Page 101 - 76_01

VOL. 76 (1), 23-44, 2010 BETA-CELL HYPERPLASIA INDUCED BY HEPATIC INSULIN...

mecanismos involucrados en la hiperplasia de la célula beta pan-
creática desarrollada por los ratones iLIRKO.

Palabras clave: Diabetes; IGF-1; Señalización; Ratón; Prolife-
ración.

1. INTRODUCTION

Type 2 diabetes results from a combination of insulin resistance
and impaired insulin secretion. While it is not clear the primary
defect in type 2 diabetes, insulin resistance is the most relevant
pathophysiological feature in the prediabetic state (1, 2). Rodent
studies have shown that insulin insensitivity in both classical and
non-classical insulin target tissues can play a role in the control of
glucose homeostasis (3). Several mouse models have been developed
to study the role of insulin resistance in various tissues (4). While
total whole body insulin resistance produced by generalized deletion
of the IR does not produce any major effect in mouse development,
these mice died one week after birth from severe ketosis (5, 6).
Combined restoration of IR function in brain, liver, and pancreatic
b cells rescues IR knockout mice from neonatal death, prevents
diabetes in a majority of animals, and normalizes adipose tissue
content, lifespan and reproductive function (7).

In a serie of studies using tissue-specific conditional knockout
of IR, the liver, brain and beta cell have also been implicated as the
key sites of insulin resistance in the development of type 2 diabetes
(8-10). The liver-specific IR knockout (LIRKO) showed that hepatic
insulin resistance is the most important in development of impaired
glucose tolerance and fasting hyperglycemia. In addition, these mice
also developed marked beta-cell hyperplasia and hyperinsulinemia
and decreased insulin clearance. With aging, however, the diabetic
state regressed, suggesting some form of compensatory mechanism,
possibly linked with the development of liver damage related to
appearance of hyperplastic nodules that might have altered glucose
production by the liver, leading to regression of the diabetic state
with aging (8). To better address the role of this important tissue in
the pathogenesis of type 2 diabetes in the adult, we developed LIRKO
mice in an inducible manner (iLIRKO).

25