With Type 1 Diabetes Developing Microalbuminuria in Comparison to Normoalbuminuric Control Subjects
ACR, albumin-to-creatinine ratio
MA was defined as an ACR >3.5 mg/mmol in male subjects and >4.0 mg/mmol in female subjects and <35 mg/mmol in two of three consecutive early-morning urine collections (3). This corresponded to an albumin excretion rate of between 20 and 200 mcg/min, as determined in 304 timed overnight urine samples using linear regression equations.
Poor glycemic control and differences in IGF-I levels and androgens, particularly in female subjects, accompany development of MA at puberty. These differences may in part account for the sexual dimorphism in MA risk during puberty and could relate to disease progression.
Microalbuminuria (MA) is a marker of incipient nephropathy in adult subjects with type 1 diabetes (1). There is an unequivocal relationship between poor glycemic control and the development of MA (2). However, independent of poor glycemic control, early diabetic complications risk is increased with the onset of puberty (3). In addition, MA risk is twofold greater in pubertal female patients compared with male patients (3), in contrast to lifetime risk of diabetic nephropathy, which is greater in male patients (4)
Puberty and sex are also independent risk factors for the development of MA (3). Pubertal onset is associated with an acceleration in the urine albumin excretion rate compared with the years during prepuberty, and this may be predictive of MA (20), and female subjects are at a twofold greater risk of MA compared with male subjects (3). This marked sexual dimorphism is also apparent in other areas at puberty, as evidenced by the increased risk in adolescent female subjects for developing retinopathy (7), obesity (5), and attenuated growth (6). These data suggest hormonal changes during puberty may effect the development of MA in susceptible individuals.
Thus, circulating GH levels are increased while circulating IGF-I levels remain low, and these changes may be more apparent in female than in male subjects (10). The integrity of GH pathways in tissues other than the liver are thought to remain intact, and both GH hypersecretion and local paracrine IGF-I production have been implicated in the pathophysiology of diabetic nephropathy.
In summary, the development of MA at puberty may reflect not only poor glycemic control but also changes in the GH-IGF-I axis and ovarian function. Changes in pubertal hormonal variables differ in those with MA, particularly in female patients, and these differences may relate to disease progression. Aggressive insulin therapy has been shown to reduce diabetic complication risk (2). However, this may confer increased weight gain and hypoglycemia (2) and predispose to the detrimental effects of peripheral hyperinsulinemia, such as the development of ovarian hyperandrogenism. Increasing the insulin dose to overcome insulin resistance may lead to further weight gain (2) and, in female patients, a cycle of insulin omission to lose weight (30). This pattern of insulin misuse has been linked to the increased risk of diabetic complications in adolescent girls during puberty (31). Our observations suggest alternative therapy directed at underlying mechanisms, such as insulin sensitizers, IGF-I therapy, and anti-androgen therapy, might also be explored in attempts to reduce progression of microvascular complications in high-risk individuals during puberty.