case 6 Flashcards
imaging of the kidneys
The kidneys can be imaged via intravenous urography, which is an x-ray technique that uses a contrast dye injected into a vein in the arm.
This can be used to look for kidney stones, urine infections, blood in the urine, or obstruction or damage to any part of the urinary tract
four metabolic phases
–Digestive & Absorptive. –Inter & Post-absorptive. –Fasting. –Strenuous exercise Brain relies on good glucose supply to meet its metabolic needs. FFAs can barely cross BB and AAs used to synthesise NTs.GLUT1 & GLUT 3 Transporters on BBB allows transport. –FFAs bound to albumin in plasma. •Blood glucose level should remain: 60mg/100ml –110mg/ml. Otherwise= hypo or hyper-glycemia
enzyme terminology
name describes function, glucokinase catalyzes the phosphorylation of glucose using ATP.
kinase-uses ATP to add high energy phosphate group onto substrate.
Phosphorylase-adds inorganic phosphate onto substrate without ATP.
Phosphatase-removes phosphate group from substrate
Dehydrogenase-oxidises substrate
Carboxylase-adds C with help of biotin
transport and trapping
GLUT transporters on cell surface: SLGT in intestine and proximal tubule, hexokinase coupled GLUT1&3. GLU 2 in liver and GLU4 is insulin dependant expressed in skeletal muscle and adipose tissue.
Hexokinase phosphorylates to give G6P, latter cant cross cell membrane due to neg charge(trapping). Phosphorylation of glucose to give G6P is 1st step of glycolysis and glycogen synthesis in liver. hexokinase or glucokinase.
4 stages of carbohydrate metabolism
- Glycolysis
- Link Reaction
- Krebs’ Cycle/ Citric Cycle
- Electron Transport Chain/ Oxidative Phosphorylation
glycolysis
catabolism (breaking down) of glucose in cytoplasm. Generates intermediates for other pathways. In aerobic conditions, generates energy. End product depends on O2, forms 2pyruvate, or lactate in anaerobic. net gain of ATP is 2 molecules for each mol of glucose.
steps in glycolysis
- An ATP molecule is hydrolysed and the phosphate attached to the glucose molecule at C-6
- Glucose 6 Phosphate is turned into fructose 6 phosphate
- Another ATP is hydrolysed, and the phosphate attached to C-1
- The hexose sugar is activated by the energy release from the hydrolysed ATP molecules. It now cannot leave the cell and is known as Hexose-1,6-biphosphate
- It is split into two molecules of Triose phosphate
- Two hydrogen atoms are removed from each Triose Phosphate, which involved dehydrogenase enzymes.
- NAD combines with the Hydrogen atoms to form reduce NAD
- Two molecules of ATP are formed- substrate level phosphorylation
- Four enzyme-catalysed reactions convert each triose phosphate molecule into a molecule of pyruvate.
link reaction
- This reaction takes place in the matrix of the mitochondrion.
- Pyruvate is actively transported into the mitochondria.
- In this step, 2 molecules of pyruvate, formed in glycolysis, are converted into 2 molecules of Acetyl Coenzyme A (Acetyl CoA).
- This reaction occurs under the influence of the enzyme pyruvate dehydrogenase.
- There is no ATP formation in this reaction.
- 4 hydrogen atoms are released which will be used later (oxidative phosphorylation) to form 6 molecules of ATP.
krebs cycle
in the matrix of the motochondrion. acetyl CoA degraded into CO2 and H+-used later in oxidative phosphorylation. 1. Acetate is offloaded from CoA and joins with Oxaloacetate to form citrate.
- Citrate is decarboxlyated and dehydrogenated to form a 5C compound.
a. The hydrogen atoms are accepted by NAD, which take them to the Electron Transport Chain
b. The Carboxyl group becomes CO2. - The 5C compound is decarboxylated and dehydrogenated to form a 4C compound.
- The 4C compound is changed into another 4C compound, and a molecule of ATP is phosphorylated.
- The second 4C compound is changed into a third 4C compound and a pair of hydrogen atoms are removed, reducing FAD.
- The third 4C compound is further dehydrogenated to regenerate oxaloacetate.
net reaction in the krebs cycle per molecule of glucose
Enter into the cycle: 2 acetyl-CoA molecules 6 molecules of water Release from the cycle: 4 carbon dioxide molecules 16 hydrogen atoms 2 molecules of coenzyme 2 molecules of ATP are formed (one acetyl CoA molecule = one ATP molecule) 6 NADH
oxidative phosphorylation/electron transport chain
per mol glucose first 3 stages carb metabolism make 4ATP 24 H+.
• 20/24 hydrogen atoms that were formed before combine with nicotinamide adenine dinucleotide (NAD+) under the influence of a dehydrogenase enzyme.
• This forms NADH and H+, which enter oxidative phosphorylation.
• 90% of ATP formation occurs in this stage – oxidative phosphorylation of the hydrogen atoms that were released during the earlier stages of glucose degradation.
• Oxidative phosphorylation is the final stage of respiration.
• It involves electron carriers embedded in the mitochondrial membrane.
• These membranes are folded into cristae, which increases the surface area for electron carriers and ATP synthase enzymes.
• Oxidative phosphorylation is the formation of ATP by the addition of an inorganic phosphate to ADP in the presence of oxygen.
• As protons flow through ATPsynthase, they drive the rotation part of the enzyme and join ADP to Pi to make ATP.
• The electrons are passed from the final electron carrier to molecular oxygen, which is the final electron acceptor.
• Hydrogen ions also join, so oxygen is reduced to water
process of chemiosmosis in oxidative phosphorylation
- Reduced NAD and FAD donate hydrogens, which are split into protons and electrons, to the electron carriers.
- The protons are pumped across the inner mitochondrial membrane using energy released from the passing of electrons down the electron transport chain.
- This builds up a proton gradient, which is also a pH gradient, and an electrochemical gradient
- Thus, potential energy builds up
- The hydrogen ions cannot diffuse through the lipid part of the inner membrane, but can diffuse through ATP synthase- an ion channel in the membrane. The flow of hydrogen ions is chemiosmosis.
- As H+ ions flow through ATPsynthase, they drive the rotation part of the enzyme and join ADP to Pi to make ATP.
summary of carbohydrate metabolism
- Glycolysis = 2 ATP molecules and 4H gained. (actually four molecules of ATP are formed, and two are expended to cause the initial phosphorylation of glucose to get the process going. This gives a net gain of two molecules of ATP).
- Link Reaction = 0 ATP molecules and 4H gained.
- Citric Acid Cycle = 2 ATP molecules and 16H gained.
- Oxidative Phosphorylation = 20H go in and 30 ATP molecules gained.
(During the entire schema of glucose breakdown, a total of 24 hydrogen atoms are released during glycolysis and during the citric acid cycle. Twenty of these atoms are oxidized in conjunction with the chemiosmotic mechanism, with the release of 3 ATP molecules per two atoms of hydrogen metabolized. This gives an additional 30 ATP molecules.) - The remaining four hydrogen atoms are released by their dehydrogenase. Two ATP molecules are usually released for every two hydrogen atoms oxidized, thus giving a total of 4 more ATP molecules.
ATP in carbohydrate metabolism
• A maximum of 38 ATP molecules are formed for each glucose molecule degraded to carbon dioxide and water.
• The maximum yield for ATP is rarely reached as:
Some hydrogens leak across the mitochondrial membrane
o Less protons to generate the proton motive force
Some ATP is used to actively transport pyruvate into the mitochondria
Some ATP is used to bring Hydrogen from reduced NAD made during glycolysis, into the cytoplasm, into the mitochondria.
• Anaerobic respiration produces a much lower yield of ATP than aerobic respiration because only glycolysis takes place in anaerobic respiration.
The electron transport chain cannot occur, as there is no oxygen to act as the final electron acceptor.
This means that the Krebs cycle stops, as there are no NAD- they are all reduced.
This prevents the link reaction from occurring.
Anaerobic respiration takes the pyruvate, and by reducing it, frees up the NAD, so glycolysis can continue, producing two molecules of ATP per glucose molecule respired.
fatty acid synthesis
most in diet. excess carbs and proteins converted to fatty acids by the liver stored as fats (triacylglycerols) in adipocytes. acetyl-Co-A is generated in mitochondria and cannot cross the membrane, it needs to be moved into the cytoplasm.
• In the mitochondria, high energy levels (high ATP/ADP) inhibit isocitrate dehydrogenase (*) and lead to an increase in citrate in mitochondria.
• Citrate can be moved to the cytoplasm and converted “back” to acetyl-CoA.
• The next step, catalysed by Acetyl CoA carboxylase (ACC) is the conversion of acetyl CoA into Malonyl-CoA.
• This is the rate limiting and regulated:
ACC is activated by citrate and insulin.
o The enzyme is active as a multi-subunit polymer stabilised by citrate.
ACC is inactivated directly by fatty acyl-CoA and by phoshorylation by AMPK.
• Next, the Malonyl CoA is converted into Fatty acyl-CoA, in the presence of the enzyme Fatty acyl synthase (FAS).
• Fatty acyl synthase (FAS) is a multi-tasking enzyme that catalyses multiple rounds of chain elongation, reduction, dehydration and reduction (actually a 7-step reaction).
triacylglycerol synthesis
• Fatty acyl-CoA is now converted into Triacylglycerol (TAG).
• To produce TAG as storage form of fatty acids, fatty acyl-CoA need to be linked up (esterified) with glycerol-3-phosphate.
• Two reactions that produce glycerol-3-P are available:
Glycerol-3-P dehydrogenase
Uniquely in the liver, glycerol kinase
o This reaction allows the glycerol part of TAGs to be used in gluconeogenesis.
- Adipocytes do not express glycerol kinase and so cannot metabolise glycerol produced during TAG mobilisation.
- The liver packages TAGs into VLDL for delivery and storage to peripheral tissues.
fatty acid catabolism: B oxidation
• The β-oxidation of fatty acids produces large amounts of energy:
Per 2-carbon unit, one FADH2, one NADH and one acetyl-CoA are produced.
Ultimately, these produce 2, 3 and 12 ATP, respectively.
Per 16-carbon (palmitoyl-) CoA, that’s 129 ATP!
ketone bodies
- Ketone bodies are an “emergency fuel” that the liver can produce to preserve glucose.
- The liver itself cannot use ketone bodies, though!
- During starvation, the ability of the liver to oxidise fatty acids released from adipocytes may be limited.
- The liver produces ketone bodies and releases them into the blood for peripheral tissues.
- Ketone bodies are highly soluble and unlike lipids can be transported without carriers.
- Increased levels of ketone bodies in blood (ketonemia) and urine (ketonuria) are observed in uncontrolled type 1 diabetes mellitus.
- The acidity of ketone bodies lowers blood pH (ketoacidosis).
pancreas
- The pancreas, in addition to its digestive functions, secretes two important hormones, insulin and glucagon, that are crucial for normal regulation of glucose, lipid, and protein metabolism.
- Although the pancreas secretes other hormones, such as amylin, somatostatin, and pancreatic polypeptide, their functions are not as well established.
physiologic anatomy of the pancreas
• The pancreas is composed of two major types of tissues:
- The acini, which secrete digestive juices into the duodenum.
- The islets of Langerhans, which secrete insulin and glucagon directly into the blood.
• The islets of Langerhans are organized around small capillaries into which its cells secrete their hormones.
cells of the islets
- Alpha cells
Constitute about 25% of the cells of the islet.
Secrete glucagon. - Beta cells
Constitute about 60% of the cells of the islet.
Secrete insulin and amylin. - Delta cells
Constitute about 10% of the cells of the islet.
Secrete somatostatin. - PP cells
Constitute about 5% of the cells of the islet.
Secrete pancreatic polypeptide.
• The close interrelations among these cell types in the islets of Langerhans allow cell-to-cell communication and direct control of secretion of some of the hormones by the other hormones.
Insulin inhibits glucagon secretion.
Amylin inhibits insulin secretion.
Somatostatin inhibits the secretion of both insulin and glucagon.
insulin
• Insulin affects carbohydrate metabolism.
• Yet it is abnormalities of fat metabolism, causing such conditions as acidosis and arteriosclerosis that are the usual causes of death in diabetic patients.
• Also, in patients with prolonged diabetes, diminished ability to synthesize proteins leads to wasting of the tissues as well as many cellular functional disorders.
• Therefore, it is clear that insulin affects carbohydrate, fat and protein metabolism.
a small protein.
• It is composed of two amino acid chains, connected to each other by disulfide linkages.
• When the two amino acid chains are split apart, the functional activity of the insulin molecule is lost.
insulin and energy abundance
- Insulin secretion is associated with energy abundance.
- That is, when there is great abundance of energy-giving foods in the diet, especially excess amounts of carbohydrates, insulin is secreted in great quantity.
• Insulin plays an important role in storing excess energy.
In the case of excess carbohydrates, it causes them to be stored as glycogen mainly in the liver and muscles.
Also, all the excess carbohydrates that cannot be stored as glycogen are converted under the stimulus of insulin into fats and stored in the adipose tissue.
In the case of proteins, insulin has a direct effect in promoting amino acid uptake by cells and conversion of these amino acids into protein.
In addition, insulin inhibits the breakdown of the proteins that are already in the cells.
synthesis of insulin
synthesized in the beta cells by the usual cell machinery for protein synthesis:
Beginning with translation of the insulin RNA by ribosomes attached to the endoplasmic reticulum to form an insulin preprohormone.
The preprohormone is then cleaved in the endoplasmic reticulum to form proinsulin.
The proinsulin is further cleaved in the Golgi apparatus to form insulin and peptide fragments.
Insulin is packaged into secretory granules
insulin in the blood
- When insulin is secreted into the blood, it circulates almost entirely in an unbound form.
- It has a plasma half-life that averages only about 6 minutes, so that it is mainly cleared from the circulation within 10 to 15 minutes.
• The insulin in the blood does two things:
1. Binds to insulin receptors in target cells.
2. The remainder is degraded by the enzyme insulinase mainly in the liver, to a lesser extent in the kidneys and muscles, and slightly in most other tissues.
• This rapid removal from the plasma is important, because, at times, it is as important to turn off rapidly as to turn on the control functions of insulin.
activation of target cell receptors
- To initiate its effects on target cells, insulin first binds with and activates a membrane receptor protein.
- It is the activated receptor, not the insulin that causes the subsequent effects.
- The insulin receptor is a combination of four subunits held together by disulfide linkages: two alpha subunits that lie entirely outside the cell membrane and two beta subunits that penetrate through the membrane, protruding into the cell cytoplasm.
- The insulin binds with the alpha subunits on the outside of the cell, but because of the linkages with the beta subunits, the portions of the beta subunits protruding into the cell become autophosphorylated.
- Thus, the insulin receptor is an example of an enzyme-linked receptor.
• One insulin molecule can only bind to one alpha subunit, therefore two insulin molecules are required for its effects to manifest.
• Autophosphorylation of the beta subunits of the receptor activates a local tyrosine kinase, which in turn causes phosphorylation of multiple other intracellular enzymes including a group called insulin-receptor substrates (IRS).
Different types of IRS (e.g. IRS-1, IRS-2, IRS-3) are expressed in different tissues.
The net effect is to activate some of these enzymes while inactivating others.
• In this way, insulin directs the intracellular metabolic machinery to produce the desired effects on carbohydrate, fat, and protein metabolism.
the end effects of insulin stimulation are:
- Within seconds after insulin binds with its membrane receptors, the membranes of about 80% of the body’s cells markedly increase their uptake of glucose.
This is especially true of muscle cells and adipose cells but is not true of most neurons in the brain.
Glucose uptake occurs as a result of translocation of multiple intracellular vesicles to the cell membranes; these vesicles carry in their own membranes multiple molecules of glucose transport proteins (GLUT4), which bind with the cell membrane and facilitate glucose uptake into the cells.
The increased glucose transported into the cells is immediately phosphorylated and becomes a substrate for all the usual carbohydrate metabolic functions e.g. glucose synthesis.
When insulin is no longer available, these vesicles separate from the cell membrane within about 3 to 5 minutes and move back to the cell interior to be used again and again as needed.
2. The cell membrane becomes more permeable to many of the amino acids, potassium ions, and phosphate ions, causing increased transport of these substances into the cell.
This causes intracellular processes occurring such as protein synthesis and fat synthesis.
3. Slower effects occur during the next 10 to 15 minutes to change the activity levels of many more intracellular metabolic enzymes.
These effects result mainly from the changed states of phosphorylation of the enzymes.
- Much slower effects continue to occur for hours and even several days.
They result from changed rates of translation of mRNAs at the ribosomes to form new proteins and still slower effects from changed rates of transcription of DNA in the cell nucleus.
This leads to controlled growth of gene expression of the cell.
In this way, insulin remoulds much of the cellular enzymatic machinery to achieve its metabolic goals.
effects of insulin on carbohydrate metabolism
- When carbohydrates are eaten, glucose is absorbed into the blood.
- This causes rapid secretion of insulin.
- The insulin in turn causes rapid uptake, storage, and use of glucose by almost all tissues of the body, but especially by the muscles, adipose tissue, and liver.
insulin promotes muscle glucose uptake and metabolism
- Normally, muscle tissue depends not on glucose for its energy but on fatty acids.
- This is because the normal resting muscle membrane is only slightly permeable to glucose, except when the muscle fibre is stimulated by insulin.
- Between meals, the amount of insulin that is secreted is too small to promote significant amounts of glucose entry into the muscle cells.
• However, under two conditions the muscles do use large amounts of glucose:
1. Moderate to heavy exercise.
o This usage of glucose does not require large amounts of insulin, because exercising muscle fibres become more permeable to glucose even in the absence of insulin because of the contraction process itself.
2. During the few hours after a meal.
o At this time the blood glucose concentration is high and the pancreas is secreting large quantities of insulin.
o The extra insulin causes rapid transport of glucose into the muscle cells.
o This causes the muscle cell during this period to use glucose preferentially over fatty acids.
storage of glycogen in muscle
- If the muscles are not exercising after a meal and yet glucose is transported into the muscle cells in abundance, then most of the glucose is stored in the form of muscle glycogen instead of being used for energy.
- The glycogen can later be used for energy by the muscle.
- It is especially useful for short periods of extreme energy use by the muscles and even to provide spurts of anaerobic energy for a few minutes at a time by glycolytic breakdown of the glycogen to lactic acid, which can occur even in the absence of oxygen
insulin promotes liver uptake storage and use of glucose
- Insulin helps store glucose as glycogen in the liver.
- Between meals, the blood glucose concentration begins to fall.
- This decreases the secretion of insulin into the bloodstream.
- The liver begins to break down glycogen into glucose, which is released back into the blood to keep the glucose concentration from falling too low.
- Mechanism by which insulin causes glucose uptake into hepatocytes includes simultaneous steps
- Insulin binds to its receptor on the hepatocytes.
- Autophosphorylation of the B subunit occurs.
- Tyrosine kinase is activated and intracellular changes happen.
- Insulin inactivates ‘glycogen phosphorylase’, the principal enzyme that causes liver glycogen to split into glucose.
* This prevents breakdown of the glycogen that has been stored in the liver cells. - Insulin causes enhanced uptake of glucose from the blood by the liver cells.
* It does this by increasing the activity of the enzyme ‘glucokinase’, which is one of the enzymes that causes the initial phosphorylation of glucose after it diffuses into the liver cells.
* Once phosphorylated, the glucose is temporarily trapped inside the liver cells because phosphorylated glucose cannot diffuse back through the cell membrane. - Insulin also increases the activities of the enzymes that promote glycogen synthesis, including especially ‘glycogen synthase’, which is responsible for polymerization of the monosaccharide units to form the glycogen molecules.
* The net effect of this mechanism is to increase the amount of glycogen in the liver, without it being broken down.
glucose release from liver to maintain blood glucose levels
- When the blood glucose level begins to fall to a low level between meals, several events transpire that cause the liver to release glucose back into the circulating blood:
1. The decreasing blood glucose causes the pancreas to decrease its insulin secretion.
2. The lack of insulin then reverses all the effects for glycogen storage, essentially stopping further synthesis of glycogen in the liver and preventing further uptake of glucose by the liver from the blood.
3. The lack of insulin (along with increase of glucagon) activates the enzyme ‘glycogen phosphorylase’, which causes the splitting of glycogen into the enzyme ‘glucose phosphate’.
4. The enzyme glucose phosphatase, which had been inhibited by insulin, now becomes activated by the insulin lack and causes the phosphate radical to split away from the glucose; this allows the free glucose to diffuse back into the blood. - Thus, the liver removes glucose from the blood when it is present in excess after a meal and returns it to the blood when the blood glucose concentration falls between meals.
- Ordinarily, about 60% of the glucose in the meal is stored in this way in the liver and then returned later.
Insulin Promotes Conversion of Excess Glucose into Fatty Acids and Inhibits Gluconeogenesis in the Liver
- As well as the glucose entering hepatocytes being used for glycogen, this glucose can be used for hepatic metabolism.
- Insulin promotes the conversion of all this excess glucose into fatty acids.
- These fatty acids are subsequently packaged as triglycerides in very-low-density lipoproteins (VLDLs) and transported in this form by way of the blood to the adipose tissue and deposited as fat.
- Insulin inhibits gluconeogenesis by:
- Decreasing the quantities and activities of the liver enzymes required for gluconeogenesis.
- Decreasing the release of amino acids from muscle and other extrahepatic tissues and in turn the availability of these necessary precursors required for gluconeogenesis.
insulin and the brain
- Brain cells are permeable to glucose and can use glucose without the intermediation of insulin.
- Brain cells only use glucose for energy.
- Therefore, it is crucial for the blood glucose levels to always be maintained.
- When the blood glucose levels drop too low, symptoms of hypoglycemic shock develop, characterised by nervous irritability that leads to fainting, seizures, and even coma.
insulin promotes fat synthesis
• Insulin influences fat storage in adipose tissue in two ways:
1. Insulin increases the utilisation of glucose by the cells in the body, which decreases the utilisation of fat, thus functioning as a fat sparer.
2. Insulin promotes fatty acid synthesis.
This occurs when more carbohydrates are ingested than can be used for immediate energy, thus providing the substrate for fat synthesis.
Fatty acid synthesis occurs in hepatocytes.
Fatty acids are then transported from the liver by way of the blood lipoproteins to the adipose cells to be stored
factors that lead to increased fatty acid synthesis in the liver include the following: 1. Insulin increases the transport of glucose into the liver cells
o After the liver glycogen concentration reaches 5-6%, this in itself inhibits further glycogen synthesis.
o Then all the additional glucose entering the liver cells becomes available to form fat.
o The glucose is first split to pyruvate in the glycolytic pathway, and the pyruvate subsequently is converted to acetyl coenzyme A (acetyl-CoA), the substrate from which fatty acids are synthesized.
factors that lead to increased fatty acid synthesis in the liver include the following: 2. An excess of citrate and isocitrate ions is formed by the citric acid cycle (Krebs cycle) when excess amounts of glucose are being used for energy.
o These ions then have a direct effect in activating acetyl-CoA carboxylase, the enzyme required to carboxylate acetyl-CoA to form malonyl-CoA, the first stage of fatty acid synthesis
factors that lead to increased fatty acid synthesis in the liver include the following:3. Most of the fatty acids are then synthesized within the liver itself and used to form triglycerides, the usual form of storage fat.
o They are released from the liver cells to the blood in the lipoproteins.
o Insulin activates lipoprotein lipase in the capillary walls of the adipose tissue, which splits the triglycerides again into fatty acids, a requirement for them to be absorbed into the adipose cells, where they are again converted to triglycerides and stored.
- Insulin inhibits the action of hormone-sensitive lipase.
This is the enzyme that causes hydrolysis of the triglycerides already stored in the fat cells.
Therefore, the release of fatty acids from the adipose tissue into the circulating blood is inhibited.
- Insulin promotes glucose transport through the cell membrane into the fat cells
Some of this glucose is then used to synthesize minute amounts of fatty acids.
The glucose also forms large quantities of α-glycerol phosphate.
This substance supplies the glycerol that combines with fatty acids to form the triglycerides that are the storage form of fat in adipose cells.
Therefore, when insulin is not available, even storage of the large amounts of fatty acids transported from the liver in the lipoproteins is almost blocked.
Insulin Deficiency Increases Use of Fat for Energy
- Fat breakdown and its use for providing energy is greatly enhanced in the absence of insulin.
- This occurs even normally between meals when secretion of insulin is minimal, but it becomes extreme in Type I diabetes mellitus when secretion of insulin is almost zero
Insulin Deficiency Causes Lipolysis of Storage Fat and Release of Free Fatty Acids
- In the absence of insulin, all the effects of insulin that cause storage of fat are reversed.
- The most important effect is that the enzyme hormone-sensitive lipase in the fat cells becomes strongly activated.
- This causes hydrolysis of the stored triglycerides, releasing large quantities of fatty acids and glycerol into the circulating blood.
- Consequently, the plasma concentration of free fatty acids begins to rise within minutes.
- This free fatty acid then becomes the main energy substrate used by essentially all tissues of the body besides the brain.
Insulin Deficiency Increases Plasma Cholesterol and Phospholipid Concentrations
- Insulin deficiency also promotes liver conversion of some of the fatty acids into phospholipids and cholesterol, two of the major products of fat metabolism.
- Cholesterol, phospholipids together with the excess triglycerides formed at the same time in the liver, are then discharged into the blood in the lipoproteins.
- Therefore, the concentration of lipoproteins is increased too.
- This high lipid concentration — especially the high concentration of cholesterol — promotes the development of atherosclerosis in people with serious diabetes
Excess Usage of Fats during Insulin Lack Causes Ketosis and Acidosis
- Insulin lack also causes excessive amounts of acetoacetic acid to be formed in the liver cells.
- This is because in the absence of insulin but in the presence of excess fatty acids in the liver cells, the carnitine transport mechanism for transporting fatty acids into the mitochondria becomes increasingly activated.
- In the mitochondria, beta oxidation of the fatty acids then proceeds very rapidly, releasing extreme amounts of acetyl-CoA.
- A large part of this excess acetyl-CoA is then condensed to form acetoacetic acid, which in turn is released into the circulating blood.
- Most of this passes to the peripheral cells, where it is again converted into acetyl-CoA and used for energy in the usual manner.
- At the same time, the absence of insulin also depresses the utilization of acetoacetic acid in the peripheral tissues.
- Thus, so much acetoacetic acid is released from the liver that it cannot all be metabolized by the tissues.
- Therefore, the levels of acetoacetic acid increase in the blood, leading to severe acidosis.
- Some of the acetoacetic acid is also converted into b-hydroxybutyric acid and acetone.
- These two substances, along with the acetoacetic acid, are called ketone bodies, and their presence in large quantities in the body fluids is called ketosis.
- In severe diabetes the acetoacetic acid and the b-hydroxybutyric acid can cause severe acidosis and coma, which often leads to death.
insulin promotes protein synthesis and storage
- Insulin stimulates transport of many of the amino acids into the cells.
Among the amino acids most strongly transported are valine, leucine, isoleucine, tyrosine, and phenylalanine. - Insulin increases the translation of messenger RNA, thus forming new proteins.
Insulin “turns on” the ribosomal machinery.
In the absence of insulin, the ribosomes simply stop working, almost as if insulin operates an “on-off” mechanism. - Over a longer period of time, insulin also increases the rate of transcription of selected DNA genetic sequences in the cell nuclei.
This forms increased quantities of RNA and still more protein synthesis—especially promoting a vast array of enzymes for storage of carbohydrates, fats, and proteins. - Insulin inhibits the catabolism of proteins.
This decreases the rate of amino acid release from the cells, especially from the muscle cells.
This results from the ability of insulin to diminish the normal degradation of proteins by the cellular lysosomes. - In the liver, insulin depresses the rate of gluconeogenesis.
It does this by decreasing the activity of the enzymes that promote gluconeogenesis.
Because the substrates most used for synthesis of glucose by gluconeogenesis are the plasma amino acids, this suppression of gluconeogenesis conserves the amino acids in the protein stores of the body.
• In summary, insulin promotes protein formation and prevents the degradation of proteins
insulin lack causes protein depletion and inc plasma amino acids
- Protein storage stops when there is a lack of insulin.
- The catabolism of proteins increases, protein synthesis stops, and large quantities of amino acids are dumped into the plasma.
- The plasma amino acid concentration rises considerably, and most of the excess amino acids are used either directly for energy or as substrates for gluconeogenesis.
- This degradation of the amino acids also leads to enhanced urea excretion in the urine.
- The resulting protein wasting is one of the most serious of all the effects of severe diabetes mellitus.
- It can lead to extreme weakness as well as many deranged functions of the organs
insulin presence on carb metabolism
Insulin promotes glucose storage as glycogen.
Increased glucose transport through the cell membrane.
Inhibits glycogen phosphorylase. This prevents the breakdown of glycogen
Activates glucokinase. This increases the phosphorylation of glucose upon entering the cell – glucose trapping.
Activates glycogen synthase. Promotes the synthesis of glycogen.
insulin lack on carb metabolism
Insulin lack promotes glycogenolysis.
Decreased glucose transport through the cell membrane.
Activates glycogen phosphorylase. This promotes the breakdown of glycogen into glucose phosphate.
Activates glucose phosphatase. This removes the radical phosphate group form glucose phosphate, thus allowing for the formation of glucose.
insulin presence on fat metabolism
Insulin promotes fat storage as triglycerides.
Inhibition of hormone-sensitive lipase. This prevents the hydrolysis of triglycerides.
Increased glucose transport through the cell membrane for synthesis of glycerol for the production of triglycerides
