The results of this study demonstrate that central obesity, as measured by waist circumference, is an independent risk factor for incident microalbuminuria in individuals with type 1 diabetes. This temporal association suggests that metabolic abnormalities that are associated with central obesity may contribute to the pathogenesis of microalbuminuria in type 1 diabetes. In contrast, no association was observed between waist circumference and change in creatinine clearance over time, further suggesting that microalbuminuria and loss of excretory kidney function may have different risk factors and pathogenic mechanisms in this population.
Previous studies in type 1 diabetes support the observed association between central obesity and incident microalbuminuria. Two cross-sectional analyses, one using data midway through the EDIC study, observed that WHR was correlated positively with AER (12
). In the Eurodiab study, baseline WHR was greater in those who had microalbuminuria at follow-up than in those who did not (16
). Although the Eurodiab study was limited by loss to follow-up and a lack of serial AER measurements, the magnitude of risk that was associated with central obesity, relative to established risk factors such as HbA1c
and baseline AER, is consistent with the results of our study.
Central obesity also has been associated with microalbuminuria among individuals without diabetes and among individuals with type 2 diabetes, suggesting that the effective mechanism is not unique to type 1 diabetes (7
). Because adjusting for BP and serum lipid concentrations resulted in only modest attenuation of the risk for incident microalbuminuria that was associated with central obesity, it is likely that other pathways contribute to this effect. Insulin resistance is associated with both central obesity and microalbuminuria and may play a prominent mediating role. No direct measures of insulin sensitivity are available in this study, but in another prospective study of individuals with type 1 diabetes, lower estimated glucose disposal rate was associated with an increased risk for overt nephropathy (14
). These observations suggest that individuals with type 1 diabetes and superimposed features of insulin resistance, or “double diabetes,” are at increased risk for microalbuminuria. Additional possible mediators of the association between central obesity and incident microalbuminuria include inflammatory proteins as well as circulating hormones that are released by visceral adipose tissue, such as adiponectin and components of the renin-angiotensin system.
Central obesity is a modifiable risk factor. Weight loss has been associated with a decrease in AER among obese individuals with overt diabetic nephropathy and among individuals without diabetes and with severe obesity (29
). Whether weight gain or weight loss is associated with change in AER among individuals with diabetes and normoalbuminuria or microalbuminuria has not been reported.
Creatinine clearance estimates GFR, which reflects excretory kidney function. In cross-section at DCCT closeout, unadjusted creatinine clearance was associated positively with waist circumference, reflecting the known relationship between body size and GFR. This association was nullified (for women) or reversed (for men) when creatinine clearance was adjusted for BSA, in accordance with standard practice. More important, however, waist circumference was not associated with rate of decline in creatinine clearance over time in this study, the first to our knowledge that has examined this relationship in type 1 diabetes. These results contrast with observations from the general population, in which central obesity has been associated with lower estimated GFR and a decline in estimated GFR over time (6
Although variation in creatinine clearance measurements in this study was wide, poor accuracy and/or precision alone likely is not the sole cause of the lack of an observed association with waist circumference, because associations of several covariates (age, DCCT treatment group, smoking status, HbA1c
, and AER) with change in creatinine clearance were identified. The slow rate of decline in creatinine clearance, relative to that expected with age alone (31
), also did not prevent observation of associations with these covariates. Alternative explanations include (1
) a time lag between microalbuminuria and decreased GFR that extends beyond the follow-up period of this study and (2
) a true disparity of the effect of central obesity on microalbuminuria versus
An effect of central obesity on GFR delayed beyond 8 yr of follow-up is feasible and cannot be excluded. Because elevated AER was among the strongest determinants of decline in GFR over time in this study, one reasonably could expect that microalbuminuria that is induced in part by central obesity eventually would lead to a decline in GFR. However, waist circumference was not a risk factor for decline in creatinine clearance among participants who already had elevated AER at DCCT closeout.
Not all individuals with type 1 diabetes and microalbuminuria progress to a significant loss of GFR, suggesting that these two measures of kidney disease are not inextricably linked (32
). Such a dissociation is consistent with the observation that some EDIC study participants lost GFR with sustained normal AER (34
). Moreover, our results are consistent with those that were observed among patients who had type 2 diabetes and were enrolled in the United Kingdom Prospective Diabetes Study, in which greater waist circumference was associated with incident albuminuria (both microalbuminuria and clinical grade albuminuria) but not with subsequent decreased kidney function (26
). Thus, microalbuminuria may reflect diffuse vascular damage that is related more directly to central obesity than is GFR (35
). The relationships between microalbuminuria and other components of kidney function, including excretory and synthetic function, merit further investigation, as does the role of central obesity in these relationships.
Weight gain and central obesity are well-characterized complications of intensive insulin therapy in type 1 diabetes (5
). Previous DCCT and EDIC study analyses have shown clearly that, on balance, intensive insulin therapy reduces the incidence of microalbuminuria and clinical grade albuminuria (3
). Thus, even with the associated weight gain, intensive therapy still has a beneficial effect on microalbuminuria and clinical grade albuminuria. Results from this study suggest that weight gain that results from intensive therapy may identify those who are at increased risk for renal complications, perhaps as a result of an inherited predisposition to insulin resistance, and may modify the pathways through which renal complications occur in type 1 diabetes (36
Results from this study identify preservation of GFR as an additional benefit of intensive insulin therapy. Compared with those who had received conventional therapy during the DCCT, individuals who had received intensive therapy had a slower decline in creatinine clearance over EDIC study follow-up. Similarly, lower HbA1c
at DCCT closeout was associated with relative preservation of creatinine clearance. These observations are consistent with previously published analyses showing that intensive therapy during the DCCT resulted in a reduced likelihood of developing a creatinine clearance <70 ml/min per 1.73 m2
and a trend toward greater mean creatinine clearance during EDIC study follow-up (4
This study has several limitations. First, radiographic quantification of body fat distribution was not available. Multiple measurements of body size were associated with incident microalbuminuria, and because these measurements were highly correlated, we could not establish conclusively that the relationship of obesity with incident microalbuminuria was attributable specifically to visceral adipose tissue. Second, the measurement method for creatinine clearance was not optimal and the duration of follow-up for this outcome may have been insufficient to detect an association with central obesity. Finally, results from a clinical trial setting may not generalize to the broader population with type 1 diabetes, who may have differing levels of self-care, medication adherence, and physical fitness, and findings from this predominantly white population may not apply to individuals of other race/ethnicity.