John R. Erbey

The association between a family history of type 2 diabetes and coronary artery disease in a type 1 diabetes population

OBJECTIVE To examine whether a potential marker for type 2 diabetes (family history) is related to CAD in type 1 diabetic subjects. The two major types of primary diabetes, type 1 and type 2, are both associated with an increased risk of developing coronary artery disease (CAD). However, the etiology and associated risk factors may differ by type of diabetes. In type 2 diabetes, CAD is likely to be linked with the insulin resistance associated with the type 2 “process,” while CAD in type 1 diabetes has, so far, been more closely linked to renal disease. Because the etiologies of type 1 and type 2 diabetes are different, it is possible that some CAD in type 1 diabetes may be related to the coexistence of type 2 diabetes susceptibility (i.e., insulin resistance). RESEARCH DESIGN AND METHODS We evaluated the interrelationships between family history of type 2 diabetes (age at onset >30 years, no insulin for 1st year) and presence of CAD in a cohort of childhood-onset type 1 diabetic subjects using the Pittsburgh Epidemiology of Diabetes Complications study (n = 658). RESULTS A first-degree family history of type 2 diabetes was reported in 112 subjects, and CAD was present in 119 subjects. Those subjects reporting a family history of type 2 diabetes were significantly older, had a longer duration of type 1 diabetes, had higher triglyceride and LDL cholesterol levels, and had a borderline significantly increased Beck depression inventory. Sex differences in CAD risk factors were also noted. Using logistic regression analysis, the odds ratio (95% CI) for the presence of CAD in association with a family history of NIDDM was 1.89 (1.27–2.84). The odds ratio (95% CI) after adjusting for disease duration, triglycerides, hypertension, Beck depression, and nephropathy status was 1.45 (0.87–2.28). CONCLUSIONS We conclude that a family history of type 2 diabetes is a risk factor for CAD in type 1 diabetic subjects. This supports the concept that insulin resistance may contribute to development of CAD in type 1 diabetes.

Subclinical Atherosclerosis and Estimated Glucose Disposal Rate as Predictors of Mortality in Type 1 Diabetes

PURPOSE To investigate the usefulness of ischemic resting electrocardiogram (ECG), ankle brachial index (ABI) <0.8, ankle brachial difference (ABD) > or = 75 mm Hg (a marker of peripheral medial arterial wall calcification), and estimated glucose disposal rate (eGDR) (a marker for insulin resistance) for predicting mortality risk in the context of standard risk factors. METHODS Data are from participants in the Pittsburgh Epidemiology of Diabetes Complications Study of 658 subjects with childhood onset Type 1 diabetes of mean age 28 years (range 8-48) and duration of diabetes 19 years (range 7-37) at baseline. Deaths were confirmed by death certificates. RESULTS There were 68 deaths from all causes during 10 years follow-up. In univariate analysis, the mortality hazard ratios and 95% confidence intervals associated with ischemic ECG (6.7, 3.7-12.1), the lowest quintile of eGDR (i.e., the most insulin resistant) (6.7, 4.1-10.9), ABI <0.8 (2.5, 1.1-5.9), and ABD > or = 75 mm Hg (6.7) were only marginally less than those conveyed by pre-existing coronary artery disease (8.4, 4.7-15.2) or overt nephropathy (7.6, 4.5-12.9). Ischemic ECG and eGDR were independent mortality predictors, together with duration of diabetes, coronary artery disease, overt nephropathy, nonhigh density lipoprotein cholesterol, and smoking history. If serum creatinine was available, it entered, and glycosylated hemoglobin replaced eGDR. CONCLUSIONS Estimated GDR and ECG ischemia are strong predictors of mortality in type 1 diabetes and may be useful in the identification of those at risk.

Do Tissue Plasminogen Activator-Plasminogen Activator Inhibitor-1 Complexes Relate to the Complications of Insulin-Dependent Diabetes Mellitus? Pittsburgh Epidemiology of Diabetes Complications Study

The purpose of this study was to examine the potential relationship of tissue plasminogen activator-plasminogen activator inhibitor-1 (tPA-PAI-1) complexes and diabetic complications in individuals with insulin-dependent diabetes mellitus (IDDM). To address this issue, data from the third follow-up visit of participants in the Epidemiology of Diabetes Complications (EDC) study were examined. There were 454 participants, aged 32 +/- 8 years, with duration of IDDM of 23 +/- 8 years. Higher levels of tPA-PAI-1 complexes were seen for both men and women with IDDM complications. Specifically, statistically significant differences were seen in men with neuropathy (1.81 +/- 0.9 versus 1.42 +/- 0.8 ng/mL, p < 0.01), microalbuminuria (1.77 +/- 1.1 versus 1.35 +/- 0.6 ng/mL, p < 0.01), retinopathy (1.67 +/- 0.9 versus 1.43 +/- 0.8 ng/mL, p < 0.05), and lower extremity arterial disease (1.93 +/- 0.7 versus 1.50 +/- 0.9 ng/mL, p < 0.05) versus men without the particular complication. In women, higher complex levels were shown for those with retinopathy (1.51 +/- 0.8 versus 1.29 +/- 1.1 ng/mL, p < 0.01). Potential mechanisms for the relationship of higher complex levels and diabetic complications include an altered fibrinolytic response and/or insulin resistance. Because the results are cross sectional, it cannot be established whether the higher concentration of complexes is a result of the presence of complications or are antecedent. Prospective follow-up will be required to determine if tPA-PAI-1 complexes are predictive of the development of IDDM complications.

Little relationship of plasminogen activator inhibitor (PAI-1) with complications of insulin-dependent diabetes mellitus: Pittsburgh epidemiology of diabetes complications study

Summary Objective: To examine the potential determinants of plasminogen activator inhibitor (PAI-1), the main regulatory component of the fibrinolytic process, and the relationship of PAI-1 with complications of insulin dependent diabetes mellitus (IDDM). Design: Cross-sectional study. Setting: Diabetes research center. Subjects: Individuals in this study were participants of the Epidemiology of Diabetes Complications study, a 10-year prospective study examining the prevalence, incidence, and interrelationships of the various complications of IDDM. Main Outcome Measures: Major complications of diabetes were assessed by standardized procedures (i.e. retinopathy [fundus photography], neuropathy [based on Diabetes Control and Complications Trial protocol], nephropathy [elevated albumin excretion rate (>200 μg/min)], coronary artery disease [myocardial infarction/angina], lower extremity arterial disease [ankle brachial index of Results: PAI-1 levels were not found to be significantly increased with any specific IDDM complication. Modelling potential correlates in linear regression analyses where PAI-1 was the dependent variable revealed independent associates with body mass index and triglycerides for males and age, fibrinogen, smoking history, and oral contraceptive use for females. Conclusions: The association of PAI-1 and other risk factors is complex with these data indicating an interdependent rather than an independent role for PAI-1 in IDDM complication development.