Genes and pathophysiology of type 2 diabetes: more than just the Randle cycle all over again

Abstract

The Randle cycle, which has been invoked to explain the reciprocal relationship between fatty acid oxidation and glucose oxidation, has long been implicated as a potential mechanism for hyperglycemia and type 2 diabetes mellitus (T2DM). Now genetic, functional genomic, and transgenic approaches have identified PPARgamma coactivators (PGC-1alpha and PGC-1beta) as key regulators of mitochondrial number and function. They regulate adaptive thermogenesis as well as glucose and fat oxidation in muscle and fat tissue, gluconeogenesis in liver, and even glucose-regulated insulin secretion in beta cells. PGC-1alpha and PGC-1beta mRNA levels and the mitochondrial genes they regulate are decreased in muscle of people with prediabetes and T2DM. A new report indicates that PGC-1alpha and PGC-1beta mRNA levels decrease with age in individuals with a genetic variant in PGC-1alpha, and these decreases correlate with alterations in whole-body glucose and fatty acid oxidation. These findings provide insights into how aging modifies genetic susceptibility to alterations in oxidative phosphorylation and T2DM.

Figure 1

Schematic of the pleiotropic effects of PGC-1α and PGC-1β. Changes in PGC-1α and PGC-1β expression levels in different tissues may explain many of the metabolic abnormalities that accompany T2DM. In muscle: decreased PGC-1α may cause decreased formation of mitochondria-rich oxidative type 1 myofibers and decreased glucose oxidation. Decreased PGC-1β expression may cause decreased fat influx and oxidation and decreased nonoxidative glucose metabolism. Subjects with the Gly482Ser PGC-1α variant appear to be more susceptible to age-related decreases in PGC-1α and PGC-1β. In the β cell: increased PGC-1α expression or function, which is observed in several animal models of diabetes, would be expected to decrease β cell dysfunction and decrease insulin secretion. In liver: increases in PGC-1α expression or function would be expected to cause increased hepatic gluconeogenesis. In fat: decreases in PGC-1α expression or function would be expected to cause decreased mitochondrial biogenesis and defective adaptive thermogenesis, possibly leading to positive energy balance and obesity. Other factors, i.e., physical activity, diet, and other gene variants, may affect PGC-1α and PGC-1β expression or function and thus susceptibility to T2DM.