Molecular clocks, type 2 diabetes and cardiovascular disease.

The westernised world is in the midst of an epidemic of type 2 diabetes and associated cardiovascular disease. These closely interlinked conditions have a common pathophysiological basis underpinned by insulin resistance and the metabolic syndrome. Contemporary changes in environmental factors on a background of genetic susceptibility are thought to account for the increases seen. Life on earth is governed by the 24-hour environment of light and darkness cycling with the rotation of the earth. Numerous metabolic and physiological pathways are coordinated to this 24-hour cycle by an endogenous clock. Recent epidemiological evidence and animal data suggest that disturbance of circadian rhythms through genetic and environmental influences on the molecular clock is pivotal in the pathogenesis of obesity, type 2 diabetes and cardiovascular disease. This review describes current knowledge on the topic.

Diurnal variation in vascular and metabolic function in diet-induced obesity: divergence of insulin resistance and loss of clock rhythm.

Circadian rhythms are integral to the normal functioning of numerous physiological processes. Evidence from human and mouse studies suggests that loss of rhythm occurs in obesity and cardiovascular disease and may be a neglected contributor to pathophysiology. Obesity has been shown to impair the circadian clock mechanism in liver and adipose tissue but its effect on cardiovascular tissues is unknown. We investigated the effect of diet-induced obesity in C57BL6J mice upon rhythmic transcription of clock genes and diurnal variation in vascular and metabolic systems. In obesity, clock gene function and physiological rhythms were preserved in the vasculature but clock gene transcription in metabolic tissues and rhythms of glucose tolerance and insulin sensitivity were blunted. The most pronounced attenuation of clock rhythm occurred in adipose tissue, where there was also impairment of clock-controlled master metabolic genes and both AMPK mRNA and protein. Across tissues, clock gene disruption was associated with local inflammation but diverged from impairment of insulin signaling. We conclude that vascular tissues are less sensitive to pathological disruption of diurnal rhythms during obesity than metabolic tissues and suggest that cellular disruption of clock gene rhythmicity may occur by mechanisms shared with inflammation but distinct from those leading to insulin resistance.

An endocrinologist's guide to the clock.

CONTEXT: It has long been recognized that a "biological clock" residing in the suprachiasmatic nucleus controls circadian or daily variations in physiological processes. Old observations are now being revisited after the discovery of the cellular mechanism of timekeeping, the molecular clock, an autoregulatory feedback loop of transcription factors that cycles over a period of approximately 24 h. Its functioning or breakdown impinges upon the physiology and pathophysiology of numerous systems, including the endocrine system and metabolism. Here we provide an introduction to those aspects of the clock most relevant to the endocrinologist. EVIDENCE ACQUISITION: Articles were identified by searching PubMed using the search terms "circadian" and "clock" and refining results to include articles relating to endocrinology and metabolism. EVIDENCE SYNTHESIS: We discuss current understanding of the mechanisms through which hormonal and metabolic axes fall under the influence of the circadian clock. Of particular interest is the complex interaction of genetic and environmental factors in determining health or disease states. CONCLUSIONS: Research into the molecular clock provides a novel window onto endocrine and metabolic disease. These advances present new avenues for diagnostic and therapeutic strategies.