We discussed the negative effects of large blood glucose fluctuations on the body in part one of this series. In part two we will discuss the effects of a large carbohydrate meal (LCM) on hormones. Examples of LCMs include bagels, bread, pasta, desserts such as cake, and so on. The hormones that are most affected by LCMs include ghrelin, insulin, epinephrine, glucagon, and cortisol. As you will read, while these hormonal effects might have had an evolutionary advantage to increase fat deposition during “feasting” conditions in prehistoric times, today they are deleterious and a major driver of metabolic disease.
Part II: Hormonal Effects of Postprandial Hyperglycemia
The One Rep
First 2 hours after a LCM: Insulin release can be two times higher than a low glycemic load food with the same amount of calories and carbohydrates.
2-4 hours after a LCM: Insulin remains high, driving down blood sugar (glucose) and stopping the release of triglycerides (fat) into the blood, causing hypoglycemia (low blood sugar) and low blood fats. This state of low blood sugar and fat paradoxically resembles the fasted state of not having eaten for hours, even though a large meal was ingested only hours before.
4-6 hours after a LCM: Low blood glucose induces release of epinephrine, glucagon, cortisol, and growth hormone, causing a rebound elevated blood glucose and elevated triglyceride levels
Ghrelin, a potent stimulator of hunger, rebounds about 4.5 hours after a LCM. This effect causes rebound hunger higher than before the LCM and a subsequent increased intake of calories when compared with a protein or fat meal of the same calories.
Hyperinsulinemia is associated with higher cancer mortality, heart disease, sodium reabsorption in the kidney leading to hypertension, activation of sympathetic nervous system, and alteration of vascular resistance.
Epinephrine causes muscular insulin resistance, increases release of fat from fat cells, and activates the sympathetic nervous system.
Cortisol induces insulin resistance, reduces bone formation, down regulates collagen (creating weaker skin), inhibits protein synthesis, and delays wound healing.
The main deleterious effects of eating LCMs are due to these hormonal disturbances, especially hyperinsulinemia. LCMs can cause a vicious cycle of weight gain by increasing hunger only a few hours after eating due to the rebound of ghrelin while the body still hasn’t fully recovered from eating the first meal.
Maximum Effort (For Experts)
Ghrelin, colloquially thought of as the “hunger hormone”, was originally discovered in the 1990s by its ability to release growth hormone, although this is of undetermined significance and not its current claim to fame . Ghrelin is released in the stomach in the fasted state and travels to the hypothalamus, where it mainly works via increasing transcription of neuropeptide Y, agouti-related peptide, and orexin-A and -B, all of which stimulate hunger. In the normal state, ghrelin is elevated in fasting, thus promoting hunger, and low during fed states, thus allowing the body to feel satiety. One study demonstrated that ghrelin infusions in humans enhances appetite, increases food intake, and subjectively decreases the affect that eating a large meal has on hunger:
In an n=9 randomized, doubled blinded cross over study, human subjects were randomized to be either infused with ghrelin or placebo. Each group ate breakfast when the infusion was started and subsequently were given an ad libitum buffet 4 hours into the infusion. Energy intake from the buffet was increased by 28% (1433 kcal vs 1126 kcal) in the ghrelin vs control group. Additionally, subjective hunger increased in the ghrelin infusion group by 46% immediately before the buffet and subjects reported no hunger reduction or quantity they felt they could eat after the ad libitum buffet. 
Another, more practical study compared ghrelin levels in humans after eating a carbohydrate, fat, or protein rich food. Fat and protein depressed ghrelin, which slowly returned to baseline over the course of 6 hours. Carbohydrates, however, caused a rebound of ghrelin to 30% higher than its baseline value after only 4.5 hours.
In an n=16 crossover study, human subjects consumed three isocaloric, isovolemic beverages that were either 80% carbohydrate, 80% fat, or 80% protein. The calorie content of each beverage was 20% of total energy expenditure (TEE) for each subject. 20% of TEE was chosen because that threshold was previously shown to cause suppression and subsequent return to baseline of ghrelin levels within 6 hours in humans. With respect to the protein and fat beverages, the carbohydrate beverage caused ghrelin to reach its nadir sooner (89 min vs 143 min (protein) vs 111 (fat)), had intermediate effects on total suppression of ghrelin (D-AUC 140 vs 186 (protein) vs 124 (fat)), and was the only macronutrient to actually increase ghrelin at any point in the study (ghrelin increased to 30% of baseline at minute 260). 
The above two studies, when combined, demonstrate that carbohydrates cause a paradoxical rise in ghrelin and that ghrelin promotes hunger. It is no surprise that a follow-up study demonstrated that eating carbohydrates before an ad libitum buffet caused a 10% higher ingestion of calories when compared with protein or lactose:
N=19 crossover study given 55g whey, 55g casein, 55g lactose, or 55g glucose load followed by a buffet 180 minutes later. Serum measurements and calorie consumption at the buffet were obtained. Energy intake was 10% higher after the glucose load and was predicted by the ghrelin levels at 120 minutes. 
To recap: A LCM causes a paradoxical rebound in ghrelin that increases hunger and causes an increase in food intake at a later meal (and most likely carbohydrates at that meal too, thus continuing the vicious obesity cycle).
The first systemic hormonal change after a large carbohydrate meal ingestion is an exaggerated release of insulin. The acute effects of insulin are to:
Decrease blood glucose by stimulating uptake into skeletal muscle, white adipose tissue, and liver
Increase sodium reabsorption in the kidney tubules, especially if hyperglycemia is present, which may lead to hypertension 
Alteration in vascular resistance via increased calcium concentration in smooth muscle cells. In an insulin sensitive individual, insulin induces vasodilation via nitric oxide production. However, in an insulin resistant individual, insulin will cause a paradoxical vasoconstriction and endothelial proliferation, which is thought to be one of the main drivers of cardiovascular disease. 
Activation of sympathetic nervous system . Activation of the sympathetic nervous system is a normal compensatory response to maintain blood pressure after postprandial splanchnic vasodilation. However, chronic sympathetic nerve activity drives hypertension and predicts future risk of insulin resistance and diabetes. It is still debated whether sympathetic activity drives metabolic syndrome or if metabolic syndrome itself causes sympathetic overactivity. 
Norepinephrine release is mediated by insulin and not glucose. Twelve healthy males within 30% of ideal body weight underwent three different clamps: Euglycemic clamps with insulin infusions of 2 mU/kg/min and 5 mU/kg/min with a variable glucose infusion to maintain basal glucose and a hyperglycemic clamp with a sustained elevated blood glucose of 125 mg/dl above basal glucose. These clamps were held for 2 hours. The serum insulin in the steady state for the 2mU infusion group was 150 uU/ml and 600 uU/mL for the 5mU infusion group. Norepinephrine increased 50% for the 2 mU insulin infusion and 117% for the 5 mU infusion. Norepinephrine did not increase for the hyperglycemic glucose clamp or control tests . This study demonstrated that sympathetic activation is most likely due to insulin and not hyperglycemia. Of these two infusions, only the 2 mU infusion maintains physiological serum insulin levels. The steady state serum insulin level was 44 uU/ml for the 2 mU infusion and 600 uU/ml for the 5 mU infusion. For comparison, another study investigated insulin response to a standard LCM of 595 kcal, of which 111.7g were carbs (75% of kcals). This meal resulted in a glucose peak of 130 mg/dl and insulin peak of 50 uU/ml after approximately 30 minutes .
The chronic effects of repeated bouts of acute hyperinsulinemia are harder to describe as it becomes difficult to distinguish the effects of hyperinsulinemia versus insulin resistance. The hormonal effects of a LCM are closely intertwined with insulin resistance, which will have its own deep dive in the near future.
The result of the exaggerated insulin response to a large carbohydrate meal is twofold: blood glucose drops below baseline and lipolysis is inhibited. The body senses that its main energy sources, blood glucose and blood free fatty acids, are low and that it is in the “fasted” state. This prompts hormonal changes that increase the amount of glucose and free fatty acids in the blood even though a large meal was consumed only hours before. This process reminds me of potassium in diabetic ketoacidosis; frequently, potassium will be elevated on a basic metabolic panel in DKA, however total body stores of potassium will be low due to diuresis. Likewise, serum "energy" will be low but total body "energy" will be high.
There exists some debate around whether reactive hypoglycemia can cause hypoglycemic symptoms such as tremors, anxiety, sweating, and decreased cognition, but what is known is that the counterregulatory hormones epinephrine, glucagon, and the sympathetic nervous system are stimulated at a blood glucose level of only 68 mg/dl. 
Glucagon- The main hormone that stimulates glycogenolysis and gluconeogenesis in the liver, thus increasing serum glucose.
Growth Hormone (GH)- GH works to increase both serum free fatty acids (FFA) and serum glucose during hypoglycemia. GH increases lipolysis by stimulating hormone sensitive lipase in adipocytes, thus liberating FFA into the serum. Meanwhile, serum glucose is increased by gluconeogenesis and increasing insulin resistance in the periphery. Insulin resistance is achieved by GH inhibiting translocation of GLUT1 and GLUT4 to the adipocyte membrane. 
Cortisol- Increased 19% by hypoglycemia. Increases lipolysis. Secretion stimulated at a blood glucose level of 58 mg/dl.
Sympathetic response- Nor-/ Epinephrine are increased 24% by hypoglycemia. The sympathetic system will be activated twice from a LCM: once from hyperinsulinemia (see above section) and once from the resultant reactive hypoglycemia. As above, this sympathetic response will drive lipolysis to increase serum free fatty acids. The sympathetic effects on the liver are dependent on either being in the fed or fasted state and result in either glycogenolysis or gluconeogenesis, respectively. Again, chronic activation of the sympathetic system can cause reduced vascular conductance, increased tone of blood vessels, and induce large artery hypertrophy. 
Positive feedback is the amplification of an effect by its own influence on the process that gives rise to it. Eating a large carbohydrate meal creates a hormonal positive feedback loop that increases the likelihood of eating another large carbohydrate meal. Through ghrelin, eating carbohydrates increases hunger within 5 hours with a subsequent increase in calories ingested. Through insulin, there will be a reactive postprandial hypoglycemia that promotes hunger as well as lipogenesis. Cortisol, epinephrine, norepinephrine, and general sympathetic efferent activation are activated and predispose to metabolic syndrome. The sole inhibitory input to the otherwise positive feedback cycle of eating a large carbohydrate meal is the prefrontal cortex; that is, knowing how deleterious chronic ingestion of LCMs is the best way to break the cycle, and that is the purpose of this white paper.
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