Molecular Basis of Insulin Resistance

Project: Research project

Project Details

Description

The incidence of Type 2 diabetes mellitus (T2DM) and the Metabolic Syndrome has reached epidemic
proportions. Human and rodent studies provide strong support for a genetic predisposition to these
pathologies. The GLUT4+/- mouse model (G4+/-) represents an example of an `At Risk'individual as male
G4+/- mice develop insulin resistance, hypertension and T2DM with age. Despite genetic predisposition, it is
clear that other factors play an important role in disease transmission and incidence. Studies have shown that
alterations in nutrients during early life `program'increased susceptibility to metabolic disease and
hypertension in adult life. However, these studies provide limited insight into the epigenetic mechanisms
underlying these processes. Consumption of a western style, high fat (HF) diet during pregnancy has also
been linked to vascular dysfunction, dyslipidemia and hyperglycemia in adults. Modulation of hepatic substrate
utilization and insulin sensitivity is crucial for maintenance of whole body glucose homeostasis as it integrates
signals from the gut, peripheral tissue and central nervous system. This process is disrupted in diseases such
as TD2M and the Metabolic Syndrome. Several models with alterations in the intrauterine (IU) milieu display
pathologic alterations in genes of hepatic glucose and lipid utilization (including PPAR? and G6Pase) often
associated with T2DM. The central hypothesis of this proposal is that consumption of a high fat (HF)
diabetogenic diet during pregnancy and lactation `programs'offspring for increased susceptibility to Metabolic
Syndrome and T2DM. We propose that increased susceptibility to the development of Metabolic Syndrome is
mediated by altered methylation of genes that regulate glucose and lipid utilization in liver. We predict dietary
intervention by adding one carbon donors will prevent these epigenetic modifications. Strong preliminary data
suggests PPAR? may play a pivotal role in mediating these effects. The contribution of enviromental factors
(IU diet) and offspring genetics (hemizygous lesion in peripheral glucose uptake, G4+/-) to alterations in
hepatic gene expression and methylation related to the incidence of T2DM and Metabolic Syndrome will be
measured. Molecular mechanisms underlying the early life programming of these metabolic derangements will
be revealed. Additional studies are proposed to test the response of high fat IU offspring to diets that alter body
weight and metabolism including a high fat diabetogenic diet or a weight loss ketogenic diet during their adult
life. Results of these studies may yield new information for setting dietary guidelines for pregnant and lactating
women that may protect offspring from enhanced susceptibility to these metabolic diseases. Type 2 diabetes mellitus (T2DM) and the Metabolic Syndrome are modern day plagues of societies in
industrialized and developing nations alike. Studies have shown that alterations in nutrients during early life
`program'increased susceptibility to metabolic disease. However, these studies provide limited insight into the
potential epigenetic mechanisms underlying these processes. This proposal seeks to define the molecular
basis underlying the programming of Metabolic Syndrome and T2DM using normal mice and ones genetically
`at risk'for developing metabolic diseases. Results of these studies may yield new information for setting
guidelines for pregnant and lactating women that may protect offspring from enhanced susceptibility to these
metabolic diseases.
StatusFinished
Effective start/end date4/1/088/31/10

ASJC

  • Endocrinology, Diabetes and Metabolism

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