[Frontiers in Bioscience 14, 1099-1115, January 1, 2009]

[Frontiers in Bioscience 14, 1099-1115, January 1, 2009]

Failure of beta-cell adaptation in type 2 diabetes: Lessons from animal models

Nurit Kaiser, Gil Leibowitz

Endocrinology and Metabolism Service, Department of Medicine, Hadassah - Hebrew University Medical Center, Jerusalem 91120, Israel

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Nutrient sensing and regulation of insulin secretion, proinsulin biosynthesis and beta-cell mass: 3.1. Nutrient stimulation of insulin secretion; 3.2. Nutrient stimulation of proinsulin biosynthesis; 3.3. Nutrient regulation of beta-cell mass
4. Determinants of efficient beta-cell compensation: 4.1. Intrinsic genetic factors and metabolic imprinting; 4.2. Metabolic cues for beta-cell compensation; 4.3. Signaling pathways involved in beta-cell compensation
5. Beta-cell failure in type 2 diabetes: 5.1. Beta-cell secretory dysfunction; 5.2. Deficient proinsulin biosynthesis; 5.3. Decreased beta-cell mass
6. Factors driving beta-cell failure: 6.1. Glucotoxicity; 6.2. Glucolipotoxicity; 6.3. Proinflammatory cytokines and adipokines; 6.4. Islet amyloid polypeptide
7. Deranged cellular pathways involved in beta-cell failure in type 2 diabetes: 7.1. Inflammatory stress; 7.2. Oxidative stress; 7.3. Endoplasmic reticulum stress
8. Concluding comments and clinical implications
9. References

1. ABSTRACT

The pancreaticbeta-cell adapts to increased nutrient availability and insulin resistance by increasing its function and mass. These processes are orchestrated by signals derived from nutrient metabolism, hormones and cytokines. Their end-result is the regulation of insulin secretion and biosynthesis, and beta-cell proliferation and apoptosis. This review focuses on the mechanisms involved in beta-cell nutrient sensing and adaptation and the potential causes of beta-cell dysfunction and death in type 2 diabetes mellitus. Understanding the mechanisms that regulate adequate beta-cell adaptation and the natural history of beta-cell failure is of utmost importance for the development of novel disease modifying treatments.