Diabetes mellitus is one of the most challenging health concerns of the 21st century. With at least 30% of the diabetic population remaining undiagnosed, effective and early diagnosis is of critical concern. Development of a diagnostic test, more convenient and reliable than those currently used, would therefore be highly beneficial. Urine as a diagnostic medium allows for non-invasive detection of biomarkers, including some associated with type 2 diabetes and its complications. This review provides a synopsis of those urinary biomarkers that potentially may provide a basis for the development of improved diagnostic tests. Three main pathways for the sourcing of potential makers are identified: kidney damage, oxidative stress and low-grade inflammation including atherosclerosis/vascular damage. This review briefly presents each pathway and some of the most relevant urinary biomarkers that may be used to monitor the development or progression of diabetes and its complications. In particular, biomarkers of renal dysfunction such as transferrin, type IV collagen and N-acetyl-beta-D-glucosaminidase might prove to be more sensitive than urinary albumin, the current gold standard, in the detection of incipient nephropathy and risk assessment of cardiovascular disease. Inflammatory markers including orosomucoid, tumour necrosis factor-alpha, transforming growth factor-beta, vascular endothelial growth factor and monocyte chemoattractant protein-1, as well as oxidative stress markers such as 8-hydroxy-2'deoxyguanosine may also be useful biomarkers for diagnosis or monitoring of diabetic complications, particularly kidney disease. However, the sensitivity of these markers compared with albumin requires further investigation.

Urinary biomarkers involved in type 2 diabetes: a review

Background. Type-2 diabetes and diabetic kidney disease have additive effects on cardiovascular risk. Furthermore, the degree of proteinuria is an independent predictor of mortality in this patient group. We hypothesized that altered kidney clearance and/or metabolism of vasoactive peptides occurring during proteinuria could link early diabetic nephropathy to cardio vascular disease (CVD). Methods. We performed a cross-sectional study of 85 incident patients (51 ± 5 years, 49 males) with type-2 diabetes and 38 age- and sex-matched controls. We further divided patients by the presence of minor ( 0.05, ρ = 0.32; P = 0.003, ρ = 0.76; P < 0.001, respectively). FMD, adiponectin and AHSG/fetuin-A levels were significantly lower, and negatively correlated with proteinuria (ρ =− 0.54; P < 0.001, ρ =− 0.56; P < 0.001, ρ =− 0.48; P < 0.001, respectively). In a multivariate regression analysis, the degrees of proteinuria (r 2 =− 0.32, P = 0.04) and plasma levels of NAMPT/visfatin (r 2 =− 0.33, P = 0.006)

Endothelial dysfunction in type-2 diabetics with early diabetic nephropathy is associated with low circulating adiponectin

OBJECTIVE —The purpose of this study was to elucidate whether serum adiponectin is associated with progression of diabetic nephropathy in type 1 diabetic patients.

RESEARCH DESIGN AND METHODS —This was a prospective follow-up study as a part of the nationwide Finnish Diabetic Nephropathy Study; 1,330 type 1 diabetic patients were followed for 5.0 ± 2.2 years. Patients were divided at baseline into three groups according to their urinary albumin excretion rate (AER) in three consecutive overnight or 24-h urine collections: 818 patients with normoalbuminuria (AER <20 μg/min), 216 patients with microalbuminuria (20 μg/min ≤ AER < 200 μg/min), and 296 patients with macroalbuminuria (AER ≥200 μg/min). Progression of albuminuria was the main outcome. Adiponectin was measured by a time-resolved immunofluorometric assay, and the values were log-transformed and adjusted for age, BMI, and sex before analysis.

RESULTS —Progression either to the next albuminuria level or to end-stage renal disease (ESRD) occurred in 193 patients. No difference in adiponectin concentrations was observed between progressors and nonprogressors in patients with normoalbuminuria or microalbuminuria. In the patients with macroalbuminuria, progression to ESRD was associated with higher adiponectin in the entire group (23.4 ± 17.1 vs. 16.0 ± 8.5 mg/l, P < 0.001) and in men ( P < 0.001) and women ( P < 0.001) separately. Progression to ESRD was also associated with systolic blood pressure, insulin dose, A1C, serum cholesterol, serum triglycerides, AER, and estimated glomerular filtration rate (eGFR). When these covariates were inserted in a Cox regression analysis, A1C, triglycerides, eGFR, and adiponectin were significantly associated with progression from macroalbuminuria.

CONCLUSIONS —Increased serum adiponectin levels predict the progression from macroalbuminuria to ESRD in type 1 diabetic patients.

https://care.diabetesjournals.org/content/diacare/31/6/1165.full.pdf

Serum Adiponectin and Progression of Diabetic Nephropathy in Patients With Type 1 Diabetes

Objective The adiponectin promoter single nucleotide polymorphism (SNP) −11391G/A is found to be associated with nephropathy in type 1 diabetic (T1D) patients among Danish, but not French, Finnish, and Swedish populations. In the present study, we identified the binding sites for transcriptional factors in the adiponectin promoter region and also evaluated the association between adiponectin promoter polymorphisms and diabetic nephropathy (DN) in T1D patients. Materials and Methods Three adiponectin promoter SNPs, including −11377C/G, −11391G/A, and −11426A/G, were genotyped with dynamic allele-specific hybridization. The subjects included 1177 American T1D patients (622 females/555 males) with or without DN. All patients are of European descent and selected from the Genetics of Kidneys in Diabetes (GoKinD) study. Results We identified four binding sites of transcriptional stimulatory protein (SP1) in the adiponectin putative promoter and found that the G allele of SNP −11377C/G altered the sequence for one of the SP1 binding sites. This polymorphism was significantly associated with DN in female T1D patients (P=.022, OR=1.352, 95% CI=1.044–1.752). Further analyses indicated the common diplotype (haplotypic genotype) H1/H1, constructed with SNPs −11377C/G and −11391G/A, was significantly associated with DN in females (P=.013), while the association of another diplotype H1/H2 with DN in females was of borderline significance (P=.071). Conclusions The present study thus provides the first evidence that SNP −11377C/G alters the sequence in one of the SP1 binding sites in the adiponectin promoter region. This polymorphism, together with another promoter SNP −11391G/A, may confer susceptibility to the development of DN in T1D patients among the GoKinD population.

A single nucleotide polymorphism alters the sequence of SP1 binding site in the adiponectin promoter region and is associated with diabetic nephropathy among type 1 diabetic patients in the Genetics of Kidneys in Diabetes Study.

Adiponectin is secreted by the adipose tissue and is downregulated in states of obesity and insulin resistance There is a growing body of evidence indicating that adiponectin has renoprotective effects and protects against the development of albuminuria in rodent experiments Adiponectin crossing the glomerular filtration barrier possibly inhibits inflammation, fibrosis and oxidative stress in kidneys through activation of AMP-activated protein kinase Moreover, microalbuminuria is a well established early sign of progressive cardiovascular and renal disease, even in subjects with preserved glomerular filtration rate Studies investigating the relationship between serum adiponectin levels and urinary albumin excretion rate (UAE) have yielded conflicting data and the mechanisms underlying the interplay between adiponectin and albuminuria remain to be elucidated This article constitutes a critical review attempting to clarify any remaining confusion about this matter Furthermore, this article examines the clinical significance of adiponectin-albuminuria interplay, suggesting that adiponectin is possibly involved in the development of albuminuria that is associated with obesity, diabetes and cardiovascular disease and may mediate, at least in part, the actions of medical treatments that influence UAE, such as angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers, thiazolidinediones, fenofibrate and diet Further studies to investigate more thoroughly the renoprotective role of adiponectin in the human setting should be carefully planned, focusing on causality and the possible influence of adiponectin on the development of albuminuria in specific clinical settings

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The role of adiponectin in renal physiology and development of albuminuria

Adiponectin is an adipose-derived protein which has anti-inflammatory and anti-atherogenic properties in addition to insulin-sensitizing effects. To date, the role of adiponectin in the pathogenesis of diabetic nephropathy remains unclear. The aim of the present study was to explore the relationship between adiponectin and renal tubular injury in diabetic nephropathy. We determined serum and urinary adiponectin levels in type 2 diabetic patients with normoalbuminuria (n = 19), microalbuminuria (n = 18), and overt diabetic nephropathy (n = 16), and then analyzed the correlations between serum and urinary adiponectin, urinary N-acetylglucosaminidase (NAG) as a clinical marker of renal tubular injury, urinary monocyte chemoattractant protein-1 (MCP-1) as an inflammatory marker in renal tubulointerstitium, and clinical markers of renal disease. Notably, serum and urinary adiponectin levels were significantly increased in patients with overt diabetic nephropathy compared to those with normoalbuminuria and microalbuminuria. In univariate linear regression analysis, serum adiponectin levels were positively correlated with serum creatinine (r = 0.648, P<0.0001), urinary albumin (r = 0.583, P<0.0001), urinary NAG (r = 0.406, P<0.01), urinary MCP-1 (r = 0.514, P<0.0001), and urinary adiponectin (r = 0.691, P<0.0001) levels in all diabetic patients. Urinary adiponectin levels were also positively correlated with serum creatinine (r = 0.729, P<0.0001), urinary albumin (r = 0.799, P<0.0001), urinary NAG (r = 0.701, P<0.0001), and urinary MCP-1 (r = 0.801, P<0.0001) levels in all diabetic patients. Multiple linear regression analysis showed that serum creatinine and urinary adiponectin levels were independently associated with serum adiponectin levels (r(2) = 0.522), and that serum creatinine, urinary NAG, urinary MCP-1, and serum adiponectin levels were independent determinants of urinary adiponectin levels (r(2) = 0.851). These results collectively indicate that renal insufficiency and tubular injury possibly play a contributory role in increases in serum and urinary adiponectin levels in overt diabetic nephropathy. We presume that an increase in circulating adiponectin in overt diabetic nephropathy might be a physiological response to mitigate renal tubular injury and to prevent the further progression of diabetic nephropathy through its anti-inflammatory and anti-atherogenic effects.

Possible relationship between adiponectin and renal tubular injury in diabetic nephropathy.

A 48-year-old woman diagnosed with acromegaly 21 years earlier presented at our hospital with a left adrenal tumor. Her medical history included breast cancer, thyroid cancer and an incompletely resected growth hormone (GH)-producing pituitary adenoma. Endocrinological and radiological examinations revealed subclinical adrenal Cushing's syndrome. She subsequently underwent left adrenalectomy, followed by glucocorticoid replacement therapy. Her GH and insulin-like growth factor-1 levels were insufficiently controlled, and pegvisomant was administered in addition to octreotide acetate. Following adrenalectomy, a giant hepatic hemangioma and papillary thyroid carcinoma in the residual right lobe developed, indicating the high risk of tumor development in patients with acromegaly.

Poorly-controlled acromegaly accompanied by subclinical adrenal Cushing's syndrome after surgery for multiple endocrine tumors.

An 82-year-old woman was referred to our hospital because of hypoalbuminemia and generalized edema. Hypercortisolemia was subsequently found as the levels of serum cortisol and plasma adrenocorticotropic hormone (ACTH) sampled in a fasting morning were 140 pg/mL and 41.9 μg/dL, respectively. These hormones were not suppressed after taking low-dose dexamethasone the previous night and increased to a mild extent in response to administration of corticotrophin-releasing hormone, suggesting presence of pituitary adenoma producing ACTH (Cushing's disease). However, intrasella localization of pituitary adenoma could not be determined by magnetic resonance imaging. Soon after administration of metyrapone was started in an attempt to reduce her cortisol levels, the patient suffered from severe pneumonia. The pulmonary infection and peripheral edema were improved with decreases in cortisol levels by continuing metyrapone administration with antibiotics and finally she was discharged from the hospital on foot. Metyrapone is a useful therapeutic choice to achieve a remission of cortisol levels in the elderly patients with Cushing's disease in association with serious hypercortisolemia impending severe infection.

Successful remission using metyrapone in an elderly patient with Cushing disease accompanied by generalized edema

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Motoko Ishikawa

Papers

Possible relationship between adiponectin and renal tubular injury in diabetic nephropathy.

Poorly-controlled acromegaly accompanied by subclinical adrenal Cushing's syndrome after surgery for multiple endocrine tumors.

Successful remission using metyrapone in an elderly patient with Cushing disease accompanied by generalized edema

Media portrayals of transitions from work to retirement in two ageing societies: the case of ageing baby boomers in Japan and Finland.