Gluconeogenesis

:Gluconeogenesis Glycogenolysis &glycogenesis are the two pathway which involved in maintenance four blood glucose level . however , the . glycogen is very limited Gluconeogenesis :is the pathway of synthesis of glucose from non – carbohydrate metabolism which maintain our blood glucose level. After the diatery .glycogen has been depleted :The site is 1. liver: does about 85% of Gluconeogenesis 2. Kidney: does about 15% of Gluconeogenesis The main substrate of Gluconeogenesis: aminoacid, lactate, pyrovate, glycerol. 1. lactate is not produced in the liver, lactate is produced in RBC, Muscels. We have top transport lactate from site of synthesis to the site of Gluconeogenesis in the liver. The cycle of transporting lactate is called cori cycle or alanine cycle. We have two cycles: Cori Alanin cycle What are these cycles? Look at the figure in the note. a. If lactate is produced in the RBC or in the muscels, lactate  in blood  liver The liver convert it to vlucose and the glucose goes to the blood and so on. This is cori cycle between RBC and liver or between muscels in an aerobic condition and the liver. b. Alanin cycle: we produce pyrovate (e.g. in the muscels) Pyrovate + Amino group  alanin comes out of the liver pyrovate  glucose Pyrovate does not come out from the muscels but the alanin comes out of the muscels and goes to the liver. In the case of cori cycle we produce only 2ATP because it is an aerobic condition (less efficient) but in the alanin cycle we convert pyrovate to glucose and produce 6 or 8 ATP (more efficient). Cori cycle It has: a. Transporting activity of substrates to liver lactate : comes from an aerobic glycolysis 2ATP b. Less efficient

Alanine cycle It has : a. Detoxification activity b. Transport substrate alanine pyrovate : comes from aerobic glycolysis 6 or 8 ATP c. More efficient

In the alanine cycle detoxification removal of amino group in the liver to convert it to urea and then expel it out . Glycolysis Glucose Lactose Gluconeogenesis But we cann't say that gluconeogenesis is the reverse of glucolysis. Thermodynamically: Revers glycolysis ΔG=+20 cal " not spontaneous " Gluconeogenesis ΔG = -7 kal " very spontaneous " But we could say that these pathways have common enzymes ( the reversible enzymes of glycolysis ) share between them of glycolysis . The irreversible enzymes of glycolysis are 3 enzymes don’t share 1- Glucose-6-phosphatase. 2- Phosphor-fructo-kinase. 3- Pyruvate kinase. We replase them with new enzymes and see what happen

Irreversible enzmes of glycolysis are replaced by gluconeogenesis enzmes. 1- pyruvate kinase is reversed by pyruvate carboxylase & PEPCK. 2- Phosph-fructo kinase is reversed by fructo 2.6 diphosphatase (disphosphatase). 3- Glucokinase (in the liver) or hexokinase (in the kidney) is reversed by glucose 6 phosphatse. We have said the amino acids ,the pyrufate & the lactate. last lecture, I kept emphasizing that lipids can't be converted into glucose. Is it true or false? Lipids are triglyceride (tryacylglylcerol). When you degrade the triglyceride, you produce glycerol. Glycerol can be converted into glyceraldehyde-3-phosphate  dihydroxy acetonphosphat These are tow intermediates of glycolysis . so, they can be converted to glucose . Now , I convert glycerol  glucose So,can we convert lipid into glucose?? 1. the answer still no . because I have converted glycerol which is trihydroxy alcohol & not lipid . the lipid is fatty acid ,not the glycerol 2. how much of trigylcerol you can breakdown to produce gylecrol to be converted to glucose ?? very little the amount of glycerol that is produced by breakdown of triacyglycerol is verry little . so,it doesnot effect the blood glucose level . therefore,the statement that lipid cannot be converted into glucose is still stand . if you have add numbers fatty acids sush as 5,7,11,you break it down by moving one acetyl coA (2carbons at the time ) until you lift at the end with 3 carbons & this is propanoate(propanoic acid ) can be converted glycerol  glucose so,this is lipid ( fatty acid ) which can be converted to glucose . but , these are add numbers fatty acids which are not present in the diet . • •

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all of the fatty acids in the diet are even no. like 16 , 18 the only time you get add numbers fatty acids is from the metabolism of certain lipidsby the intestinal flora which produce very little amount of add numbers fatty acids which we maight absorb . if we absorb & degrade it we produce propanoic acid . so,still my statement stands : lipids cannot be converted into glucose but glucose can be converted into lipid

 As we go throw the day , the glucose is contributed by glocogenolysis to mentain blood glocoseis verry low . But, the blood glucose level is always steady So, gluconeogenesis will contribute to maintenance of glucose blood level . As the glycolgen decreases during fasting ,the gluconeogenesis glucose increases . So, after a certeain time period of fasting , blood glucose level is not mentained by glycogenolysis  The gluconeogenesis is strictly regulated at the enzyme PEPCK - PEPCK catalysis the regulatory step of gluconeogenesis . - It is mainly regulated by the level of GTP . - If GTP lower ,PEPCK is inhipted . - Glucagon is an indication of low blood glucose level . therefore , it is required to stimulate the pathways which produse glucose sush as gluconeogenesis one of the enzymes that regulate gluconeogenesis is PEPCK . Therefore , glucagon stimulate PEPCK , while insulin inhipit PEPCK . There is notion that donot eat sucrose for diabetic because it will increase blood glucose level but for example take milke because milke is lactose which is mainly galactose metabolism of galactose occure in the liver Galactose galactokinase galactose 6 phosphate uriclyl transferase UDP-galactose

Free glucose

UDP-glucose

epimerase

Comes out to blood to mentain glucose level Another n otion that diabetic can eat fruit because it is fructose which doesnot increase blood glucose level . Fructose

fructokinase

fructose 6 phosphate isomerase Free glucose

galactose 6 phosphate

Free glucose comer out to blood & increase blood glucose level .

In diabetic doesn't have ionsulin, he has glucagon only. So what ever fructose produce in the liver will be thrown into blood. So, this notion of eating fruit & milk for diabetic is rubbish because both galactose & fructose metabolized by being converted into glucose in the Liver. *Fructose is also taken up by the adipose tissue in large quantity. Chexokinase phosphorylate glucose into glucose phosphate but it’s name is hexokinase , so it phosphorylate all hexoses) so, glyceraldehyde3phosphate Fructose hexokinase fructose 6 phosphate by aldolaste glucerol it split into Glyceraldehde 3phosphate is used in synthesis of triacylglycerol (lipid). There fore, there is diffreintial metabolism of fructose by the adipose tissue & by the liver. *all monosaccharides must first be converted into glucose before it can be metabolized. So, we call these pathways "glucose metabolic pathway". Glucose homeostasis:* The plasma glucose concentration reflects the balance between:1. intake (how much glucose u take). 2. tissue utilization. 3. endogenous synthesis. ‫توازن بين كم الجلوكوز أ ُنتج وكم جلوكوز استهلك‬ You have to balance all these three to maintain the blood glucose level between 80-120 mg/dl. *Insulin promotes up take of glucose thus decreasing plasma glucose. Glucagon stimulates both release of glucose from glycogen store & it is denovo synthesis ‫يعني‬ glucagon stimulate both glycogenolysis & gluconeogenesis causing an increase in plasma glucose. *Glucose itself stimulate the secretion of insulin if the glucose level rises in the vicinity (‫ )بجوار‬of B cells of the pancreas , that insulin is released after we take glucose in by the glut . Insulain suppresses the secretion of glucagon. *We have a very complex interaction of these pathways which I have talked about to maintain the blood glucose level strickty between 80-120 mg/dl.