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Pathogenesis of Type 2 Diabetes Mellitus

Jack L. Leahy

Contents

Introduction Genetic Predisposition Environment

Acquired Organ Dysfunction Insulin Resistance vs Beta-Cell Dysfunction P-Cell Dysfunction in Type 2 Diabetes Insulin Resistance in Type 2 Diabetes Summary

Acknowledgement References

Summary

The pathophysiology of type 2 diabetes is complex, with many different elements acting to cause the disease. This review proposes a sequence of events that is based on a careful analysis of the human and animal model literature. It seems certain that a genetic predisposition is needed although, until recently, little was known about specific genetic mutations. Whether the diabetes phenotype then occurs depends on a large number of environmental factors that share an ability to stress the glucose homeostasis system by promoting insulin resistance or worsening B-cell function. We propose that a lowered B-cell mass through genetic and/or B-cell cytotoxic factors is an important predisposing factor for glucose intolerance. As the blood glucose level rises to a minor degree above normal, acquired defects in the glucose homeostasis system occur—a key early one is an impaired first phase insulin response to a meal —that cause the blood glucose level to rise further into the prediabetes range. This increase in glycemia, perhaps in concert with hyperlipidemia, causes additional deterioration in B-cell function and, to a smaller extent, resistance, resulting in a blood glucose level that continues to rise to full blown diabetes. This sequence provides insight into prevention and treatment of type 2 diabetes. One can modify predisposing environmental factors, although that is not easily done. Alternatively, one expects that, as the molecular basis for the organ dysfunctions are discovered (B-cell dysfunction and death, and muscle and hepatic insulin resistance), novel therapies will be developed that target those defects.

Key Words: B-Cell dysfunction; insulin resistance; glucose toxicity; lipotoxicity; B-cell apoptosis.

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