Nephropathy of type II diabetes: Evidence for hereditary factors?

Abstract

Family studies point to an important genetic element in the genesis of diabetic nephropathy, but it is not known whether renal abnormalities are present prior to the onset of diabetes. To address this issue we examined all consecutive patients suffering from type II diabetes with a duration of more than 10 years who attended a diabetes outpatient clinic. Ninety-four patients had nephropathy, 307 did not. All offspring who were phenotypically normal (no hypertension, normal oral glucose tolerance, non-smoking) and agreed to participate were examined, 26 from nephropathic and 30 from non-nephropathic diabetic parents. They were compared with 30 offspring matched for age, gender and BMI from non-diabetic parents as controls. We measured urinary albumin excretion under baseline conditions and at several time points after ingestion of 300 g cooked beef and submaximal treadmill exercise, respectively. In addition, casual blood pressure, ambulatory blood pressure, urinary albumin and urinary alpha-1-microglobulin were measured. Primary renal disease was excluded by clinical examination. Under baseline conditions, median urinary albumin excretion rate (AER; microgram/min) was significantly (P < 0.005) higher in offspring of nephropathic type II diabetic patients (7.8; range 1.04 to 19.5) than in the offspring of non-nephropathic type II diabetic patients (4.8; 0.36 to 17.5) and controls (4.4; 0.16 to 18.4). Submaximal treadmill exercise caused a greater proportional increase of AER in offspring of nephropathic type II diabetics (median 16-fold) than in offspring of non-nephropathic diabetic patients (6.3-fold) or controls (4.8-fold). In offspring of nephropathic diabetic patients casual and particularly ambulatory systolic blood pressures were significantly higher, but AER was not correlated with blood pressure. In summary, higher values, albeit within the normal range, for baseline and postexercise albuminuria were noted in phenotypically normal offspring of parents with type II diabetes and nephropathy. The observation suggests that changes in transglomerular albumin traffic are demonstrable prior to the onset of diabetes and diabetic nephropathy in subjects with a potential genetic predisposition to these conditions.

Segregation analysis of urinary albumin excretion in families with type 2 diabetes.

“…Previous studies of nondiabetic siblings and offspring of cases with type 2 diabetes and nephropathy have also suggested that genetic factors contribute to elevated albumin excretion (32)(33)(34). However, these studies were relatively small and, unlike the present study of UAE in extended families, they could not yield estimates of the mode of inheritance of the putative major genetic locus influencing albumin excretion, which has potential utility for gene mapping studies.…”

Peroxisome Proliferator-Activated Receptor-γ2 Polymorphism Pro12Ala Is Associated With Nephropathy in Type 2 Diabetes

“…In this regard, the prevalence of microalbuminuria has been reported to be significantly higher in Mexican-American than in non-Hispanic white diabetic subjects (21,22), and higher UAEs have been observed in offspring of patients with type 2 diabetes (23). Strojek et al (8) recently reported higher UAE rates in healthy offspring of diabetic parents with nephropathy versus those without nephropathy. Furthermore, the risk of developing diabetic nephropathy has been linked to different chromosomes, including chromosome 3 (10), on which the gene encoding PPAR-␥2 is located.…”

DHEA Induces 11β-HSD2 by Acting on CCAAT/Enhancer-Binding Proteins

“…28 -32 Furthermore, salt sensitivity, at least in part attributable to reduced 11␤-HSD2 activity, 33 and hypertension are risk factors associated with diabetes. 34,35 Lavery et al 36 provided evidence for an association between mutations in HSD11B2 and diabetic nephropathy. Recent studies suggested that DHEA might have beneficial effects in obese Zucker rats with diabetic nephropathy.…”