Type 2 Diabetes: What Determines Susceptibility?

Individuals who are obese have an increased risk of several life-threatening illnesses such as type 2 diabetes, heart disease, and cancer. Understanding the molecular details of how a high-fat diet translates to obesity and its related health issues is crucial for developing ways to prevent and treat this health threat.

Previous work has shown that the uptake of diet-derived fats known as triglyceride-rich lipoproteins (TGRLs) promotes glucose intolerance (the central cause of type 2 diabetes).

New research by David Hui and colleagues at the University of Cincinnati, Cincinnati, has shown that mice lacking the cell surface protein LDL receptor-related protein-1 (LRP1) in their fat tissue are protected from obesity and glucose intolerance induced by a high-fat diet.

These changes were associated with delayed clearance of TGRLs from the body after eating, decreased body weight, decreased fat storage, and increased energy expenditure, indicating a crucial role for LRP1 in translating a high-fat diet into obesity and glucose intolerance.

First article: Adipocyte LDL receptor-related protein-1 expression modulates postprandial lipid transport and glucose homeostasis in mice, Journal of Clinical Investigation, October 18, 2007

Genetic differences that confer susceptibility to type 2 diabetes

The risk of developing type 2 diabetes increases with reduced physical activity, obesity, and age. However, not all individuals who are exposed to these risk factors develop the disease, indicating that genetic makeup has an influence on disease susceptibility.

A decrease in expression of a specific set of genes in skeletal muscle is associated with type 2 diabetes. To determine whether this decrease is an inherited or acquired component of susceptibility to type 2 diabetes Charlotte Ling and colleagues at Lund University, Sweden, analyzed the expression of one gene (NDUFB6) in muscle biopsies from young and elderly twins.

As genetic and acquired (epigenetic and nongenetic) factors were found to influence NDUFB6 expression in human muscle the authors suggested that an interplay between genetic and epigenetic factors confers an age-dependent susceptibility to type 2 diabetes.

Second article: Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle, Journal of Clinical Investigation, October 18, 2007