THE LIVER AND GLUCONEOGENESIS
Explain why glucose is an important metabolic fuel
All tissues would prefer to use glucose – which makes its availability limited. But tissues also have different levels of importance, so we introduce a system where we control how a tissue can obtain (by the GLUT channel type on its membrane) and use glucose (by the hexokinase/glucokinase contained within it). Therefore, we can ensure that whatever glucose is in the blood goes to the tissue we want it to. Glucose is especially important in erythrocytes, which cannot use other sources of energy or aerobic respiration, and therefore depend on glucose and NADPH they form with it to maintain their membrane integrity. On top of that, we cannot have glucose levels be too high, because it is damaging and osmotically active, so we say that normal levels are between 3.9-6.2mM, and that the average fasting range should be 4.4-5mM for an adult.
Glucose is important both as a source of energy, and as a source of NADPH – which is needed for anabolic reactions=synthesis of fatty acids, steroids.
Describe the sources of glucose that are available to the body (diet, liver glycogen, other metabolites by gluconeogenesis)
Glucose is made available by glucagon from the liver, and removed from the blood by insulin, the levels of which closely follow the pattern of glucose levels, but are much much lower in concentration.
Outline the process of gluconeogenesis in the liver from lactate or oxaloacetate
Occurs after 8h of fasting when liver storages start to deplete – is done in the liver and kidney. Lactate – the Cori cycle converting lactate into pyruvate in the liver (lactate comes from red blood cells and muscle cells) Oxaloacetate – is the four carbon acceptor compound to which acetyl CoA is added in the Krebs Cycle. ACETYL COA CANNOT BE CONVERTED INTO GLUCOSE IN HUMANS
Glycerol-3-phosphate – (coming from adipose tissue breakdown of glycerides)
Glucogenic amino acids – NOT Leu and Lys!! (mainly alanine)
Dietary fructose and galactose
Gluconeogenesis requires ATP. Where does this ATP come from? (not from glucose, because if we had it, then we wouldn't be making more). The energy comes from B-oxidation of fatty acids. Therefore, gluconeogenesis is fully dependent on B-oxidation of fatty acids in the liver.
Because there is fatty acid metabolism involved in gluconeogenesis, there will be acetyl CoA produced from the fatty acid - which cannot be converted into glucose. This acetyl CoA is converted into a ketone body, an alternative form of energy for cells, including brain cells. That is why chronic hypoglycaemia causes the levels of ketone bodies to rise.
What is the issue with glucogneogenesis? It is not the simple reversal of glycolysis. Why? Well in glycolysis you have irreversible steps (kinase involving steps) – which means that ATP was used, they cannot be simply reversed but must be bypassed – so new enzymes are needed.
How is it regulated? Stress hormones such as glucagon or cortisol upregulate gluconeogenesis.
Diabetes Mellitus Gluconeogenesis is one the major contributors to the hyperglycaemia that is seen in diabetic patients as cells ‘feel’ starved of nutrients and so send out hormonal signals to increase glucose levels in the blood via gluconeogenesis.
Alcohol metabolism uses a lot of NAD which would be needed to produce energy, so a lot of lactic acid is formed.
Alcoholics are very susceptible to hypoglycemia. In addition to poor nutrition and the fact that alcohol is metabolized to acetate (acetyl-CoA), the high amounts of cytoplasmic NADH formed by alcohol dehydrogenase and acetaldehyde dehydrogenase interfere with gluconeogenesis. High NADH favors the formation of:
• Lactate from pyruvate
• Malate from OAA in the cytoplasm
• Glycerol 3-phosphate from DHAPhe efect is to divert important gluconeogenic substrates from entering the pathway.
Discuss the time course of blood glucose homeostasis after a meal – done in previous posts Summarise the roles of insulin and glucagon in maintaining glucose homeostasis – done in previous posts Describe the role of the liver in glucose uptake and in glucose production – done in previous posts