Lilly lecture 1990. Molecular defects in diabetes mellitus

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Diabetes mellitus involves hyperglycemia, often linked to islet amyloid in non-insulin-dependent diabetes mellitus (NIDDM).
• Insulin resistance is a key factor in diabetes pathogenesis.
• Glucose transport regulation is crucial for maintaining blood glucose homeostasis.

Purpose of the Study:

• To elucidate the molecular basis of hyperglycemia in diabetes mellitus.
• To identify molecular defects contributing to insulin resistance.
• To understand the regulation of glucose transport.

Main Methods:

• Biochemical and molecular biology techniques were employed.
• Characterization of the insulin receptor gene in patients with extreme insulin resistance.
• Analysis of glucose transporter gene families and expression patterns.

Main Results:

• Identified islet amyloid polypeptide (IAPP) as the major protein component of islet amyloid, related to neuropeptides.
• Discovered mutations in the insulin receptor gene impairing function in extreme insulin resistance.
• Revealed a family of glucose transporter proteins involved in tissue-specific glucose transport.
• Demonstrated that depletion of specific glucose transporter isoforms contributes to insulin resistance in adipose tissue.

Conclusions:

• Molecular biology provides critical insights into diabetes pathogenesis, including islet amyloid formation and insulin resistance.
• IAPP is a novel beta-cell secretory product with an undetermined physiological role.
• Understanding insulin receptor and glucose transporter defects is key to addressing insulin resistance.