Flashcards in case 6 Deck (125):
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.
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
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
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
2. Link Reaction
3. Krebs’ Cycle/ Citric Cycle
4. Electron Transport Chain/ Oxidative Phosphorylation
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
1. An ATP molecule is hydrolysed and the phosphate attached to the glucose molecule at C-6
2. Glucose 6 Phosphate is turned into fructose 6 phosphate
3. Another ATP is hydrolysed, and the phosphate attached to C-1
4. 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
5. It is split into two molecules of Triose phosphate
6. Two hydrogen atoms are removed from each Triose Phosphate, which involved dehydrogenase enzymes.
7. NAD combines with the Hydrogen atoms to form reduce NAD
8. Two molecules of ATP are formed- substrate level phosphorylation
9. Four enzyme-catalysed reactions convert each triose phosphate molecule into a molecule of pyruvate.
• 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.
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.
2. 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.
3. The 5C compound is decarboxylated and dehydrogenated to form a 4C compound.
4. The 4C compound is changed into another 4C compound, and a molecule of ATP is phosphorylated.
5. The second 4C compound is changed into a third 4C compound and a pair of hydrogen atoms are removed, reducing FAD.
6. 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)
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
1. Reduced NAD and FAD donate hydrogens, which are split into protons and electrons, to the electron carriers.
2. The protons are pumped across the inner mitochondrial membrane using energy released from the passing of electrons down the electron transport chain.
3. This builds up a proton gradient, which is also a pH gradient, and an electrochemical gradient
4. Thus, potential energy builds up
5. 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.
6. 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
1. 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).
2. Link Reaction = 0 ATP molecules and 4H gained.
3. Citric Acid Cycle = 2 ATP molecules and 16H gained.
4. 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.)
5. 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).
• 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:
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 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).
• 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:
1. The acini, which secrete digestive juices into the duodenum.
2. 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
1. Alpha cells
Constitute about 25% of the cells of the islet.
2. Beta cells
Constitute about 60% of the cells of the islet.
Secrete insulin and amylin.
3. Delta cells
Constitute about 10% of the cells of the islet.
4. 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 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:
1. 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.
4. 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
1. Insulin binds to its receptor on the hepatocytes.
2. Autophosphorylation of the B subunit occurs.
3. Tyrosine kinase is activated and intracellular changes happen.
4. 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.
5. 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.
6. 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.
1. 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.
2. 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
1. 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.
2. 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.
3. 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.
4. 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.
5. 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
insulin lack on fat metabolism
Insulin lack promotes the breakdown of triglycerides into fatty acids.
Activation of hormone-sensitive lipase. This promotes the hydrolysis of triglycerides.
Decreased glucose transport through the cell membrane. Therefore, a lack of glycerol is produced and so less triglycerides are formed.
Increased liver conversion of fatty acids into phospholipids and cholesterol, which enter the blood and can lead to atherosclerosis.
Increased formation of acetoacetic acid in hepatocytes and decreased utilisation of acetoacetic acid in the peripheries. This leads to acidosis. Acetoacetic acid can be converted into ketone bodies – ketosis. Together, this is called ketoacidosis.
insulin presence on protein metabolism
Insulin promotes protein storage.
Stimulates transport of amino acids into cells.
Increases translation of mRNA, thus forming new proteins.
Increases the rate of transcription of selected DNA sequences in the cell nuclei.
Inhibits protein catabolism.
In the liver, insulin decreases the rate of gluconeogenesis.
insulin lack on protein metabolism
Insulin lack promotes the catabolism of proteins into amino acids.
Excess amino acids are used either directly for energy or as substrates for gluconeogenesis.
Excess amino acids leads to enhanced urea excretion in the urine.
Protein wasting and muscle weakness.
mechanism of insulin secretion
1. Insulin secretion occurs in the pancreatic beta cells in response to increased blood glucose concentration.
2. The beta cells have a large number of glucose transporters (GLUT-2) that permit a rate of glucose influx that is proportional to the blood concentration in the physiologic range.
3. Once inside the cells, glucose is ‘phosphorylated’ to glucose-6-phosphate by glucokinase.
This is the rate limiting step for glucose metabolism in the beta cell.
4. The glucose-6-phosphate is subsequently ‘oxidized’ to form adenosine triphosphate (ATP), which inhibits the ATP-sensitive potassium channels of the cell.
5. Closure of the potassium channels depolarizes the cell membrane, thereby opening voltage-gated calcium channels, which are sensitive to changes in membrane voltage.
6. This produces an influx of calcium that stimulates fusion of the docked insulin-containing vesicles with the cell membrane and secretion of insulin into the extracellular fluid by exocytosis.
effects on insulin secreetion
• Somatostatin and norepinephrine (by activating a-adrenergic receptors), inhibit exocytosis of insulin.
• Sulfonylurea drugs stimulate insulin secretion by binding to the ATP-sensitive potassium channels and blocking their activity.
This results in a depolarizing effect that triggers insulin secretion, making these drugs very useful in stimulating insulin secretion in patients with type II diabetes.
control of insulin secretion
• Insulin secretion is primarily controlled by blood glucose concentration.
• Blood amino acids and other factors also play important roles in controlling insulin secretion
inc blood glucose stimulates insulin secretion
• At the normal fasting level of blood glucose, there is minimal insulin secretion.
• If the blood glucose concentration is suddenly increased to a level two to three times normal and kept at this high level thereafter, insulin secretion increases markedly in two stages:
1. Plasma insulin concentration increases almost 10-fold after the acute elevation of the blood glucose.
o This results from immediate release of insulin in preformed granules in the beta cells of the pancreas.
o Once these granules run out, the initial high rate of secretion is not maintained.
2. Insulin secretion rises a second time and reaches a new plateau - this time usually at a rate of secretion even greater than that in the initial phase.
o This secretion results both from additional release of preformed insulin, but mainly from activation of the enzyme system that synthesizes and releases new insulin from the cells.
o This stage continues for as long as glucose levels stimulate beta cells
factors that stim insulin secretion
• Amino Acids - amino acids strongly potentiate the glucose stimulus for insulin secretion.
• Incretin Hormones (GLP-1 and GIP)
GLP 1 and GIP on insulin
These are a group of metabolic hormones that stimulate the secretion of insulin before the blood food enters the duodenum (i.e. before the blood glucose levels rise) - anticipatory” increase in blood insulin.
This prepares the body for the rise in the blood glucose levels that will occur.
Also, they inhibit glucagon release from the alpha cells.
The two main incretin hormones are:
o Glucagon-like peptide-1 (GLP-1)
o Gastric inhibitory peptide (GIP)
Mechanism of Action:
o GIP and GLP-1 are secreted by enterocytes into the blood.
o The enzyme dipeptydylpeptidase-4 (DDP4) degrades these hormones and makes them inactive.
o But, the degradation isn’t sufficient enough and so majority of these hormones remain active and can therefore pass to the pancreas and exhibit their effects of stimulating insulin secretion and decreasing glucagon secretion.
• Glucagon is a hormone secreted by the alpha cells of islets of Langerhans when the blood glucose concentration falls.
• It increases the blood glucose concentration - opposite of insulin
effects of glucagon on glucose metabolism
• The major effects of glucagon on glucose metabolism are:
1. The breakdown of liver glycogen (glycogenolyisis).
2. Increased gluconeogenesis in the liver.
3. Inhibit insulin secretion.
• Both these effects increase the availability of glucose for the use by the cells in the body
• This is the most important effect of glucagon.
• This occurs via the activation of adenylyl cyclase and cAMP.
• In the pathway for glycogenolysis, each succeeding product is produced in greater quantity than the preceding product.
• Therefore, it represents a potent amplifying mechanism.
• This explains how only a few micrograms of glucagon can cause the blood glucose level to double or increase even more within a few minutes.
• Once the glycogen stores have been utilized, gluconeogenesis occurs.
• This occurs because glucagon increases the rate of amino acid uptake by hepatocytes and then the conversion of many of the amino acids to glucose by gluconeogenesis.
• This is achieved by activating multiple enzymes that are required for amino acid transport and gluconeogenesis, especially activation of the enzyme system for converting pyruvate to phosphoenolpyruvate, a rate-limiting step in gluconeogenesis.
effects of glucagon on lipid metabolism
• Glucagon activates adipose cell lipase, making increased quantities of fatty acids (lipolysis) available to the energy systems of the body.
• Glucagon also inhibits the storage of triglycerides in the liver, which prevents the liver from removing fatty acids from the blood; this also helps make additional amounts of fatty acids available for the other tissues of the body.
inc blood glucose inhibits glucagon secretion
• The blood glucose concentration is by far the most potent factor that controls glucagon secretion.
• The effect of blood glucose concentration on glucagon secretion is in exactly the opposite direction from the effect of glucose on insulin secretion.
• A decreased blood glucose concentration from its normal fasting level (90 mg/100 ml) of blood down to hypoglycaemic levels can increase the plasma concentration of glucagon.
• Conversely, increasing the blood glucose to hyperglycaemic levels decreases plasma glucagon
inc blood amino acids stimiulate glucagon secretion
• High concentrations of amino acids, as occur in the blood after a protein meal stimulate the secretion of glucagon.
• This is the same effect that amino acids have in potentiating insulin secretion.
• Thus, in this instance, the glucagon and insulin responses are not opposites.
• The importance of amino acid stimulation of glucagon secretion is that the glucagon then promotes rapid conversion of the amino acids to glucose, thus making even more glucose available to the tissues.
exercise stimulates glucagon secretion
• In exhaustive exercise, the blood concentration of glucagon often increases.
• What causes this is not understood, because the blood glucose concentration does not necessarily fall.
• A beneficial effect of the glucagon is that it prevents a decrease in blood glucose
• Somatostatin inhibits glucagon and insulin secretion.
• The delta cells of the islets of Langerhans secrete the hormone somatostatin.
• Factors that stimulate somatostatin secretion:
1. Increased blood glucose
2. Increased amino acids
3. Increased fatty acids
4. Increased concentrations of incretin hormones
• In turn, somatostatin has multiple inhibitory effects as follows:
1. Somatostatin acts locally within the islets of Langerhans themselves to depress the secretion of both insulin and glucagon.
2. Somatostatin decreases the motility of the stomach, duodenum, and gallbladder.
3. Somatostatin decreases both secretion and absorption in the gastrointestinal tract.
• The role of somatostatin is to extend the period of time over which the food nutrients are assimilated into the blood.
• At the same time, the effect of somatostatin to depress insulin and glucagon secretion decreases the utilization of the absorbed nutrients by the tissues, thus preventing rapid exhaustion of the food and therefore making it available over a longer period of time.
• Diabetes mellitus is a syndrome of impaired carbohydrate, fat, and protein metabolism caused by either lack of insulin secretion or decreased sensitivity of the tissues to insulin.
• There are two general types of diabetes mellitus:
Type I diabetes, also called insulin-dependent diabetes mellitus (IDDM), is caused by lack of insulin secretion.
Type II diabetes, also called non–insulin-dependent diabetes mellitus (NIDDM), is caused by decreased sensitivity of target tissues to the metabolic effect of insulin. This reduced sensitivity to insulin is often called insulin resistance.
• In both types of diabetes mellitus, there is a decrease in the uptake of glucose and so the blood glucose concentration increases.
• Cell utilization of glucose falls increasingly lower, and utilization of fats and proteins increases.
epidemiology of diabetes
o 3.8 million currently
o 5 million estimated by 2025
o Most cases= Type 2 diabetes
o NHS costs- £16.9 billion by 2035
signs and symptoms
• Common symptoms:
Frequent urination (polyuria)
Increased thirst (polydipsia)
Increased hunger (polyphagia)
Dry mouth (xerostomia)
type 1 diabetes-lack of insulin production by B cells of the pancreas
• Injury to the beta cells of the pancreas or diseases that impair insulin production can lead to type I diabetes.
• Causes of Type 1 Diabetes:
o Autoimmune disorders - destruction of beta cells.
o Viral infections – destruction of beta cells.
o Genes play a role in the susceptibility of developing Type 1 Diabetes.
• 90% of the islet of Langerhans need to be destroyed to develop type 1 diabetes. Therefore, the usual onset of type I diabetes occurs in teenage years - “juvenile diabetes mellitus”
• Type I diabetes may develop very abruptly, over a period of a few days or weeks, with three principal sequelae:
1. Increased blood glucose
2. Increased utilization of fats for energy for formation of cholesterol by the liver.
3. Depletion of the body’s proteins for use of energy within the cells themselves.
glucose in the urine and dehydration
• The high blood glucose causes more glucose to filter into the renal tubules than can be reabsorbed, and the excess glucose spills into the urine.
• The very high levels of glucose can cause dehydration.
This occurs partly because glucose does not diffuse easily through the pores of the cell membrane, and the increased osmotic pressure in the extracellular fluids causes osmotic transfer of water out of the cells.
• In addition to the direct cellular dehydrating effect of excessive glucose, the loss of glucose in the urine causes osmotic diuresis.
That is, the osmotic effect of glucose in the renal tubules greatly decreases tubular reabsorption of fluid.
The overall effect is massive loss of fluid in the urine (due to glucose drawing in water into the urine), causing dehydration of the extracellular fluid, which in turn causes compensatory dehydration of the intracellular fluid.
• Thus, polyuria (excessive urine excretion), intracellular and extracellular dehydration, and increased thirst are classic symptoms of diabetes.
chronic high glucose conc causes tissue injury
• Chronic high glucose concentration (i.e. in diabetes mellitus) causes blood vessels in multiple tissues throughout the body to function abnormally and undergo structural changes that result in inadequate blood supply to the tissues.
This in turn leads to increased risk for:
End-stage kidney disease
Retinopathy and blindness (eyes)
Ischemia and gangrene of the limbs
Autonomic nervous system dysfunction
• Peripheral neuropathy, which is abnormal function of peripheral nerves, and autonomic nervous system dysfunction can result in impaired cardiovascular reflexes, impaired bladder control, decreased sensation in the extremities, and other symptoms of peripheral nerve damage.
• In addition, hypertension, secondary to renal injury, and atherosclerosis, secondary to abnormal lipid metabolism, often develop in patients with diabetes and amplify the tissue damage caused by the elevated glucose.
Diabetes Mellitus Causes Increased Utilization of Fats and Metabolic Acidosis
• The shift from carbohydrate to fat metabolism in diabetes increases the release of keto-acids, such as acetoacetic acid and b-hydroxybutyric acid, into the plasma more rapidly than they can be taken up and oxidized by the tissue cells.
• As a result, the patient develops severe metabolic acidosis from the excess keto-acids, which, in association with dehydration due to the excessive urine formation, can cause severe acidosis.
• This leads rapidly to diabetic coma (pH
diabetes mellitus causes depletion of the bodys proteins
• Failure to use glucose for energy leads to increased utilization and decreased storage of proteins as well as fat.
• Therefore, a person with severe untreated diabetes mellitus suffers rapid weight loss and asthenia (lack of energy) despite eating large amounts of food (polyphagia).
• Without treatment, these metabolic abnormalities can cause severe wasting of the body tissues and death within a few weeks.
Type II Diabetes - Resistance to the Metabolic Effects of Insulin
• Type II diabetes is far more common than type I, accounting for about 90% of all cases of diabetes mellitus.
• In most cases, the onset of type II diabetes occurs after age 40, often between the ages of 50 and 60 years, and the disease develops gradually.
• Therefore, this syndrome is often referred to as “adult-onset diabetes”.
• There is an increasing prevalence of obesity, the most important risk factor for type II diabetes in children as well as in adults
risk factors for type 2
Age (>40 years; >25 years for South Asian people)
Genetics (family history)
Ethnicity (South Asian, Chinese, African-Caribbean or black African origin)
Insulin resistance (metabolic syndrome)
Polycystic ovary syndrome (PCOS)
Excess formation of glucocorticoids (Cushing’s syndrome)
Excess formation of growth hormone (Acromegaly)
• Type II diabetes, in contrast to type I, is associated with increased plasma insulin concentration (hyperinsulinemia).
• This occurs as a compensatory response by the pancreatic beta cells for diminished sensitivity of target tissues to the metabolic effects of insulin (intracellularly) - insulin resistance.
• The decrease in insulin sensitivity impairs carbohydrate utilization and storage, raising blood glucose and stimulating a compensatory increase in insulin secretion.
• Excess weight gain and obesity lead to development of insulin resistance and impaired glucose metabolism. This is usually a gradual process.
reasons for insulin resistance
1. It is suggested that there are fewer insulin receptors, especially in the skeletal muscle, liver, and adipose tissue, in obese than in lean subjects.
2. Most of the insulin resistance appears to be caused by abnormalities of the intracellular signaling pathways that link receptor activation with multiple cellular effects.
Impaired insulin signaling appears to be closely related to toxic effects of lipid accumulation in tissues (obesity) – TNF-α.
This can also occur as a result of gene mutations then encode dysfunctional intracellular proteins involved in this signaling
• Insulin resistance is part of a cascade of disorders that is often called the “metabolic syndrome”.
• Features of metabolic syndrome include:
1. Obesity - especially accumulation of adipose tissue in the abdominal cavity around the visceral organs
2. Insulin resistance - leading to increased blood glucose concentration
3. Fasting hyperglycemia
4. Lipid abnormalities such as increased blood triglycerides (cause atherosclerosis) and decreased blood HDL-cholesterol
development of type 2 during prolonged insulin resistance
• With prolonged and severe insulin resistance, even the increased levels of insulin are not sufficient to maintain normal glucose regulation.
• As a result, moderate hyperglycemia occurs after ingestion of carbohydrates in the early stages of the disease.
• In the later stages of type II diabetes, the pancreatic beta cells become “exhausted” and are unable to produce enough insulin to prevent more severe hyperglycemia, especially after the person ingests a carbohydrate-rich meal.
• Some obese people, although having marked insulin resistance and greater than normal increases in blood glucose after a meal, never develop clinically significant diabetes mellitus; apparently, the pancreas in these people produces enough insulin to prevent severe abnormalities of glucose metabolism
hypoglycaemia and effect on cognition
• In a state of moderate hypoglycaemia, the CNS usually becomes quite excitable, because hypoglycaemia sensitizes neuronal activity.
• Sometimes various forms of hallucinations result, but more often the patient simply experiences extreme nervousness, trembles all over, and breaks out in a sweat.
• In the state of severe hypoglycaemia, clonic seizures and loss of consciousness are likely to occur.
• As the glucose level falls still lower, the seizures cease and only a state of coma remains.
• It is difficult by simple clinical observation to distinguish between diabetic coma as a result of insulin-lack acidosis and coma due to hypoglycemia caused by excess insulin.
• The acetone breath and the rapid, deep breathing of diabetic coma are not present in hypoglycemic coma.
treatment for hypoglycemic shock or coma
Immediate intravenous administration of large quantities of glucose.
o This usually brings the patient out of shock within a minute or more.
Also, the administration of glucagon can cause glycogenolysis in the liver and thereby increase the blood glucose level extremely rapidly.
• If treatment is not effected immediately, permanent damage to the neuronal cells of the central nervous system often occurs
Investigations for Diagnosis of Diabetes Mellitus
• Blood Glucose
• Urine test for proteins and glucose (and ketones).
• HbA1C (Glycated Haemoglobin – when Hb in the blood joins with glucose) to identify average plasma glucose concentration over prolonged periods of time.
Chronic elevated levels of plasma glucose causes glucose to attach to Hb and it remains that way.
Time period correlates to about 4 weeks to 3 months.
• Blood Pressure (Hypertension)
• Blood Fats (Lipids)
• Arterial blood gases
• Blood pH
• The usual methods for diagnosing diabetes are based on various chemical tests of the urine and the blood.
• Urinary Glucose:
A normal person loses undetectable amounts of glucose, whereas a person with diabetes loses glucose in small to large amounts, in proportion to the severity of disease and the intake of carbohydrates.
• Urinary Protein/ Proteinuria:
Low levels of protein in urine are normal.
Protein in the urine indicates diabetic kidney disease.
• Urinary Ketones:
Ketones (such as acetoacetic acid) may be present in the urine.
This indicates ketoacidosis of the body.
blood glucose tests
• A random venous plasma glucose concentration ≥ 11.1 mmol/l or
• A fasting plasma glucose concentration ≥ 7.0 mmol/l (whole blood ≥ 6.1 mmol/l) or
• Two hour plasma glucose concentration ≥ 11.1 mmol/l two hours after 75g anhydrous glucose in an oral glucose tolerance test (OGTT).
• In type I diabetes, plasma insulin levels are very low or undetectable during fasting and even after a meal.
• In type II diabetes, plasma insulin concentration may be several-fold higher than normal and usually increases to a greater extent after ingestion of a standard glucose load during a glucose tolerance test.
glucose tolerance test
• When a normal, fasting person ingests 1 gram of glucose per kilogram of body weight, the blood glucose level rises from about 90 mg/100 ml to 120 to 140 mg/100 ml and falls back to below normal in about 2 hours.
• In a person with diabetes, the fasting blood glucose concentration is almost always above 110 mg/100 ml and often above 140 mg/100 ml.
• Also, the glucose tolerance test is almost always abnormal.
• On ingestion of glucose, these people exhibit a much greater than normal rise in blood glucose level and the glucose level falls back to the control value only after 4 to 6 hours; furthermore, it fails to fall below the control level.
• The low fall of this curve and its failure to fall below the control level demonstrate that either:
1. The normal increase in insulin secretion after glucose ingestion does not occur.
2. There is decreased sensitivity to insulin.
• A diagnosis of diabetes mellitus can usually be established on the basis of such a curve, and type I and type II diabetes can be distinguished from each other by measurements of plasma insulin, with plasma insulin being low or undetectable in type I diabetes and increased in type II diabetes.
• Small quantities of acetoacetic acid in the blood, which increase greatly in severe diabetes, are converted to acetone.
• This is volatile and vaporized into the expired air.
• A diagnosis of type I diabetes mellitus can be made by smelling acetone on the breath of a patient (smells of nail varnish remover)
• Also, keto-acids can be detected in the urine, and their quantitation aids in determining the severity of the diabetes.
• Type 2 diabetes:
In the early stages, keto-acids are usually not produced in excess amounts.
However, when insulin resistance becomes very severe and there is greatly increased utilization of fats for energy, keto-acids are then produced in persons with type II diabetes.
• HbA1c indicates your blood glucose levels for the previous three months.
• The HbA1c measures the amount of glucose that is being carried by the red blood cells in the body.
• HbA1c targets:
For most adults with diabetes, the HbA1c target is
• Glucose levels
• Acetoacetate and acetone – testing for ketoacidosis
• Sodium ions – in diabetes, hypernatremia (increased sodium levels). This occurs due to osmotic diuresis in hyperglycaemia. Because glucose does not penetrate cells in the absence of insulin, hyperglycaemia further dehydrates the ICF compartment. To compensate for this, sodium ions move out of the cells into the ECF, taking water with them, in order to increase the water content of blood (therefore aiming to decrease the osmolality of the blood).
• Potassium ions – in diabetics, hyperkalemia occurs, usually as a result of ketoacidosis. This is because the body tries to take H+ ions out of the blood by exchanging them for K+ ions, via the H+/K+ exchanger.
• Bicarbonate ions
• Creatinine – in diabetes, this would increase due to the breakdown of muscles due to the lack of insulin effect (protein can’t be stored).
• Urea – this will increase in diabetes because as more protein is broken down, more ammonia (a product of deamination) needs to be excreted from the body.
• Osmolality – this is the concentration of a solution. In diabetes, this increases due to the presence of increased glucose in the blood, thus concentrating the blood. The body secretes ADH to try and reabsorb more water in the kidneys.
• Total protein – in diabetes, this will increase because of the breakdown of muscle, thus the breakdown amino acids enter the blood
arterial blood gases
• pO2 – in the state of acidosis, this will deplete.
• pCO2 – in the state of metabolic acidosis, this will increase greatly to provide respiratory compensation.
Blood pH will be lower than the normal range in the case of acidosis
Which test would establish the patient's current level of glycaemic control?
blood glucose test
Which test would establish the patient's level of glycaemic control over the past 2 to 3 hours?
Which test would establish the patient's longer-term level of glycaemic control?
Which test would be most appropriate if the patient presents with oedema?
Which test would be used to confirm a diagnosis of acidosis?
Which test would be used to diagnose intestinal malabsorption?
H breath test
how can diabetes affect the eye
The retina is the light-sensitive layer of cells at the back of the eye that converts light into electrical signals. The signals are sent to the brain and the brain turns them into the images you see.
The retina needs a constant supply of blood, which it receives through a network of tiny blood vessels. Over time, a persistently high blood sugar level can damage these blood vessels in three main stages:
• tiny bulges develop in the blood vessels, which may bleed slightly but don’t usually affect your vision – this is known as background retinopathy
• more severe and widespread changes affect the blood vessels, including more significant bleeding into the eye – this is known as pre-proliferative retinopathy
• scar tissue and new blood vessels, which are weak and bleed easily, develop on the retina – this is known as proliferative retinopathy and it can result in some loss of vision
You're at a greater risk if you:
• have had diabetes for a long time
• have a persistently high blood sugar (blood glucose) level
• have high blood pressure
• have high cholesterol
• are pregnant
• are of Asian or Afro-Caribbean background
By keeping your blood sugar, blood pressure and cholesterol levels under control, you can reduce your chances of developing diabetic retinopathy
symptoms of diabetic retinopathy
You won't usually notice diabetic retinopathy in the early stages, as it doesn't tend to have any obvious symptoms until it's more advanced.
However, early signs of the condition can be picked up by taking photographs of the eyes during diabetic eye screening.
Contact your GP or diabetes care team immediately if you experience:
• gradually worsening vision
• sudden vision loss
• shapes floating in your field of vision (floaters)
• blurred or patchy vision
• eye pain or redness
These symptoms don't necessarily mean you have diabetic retinopathy, but it's important to get them checked out. Don't wait until your next screening appointment.
diabetic eye screening
Everyone with diabetes who is 12 years old or over is invited for eye screening once a year.
Screening is offered because:
• diabetic retinopathy doesn't tend to cause any symptoms in the early stages
• the condition can cause permanent blindness if not diagnosed and treated promptly
• screening can detect problems in your eyes before they start to affect your vision
• if problems are caught early, treatment can help prevent or reduce vision loss
The screening test involves examining the back of the eyes and taking photographs. Depending on your result, you may be advised to return for another appointment a year later, attend more regular appointments, or discuss treatment options with a specialist
treatment for diabetic retinopathy
Treatment for diabetic retinopathy is only necessary if screening detects significant problems that mean your vision is at risk.
If the condition hasn't reached this stage, the above advice on managing your diabetes is recommended.
The main treatments for more advanced diabetic retinopathy are:
• laser treatment
• injections of medication into your eyes
• an operation to remove blood or scar tissue from your eyes
treatment for type 1
Aim - to administer enough insulin so that the patient will have carbohydrate, fat, and protein metabolism that is as normal as possible.
INSULIN is available in several forms.
“Regular” insulin has a short duration of action that lasts from 3-8 hours.
Other forms of insulin (precipitated with zinc or with various protein derivatives) are absorbed slowly from the injection site and therefore have effects that last as long as 10-48 hours.
Ordinarily, a patient with severe type I diabetes is given a single dose of a longer-acting insulin each day to increase overall carbohydrate metabolism throughout the day.
Then additional quantities of regular insulin are given during the day at those times when the blood glucose level tends to rise too high, such as at mealtimes.
treatment for type 2
In persons with type II diabetes, DIETING and EXERCISE are usually recommended in an attempt to induce WEIGHT LOSS and to reverse the insulin resistance.
If this fails, drugs may be administered to increase insulin sensitivity (THIAZOLIDINEDIONES and METFORMIN) or to stimulate increased production of insulin by the pancreas (SULFONYLUREAS e.g Gliclazide)
In many persons, however, exogenous INSULIN must be used to regulate blood glucose.
In the past, the insulin used for treatment was derived from animal pancreata. However, human insulin produced by the recombinant DNA process has become more widely used because some patients develop immunity and sensitization against animal insulin, thus limiting its effectiveness.
Osmoreceptor-ADH Feedback System (Thirst)
• The osmoreceptor-ADH feedback system controls the extracellular fluid sodium concentration and osmolarity.
• When osmolarity (plasma sodium concentration) increases above normal (dehydration/thirst) because of water deficit, for example, this feedback system operates as follows:
1. An increase in extracellular fluid osmolarity (increase in plasma sodium concentration) causes osmoreceptor cells, located in the anterior hypothalamus near the supraoptic nuclei, to shrink.
2. Shrinkage of the osmoreceptor cells causes them to send nerve signals to additional nerve cells in the supraoptic nuclei, which then relay these signals down the stalk of the pituitary gland to the posterior pituitary.
3. These action potentials conducted to the posterior pituitary stimulate the release of ADH, which is stored in secretory granules (or vesicles) in the nerve endings.
4. ADH enters the blood stream and is transported to the kidneys, where it increases the water permeability of the late distal tubules, cortical collecting tubules, and medullary collecting ducts.
5. The increased water permeability in the distal nephron segments causes increased water reabsorption and excretion of a small volume of concentrated urine.
consequences of ADH
• Thus, water is conserved in the body while sodium and other solutes continue to be excreted in the urine.
• This causes dilution of the solutes in the extracellular fluid, thereby correcting the initial excessively concentrated extracellular fluid.
• The opposite sequence of events occurs when the extracellular fluid becomes too dilute (hypo-osmotic).
Excess water ingestion and a decrease in extracellular fluid osmolarity,
Less ADH is formed,
The renal tubules decrease their permeability for water,
Less water is reabsorbed,
Large volume of dilute urine is formed.
This in turn concentrates the body fluids and returns plasma osmolarity toward normal.
self managment of chronic illness
• Reasons for poor self-management of long-term conditions:
1. Information overload / care regiments too complex:
o Most know why they should
2. No change strategies
o Most don’t know how
3. Ineffective action plans
o Most don’t know what to do specifically
• Common Psychological Problems:
Initial adjustment’ illness representation (shock)
Later adjustment after the ‘Honeymoon’ (anger)
Specific (phobias, depression)
7 factors predictive of early disease and death
not maintaining ideal weight (being under or over);
snacking between meals,
not having breakfast each day;
not sleeping 7-8 hours a day or more than 8 hours;
taking more than 5 units of alcohol in a session;
not taking regular exercise
(kg/m2) = mass (kg) / height (m)2
Obesity classified as:
mild (20-40%) or Grade 1 (25.29.9 BMI),
moderate (41-100%) Grade 2 (30-39.9 BMI),
severe (100%+) Grade 3 (40+ BMI).
facts about obesity
Around 60% of all adults are more than 10% overweight
65% men classified as obese this month
Obesity results in more sedentary lifestyle
Dietary fibre absorbs fat and may prevent of CVD
Adipose tissue involved with pro-inflammation
facts about smoking
• Lifestyle disease accounts for 70-80% of all deaths. Most of the
mortality can be explained by smoking related activity
• CHD and Cancer (Doll & Hill 1954)
• Smoking has synergistic effect on other disease risk factors
• Trends are down from 50%- 20%
• Who smokes? 25-34 men / 45-54 women
• 2/3 of smokers want to give up
• Different factors involved at the stages of smoking: Initiation;
Maintenance; Cessation; Relapse
facts about excersize
Strong association between lack of physical fitness & all cause
mortality especially CVD and Cancer
Relationship between occupational activity & CHD & leisure
time activity & CHD
Most (85%) adults do not take enough exercise & lacking in 3
3 important aspects: Frequency….Intensity…..Duration
Half UK 7s do not do enough exercise - girls far less active than
Just 51% of the 6,500 children monitored achieved 1 hour
physical activity each day.
why do people self manage
Self-management talk comes from them
Tasks are manageable
They feel supported
They believe they have the ability
They have an effective plan
Events can increase motivation – find teachable moments
improved communication and health outcome
Systematic review correlation between effective physician-patient communication and improved patient health outcomes:
o Improve QoL, reduce anxiety & distress, improve patient satisfaction
o Improve pain physical functioning symptom management
o Enhance knowledge of medicines adherence
o Promote lifestyle changes
Use of psychological framework in consultation enhances good communication skills.
central role of beliefs: illness perceptions
Thought patterns derived from
o Social messages
o Level of understanding
o Quality of communication
Attributions about cause important
key behaviours to address
Motivation to change lifestyle
psychological approach offer
Teach people how to manage themselves.
Help people understand themselves better – links thoughts and feelings with behaviour.
Gives people strategies to change lifestyle
“A structures, directive technique to recognise and overcome ambivalence in order to change attitudes and behaviour”.
It encourages careful listening.
It supports self-efficacy.
It allows the doctor to work with (not against) ambivalence to change.
It identifies peoples own solution to the problem – increasing intention to change.
assessing readiness to change
Use the 10 point scale
There are two dimensions to feedback:
(1) support (2) challenge
goal setting and action planning
Key point: suggestion comes from the patient and goals and plans are negotiated and not imposed.
action planning for self managment
Good action plans increase intention to change (predicts actual change).
Get behavioural – focus on behaviours to reach self-management goals.
Agree how often, how much, when, with who.
Identify and overcome problems that may be encountered - but focus on solutions.
Ask what help / support they might need.
summary of managing change and supporting patient self managment
LTCs need substantial self-management – your job is to help their motivation.
Patients have to make their choices (not changing is a choice) support their autonomy.
Shared decision making leads to better outcomes.
Explore options, pros & cons, risks, probabilities of treatments.
Acknowledge barriers but focus on solutions.
Avoid the expert trap – remember to build self-efficacy.
Train to help patients come up SMART goals & detailed plans
Nonn alcoholic liver disease
A healthy liver should contain little or no fat. It's estimated that up to one in every three people in the UK has early stages of NAFLD where there are small amounts of fat in their liver.
Early-stage NAFLD doesn't usually cause any harm, but it can lead to serious liver damage, including cirrhosis, if it gets worse. Having high levels of fat in your liver is also associated with an increased risk of problems such as diabetes, heart attacks and strokes.
If detected and managed at an early stage, it's possible to stop NAFLD getting worse and reduce the amount of fat in your liver.