Does the Prediabetic Cyclist Need to Worry? (Continued Part 2)
Part 2: Exercise Hormonal Changes Which Raise Glucose
What endurance adaptations allow for an elevated glucose response?
Exercise physiologists agree on three, and hypothesize as many as five possible exercise-related hormonal changes which allow endurance athletes to sustain glucose levels. These are in order of impact:
1) Increased glucagon relative to insulin levels
2) Increased liver sensitivity to glucagon
3) Increased catecholamines, and possibly,
4) Increased growth hormone, and
5) IL-6 levels.
Let’s briefly discuss each in turn.
Exercise changes the balance between glucose regulating hormones: glucagon and insulin.
Insulin’s function is to tamp down blood glucose levels. During exercise, if insulin was the dominant hormone, glucose levels drop. Considering that a low glucose level during exercise is undesirable, a normal exercise response is for insulin levels to decrease. Insulin has a partner hormone also produced from the pancreas, glucagon.
The two hormones represent the ying-yang of blood glucose tuning, as they simultaneously circulate in the blood. Glucagon counters insulin’s lowering action by raising glucose levels. During the course of building stamina the relative amount of glucagon-to-insulin shifts in favor of glucagon, significantly raising glucose levels.
Dr. Frampton reviewed all studies to-date relating to glucagon and insulin levels following 30 minutes of exercise. In five studies reviewed, glucagon levels were higher than at the start. From the more numerous insulin studies, he concluded, “that aerobic exercise significantly decreased insulin concentrations relative to resting.” [Frampton 2021]
Not only is this glucose-increasing hormonal change an established finding, but the binary shift persists after exercise ends. One outcome of this glucagon-tilted shift inclines the liver to release more glucose into the blood, explaining hyperglycemia.
Exercise increases the liver’s sensitivity to glucagon.
Not only has the hormonal balance shifted in favor of glucagon, but an athletically trained liver becomes more sensitive to glucagon’s influence. The same dose of glucagon injected into a trained athlete will cause the liver to release more glucose than the same dose given to someone untrained.
Supporting studies performed on rat livers reveal that following endurance exercise, the liver produces more glucose in response to glucagon. [Podolin] In rats, this endurance-trained liver response appears to be the result of more numerous glucagon receptors. [Légaré] More receptors binding glucagon encourage the sensitized liver to amplify glucose output, even at rest.
Exercise increases catecholamines.
Exceeding casual-level exercise elicits a flight-or-fight response with an outpouring of epinephrine and norepinephrine. The liver responds to the two catecholamines, by surging glucose into the blood.
One of the major reasons why athletes can raise their glucose higher than normal lies in their ability to bathe the body in a potent torrent of catecholamines. This surge wells up from an oversized catecholamine reservoir in the adrenal glands. Some have taken to call the augmented catecholamine adrenal adaptation, the “Sports Adrenals”.
Winning or losing a competition often hinges on the timely injection of catecholamines. Research reveals that athletic performance correlates with norepinephrine levels up until the moment of exhaustion. These higher levels of catecholamines have been found to persist past exercise through to the remainder of the day, and even well into the sleep cycle.
Seven athletes when compared with eight sedentary men over a 24 hour period were found to have twice as high total epinephrine and norepinephrine blood concentrations. Greater levels were recorded during sleep. [Dela]
While catecholamines might explain why a liver releases more glucose after exercise, some researchers discount the effect, saying that catecholamine levels are halved when blood transits the intestines en-route to the liver. In response, others point out the liver’s dual blood supply, with a separate direct feed bypassing the intestines.
To what degree and effect higher catecholamine levels contribute to liver glucose release after exercise is controversial. Doctors recognize a catecholamine-producing adrenal tumor called a pheochromocytoma which may cause diabetic glucose levels, so one might not be able to outright dismiss “Sports Adrenals” as a contributor to hyperglycemia outside of exercise.
Growth Hormone, another possibility.
Acromegaly is a disease resulting from too much growth hormone. One symptom is hyperglycemia. Interestingly, endurance athletes, especially non-senior athletes can increase their growth hormone levels after exercise. The level of resulting growth hormone, like catecholamines, is proportional to the degree of exercise effort and duration. [Perriello 1990] Growth hormone is also known to be connected to a diabetic phenomenon, called the dawn phenomenon.
In seven healthy moderately trained men in their twenties, growth hormone was measured for 24 hours after exercise. Blood growth hormone concentrations were 60% higher on exercise days than on the rest days. [Kanaley 1997]
The dawn phenomenon is hyperglycemia taking place in the early morning. Seen in insulin-dependent diabetics, the high sugars are the result of abnormal nighttime spikes of growth hormone secretion. A similar increase in glucose occurs for those suffering from insomnia. While growth hormone may play a part in raising glucose for younger athletes, the exercise bump diminishes with age. By the fifth decade of life, the growth hormone exercise-boost dwindles to negligible levels. [Wideman 2002]
Lastly, IL-6.
IL-6 comes from a family of muscle-communicating substances known as Myokines. Myokines are released by muscles in response to contraction. After release, myokines influence other organs. While research into IL-6 is more recent and less well-established than previous hormones discussed, IL-6 has been shown to stimulate glucagon release from the pancreas. In addition, some researchers speculate that IL-6 might directly influence the liver to release glucose.
Any reassurance that endurance exercise-related hyperglycemia doesn’t lead to diabetes?
At this junction, the burning question, “Should people with exercise-related hyperglycemia worry about going on to diabetes and diabetic complications?” can be addressed with some known facts.
Even though prediabetes is diagnosed through glucose tests, glucose is not the fundamental metabolic defect. Consider this enigma. For many years, many have claimed that the attachment of glucose onto protein, protein glycation is the cause of diabetic ills. Four large-scale studies, spanning decades failing to demonstrate that drugs designed to lower blood sugar do not prevent heart attacks, didn’t cause theory disciples to question whether glucose is the fundamental problem.
Only recently, the Sodium–glucose cotransporter 2 (SGLT2) inhibitors, (empagliflozin and canagliflozin) and the drug liraglutide, have been found to lower the risk of heart attacks and strokes in diabetes. These drugs have other recognized beneficial effects outside of lowering glucose, and therefore their ability to lower the risk of heart attacks and strokes may not be due to glucose-lowering effects.
Consider the question from a different angle, “What causes diabetic hyperglycemia?” The core factors leading from prediabetes to T2DM are the same defects underlying diabetic complications: insulin resistance, chronic inflammation eventually resulting in beta-cell failure within the pancreas.
Genetics plays a part, but remember that as recently as the first half of the 20th century, T2DM was a rare disease. There is strong agreement in the scientific community that these underlying deviations in physiology lead to diabetic hyperglycemia. Conversely, the causes of prediabetic hyperglycemia aren’t the same as those which drive conventional prediabetes to diabetes causes.
Endurance exercise-related hyperglycemia is not caused by any of the above prediabetic or diabetic processes. Setting aside for the moment possible damage caused by circulating high blood glucose, (protein glycation), how does the future health risk calculation change?
The commonly used diabetic test, Hemoglobin A1c, relies on the attachment of glucose to the hemoglobin protein, aka glycation. (Glycation is a non-enzymatic reaction, irreversible and concentration-dependent, in which glucose or other carbohydrates are added onto proteins or other molecules.) Glucose levels in red cells, cells lining blood vessels, pancreas, and the brain mirror blood levels. (The pancreas needs to be able to sense glucose levels and the brain cannot be denied glucose.) Other cells tightly control entry, so internal glucose concentrations vary from blood levels.
Even then, glucose inside cells attaches to molecules through a slightly different process called glycosylation. Glycosylation, by contrast is an enzymatically-controlled and purposeful process. One familiar example is the ABO blood type. The different blood types come about by genetically determined, regulated, enzymatically driven attachments of sugars to proteins. Among many vital cell functions, glycosylation serves to increase or decrease enzyme activity.
So far as can be gleaned from mouse experiments, the diabetic tissue injury is the result of dysregulated glycosylation enzyme activity. (For those curious, look up, “O-GlcNAc glycosylation”) Diabetic injury takes place inside cells where the conditions are not necessarily the same as HgbA1c in the blood. Prediabetic HgbA1c levels do not cause diabetes, other related factors indirectly do.
This is an important point and distinction. The diagnosis of prediabetes and diabetes depends upon measuring a secondary change, in glucose or HgbA1c. Scientists do not agree whether the mildly elevated levels of glucose seen in prediabetes cause diabetes because other factors need to be present and other conditions can lead to hyperglycemia.
A secondary outcome might have more than one cause. For example, many athletes have physiologically enlarged left ventricles (Athlete’s heart). Enlarged left ventricles are the hallmark of left ventricular heart failure, yet athletes are not in heart failure. Clearly, not all left ventricular hypertrophy or enlargement is pathologic. The “Athlete’s heart” enlargement bears a superficial, look-alike resemblance to a disease process, yet is a healthy, fitness adaptation.
Athletes generally do not have insulin resistance.
Both aerobic and resistance exercise are known to lower insulin resistance. Athletes have lower insulin resistance compared to the sedentary person. Insulin resistance is a concept describing the body’s requirement for a higher blood level of insulin to elicit normal physiology. An overweight prediabetic’s insulin resistance drives the pancreas to manufacture ever-increasing amounts of insulin. At a certain point, the beta-cells of the pancreas which make insulin, perish from overwork. Insulin resistance of the pancreas results in T2DM.
Increasingly, physicians regard insulin resistance as the primary pathology behind “poor lifestyle choice” diseases. Insulin resistance of blood vessels and kidneys results in high blood pressure. Insulin resistance of fat results in obesity. Insulin resistance of the brain results in dementia. Since exercise reverses the major determinant of insulin resistance in the body, muscle, regular exercisers are not likely to be insulin-resistant. (At the conclusion, a table of addressable, but underrecognized causes of insulin resistance can be found.)
Take the example of the active Type 1 diabetic. They can live a long healthy life compared to Type 2 diabetics with the same glucose level, if their insulin resistance levels are low. For those of you who might wish to read one such physician and Type 1 diabetic’s personal story, consider Dr. Bernstein’s Diabetes Solution: The Complete Guide to Achieving Normal Blood Sugars.
Athletes do not generally have chronic inflammation.
Obesity and T2DM can rightfully be regarded as chronic inflammatory diseases. Nearly all Type 2 diabetics have elevated biomarkers of chronic inflammation. Regular exercisers by contrast have low inflammatory biomarkers. Studies have even demonstrated an inverse relationship between the level of physical activity and the serum inflammatory biomarkers. One such well-established marker of chronic inflammation is High-sensitivity C-reactive protein (hsCRP).
In many studies, exercise decreases average hsCRP in both healthy adults and those with metabolic disease. While strenuous exercise transiently increases inflammatory markers, these quickly subside afterwards. The overweight prediabetic and diabetic have chronically elevated hsCRP levels which are significantly higher compared to nondiabetics, in particular to those who exercise regularly. [Cunha]
Researchers agree that inflammation drives and underlies tissue damage in prediabetes and T2DM. Regular exercisers don’t generally have chronic inflammation.
Can hyperglycemic athletes have pancreatic beta-cell dysfunction? At first glance . . . .
Exercise is known to improve the performance of the beta-cell, the pancreatic mover and shaker of insulin production. Upon that first bite of food, a superbly performing beta-cell promptly secretes sufficient insulin to dampen the rise in blood glucose.
However, physically trained individuals have a markedly blunted insulin response to food. Like “Johnny come lately,” their pancreatic beta-cell, output begins low and slow, but catches up later.
In the graph above, the light blue line plots a low and slow athletic insulin response when tested with the Glucose Tolerance Test (GTT). This blunted response means that the initial surge in insulin response to a GTT challenge is less robust, a less than obvious finding unless one is measuring insulin, a test not normally performed with patients. Despite of low insulin, the glucose curve was fine.
After ten days, Dr. Heath asked athletes to stop exercising. Their insulin output “normalized” and increased, matching sedentary controls. (Red line) However, their GTT glucose numbers worsened. Upon resuming exercise, their glucose curve recovered.
One might draw an analogy to the Athletic Heart enlargement, mentioned earlier. This curious response makes sense if one realizes that an exercising athlete has an exquisitely high insulin sensitivity, match-paired to their blunted insulin response. An exercise holiday reduces their muscle-primed insulin sensitivity and correspondingly raises their insulin response. Another way of saying this is their insulin resistance increased when they no longer exercised. [Heath 1983]
Exercise not only decreases systemic insulin resistance, decreasing the workload on beta-cells, but also improves beta-cell health. Keep in mind that regular exercisers have earned a low systemic insulin resistance; we’ll see why this is a key reason not to overly worry.
(Last part in this chapter, Part 3: What About Me Specifically? will share some useful tips going forward.)
