| VIVO Pathophysiology | Endocrine Pancreas |
Insulin
Insulin is synthesized in significant quantities only from β cells in the islets of the pancreas. It is a small protein, consising of 51 amino acids in most animals. The insulin mRNA is translated and processed to a single chain called proinsulin, which consists of three domains: an amino-terminal B chain, a carboxy-terminal A chain and a connecting peptide in the middle known as the C peptide. Within the endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases which excise the C peptide. The A and B chains are bonded to each other by disulfide (-S-S-) bonds,thereby generating the mature form of insulin. Insulin and free C peptide are packaged into secretory granules which accumulate in the cytoplasm. When the β cell is appropriately stimulated, insulin is secreted by exocytosis and diffuses into islet capillary blood. C peptide is also secreted into blood, but has no known biological activity.
The amino acid sequence of insulin is highly conserved among vertebrates, and insulin from one mammal almost certainly is biologically active in another. Until 1982, diabetic patients were treated with insulin extracted from pig pancreas, but synthetic (recombinant) forms of insulin are now used exclusively and a large number of recombinant insulin preparations have been created that have activities ranging from ultrashort to long-acting.
Like the receptors for other protein hormones, the receptor for insulin is embedded in the plasma membrane. The insulin receptor is composed of two alpha subunits and two beta subunits linked by disulfide bonds. The alpha chains are entirely extracellular and house insulin binding domains, while the linked beta chains penetrate through the plasma membrane.
The insulin receptor is a tyrosine kinase. In other words, it functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins. Binding of insulin to the alpha subunits causes the beta subunits to phosphorylate themselves (autophosphorylation), thus activating the catalytic activity of the receptor. The activated receptor then phosphorylates a number of intracellular proteins, which in turn alters their activity and generates a biological response.
Physiologic Effects of Insulin
Stand on a streetcorner and ask people if they know what insulin is, and many will reply, "Doesn't it have something to do with blood sugar?" Indeed, that is correct, but such a response is a bit like saying "Mozart? Wasn't he some kind of a musician?"
Insulin is a key player in the control of intermediary metabolism, and the big picture is that it organizes the use of fuels for either storage or oxidation. Through these activities, insulin has profound effects on both carbohydrate and lipid metabolism, and significant influences on protein and mineral metabolism. Consequently, derangements in insulin signalling have widespread and devastating effects on many organs and tissues.
Insulin and Carbohydrate Metabolism
Glucose is liberated from dietary carbohydrate such as starch or sucrose by hydrolysis within the small intestine, and is then absorbed into the blood. Elevated concentrations of glucose in blood stimulate release of insulin, and insulin acts on cells thoughout the body to stimulate uptake, utilization and storage of glucose. The effects of insulin on glucose metabolism vary depending on the target tissue. Three important effects are:
1. Insulin facilitates entry of glucose into muscle, adipose and several other tissues. The only mechanism by which cells can take up glucose is by facilitated diffusion through a family of hexose transporters. In many tissues - muscle being a prime example - the major transporter used for uptake of glucose (called GLUT4) is made available in the plasma membrane through the action of insulin.
When insulin concentrations are low, GLUT4 glucose transporters are present in cytoplasmic vesicles, where they are useless for transporting glucose. Binding of insulin to receptors on such cells leads rapidly to fusion of those vesicles with the plasma membrane and insertion of the glucose transporters, thereby giving the cell an ability to efficiently take up glucose. When blood levels of insulin decrease and insulin receptors are no longer occupied, the glucose transporters are recycled back into the cytoplasm.
It should be noted here that there are some tissues that do not require insulin for efficient uptake of glucose: important examples are brain and the liver. This is because these cells don't use GLUT4 for importing glucose, but rather, another transporter that is not insulin-dependent.
2. Insulin stimulates the liver to store glucose in the form of glycogen. A large fraction of glucose absorbed from the small intestine is immediately taken up by hepatocytes, which convert it into the storage polymer glycogen.
Insulin has several effects in liver which stimulate glycogen synthesis. First, it activates the enzyme hexokinase, which phosphorylates glucose, trapping it within the cell. Coincidently, insulin acts to inhibit the activity of glucose-6-phosphatase. Insulin also activates several of the enzymes that are directly involved in glycogen synthesis, including phosphofructokinase and glycogen synthase. The net effect is clear: when the supply of glucose is abundant, insulin "tells" the liver to bank as much of it as possible for use later.
3. A well-known effect of insulin is to decrease the concentration of glucose in blood, which should make sense considering the mechanisms described above. Another important consideration is that, as blood glucose concentrations fall, insulin secretion ceases. In the absense of insulin, a bulk of the cells in the body become unable to take up glucose, and begin a switch to using alternative fuels like fatty acids for energy. Neurons, however, require a constant supply of glucose, which in the short term, is provided from glycogen reserves.
When insulin levels in blood fall, glycogen synthesis in the liver diminishes and enzymes responsible for breakdown of glycogen become active. Glycogen breakdown is stimulated not only by the absense of insulin but by the presence of glucagon, which is secreted when blood glucose levels fall below the normal range.
Insulin and Lipid Metabolism
The metabolic pathways for utilization of fats and carbohydrates are deeply and intricately intertwined. Considering insulin's profound effects on carbohydrate metabolism, it stands to reason that insulin also has important effects on lipid metabolism, including the following:
1. Insulin promotes synthesis of fatty acids in the liver. As discussed above, insulin is stimulatory to synthesis of glycogen in the liver. However, as glycogen accumulates to high levels (roughly 5% of liver mass), further synthesis is strongly suppressed.
When the liver is saturated with glycogen, any additional glucose taken up by hepatocytes is shunted into pathways leading to synthesis of fatty acids, which are exported from the liver as lipoproteins. The lipoproteins are ripped apart in the circulation, providing free fatty acids for use in other tissues, including adipocytes, which use them to synthesize triglyceride.
2. Insulin inhibits breakdown of fat in adipose tissue by inhibiting the intracellular lipase that hydrolyzes triglycerides to release fatty acids.
Insulin facilitates entry of glucose into adipocytes, and within those cells, glucose can be used to synthesize glycerol. This glycerol, along with the fatty acids delivered from the liver, are used to synthesize triglyceride within the adipocyte. By these mechanisms, insulin is involved in further accumulation of triglyceride in fat cells.
From a whole body perspective, insulin has a fat-sparing effect. Not only does it drive most cells to preferentially oxidize carbohydrates instead of fatty acids for energy, insulin indirectly stimulates accumulation of fat in adipose tissue.
Other Notable Effects of Insulin
In addition to insulin's effect on entry of glucose into cells, it also stimulates the uptake of amino acids, again contributing to its overall anabolic effect. When insulin levels are low, as in the fasting state, the balance is pushed toward intracellular protein degradation.
Insulin also increases the permiability of many cells to potassium, magnesium and phosphate ions. The effect on potassium is clinically important. Insulin activates sodium-potassium ATPases in many cells, causing a flux of potassium into cells. Under certain circumstances, injection of insulin can kill patients because of its ability to acutely suppress plasma potassium concentrations.
Control of Insulin Secretion
The most potent stimulus for secretion of insulin is elevated blood concentrations of glucose. This makes sense because insulin is "in charge" of facilitating glucose entry into many cells. Certain features of this process have been clearly and repeatedly demonstrated, yielding the following model:
- Glucose is transported into the beta cell by facilitated diffusion through a glucose transporter (GLUT1, GLUT2 or GLUT3); elevated concentrations of glucose in extracellular fluid lead to elevated concentrations of glucose within the beta cell.
- Elevated concentrations of glucose within the beta cell ultimately leads to membrane depolarization and an influx of extracellular calcium. The resulting increase in intracellular calcium is thought to be one of the primary triggers for exocytosis of insulin-containing secretory granules. The mechanisms by which elevated glucose levels within the beta cell cause depolarization is not clearly established, but seems to result from metabolism of glucose and other fuel molecules within the cell, perhaps sensed as an alteration of ATP:ADP ratio and transduced into alterations in membrane conductance.
- Increased levels of glucose within beta cells also appears to activate calcium-independent pathways that participate in insulin secretion.
Stimulation of insulin release is readily observed in whole animals or people. The normal fasting blood glucose concentration in humans and most monogastric mammals is 80 to 90 mg per 100 ml, associated with very low levels of insulin secretion.
The figure to the right depicts the effects on insulin secretion when enough glucose is infused to maintain blood levels two to three times the fasting level for an hour. Almost immediately after the infusion begins, plasma insulin levels increase dramatically. This initial increase is due to secretion of preformed insulin, which is soon significantly depleted. The secondary rise in insulin reflects the considerable amount of newly synthesized insulin that is released immediately. Clearly, elevated glucose not only simulates insulin secretion, but also transcription of the insulin gene and translation of its mRNA.
In addition to the direct stimulatory effects of elevated blood glucose levels, there are several other factors that promote insulin secretion:
- Some neural stimuli (e.g. sight and taste of food) and increased blood concentrations of other fuel molecules, including amino acids and fatty acids, also promote insulin secretion.
- Several gastrointestinal hormones are secreted in response to nutrients in the intestine and enhance the secretion of insulin. These hormones include glucose-dependent insulinotropic peptide and glucagon-like peptide 1.
Insulin Deficiency and Excess Diseases
Diabetes mellitus, arguably the most important metabolic disease of man, is an insulin deficiency state. It also is a significant cause of disease in animals such as dogs and cats. Two principal forms of this disease are recognized:
- Type 1 or insulin-dependent diabetes mellitus is the result of a frank deficiency of insulin. The onset of this disease typically is in childhood. It is due to destruction pancreatic beta cells, most likely the result of autoimmunity to one or more components of those cells. Many of the acute effects of this disease can be controlled by insulin replacement therapy. Maintaining tight control of blood glucose concentrations by monitoring, treatment with insulin and dietary management will minimize the long-term adverse effects of this disorder on blood vessels, nerves and other organ systems, allowing a healthy life.
- Type 2 or non-insulin-dependent diabetes mellitus begins as a syndrome of insulin resistance. That is, target tissues fail to respond appropriately to insulin. Typically, the onset of this disease is in adulthood. Despite monumental research efforts, the precise nature of the defects leading to type II diabetes have been difficult to ascertain, and the pathogenesis of this condition is plainly multifactorial. Obesity is clearly a major risk factor, but in some cases of extreme obesity in humans and animals, insulin sensitivity is normal. Because there is not, at least initially, an inability to secrete adequate amounts of insulin, insulin injections are not useful for therapy. Rather the disease is controlled through dietary therapy and hypoglycemic agents. However, a substantial number of those with type 2 diabetes progress to requiring insulin.
Hyperinsulinemia or excessive insulin secretion is most commonly a consequence of insulin resistance, associated with type 2 diabetes or the metabolic syndrome. More rarely, hyperinsulinemia results from an insulin-secreting tumor (insulinoma) in the pancreas. Hyperinsulinemia due to accidental or deliberate injection of excessive insulin is dangerous and can be acutely life-threatening because blood levels of glucose drop rapidly and the brain becomes starved for energy (insulin shock).
References
Petersen MC, Shulman GI. Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev. 2018; 98:2133-2223.
Rahman MS, Hossain KS, Das S, Kundu S, Adegoke EO, et al. Role of Insulin in Health and Disease: An Update. Int J Mol Sci. 2021; 22:6403.
Riachi R, Khalife E, Kędzia A, Niechciał E. Understanding Insulin Actions Beyond Glycemic Control: A Narrative Review. J Clin Med. 2025; 14:5039.
 Functional Anatomy of the Endocrine Pancreas |
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Updated April, 2026. Send comments to Richard.Bowen@colostate.edu
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