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The Burden of Prediabetes
Prediabetes is a condition defined by the presence of impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) that has not yet reached the threshold for type 2 diabetes mellitus (T2D); the metabolic syndrome is also considered a prediabetes equivalent (1,2). Prediabetes raises short-term absolute risk of T2D by 3- to 10-fold (2). In the United States, 86 million people, or 37% of the US population, have prediabetes, and it is estimated that up to 70% of people with prediabetes may develop T2D during their lifetimes (3,4).
According to a National Health and Nutrition Examination Survey (NHANES) conducted in 2010, while one-third of US residents have prediabetes, only 11% have received a formal diagnosis from a physician (5). In a 2006 NHANES study, no patients reported receiving oral antihyperglycemic agents, while the percentage who received a physician recommendation for exercise or diet was 31.7% and 33.4%, respectively. Furthermore, among those diagnosed with prediabetes, 68% had tried to lose or control their weight, 60% had reduced dietary fat or calories, 55% had increased their physical activity or exercise, and 42% had engaged in all 3 activities (6).
Prediabetes is a state of abnormal glucose homeostasis characterized by the presence of IFG, IGT, or both. This abnormal glucose homeostasis is a result of both beta-cell failure and insulin resistance (2,7-9). Prediabetes and subsequent T 2D  likely develop as a result of polygenic defects that predispose affected individuals to the disease. Environmental factors such as a sedentary lifestyle and a high-fat diet can exacerbate defects in both insulin secretion from pancreatic beta-cells and insulin action in muscle and adipose tissues.
The modest hyperglycemia characteristic of the prediabetic state (A1C 5.5% to 6.4%) results in glucotoxicity, while in overweight individuals (particularly those with central adiposity), elevated free fatty acid (FFA) levels lead to lipotoxicity. Both gluco- and lipotoxicity worsen beta-cell secretion, which in turn aggravates hyperglycemia (1,2,7-9).
IFG and IGT represent the transitional states of abnormal glucose regulation that occur between normal glucose homeostasis and T2D (4). Both muscular and hepatic insulin resistance are present in individuals with IFG and/or IGT. Individuals with isolated IFG have hepatic insulin resistance and normal muscle insulin sensitivity, while individuals with isolated IGT have normal to slightly decreased hepatic insulin sensitivity and moderate to severe muscle insulin resistance.
Isolated IFG is associated with decreased first-phase (0-10 min) insulin secretory response to intravenous (IV) glucose, decreased early phase (first 30 min) insulin response to oral glucose, and normal late-phase (60-120 min) insulin response. Isolated IGT is associated with decreased early phase insulin response to oral glucose and results in a severe deficit in late-phase insulin secretion (4).
A wide variety of organ systems are involved in T2D  pathophysiology , with many defects contributing in the progression from prediabetes to T2D. The primary defects that lead to T2D are impaired insulin secretion from beta-cells, impaired insulin action in muscle, and increased hepatic glucose production (10). (For more information, see the T2D section.) The complex interplay between these defects contributes to the ongoing progression of T2D.
The intermediate condition of prediabetes constitutes inherent disease risk for the progression to diabetes. The rate of progression to diabetes for patients with IGT was 11% per year over the 3-year follow-up period of the Diabetes Prevention Program (11). For persons with both IFG and IGT, the cumulative incidence of diabetes by 6 years may be as high as 65% (compared with levels of approximately 5% for individuals with normal glucose levels) (2).
Economic Burden
In 2012, prediabetes accounted for $44 billion dollars in direct medical expenditures (12). Even only modestly elevated blood glucose levels are associated with an increased risk of coronary heart disease (CHD), hypertension, retinopathy, and mortality (13). A study conducted in 2009 by Zhang and colleagues used medical claims data to estimate per capita excess healthcare use associated with prediabetes, and combined these data with national estimates of healthcare use and medical costs to calculate national expenditures related to prediabetes. Patients with confirmed prediabetes had approximately 34% more ambulatory visits per year compared to the general population—ranging from 9% more visits for cardiovascular disease (CVD) and peripheral vascular disease to 92% more visits for hypertension.
Children and Adolescents 
Prediabetes is uncommon in children younger than 10 years of age. However, prevalence has risen steadily among adolescents (14). According to NHANES data, during 1999-2002, the unadjusted prevalence of prediabetes (defined as A1C 5.7% to 6.5% or IFG) among US adolescents aged 12 to 17 years was 13.3%. This figure rose to 14.6% in 2003-2006 and to 17.9% in the 2007-2010 survey period. These data suggest a 4.6% increase in prediabetes among US adolescents over the entire 11-year period.
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2.   Garber AJ, Handelsman Y, Einhorn D, et al. Diagnosis and management of prediabetes in the continuum of hyperglycemia: when do the risks of diabetes begin? A consensus statement from the American College of Endocrinology and the American Association of Clinical Endocrinologists. Endocr Pract. 2008;14:933-946.
3.   Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States, 2014. In: Services USDoHaH, ed. Atlanta, GA: U.S. Department of Health and Human Services; 2014. Available at:
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6.   Centers for Disease Control and Prevention. Self-reported prediabetes and risk-reduction activities—United States, 2006. MMWR Morb Mortal Wkly Rep. 2008;57:1203-1205.
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11. Diabetes Prevention Program Research Group, Knowler WC, Barrett-Connor E, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.
12. Dall TM, Yang W, Halder P, et al. The economic burden of elevated blood glucose levels in 2012: diagnosed and undiagnosed diabetes, gestational diabetes mellitus, and prediabetes. Diabetes Care. 2014;37:3172-3179.
13. Zhang Y, Dall TM, Chen Y, et al. Medical cost associated with prediabetes. Popul Health Manag. 2009;12:157-163.
14. Bullard KM, Saydah SH, Imperatore G, et al. Secular changes in U.S. Prediabetes prevalence defined by hemoglobin A1c and fasting plasma glucose: National Health and Nutrition Examination Surveys, 1999-2010.Diabetes Care. 2013;36:2286-2293.

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