Lessons learned at the bedside have taught us a great deal about the pathophysiology, genetics, and impact of interventions to prevent and treat type 2 diabetes. 

From pathophysiological studies we have learned the critical importance of the degree of insulin sensitivity as a determinant of the beta-cell’s insulin response.  With this understanding, it has become evident that it is the progressive loss of beta-cell function that is the basis for the increase in fasting and post-prandial glucose observed across the range of glucose tolerance, from normal to diabetes.

Genetic studies have identified a large number of mutations linked to type 2 diabetes, most of which are in genes that determine beta-cell function.  However, these genetic variants do not readily explain differences in the risk of type 2 diabetes in different ethnic groups.

Approaches to slow the development and progression of type 2 diabetes have focused on lifestyle intervention and medications.  In all instances, improved beta-cell function is associated with a slowing of the increase in glycemia that defines progression of the disease.  However, alternate approaches are needed to better prevent the development of hyperglycemia.  As normalizing glucose concentrations in individuals with impaired glucose metabolism reduces the risk of progression to diabetes, doing so with more aggressive approaches may be valuable, and is currently being tested in a clinical trial.

Aside from the loss of beta-cell function in type 2 diabetes, a reduction in the number of beta cells has also been clearly demonstrated in the disease.  Lessons in the laboratory have supplemented those from the bedside and identified that the basis for this loss is multiple, including the deposition of islet amyloid.  From studies using animal models, it has been shown that the formation of islet amyloid results in oxidative stress and inflammation, leading to the loss of beta cells by apoptosis.

With the increasing prevalence of diabetes, a greater understanding of its pathophysiological basis should provide additional opportunities for interventions to reduce the burden of hyperglycemia.