Type 2 diabetes

Introduction

Type 2 diabetes is a chronic and progressive disease that is frequently linked with long-term microvascular events that cause morbidity (neuropathy, nephropathy, retinopathy, micro-angiopathy) as well as macrovascular events that cause morbidity and mortality (coronary artery disease, stroke, peripheral vascular disease). Moreover, type 2 diabetes is the primary cause of end-stage renal disease worldwide. The life-threatening complications of this disease constitute a significant unmet medical need worldwide, particularly because the prevalence of type 2 diabetes has soared in recent years as a result of changing eating habits and lifestyles.

The therapeutic goals with every type 2 diabetes patient are maintenance of eug-lycemia (a normal level of glucose in the blood) and evasion of long-term diabetic complications, including the prevention of cardiovascular events. Several classes of oral antidiabetic drugs, including insulin, are available to manage glycemic control and the aforementioned microvascular complications. However, these agents neither provide a cure for type 2 diabetes nor have a significant effect on the disease's macrovascular complications.

Although several clinical trials in type 2 diabetes patients have demonstrated that some of these antidiabetic drugs decrease the risk of cardiovascular events, until recently there were no data correlating the use of an antidiabetic agent with the actual incidence of cardiovascular disease (CVD) in patients at high risk of a fatal cardiovascular result. The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) study, the results of which were released in late 2005, was the first large-scale clinical trial to report on the efficacy of a specific antidiabetic drug, pioglitazone (Takeda/Eli Lilly's Actos), in suppressing risk factors for macrovascular morbidity and mortality and the actual incidence of fatal and nonfatal cardiovascular events in type 2 diabetes patients who had previously experienced a cardiovascular episode (Dormandy et al, 2005).

TYPE 2 DIABETES: DISEASE BACKGROUND AND PREVALENCE

Pathophysiology and Risk Factors

Type 2 diabetes (also called insulin-independent diabetes mellitus or adult onset diabetes) is a chronic and complex metabolic disorder characterized by insulin resistance (attenuated responsiveness of peripheral tissue to insulin) and diminished insulin secretion by the beta (ß) cells in the pancreatic islets of Langerhans. Figure 36.1 displays this process and the complications of the disease. Insulin is a principal anabolic hormone that is necessary for the homeostatic regulation of carbohydrate, fat, and protein metabolism.



Figure 1 Onset and Complications of Type 2 Diabetes

Multiple genetic defects that respond to environmental factors (e.g., obesity, lack of physical activity) initiate the diabetic process in susceptible persons. Insulin resistance in liver, skeletal muscle, and adipose tissue is the first indication of disease in prediabetic individuals. Researchers believe that the insulin resistance in these tissues occurs at the level of the insulin receptor and/or post-receptor signaling pathways for insulin. In addition to insulin resistance, dysfunctional pancreatic ß cells are central to the pathophysiology of type 2 diabetes. The progressive loss in insulin secretion from ß cells, as a consequence of impaired glucose-stimulated insulin secretion, places added stress on these cells to produce additional insulin so as to overcome the insulin-resistant state in type 2 diabetes ...