Nephropathy in type 1 diabetes: a manifestation of insulin resistance and multiple genetic susceptibilities? Further evidence from the Pittsburgh Epidemiology of Diabetes Complication Study.
BACKGROUND
The pathogenesis of diabetic nephropathy remains unclear, although previous reports implicate a wide range of putative genetic and metabolic factors.


METHODS
Incident and prevalent cases of overt nephropathy (ON), defined as an albumin excretion rate>200 microg/min in at least two of the three timed urines, from the Pittsburgh Epidemiology of Diabetes Complication Study (a prospective epidemiologic study of an incident cohort of childhood onset type 1 diabetic subjects) were studied.


RESULTS
Incidence analyses reveal differences in univariate baseline risk factors that predict ON within 5 years of measurement [low-density lipoprotein (LDL) cholesterol, triglycerides, white blood cell count, and hypertension] and those that predict in the long-term, that is, 6 to 10 years after baseline, hemoglobin A1 (Hb A1). Estimated glucose disposal rate (calculated using a formula derived from euglycemic-hyperinsulinemic clamp studies), however, strongly (P < 0.001) predicted ON throughout follow-up. Comparing individuals who were most susceptible to ON (those with an onset before 20 years duration of type 1 diabetes and before the development of other advanced complications) with the least susceptible (late or no occurrence of ON despite the development of other advanced complications) revealed otherwise undetected genetic associations [that is, apolipoprotein E (Apo E), angtiotensin-converting enzyme insertion/deletion (ACE I/D), and lipoprotein lipase (LPL) HindIII polymorphism) with odds ratios ranging from 2.9 to 7.1.


CONCLUSIONS
In type 1 diabetes insulin resistance is an underlying risk state for ON, which may be accelerated by other disturbances (for example, hypertension and dyslipidemia). A novel approach to classifying (that is, phenotyping) subjects, which compares those at the extremes of susceptibility, reveals strong genetic associations and important interactions with other risk factors not otherwise apparent.
Orchard
Trevor J
TJ
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, DLR Building, 35123 Fifth Avenue, Pittsburgh, PA 15213, USA. tjo@pitt.edu
Chang
Yue-Fang
YF
Ferrell
Robert E
RE
Petro
Nancy
N
Ellis
Demetrius E
DE
D000293:Adolescent; D000328:Adult; D001057:Apolipoproteins E / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008071:Lipoprotein Lipase / Q000235:genetics; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors
D001057:Apolipoproteins E; D008071:Lipoprotein Lipase; D007703:Peptidyl-Dipeptidase A