85. Insulin and glucagon Flashcards
Pancreas
The pancreas is an endocrine system, which regulates the nutrient supply of tissues and cells. the most important thing is the constancy of plasma nutrient and metabolite levels.
The hormones of the pancreas ensure that the concentration of plasma glucose stays constant.
Main hormones:
- Insulin - stimulation of anabolic and storing processes in every cell of the organism. Stimulates glucose intake of tissues and decrease plasma glucose concentration.
- Glucagon - glucagon mobilizes carbohydrate stores of the liver and elevates plasma glucose levels. During the intervals between food intakes, the replacement of the decreasing amount of plasma glucose is ensured by the carbohydrate-mobilizing action of glucagon.
Morphology of the pancreas
- Exocrine and endocrine gland.
- Most of the gland functions as an exocrine gland, with its digestive enzymes and buffers it has a role in digestive processes.
- A (alpha), B (beta), D (delta) and F cells.
The four types of cells produce four separate peptide hormones:
– insulin,
– glucagon,
– somatostatin, and
– pancreatic polypeptide.
B-cells: insulin
B-cells: insulin
major role:
-stimulation of anabolic and storage processes.
-regulates the amount of glucose in the blood. The lack of insulin causes a form of diabetes.
A cells: glucagon
- Act only in the liver major role: -increases plasma glucose level. -decrease of glycogen synthesis -stimulation of GNG
D-cells: somatostatin
major roles:
– inhibition of insulin and glucagon overproduction:
• inhibiting the activity of A and B cells
– inhibition of every phase of digestion:
• motility decreases
• secretion decreases
F cells: pancreatic polypeptide (PP)
major role:
– biliary secretion and secretion of pancreatic
enzymes decrease.
-gastric secretion and motility increase.
-protein intake enhances its secretion
Regulation: paracrine activity
- B cells, while releasing insulin into the bloodstream as the effect of hyperglycemia, exert a negative influence on the glucagon synthesis and secretion of the neighboring A cells.
- Direct stimuli for glucagon secretion are low plasma glucose levels (hypoglycemia). Glucagon, produced under these circumstances, directly stimulates insulin secretion of B cells.
- Somatostatin of D cells (production of which is stimulated by glucagon) has a negative influence on the hormone production of both A and B cells.
Somatostatin protects the organism from the possible glucagon and insulin overproduction.
Regulation: plasma glucose
Production of hormones are directly influenced by glucose and amino acid levels of the plasma circulating in the pancreas. Their high plasma levels stimulate insulin secretion, while their low plasma levels induce glucagon secretion.
Preparing effect of glucagon
First the stored, then the newly synthesized insulin is secreted by the effect of the elevating glucose levels.
In case of the food consumption with high glucose content, B (beta) cells are “informed” about the absorbing energy sources well before the actual increase of plasma glucose levels.
In case of ingestion of carbohydrates, GIP (gastric inhibitory peptide, recently: glucose dependent insulinotropic peptide) and enteroglucagon are liberated, which increase the secretion of insulin in advance (feed-forward), so that later absorbed glucose could already be “waited” by an increased insulin concentration in the plasma. This phenomenon ensures that even in case of high loads of glucose, the concentration of plasma glucose is not increased so high that it could be wasted by secretion into the urine.
• The essence of the process that glucose entering the intestine tract immediately elicits the secretion of GIP and enteroglucagon. This stimulates insulin production of B cells very quickly via the circulation well before absorption of glucose from food.
• The figure shows two stages:
– 1. If the feed-forward mechanism did not work, insulin production would only induce just when glucose is already absorbed. There would be no time for storing, concentration of glucose would rise so high, that it would reach renal Tm value (see: Renal Function) and would leave the body.
– 2. The above predicting mechanism prevents this.
Stimulation of B cells
The most important regulators of insulin secretion are plasma glucose levels. In case of elevated plasma glucose levels, GLUT2 type transporters allow a high amount of glucose to enter B cells since this glucose transporter has low affinity and high capacity This has two main effects:
• 1. Glucose-6-P levels of the cell will increase intracellularly because of the high capacity glucokinase activity. This directly stimulates insulin secretion.
• 2. Most of the internalized glucose is utilized to produce ATP. Elevated ATP levels close ATP sensitive potassium channels, and depolarization occurs (see also details in chapter: Nervous System, sections: Types of Ion Channels, Energy Sensor). This causes the influx of a high amount of calcium into the cell, which results in the immediate release of insulin stores. At the same time, de novo synthesis of insulin becomes also increased. The process is possibly also amplified by a PLC - IP3 - Ca2+ pathway.
• 3. Enteroglucagon and GIP enhance release of insulin and also initiate its synthesis through the cAMP system.
• Corresponding with the above effects, secretion of insulin is a biphasic process. At the beginning, a vast amount of insulin can instantly enter the bloodstream from insulin reserves, while later de novo synthesized insulin is secreted, leading to a further elevation of serum insulin. Synthesis starts with the production of preproinsulin. This is a single, long polypeptide chain. Cleaving a smaller peptide the previously described proinsulin and insulin are formed
Neural effects
Synthesis of insulin and glucagon are also under control of the autonomic nervous system.
Sympathetic effects are mediated by alpha and beta receptors, while parasympathetic effects are mediated by acetylcholine receptors.
Sympathetic system facilitates or inhibits in a complex way. Blocking (through alpha-2 receptors) is advantageous in stress: insurance of high plasma glucose levels. Blocking of the insulin release here inhibits storage function of insulin (the basal insulin secretion is enough to allow glucose intake in the muscle!)
• Transient insulin secretion through the vagus nerve has also a great importance. When the animal puts food into its mouth, secretion of insulin can be induced by a reflex arc. This is the first “feed-forward” mechanism described, which is also strengthened by the already mentioned GIP and enteroglucagon effects.
Glucose transporters
Glucose gets through the membrane by glucose transporters (GLUT).
- In some tissues glucose transporters are regulated by insulin. (insulin dependent and independent tissues)
- There are seven subfamilies of glut transporters.
Hormone-receptor interaction
Hormones bind to receptors in dimer forms.
This results in the change in conformation of transmembrane receptors, together with phosphorylation of enzymes and regulator proteins.
The cellular basis of the effect is formed by the insulin receptor consisting of two alpha subunits, which can be found in the cytoplasm of all cells.
Two insulin molecules bind to these subunits, causing a conformation change in the intracellularly located beta subunits. Further on, protein kinase enzymes are activated intracellularly, which is responsible for all actions.
Insulin effects
The effects of insulin can be divided into two major group.
1. Glucose uptake
Insulin is involved in the regulation of glucose uptake into the cells. Tissues are insulin dependent or insulin independent.
2.Metabolic effects
In this respect insulin acts on virtually all cells of the body: these are the metabolic effect of insulin. As a result, Insulin finally increases storing and anabolic processes.
Insulin independent tissues and dependent tissues
Insulin independent tissues:
Vital tissues: • brain cells (GLUT1) • red and white blood cells (GLUT1) • brain capillaries (GLUT2) • liver (GLUT3) • basic uptake in muscle and adipose (GLUT1)
Insulin dependent tissues:
– All the rest of the tissues:
• muscle
• adipose tissue
Insulin effects on glucose uptake
Tissues metabolizing glucose only can take up glucose without the presence of insulin. These tissues are usually considered as insulin independent tissues. Here is considered brain tissue (transported by GLUT1 type transporter), red blood cells, leukocytes, endothelial cells (GLUT1 transporter), intestinal glucose uptake on the luminal side of the mucosa, brain capillaries (GLUT2 transporter), and the liver (GLUT3 transporter). Latter transporter is special in a sense that it is able to transport glucose in both directions: from the blood into the cell and from the cell into the blood. Liver is able to utilize other energy sources, though, being the central organ of carbohydrate metabolism, it is also able to perform insulin-independent glucose uptake. All the rest of the tissues depend on insulin concerning glucose-uptake. The largest organs of this type are muscle and adipose tissue (containing GLUT4 type insulin-dependent transporters). These tissues are unable to uptake glucose without insulin, since glucose uptake is also regulated through insulin receptors.
• A special case is the B-cell of the Langerhan’s islet. here GLUT2 receptors contribute to the regulation of insulin release.
• On the luminal side of the intestinal mucosa glucose transporter is not the member of the GLUT family, but the basolateral glucose transporter is a GLUT2 protein. The fifth member of the GLUT family supports fructose uptake in the gut (both luminal and basolateral GLUT5 transporters
Metabolic effects of insulin
Insulin increases overall anabolic processes. Insulin increases glycogen, protein, and fat syntheses. The effects are bilateral in all cases. Partly, it decreases degradation speed of precursors by inhibiting enzymes of glycogen, protein, and fat catabolism, partly stimulates synthetic enzymes of these three substances. In the liver and adipose tissue, insulin increases glucose utilization (burning of glucose). This provides energy for the synthesis of fat.
Carbohydrate metabolism
– incorporates amino acids into proteins: GNG – glucose level decreases
• insulin-dependentglucoseuptakeofcellsincrease • glucoseoxidationincreases
• glycogen synthesis increases
• absorptionofglucosedecreases
• Lipid metabolism:
– triglyceride synthesis increase
– degradation of lipids decrease
– stimulates fatty acid synthesis from AcCoA
• Protein metabolism:
– stimulates amino acid uptake of every cell except for liver
– enhances protein synthesis
– decreases protein degradation
– positive nitrogen balance
Insulin and glucagon effects
It is important to emphasize that every action of glucagon antagonizes insulin, glucagon however acts only on the liver!
Glucose metabolism
In animals with single-compartment stomach, glucose is the basis of energy metabolism. Glucose is absorbed from the intestines and stored in the liver or muscles. Only the liver is capable of releasing glucose (synthesized or stored) into the bloodstream. Organs degrade glucose to carbon dioxide and water, or, in case of anaerobic circumstances, they produce lactic acid, which after being transported back to the liver (Cori- cycle), is converted to glucose again.
• Glucose may be stored, burnt, or converted into fat. Glucose may be resynthesized from lactic acid, glycerol, and amino acids, but not from fatty acids.
• These processes are described in detail by biochemistry, here we summarize the most important information briefly, for the sake of better understanding of insulin/glucagon effects!
Glucose, originated from the liver or absorbed from the intestines, elevates plasma glucose levels. Glucose uptake of insulin dependent or independent tissues decreases plasma glucose levels (in the figure: liver, red blood cells, muscle, adipose tissue, neurons). Glucose begins to leave the body through the kidney when reaches a plasma concentration of 10 mmol/liter (see earlier).
• Internalized glucose may be converted to carbon dioxide and water or among anaerobic conditions lactic acid is produced, which may be used to synthesize to glucose again. Fats mobilized from adipose tissue are transported to the liver.
Diabetes mellitus
The discussion of the disease is the subject of pathology and pathophysiology. However, here we describe some physiological features of the disease to demonstrate how the deficiency of the production of a hormone may lead to the collapse of the entire metabolism.
Diabetes – protein metabolism
Deficiencies of insulin, as a main anabolic hormone, determines changes of the protein metabolism. The degradation of proteins results in a negative nitrogen balance, parallel with it the organism loses potassium, as well. Loss of potassium is paired with loss of water, resulting in dehydration.
