https://www.kidney-international.org/article/S0085-2538(15)48863-5/pdf

Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64).

The Wisconsin epidemiologic study of diabetic retinopathy. VI: Retinal photocoagulation

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(10)60576-4.pdf

Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial

Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality in the United States.1 Primary prevention and secondary prevention of CVD are public health priorities.2 Substantial data indicate that CVD is a life course disease that begins with the evolution of risk factors that in turn contribute to the development of subclinical atherosclerosis.3,4 Subclinical disease culminates in overt CVD.5,6 The onset of CVD itself portends an adverse prognosis with greater risk of recurrent events, morbidity, and mortality.7,8 It is also increasingly clear that although clinical assessment is the keystone of patient management, such evaluation has its limitations.9–12 Clinicians have used additional tools to aid clinical assessment and to enhance their ability to identify the “vulnerable” patient at risk for CVD, as suggested by a recent National Institutes of Health (NIH) panel.13,14 Biomarkers are one such tool to better identify high-risk individuals, to diagnose disease conditions promptly and accurately, and to effectively prognosticate and treat patients with disease. This review provides an overview of the molecular basis of biomarker discovery and selection and the practical considerations that are a prerequisite to their clinical use.

The term biomarker (biological marker) was introduced in 1989 as a Medical Subject Heading (MeSH) term: “measurable and quantifiable biological parameters (eg, specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, environmental exposure and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development, epidemiologic studies, etc.” In 2001, an NIH working group standardized the definition of a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” …

Biomarkers of cardiovascular disease: molecular basis and practical considerations.

The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XVII. The 14-year incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes

Clinical risk factors for nephropathy were assessed in a population-based study of Rochester, Minnesota, residents with diabetes mellitus initially diagnosed between 1945 and 1969 (incidence cohort). The 1031 Rochester residents with non-insulin-dependent diabetes mellitus (NIDDM) were followed through their complete medical records in the community to 1 January 1982. The prevalence of persistent proteinuria was 8.2% at the diagnosis of NIDDM. Among those initially free of persistent proteinuria, the subsequent incidence was 15.3/1000 person-yr. Twenty years after the diagnosis of diabetes, the cumulative incidence of persistent proteinuria was 24.6%. A proportional hazards model identified the following risk factors for persistent proteinuria in NIDDM: elevated initial fasting blood glucose (P less than .01); older age at onset of diabetes (P less than .01); male gender (P = .05); and presence of macrovascular disease (P = .05), diabetic retinopathy (P = .05), or glycosuria (P = .07) at the diagnosis of diabetes. Separate analyses controlling for attained age indicated no association between duration of NIDDM and the incidence of persistent proteinuria. Stratified analysis of the two most significant risk factors (fasting blood glucose and age) indicated that hyperglycemia was a stronger risk factor for proteinuria in younger diabetic subjects, perhaps because of a competing risk of death in the elderly diabetic patient. In contrast to a recently described decreasing secular trend of proteinuria in Danish insulin-dependent diabetes mellitus patients, there was no decrease over the past 40 yr in proteinuria risk in this NIDDM incidence cohort.

Epidemiology of persistent proteinuria in type II diabetes mellitus. Population-based study in Rochester, Minnesota.

Among the 1135 Rochester residents discovered to have diabetes in the period 1945–69, the prevalence of retinopathy was 2.6% at the time of initial diagnosis. Among those free of retinopathy at diagnosis of diabetes, the subsequent incidence of any retinopathy was 17.4 per 1000 person-years and for proliferative retinopathy alone was 1.6 per 1000 person-years, based on 12,000 person-years of follow-up. The incidence rate of retinopathy was almost three times greater among residents with insulin-dependent (IDDM) than with non-insulin-dependent diabetes (NIDDM); however, the actual number of retinopathy cases was over four times greater among the more numerous residents with NIDDM. By 20 yr after diagnosis of diabetes, the cumulative incidence of retinopathy approached 70% among IDDM subjects and was 30% and 36%, respectively, among the obese and nonobese NIDDM residents. The epidemiologic patterns for proliferative retinopathy were qualitatively similar to those for nonproliferative retinopathy. The risk of blindness was greater among those with proliferative than with nonproliferative retinopathy but was substantial even for those without retinopathy. Most blindness was caused by factors other than isolated diabetic retinopathy.

Incidence of diabetic retinopathy and blindness: a population-based study in Rochester, Minnesota.

Retinopathy is an important sequela of diabetes mellitus, but clinical risk factors for this condition have rarely been assessed in a geographically defined population. In this population-based study, the 1135 Rochester, Minnesota, residents with diabetes mellitus initially diagnosed between 1945 and 1969 (incidence cohort) were followed through their complete medical records in the community to January 1, 1982. Because most of the cases of diabetic retinopathy in Rochester residents developed in patients with non-insulin-dependent diabetes mellitus (NIDDM), risk factors for diabetic retinopathy were examined in this group (N = 1031). A proportional hazards model identified the following risk factors for diabetic retinopathy in NIDDM: elevated initial fasting blood glucose level, marked obesity, and earlier age at onset of diabetes. Stratified analyses indicated that duration of diabetes was also significantly associated with an increased risk of retinopathy. Two secular trends, increasing detection of "mild" NIDDM and decreasing risk of diabetic retinopathy, had a major effect on retinopathy risk assessment. These data also suggest that insulin therapy is not an independent risk factor for diabetic retinopathy.

L. J. Melton

Papers

Epidemiology of persistent proteinuria in type II diabetes mellitus. Population-based study in Rochester, Minnesota.

Incidence of diabetic retinopathy and blindness: a population-based study in Rochester, Minnesota.

Risk factors for diabetic retinopathy: a population-based study in Rochester, Minnesota.