Choroidal thickness in relation to urinary albumin excretion rate in type 2 diabetes mellitus without retinopathy

Background To evaluate choroidal thickness (CT) in diabetic patients without diabetic retinopathy (DR) in relation to the urinary albumin excretion rate (UAER). Methods This is a prospective case-control study that included a consecutive sample of 120 patients with type 2 diabetes without clinically evident DR and a group of 60 matched healthy controls. Diabetic patients were included in two groups according to their UAER (normoalbuminuria and microalbuminuria). Complete ophthalmological examination was performed followed by optical coherence tomography (SD-OCT) for retinal and choroidal assessment. Twenty-four-hour urine samples were collected for UAER and blood samples for HbA1c and serum creatinine were obtained. Results The study included 180 eyes from 180 subjects in three groups. Patients with higher levels of albuminuria had a thinner choroid than normal controls, with decremental thinning as albuminuria progressed. Diabetics with normoalbuminuria showed no significant differences from controls. Choroidal thickness showed a significant moderate negative correlation with UAER (r = − 0.58, p < 0.001). Multiple regression analyses for diabetic patients with microalbuminuria demonstrated that UAER is the most important determinant of subfoveal choroidal thickness (SFCT) (p < 0.001). Conclusions Decreased CT was significantly correlated with UAER in diabetic patients without retinopathy and otherwise normal kidney functions. This decrease in thickness might be a predictor of DR.

Protective Effects of Bariatric Surgery on Kidney Functions by Inhibiting Oxidative Stress Responses Through Activating PPARα in Rats With Diabetes

ObjectiveThe aim of this study was to explore the protective effects and the regulatory mechanisms of bariatric surgery on kidney injury in diabetic rats.MethodsWe established a useful type 2 diabetic rat model using high-fat and high-sugar diet feeding following low-dose streptozotocin (STZ) treatment. Sprague–Dawley (SD) rats were randomly divided into the following groups: control (Con) group, diabetic nephropathy (DN) group, and duodenal–jejunal bypass (DJB) surgery group. The food intake and body weight of rats were monitored and the glucose tolerance test (OGTT) test was performed every 2 weeks. The glomerular filtration rate (GFR) and urinary albumin excretion rate (UAFR) were measured to assess renal function. Hematoxylin–eosin (H&amp;E), periodic acid–Schiff (PAS), and Masson staining were used to evaluate renal histopathological changes. TUNEL assay was performed to detect cell apoptosis. The expressions of oxidative stress factors and inflammatory factors in the renal tissues of rats were detected by ELISA. The expressions of PPARα, reactive oxygen species (ROS), and NF-κB were detected by immunofluorescence. For in vitro experiment, HK2 cells cultured with high glucose were treated with PPARα agonist, PPARα antagonist, and adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) agonist. The expressions of AMPK/PPARα/NF-κB signaling pathway-related proteins were detected by Western blot.ResultsBariatric surgery improved the glucose tolerance of DN rats. The GFR was decreased, the promotion of urinary albumin excretion rate (UAER) was inhibited, and the renal injury was alleviated. The extracellular matrix fraction was decreased and the renal function was improved. Meanwhile, bariatric surgery activates PPARα, inhibits ROS release, reduces oxidative stress injury, and reduces renal cell apoptosis. In vitro experiment results showed that the AMPK activator could activate PPARα, downregulate NF-κB, and inhibit inflammatory response. The phosphorylation of AMPK was inhibited by PPARα antagonism.ConclusionBariatric surgery can activate PPARα, inhibit oxidative stress injury, and improve glucose metabolism and renal function in DN rats.

Predictors of Change in Skin Intrinsic Fluorescence in Type 1 Diabetes: The Epidemiology of Diabetes Complications study

Background Skin intrinsic fluorescent (SIF) scores are indirect measures of advanced glycation end-products (AGEs). SIF scores are cross-sectionally associated with type 1 diabetes (T1D) complications such as increased albumin excretion rate (AER), coronary artery calcification (CAC) and neuropathy. We assessed predictors of SIF score change in those with T1D. Methods Data from the 30-year longitudinal Epidemiology of Diabetes Complications (EDC) study of childhood-onset T1D were used to assess AGEs measured with a SIF score produced by the SCOUT DS® device. SIF scores were assessed twice in 83 participants: between 2007-08 and again between 2010-14. Regression analyses were used to assess independent predictors of SIF score change Results At baseline, mean age was 47.9 ± 6.9 years, diabetes duration was 36.7 ± 6.4 years, and median glycosylated hemoglobin (HbA1c) was 7.1 (interquartile range: 6.5, 8.5). During a mean follow-up of 5.2 ± 0.9 years, mean change in SIF score was 2.9 ± 2.8 arbitrary units. In multivariable linear regression models, log HbA1c ( P < 0.001), log estimated glomerular filtration rate (eGFR) ( P < 0.001), overt nephropathy (defined as AER ≥ 200 µg/min, P = 0.06), and multiple daily insulin shots/pump use (MDI) exposure years ( P = 0.02) were independent predictors of SIF score change. Conclusions Increases in SIF score over 5 years were related to increased glycemic levels and decreased kidney function (eGFR). MDI and glomerular damage were related to a decreased SIF score. This is one of the first studies with repeated SIF assessments in T1D and provides unique, albeit preliminary, insight about these associations.

Inherited or Acquired in Hipertension and Cronic Kidney Disease in Diabetes Mellitus Patients?

Diabetic kidney disease (DKD) is a common and serious microvascular complication of diabetes mellitus (DM), which is characterized by an elevated urinary albumin excretion rate, elevated blood pressure, and declined renal function. Approximately 30-40% of DM patients will develop DKD, which is the leading cause of end-stage renal disease (ESRD) and renal failure. Genetic factors appear critical in DKD pathogenesis based upon the evidence including aggregation in families, variable incidence rates of DKD between different races, and the highly heritable nature of diabetic renal clinic and histologic changes. Each 10 mmHg increase in mean systolic blood pressure (BP) was associated with a 15% increase in the hazard ratio for development of both micro- and macroalbuminuria and impaired kidney function defined as eGFR <60 ml/min per 1.73 m2 or doubling of the blood creatinine level. Broadly, a baseline systolic BP >140 mmHg in patients with DM2 has been associated with higher risk of ESRD and death. The ACE genes may predict diabetic nephropathy in some groups, the rate of progression and the antiproteinuric response to ACE inhibitors.

Correlation between serum carnosinase concentration and renal damage in diabetic nephropathy patients

Diabetic nephropathy (DN) is one of the major complications of diabetes and contributes significantly towards end-stage renal disease. Previous studies have identified the gene encoding carnosinase (CN-1) as a predisposing factor for DN. Despite this fact, the relationship of the level of serum CN-1 and the progression of DN remains uninvestigated. Thus, the proposed study focused on clarifying the relationship among serum CN-1, indicators of renal function and tissue injury, and the progression of DN. A total of 14 patients with minimal changes disease (MCD) and 37 patients with DN were enrolled in the study. Additionally, 20 healthy volunteers were recruited as control. Further, DN patients were classified according to urinary albumin excretion rate into two groups: DN with microalbuminuria (n = 11) and DN with macroalbuminuria (n = 26). Clinical indicators including urinary protein components, serum carnosine concentration, serum CN-1 concentration and activity, and renal biopsy tissue injury indexes were included for analyzation. The serum CN-1 concentration and activity were observed to be the highest, but the serum carnosine concentration was the lowest in DN macroalbuminuria group. Moreover, within DN group, the concentration of serum CN-1 was positively correlated with uric acid (UA, r = 0.376, p = 0.026) and serum creatinine (SCr, r = 0.399, p = 0.018) and negatively correlated with serum albumin (Alb, r = − 0.348, p = 0.041) and estimated glomerular filtration rate (eGRF, r = − 0.432, p = 0.010). Furthermore, the concentration of serum CN-1 was discovered to be positively correlated with indicators including 24-h urinary protein–creatinine ratio (24 h-U-PRO/CRE, r = 0.528, p = 0.001), urinary albumin-to-creatinine ratio (Alb/CRE, r = 0.671, p = 0.000), urinary transferrin (TRF, r = 0.658, p = 0.000), retinol-binding protein (RBP, r = 0.523, p = 0.001), N-acetyl-glycosaminidase (NAG, r = 0.381, p = 0.024), immunoglobulin G (IgG, r = 0.522, p = 0.001), cystatin C (Cys-C, r = 0.539, p = 0.001), beta-2-microglobulin (β2-MG, r = 0.437, p = 0.009), and alpha-1-macroglobulin (α1-MG, r = 0.480, p = 0.004). Besides, in DN with macroalbuminuria group, serum CN-1 also showed a positive correlation with indicators of fibrosis, oxidative stress, and renal tubular injury. Taken together, our data suggested that the level of CN-1 was increased as clinical DN progressed. Thus, the level of serum CN-1 might be an important character during the occurrence and progression of DN. Our study will contribute significantly to future studies focused on dissecting the underlying mechanism of DN.

Interference with TGFβ1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic Syndrome

The role of cannabinoid receptors in nephropathy is gaining much attention. This study investigated the effects of two neutral CB1 receptor antagonists, AM6545 and AM4113, on nephropathy associated with metabolic syndrome (MetS). MetS was induced in rats by high-fructose high-salt feeding for 12 weeks. AM6545, the peripheral silent antagonist and AM4113, the central neutral antagonist were administered in the last 4 weeks. At the end of study, blood and urine samples were collected for biochemical analyses while the kidneys were excised for histopathological investigation and transforming growth factor beta 1 (TGFβ1) measurement. MetS was associated with deteriorated kidney function as indicated by the elevated proteinuria and albumin excretion rate. Both compounds equally inhibited the elevated proteinuria and albumin excretion rate while having no effect on creatinine clearance and blood pressure. In addition, AM6545 and AM4113 alleviated the observed swelling and inflammatory cells infiltration in different kidney structures. Moreover, AM6545 and AM4113 alleviated the observed histopathological alterations in kidney structure of MetS rats. MetS was associated with a ten-fold increase in urine uric acid while both compounds blocked this increase. Furthermore, AM6545 and AM4113 completely prevented the collagen deposition and the elevated expression of the TGFβ1 seen in MetS animals. In conclusion, AM6545 and AM4113, possess reno-protective effects by interfering with TGFβ1-mediated renal inflammation and fibrosis, via peripheral action.

The expression of POMC and AgRP in brain and kidney tissues at different stages of diabetic nephropathy rats

Objective To explore the changes of proopiomelanocortin (POMC) and Agouti-Related Peptide (AgRP) expression in brain and kidney tissues under insulin intervention at different stages of diabetic nephropathy (DN) rats. Methods The male Sprague-Dawley (SD) rats of DN were treated with high-fat diet for 8 weeks and induced by intraperitoneally injection of streptozotocin (30 mg/kg) for one time. Then DN rats were also injected insulin subcutaneously at 2–5 U/(kg·24 h) from initiation of the streptozotocin. Kidney tissue, blood sample, and 24 h-urine were collected to detect the ratio of kidney/body weight, blood glucose and 24-h urinary albumin excretion rate at different stages (4, 8, 12, and 16 weeks). Immunohistochemistry assay was used to measure the expression of POMC and AgRP at different stages of DN rats. Results The DN rats were established successfully. With the progression of DN, blood glucose, 24-h urinary albumin excretion rate and kidney body weight ratio increased significantly, while decreased when insulin was injected. Immunohistochemistry showed that the expression levels of POMC were decreased gradually in brain and kidney tissues. Conversely, the expression of AgRP in kidney was highest at week 8 and then decreased gradually. The effect of insulin on normalizing POMC and AgRP expression in brain and renal tissues was also observed in DKD rats. Conclusion With the progression of DN, the expression of POMC and AgRP in kidney tissues was observed at different stages of disease, and their expressions were significantly normalized by insulin. The mechanism of in situ expression of POMC and AGRP in kidney to the progression of DN needs further investigations.

Accelerated whole-body protein catabolism in subjects with type 2 Diabetes Mellitus and albuminuria

Background Albuminuria develops in ~40% of subjects with Type 2 Diabetes Mellitus (T2DM), and is often associated with malnutrition, severe comorbidities and decreased life expectancy. The association between albuminuria and altered whole body protein turnover in T2DM is currently unknown. Objective To assess whole body protein degradation and synthesis in type 2 diabetes with and without albuminuria. Methods Fourteen T2DM male subjects, with either increased [AER+] or normal [AER-] urinary albumin excretion rate, and eleven age-matched male healthy controls, were infused with phenylalanine [Phe] and tyrosine [Tyr] tracers. Post-absorptive rates of appearance (Ra) of Phe (= protein degradation) and Tyr, Phe hydroxylation to Tyr (Hy) (catabolic pathway), and Phe disposal to protein synthesis [PS], were determined. Results Phe and Tyr Ra were not different among the groups. However, in T2DM [AER+], the fraction of Phe disposal to hydroxylation was ~50% and ~25% greater than that of both controls and T2DM [AER-] (p<0.006 and p = 0.17, respectively). Conversely, as compared to controls, the fractional Phe disposal to PS was ~10% lower in T2DM [AER+] (p<0.006), and not different from that in T2DM [AER-]. As a consequence, in T2DM [AER+], the ratio between the fractional Phe disposal to hydroxylation and that to PS was ~70% greater (p = 0.005) than that in healthy controls, whereas in the T2DM [AER-] this ratio was ~30% greater than in controls (p = 0.19). Conclusions On the basis of the kinetics of the essential amino acid phenylalanine, T2DM subjects with increased AER exhibit a catabolic pattern of whole body protein turnover.

DIABETES INDUCED MICROALBUMINURIA - A CRITICAL REVIEW

Microalbuminuria is a marker and a risk factor of diabetic renal complications commences its role in path-ogenesis of nephropathy at its third stage, the stage of incipient nephropathy. Microalbuminuria is followed by overt nephropathy and end- stage renal disease of irreversible renal damage. Early detection of microal-buminuria has a decisive role in the healthy survival of diabetics. Urine albumin excretion rate and albumin creatinine ratio on timed urine samples, early morning samples or spot urine are of beneficial use. Ayurve-da describes diabetes mellitus as Prameha roga in which the major pathogenesis takes precedence in Moot-rasaya. Microalbuminuria can be described as Prameha Janya Vrikka Roga. It occurs due to Sanga (ob-struction), Vimarga Gamana (abnormal movement) of albumin; one of the constituents of Raktadhatu (blood) through Rakta and Mootra Vaha Srotas (channels of blood and urine). Medicines which are Pramehaghna (anti-diabetic), Mootra and Raktavaha Srothosodhana (cleanse the channels) may be of good worth to rectify the pathology of microalbuminuria providing an improved life for diabetics.