Like all living beings, human physiological processes are influenced by circadian rhythms. The disruption of our internal clocks due to increasingly unbalanced lifestyles is directly linked to the explosive increase in type 2 diabetes cases. By what mechanism? A team from the University of Geneva (UNIGE) and Geneva University Hospitals (HUG) in Switzerland has lifted part of the veil: this disruption affects fat metabolism in the cells that secrete glucose-regulating hormones. Sphingolipids and phospholipids, fats found on the cell membrane, appear to be particularly affected. This change in lipid profiles then leads to a stiffening of the membrane of these cells. These findings, published in the journal PLOS Biology, provide further evidence of the importance of the circadian rhythm in metabolic disorders.

Diabetes and the Circadian Rhythm

The proportion of people with diabetes has increased significantly in recent decades. According to the International Diabetes Federation (IDF), around 589 million adults (aged 20 to 79) worldwide live with diabetes — that’s about 1 in 9 adults. Diabetes is a chronic metabolic disorder in which the body does not produce enough insulin or does not use it properly. This causes blood sugar levels to rise permanently, which can damage blood vessels and nerves in the long term. Type 1 diabetes is usually caused by an autoimmune reaction, while type 2 diabetes is often linked to lifestyle factors such as diet, lack of exercise, and genetic predisposition.

The circadian rhythm—our internal biological clock—has a direct influence on metabolism and thus also on the risk of diabetes. The circadian rhythm controls how well our body can regulate blood sugar. Disruptions promote insulin resistance and increase the risk of developing diabetes.

1. Regulation of Insulin and Blood Sugar

Many metabolic processes follow a day-night rhythm. The body’s sensitivity to insulin is highest in the morning and decreases throughout the day. If this rhythm is disrupted (e.g., by eating late, shift work, lack of sleep), the body is less able to use insulin, causing blood sugar to rise.

2. Lack of Sleep and Impaired Glucose Tolerance

Too little or irregular sleep leads to reduced glucose tolerance and insulin resistance—two key mechanisms for type 2 diabetes. Even a few nights of sleep deprivation can cause measurable deterioration.

3. Hormonal Changes

Hormones such as cortisol and melatonin also follow the circadian rhythm.

• Elevated cortisol at the wrong time of day increases blood sugar levels.
• Low melatonin levels or mutations in the melatonin receptor (MTNR1B) are associated with an increased risk of diabetes.

4. Influence of Shift Work

People who work at night or have frequently changing shifts have a significantly increased risk of type 2 diabetes. The reason: permanent shift of the internal clock, incorrect timing of meals, and sleep deficits.

5. Meal times

Late or very irregular meals disrupt the circadian rhythm of the pancreas. This results in less or inappropriate insulin secretion, which puts strain on the metabolism in the long term.

The Influence of Lipids

Lipids are a diverse group of naturally occurring fats and fat-like substances. What they have in common is that they are not soluble or only poorly soluble in water, but are highly soluble in fat-soluble (lipophilic) solvents.

The most important lipids include:

• Fats (triglycerides): the body’s energy stores.
• Phospholipids: Main components of cell membranes.
• Sterols (e.g., cholesterol): Building blocks for hormones and cell membranes.
• Fatty acids: Basic building blocks of many lipids; can be saturated or unsaturated.

Lipids have a variety of cellular functions. As one of the main components of cell membranes, they are involved in the signaling pathways through which cells communicate with each other and with their environment. “We have known for some time that disruption of circadian clocks is closely linked to metabolic diseases such as type 2 diabetes, in which the body is no longer able to effectively regulate blood sugar levels,” explained Charna Dibner, professor in the departments of surgery and cell physiology and metabolism, as well as at the Diabetes Center of the UNIGE and HUG medical faculties, who led this research. “It is also known that lipids play an important role in metabolic disorders. However, the influence of the circadian rhythm on lipid functions was previously unknown.”

A Complex in Vitro Model of Human Molecular Clocks

The islets of Langerhans are clusters of different types of endocrine cells in the pancreas that are specifically responsible for secreting insulin and glucagon, the hormones that regulate blood sugar levels. To understand how lipids are influenced by circadian rhythms, the scientists analyzed the fluctuation profiles of more than 1,000 lipids in human islets from people with type 2 diabetes and healthy individuals. The experimental design used by the researchers is particularly complex. “When we examine a muscle, for example, we can perform a biopsy every hour. With internal organs such as the heart, liver, or pancreas, as in this case, that is of course impossible. We therefore had to develop a model for disrupted molecular clocks in vitro using human pancreatic islets,” explained Volodymyr Petrenko, a researcher in Charna Dibner’s laboratory and first author of this study.

In a living organism, a central clock in the brain coordinates the peripheral clocks in the cells of all organs according to external stimuli. In the laboratory, scientists therefore artificially replaced this central clock in order to resynchronize the cells. In fact, each cell in vitro retains its own rhythm, but without overall coordination. However, the researchers’ work aimed precisely at understanding how rhythms formed in a multicellular population and necessary for the function of the endocrine pancreas as a whole control intracellular lipid metabolism.

A Stiffening of the Membrane

A comparison of the islet cells of people with type 2 diabetes and healthy people showed that lipid profiles fluctuate much more throughout the day than previously thought. And it is not only the lipid profiles of the islet cells of diabetics and non-diabetics that differ, but also the way they fluctuate throughout the day. In addition, the scientists observed a particularly large change in the temporal profile of phospholipids and sphingolipids, two classes of lipids that are the main components of the cell membrane. Recent studies have shown a link between these phospho- and sphingolipids and the loss of insulin production capacity typical of type 2 diabetes.

The researchers’ study points in the same direction: they observed that islet cells with disrupted clocks showed an accumulation of phospho- and sphingolipids, which stiffened the membrane. This can impair the cell’s ability to recognize environmental signals and thus release insulin when needed. In addition, the scientists were able to reproduce the phenomenon in healthy pancreatic cells by artificially disrupting their circadian clocks. The studies are continuing in order to understand the exact cause and mechanism of this phenomenon. This work establishes for the first time a direct link between the disruption of circadian clocks and the lipid changes typical of diabetics.