Familial Risk Factors for Microvascular Complications and Differential Male-Female Risk in a Large Cohort of American Families with Type 1 Diabetes

Abstract

Context: Type 1 diabetes (T1D) complications are responsible for much of the disease morbidity. Evidence suggests that familial factors exert an influence on susceptibility to complications. Objectives:We investigated familial risk factors and gender differences for retinopathy, nephropathy, and neuropathy. Design and Setting:This study was a case-control design nested on a cohort of T1D families. We collected data (questionnaire, medical records) starting in 1988. Follow-up has been ongoing since 2004.Patients: There were 8114 T1D patients among 6707 families. All patients had T1D onset age younger than 30 yr and required insulin treatment. Patients who remained without a complication after more than 15 yr of diabetes were considered to be without that complication for our analyses. Results:A complication in a sibling increased the risk for that complication among probands: odds ratio 9.9 (P Ͻ 0.001) for retinopathy, 6.2 for nephropathy (P Ͻ 0.001), and 2.2 for neuropathy (P Ͻ 0.05). Compared with male probands, a female T1D proband had 1.7-fold higher retinopathy risk (P Ͻ 0.001) and 2-fold higher neuropathy risk (P Ͻ 0.001). T1D cases with onset between ages 5 and 14 yr had an increased complications risk compared with subjects diagnosed either at a very young age or after puberty. The presence of one complication significantly increased the risk for others. If a parent had type 2 diabetes, the risk for nephropathy increased (odds ratio 1.9, P Ͻ 0.01, but T1D in a parent did not increase the risk). Conclusions:We confirmed that familial factors influence T1D microvascular pathologies, suggesting a shared genetic basis for complications, perhaps independent of T1D susceptibility. We also found an unexpected increased female risk for complications. R ETINOPATHY, NEPHROPATHY, and neuropathy are long-term microvascular complications responsible for much of the morbidity in type 1 diabetes and type 2 diabetes. Retinopathy, a major cause of blindness (1), occurs in up to 50% of type 1 diabetes patients and in about 10% of patients with type 2 diabetes who have had the disease for 15 or more years (2). Ten to 20% (cumulative prevalence) of type 1 diabetes patients have established nephropathy (3-7), a leading cause of end-stage renal failure and the primary cause of excess mortality in type 1 diabetes patients (8). Diabetic neuropathies affect different parts of the nervous system and present with diverse clinical manifestations. Evidence suggests that familial factors exert a strong influence on susceptibility to complications (8 -11); and a family history of type 2 diabetes has been reported to be a risk factor for diabetic nephropathy in type 1 diabetes patients (12).Our goals were to identify familial risk factors for diabetic microvascular complications and to examine how these risk factors influence retinopathy, nephropathy, and neuropathy onset. We analyzed data from the large cohort of type 1 diabetes patients and families assembled over 25 yr by the Human Biological Data Interchange (HBDI), a program of the...

Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes

“…This increase in blood pressure is reversed by either exogenous estrogen, the GPR30 agonist G-1, or the AT 1 receptor antagonist olmesartan, suggesting that activation of the ACE-ANG II-AT 1 receptor axis is negatively influenced by the GPR30 estrogen receptor in this model (9,24). Clinical and experimental studies suggest that females are not afforded protection from diabetic pathologies including renal injury compared with males (4,6,19,29,50). The exact mechanism for the loss of protection is not known particularly in the setting of hypertension.…”

Effect of Parental Type 2 Diabetes on Offspring With Type 1 Diabetes

“…Previous studies have indeed shown an association with intermediate markers of cardiovascular disease such as carotid intima-media thickness (17) as well as with cardiovascular disease itself (13). Regarding microvascular complications, a family history of type 2 diabetes has been associated with diabetic retinopathy (18) and with diabetic nephropathy in some (13)(14)(15)18) but not all (11) studies. In the present study we did not observe any association between a parental history of type 2 diabetes and microvascular complications despite a long duration of type 1 diabetes and despite differences in the metabolic risk profile.…”

Microvascular and Macrovascular Complications in Children and Adolescents with Type 1 Diabetes

“…Family history of cardiovascular risk factors is associated with increased risk of microvascular complications in the offspring (Monti et al, 2007;Seaquist et al, 1989). A high body mass index (BMI) represents another potential risk factor for microvascular complications in youth with type 1 diabetes (Stone et al, 2006).…”