L17 Absorptive and Postabsorptive States PDF

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L17 Absorptive and Postabsorptive States...

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DIG F2

02/03/18

L16: Absorptive/Post-absorptive States & Metabolic Disorders  

Absorptive state: a fed state, when food is in the GIT and nutrients are being actively absorbed into the blood or lymph Post-absorptive state: fasting state, when nutrients are not being absorbed

Absorptive state  The hormone-sensitive tissues of energy metabolism are: o Liver o Muscle o Adipose tissue  

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Absorbed nutrients (monosaccharides, amino acids and lipids) enter the portal blood and therefore first go to the liver Glucose o Glucose first passes into the liver via the enterohepatic circulation.  In the liver it can be converted into glycogen or when it is in excess it can be converted into Triglycerides. o Glucose can also be taken up by muscle tissue and converted into glycogen. o Glucose can be taken up by adipose tissue and converted into triglycerides. o Glucose can be taken up by other tissues and be used to produce energy via the Krebs cycle. Amino acids o Amino acids can be taken up by the liver to generate energy and keto acids. o Amino acids can also be taken by the muscle tissue to produce proteins Triglycerides Triglycerides are predominantly going to be deposited by adipose tissue. o Triglycerides cannot pass through the cell membrane freely. o They first undergo lipolysis to produce free fatty acids and glycerol. o The FFA and glycerol can now be taken up by the adipose tissue and are then esterified back to triglycerides to be stored in the adipose tissue.

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Insulin  Insulin is secreted by β-cells of the pancreas when there is high concentration of glucose or amino acids in the blood  Insulin secretion mechanism: o GLUT-2 is the transporter responsible for β-cell glucose uptake o o o o

Glucose metabolism increases intracellular ATP concentration  inhibits the activity of ATP sensitive K+ channels (KATP) This results in depolarisation of the cell as K+ efflux is reduced Depolarisation causes voltage gated Ca2+ channels to open Increased intracellular calcium causes exocytosis of insulin

Insulin regulates the transport of glucose into muscle and adipose tissue  Muscle and adipose tissue both need insulin in order for their cells to take up glucose.  GLUT-4 is a glucose transporter stored within the muscle cells and adipocytes.  Insulin binds to receptors on the cell surface and ultimately results in translocation of GLUT-4 to the plasma membrane  This allows for enhanced glucose uptake.

Feedback control of Insulin after a meal  The Switch from the Post-absorptive state to the Absorptive state is due to an increase in glucose & insulin in the blood.  You have just had a meal  You enter the absorptive state: o Food enters the GIT and nutrients (e.g. glucose) are actively absorbed into the blood.  This results in an increase blood glucose concentration.  Increase in blood glucose is sensed by beta cells  insulin exocytosis  Insulin causes increased GLUT-4 expression on the surface on cells, in particular muscle and adipocytes.  This allows these cells to take glucose in from circulation.  Therefore, blood glucose concentration falls.  This means stimulus for insulin secretion is removed  blood insulin concentration falls  you are now back in post absorptive state.

Matching of Insulin and Glucose

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Insulin and glucose levels match each other: o Increase in glucose concentration in blood triggers insulin release. o As insulin is released it causes decreases in blood glucose concentration o

This decrease in blood glucose concentration in turn causes a decrease in blood insulin concentration.  Note characteristic lag

What are the effects of insulin on the liver, adipose tissue and muscle tissue during the absorptive state?

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During the absorptive state nutrients (e.g. glucose) are absorbed into the blood. Glucose concentration in the blood increases. Therefore in the fasted state insulin levels are high in the fed state Insulin has the following effects on the tissues:

1. Liver  The uptake of glucose by the liver is not insulin sensitive: o Glucose enters hepatocytes through GLUT-2 transported (NOT insulin sensitive) down its concentration gradient.  Once glucose enters hepatocytes it is converted into glucose-6-phosphate (enhanced by insulin)  Glycogenesis (Glycogen synthesis) o Glucose 6 phosphate is converted into glycogen (enhanced by insulin)  Glycogenolysis: o Insulin also inhibits glycogenolysis (glycogen breakdown)  Glycolysis o Insulin also enhances glycolysis  Lipogenesis o If Glucose is in excess it is converted into Acetyl CoA  converted into triglycerides. o This is known as lipogenesis and is also enhanced by insulin.  Therefore, in total Glycogen synthesis, Glycolysis and Fat synthesis (in times of excess) will all be up due to insulin.

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NB: In diagram: o Green arrows represent events activated by insulin o Red arrow represent events inhibited by insulin.

2. Muscle

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The uptake of glucose by muscles is insulin sensitive: o Insulin binds to the insulin receptors on the plasma membrane o This triggers translocation of GLUT-4 to the plasma membrane  more glucose can enter the cell The insulin then drives Glycogen synthesis, Glycolysis and Protein synthesis. Therefore, glucose uptake, glycogen synthesis, glycolysis and protein synthesis are all enhanced by insulin.

3. Adipocytes

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The uptake of glucose by adipocytes is insulin sensitive: o Insulin binds to the insulin receptors on the plasma membrane o This triggers translocation of GLUT-4 to the plasma membrane  more glucose can enter the cell Insulin then enhances glycolysis and lipogenesis (triglyceride synthesis) It also inhibiting lipolysis (breakdown of triglycerides) o Mechanism:  Insulin inhibits hormone sensitive lipase (HSL).  Therefore, TG cannot be broken down into fatty acids  Therefore, FA cannot be transported out of the adipocyte, so stay stored. Insulin also stimulates synthesis of lipoprotein lipase, which then moves to the surface of endothelial cells: o This enzyme allows chylomicrons to release free fatty acids. o Free fatty acids then enter adipocytes and are re-esterified. Therefore, insulin drives glucose uptake, glycolysis and TG synthesis, it also inhibits lipolysis.

Post-absorptive state:

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In the post-absorptive state, you need to utilise your body’s energy stores because glucose is not being absorbed from the GIT There are 2 types of reaction in which this can occur:

1. Glucose-supplying reactions  These reactions generate glucose (~750 calories/day)  Glucose is produced in the liver by: o Glycogenolysis (breaking down glycogen) o Gluconeogenesis (new synthesis) from amino acids, lactate and glycerol:  In adipose tissue Triglycerides are broken down to produce glycerol and FFA. (lipolysis).  Glycerol is transported to the liver where it undergoes gluconeogenesis to produce glucose.  Additionally, Lactate and amino acids are transported from muscle tissue to the liver to also undergo gluconeogenesis and produce glucose.

2. Glucose-sparing reactions

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These reactions generate energy substrates other than glucose. These include fatty acids & ketone bodies (~2500 calories/day) o There are 2x more calories in TG than glycogen or protein. Mechanism: o Lipolysis occurs within adipose tissue resulting in the breakdown of TG into Free fatty acids.  FFA are then used in β-oxidation, at either muscles tissue or other tissue, to produce energy. o In the liver excess FFA are converted into ketone bodies.  These then end up in other tissues where they are converted into acetyl CoA  Acetyl Co A then enters the Krebs cycle to produce energy

NB: Both glucose-supplying and glucose sparing reactions are essential for preserving plasma glucose levels in the brain

Diabetes mellitus  Characterised by high blood sugar

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There is an increased ratio of hormones that  blood sugar (glucagon, adrenaline, growth hormone) compared to insulin. Diabetes is primarily due to insulin deficiency or insulin resistance 2 types: o Type I diabetes:  Insulin deficiency  Autoimmune  destruction of beta cells  loss of insulin production  Young onset  Treatment: Insulin  Severe metabolic derangement due to inability to utilise glucose (and thus reduced cellular energy)  Therefore, you switch to other fuels (amino acids, lipids).  This leads to marked weight loss  Metabolic disturbance (hyperlipidaemia, ketoacidosis (DKA) o Type II diabetes:  Insulin resistance  Prevalence increases with age  Linked to obesity  Treatment: lifestyle (diet, exercise), tablets (insulin stimulators, potentiators) or insulin.  Less severe metabolic derangements since some insulin action is still present  It causes long-term damage due to high glucose level and lipid abnormalities

What are the effects of insulin on the liver, adipose and muscle tissue in a diabetic patients?  Diabetic  Insulin deficiency/insulin resistance

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1. Liver o o

Glucose can enter the hepatocytes because the GLUT-2 transporter is NOT insulin sensitive Lack of insulin results in:   Glycogen synthesis (usually stimulated by insulin)   glycogenolysis (usually inhibited by insulin)  Any glycogen already present in the liver is broken down as the insulin is not present to inhibit this

2. Muscle o Lack of insulin results in:  Glucose not being able to enter the muscle cell because GLUT-4 transporter is insulin sensitive ( glucose uptake)  This results in an  in extracellular glucose   breakdown of proteins to amino acids as the amino acids will be used as substrates for gluconeogenesis to produce energy. o This leads to muscle wasting o This is normally inhibited by insulin. 3. Adipocytes o Lack of insulin result in:  Glucose not being able to enter the muscle cell because GLUT-4 transporter is insulin sensitive ( glucose uptake)  This results in an  in extracellular glucose   lipolysis o Breakdown of fat releases fatty acids into the circulation (as an alternative energy source to glucose) causing  Acetyl CoA Metabolic derangement in a diabetic  Level of glucose in blood is high because: o When we consume glucose via diet Uptake cannot be stimulated. o Lack of insulin-mediated inhibition of glycogenolysis and lipolysis 

o (In a diabetic the glucose level exceeds the renal threshold). You also have  circulating levels of fatty acids and  level of ketones o Lack of insulin-mediated inhibition lipolysis o FA are directed to the liver for use in β-oxidation  liberates energy + acetyl coA o In diabetes the high levels of acetyl coA generated in hepatocytes inhibit the citric acid (krebs) cycle within the liver. o Therefore, acetyl coA is pushed towards ketogenesis (producing ketone bodies)  Ketone formation  20-fold in uncontrolled type I diabetics  Ketones are acidic and so these leads to acidosis  Acetoacetate is produced.  Acetone is a spontaneous breakdown product of Acetoacetate. It is a volatile gas that escapes on breath and has a characteristic smell o The ketones then enter the blood and are transported to extrahepatic tissues (especially brain) o They are reconverted into acetyl coA which is then used to produce energy.

Clinical features of Uncontrolled diabetes  Polyuria/polydipsia/dehydration

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02/03/18

When glucose level exceeds 10mmol/L the renal threshold for glucose resorption is exceeded. This results in  Glycosuria (glucose in urine): When glucose is in the urine it pulls a lot of water with it via osmosis forming a large volume of urine.  This results in polyuria, which in turn causes dehydration and so polydipsia. Blurred vision o High glucose in the blood causes water to be pulled out of the lens via osmosis so the lens changes shape causing blurred vision. o

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Infections, e.g. thrush  High blood glucose concentration result in impaired cellular immune response Weight loss (due to muscle wasting and fat wasting) o Absorbed glucose is unavailable as it can’t enter cells (lack of insulin) o Therefore, you have to use your stored energy i.e breaking down muscle and fat down. Ketosis/confusion/coma due to: o Acidosis o Dehydration o Electrolyte disturbance

Treatment of Uncontrolled Diabetes  Rehydration with IV saline.  Give insulin via infusion or regular s/c or i/m injections  Monitor +/- correct serum electrolytes: o Potassium disturbance is common because insulin usually activates sodium-potassium ATPases in many cells, causing a flux of potassium into the cell. o Insulin can kill patients because of its ability to acutely supress plasma potassium concentrations  Treat underlying cause: Other infection or illness

Impact of chronic diabetes:

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High glucose may also have direct adverse metabolic effects. However it is unclear why high glucose is toxic Hypotheses: o “Advanced glycation end-products”  high glucose may cause nonenzymatic glycation of proteins, altering their function  E.g. haemoglobin can be glycated (not harmful) (useful test for long-term diabetic control) o “Sorbitol toxicity”  sorbitol is generated from glucose by aldol reductase, this can further glycate other tissues.

Chronic Uncontrolled Diabetes: Microvascular complications:  Retinopathy: o Growth of friable and poor-quality new blood vessels in the retina  more likely to burst  eye filled with blood  leads to blindness o Macular oedema which can lead to severe vision loss or blindness  Nephropathy o Excess blood glucose overworks the kidneys  Damage to the kidney  lead to chronic renal failure, eventually requiring dialysis  Neuropathy o High BG concentration damages the BV that supply nutrients to nerves  nerve damage o Abnormal and  sensation. o This initially begins with the feet but then later progresses to fingers and hands o When combined with damaged blood vessels that supplies limbs this can lead to diabetic foot (delayed wound healing, infection or gangrene of the foot) Chronic Uncontrolled Diabetes: Macrovascular complications:  Atherosclerosis o Hyperlipidaemia is common in diabetes. o You will have high circulating VLDL and LDL  these are atherogenic o Atherosclerosis increases risk of blood clots which cause:  Stroke  Heart attack  Peripheral vascular disease  Hepatic steatosis (‘fatty liver’) o Fatty acids are taken up by the liver and converted to triacylglycerol o This can be deposited in the liver  lead to tissue damage Long-term treatment of diabetes  Reduce vascular risk o Lipid lowering drugs o Reduced blood pressure o Aspirin o Avoid smoking  Tight regulation of blood glucose o Diet o Home monitoring o Adjustment of tablets/insulin...