Thursday, February 14, 2013

Insulin's Role in Blood Glucose Regulation

"Insulin is important in the regulation of blood sugar, but its importance has been exaggerated because of the diabetes/insulin industry. Insulin itself has been found to account for only about 8% of the "insulin-like activity" of the blood, with potassium being probably the largest factor. There probably isn't any process in the body that doesn't potentially affect blood sugar.

When I initially read this quotation posted by one of Dr. Peat’s ardent followers on Facebook, it caught my attention because I was under the impression that insulin was the dominant factor in regulating blood glucose levels.

Normally, when blood levels increase, the beta-cells of the pancreatic islets secrete insulin into the bloodstream, where it binds to insulin receptors on organs and tissues throughout the body.  The adipose tissue, liver, and muscles are the principle sites that insulin exerts its actions on.  In effect, insulin is a storage hormone that rapidly clears nutrients out of the bloodstream.

(1) In the fat tissue, insulin suppresses the mobilization of fatty acids and promotes the synthesis of fatty acids and triglycerides.
(2) In the liver, insulin inhibits gluconeogenesis and glycogen breakdown and stimulates glucose oxidation and glycogen synthesis.
(3) In the muscles, insulin stimulates amino acid uptake and protein synthesis.

According to some of the most widely read physiology textbooks, in the absence of insulin all of the above processes become impaired, and fatty acids and amino acids are released in large amounts into the bloodstream from the fat tissue and muscles, respectively.  In the liver, these fatty acids are used to generate ketone bodies and the amino acids, substrates for gluconeogenesis, are used to generate glucose.  Because fatty acids flow to the liver at a high rate, and because insulin normally stimulates the use of ketone bodies by cells in the body, ketone bodies—namely acetone—accumulate in the bloodstream, thereby leading to acidosis, coma, and death.

I think most people are also aware of experiments in isolated segments of animal tissue, in which blood glucose levels are incrementally increased in the absence of insulin (ex vivo).  In these experiments, despite increasing blood glucose levels by up to 800 mg/dL, which is 10-fold greater than the normal fasting blood glucose levels, the levels of glucose inside cells do not change much at all.  What this means is that, without insulin, regardless of how high blood glucose levels rise, the entry of glucose into cells is prevented, and this is, for all intents and purposes caused by a rise in NEFA and ketone body levels.

More recently, based on better, and more physiological, experiments, it has been suggested that there could be constitutively active glucose transporters; that is, proteins embedded in the plasma membrane that, in an insulin-independent manner, transport glucose into cells.1 These transport proteins are regulated by the unequal distribution of free glucose molecules between the blood and inside the cell (i.e., the concentration gradient across the plasma membrane), and the efficiency with which the glycolytic enzymes function.

So it is possible that insulin assumes a secondary, or conditional, role in the regulation of blood glucose levels under some circumstances.  In the fasting state, when blood glucose levels fall, glucose is transported into cells with, at the most, very little help from insulin . . . this process being only limited by the rate at which the glycolytic enzymes function.  

But when blood glucose levels rise, as in after a carbohydrate-laden meal, the beta-cells begin to secrete insulin, and insulin (1) suppresses the mobilization of fatty acids, (2) suppresses hepatic glucose production, and (3) stimulates the recruitment of glucose transport proteins to the plasma membrane, whereby insulin-sensitive cells sprout orders of magnitude more glucose transport proteins.  In this way, glucose is cleared as rapidly as it rises in the blood, because of insulin’s permissive effects, such that blood glucose levels don’t fall out of range too much.

So, although insulin may not be the be-all and end-all regulator of the rate at which glucose is transported into cells, it is by no means a minor player as asserted by Dr. Peat. (Actually insulin is a protective compensatory adaptation to the rising levels of the counterregulatory hormones that occurs naturally with aging.)

As to potassium, it is known that inappropriately dosed insulin injections can uncomfortably lower blood potassium levels (hypokalemia), as insulin shifts potassium into cells.

By neutralizing ROS, potassium has also been hypothesized to improve insulin sensitivity.2 Though, this is not having 'insulin-like action.' (As an aside, to date, the use of antioxidants to treat diabetes has been abysmally unsuccessful.)  

But then again, high potassium levels (hyperkalemia), in turn, stimulates the secretion of aldosterone, which could worsen insulin sensitivity.3 This is the same mechanism by which salt-restricted diets induce insulin resistance.4

Potassium has another important role in blood glucose regulation in the beta-cells.  Without going into too much detail, when blood glucose levels rise, the beta-cells uptake glucose, which is then oxidized to generate ATP.  This newly generated ATP, thereafter, binds the ATP-sensitive potassium channels in the plasma membrane that close upon this interaction with ATP, enabling potassium to accumulate intracellularly.  As a result, the membrane depolarizes, stimulating the opening of the voltage-gated calcium channels that then allow calcium to move into the beta-cell in droves, triggering insulin secretion.

It is conceivable that a deficiency of potassium could impair insulin’s action (e.g., diuretics that deplete potassium have been shown to induce insulin resistance).  But as far as potassium having insulin-like action, I don’t see any evidence for this.

Insulin’s actions are blocked by elevated levels of NEFA and the counterregulatory hormones, in which case, the resulting inhibition of the glycolytic enzymes would block the procession of glycolysis, leading to the accumulation of free glucose molecules that could move out into the extracellular space.  This plays an important regulatory role while fasting (a period of time when glucose availability is limited) and while under stress, by preventing glucose from being used up too quickly . . . otherwise, shock would manifest.

Insulin can be conceived to boost, in a permissive manner, the clearance of glucose from the blood so that after eating a carbohydrate-laden meal, per the mechanisms described above, blood glucose levels don’t fall out of range too much or for too long.  Gastrointestinal hormones play a role in blood glucose regulation as well, but they do so by potentiating the stimulation of insulin secretion from the pancreatic beta-cells.

In conclusion, insulin occupies a major role in blood glucose regulation—not a minor one.  A rise in glucose is always quickly accompanied by a rise in insulin in the bloodstream, and insulin suppresses the factors that inhibit the rapid clearance and oxidation of glucose, which are processes that would occur too inefficiently otherwise (that is, if glucose were to stimulate its own uptake and oxidation).  A situation like this would only occur during a fast or ketogenic diet, cases in which fasting glucose levels would run parallel with low insulin levels, prompting a slow and controlled rate of glucose use.  This is the scenario that Dr. Peat is probably alluding to.


1. Sonksen PH. Insulin, growth hormone and sport. The Journal of endocrinology. 2001;170(1):13–25. Available at: Accessed February 14, 2013.
2. Ando K, Matsui H, Fujita M, Fujita T. Protective effect of dietary potassium against cardiovascular damage in salt-sensitive hypertension: possible role of its antioxidant action. Current vascular pharmacology. 2010;8(1):59–63. Available at: Accessed February 14, 2013.
3. Kraus D, Jäger J, Meier B, Fasshauer M, Klein J. Aldosterone inhibits uncoupling protein-1, induces insulin resistance, and stimulates proinflammatory adipokines in adipocytes. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et métabolisme. 2005;37(7):455–9. doi:10.1055/s-2005-870240.
4. Garg R, Williams GH, Hurwitz S, Brown NJ, Hopkins PN, Adler GK. Low-salt diet increases insulin resistance in healthy subjects. Metabolism: clinical and experimental. 2011;60(7):965–8. doi:10.1016/j.metabol.2010.09.005.