Nephropathy (NP) is a frequent, devastating consequence of non-insulin- dependent diabetes mellitus (NIDDM) and hypertension (HTN). The prevalence of NP is particularly high among African Americans (AAs). AA women with a history of gestational diabetes mellitus (GDM) are at high risk for NIDDM and HTN and probably NP. Persistent urinary albumin excretion,, microalbumnuria (MA), is the earliest clinical evidence of many cases of NP. MA may precede the onset of clinical diagnosis of NIDDM and/or HTN. The frequency of MA prior to the onset of these clinical disorders in this high risk population is unknown. The proposed study will estimate these rates. The factors which cause MA are uncertain. We propose to test the hypothesis that insulin resistance (IR) is a phenotype influenced by genes in or near the Major Histocompatibility Complex (MHC) that results in increased occurrence and rate of progression of kidney dysfunction and this relationship is in part independent of the relationship between IR and two of its hypothesized sequelae, HTN and dyslipidemia both of which have been hypothesized as causes of MA. We will test the hypothesis that IR and the hyperinsulinemia which it causes lead to elevated fibrinogen levels and impaired fibrinolytic activity which results in MA in combination with hyperglycemia, HTN and dyslipidemia. We propose to test the hypotheses in a longitudinal study of a well established cohort of AA women who presented with GDM (N=450) and an additional cohort of recent GDMs (N=100). We will assess their status with respect to the genetic phenotype IR and possible genetic markers of the phenotype and MA (HLA-DR and DQ). We also propose to assess its hypothesized biochemical and physiological sequelae HTN, dyslipidemia, (hyperinsulinemia, hyperfibrinogenemia, hyperplasminogen activator inhibitor-1 activity) as well as possible confounders, e.g. smoking and dietary protein intake. Urinary albumin excretion rate (UAER) and MA will be assessed. Kidney function will be assessed by a 24 hour creatinine clearance (CC). The women will be examined three times over five years. The statistical analyses are designed to determine the influence of IR and the relative contribution of each of its sequelae and their interaction in the occurrence of MA and the change in UAER and CC over time. The goal is to understand the role of these factors that lead to MA and ultimately to prevent NP.
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