Circadian Etiology of Type 2 Diabetes Mellitus

Abstract

The epidemic of Type 2 diabetes mellitus necessitates development of novel therapeutic and preventative strategies to attenuate expansion of this debilitating disease. Evidence links the circadian system to various aspects of diabetes pathophysiology and treatment. The aim of this review will be to outline the rationale for therapeutic targeting of the circadian system in the treatment and prevention of Type 2 diabetes mellitus and consequent metabolic comorbidities.

FIGURE 1.

Pathophysiology of Type 2 diabetes mellitus Type 2 diabetes (T2DM) is a complex metabolic disease in which the pathophysiology involves an interaction between genetic predisposition and environmental triggers. Hyperglycemia develops as a result of pancreatic islet failure in lieu of systemic insulin resistance. Islet failure in T2DM is associated with a deficit in β-cell mass and function and increased glucagon secretion. Insulin resistance in T2DM primarily manifests at the level of skeletal muscle, liver, and adipose tissue, and is characterized by impaired insulin-stimulated glucose disposal, failure to suppress hepatic glucose production, and elevated adipose tissue lipolysis and inflammation.

FIGURE 2.

Organization and molecular structure of the mammalian circadian system To provide efficient coordination of circadian timing, the mammalian circadian system is organized as a multi-level hierarchical oscillator network. Changes in the LD cycle are perceived by specialized ganglion cells in the retina, synchronizing the central pacemaker of the circadian system in the SCN to the solar day. The main function of the SCN clock appears to coordinate and synchronize cell-autonomous circadian oscillators present in a wide array of peripheral tissues (e.g., skeletal myocytes, hepatocytes, adipocytes, and pancreatic islet cell subtypes) via a combination of neuronal, humoral, and behavioral cues, thus integrating a complex multi-level hierarchical oscillator network. The molecular make up of circadian oscillators consists of the transcriptional activators CLOCK and its heterodimer BMAL1, along with repressor genes that encode period (PER1, 2) and cryptochrome (CRY1, 2) proteins. This regulatory mechanism ensures the generation of 24-h cycles of transcription and translation. Specifically, the CLOCK: BMAL1 heterodimer is essential for the generation of circadian rhythms of transcription through DNA binding to conserved promoter regions (E-boxes) of numerous clock-controlled genes critical for regulation of diverse cellular functions and metabolic pathways.