamic responses to increased plasma amino acid concentrations. The concomitant decrease in these hemodynamic responses and in kidney size with strict glycemic control suggests that these phenomena are related and influenced by the metabolic state.     

The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes

The microvascular complications of diabetes mellitus may be caused, in part, by poor glycemic control. Diabetic patients who have received renal allografts may have new glomerular lesions that are manifested structurally by increases in mesangial and glomerular volume. Successful pancreas transplantation produces long-term normoglycemia and provides a unique opportunity to evaluate the impact of the normalization of the blood glucose level on the development of the renal lesions typical of diabetes mellitus in transplanted kidneys. We obtained biopsy specimens from the functioning renal allografts of 12 patients with insulin-dependent (Type I) diabetes before successful pancreas transplantation (performed one to seven years after renal transplantation) and repeated the biopsy at least 1.9 years later. In renal biopsy specimens obtained before pancreas transplantation, the mesangial volume was normal or modestly increased and the glomerular basement membrane was moderately thickened. At follow-up, no progression could be detected in any structural measure in the glomerulus. Furthermore, the recipients of pancreas transplants had smaller glomerular volumes than 13 matched diabetic patients who were recipients of renal allografts but who did not undergo pancreas transplantation (mean +/- SD, 1.80 +/- 0.55 vs. 2.47 +/- 0.73 x 10(6) microns 3; P = 0.02) and showed markedly less mesangial expansion (mesangial-volume fraction, 0.19 +/- 0.07 vs. 0.31 +/- 0.10 microns 3 per cubic micrometer; P = 0.004). We conclude that successful pancreas transplantation is associated with significantly less severe diabetic glomerulopathy in kidneys previously transplanted into diabetic patients. These data support the hypothesis that normoglycemia can prevent the progression of diabetic glomerulopathy in humans.     

Development of renal structural lesions in type-1 diabetic patients with microalbuminuria

Kidney biopsies were obtained in 18 type-1 diabetic patients with microalbuminuria and again 8 years later. Over the first 30 months, a treatment protocol (conventional versus intensified treatment) was followed. The biopsies were embedded into plastic and sectioned serially. The volume of individual glomeruli and the vascular pole area was determined. The number of glomeruli showing capsular drops, fibrinoid lesions, adhesions, extra efferent arterioles and corpuscles totally occluded were counted and expressed as a percentage of the total number of corpuscles. Cortical interstitium and degenerated tubules were estimated by point counting. From baseline to the 8-year biopsy, the group of patients showed significant increase in interstitial volume fraction, mean glomerular volume and vascular pole area. The frequency of glomerular occlusion, fibrinoid lesions, adherences and extra efferent arterioles increased, whereas the frequency of capsular drops did not change, and degenerated tubular profiles showed a non-significant increase. No correlation was seen between these light microscopic observations and the concomitant development of diabetic glomerulopathy. Increase in albumin excretion rate was associated with increase in glomerular volume and vascular pole area. No correlation was seen with the glomerular filtration rate, blood pressure or metabolic control. The increase in structural parameters illustrates the slowly ongoing alteration of renal structures in type-1 diabetic patients with microalbuminuria.     

Glomerular structural changes in pregnant, diabetic, and pregnant-diabetic rats

Kidneys enlarge both during pregnancy and in diabetes. The enlargement and morphology of glomeruli was studied during pregnancy and in diabetes in order to examine possible similarities, differences, and interactions in the growth in these conditions. Morphometric investigations were performed on glomeruli in pregnant rats, in rats with 2 weeks' diabetes, and in pregnant-diabetic rats. Kidneys were enlarged 22% in the midterm pregnant rats compared with controls, 74% in diabetic rats, and a further 21% in pregnant-diabetic rats. Glomerular volume was enlarged by 26% during midterm pregnancy in normal animals. Diabetes induced an enlargement in glomerular volume of 58% and a further 18% in midterm diabetic animals due to pregnancy. Within the glomerulus, pregnancy in normal animals induced minor non-significant changes. Diabetes induced significant increase in several parameters: mesangial volume and cell volume, capillary and glomerular basement membrane volume, capillary wall surface area, foot process width, filtration slit length, and nuclear number. Pregnancy in diabetic animals induced no significant additional changes. In conclusion, kidney enlargement in pregnancy shows very few glomerular changes in either normal or diabetic animals. Enlargement of glomeruli in diabetes involves hypertrophy and hyperplasia concurrent with several morphological changes within the glomerulus.     

Renal structures in type 2 diabetic patients with elevated albumin excretion rate

Renal biopsies were obtained from type 2 diabetic patients with elevated albumin excretion. The aim was to obtain quantitative structural data to correlate with clinical findings. Biopsies from 27 diabetic patients and 12 non-diabetic cases were analysed. Stereological methods were applied by light- and electron microscopy. Diabetic patients showed quantitatively markedly expressed diabetic glomerulopathy, but also an increase in glomerular volume, in prevalence of new-vessel formation at the vascular pole, prevalence of glomerular occlusion and in interstitial volume fraction. A significant correlation was not observed between the degree of interstitial and glomerular involvement. The glomerular hypertrophy is interpreted as a compensatory phenomenon, leading to preservation of filtration surface in the open glomeruli. Close correlation was seen between glomerulopathy and glomerular function, and also with the stage of retinopathy. New vessel formation at the vascular pole was most frequent in patients with proliferative retinopathy. Signs of non-diabetic glomerulopathy were not observed, but various atypical ultrastructural changes accompanying the advanced stages are illustrated. Our present findings correspond to data from type I diabetic patients. It is emphasised that all compartments of the kidney are affected by the diabetic state. It is suggested that the interstitial and glomerular lesions are influenced by different factors.     

Renoprotective effect of a dopamine D3 receptor antagonist in experimental type II diabetes

Diabetic nephropathy is the leading cause of end-stage renal disease. Dopamine receptors are involved in the regulation of renal hemodynamics and may play a role in diabetes-induced hyperfiltration. To test this hypothesis, we investigated the renal effect of a dopamine D3 receptor antagonist (D3-RA) in hypertensive type II diabetic SHR/N-cp rats. Lean and obese SHR/N-cp rats were randomly assigned to D3-RA, angiotensin-converting enzyme inhibitor (ACE-i), or D3-RA+ACE-i treatment or control conditions. Treated animals were given the D3-RA A-437203 (10 mg/kg/body weight (BW)/day) or the ACE-i trandolapril (0.3 mg/kg BW/day) or a combination of both. At 6 months following perfusion, fixed kidneys were analyzed by morphological and stereological methods. Indices of renal damage (glomerulosclerosis, glomerulosclerosis damage index (GSI), tubulointerstitial and vascular damage), glomerular geometry and functional variables such as urinary albumin excretion, glomerular filtration rate, blood pressure, blood chemistry and BW were determined. The GSI (score 0-4) was significantly higher (P<0.05) in untreated diabetic animals (1.62+/-0.3) compared to nondiabetic controls (0.4+/-0.2) and the treatment groups (D3-RA: 0.31+/-0.12; ACE-i: 0.29+/-0.1; combination treatment: 0.12+/-0.01). Urinary albumin excretion (mg/24 h) was higher in untreated diabetic controls (102+/-19) compared to nondiabetic controls (31+/-12) and the treatment groups (D3-RA: 44+/-15; ACE-i: 41+/-13; combination treatment: 15+/-8). Mean glomerular volume was higher in untreated diabetic animals compared to nondiabetic controls and to the treatment groups. Desmin expression, a marker of podocyte damage, was elevated in untreated diabetic controls and diminished in all treatment groups. These data suggest that in a model of type II diabetes, the dopamine D3-RA had a beneficial effect on renal morphology and albuminuria, which was comparable in magnitude to that of ACE-i treatment.     

Focal segmental glomerular hyalinosis and/or sclerosis in rats with congenital unilateral hydronephrosis.

Focal segmental glomerular hyalinosis and/or sclerosis (FSHS) was observed in five Wistar-Imamichi rats with congenital unilateral hydronephrosis (CUH rats). Marked proteinuria (164.9 +/- 138.4 mg/day) was observed in the CUH rats. Immunoperoxidase staining for IgM, C3 and IgG was positive in the glomeruli, showing in a focal, segmental pattern that corresponded to the areas of FSHS seen by light microscopy. These glomerular findings were extremely similar to those of human focal glomerular sclerosis (FGS). FSHS was found to be common to both the hydronephrotic kidney and the contralateral kidney without hydronephrosis. Morphometry revealed that the glomerular area of the juxtamedullary glomeruli was greater than that of superficial glomeruli in control rats (11,037 micron2 vs. 6,847 microns2). On the other hand, glomerular hypertrophy was observed in non-sclerotic glomeruli of CUH rats (superficial glomeruli; 12,477-16,123 microns2, juxtamedullary glomeruli; 14,635-18,418 microns2). Also, a decreased in the number of glomeruli within the range 1.8-4.1 per unit area (1 mm2) was seen in CUH rats compared with control rats (mean 4.4). These results suggest that the increased rate of development of FSHS is based on hyperfiltration in the remaining functional nephrons.     

Cystatin C as an early biomarker of nephropathy in patients with type 2 diabetes

This study was done to evaluate clinical usefulness of cystatin C levels of serum and urine in predicting renal impairment in normoalbuminuric patients with type 2 diabetes and to evaluate the association between albuminuria and serum/urine cystatin C. Type 2 diabetic patients (n = 332) with normoalbuminuria (n = 210), microalbuminuria (n = 83) and macroalbuminuria (n = 42) were enrolled. Creatinine, urinary albumin levels, serum/urine cystatin C and estimated glomerular filtration rate (eGFR by MDRD [Modification of Diet in Renal Disease] and CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration] equations) were determined. The cystatin C levels of serum and urine increased with increasing degree of albuminuria, reaching higher levels in macroalbuminuric patients (P < 0.001). In multiple regression analysis, serum cystatin C was affected by C-reactive protein (CRP), sex, albumin-creatinine ratio (ACR) and eGFR. Urine cystatin C was affected by triglyceride, age, eGFR and ACR. In multivariate logistic analysis, cystatin C levels of serum and urine were identified as independent factors associated with eGFR < 60 mL/min/1.73 m(2) estimated by MDRD equation in patients with normoalbuminuria. On the other hand, eGFR < 60 mL/min/1.73 m(2) estimated by CKD-EPI equation was independently associated with low level of high-density lipoprotein in normoalbuminuric patients. The cystatin C levels of serum and urine could be useful markers for renal dysfunction in type 2 diabetic patients with normoalbuminuria.     

Constant glomerular filtration rate in diabetic nephropathy. Correlation to blood pressure and blood glucose control

Twenty-one patients with diabetes of type I and diabetic nephropathy with reduced glomerular filtration rate (GFR) were followed prospectively with regard to GFR, proteinuria, blood pressure and glucosylated haemoglobin (HbA1). All patients were on antihypertensive treatment. The mean rate of decline in GFR was only 0.38 ml/month = 4.6 ml/year. In one third of the patients, GFR remained constant at a reduced level for at least 24 months. Mean plasma clearance of 51Cr-EDTA in this group was 48.3 +/- 14.6 ml/min/1.73 m2 body surface at entry and 48.0 +/- 13.6 at the time of evaluation. The patients with constant GFR had significantly less proteinuria and lower systolic as well as mean arterial pressure during the study than patients with falling GFR. They also had significantly lower mean HbA1 and fewer very high HbA1 values than patients who deteriorated. The data thus indicate that a combination of good metabolic control and effective blood pressure control may strongly delay the progression of renal insufficiency in diabetic nephropathy. They also show that low degree of proteinuria is a marker of good prognosis.     

Slowly progressing type 1 diabetes: persistence of islet cell autoantibodies is related to glibenclamide treatment

BACKGROUND: Several experimental studies in rats have demonstrated that sulfonylurea treatment increases autoantigen expression in B-cells. This phenomenon may be deleterious for the preservation of residual beta cell function in patients with slowly progressing type 1 diabetes or latent autoimmune diabetes of adult (LADA). AIM/HYPOTHESIS: The aim of the present study was to evaluate whether the exclusion of glibenclamide in the treatment of ICA positive type 2 diabetic patients may diminish or halt the humoral autoimmune response against B-cells as well as improve metabolic control and insulin secretion. SUBJECTS AND METHODS: Fourteen type 2 diabetic patients with pancreatic autoimmunity (ICA+ and GABA+) and treated with insulin and glibenclamide (duration of disease 2.0 +/- 2.2, range 0.1-7 years and age 53 +/- 12.5, range 36-75 years) were studied. Patients were randomly assigned to two treatment groups, Group 1: insulin monotherapy (n = 8, age 53 +/- 6.4 years) (Exclusion of glibenclamide) and, Group 2: insulin plus glibenclamide (n = 6, age 53.5 +/- 16.9) (Unmodified treatment). Both groups were investigated at the beginning of the study and after one year for the following parameters: ICA and anti-GAD65 antibodies, fasting glucose and fasting C-peptide. RESULTS: In group 1, six out of eight patients became ICA negative while all patients in group 2 remained ICA positive (p = 0.0097). Fasting glucose concentrations improved in group 1 (4.6 +/- 2.8) in relation to group 2 (11.5 +/- 5.5, p = 0.0023) after one year of treatment. No differences were found for anti-GAD antibodies and fasting C-Peptide between the groups. CONCLUSIONS: These data show that exclusion of glibenclamide in the treatment of ICA+ type 2 diabetic patients partially decreases specific autoimmunity against endocrine pancreatic cells and improves metabolic control. This may reflect decreased expression of B-cell autoantigens suggesting that insulin monotherapy is a better choice for the treatment of LADA.     

On glomerular structural alterations in type-1 diabetes

Glomerular structural modifications were measured in kidney biopsies from two follow-up studies in type-1 diabetic patients with microalbuminuria and in kidney donors. Stereologic methods were used to obtain data on glomerular composition and absolute quantities per glomerulus to supplement data on diabetic glomerulopathy previously published. Diabetic patients at baseline (n=37) showed significant changes compared with controls (n=11). The volume fraction of tuft/glomerulus was increased, the proportion of capillary surface facing peripheral basement membrane was decreased (0.72+/-0.04 vs 0.77+/-0.03, P=0.0008), the ratio of mesangial surfaces, urinary/capillary, was decreased (0.67+/-0.17 vs 1.11+/-0.28, P<10(-4)), and the average capillary diameter was increased (8.9+/-0.9 microm vs 7.5+/-1.0 microm, P=0.0002). The total volume of mesangial extracellular material per glomerulus was increased (P=0.01), whereas glomerular volume was not significantly different from controls. Follow-up biopsies after antihypertensive treatment with ACE-inhibitor (n=7) or beta-blocker (n=6; 36-48 months) and after intensive insulin treatment (n=7; 24-33 months) showed no change. In a conventionally treated group (n=9), the glomerular volume, the volume of extracellular material/glomerulus, and the capillary length increased. The mean capillary diameter did not correlate with the glomerular volume. In conclusion, the development of diabetic glomerulopathy entails structural modifications of the glomerular tuft. Antihypertensive and intensified insulin treatment seem to slow the progression of ultrastructural changes.     

血浆型凝溶胶蛋白和纤连蛋白在糖尿病肾病肾组织的表达及其临床病理资料分析

目的 对血浆型凝溶胶蛋白(pGSN)和纤连蛋白(FN)在糖尿病肾病(DN)患者肾组织的表达及其临床病理学资料进行分析.方法 根据临床诊断,将肾活检诊断为DN的67例患者分为4组:DN或糖尿病(DM)组、DM或DN合并高血压组、DM或DN合并其他肾脏病组和单纯诊断为其他肾脏疾病组,而后者又可分为血糖正常和血糖升高两种.利用免疫组织化学方法检测pGSN和FN在上述组织的石蜡切片的表达情况,与临床资料结合进行统计学分析.结果 pGSN和FN主要表达在肾小球和肾小管中,尤其在纤维化的肾小球和肾小管表达最为明显,两者均与肾小球的硬化率(硬化肾小球/总肾小球数)相关,而与其他的临床指标没有明显相关性.在四组临床诊断分组中,临床DM症状不典型伴有肾脏改变且血糖升高组,其肾小球滤过率(eGFR)明显降低(P＜0.05).而血糖正常组,其凝血酶原时间(PT)、血糖、丙氨酸转氨酶(ALT)、二氧化碳结合力及糖化血红蛋白相较于其他组有统计学意义(P＜0.05).而DM或DN伴有高血压组的患者其凝血项检查中的凝血酶原时间活动度(PT％)、凝血酶原时间国际标准化比值(PTINR)、凝血酶时间(TT)的差异有统计学意义(P＜0.05),ATL、天冬氨酸氨基转移酶(AST)明显降低(P＜0.05).结论 pGSN和FN反映肾小球的纤维化程度.临床上不能明确诊断为DN的病人,肾活检确诊时其肾功能的损害更严重.伴有高血压的DN患者,其凝血系统及肝功发生明显变化.     

Insulin secretion and sensitivity during oral glucose tolerance test in Korean lean elderly women

Impaired glucose tolerance (IGT) and type 2 diabetes including undiagnosed isolated postchallenge hyperglycemia (IPH) are common in the elderly. The aim of this study was to investigate the insulin secretion and sensitivity in Korean elderly lean diabetic women. Forty-one lean women aged 65-88 years took 2 hr oral glucose tolerance test (OGTT) and were stratified according to the WHO criteria (normal glucose tolerance [NGT], n=20; IGT, n=6; and type 2 diabetics, n=15 including seven IPH). HbA1c and fructosamine progressively increased from the NGT to the diabetic subjects (p=0.006 and p=0.001, respectively). Compared with subjects with NGT, the insulinogenic index, a marker of early insulin secretion and the AUC(ins), a marker of total insulin secretion, decreased significantly in diabetic group [0.53 (-0.44 -1.45) vs. 0.18 (0.00 -1.11), p=0.03 and 306+/-165 vs. 199+/-78 pmol/L, p=0.02 respectively]. A significant difference was found in the AUC(c-peptide) among each group (221+/-59 vs. 206+/-34 vs. 149+/-51 pmol/L, p=0.001 for each). The homeostasis model assessment of insulin resistance (HOMA-IR), a marker of insulin resistance, was not different among the groups. We conclude that compared with NGT subjects, elderly lean women with diabetes have impaired oral glucose-induced insulin secretion but have relatively preserved insulin sensitivity. This suggests that insulin resistance is not necessarily an essential component of Korean elderly lean diabetic women.     

Tumor Necrosis Factor (TNF-��) and C-reactive Protein (CRP) are Positively Associated with the Risk of Chronic Kidney Disease in Patients with Type 2 Diabetes

Purpose

Chronic low-grade inflammation may induce chronic kidney disease in patients with type 2 diabetes. This study investigated the relation between inflammatory biomarkers and chronic kidney disease in patients with type 2 diabetes, which has not yet been reported in Asian populations.

Materials and Methods

A cross-sectional study was performed in 543 patients recruited from diabetic clinics for an ongoing, prospective study. Multivariate logistic regression was used to evaluate the association between inflammatory biomarkers and the presence of chronic kidney disease (estimated glomerular filtration rate < 60 mL/min per 1.73 m² by the simplified Modification of Diet in Renal Disease equation using plasma creatinine).

Results

The risk of chronic kidney disease increased in the highest quartiles of C-reactive protein (CRP) [multivariate odds ratio (OR) = 3.73; 95% CI = 1.19-1.70] and tumor necrosis factor-α (multivariate OR = 4.45; 95% CI = 1.63-12.11) compared to the lowest quartiles after adjustments for age, sex, zinc intake, and other putative risk factors for chronic kidney disease.

Conclusion

Our results suggest that CRP and tumor necrosis factor-α may be independent risk factors for chronic kidney disease in patients with type 2 diabetes. A causal mechanism of this association should be evaluated in a follow-up study of Korean patients with type 2 diabetes.     

Measurement of renal plasma flow and glomerular filtration rates in diabetic subjects]

To clarify the problem in the measurement of renal plasma flow and glomerular filtration rates in diabetes, the effect of glucose on the determination of para-aminohippuric acid (PAH) and inulin was examined. The concentration of urinary PAH in glucosuric diabetic subjects decreased after the storage of urine samples because of the glycation of PAH. Therefore, glucose must be removed by the acid treatment before the determination of the concentrations of urinary PAH. Since glucose can interfere with the assay of inulin, the sample must be treated with NaOH prior to the determination of the inulin concentration. GFR of the subjects with type 2 diabetes was next examined. GFR in the subjects with a duration of diabetes less than 10 years was significantly higher than that in the subjects with a duration of diabetes more than 10 years. Thus, the subjects with short-term type 2 diabetes may present with hyperfiltration similar to the subjects with short-term type 1 diabetes.     

Serum uric acid level and fractional excretion of urate in fluid and electrolyte disturbances]

Changes in renal urate clearance may reflect altered glomerular dynamics more precisely than other commonly used indices. Extracellular fluid volume expansion is known to be correlated with uricosuria, while volume depletion is associated with decreased urate excretion. The diagnostic usefulness of measuring serum urate levels and fractional excretions of urate in SIADH, incipient diabetic nephropathy, and prerenal azotemia have been reviewed. In SIADH, profound hypouricemia and markedly increased fractional excretion of urate (FEUA) accompany the extracellular fluid volume expansion. In prerenal azotemia, decreased FEUA may represent a reliable indicator of prerenal azotemia in the differential diagnosis of acute renal failure. In incipient diabetic nephropathy, glomerular hyperfiltration may increase renal urate clearance and lower the serum uric acid level. Hypouricemia may also predict the future progression of incipient nephropathy in type II diabetes.     

Deficiency of endothelial nitric-oxide synthase confers susceptibility to diabetic nephropathy in nephropathy-resistant inbred mice

Recent studies have implicated dysfunctional endothelial nitric-oxide synthase (eNOS) as a common pathogenic pathway in diabetic vascular complications. However, functional consequences are still incompletely understood. To determine the role of eNOS-derived nitric oxide (NO) in diabetic nephropathy, we induced diabetes in eNOS knockout (KO) and wild-type (WT) mice on the C57BL6 background, using low-dose streptozotocin injection, and we investigated their glomerular phenotype at up to 20 weeks of diabetes. Although the severity of hyperglycemia in diabetic eNOS KO mice was similar to diabetic WT mice, diabetic eNOS KO mice developed overt albuminuria, hypertension, and glomerular mesangiolysis, whereas diabetic WT and nondiabetic control mice did not. Glomerular hyperfiltration was also significantly reduced in diabetic eNOS KO mice. Electron micrographs from diabetic eNOS KO mice revealed an injured endothelial morphology, thickened glomerular basement membrane, and focal foot process effacement. Furthermore, the anionic sites at glomerular endothelial barrier estimated by cationic ferritin binding were reduced in diabetic eNOS KO mice. In aggregate, these results demonstrate that deficiency of eNOS-derived NO causes glomerular endothelial injury in the setting of diabetes and results in overt albuminuria and glomerular mesangiolysis in nephropathy-resistant inbred mice. The findings indicate a vital role for eNOS-derived NO in the pathogenesis of diabetic nephropathy.     

The diabetic foot in Cameroon

A five-month long study has been conducted in the unit of Endocrinal and Metabolic diseases of the Yaounde Central Hospital, at the National Centre for Diabetes and Hypertension and at the Baptiste d'Eloug-ébé Health Centre. After giving their consent, all diabetic patients were included whether or not they presented with diabetic foot 300 patients were included, 278 suffering from a type 2 diabetes, MIF sex-ratio: 1.2 mean age: 55 +/- 12 years. The global prevalence of the diabetic foot was found to be as high as 13% (n=39), ranging from 25.6% (inpatient) to 11.1 % (outpatients). The mean age for patients presenting with a diabetic foot was 57 +/- 9 years. A type 2 diabetes was diagnosed in 38 of those patients. Most patients had grade 0 (43.6%) or grade 1 (30.8%) lesions, according to the Wagner classification. None presented with grade 5 lesions. A strong correlation between the following risk factors and the evidence of a diabetic foot was noticed, with regard to: an history of foot ulcer (p < 0.0001), a neuropathy revealed by the graduated tuning fork (p < 0.005), foot deformations (p < 0.05), a neuropathy revealed by the monofilament 10-g (p < 0.03). Few patients ever had a foot examination: 14% (n=42). Diabetes mellitus, a non transmissible disease, is a world-wide epidemic, especially in developing countries (Africa, Asia), the diabetic foot being one of the most severe and frequent complication. Its cost is among the highest of the diabetes chronic complications. The struggle against that burden relies upon the prevention (education of patients and care givers, early detection of the lesions) and upon a multidisciplinary approach and treatment. In sub-Saharan Africa and especially in Cameroon, emphasis must be put on education of both patients and care givers.     

Comparison of renal morphology in the Streptozotocin and the SHR/N-cp models of diabetes

The Streptozotocin (STZ) model of diabetes is commonly used for studies of diabetic nephropathy although the histological lesions of the kidney are mild and do not resemble those seen in diabetic patients. The SHR/N-cp rat model of type II diabetes spontaneously develops pronounced abnormalities in renal histology. In the present study, we compared renal morphology in the STZ rat and the diabetic SHR/N-cp rat. Sprague-Dawley rats received STZ, developed diabetes after 2 days and were treated with insulin. In the SHR/N-cp rat, obesity is inherited as an autosomal recessive trait. The progeny are either lean (used as controls) or obese and diabetic. After 6 months of observation, STZ and SHR/N-cp rats were killed. The renal damage was evaluated by assessing damage indices and by using stereological techniques. In addition, immunohistochemistry and electron microscopy were performed. The glomerular and tubulointerstitial changes were much more pronounced in the diabetic SHR/N-cp compared to the STZ model. In parallel glomerular PCNA+cells were significantly more frequent and expression of TGF-beta and PDGF by immunohistochemistry in glomeruli and in the tubulointerstitial space was more pronounced in SHR/N-cp compared to STZ rats. The glomeruli of SHR/N-cp contained less and larger podocytes as well as smaller mesangial cells embedded in more mesangial matrix compared to STZ. Similarly, less, but larger endothelial cells were found in SHR/N-cp than in STZ rats. The mean glomerular volume was similarly increased in the two models. Albumin excretion was only modestly increased in STZ diabetes, but pronounced in the SHR/N-cp rat. Although the STZ model of diabetes exhibits numerous biochemical sequelae of hyperglycemia, the morphological lesions are unimpressive. In contrast, the diabetic SHR/N-cp exhibits marked structural lesions, particularly podocyte damage and mesangial expansion that promise to make it a more suitable model for investigation of diabetic glomerulosclerosis.