Physiology of Disease Prevention Observational Study in Clinical Practice

It is well known that the Type 2 diabetes and vascular disease are preceded by over ten years by metabolic dysfunction and anatomic changes that can be quantified. In order to develop effective preventive strategies and reduce the cost burden to the health care system, recognition of the earliest pathophysiology of Type 2 diabetes and vascular disease is clinically relevant. In patients with risk factors for type 2 diabetes and/or vascular disease, we have quantified this dysmetabolic state using glucose tolerance testing to quantify insulin resistance and beta cell function while measuring vascular biomarkers as well as Intima-media thickness and carotid plaque to characterize cardiovascular risk. The interval retrospective evaluation of data from patient records, reflect the effectiveness of the various treatments implemented in clinical practice.

Prevalence of "prediabetes" among American adults is estimated to be ~84 million, or one out of three Americans. Over a 5-7 year period approximately one third of these prediabetic individuals will progress to type 2 diabetes. Prediabetes is a heterogenous group comprised of individuals with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and increased A1c (5.7-6.4%). Although different pathophysiologies are present in individuals with IFG and IGT, their conversion rate to overt type 2 diabetes mellitus (T2DM) is similar.

Prospective epidemiologic studies have demonstrated that ~40% of subjects who progress to T2DM over 5 years had Normal glucose tolerance (NGT) at baseline, suggesting that a large group of NGT subjects also are at increased T2DM risk. It has previously been demonstrated that a 1-hour plasma glucose concentration >155 mg/dl identifies a subgroup of NGT subjects with high future T2DM risk.

Further, multiple studies have demonstrated that background retinopathy, microalbuminuria, and peripheral neuropathy are present in 10-20% of prediabetic individuals. Compared with normoglycemic patients, those with prediabetes were associated with a 13-30% higher risk for composite cardiovascular disease.

Insulin resistance is a common causal feature of many of the pathophysiologic mechanisms linking macrovascular disease and type 2 diabetes. Because hyperglycemia is the major factor responsible for the development of microvascular complications, it logically follows that prevention of progression of prediabetes to overt diabetes should retard/prevent the development of the microvascular complications. From the measurement of plasma glucose, insulin, and c-peptide levels during the oral glucose tolerance test, one can derive measures of the two core defects responsible for the development of T2DM, i.e. insulin resistance and beta cell dysfunction as well as the degree of dysglycemia.