Pathogenesis

There are two underlying mechanism that lead to the onset of clinical T2D: inadequate insulin action in target tissues (insulin resistance) and inadequate secretion from pancreatic ^-cells (Fig. 1) (14). Insulin resistance arises prior to the onset of clinical disease, but predicts the development of diabetes (15-17). Environmental factors, particularly obesity and a sedentary lifestyle, are important contributors to the development of diabetes, largely because of their effects on insulin sensitivity (18-20). When target tissues become insulin resistant, glucose uptake is decreased, hepatic glucose production increases, and lipolysis is enhanced. In muscle, the increased free fatty acid (FFA) availability accelerates fat oxidation, resulting in decreased insulin-mediated glucose uptake and disposal. In the liver, elevated FFAs promote gluconeogenesis and increase hepatic glucose output.

When inadequate insulin secretion from pancreatic ^-cell dysfunction is also present, hyperglycemia develops, heralding the onset of T2D (14-17). In the natural history of progression to diabetes, ^-cells initially increase insulin secretion in response to insulin resistance and, for a period of time, are able to effectively maintain glucose levels below the diabetic range. However, when ^-cell function begins to decline, insulin production is inadequate to overcome the insulin resistance, and blood glucose levels rise. Insulin resistance, once established, remains relatively stable over time. Therefore, progression of T2D is a result of worsening ^-cell function with pre-existing insulin resistance.

Ominous Octet Diabetes

Fig. 1. Defects in the pancreas and in target tissues for insulin action in type 2 diabetes. In the non-diabetic individual, insulin suppresses hepatic glucose output, stimulates glucose uptake and utilization in muscle and adipose tissue, and suppresses lipolysis in adipose tissue. When these tissues become resistant to the actions of insulin, hepatic glucose production increases, glucose uptake is decreased, and lipolysis is enhanced. Increased free fatty acids (FFAs) from lipolysis stimulate cellular uptake of FFAs and lipid oxidation. In muscle, the increased FFA availability accelerates fat oxidation, resulting in decreased insulin-mediated glucose uptake and utilization. In the liver, elevated FFAs stimulate gluconeogenesis and increase hepatic glucose output. When P-cell dysfunction is present, insulin resistance in the target tissues leads to hyperglycemia and to the development of type 2 diabetes. (From DeFronzo, R. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Copyright © 2009 American Diabetes Association from Diabetes, 2009; 58:773-795. Reprinted with permission from the American Diabetes Association.)

Fig. 1. Defects in the pancreas and in target tissues for insulin action in type 2 diabetes. In the non-diabetic individual, insulin suppresses hepatic glucose output, stimulates glucose uptake and utilization in muscle and adipose tissue, and suppresses lipolysis in adipose tissue. When these tissues become resistant to the actions of insulin, hepatic glucose production increases, glucose uptake is decreased, and lipolysis is enhanced. Increased free fatty acids (FFAs) from lipolysis stimulate cellular uptake of FFAs and lipid oxidation. In muscle, the increased FFA availability accelerates fat oxidation, resulting in decreased insulin-mediated glucose uptake and utilization. In the liver, elevated FFAs stimulate gluconeogenesis and increase hepatic glucose output. When P-cell dysfunction is present, insulin resistance in the target tissues leads to hyperglycemia and to the development of type 2 diabetes. (From DeFronzo, R. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Copyright © 2009 American Diabetes Association from Diabetes, 2009; 58:773-795. Reprinted with permission from the American Diabetes Association.)

Despite major advances in understanding the pathophysiology of T2D, unraveling the complex link between genetic risk and environmental factors in this burgeoning epidemic has proven difficult (21). Linkage approaches have clarified the etiology of monogenic diabetic syndromes and congenital lipodystrophies, and candidate gene association studies have identified a number of common variants implicated in T2D. Several genetic loci have now been reproducibly associated with T2D in genome-wide scans. For example, common variants in the gene that encodes the transcription factor 7-like 2 (TCF7L2), involved in the control of insulin secretion, have been strongly associated with T2D (22). At the individual level, carrying the TCF7L2-risk allele increases T2D risk 50%. However, at the population level, the attributable risk is lower than 25% and varies with the allele frequency. The presence of the TCF7L2 rs7903146-risk allele increases TCF7L2 gene expression in ^-cells, possibly impairing glucagon-like peptide-1-induced insulin secretion and/or the production of new mature P-cells. It is expected that the detection of other such genes in genome-wide association scans will help elucidate the genetic architecture and pathophys-iology of T2D.

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