Sushil G. Rane and E. Premkumar Reddy

Fels Institute For Cancer Research And Molecular Biology, Temple University, School Of Medicine, 3307 North Broad Street. Philadelphia, PA 19140

TABLE OF CONTENTS

1. Abstract

2. Introduction

3. Diabetes

3.1. The disease
3.2. Type 1 Diabetes or IDDM

3.2.1. Spontaneous animal models of IDDM

3.2.1.1. The non-obese diabetic (NOD) mouse model for Type I diabetes
3.2.1.2. The BB rat

3.2.2. Experimentally induced models

3.3. Type 2 Diabetes or NIDDM

4. Insulin signaling and its components

5. Phenotype of mice with altered insulin signaling intermediates

6. Beta cell Mass and Diabetes

7. Factors regulating beta cell growth

8. Models of beta cell proliferation in diabetes.

9. Cyclin/CDK complexes in cell cycle

9.1. Negative regulation of CDKs
9.2. Downstream Targets of CDKs

10. Cell cycle in beta cells

11. Cdk4 determines beta cell proliferation potential

12. Perspective

13. References

1. ABSTRACT

Diabetes mellitus ensues as a consequence of the body's inability to respond normally to high blood glucose levels. The onset of diabetes is due to several pathological changes, which are a reflection of either the inability of the pancreatic beta cells to secrete sufficient insulin to combat the hyperglycemia or a state of insulin resistance in target tissues. However, the significance of changes in beta cell mass and decreased beta cell proliferation or growth in progression of diabetes has been under-appreciated. Beta cells, like all other cells of our body are under the regulatory checks and balances enforced by changes in cell cycle progression. However, very little is known regarding the key components of the cell cycle machinery regulating cell cycle control of beta cells. Knowledge of key elements involved in cell cycle regulation of beta cells will go a long way in improving our understanding of the replication capacity and developmental biology of beta cells. This information is essential for us to design new approaches that can be used to correct beta cell deficiency in diabetes. This review focuses on the current knowledge of factors important for proliferation of beta cells and proposes a cell cycle model for regeneration of the beta cell population lost or reduced in diabetes.