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Glucagon and Insulin – Regulators of Glucose

María Laura Márquez

Glucagon and Insulin are both hormones produced and excreted by the pancreas. The islets of Langerhans located inside contain the alpha cells responsible for producing glucagon and the beta cells that produce Insulin. These two hormones cooperate to maintain healthy levels of blood glucose.

Under normal circumstances, plasma glucose concentration determines our insulin levels When blood sugar rises, the beta cells in the pancreas release insulin to transport glucose to our cells for energy. When blood sugar levels are low, the circulation of insulin ceases. This response maintains glucose levels within a normal range.

Glucose Homeostasis roles.
Glucose homeostasis: roles of insulin and glucagon. [1]

“Glucose homeostasis: roles of insulin and glucagon. 1A. For nondiabetic individuals in the fasting state, plasma glucose is derived from glycogenolysis under the direction of glucagon (1). Basal levels of insulin control glucose disposal (2). Insulin’s role in suppressing gluconeogenesis and glycogenolysis is minimal due to low insulin secretion in the fasting state (3). 1B. For nondiabetic individuals in the fed state, plasma glucose is derived from ingestion of nutrients (1). In the bi-hormonal model, glucagon secretion is suppressed through the action of endogenous insulin secretion (2). This action is facilitated through the paracrine route (communication within the islet cells) (3). Additionally, in the fed state, insulin suppresses gluconeogenesis and glycogenolysis in the liver (4) and promotes glucose disposal in the periphery (5). 1C. For individuals with diabetes in the fasting state, plasma glucose is derived from glycogenolysis and gluconeogenesis (1) under the direction of glucagon (2). Exogenous insulin (3) influences the rate of peripheral glucose disappearance (4) and, because of its deficiency in the portal circulation, does not properly regulate the degree to which hepatic gluconeogenesis and glycogenolysis occur (5). 1D. For individuals with diabetes in the fed state, exogenous insulin (1) is ineffective in suppressing glucagon secretion through the physiological paracrine route (2), resulting in elevated hepatic glucose production (3). As a result, the appearance of glucose in the circulation exceeds the rate of glucose disappearance (4). The net effect is postprandial hyperglycemia (5).”1 

Whereas high blood sugar triggers insulin secretion, low blood glucose levels produce glucagon. This hormone prompts the liver to start decomposing sugar in the form of glycogen. Once glycogen breaks down to glucose and enters the bloodstream, insulin helps transport it to the cells for energy production. Occasionally, glucagon can induce the liver and muscles to synthesize glucose from non-carbohydrate sources such as proteins.

The relationship between beta cells and glucose

“The β-cells respond to many nutrients in the blood circulation, including glucose, other monosaccharides, amino acids, and fatty acids. Glucose is evolutionarily the primary stimuli for insulin release in some animal species, because it is a principal food component and can accumulate immediately after food ingestion. Indeed, in rodents and humans, the amplitude of insulin secretion induced by glucose is much larger compared with that stimulated by protein or fat. Oral ingestion of 75 g of glucose will cause plasma insulin to rise from a basal level (20–30 pmol/L) to 250–300 pmol/L in 30 min, while intake of a similar amount of fat or a fat plus protein diet will only increase plasma insulin levels to 50 and 60 pmol/L, respectively, in human subjects. While glucose is the obligate fuel source for neurons, other cells, including β-cells can use alternative fuel sources during brief periods of starvation, an adaptation that could predispose them to glucolipotoxicity.”3

The roles of Insulin

Insulin promotes the entry of glucose into the cells and supports the synthesis of lipids. This essentially cleans up excess sugar from the plasma glucose.

“Until recently, insulin was the only pancreatic β-cell hormone known to lower blood glucose concentrations. Insulin, a small protein composed of two polypeptide chains containing 51 amino acids, is a key anabolic hormone that is secreted in response to increased blood glucose and amino acids following ingestion of a meal. Like many hormones, insulin exerts its actions through binding to specific receptors present on many cells of the body, including fat, liver, and muscle cells. The primary action of insulin is to stimulate glucose disappearance.”4

In other words, insulin prevents mechanisms that would flood the bloodstream with excess glucose,  including the inhibition of glycogen, lipids, and protein breakdown. It also inhibits the buildup of ketone bodies when fats break down for energy at a faster rate, causing ketoacidosis, a life-threatening problem.

Function of Glucagon

As mentioned above, glucagon responds to low blood glucose levels by breaking down the macromolecule glycogen into glucose, and releasing it into the bloodstream. Glucagon brings blood sugar up while insulin brings blood sugar down. It also induces lipolysis, or the enzymatic breakdown of lipids into free fatty acids.

“Glucagon is part of a homeostatic hormonal system developed to protect against serious decreases in blood glucose—glucose ‘counter-regulation’. This mechanism is the combination of processes that act to protect against the development of hypoglycaemia and (should this occur) restore normoglycaemia. Hypoglycaemia suppresses insulin secretion from β-cells and stimulates glucagon secretion from islet α-cells, normalizing blood glucose levels. Even small changes in glucagon can greatly increase blood glucose; the addition of minimal doses of glucagon (0.50 ng/kg/min) is known to induce long-lasting hyperglycaemia. Glucagon acts exclusively on the liver, where it stimulates both glycogenolysis (the breakdown of glycogen into glucose) and gluconeogenesis (the formation of new glucose molecules), increasing glucose output within minutes. Under certain conditions, glucagon can also stimulate production of ketone bodies in the liver, which during fasting or prolonged hypoglycaemia may substitute partially for glucose in meeting the brain’s energy needs.”5

“When the circulating glucose level rises, glucagon secretion is suppressed. This is likely to be via the reduction of P/Q-type Ca2+ channel activity in α-cells. Such inhibitory effect can be achieved by lowering the amplitude or the firing frequency of APs, by influencing membrane depolarization or repolarization, respectively. The change of membrane potential is a result of glucose metabolism or transport (via electrogenic sodium-glucose co-transporter 2 transporters), which leads to the alteration of membrane ion conductance. α-Cells are equipped with ATP-sensitive K+ channels (KATP channels) of the same molecular identity as in β-cells. Increasing glucose concentrations result in increased glucose metabolism and ATP production, inhibiting the KATP channel. This in turn leads to membrane depolarization. Consequently, the amplitude of APs reduces due to voltage-dependent inactivation of Nav channels. As a result, APs, although still being generated, cannot reach the voltage that is sufficient to open P/Q-type Ca2+ channels. The result is that secretion of glucagon is reduced.”6

 

The glucose control of glucagon secretion
The glucose control of glucagon secretion from α-cells via intrinsic mechanisms. (A) KATP channels and SGLT2 depolarize the cell, decreasing action potential height and therefore P/Q activity. This results in reduced glucagon secretion. (B) TASK1 and store-operated channels (SOC) have been proposed to increase repolarizations in the cell, decreasing action potential frequency, and therefore glucagon secretion.”[7]

Terminology used to describe levels of Insulin

Hypoinsulinemia

It refers to lower insulin levels than normal, leading the body cells  to an insufficient glucose uptake, and the later rise in blood sugar. Some patients with diabetes type 2 experience low insulin levels due to a problem with the beta cells in the islets of Langerhans responsible for insulin production.

A miscalculation in insulin treatments can lead to high insulin levels, causing a sudden drop in blood glucose (hypoglycemia). If there is no insulin at all, the patient will need insulin injections, as it is common in people with diabetes type 1.

Hyperinsulinemia

It indicates an abnormally high level of blood glucose as a consequence of glucose metabolism disorders. It can also occur during the administration of insulin injections to battle diabetes, and in people with metabolic syndrome.

“Hyperinsulinemia in the basal state of any origin produces widespread insulin resistance. All tissues that have insulin receptor pathways will be affected, including the pancreatic β-cell, and possibly the brain. Defective insulin signaling at the β-cell impairs glucose-stimulated insulin release. At steady state, basal hyperinsulinemia generates and sustains insulin resistance, irrespective of where the pathology started. Hyperinsulinemia, insulin resistance, and impairment of glucose-stimulated insulin release are intertwined biologically. A single process (hyperinsulinemia) could generate all three simultaneously.”8

Insulin resistance

It occurs when the insulin level is normal or raised, but is ineffective in the glucose metabolism. Consequently, our cells become “resistant” to insulin, leading to uncontrolled high blood glucose despite the relatively high circulating insulin.

“Resistance to the biological effects of insulin is a hallmark feature of the MS (metabolic syndrome) and an important contributing factor in the pathogenesis of T2D (type 2 diabetes). In the early stages of insulin resistance, the pancreas compensates by increasing the secretion of insulin into the bloodstream in an attempt to overcome defects in peripheral insulin action. In response to this increased demand for insulin production, the β-cells hypertrophy. Under fasting conditions, basal compensation is sufficient to maintain blood glucose in the normal range. Following a meal though, when glucose is rapidly absorbed from the gut, a relative lack of insulin due to inadequate compensation is detected as the glucose excursion over time is exaggerated. This inability to take up and dispose of glucose appropriately following a meal or glucose challenge is known as glucose intolerance.”9

 

References:

(1, 2, 4) Glucose Metabolism and Regulation: Beyond Insulin and Glucagon. Aronoff, S.L., Berkowitz, K., Shreiner, B. & Want, L. Diabetes Spectrum. 2004. http://spectrum.diabetesjournals.org/content/17/3/183.full 

(3) Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell Dysfunction in Diabetes. Fu, Z., Gilbert, E.R.& Liu, D. Current Diabetes Reviews. 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934755/ 

(5, 6, 7) Glucagon secretion from pancreatic α-cells. Briant, L., Salehi, A., Vergari, E., Zhang, Q. & Rorsman, P. Upsala Journal of Medical Sciences. 2016. https://www.tandfonline.com/doi/full/10.3109/03009734.2016.1156789 

(8) Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training. Roberts, C.K.,  Hevener, A.L. & and Barnard, R.J. Comprehensive Physiology. 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4129661/

(9) Insulin Resistance and Hyperinsulinemia: Is hyperinsulinemia the cart or the horse?. Shanik, M.H., Xu, Y., Škrha, J., Dankner, R., Zick, Y. & Roth, J. Diabetes Care. 2008. http://care.diabetesjournals.org/content/31/Supplement_2/S262.full

 

María Laura Márquez
13 October, 2018

Written by

María Laura Márquez, general doctor graduated from The University of Oriente in 2018, Venezuela. My interests in the world of medicine and science, are focused on surgery and its breakthroughs. Nowadays I practice my profession...read more:

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