“It’s not stress that kills us; it is our reaction to it.”
— Hans Selye
In his book, The Stress of Life, published in 1956, physician and researcher Hans Selye opened the door to understanding the relationship between stress and its effects on the human body and mind. Stress comes in many forms, and human beings who are subjected to it manifest it in a myriad of ways. Last week’s Study Spotlight examined the effects of chronic continuous low-level inflammation on the gut microbiome and its possible contribution to the risk of developing Alzheimer’s-type dementia later in life.
Such chronic, continuous, low-level inflammation is also a hallmark of obesity and type II diabetes mellitus. Though often characterized by BMI alone, the pathophysiology of true obesity (not just being overweight) involves a hyperreactive inflammatory response. This imbalance of normal immune function may be one reason that obesity is associated with an increased risk of developing type 2 diabetes. The risk of developing diabetes is over 3-fold higher in overweight individuals and more than 10-fold higher in obese individuals compared with lean individuals.
Obesity appears to lead to the development of type II diabetes through the induction of insulin resistance. Insulin resistance can result in fat cell dysfunction. A consequence is the growth of the adipose cells and increased adipose tissue inflammation and fibrosis. This can affect the liver, leading to unrestrained hepatic glucose production (hGP), which is a key driver of fasting hyperglycemia in diabetes. Such liver involvement is also believed to contribute to hepatic steatosis that can progress to metabolic dysfunction-associated fatty liver disease (MAFLD). MAFLD is present in more than 70% of people with type 2 diabetes and is the most common reason for fibrosis and liver failure.
However, exactly how this occurs remains poorly understood. It is generally thought impaired cellular insulin signaling is the primary driver of insulin resistance. However, this week’s study suggests that overeating (overnutrition) increases the stress hormone norepinephrine. This, in turn, causes increased activity of the sympathetic nervous system (SNS). Using a mouse model, researchers demonstrated that reducing catecholamine (CA, e.g., norepinephrine) release from the SNS protects against overnutrition-induced insulin resistance and hyperglucagonemia, adipose tissue dysfunction, and fatty liver disease. This suggests that “A key mechanism through which heightened sympathetic nervous system activity (SNA) induces insulin resistance is by triggering adipose tissue lipolysis. Increased SNA emerges as a critical driver in the pathogenesis of overnutrition-induced insulin resistance and metabolic disease independent of cellular insulin signaling.” In other words, it may be over-activation of the sympathetic nervous system, responsible for the flight, fight, or freeze response, associated with overeating that paves the way for the development of obesity and obesity-related type II diabetes.
- The study utilized a murine model, and thus, as always, there must be caution in applying that directly to human beings.
- The study highlighted several important points:
- Overnutrition leads to a rapid impairment of insulin action along with increased sympathetic nerve activity (SNA) and adipose tissue lipolysis despite intact cellular insulin signaling
- These specific mice, THΔper mice, constitute a mouse model of peripherally restricted catecholamine (CA) deficiency that allows the study of the CA released from the SNS; in other words, these genetically engineered mice are normal in every way but one: They cannot produce stress hormones (CA) outside of their brains and central nervous systems.
- As such, these mice were protected from HFD-induced glucose intolerance and insulin resistance and maintained hepatic insulin sensitivity despite comparable weight and adiposity gain, food intake, and cellular insulin signaling.
- These mice were likewise protected from key manifestations of HFD-induced metabolic disease, including adipose tissue dysfunction and fatty liver.
- Increased adipose tissue lipolysis is a key mechanism through which increased SNA induces insulin resistance.
- Overall, these findings suggest that increased activity of the sympathetic nervous system is “a key driver of insulin resistance and metabolic disease in diet-induced obesity.”
The Caveat:
This current research suggests a model in which overeating and obesity increase sympathetic nervous system activity, which causes, over time, insulin resistance and the development of type II diabetes. Increased sympathetic nervous system activity is a hallmark of other chronic disabilities and diseases (CDD) like congestive heart failure. Identifying commonalities of pathogenesis may help explain the link between apparently disparate CDD and also lead to possible treatments that target the cause of illness instead of many of the current therapies that only address the symptoms of conditions like diabetes.
This also offers an opportunity to explore the possible role of other initiators of chronic low-level activity of the sympathetic nervous system in the pathogenesis of chronic disabilities and diseases. Could stress, and particularly eating (and overeating) under stressful conditions, contribute to the development of obesity and type II diabetes in an independent manner? Could how we eat play a significant role in maintaining our health and wellness or risk of developing disability and disease?
The fact that simply overeating (at least in the mice in this study) increased the stress hormone norepinephrine within days suggests a potent link between what and how we eat food and how that information affects our nervous system downstream. Without the ability to transmit this information through the nervous system, although these genetically engineered mice got just as obese as normal mice, they did not develop metabolic disease. These insights may also help explain the clinical observation of why some obese (by BMI measures) individuals develop diabetes while others don’t and why stress can worsen diabetes even with little weight gain.
Lead researcher Christopher Buettner from Rutgers University commented, “Many types of stress — financial stress, marital stress, the stress associated with living in dangerous areas or suffering discrimination or even the physical stress that comes from excessive alcohol consumption — all increase diabetes and synergize with the metabolic stress of obesity. Our finding that even obesity principally induces metabolic disease via increased stress hormones provides new insight into the common basis for all these factors that increase the risk of diabetes. Stress and obesity, in essence, work through the same basic mechanism in causing diabetes, through the actions of stress hormones.”
How we eat and how we live is becoming as increasingly important as what we eat. As M.F.K. Fisher richly observed, “It seems to me that our three basic needs, for food and security and love, are so mixed and mingled and entwined that we cannot straightly think of one without the others. So it happens that when I write of hunger, I am really writing about love and the hunger for it, and warmth and the love of it and the hunger for it… and then the warmth and richness and fine reality of hunger satisfied… and it is all one.”
The Study:
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