No abstract

OBJECTIVE -Increased urinary excretions of several plasma proteins with different molecular radii Ͻ55 Å and different isoelectric points (pI), such as IgG, ceruloplasmin, transferrin, and orosomucoid, have been independently reported to precede the development of microalbuminuria in diabetic patients. We examined whether increases in urinary excretions of these proteins would be in parallel in the same patient.RESEARCH DESIGN AND METHODS -Urinary excretion rates of proteins mentioned above in timed overnight urine samples were evaluated in 61 normoalbuminuric type 2 diabetic patients (group D) aged 40 -60 years and in 17 age-matched control subjects (group C).RESULTS -The excretion rates of these proteins were significantly higher in group D than in group C. These exhibited a strong linear correlation with each other and had a weak correlation with the excretion rate of N-acethylglucosaminidase. The excretion rate of ␣ 2 -macroglobulin with large molecular radii of 88 Å was not different between groups C and D, nor did they have any correlations with the excretion rates of the other proteins. Creatinine clearance and blood pressure levels in group D were significantly higher than those in group C. CONCLUSIONS -In normoalbuminuric diabetic patients, excretion rates of plasma proteins with molecular radii Ͻ55 Å increased in parallel with each other. In view of our previous finding that urinary excretions of these plasma proteins selectively increased in parallel with enhanced glomerular filtration rate after acute protein loading, the present finding may be explained by renal hemodynamic changes, such as increased intraglomerular hydraulic pressure. Diabetes Care 27:1176 -1181, 2004D iabetic nephropathy is the most frequent cause of entering renal replacement therapy in industrialized countries such as the U.S., European countries, Australia, New Zealand, and Japan (1). Early recognition of renal changes increases the chance of preventing the development of diabetic nephropathy. Although microalbuminuria is generally recognized as the best available noninvasive predictor of diabetic nephropathy, several studies including ours have shown that increased urinary excretions of some kinds of plasma proteins with different molecular radii Ͻ55 Å and different isoelectric points (pIs) such as IgG (2-4), transferrin (5-8), ceruloplasmin (4,9), and orosomucoid (10) may precede the development of microalbuminuria in diabetic patients. Kazumi et al. (11) reported that increased urinary transferrin excretion could predict the development of microalbuminuria in type 2 diabetic patients.Recently, we found that urinary excretions of plasma proteins with molecular radii Ͻ55 Å (IgG, IgG4, ceruloplasmin, transferrin, and orosomucoid, abbreviated to small-sized plasma proteins group [SPP]) selectively increased irrespective of their pI despite no increased urinary excretion of albumin (molecular radii ϭ 36 Å, smaller than that of IgG, IgG4, and ceruloplasmin) when glomerular filtration rate (GFR) was increased by acute protein load...

Abstract. Decreased circulating levels of adiponectin, a novel adipose-derived adipocytokine, in obesity possibly contribute to the development of insulin resistance which is a major factor in the pathogenesis of type 2 diabetes. The present study was conducted to examine whether circulating and adipose tissue adiponectin levels are modulated by chronic treatment with metformin and intensive treatment with insulin in murine models of obesity and type 2 diabetes, db/db mice with a C57BL/KsJ genetic background. Nine-week-old male db/db mice were treated with metformin, insulin, and vehicle for 4 weeks. Expectedly, metformin treatment led to inhibition of weight gain and improvement of hyperinsulinemia. Insulin treatment lowered fasting blood glucose levels to normal values, although it sustained hyperinsulinemic state. However, after 4 weeks of treatment, serum adiponectin levels were not significantly elevated in either metformin-treated or insulin-treated db/db mouse group (14.2 ± 0.7 and 16.7 ± 1.0 mg/ml, respectively) compared to vehicle-treated group (14.9 ± 0.6 mg/ml). Similarly, adipose tissue adiponectin levels determined by Western blot analysis were not increased in either metformin-treated or insulin-treated group relative to vehicle-treated group. Recent studies have shown that adiponectin possibly has the same physiological effects on lipid and glucose metabolism that metformin has. Therefore, an elevation in blood concentration of metformin following the treatment might lead to suppression in adiponectin synthesis in adipose tissue, independent of inhibition in weight gain and improvement in hyperinsulinemia by metformin treatment. The present results indicate that adiponectin is not involved in the mechanism by which metformin treatment enhances insulin sensitivity. Moreover, our results suggest that adiponectin synthesis in adipose tissue may be suppressed under hyperinsulinemic state sustained by insulin treatment, even though hyperglycemia is markedly reduced. We conclude that antidiabetic treatment with metformin and insulin does not affect circulating and adipose tissue adiponectin levels.

Abstract. 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.

No abstract