title: 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.
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. ashuldin@medicine.umaryland.edu
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.forename: John C
authors.initials: JC
authors.lastname: McLenithan
mesh_terms: D000367:Age Factors; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology*; D004032:Diet; D005223:Fats / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005796:Genes; D014644:Genetic Variation; D005943:Gluconeogenesis; D006801:Humans; D006943:Hyperglycemia / Q000209:etiology / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D022722:Thermogenesis; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D005223:Fats; D005227:Fatty Acids; D007328:Insulin; D012333:RNA, Messenger; D014157:Transcription Factors