Chronobiology and Type 2 Diabetes Mellitus

When patients tell us that they think the stress of their job or lifestyle caused their diabetes, we often talk to them about how they could make their lifestyles healthier. We may even discuss the effect stress can exert on cortisol regulation, which could contribute to diabetes but certainly does not cause it. But how often do we consider the causal role circadian rhythms play in the development of hyperglycemia? Examples of environmental influences that alter circadian rhythms include shift work—especially rotating shifts—and inadequate sleep, which are common risk factors for diabetes.

When people think of circadian rhythms, they don’t typically think of the molecular mechanisms that underlie these patterns. Circadian clocks are ancient programming that has been conserved in most organisms. They represent a complex time-keeping mechanism that is controlled both at the level of gene transcription and protein translation to coordinate body processes throughout the ambient 24-hour light/dark cycle. While the circadian pattern of regulation of these genes is set by the Earth’s 24-hour cycle, there is some modulation of these genes by certain environmental cues such as exposure to light, temperature and food intake, thereby allowing adaptation to schedules other than the classic 9-to-5 schedule.

Controlling circadian rhythms

In mammals, the circadian system is organized as a multilevel oscillator network. The pacemaker (or master clock) is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, where it receives information from specialized ganglion cells in the retina, synchronizing the body’s clock to the solar day. In fact, exposure to sunlight is the most important stimulus to develop and maintain the body’s clock. The SCN then establishes the circadian rhythms throughout the body using a combination of neural, endocrine and systemic outputs. The pancreatic beta-cell is actually one of the organs in the body that responds to the output from the SCN to develop a circadian pattern to the oscillations of islet cell gene transcription and insulin secretion. The most detailed studies have been completed in animal models of diabetes in which experimental disruption of circadian rhythms led to a rise in glucose, accelerated loss of beta-cell function, decreased beta-cell mass and increased insulin resistance. In contrast, studies of rats who were not prone to diabetes found no disruption of circadian rhythms on glucose homeostasis. Human studies are still needed to confirm these findings but they do suggest that if one is prone to diabetes, i.e., has a family history of diabetes, then interruption of circadian rhythms could potentially accelerate the progression to hyperglycemia.

Genetic regulation of the circadian clock

At the molecular level, the mammalian circadian clock is composed of several “clock genes” and proteins involved in hour transcription-translation feedback loops that function on a 24-hour clock. One arm of this loop includes activation of the genes Circadian Locomotor Output Cycles Kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1) that encode the basic helix-loop-helix Per-Arnt-Single-minded (bHLH-PAS) proteins that form the CLOCK-BMAL1 activator complexes and initiate transcription of target genes by binding to specific DNA sequences (E-boxes) in their promoter regions. These target genes include Period (Per1/2/3) and Cryptochrome (Cry1/2), which make up the negative limb of the feedback loop. PER and CRY proteins form heterodimers and inhibit the transcriptional activation by CLOCK-BMAL1, allowing the circadian cycle to repeat itself. Posttranslational modifications of clock-regulated proteins such as phosphorylation, ubiquitination and sumoylation control stability of proteins necessary to establish the 24-hour-clock period and maintain the ongoing progression of the circadian cycle. GWAS studies have shown that approximately 3-20 percent of all genes may be under circadian control. In general, these are genes related to vital cellular processes and functions.

Beta-cells and circadian rhythms

Normal pancreatic beta-cell function involves continuous pulsatile insulin release to maintain glucose homeostasis augmented by larger pulses in response to stimuli such as meals. We often are taught that the development of Type 2 diabetes starts with a “loss of first phase and delayed/prolonged second phase insulin release.” We now know that changes in the insulin secretion patterns start prior to the onset of hyperglycemia as even normoglycemic first-degree relatives of patients with Type 2 diabetes demonstrate abnormalities in the secretion of insulin. While the progressive loss of insulin secretory capability clearly plays a role in diabetes development, we do not know how to predict when this will happen or how quickly it will develop. Molecular studies have shown that loss of beta-cells through apoptosis can be increased by prolonged exposure to high glucose levels and/or high free fatty acid levels, which activate endoplasmic reticulum, oxidative and inflammatory stress pathways, leading to cell death. Loss of beta-cell insulin secretory ability is also multifactorial, including changes in glucose transport, glucose oxidation, increase in reactive oxygen species (ROS), leading to mitochondrial dysfunction and impaired exocytosis. Appropriate circadian activation of the feedback loops controlled by the CLOCK and BMAL1 genes could help maintain the balance of oxidative stress and mitochondrial function in the beta-cell, thereby maintaining beta-cell mass through controlled apoptosis and appropriate insulin secretion. In fact, animal studies of genes identified as playing a role in controlling this feedback loop have shown that targeted disruption of the beta-cell molecular clock, depending on the specific gene, can lead to abnormalities at all levels of glucose sensing, insulin secretion and maintenance of beta-cell mass. These data suggest that any disruption of the circadian clock could lead to hyperglycemia and Type 2 diabetes.

Control of the beta-cell molecular clock is not only internal but also external through stimuli such as cortisol and leptin. These hormones are known to have very specific circadian patterns, including controlling the morning rise in glucose prior to awakening for the day. Studies have shown that disruption of the light-dark cycle, whether in the experimental setting with animal models or through shift work, travel or loss of sleep, causes alteration in levels of cortisol. Similarly, stress can lead to sustained increases in cortisol. Taken together, disruption of the circadian patterns for these hormones could play a role in altered beta-cell function, leading to sustained hyperglycemia.

Alteration of circadian rhythms in Type 2 diabetes

Epidemiologic surveys of workers in a variety of professions have shown that rotational shift work is associated with an increased incidence of Type 2 diabetes. Rotational shift-work jobs entail shift changes every few days, such as from day shift to afternoon shift to night shift and then several days off before the cycle starts over. Additionally, changes in sleep patterns or decreased sleep have been associated with an increase in Type 2 diabetes. Studies in humans have shown that acute loss of sleep can impact glucose homeostasis in as little as one to three weeks. What is not definitively known is whether this only occurs in those at risk for Type 2 diabetes, as observed in the animal studies, or if the changes in glucose also occur in those with no family history of Type 2 diabetes. Despite large GWAS studies, the gene(s) responsible for Type 2 diabetes remains largely unknown. With regard to the role of the circadian clock in maintenance of beta-cell health, one must consider that subtle mutations in one or more of the clock-regulated genes could lead to a predisposition to Type 2 diabetes that is then exacerbated by a lifestyle with a fluctuating light-dark cycle.

Summary

Molecular studies have identified genes that are crucial for maintaining circadian rhythms. Targeted disruption of some of these genes has led to Type 2 diabetes in animal studies. Lifestyle factors such as shift work and high levels of stress lead to alterations in circadian rhythms and may disrupt the molecular clock mechanisms, resulting in permanent alterations of pancreatic beta-cell function. The clinical implication of tying together these pieces of information is that the patients are probably right when they say that stress caused their diabetes—or at least partially right, because the stress, whether physical or emotional, probably altered the patterns of their circadian clock, thereby bringing on their diabetes at a younger age than would have been expected from their genetic predisposition.

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About our expert: Kathleen Wyne, MD, PhD, FACE, FNLA, Associate Professor, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Wexner Medical Center, Columbus, OH