As seen in Psychology Today.

Three of the most burdensome and unfortunately commons conditions affecting people in the United States are obesity, diabetes, and depression. The Centers for Disease Control & Prevention found that the prevalence of obesity in 2017-18 in the United States was 42.4% (around 138 million people). Meanwhile, the CDC estimates that around 10% of Americans have diabetes (of which 90-95% have type 2 diabetes), and that 7.6% of Americans 12 years of age and older may suffer from depression in any given 2-week period.

Apart from being serious conditions in their own rights, the probability of having one significantly increases the odds of having another. Most patients with type 2 diabetes are also obese and many obese patients are either diabetic or at risk of becoming diabetic. Furthermore, patients with type 2 diabetes are 2 to 3 times more likely to struggle with depression than patients without diabetes, while a diagnosis of major depressive disorder shows a strong correlation with diabetes. Between 40% and 60% of patients with depression experience glucoregulatory mechanism disruptions that are oftentimes an indication of increased risk for type 2 diabetes. Studies have also found a link between obesity and depression, though the directionality of this relationship continues to be a matter of intense debate.

Given that there is such a high instance of overlap, it seems reasonable to assume that there is an etiology or underlying mechanism that increases the probability of developing all three. Recent research has indicated that one possible explanation is brain insulin resistance.

Glucose and Insulin

After consuming a meal, your body breaks down the carbohydrates that you eat into glucose, a simple sugar that your cells can use as fuel. As more glucose enters the bloodstream from the digestive tract, insulin, a hormone produced by beta-cells in the pancreas, is released. Insulin binds with fat and muscle cells’ insulin receptors, which then begins a cascade of effects that ultimately allow glucose to enter these cells. As more glucose enters the cells, it dissipates from the bloodstream. Insulin production decreases as glucose levels fall, and the remaining insulin in the bloodstream is broken down by the appropriately named insulin-degrading enzyme (IDE). When there is excess glucose, insulin helps usher it to the liver where it is stored for later use between meals or when the body needs an extra jolt of energy during strenuous activities.

If blood glucose levels remain too high for too long (a condition known as hyperglycemia), this can lead to a wide range of extremely serious health problems, even death. This is just one reason why proper insulin regulation is so vital.

Diabetes Type 1, Diabetes Type 2, and Prediabetes

Patients with type 1 diabetes make very little insulin, if they make insulin at all. In most cases, onset is early in life.

Patients with type 2 diabetes, meanwhile, either do not make enough insulin to properly regulate their blood glucose levels or their body does not adequately respond to insulin.

In most instances, patients with type 2 diabetes do not suddenly become unable to properly regulate their blood glucose levels. Rather, it is something that develops over time as cells throughout the body build up a tolerance to insulin, often because they are frequently in a state of hyperglycemia. There is evidence that genetic factors may also play a significant role. These individuals become increasingly

resistant to insulin’s signals to absorb glucose from the bloodstream and, for that reason, they develop what is known as insulin resistance.

As the body becomes less sensitive to insulin—i.e. as the body becomes more insulin-resistant—the pancreas is forced to produce more insulin to maintain healthy blood glucose levels. When individuals begin to develop insulin resistance their pancreas continues to make enough of the hormone to keep their blood sugar levels in a healthy range, but these individuals become prediabetic. An estimated 34.5% of the nation’s adult population is prediabetic. It is only after their pancreas ceases to be able to produce sufficient insulin to maintain a healthy blood glucose level that they become diabetic.

Brain Insulin Resistance

Different kinds of cells throughout the body can become insulin resistant. Any cell that has insulin receptors and responds to insulin signaling can build up a tolerance to the hormone and this includes brain cells (neurons).

While this may not seem like a controversial position today, researchers in the past believed that the brain was an insulin-insensitive organ because glucose uptake occurs in the brain independently of insulin signaling. Despite this insulin-independent means of glucose uptake, research in the past decade has shown repeatedly that insulin receptors do exist in certain parts of the brain and that they do have an impact on glucose uptake. The regions of the brain with the highest concentration of insulin receptors are the olfactory bulb, hypothalamus, hippocampus, cerebral cortex, striatum, and cerebellum.

Unlike the rest of the body, where insulin receptors serve as gatekeepers to allow glucose transport into cells through insulin signaling, insulin receptors in the brain often serve additional functions. A prime example is the hypothalamus, the region of the brain that can be thought of as the control center for appetite and metabolism. It is heavily influenced by insulin signaling, which in turn influences energy metabolism throughout the body. This includes functions like hepatic glucose production, glucose uptake into the muscles and adipose tissues, and insulin release. Like other parts of the body, when the hypothalamus becomes insulin resistant, more insulin signaling is needed to get it to function correctly. This lack of insulin sensitivity, like other forms of insulin resistance, is linked to increased visceral fat accumulation and obesity, though the directionality of this connection is unclear. What seems likely is that the two phenomena, obesity and insulin resistance, fuel one another.

Brain Insulin Resistance, Alzheimer’s Disease, and Depression

Another frequent comorbidity with brain insulin resistance and type 2 diabetes is Alzheimer’s disease (AD). Researchers have found that AD is twice as common in patients with type 2 diabetes than it is with patients who do not have type 2 diabetes. The correlation between the two is so strong that AD is often referred to as type 3 diabetes. Given that two of the hallmarks of AD are declines in spatial cognition and memory, it would seem reasonable to assume that the part of the brain most responsible for these two functions would also be most vulnerable to insulin resistance. This turns out to be true. The hippocampus, which plays a major role in memory and spatial orientation, is also one of the brain regions with the highest concentrations of insulin receptors, and data shows that changes in insulin signaling can adversely affect hippocampal plasticity and function. In addition to being central to memory and spatial cognition, the hippocampus is also a crucial part of the neural motivational network (i.e. the network that oversees the reward system in the brain) and the network of

the brain that regulates mood. Dysregulation of this network, and dysfunction of the hippocampus in particular, has been shown to be an indicator of major depressive disorder.

It is likely that there are numerous other factors that may independently give rise to the three subjects of this post—obesity, diabetes, and depression. It is also possible that the correlation between these three conditions is coincidental. However, what is certain is that a diet that produces chronic states of hyperglycemia is putting unnecessary stress on a myriad of the body’s systems—most certainly the endocrine system and almost certainly many of the networks in the brain—and that this constant stress is leading to a rise in chronic illnesses.

Rather than relying entirely on pharmaceutical remedies alone to treat these conditions, it may be best to let food be thy medicine by avoiding heavily processed foods and switching to a diet rich in fruits, vegetables, whole grains, and lean proteins.

Dr. Ahmad reports no conflict of interest. He is not a speaker, advisor, or consultant and has no financial or commercial relationship with any biopharmaceutical entity whose product/device may have been mentioned in this article.