Norma) glucose tolerance


Type 2 DM

Insulin resistance -►

ft-cel[ dysfunction -ft-cell failure -►

li-cell mass li-cel[ mass lowered 40% lowered 40%-60%

Raised hepatic glucose production

Fig. 1. Proposed sequence of the key pathological features of type 2 diabetes as discussed in this review.

these changes have been most evident in children—numerous studies have reported the epidemic of childhood obesity (5) and its root causes of reduced physical activity and high caloric intake (6,7).

Although returning to healthy lifestyles likely would reverse the rising incidence of type 2 diabetes, this may be an impractical solution. Instead the current focus is to investigate the pathogenesis, hoping to develop pharmaceuticals that target the key pathogenic elements. We entered the 1990s knowing that type 2 diabetes was characterized by the triad of B-cell dysfunction, excess glucose production from the liver, and insulin resistance, defined as impaired insulin-mediated glucose clearance into skeletal muscle (8). However, the link among these organs was unknown. Considerable insight has been gained over the last decade, although much remains to be learned. This review provides an overview of the current understanding of the pathogenesis of type 2 diabetes (Fig. 1). A major focus of the proposed sequence relates to defects in the mass and function of islet B-cells, as they are known to be important elements in the early stages of the disease.

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