“Contrary to popular belief, insulin is not needed for glucose uptake and utilization in man.”

(Manninen, 2004)

In a world where we learn the primary function of insulin is to facilitate cellular glucose uptake, the statement above is nothing short of revolutionary. Indeed, though, as the author goes on to say:

“Contrary to popular belief supported by the leading physiology and biochemistry textbooks, there is sufficient population of glucose transporters in all cell membranes at all times to ensure enough glucose uptake to satisfy the cell's respiration, even in the absence of insulin. Insulin can and does increase the number of these transporters in some cells but glucose uptake is never truly insulin dependent.”

This might shock many people, especially those living with type 1 or type 2 diabetes. But it’s true: most glucose transporters do not require insulin to take glucose into cells. GLUT4, the most abundant glucose transporter in adipose tissue, skeletal and cardiac muscles, is insulin-sensitive and its translocation to the cell membrane is stimulated by insulin, but it can also participate in non-insulin mediated glucose uptake, such as during physical activity. (In fact, exercise is the most potent stimulus for increased skeletal muscle GLUT4 expression.) So why, then, do most people—including many medical and nutrition professionals—think of insulin primarily as a “blood sugar hormone?”

There’s no doubt that insulin does play a primary role in regulating blood glucose, but not for the reason we usually think. As mentioned, glucose uptake in the body is never truly dependent on insulin. The main role of insulin in gluco-regulation may be to counteract the effects of glucagon. And with about 88% of people surveyed last year meeting criteria for being “metabolically unhealthy,” and most of this stemming from metabolic syndrome or chronically high insulin, there’s a good reason insulin and insulin resistance garner the lion’s share of health headlines. But what about glucagon, an insulin counter-regulatory hormone?

Glucagon is secreted by the alpha cells in the pancreas, and it has opposite effects to those of insulin: whereas insulin inhibits lipolysis and ketogeniesis (the breakdown of fats and generation of ketones, respectively), glucagon stimulates these. Insulin is anti-catabolic; glucagon is catabolic. We can see this in the way individuals with untreated type 1 diabetes (T1D) waste away: this is the effect of glucagon run amok when insulin is absent or insufficient for keeping it in check. As Dr. Roger Unger, an expert in this field, wrote: “the catabolic actions heretofore considered the direct consequences of insulin lack are actually mediated by a relative or absolute excess of glucagon to insulin.”

Whereas insulin lowers blood glucose (BG) in the postprandial or fed state, glucagon raises BG in the fasted state, whether that means during a long term fast or simply overnight or for long spans between meals when food hasn’t been consumed for several hours. It does this by stimulating glycogenolysis and gluconeogenesis in the liver. It can also catabolize muscle proteins to generate glucose from amino acids, which explains the wasting seen in untreated T1D. 

Hyperglycemia—particularly in the case of T1D but also possibly in individuals with insulin resistance—does not necessarily result from an inability of cells to take up glucose, but rather, from uncontrolled hepatic production and release of glucose: “The use of tracer glucose infusions has shown not only that hyperglycaemia in the face of insulin deficiency is the result of over-production of glucose by the liver but also that insulin infusion lowers blood glucose by inhibiting hepatic glucose production.”

A paper published after the one cited above corroborates:

“When insulin is administered to people with diabetes who are fasting, blood glucose concentrations falls. It is generally assumed that this is because insulin increases glucose uptake into tissues. However, this is not the case and is just another metabolic legend arising from in vitro rat data. It has been shown that insulin at concentrations that are within the normal physiological range lowers blood glucose through inhibiting hepatic glucose production.” (Manninen, 2004)

Hyperglycemia, or even a normal rise in BG such as occurs after a meal, normally elicits an increase in insulin in order to lower the BG, and the presence of insulin suppresses glucagon secretion. When insulin is absent, however, as in T1D, or when pancreatic alpha cells are not responding to insulin properly (as may occur in T2D), the elevation of BG stimulates glucagon secretion: “This adds an endogenous source of glucose to the exogenous glucose from the meal.” No wonder BG is so high postprandially in those with T1 or T2D—even higher than would be expected solely from the carbohydrate content of a meal.

Beyond control of BG, stimulating lipolysis and ketogenesis, and inhibiting fatty acid synthesis, glucagon crosses the blood-brain barrier and appears to regulate appetite and satiety via effects in the central nervous system. (Evidence indicates a small amount of glucagon synthesis occurs within the brain stem as well, and some is also produced in the eneteroendocrine L-cells of the intestinal mucosa.) It has also been shown to enhance metabolic rate through activation of brown adipose tissue and inducing a thermogenic effect. For these reasons, glucagon action is an attractive target for drugs and other therapies intended for fat loss. Some overlaps between glucagon and GLP-1 action may explain the modest weight loss observed in people with or without T2D treated with GLP-1 receptor agonist drugs. 

Individuals on low-carb or ketogenic diets sometimes fear the glucose-raising effects of glucagon. However, gluconeogenesis (GNG) in the context of a low-carb or ketogenic diet is different from that which occurs on a high-carb diet or, more specifically, when hepatic glycogen is full: “The hyperglycemic property of glucagon is further enhanced when hepatic glycogen levels are high and diminished when glycogen levels are low, such as in fasted animals, diabetic animals with ketosis, or patients with liver cirrhosis.”

Of course, one need not fast, nor have diabetes or cirrhosis in order for hepatic glycogen to be low. This occurs naturally on low-carb or ketogenic diets, and since the body and brain always need some glucose, even on a strict ketogenic diet, keto dieters can thank glucagon for keeping them alive and helping their brain fire on all cylinders. In the context of a low-carb or keto diet, GNG doesn’t typically cause hyperglycemia; it merely maintains BG within a healthy range, preventing it from falling to dangerously low levels. People following low-carb diets for fat loss or blood glucose control need not fear glucagon-induced GNG causing chronically elevated BG and the undesirable metabolic sequelae that would result. The context of glucose appearing in the blood is entirely different than on a high-carb diet with hepatic glycogen fully replete. (Ben Bikman, PhD, a researcher focused on insulin and well known in the ketogenic community, gave an informative talk on this topic in 2018: Insulin vs. Glucagon: The relevance of dietary protein.)

Glucagon is a fascinating hormone with powerful influences on several areas of interest, including types 1 and 2 diabetes, fat loss, appetite regulation and more. The following articles and video are recommended for learning more about glucagon:

• Unger RH, Cherrington AD. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J Clin Invest. 2012;122(1):4–12. doi:10.1172/JCI60016.
• Müller TD, Finan B, Clemmensen C, DiMarchi RD, Tschöp MH. The New Biology and Pharmacology of Glucagon. Physiol Rev. 2017 Apr;97(2):721-766. doi: 10.1152/physrev.00025.2016.
• Sonksen P1, Sonksen J. Insulin: understanding its action in health and disease. Br J Anaesth. 2000 Jul;85(1):69-79. doi:10.1093/bja/85.1.69

Roger Unger: Rolf Luft Award 2014, Prize Lecture. A New Biology for Diabetes.