Genetics of type II diabetes

Area of Science:

• Genetics and Molecular Biology
• Endocrinology and Metabolism

Background:

• Type II or non-insulin dependent diabetes mellitus (NIDDM) is a common disease with complex genetic underpinnings.
• Understanding the genetic basis of NIDDM is crucial for developing effective therapeutic strategies.
• Previous research has focused on identifying candidate genes involved in insulin production and action.

Purpose of the Study:

• To identify and map genes associated with NIDDM.
• To explore novel candidate genes expressed in pancreatic islets.
• To investigate the genetic basis of monogenic disorders of carbohydrate metabolism as a model for NIDDM.

Main Methods:

• Isolation and mapping of candidate genes using simple sequence repeat polymorphisms (SSRPs) and sequence-tagged sites (STSs).
• Mutation screening via single-strand conformational polymorphism analysis and sequencing.
• Generation of expressed sequence tags (ESTs) from human pancreatic islet mRNA using differential display.
• Positional cloning and gene mapping for familial hyperinsulinism (HI).

Main Results:

• Identified 42 novel cDNAs preferentially expressed in pancreatic islets, with 69% being novel genes.
• Mapped several islet genes to human chromosomes using ESTs and SSRPs.
• Identified the sulfonylurea receptor (SUR1) gene mutations in familial hyperinsulinism patients, revealing its role in the ATP-sensitive K+ channel.

Conclusions:

• The strategy of identifying and mapping islet-specific genes is effective for discovering NIDDM candidate genes.
• Studying monogenic disorders like HI provides insights into the molecular mechanisms relevant to NIDDM.
• Future research will leverage the Human Genome Project to identify NIDDM-predisposing genes and requires continued family studies.