CHARACTERISTICS OF T2D? John Frusciante Guitar Lesson Dvd on this page. WHAT ARE THE CHALLENGES. From the triumvirate to the ominous octet: A new paradigm for the treatment of type 2 diabetes mellitus. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus.
Zambelli Iso Plus 6000. From the Triumvirate to the Ominous Octet: A New. - BANTING LECTURE From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus Ralph A. DeFronzo Insulin resistance in muscle and liver and -cell failure represent the core pathophysiologic defects in type 2 diabetes. It now is recognized that the -cell failure occurs much earlier and is more severe than previously thought. Subjects in the upper tertile of impaired glucose tolerance (IGT) are maximally/nearmaximally insulin resistant and have lost over 80% of their -cell function. In addition to the muscle, liver, and -cell (triumvirate), the fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), -cell (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (insulin resistance) all play important roles in the development of glucose in tolerance in type 2 diabetic individuals. Collectively, these eight players comprise the ominous octet and dictate that: 1) multiple drugs used in combination will be required to correct the multiple pathophysiological defects, 2) treatment should be based upon reversal of known pathogenic abnormalities and not simply on reducing the A1C, and 3) therapy must be started early to prevent/slow the progressive -cell failure that already is well established in IGT subjects.
A treatment paradigm shift is recommended in which combination therapy is initiated with diet/exercise, metformin (which improves insulin sensitivity and has antia therogenic effects), a thiazolidinedione (TZD) (which improves insulin sensitivity, preserves -cell function, and exerts antia therogenic effects), and exenatide (which preserves -cell function and promotes weight loss). Sulfonylureas are not recommended because, after an initial improvement in glycemic control, they are associated with a progressive rise in A1C and progressive loss of -cell function.
NATURAL HISTORY OF TYPE 2 DIABETES The natural his tory of type 2 diabetes has been well described in multiple populations (1–16) (rev. Individuals destined to develop type 2 diabetes inherit a set of genes from their parents that make their tissues resistant to insulin (1,16,19–24). In liver, the insulin resistance is manifested by an overproduction of glucose during the basal state despite the presence of fasting hyperinsulinemia (25) and an impaired suppression of hepatic glucose production (HGP) in response to insulin (26), as occurs following a meal (27). In muscle (19,26,28,29), the insulin resistance is manifest by im- From the Diabetes Division, University of Texas Health Science Center, San An tonio, Texas. Corresponding author: Ralph A.
DeFronzo, albarado@uthscsa.edu. DOI: 10.2337/db09-9028 © 2009 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See -nc-nd/3.0/ for details. Paired glucose uptake following ingestion of a carbohydrate meal and results in postprandial hyperglycemia (27). Although the origins of the insulin resistance can be traced to their genetic background (17,20), the epidemic of diabetes that has enveloped westernized countries is related to the epidemic of obesity and physical inactivity (30). Both obesity (31) and decreased physical activity (32) are insulin-resistant states and, when added to the genetic burden of the insulin resistance, place a major stress on the pancreatic -cells to augment their secretion of insulin to offset the defect in insulin action (1,17). As long as the -cells are able to augment their secretion of insulin sufficiently to offset the insulin resistance, glucose tolerance remains normal (33).