• Insulin is produced by beta cells in the pancreas — Once released, it travels through your bloodstream and attaches to receptors on the surface of your cells. This connection signals the cells to open specialized channels so glucose can flow inside and fuel the chemical reactions that sustain life. When this process runs smoothly, every organ in your body has access to the energy it requires.

• After a meal, this system springs into action — As blood sugar rises from the carbohydrates you eat, your pancreas quickly senses the change and responds by releasing insulin. The hormone acts almost immediately, moving glucose out of the blood and into your cells, preventing sugar levels from climbing too high. This not only protects you from dangerous spikes in blood sugar but also ensures that your cells have a constant stream of energy to draw upon.

• Insulin plays a stabilizing role in your body’s overall energy — Although insulin’s work happens on a microscopic level, the impact is enormous. From the way your brain processes thoughts to the way your muscles contract during movement, every action depends on insulin’s ability to keep energy flowing.

• Insulin also affects how your body stores and manages that energy — It signals when to store glucose in your liver and muscles as glycogen, a form of backup fuel you can draw on later when you are active or between meals. It influences how much fat is stored, how muscle tissue is preserved, and even how hungry or full you feel.

By integrating these signals, insulin makes sure that your energy needs are met not just in the moment but in the hours and days that follow. Its goal is always the same — to match the supply of fuel with the demands of your cells, so your body and brain function without interruption.

• Modeling RORβ effects in mice — To test how this genetic change influences behavior, researchers engineered mice with RORβ overexpressed specifically in pancreatic β cells. During the light phase, the animals showed depression-like behaviors, while during the dark phase, which is normally their active period, they exhibited mania-like behaviors. This alternating rhythm mirrored the mood swings of bipolar disorder.

• Suppressed insulin tied to hippocampal hyperactivity — In the light phase, RORβ overexpression suppressed insulin release from pancreatic islets. This was accompanied by increased hippocampal activity. Since the hippocampus regulates mood, memory, and stress responses, the findings revealed that reduced pancreatic insulin coincided with abnormal hyperactivity in mood-related brain circuits.

• Carryover effects into the dark phase — The hippocampal hyperactivity seen during the light phase influenced pancreatic function later in the cycle. By the dark phase, insulin release rebounded to higher-than-normal levels, hippocampal activity dropped, and the mice shifted into mania-like behavior. The study showed how disruptions in one part of the cycle set the stage for opposite changes in the next.

• Discovery of a circadian feedback loop — Researchers identified a feedback circuit connecting pancreatic insulin release with hippocampal neuronal activity. Insulin influenced how the hippocampus functioned, and hippocampal activity fed back to alter pancreatic insulin secretion. This loop was governed by circadian rhythms, meaning that time-of-day changes were central to the observed mood fluctuations.

The findings suggest that the alternating depressive lows and manic highs of bipolar disorder stem from a dysregulated pancreas-hippocampus circuit. Metabolic and mood symptoms represent two sides of the same biological process, linked through circadian feedback.

• Broader relevance to other conditions — Although focused on bipolar disorder, the results also apply to conditions where metabolic dysfunction and mood instability appear together, including major depression and schizophrenia. Because RORβ also regulates circadian timing, the work highlights the therapeutic potential of strategies that align with daily rhythms, such as medication scheduling, light therapy, or dietary timing.

• A new perspective placed insulin resistance at the center of bipolar pathology — A Translational Psychiatry perspective argued that lithium’s therapeutic power could be explained not only by its influence on neurotransmission but also by its ability to restore insulin signaling inside the brain.

Lithium acts on the PI3K/Akt pathway and its downstream target glycogen synthase kinase 3 (GSK3), which are both central to insulin’s role in regulating neuronal energy use. By modulating these pathways, lithium improves glucose uptake in neurons, ensuring they have the energy needed for stable function. This reframed bipolar disorder as a problem of energy dysregulation, not just neurotransmitter imbalance.¹¹

• A proof-of-concept trial tested the metabolic model in patients — That same year, researchers from the University of Pittsburgh and Dalhousie University conducted a clinical trial with 45 middle-aged patients suffering from treatment-resistant bipolar depression.

On average, participants had been ill for more than 25 years, failed nearly a dozen psychiatric medications, and lived with unremitting symptoms. They were randomized to receive either metformin, a common insulin-sensitizing drug, or a placebo, while continuing their usual psychiatric care.¹²

• Metformin improved both insulin sensitivity and psychiatric symptoms — Within weeks, patients receiving metformin began to improve. By 14 weeks, half had regained insulin sensitivity, and this biological change coincided with sharp reductions in depression and anxiety.

Improvements persisted for up to 26 weeks, marking a dramatic turnaround for individuals who had seen little relief in decades. According to study coauthor Dr. Jessica Gannon:

“Given that the only other therapy that works comparably well is electroconvulsive therapy — a procedure that involves applying electrical current to the patient’s brain, causing a controlled seizure — achieving the same result just by restoring insulin sensitivity seems astounding.”¹³

• The type of sugar you consume plays an important role — When you eat a piece of whole fruit, the natural sugars are packaged with fiber, vitamins, and minerals that slow absorption and ease the demand on your pancreas. But when you drink a soda or eat candy loaded with refined sugar, there are no such buffers.

Glucose floods into your bloodstream, your blood sugar rises rapidly, and your pancreas responds by releasing large amounts of insulin. When this happens repeatedly, day after day, your cells begin to dull their response to insulin, and resistance takes hold.

• The kinds of fats you eat also matter — Seed oils such as soybean and corn oil have become a staple in modern processed foods. These oils are highly unstable, breaking down easily into harmful byproducts, especially when heated.

Over time, these byproducts damage your cells and interfere with how they respond to insulin. They also change the very makeup of your cell membranes, which disrupts the function of insulin receptors and makes it even harder for your cells to use glucose effectively.

• Beyond diet, environmental exposures add to the problem — Certain plastics release chemicals that act as endocrine disruptors, impairing the way your hormones work. Constant exposure to electromagnetic fields (EMFs) from electronic devices has also been shown to influence cellular stress responses. These hidden factors layer onto an already heavy metabolic load, making it even more difficult for your body to keep insulin signaling on track.

• Lifestyle patterns further push the balance in the wrong direction — Chronic stress keeps cortisol levels elevated, and cortisol directly reduces your cells’ sensitivity to insulin. Poor sleep disrupts the hormones that regulate hunger and blood sugar, making you more likely to crave sugary or starchy foods while also leaving your body less able to handle them.

Physical inactivity exacerbates these problems. When your muscles are not regularly contracting and using glucose for fuel, the sugar remains in your bloodstream, and your pancreas is forced to release more insulin to try to keep up.

• All of these factors overlap in ways that strain your metabolism — They create an environment where insulin is constantly working harder to move glucose into your cells, while your cells are responding less and less. Over time, the result is a system that can no longer keep up, leaving you vulnerable to a cascade of health problems that begin with impaired energy regulation.

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Via https://articles.mercola.com/sites/articles/archive/2025/11/03/insulin-resistance-and-mental-health.aspx