Mathematical models of mechanisms underlying long-term type 2 diabetes progression

We develop a series of mathematical models incorporating proposed mechanisms underlying the development of two essential features of long-term type 2 diabetes progression: insulin resistance and ¯-cell dysfunction. Reduced insulin-stimulated plasma glucose uptake (insulin resistance) and inadequate insulin production by ¯ cells (¯-cell dysfunction) lead to a number of metabolic irregularities. We study the interaction of oxidative stress and mitochondrial dysfunction in the development of skeletal muscle insulin resistance, focusing on mitochondrial superoxide production and the functional and physical heterogeneities among mitochondria. We explore primary determinants in ¯-cell failure, from the perspective of endoplasmic reticulum stress and the unfolded protein response. We conclude with a basis for age-related insulin resistance, an explanation of the fundamental role of nutrient excess in the decline of metabolic health, and an identification of the interplay of cellular and molecular mechanisms important in metabolic dysregulation.