Phenotypic alterations in insulin-deficient mutant mice

Area of Science:

• Endocrinology
• Developmental Biology
• Genetics

Background:

• Insulin is crucial for glucose homeostasis.
• The role of insulin in pancreatic islet development is not fully understood.

Purpose of the Study:

• To investigate the role of insulin in pancreatic development and function.
• To determine the impact of complete insulin deficiency on islet cell development and survival.

Main Methods:

• Gene targeting to disrupt both mouse insulin genes (Ins1 and Ins2).
• LacZ insertion at the Ins2 locus for beta-cell identification.
• Cytochemistry, immunocytochemistry, and reverse transcription-coupled PCR to analyze cell types and gene expression.
• Morphometric analysis of pancreatic islets.

Main Results:

• Double nullizygous pups exhibited growth retardation, diabetes mellitus, ketoacidosis, and liver steatosis, leading to death within 48 hours.
• Pancreas organogenesis and endocrine cell differentiation (alpha, beta, delta, PP cells) occurred despite insulin deficiency.
• Reduced mRNA levels for somatostatin and pancreatic polypeptide were observed.
• Islets of Langerhans were enlarged in insulin-deficient pups.

Conclusions:

• Insulin is essential for survival postnatally but not for initial pancreatic organogenesis or endocrine cell differentiation.
• Insulin may act as a negative regulator of islet cell growth, as indicated by enlarged islets in insulin-deficient mice.
• Further research is needed to elucidate the molecular mechanisms underlying insulin's control over islet cell growth.