The hormone insulin is produced by the beta cells in our pancreas. It is basically a protein comprising as many as 51 amino acids that are enclosed inside two peptide chains - while 21 amino acids are contained in an A chain and a B chain contains the remaining 30 amino acids. These two peptide chains are linked by a pair of disulfide bridges. Moreover, another disulfide chain also exists on the inside (intra-chain). Human insulin has a molecular weight of 5808.
It may be noted that there is a slight difference in the composition of amino acids of the human insulin and insulins of two other mammals that have been employed for remedial insulin replacement. Compared to the human insulin, that of the pork differs just by a single amino acid alanine in place of threonine at the B chain's carboxyl terminus. On the other hand, beef insulin is different from the human insulin as it contains three amino acids-alanine rather than threonine plus valine in place of isoleucine.
The circulatory half-life of endogenous insulin is about three to five minutes. Insulinases present in our kidney, liver and placenta mainly catabolize endogenous insulin. About 50 per cent of insulin is taken away in just one pass via our liver.
Insulin Resistance Syndrome (IRS)
On average, the pancreas of a healthy adult human secretes anything between 40 units and 50 units of insulin daily. Normally, the basic insulin composition in the bloodstream of a fasting human is 10 μU/mL (61 pmol/L or 0.4 ng/mL). The concentration of insulin in the bloodstream of common control subjects rarely goes beyond 100 μU/mL or 610 pmol/L after taking a normal meal. However, about 8 minutes to 10 minutes after eating food there is a rise in peripheral insulin strength in the blood and the peak in peripheral insulin concentration in the bloodstream is seen about 30 minutes to 45 minutes after consuming food. Following this, the concentration of post-prandial (after meal, particularly after dinner) plasma glucose falls rapidly and the level of concentration again goes back to the standard or normal values after about 90 minutes to 120 minutes of taking the meal.
Basal insulin secretion: This happens when there are no exogenous (external) stimuli. Basal insulin secretion is the amount of insulin that is secreted by the pancreatic beta cells when an individual is fasting. While we are aware that when the levels of plasma glucose are lower than 80 mg/dL to 100 mg/dL (between 4.4 mmol/L and 5.6 mmol/L) it does not promote secretion of insulin, it has been shown in vitro studies that glucose must essentially be present for almost all other familiar insulin secretion regulators to remain effectual.
Stimulated insulin secretion: This occurs as a result of exogenous stimuli. In vivo studies have revealed that stimulated insulin secretion is actually a reaction of the B cells (white cells) to the foods ingested. Glucose is the most powerful stimulant of insulin release. The pancreas of a perfused rat has shown a biphasic insulin secretion as a reaction to glucose. When the concentration of glucose in our system rises abruptly, initially there is a burst of insulin released for a brief period (known as the early phase). In case, the glucose level remains constant at this stage, the release of insulin drops slowly and subsequently starts increasing once more to a stable level (known as the late phase). Nevertheless, the continued elevated levels of glucose stimulation cause the B cells' reversible desensitization in reaction to glucose, but never to any other type of stimulation.
It is known that glucose goes into the B cells in the pancreas through a process called passive diffusion and this is made easier by a particular membrane protein known as glucose transporter-2. Some data is available that hints that glucose metabolism is necessary for stimulating the release of insulin. The stem that restricts the pace of metabolism of glucose by the B cells in the pancreas seems to be the introduction of a phosphoryl group (phosphorylation) of glucose with a low-affinity enzyme called glucokinase.
It has been found that calcium is required for the release of insulin. Therefore, it has been suggested that the mature granules that contain insulin in the B cells should directly bind with microtubules which contract after they come in contact with elevated intracellular insulin and by this means expel the granules.
The action of insulin starts by binding this pancreatic hormone to a receptor present on the outside of the targeted cell membrane. It appears that several cells in our body possess particular insulin receptors on their surface. Actually, in the instance of the liver as well as the muscle cells insulin binding to their receptors is related to the biologic reaction of these two tissues to this pancreatic hormone. It has been found that the receptors on the surface of the liver and muscle cells rapidly bind insulin with elevated specificity as well as with an attraction that is sufficiently high to attach picomolar quantities.
Scientists have found that insulin receptors are basically membrane glycoproteins comprising two sub-units - the first one is alpha sub-unit (MW 130,000), comparatively larger and extending further than the cells (extra-cellularly). This sub-unit is involved in the process of binding the insulin molecule. The second is the beta sub-unit (MW 90,000). This sub-unit mainly contains the cytoplasm as well as a tyrosine kinase, which is activated when insulin molecules bind with the receptors and leads to autophosphorylation (introducing an organic compound to a phosphoryl group using light in the form of an energy source) of the beta sub-unit. In turn, this reactive substance phosphorylates an arrangement of nine substrates within the cells, starting from the insulin receptor substrate-1 (also known as IRS-1) as well as the insulin receptor substrate-2 (also referred to as IRS-2).
Each of these motivates substrates (any substance which is acted upon during a biochemical reaction) resulting in the activation of one among the seven forms of phosphatidylinositol-3-kinase, which have been identified so far. Subsequently, all the phosphatidylinositol-3-kinase phosphorylate other different substances within the cells (intracellular) to spread the insulin signal further for augmented glucose transportation, enhance synthesis of lipid and glycogen as well as activation of different metabolic pathways. Following the binding of an insulin molecule to a receptor, the figure of insulin receptor complexes is suppressed or internalized. Nevertheless, there is some dispute over whether the suppressed complexes have any role in insulin's additional activities or whether they restrict the sustained action of insulin by means of exposing insulin to lysosomes, which are known to be intracellular foragers.
It is worth mentioning here that any kind of anomaly in the affinity or the concentration, or both, the insulin receptors will have an effect on the action of insulin. A phenomenon called 'down-regulation' occurs when there is a decrease in the number of insulin receptors' response to constantly high levels of insulin circulating in the bloodstream, possibly owing to an augmented degradation within the cells. On the contrary, when the levels of insulin are low, there is an up-regulation in the binding of the insulin molecules to their receptors. Certain conditions are related to high levels of insulin and decreased binding of the insulin receptors to their receptors and they may include an elevated carbohydrate intake, obesity, and possibly a constant overinsulinization from outside organism (exogenous). On the other hand, fasting and exercise are the two main conditions that are related to decreased levels of insulin and augmented binding of insulin molecules to their receptors. Binding of insulin molecules to their receptors is also decreased in the presence of too much cortisol - a steroid hormone. However, scientists are yet to ascertain whether the hormone directly affects this or it happens due to an increase in the levels of insulin as a result of being mediated by something associated with it.
One of the main roles played by insulin is enhance the body's ability to store nutriments that have been ingested through foods. While insulin has a direct or oblique effect on all the body tissues, this article will mainly and briefly discuss common impact insulin has on the three main body tissues that particularly work to store energy - muscle, liver and the adipose tissue.
The consequences of the substances produced by the endocrine cells on the neighbouring cells are known as 'paracrine' effects. These effects are contrary to the activities that occur at places that are away from the cells secreting these products and are known as the 'endocrine' effects. The B and D cells' paracrine effects on the neighbouring A cells are of great significance inside the endocrine pancreas. In fact, the pancreatic A cells are targeted first by insulin, which are located at the outside edge of the pancreatic islets. The secretion of glucagon by the pancreatic A cells is reduced when there is insulin. Moreover, somatostatin, a substance secreted by the D cells in reaction to nearly all similar stimuli that incite the release of insulin, also works to slow down the secretion of glucagon.
As glucose only fuels B cells and D cells (which produce substances that restrain the A cells), amino acids not only stimulate glucagon, but also insulin, the amounts and type of islet hormones secreted when one is taking his/ her meal subject to the proportion of the carbohydrates to protein ingested by the individual. The more amount of carbohydrate consumed by an individual, the lesser amount of glucagon will be released by the absorbed amino acids. On the other hand, a meal that mostly contains protein will lead to the release of comparatively more amounts of glucagon. This is primarily owing to the fact that amino acids are not as effectual in promoting the release of insulin when hyperglycemia does not coexist. Nevertheless, amino acids work to potently arouse the pancreatic A cells.
Liver: The liver is the body's first main organ that insulin reaches through the bloodstream. Insulin acts on the liver in two very important ways, which are discussed below.
Insulin supports anabolism: This peptide hormone released by the pancreas works to promote the synthesis of glycogen as well as its storage. Simultaneously, it also slows down the breakdown of glycogen. The consequences of insulin's actions are mediated by alteration in the actions of the enzymes that are present in the pathway of glycogen synthesis. Most of the glycogen is stored in the liver, which can accommodate anything between 100 g and 110 g glycogen, which is about 440 kcal energy. Insulin also works to augment the synthesis of triglyceride and protein, in addition to the formation of VLDL (very low density lipoprotein) by our liver. In addition, insulin also helps to restrain gluconeogenesis, while encouraging glycolysis by means of its influence on the different enzyme in the glycolytic pathway.
Insulin restrains catabolism: This pancreatic hormone works to overturn the catabolic actions that occur during state after absorption of ingested foods by means of slowing down gluconeogenesis, ketogenesis and glycogenolysis.
Muscle: Insulin also supports the synthesis of protein in the muscles by means of augmenting the transportation of amino acid and also by invigorating the synthesis of ribosomal protein. Besides this, insulin encourages synthesis of glycogen for restoring the glycogen reserves depleted due to rigorous activities of the muscles. This is achieved by augmenting the transportation of glucose to the muscle cells, by restricting the actions of glycogen phosphorylase as well as by increasing the action of glycogen synthase.
Normally, anything between 500 g and 600 g glycogen is accumulated in the muscle tissues of a healthy man weighing about 70 kg. However, owing to the absence of glucose 6-phosphates in these tissues, it is not possible to utilize the stored glycogen in the form of a resource of blood glucose, apart from providing the liver with lactate in some other way to convert it into glucose.
Adipose tissue: Energy can be stored most efficiently as fat in its triglyceride state. Every gram of the stored triglyceride supplies us with 9 kcal energy. This is much higher than the 4 kcal energy per gram usually supplied by carbohydrate or protein. In a normal man with 70 kg body weight, the adipose tissues contain as much as 100,000 kcal energy. On its part, insulin works to encourage storage of triglycerides in the adipocytes by several means. First, insulin encourages lipoprotein lipase production, which causes hydrolysis (a chemical reaction wherein a substance reacts with water to form different other compounds) of triglycerides from lipoproteins that are in circulation. It may be mentioned here that lipoprotein lipase is a variety of lipoprotein that binds to the endothelial cells present in the adipose tissue as well as different vascular beds.
Second, insulin augments triglyceride storage in adipose tissues by augmenting the transportation of glucose to the fat cells, thereby enhancing the disposal of a-glycerol phosphate, a compound that is employed in the conversion of fatty acids into triglycerides by means of a process known as esterification. Third, insulin also restricts or slows down the lipolysis of triglycerides by holding back intracellular lipase, which is also known as 'hormone sensitive lipase'. Such decrease in the flux of fatty acid to the liver seems to be a vital controlling factor in insulin activity for reducing the output of hepatic glucose as well as hepatic gluconeogenesis.
