Defective insulin secretion in hepatocyte nuclear factor 1alpha-deficient mice

Area of Science:

• Endocrinology and Metabolism
• Molecular Biology
• Genetics

Background:

• Mutations in the hepatocyte nuclear factor (HNF) 1alpha gene are linked to maturity-onset diabetes of the young (MODY) 3.
• MODY 3 is characterized by impaired insulin secretion, but the underlying defects are not fully understood.

Purpose of the Study:

• To investigate the role of HNF-1alpha in insulin secretion and beta cell function.
• To define the nature of insulin secretory defects in HNF-1alpha-deficient mice.

Main Methods:

• Comparison of insulin secretion and glucose/arginine response in HNF-1alpha (+/+), (+/-), and (-/-) mice.
• Analysis of intracellular calcium responses in pancreatic islets.
• Assessment of glucokinase and insulin gene transcription.
• Measurement of beta cell mass and pancreatic insulin content.

Main Results:

• Homozygous HNF-1alpha (-/-) mice exhibited significantly higher blood glucose levels compared to wild-type and heterozygous littermates.
• Insulin secretory responses to glucose and arginine in HNF-1alpha (-/-) mice were severely reduced (<15%) with diminished intracellular calcium responses.
• These defects were not attributable to reduced glucokinase or insulin gene transcription, nor to decreased beta cell mass.
• Pancreatic insulin content was slightly lower in HNF-1alpha (-/-) mice.

Conclusions:

• A null mutation in the HNF-1alpha gene leads to diabetes in homozygous mice due to impaired beta cell response pathways.
• HNF-1alpha plays a critical role in maintaining normal beta cell function and insulin secretion.
• These findings provide strong evidence for HNF-1alpha's essential role in glucose homeostasis.