Mannose-Binding Lectin as a Predictor of Microalbuminuria in Type 1 Diabetes

Abstract

A substantial portion of type 1 diabetic patients develop diabetic nephropathy, whereas others seem to be protected from this complication. Persistent microalbuminuria (urinary albumin excretion rate [UAER] of 30 -300 mg/24 h) is an established risk factor for the development of overt diabetic nephropathy, characterized by albuminuria Ͼ300 mg/24 h (1). Microalbuminuria may be regarded as an early marker of diabetic kidney disease, as early renal structural lesions can be detected at this stage (2). Genetic susceptibility, metabolic abnormalities, hemodynamic changes, upregulated growth factors, and cytokines may all play a part in the development of diabetic glomerulopathy, although the complex pathogenesis of diabetic nephropathy is not fully understood (1). It has been suggested that inflammation and complement activation are involved in the pathogenesis of diabetic microvascular complications (3-6). Mannose-binding lectin (MBL; also known as mannan-binding lectin) can activate the complement system independent of antibodies via MBL-associated serine proteases, thereby initiating the so-called MBL pathway of complement activation (7). Through this pathway, MBL plays an important role in the innate immune system. The level of MBL varies considerably among individuals, mainly because of frequently occurring polymorphisms within exon 1 as well as in the promoter region of the MBL2 gene on chromosome 10 (8). High levels of MBL are known to protect against invading microorganisms (9,10) and in other situations may mediate detrimental inflammation through exaggerated complement activation (11,12). In a recent cross-sectional study, it was demonstrated that in normoalbuminuric type 1 diabetic patients, circulating MBL levels correlate positively with the UAER (4). Higher levels of MBL have been found to be associated with micro-and macrovascular complications in type 1 diabetic patients (5). However, no prospective studies have evaluated the association between MBL and subsequent development of microvascular complications. In the present study, MBL was measured 3 years after diabetes onset in a large inception cohort of newly diagnosed type 1 diabetic patients. These patients were followed for a median of 18 years to evaluate in a prospective design the association between baseline MBL concentrations and the development of persistent microalbuminuria. The change in MBL levels during 15 years of diabetes was also assessed.

Protection from inflammatory disease in insulin resistance: the role of mannan-binding lectin

“…These observations seem to contradict recent articles describing increased MBL concentrations in patients with type 1 diabetes with microvascular complications [29][30][31][32][33]. However, MBL plays a dual role in modifying inflammatory responses to injury [34].…”

Mannose-binding lectin deficiency attenuates renal changes in a streptozotocin-induced model of type 1 diabetes in mice

“…Diabetic nephropathy was more prevalent among type 1 diabetic patients with a high MBL expression genotype and high circulating MBL levels than among patients with a low MBL genotype and low serum MBL levels [5]. In a recent study in type 1 diabetic patients, followed for 18 years from diagnosis, high MBL level at baseline was a significant predictor of the development of either microalbuminuria or overt nephropathy [7].…”

“…Furthermore, in a cohort study of type 1 diabetic patients followed for 18 years from diagnosis, serum MBL was a significant predictor of later renal impairment. In patients with MBL levels above the median, 41% developed micro-or macroalbuminuria, in contrast to 26% of patients with levels below the median [7]. To evaluate a potential specific effect of MBL on the pathogenesis of diabetic kidney disease, we induced type 1 diabetes in wild-type and genetically modified MBL double knockout mice and examined the functional and structural renal changes.…”

Increased All-Cause Mortality in Patients With Type 1 Diabetes and High-Expression Mannan-Binding Lectin Genotypes: A 12-Year Follow-up Study

“…Several studies have demonstrated the close association between the lectin pathway of complement activation and diabetic nephropathy. In particular, high concentrations of the carbohydrate pattern-recognition molecule mannan-binding lectin (MBL), which initiates complement activation, are linked to diabetic nephropathy defined by urinary albumin excretion rate (2)(3)(4)(5)(6)(7)(8). In the present cohort, we previously showed the cross-sectional association between MBL2 genotype and diabetic nephropathy (2).…”